US20040235818A1 - Aromatic sulfone hydroxamic acid metalloprotease inhibitor - Google Patents

Aromatic sulfone hydroxamic acid metalloprotease inhibitor Download PDF

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US20040235818A1
US20040235818A1 US10/747,796 US74779603A US2004235818A1 US 20040235818 A1 US20040235818 A1 US 20040235818A1 US 74779603 A US74779603 A US 74779603A US 2004235818 A1 US2004235818 A1 US 2004235818A1
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alkyl
group
aryl
heteroaryl
alkoxy
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Thomas Barta
Daniel Becker
Louis Bedell
Terri Boehm
Jeffery Carroll
Gary DeCrescenzo
Yvette Fobian
John Freskos
Daniel Getman
Susan Hockerman
Carol Howard
Stephen Kolodziej
Madeleine Li
Joseph McDonald
Deborah Mischke
Joseph Rico
Nathan Stehle
Michael Tollefson
William Vernier
Clara Villamil
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Pharmacia LLC
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Pharmacia LLC
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Priority claimed from US09/191,129 external-priority patent/US20010014688A1/en
Priority claimed from US09/256,948 external-priority patent/US20010039287A1/en
Application filed by Pharmacia LLC filed Critical Pharmacia LLC
Priority to US10/747,796 priority Critical patent/US20040235818A1/en
Assigned to PHARMACIA CORPORATION reassignment PHARMACIA CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BARTA, THOMAS E., Bedell, Louis J., VERNIER, WILLIAM F., LI, MADELEINE H., Carroll, Jeffery N., Fobian, Yvette M., FRESKOS, JOHN N., HOCKERMAN, SUSAN L., RICO, JOSEPH G., VILLAMIL, CLARA I., HOWARD, CAROL P., MCDONALD, JOSEPH J., STEHLE, NATHAN W., BECKER, DANIEL P., KOLODZIEJ, STEPHEN A., TOLLEFSON, MICHAEL B., BOEHM, TERRI L., DECRESCENZO, GARY A., MISCHKE, DEBORAH A., GETMAN, DANIEL P.
Publication of US20040235818A1 publication Critical patent/US20040235818A1/en
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Definitions

  • This invention is directed to proteinase (protease) inhibitors, and more particularly to the use of aromatic sulfone hydroxamic acid compounds that, inter alia, are selective inhibitors of matrix metalloproteinases in a process for treating conditions associated with pathological matrix metalloproteinase activity, the selective inhibitors themselves, compositions of proteinase inhibitors, intermediates for the syntheses of proteinase inhibitors, and processes for the preparation of proteinase inhibitors.
  • Connective tissue, extracellular matrix constituents and basement membranes are required components of all mammals. These components are the biological materials that provide rigidity, differentiation, attachments and, in some cases, elasticity to biological systems including human beings and other mammals.
  • Connective tissues components include, for example, collagen, elastin, proteoglycans, fibronectin and laminin.
  • Th se biochemicals makeup or are components of structures, such as skin, bone, teeth, tendon, cartilage, basement membrane, blood vessels, cornea and vitreous humor.
  • Degradation of connective tissue or connective tissue components is carried out by the action of proteinase enzymes released from resident tissue cells and/or invading inflammatory or tumor cells.
  • a major class of enzymes involved in this function are the zinc metalloproteinases (metalloproteases).
  • the metalloprotease enzymes are divided into classes with some members having several different names in common use. Examples are: collagenase I (MMP-1, fibroblast collagenase; EC 3.4.24.3); collagenase II (MMP-8, neutrophil collagenase; EC 3.4.24.34), collagenase III (MMP-13), stromelysin 1 (MMP-3; EC 3.4.24.17), stromelysin 2 (MMP-10; EC 3.4.24.22), proteoglycanase, matrilysin (MMP-7), gelatinase A (MMP-2, 72 kDa gelatinase, basement membrane collagenase; EC 3.4.24.24), gelatinase B (MMP-9, 92 kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11), metalloelastase (MMP-12, HME, human macrophage elastase) and membrane
  • the uncontrolled breakdown of connective tissue by metalloproteases is a feature of many pathological conditions. Examples include rheumatoid arthritis, osteoarthritis, septic arthritis; corneal, epidermal or gastric ulceration; tumor metastasis, invasion or angiogenesis; periodontal disease; proteinuria; Alzheimers Disease; coronary thrombosis and bone disease. Defective injury repair processes also occur. This can produce improper wound healing leading to weak repairs, adhesions and scarring. These latter defects can lead to disfigurement and/or permanent disabilities as with post-surgical adhesions.
  • TNF- ⁇ tumor necrosis factor
  • TNF- ⁇ is a cytokine that at present is thought to be produced initially as a 28 kD cell-associated molecule. It is released as an active, 17 kD form that can mediate a large number of deleterious effects in vitro and in vivo.
  • TNF can cause and/or contribute to the effects of inflammation, rheumatoid arthritis, autoimmune disease, multiple sclerosis, graft rejection, fibrotic disease, cancer, infectious diseases, malaria, mycobacterial infection, meningitis, fever, psoriasis, cardiovascular/pulmonary effects such as post-ischemic reperfusion injury, congestive heart failure, hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage and acute phase responses like those seen with infections and sepsis and during shock such as septic shock and hemodynamic shock.
  • Chronic release of active TNF can cause cachexia and anorexia.
  • TNF can be lethal, and TNF can help control the growth of tumor cells.
  • TNF- ⁇ convertase is a metalloprotease involved in the formation of soluble TNF- ⁇ .
  • Inhibition of TNF- ⁇ convertase (TACE) inhibits production of active TNF- ⁇ .
  • TACE TNF- ⁇ convertase
  • Compounds that inhibit both MMPs activity and TNF- ⁇ production have been disclosed in WIPO International Publication Nos. WO 94/24140, WO 94/02466 and WO 97/20824.
  • Compounds that inhibit MMPs such as collagenase, stromelysin and gelatinase have been shown to inhibit the release of TNF (Gearing et al. Nature 376, 555-557 (1994), McGeehan et al., Nature 376, 558-561 (1994)).
  • MMP inhibitors There remains a need for effective MMP inhibitors.
  • TNF- ⁇ convertase inhibiting agents There remains a need for effective TNF- ⁇ convertase inhibiting agents.
  • MMPs are involved in other biochemical processes in mammals as well. Included is the control of ovulation, post-partum uterine involution, possibly implantation, cleavage of APP ( ⁇ -Amyloid Precursor Protein) to the amyloid plaque and inactivation of ⁇ 1 -protease inhibitor ( ⁇ 1 -PI). Inhibition of these metalloproteases permits the control of fertility and the treatment or prevention of Alzheimers Disease. In addition, increasing and maintaining the levels of an endogenous or administered serine protease inhibitor drug or biochemical such as ⁇ 1 -PI supports the treatment and prevention of diseases such as emphysema, pulmonary diseases, inflammatory diseases and diseases of aging such as loss of skin or organ stretch and resiliency.
  • diseases such as emphysema, pulmonary diseases, inflammatory diseases and diseases of aging such as loss of skin or organ stretch and resiliency.
  • Inhibition of selected MMPs can also be desirable in other instances.
  • Treatment of cancer and/or inhibition of metastasis and/or inhibition of angiogenesis are examples of approaches to the treatment of diseases wherein the selective inhibition of stromelysin, gelatinase A or B, or collagenase III appear to be the relatively most important enzyme or enzymes to inhibit especially when compared with collagenase I (MMP-1).
  • a drug that does not inhibit collagenase I can have a superior therapeutic profile.
  • Osteoarthritis another prevalent disease wherein it is believed that cartilage degradation of inflamed joints is at least partially caused by MMP-13 released from cells such as stimulated chrondrocytes, may be best treated by administration of drugs one of whose modes of action is inhibition of MMP-13. See, for example, Mitchell et al., J. Clin. Invest., 97:761-768 (1996) and Reboul et al., J. Clin. Invest., 97:2011-2019 (1996).
  • Inhibitors of metalloproteases are known. Examples include natural biochemicals such as tissue inhibitors of metalloproteinases (TIMPs), ⁇ 2 -macroglobulin and their analogs or derivatives. These endogenous inhibitors are high molecular weight protein molecules that form inactive complexes with metalloproteases. A number of smaller peptide-like compounds that inhibit metalloproteases have been described. Mercaptoamide peptidyl derivatives have shown ACE inhibition in vitro and in vivo. Angiotensin converting enzyme (ACE) aids in the production of angiotensin II, a potent pressor substance in mammals and inhibition of this enzyme leads to the lowering of blood pressure.
  • ACE angiotensin converting enzyme
  • MMP metalloprotease
  • Hydroxamate group-containing MMP inhibitors are disclosed in a number of published patent applications such as WO 95/29892, WO 97/24117, WO 97/49679 and EP 0 780 386 that disclose carbon back-boned compounds, and WO 90/05719, WO 93/20047, WO 95/09841 and WO 96/06074 that disclose hydroxamates that have a peptidyl back-bones or peptidomimetic back-bones, as does the article by Schwartz et al., Progr. Med. Chem., 29:271-334(1992) and those of Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997) and Denis et al., Invest. New Drugs, 15(3): 175-185 (1997).
  • MMP inhibitors One possible problem associated with known MMP inhibitors is that such compounds often exhibit the same or similar inhibitory effects against each of the MMP enzymes.
  • batimastat the peptidomimetic hydroxamate known as batimastat is reported to exhibit IC 50 values of about 1 to about 20 nanomolar (nM) against each of MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9.
  • Marimastat another peptidomimetic hydroxamate was reported to be another broad-spectrum MMP inhibitor with an enzyme inhibitory spectrum very similar to batimastat, except that marimastat exhibited an IC 50 value against MMP-3 of 230 nM. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997).
  • MMP inhibitors such as batimastat, marimastat and the hydroxamates of WO 98/37877 and WO 98/38163 exhibit a broad spectrum of activity against MMPS, those compounds are not particularly selective in their inhibitory activity. This lack of selectivity may be the cause of the musculoskeletal pain and stiffness observed with their use.
  • the disclosure that follows describes a process for treating a host mammal having a condition associated with pathological matrix metalloprotease activity that utilizes a compound that selectively inhibits one or more MMPs, while exhibiting less activity against at least MMP-1.
  • the present invention is directed to a treatment process that comprises administering a contemplated aromatic sulfone hydroxamic acid metalloprotease inhibitor in an effective amount to a host mammal having a condition associated with pathological metalloprotease activity.
  • a contemplated molecule inter alia, exhibits excellent inhibitory activity of one or more matrix metalloprotease (MMP) enzymes, such as MMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibition at least of MMP-1.
  • MMP matrix metalloprotease
  • a contemplated compound exhibits an IC 50 value ratio against one or more of MMP-2, MMP-9 or MMP-13 as compared to its IC 50 value against MMP-1, e.g., IC 50 MMP-2:IC 50 MMP-1, that is less than about 1:10, preferably less than about 1:100, and most preferably less than about 1:1000 in the in vitro inhibition assay utilized hereinafter.
  • the invention also contemplates particular compounds that selectively inhibit the activity of one or more of MMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibition at least of MMP-1, as well as a composition containing such a MMP inhibitor as active ingredient.
  • ком ⁇ онентs such as those of Examples 16, 498, 667, 672 and 684 that selectively inhibit the activity of one or more of MMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibition at least of MMP-7, as well as a composition containing such a MMP inhibitor as active ingredient.
  • the invention further contemplates intermediates in the preparation of a contemplated aromatic sulfone hydroxamic acid molecule and a process for preparing an aromatic sulfone hydroxamic acid molecule.
  • one embodiment of the present invention is directed to a treatment process that comprises administering a contemplated aromatic sulfone hydroxamic acid metalloprotease inhibitor that selectively inhibits matrix metalloprotease activity as above in an effective amount to a host mammal having a condition associated with pathological metalloprotease activity.
  • the administered enzyme inhibitor corresponds in structure to formula I, below, or a pharmaceutically acceptable salt thereof:
  • R 1 and R 2 are both hydrido or R 1 and R 2 together with the atoms to which they are bonded form a 5- to 8-membered ring containing one, two or three heteroatoms in the ring that are oxygen, sulfur or nitrogen.
  • R 3 in formula I is an optionally substituted aryl or optionally substituted heteroaryl radical.
  • a contemplated substituent is selected from the group consisting of an aryl, heteroaryl, aralkyl, heteroaralkyl, aryloxy, arylthio, aralkoxy, heteroaralkoxy, aralkoxyalkyl, aryloxyalkyl, aralkanoylalkyl, arylcarbonylalkyl, aralkylaryl, aryloxyalkylaryl, aralkoxyaryl, arylazoaryl, arylhydrazinoaryl, alkylthioaryl, arylthioalkyl, alkylthioaralkyl, aralkylthioalkyl, an aralkylthioaryl radical, the sulfoxide or sulfone of any of the thio substituents,
  • the substituent bonded to the aryl or heteroaryl radical of which the R 3 radical is comprised itself can be substituted with one or more substituents; i.e., the substituting substituent is optionally substituted.
  • the last-named substituent is independently selected from the group consisting of a cyano, perfluoroalkyl, trifluoromethoxy, trifluoromethylthio, haloalkyl, trifluoromethylalkyl, aralkoxycarbonyl, aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocycl
  • amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of an alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl and an alkanoyl group, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring containing zero to two additional heteroatoms that are nitrogen, oxygen or sulfur and which ring itself is (a) unsubstituted or (b) substituted with one or two groups independently selected from the group consisting of an aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalky
  • the carbonylamino nitrogen is (i) unsubstituted, or (ii) is the reacted amine of an amino acid, or (iii) substituted with one or two radicals selected from the group consisting of an alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzofused heterocycloalkyl, benzofused heterocycloalkyl, benzofused cycloalkyl, and an N,N-dialkylsubstituted alkylamino-alkyl group, or (iv) the carboxamido nitrogen and two substituents bonded thereto together form a 5- to 8-membered heterocyclo, heteroaryl or benzofused heterocycloalkyl ring that is itself unsubstituted or substituted with one or two radicals independently selected from the group consisting of an alkyl, alkoxy
  • amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of alkyl, aryl, and heteroaryl, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, and an aminoalkyl group
  • aminoalkyl nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents independently selected from the group consisting of an alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and an alkanoyl group, or (iii) wherein the aminoalkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring.
  • the R 3 substituent is Ph-Q-A-R-E-Y wherein Ph is phenyl substituted at the 4-position relative to the depicted SO 2 group, and -Q-A-R-E-Y is a substituent in which Q is a 5- to 7-membered heterocyclic ring containing one or two nitrogen atoms, one of which is bonded the depicted phenyl group, and whose remaining members are defined hereinafter for the substituent G-A-R-E-Y.
  • a compound of formula I is a compound of more general formula A, wherein R 3 , R 1 and R 2 are as defined before and R 20 is defined below.
  • the substituent R 20 is (a) —O—R 21 , where R 21 is selected from the group consisting of a hydrido, C 1 -C 6 -alkyl, aryl, ar-C 1 -C 6 -alkyl group and a pharmaceutically acceptable cation, (b) —NH—O—R 22 wherein R 22 is a selectively removable protecting group such as a 2-tetrahydropyranyl., benzyl, p-methoxybenzyl (MOZ), carbonyl-C 1 -C 6 -alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide synthesis resin and the like, wherein the trisubstituted silyl group is substituted with C 1 -C 6 -alkyl, aryl, or ar-C 1 -C 6 -alkyl or a mixture thereof, (c) —NH—O—R 14 , where R 14 is hydri
  • R 1 and R 2 together with the atoms to which they are bonded form a 6-membered ring.
  • An R 3 radical preferably has a length that is greater than that of a pentyl group [a —(CH 2 ) 4 CH 3 chain], more preferably greater than about that of a hexyl group [a —(CH 2 ) 5 CH 3 chain], and most preferably greater than an octyl group [a —(CH 2 ) 7 CH 3 chain].
  • An R 3 radical preferably has a length that is less than that of an icosyl group [a —(CH 2 ) 19 CH 3 chain], and more preferably a length that is less than that of a stearyl group [a —(CH 2 ) 17 CH 3 chain).
  • a preferred R 3 group contains two or more 5- or 6-membered rings.
  • a contemplated R 3 group when rotated about an axis drawn through the SO 2 -bonded 1-position and the substituent-bonded 4-position of a 6-membered ring or the SO 2 -bonded 1-position and substituent-bonded 3- or 4-position of a 5-membered ring, defines a three-dimensional volume whose widest dimension has the width in a direction transverse to that axis to rotation of about one furanyl ring to about two phenyl rings.
  • a R 3 radical be a single-ringed aryl or heteroaryl group that is 5- or 6-membered, and is itself substituted at its own 4-position when a 6-membered ring or at its own 3- or 4-position when a 5-membered ring with an optionally substituted substituent selected from the group consisting of one other single-ringed aryl or heteroaryl group, a C 3 -C 14 alkyl group, a N-piperidyl group, a N-piperazyl group, a phenoxy group, a thiophenoxy group, a 4-thiopyridyl group, a phenylazo group and a benzamido group.
  • the substituent of the 5- or 6-membered aryl or heteroaryl group can itself be substituted as discussed before.
  • a preferred compound for use in a contemplated process has a structure that corresponds to formula II, below, or a pharmaceutically acceptable salt thereof:
  • R 14 is hydrido, a pharmaceutically acceptable cation or C(W)R 15 where W is O or S and R 15 is selected from the group consisting of an C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alkoxy, heteroaryl-C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl-C 1 -C 6 -alkyl, aryloxy, ar-C 1 -C 6 -alkoxy, ar-C 1 -C 6 -alkyl, heteroaryl and amino C 1 -C 6 -alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C 1 -C 6 -alkyl, aryl, ar-C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl-C 1 -
  • m is zero, 1 or 2;
  • n is zero, 1 or 2;
  • p is zero, 1 or 2;
  • one of X, Y and Z is selected from the group consisting of C(O), NR 6 , O, S, S(O), S(O) 2 and NS(O) 2 R 7 , and the remaining two of X, Y and Z are CR 8 R 9 , and CR 10 R 11 , or
  • n is zero and X, Y and Z together constitute a moiety selected from the group consisting of
  • R 6 and R 6 ′ are independently selected from the group consisting of hydrido, formyl, sulfonic-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxycarbonyl-C 1 -C 6 -alkyl, hydroxycarbonyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylcarbonyl-C 1 -C 6 -alkyl, R 8 R 9 -aminocarbonyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxycarbonyl-C 1 -C 6 -alkylcarbonyl, hydroxycarbonyl-C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkylcarbonyl-C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonylcarbonyl, hydroxycarbonylcarbonylcarbonylcarbonyl
  • R 7 is selected from the group consisting of a arylalkyl, aryl, heteroaryl, heterocyclo, C 1 -C 6 -alkyl, C 3 -C 6 -alkynyl, C 3 -C 6 -alkenyl, C 1 -C 6 -carboxyalkyl and a C 1 -C 6 -hydroxyalkyl group;
  • R 8 and R 9 and R 10 and R 11 are independently selected from the group consisting of a hydrido, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkanoyl, aroyl, aryl, ar-C 1 -C 6 -alkyl, heteroaryl, heteroar-C 1 -C 6 -alkyl, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, thio]-C 1 -C 6 -alkyl, C 1 -C 6 -alkylthio-C 1 -C 6 -alkyl, cycloalkyl, cycloalkyl-C 1 -C 6 -alkyl, heterocycloalkyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, aralkoxy-C 1 -C 6 -C 6
  • R 12 and R 12 ′ are independently selected from the group consisting of a hydrido, C 1 -C 6 -alkyl, aryl, ar-C 1 -C 6 -alkyl, heteroaryl, heteroaralkyl, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, thiol-C 1 -C 6 -alkyl, cycloalkyl, cycloalkyl-C 1 -C 6 -alkyl, heterocycloalkyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, aryloxy-C 1 -C 6 -alkyl, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6
  • R 13 is selected from the group consisting of a hydrido, benzyl, phenyl, C 1 -C 6 -alkyl, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl and a C 1 -C 6 -hydroxyalkyl group;
  • G-A-R-E-Y is a substituent that preferably has a length greater than that of a pentyl group, and more preferably has a length greater than that of a hexyl group.
  • the substituent G-A-R-E-Y preferably has a length that is less than that of an icosyl group, and is more preferably less than that of a stearyl group. In this substituent:
  • G is an aryl or heteroaryl group
  • A is selected from the group consisting of
  • R 18 is hydrogen C 1 -C 4 -alkyl, or phenyl; or
  • A is absent and G is bonded directly to R;
  • R is a moiety selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio,
  • E is selected from the group consisting of
  • the moiety Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl, aralkyl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of an alkanoyl, halo, nitro, aralkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy
  • a particularly preferred compound for use in a contemplated process corresponds in structure to formula III, below, or a pharmaceutically acceptable salt thereof:
  • m, n, p, X, Z. Y and R 14 are as defined above for formula II, and the R 3 radical that is defined below is a sub-set of the previously discussed G-A-R-E-Y substituents.
  • R 3 is a radical that is comprised of a single-ringed aryl or heteroaryl group that is 5- or 6-membered, and is itself substituted at its own 4-position when a 6-membered ring and at its own 3- or 4-position when a 5-membered ring with a substituent selected from the group consisting of a thiophenoxy, 4-chlorophenoxy, 3-chlorophenoxy, 4-methoxyphenoxy, 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluorophenoxy, 4-fluorothiophenoxy, phenoxy, 4-trifluoromethoxy-phenoxy, 4-trifluoromethylphenoxy, 4-(trifluoromethylthio)-phenoxy, 4-(trifluoromethylthio)-thiophenoxy, 4-chloro-3-fluorophenoxy, 4-isopropoxyphenoxy, 4-isopropylphenoxy, (2-methyl-1,3-benzothiazol-5-
  • a more particularly preferred compound for use in a contemplated process has a structure that corresponds to formula IV, below, or a pharmaceutically acceptable salt thereof:
  • R 3 is as defined above for formula I, more preferably as defined for formula II (wherein this R 3 group is the G-A-R-E-Y substituent), and more preferably still as defined for formula III, and
  • Z is selected group the group consisting of O, S, NR 6 , SO, SO 2 , and NSO 2 R 7 ,
  • R 6 is selected from the group consisting of hydrido, C 1 -C 5 -alkyl, C 1 -C 5 -alkanoyl, benzyl, benzoyl, C 3 -C 5 -alkynyl, C 3 -C 5 -alkenyl, C 1 -C 3 -alkoxy-C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, heteroaryl-C 1 -C 6 -alkyl, C 1 -C 5 -hydroxyalkyl, C 1 -C 5 -carboxyalkyl, C 1 -C 5 -alkoxy C 1 -C 5 -alkylcarbonyl, and NR 8 R 9 —C 1 -C 5 -alkylcarbonyl or NR 8 R 9 —C 1 -C 5 -alkyl wherein R 8 and R 9 are independently hydrido, C 1 -C 5 -alkyl
  • R 7 is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, C 1 -C 6 -alkyl, C 3 -C 6 -alkynyl, C 3 -C 6 -alkenyl, C 1 -C 6 -carboxyalkyl and a C 1 -C 6 -hydroxyalkyl group.
  • a still more preferred group of compounds for use in a contemplated process correspond in structure to formula V, below, or a pharmaceutically acceptable salt thereof:
  • W and Q are independently oxygen (O), NR 6 or sulfur (S), and R 6 is as defined in formula IV;
  • q is zero or one such that when q is zero, the trifluoromethyl group is bonded directly to the depicted phenyl ring.
  • ring structure Q is a substituent of the depicted phenyl ring and can itself be substituted.
  • Substituent Q including the depicted nitrogen atom is a heterocylic ring that contains 5- or 7-members, preferably 6-members, and can contain zero or one additional nitrogen atom.
  • the substituents of Q such as A-R-E-Y, R-E-Y and E-Y are as defined before, and such a substituent is bonded at the 4-position relative to that depicted nitrogen atom when Q is a 6- or 7-membered ring and at the 3- or 4-position relative to that depicted nitrogen when Q is a 5-membered ring.
  • the remaining members of such a Q-beraing substituent e.g., A-R-E-Y
  • R 20 , X, Y, Z, m, n, and p of the ring system and g are as before described, with Z preferably being O or NR 6 .
  • the compounds of formulas IX, IX-1, IX-2, X, XI, XI-1, XI-2 and XII, below, are more particularly preferred among the compounds of formula VIC, formula VIC-1, formula VIC-2, and formula VIII.
  • Z is as before described, with Z preferably being O or NR 6
  • substituent Q is a 6-membered ring, as is shown.
  • the A moiety of the Q ring substituent -A-R-E-Y e.g.
  • a compound of formulas A, B, and I-VI, VI VIC, VIC-1, VIC-2, VIII, IX, IX-1, IX-2, X, XI, XI-1, XI-2 and XII, a R 20 group is preferably —NH—O—R 22 as defined above, and such a compound can also be present as a pharmaceutically acceptable salt.
  • g is 2 in formulas B, VIC, VIC-1, VIC-2 and VII.
  • the present invention also contemplates a precursor or intermediate compound that is useful in preparing a compound of formulas I-X.
  • Such an intermediate compound corresponds in structure to formula VI, below:
  • m, n, p, X, Z and Y are as defined above for formula II, g is zero, 1 or 2 and R 24 is R 3 as defined in formulas I, III or IV, is the substituent G-A-R-E-Y of formula II (formula VIA) or is R 3 ′, an aryl or heteroaryl group that is substituted with a coupling substituent reactive for coupling with another moiety (formula VIB), such as a nucleophilically displaceable leaving group, D.
  • a coupling substituent reactive for coupling with another moiety such as a nucleophilically displaceable leaving group, D.
  • Exemplary nucleophilically displaceable leaving groups, D include a halo (fluoro, chloro, bromo, or iodo) nitro, azido, phenylsulfoxido, aryloxy, C 1 -C 6 -alkoxy, a C 1 -C 6 -alkylsulfonate or arylsulfonate group and a trisubstituted ammonium group in which the three substituents are independently aryl, ar-C 1 -C 6 -alkyl or C 1 -C 6 -alkyl.
  • R 20 is (a)—O—R 21 , where R 21 is selected from the group consisting of a hydrido, C 1 -C 6 -alkyl, aryl, ar-C 1 -C 6 -alkyl group and a pharmaceutically acceptable cation, (b)—NH—O—R 22 wherein R 22 is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), carbonyl-C 1 -C 6 -alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide synthesis resin and the like, wherein the trisubstituted silyl group is substituted with C 1 -C 6 -alkyl, aryl, or ar-C 1 -C 6 -alkyl or a mixture thereof, (c)—NH—O—R 14 , where R 14 is hydrido, a pharmaceutically
  • a particularly preferred precursor intermediate to an intermediate compound of formula VI is an intermediate compound of formula VII
  • a benefit of this invention is the provision of a compound and composition effective for selectively inhibiting certain metalloproteinases, such as one or more of MMP-2, MMP-9 and MMP-13, associated with pathological conditions such as, for example, rheumatoid arthritis osteoarthritis, septic arthritis, corneal, epidermal or gastric ulceration, tumor metastasis, invasion or angiogenesis, periodontal disease, proteinuria, Alzheimer's Disease, coronary thrombosis and bone disease.
  • pathological conditions such as, for example, rheumatoid arthritis osteoarthritis, septic arthritis, corneal, epidermal or gastric ulceration, tumor metastasis, invasion or angiogenesis, periodontal disease, proteinuria, Alzheimer's Disease, coronary thrombosis and bone disease.
  • An advantage of the invention is the provision of compounds, compositions and methods effective for treating such pathological conditions by selective inhibition of a metalloproteinase such as MMP-2, MMP-9 or MMP-13 associated with such conditions with minimal side effects resulting from inhibition of other metalloproteinases, such as MMP-1, whose activity is necessary or desirable for normal body function.
  • a metalloproteinase such as MMP-2, MMP-9 or MMP-13 associated with such conditions with minimal side effects resulting from inhibition of other metalloproteinases, such as MMP-1, whose activity is necessary or desirable for normal body function.
  • Yet another advantage of the invention is the provision of a process for preparing such compounds.
  • Another benefit is the provision of a method for treating a pathological condition associated with abnormal matrix metalloproteinase activity.
  • a further advantage of the invention is the provision of a process for preparing such compositions.
  • certain aromatic sulfone hydroxamic acids are effective for inhibition of matrix metalloproteinases (“MMPs”) believed to be associated with uncontrolled or otherwise pathological breakdown of connective tissue.
  • MMPs matrix metalloproteinases
  • these certain aromatic sulfone hydroxamates are effective for inhibition of one or more enzymes such as MMP-2, MMP-9 and MMP-13, which can be particularly destructive to tissue if present or generated in abnormal quantities or concentrations, and thus exhibit a pathological activity. Included in that pathological activity is the assistance of tumors and tumor cells in the process of penetrating basement membrane, and developing a new or improved blood supply; i.e., angiogenesis.
  • aromatic sulfone hydroxamates are selective in the inhibition of one or more of MMP-2, MMP-9 and MMP-13 without excessive inhibition of other collagenases essential to normal bodily function such as tissue turnover and repair. More particularly, it has been found that a contemplated aromatic sulfone hydroxamate of the invention, or a pharmaceutically acceptable salt thereof, is particularly active in inhibiting of one or more of MMP-2, MMP-9 and MMP-13 in an in vitro assay that is predictive of in vivo activity. In addition, while being selective for one or more of MMP-2, MMP-9 and MMP-13, a contemplated aromatic sulfone hydroxamate, or its salt, has a limited or minimal in vitro inhibitory effect on MMP-1.
  • a substantial difference in activity corresponds to a compound exhibiting an IC 50 value against one or more of MMP-2, MMP-9 and MMP-13 that is about 0.1 times that of the compound against MMP-1, and more preferably 0.01 times that against MMP-1 and most preferably 0.001 times that against MMP-1, or more.
  • some compounds exhibit selectivity differences measured by IC 50 values that exceed the bounds of the assay at the number 100,000-fold. These selectivities are illustrated in the Inhibition Tables hereinafter.
  • a contemplated compound can inhibit the activity of MMP-2 compared to MMP-9 or MMP-13 and MMP-1.
  • a contemplated compound can inhibit the activity of MMP-13 and MMP-2, while exhibiting less inhibition against MMP-1 and MMP-9.
  • a contemplated compound can inhibit the activity of a MMP enzyme, while having less of an effect on tumor necrosis factor release.
  • Inhibition of MMP-2 and MMP-9 can be desirable for inhibition of tumor growth, metastasis, invasion and/or angiogenesis.
  • a profile of selective inhibition of MMP-2 and MMP-9 relative to MMP-1 can provide a therapeutic advantage.
  • Yet another advantage of a contemplated compound is the selectivity with respect to tumor necrosis factor release and/or tumor necrosis factor receptor release that provides the physician with another factor to help select the best drug for a particular patient. While not wishing to be bound by theory, it is believed that there are several factors to this type of selectivity to be considered.
  • the first is that presence of tumor necrosis factor can be desirable for the control of cancer in the organism, so long as TNF is not present in a toxic excess. Thus, uncontrolled inhibition of release of TNF cad be counterproductive and actually can be considered an adverse side effect even in cancer patients.
  • selectivity with respect to inhibition of the release of the tumor necrosis factor receptor can also be desirable. The presence of that receptor can be desirable for maintaining a controlled tumor necrosis level in the mammal by binding excess TNF.
  • a contemplated selective MMP inhibitor compound useful in a contemplated process can be administered to by various routes and provide adequate therapeutic blood levels of enzymatically active inhibitor.
  • a compound can be administered, for example, by the oral (IG, PO) or intravenous (IV) routes.
  • Oral administration is advantageous if the patient is ambulatory, not hospitalized, physically able and sufficiently-responsible to take drug at the required intervals. This is true even if the person is being treated with more than one drug for one or more diseases.
  • IV drug administration is an advantage in a hospital setting wherein the dose and thus the blood levels can well controlled.
  • a contemplated inhibitor can also be formulated for IM administration if desired. This route of administration can be desirable for the administration of prodrugs or regular drug delivery to patients that are either physically weak or have a poor compliance record or require constant drug blood levels.
  • the present invention is directed to a treatment process that comprises administering a contemplated aromatic sulfone hydroxamic acid metalloprotease inhibitor, or a pharmaceutically acceptable salt thereof, in an effective amount to a host mammal having a condition associated with pathological matrix metalloprotease activity.
  • a contemplated aromatic sulfone hydroxamate inhibitor compound useful in such a process inhibits the activity of one or more of MMP-2, MMP-9 and MMP-13, and exhibits substantially less inhibitory activity against at least MMP-1 in the in vitro assay noted above and discussed in detail hereinbelow.
  • An aromatic sulfone hydroxamate inhibitor compound for use in a contemplated process corresponds in structure to formula I, below:
  • R 1 and R 2 are both hydrido. In another embodiment, R 1 and R 2 together with the atoms to which they are bonded form a 5- to 8-membered ring containing one, two or three heteroatoms in the ring that are oxygen, sulfur or nitrogen.
  • R 1 and R 2 together with the atoms to which they are bonded form a five-to eight-membered ring that contains one or two heteroatoms in the ring, although R 1 and R 2 together with the atoms to which they are bonded form a 5- to 8-membered ring containing one, two or three heteroatoms.
  • the heterocyclic ring can itself also be substituted with up to six C 1 -C 6 -alkyl groups or groups that comprise a another 5- to 8-membered carbocyclic or heterocyclic ring, an amino group, or contain one or two oxo (carbonyl) groups.
  • R 3 in formula I is an optionally substituted aryl or optionally substituted heteroaryl radical. That R 3 radical is selected from the group consisting of an aryl, heteroaryl, aralkyl, heteroaralkyl, aralkoxy, heteroaralkoxy, aralkoxyalkyl, aryloxyalkyl, aralkanoylalkyl, arylcarbonylalkyl, aralkylaryl, aryloxyalkylaryl, aralkoxyaryl, arylazoaryl, arylhydrazinoaryl, alkylthioaryl, arylthioalkyl, alkylthioaralkyl, aralkylthioalkyl, an aralkylthioaryl radical, the sulfoxide or sulfone of any of the thio substituents, and a fused ring structure comprising two or more 5- or 6-membered rings selected from the group consisting of aryl,
  • R 3 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a cyano, perfluoroalkyl, trifluoromethylalkyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy, aralkylthio, aralkylamino, heterocyclo, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, a
  • amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of an alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl and an alkanoyl group, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring containing zero to two additional heteroatoms that are nitrogen, oxygen or sulfur and which ring itself is (a) unsubstituted or (b) substituted with one or two groups independently selected from the group consisting of an aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalky
  • the carboxamido nitrogen is (i) unsubstituted, or (ii) is the reacted amine of an amino acid, or (iii) substituted with one or two radicals selected from the group consisting of an alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzofused heterocycloalkyl, benzofused heterocycloalkyl, benzofused cycloalkyl, and an N,N-dialkylsubstituted alkylamino-alkyl group, or (iv) the carboxamido nitrogen and two substituents bonded thereto together form a 5- to 8-membered heterocyclo, heteroaryl or benzofused heterocycloalkyl ring that is itself unsubstituted or substituted with one or two radicals independently selected from the group consisting of an alkyl, alkoxy
  • amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of alkyl, aryl, and heteroaryl, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, and an aminoalkyl-group
  • aminoalkyl nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents independently selected from the group consisting of an alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and an alkanoyl group, or (iii) wherein the aminoalkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring.
  • a compound of formula I can also be used in the form of a pharmaceutically acceptable salt.
  • the R 3 radical has a length that is greater than that of a pentyl group [a —(CH 2 ) 4 CH 3 chain], is more preferably greater than about the length of a hexyl group [a —(CH 2 ) 5 CH 3 chain), and most preferably is greater than about the length of an octyl group [a —(CH 2 ) 7 CH 3 chain].
  • a R 3 group has a length that is less than that of an icosyl group [eicosyl; a —(CH 2 ) 19 CH 3 chain), and more preferably, a length that is less than that of a stearyl group [a —(CH 2 ) 17 CH 3 chain).
  • a contemplated R 3 radical defines a three-dimensional volume whose widest dimension has the width of about one furanyl ring to about two phenyl rings in a direction transverse to that axis to rotation.
  • a compound of formula I is a compound of more general formula A, wherein R 3 , R 1 and R 2 are as defined before and R 20 is defined below.
  • the substituent R 20 is (a)—O—R 21 , where R 21 is selected from the group consisting of a hydrido, C 1 -C 6 -alkyl, aryl, ar-C 1 -C 6 -alkyl group and a pharmaceutically acceptable cation, (b)—NH—O—R 22 wherein R 22 is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), carbonyl-C 1 -C 6 -alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide synthesis resin and the like, wherein the trisubstituted silyl group is substituted with C 1 -C 6 -alkyl, aryl, or ar-C 1 -C 6 -alkyl or a mixture thereof, (c) —NH—O—R 14 , where R 14 is hydrido,
  • R 1 and R 2 groups that together form a contemplated heterocyclic ring are shown in the Tables that follow hereinafter, as well as in the descriptions of those 5- to 8-membered rings and the specific Examples, as are several contemplated aromatic sulfone hydroxamic acid compounds.
  • R 1 and R 2 of formula I or formula A together with the atom to which they are bonded form a 5- to 8-membered ring that contains one, two or three heteroatoms. Most preferably, that ring is a 6-membered ring that contains one heteroatom located at the 4-position relative to the position at which the SO 2 group is bonded.
  • Other preferred compounds for use in a contemplated process correspond in structure to one or more of formulas II, III, IV or V, which are discussed hereinafter.
  • a preferred compound used in a contemplated process has a structure that corresponds to formula II, below:
  • R 14 is hydrido, a pharmaceutically acceptable cation or C(W)R 15 where W is O or S and R 15 is selected from the group consisting of an C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alkoxy, heteroaryl-C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl-C 1 -C 6 -alkyl, aryloxy, ar-C 1 -C 6 -alkoxy, ar-C 1 -C 6 -alkyl, heteroaryl and amino C 1 -C 6 -alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C 1 -C 6 -alkyl, aryl, ar-C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl-C 1 -
  • m is zero, 1 or 2;
  • n is zero, 1 or 2;
  • p is zero, 1 or 2;
  • one of X, Y and Z is selected from the group consisting of C(O), NR 6 , O, S, S(O), S(O) 2 and NS(O) 2 R 7 , and the remaining two of X, Y and Z are CR 8 R 9 , and CR 10 R 11 , or
  • n is zero and X, Y and Z together constitute a moiety selected from the group consisting of
  • R 6 and R 6 ′ are independently selected from the group consisting of hydrido, formyl, sulfonic-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxycarbonyl-C 1 -C 6 -alkyl, hydroxycarbonyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylcarbonyl-C 1 -C 6 -alkyl, R 8 R 9 -aminocarbonyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxycarbonyl-C 1 -C 6 -alkylcarbonyl, hydroxycarbonyl-C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkylcarbonyl-C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonylcarbonyl, hydroxycarbonylcarbonylcarbonylcarbonyl
  • R 7 is selected from the group consisting of a arylalkyl, aryl, heteroaryl, heterocyclo, C 1 -C 6 -alkyl, C 3 -C 6 -alkynyl, C 3 -C 6 -alkenyl, C 1 -C 6 -carboxyalkyl and a C 1 -C 6 -hydroxyalkyl group;
  • R 8 and R 9 and R 10 and R 11 are independently selected from the group consisting of a hydrido, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkanoyl, aroyl, aryl, ar-C 1 -C 6 -alkyl, heteroaryl, heteroar-C 1 -C 6 -alkyl, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, thiol-C 1 -C 6 -alkyl, C 1 -C 6 -alkylthio-C 1 -C 6 -alkyl, cycloalkyl, cycloalkyl-C 1 -C 6 -alkyl, heterocycloalkyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, aralkoxy-C 1 -C 6 -C 6
  • R 12 and R 12 ′ are independently selected from the group consisting of a hydrido, C 1 -C 6 -alkyl, aryl, ar-C 1 -C 6 -alkyl, heteroaryl, heteroaralkyl, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, thiol-C 1 -C 6 -alkyl, cycloalkyl, cycloalkyl-C 1 -C 6 -alkyl, heterocycloalkyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, aryloxy-C 1 -C 6 -alkyl, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6
  • R 13 is selected from the group consisting of a hydrido, benzyl, phenyl, C 1 -C 6 -alkyl, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl and a C 1 -C 6 -hydroxyalkyl group;
  • G-A-R-E-Y is a substituent that preferably as a length greater than that of a pentyl group, and ore preferably has a length greater than that of a hexyl group.
  • the substituent G-A-R-E-Y preferably has a length that is less than that of an icosyl group, and is more preferably less than that of a stearyl group. In this substituent:
  • G is an aryl or heteroaryl group
  • A is selected from the group consisting of
  • R 18 is hydrogen C 1 -C 4 -alkyl, or phenyl
  • R is a moiety selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio,
  • E is selected from the group consisting of
  • the moiety Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl, aralkyl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of an alkanoyl, halo, nitro, aralkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy
  • the substituent -G-A-R-E-Y preferably contains two to four carbocyclic or heterocyclic rings, including the aryl or heteroaryl group, G. More preferably, each of those rings is 6-membered. Additional separate preferences for a compound of formula II include: (a) that A is —O— or —S—, (b) R is an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, (c) E is absent, and (d) Y is selected from the group consisting of hydrido, an alkyl, alkoxy, perfluoroalkoxy and a perfluoroalkylthio group.
  • a more preferred compound for use in a contemplated process has a structure that corresponds to formula III, below:
  • R 3 is a single-ringed aryl or heteroaryl group that is 5- or 6-membered, and is itself substituted at its own 4-position when a 6-membered ring and at its own 3- or 4-position when a 5-membered ring with a substituent selected from the group consisting of a thiophenoxy, 4-chloro-phenoxy, 3-chlorophenoxy, 4-methoxyphenoxy, 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluoro-phenoxy, 4-fluorothiophenoxy, phenoxy, 4-trifluoro-methoxyphenoxy, 4-trifluoromethylphenoxy, 4-(trifluoromethylthio)phenoxy, 4-(trifluoromethyl-thio)thiophenoxy, 4-chloro-3-fluorophenoxy, 4-isopropoxyphenoxy, 4-isopropylphenoxy, (2-methyl-1,3-benzothiazol-5-yl)oxy, 4-
  • R 14 is hydrido, a pharmaceutically acceptable cation or C(W)R 15 where W is O or S and R 15 is selected from the group consisting of an C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alkoxy, heteroaryl-C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl-C 1 -C 6 -alkyl, aryloxy, ar-C 1 -C 6 -alkoxy, ar-C 1 -C 6 -alkyl, heteroaryl and amino C 1 -C 6 -alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C 1 -C 6 -alkyl, aryl, ar-C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl-C 1 -
  • m is zero, 1 or 2;
  • n is zero, 1 or 2;
  • p is zero, 1 or 2;
  • one of X, Y and Z is selected from the group consisting of C(O), NR 6 , O, S, S(O), S(O) 2 and NS(O) 2 R 7 , and the remaining two of X, Y and Z are CR 8 R 9 , and CR 10 R 11 , or
  • n is zero and X, Y and Z together constitute a moiety selected from the group consisting of
  • R 6 and R 6 ′ are independently selected from the group consisting of hydrido, formyl, sulfonic-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxycarbonyl-C 1 -C 6 -alkyl, hydroxycarbonyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylcarbonyl-C 1 -C 6 -alkyl, R 8 R 9 -aminocarbonyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxycarbonyl-C 1 -C 6 -alkylcarbonyl, hydroxycarbonyl-C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkylcarbonyl-C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonylcarbonyl, hydroxycarbonylcarbonylcarbonylcarbonyl
  • R 7 is selected from the group consisting of a arylalkyl, aryl, heteroaryl, heterocyclo, C 1 -C 6 -alkyl, C 3 -C 6 -alkynyl, C 3 -C 6 -alkenyl, C 1 -C 6 -carboxyalkyl and a C 1 -C 6 -hydroxyalkyl group;
  • R 8 and R 9 and R 10 and R 11 are independently selected from the group consisting of a hydrido, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkanoyl, aroyl, aryl, ar-C 1 -C 6 -alkyl, heteroaryl, heteroar-C 1 -C 6 -alkyl, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, thiol-C 1 -C 6 -alkyl, C 1 -C 6 -alkylthio-C 1 -C 6 -alkyl, cycloalkyl, cycloalkyl-C 1 -C 6 -alkyl, heterocycloalkyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, aralkoxy-C 1 -C 6 -C 6
  • R 12 and R 12 ′ are independently selected from the group consisting of a hydrido, C 1 -C 6 -alkyl, aryl, ar-C 1 -C 6 -alkyl, heteroaryl, heteroaralkyl, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, thio]-C 1 -C 6 -alkyl, cycloalkyl, cycloalkyl-C 1 -C 6 -alkyl, heterocycloalkyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, aryloxy-C 1 -C 6 -alkyl, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6
  • R 13 is selected from the group consisting of a hydrido, benzyl, phenyl, C 1 -C 6 -alkyl, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl and a C 1 -C 6 -hydroxyalkyl group.
  • a compound of formula III as a pharmaceutically acceptable salt is also contemplated.
  • R 14 be hydrido, or that W of the C(W)R 15 pro-drug form be 0 and R 15 be a C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alkoxy, heteroaryl-C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl-C 1 -C 6 -alkyl, or aryloxy group.
  • a still more preferred compound for use in a contemplated process corresponds in structure to formula IV, below:
  • R 3 is as defined above as to formulas I, III and more preferably as defined as to formula II (wherein the R 3 radical is the substituent G-A-R-E-Y). Most preferably, R 3 is as defined in formula III.
  • Z is selected group the group consisting of O, S, NR 6 , SO, SO 2 , and NSO 2 R 7 ,
  • R 6 is selected from the group consisting of hydrido, C 1 -C 5 -alkyl, C 1 -C 5 -alkanoyl, benzyl, benzoyl, C 3 -C 5 -alkynyl, C 3 -C 5 -alkenyl, C 1 -C 3 -alkoxy-C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, heteroaryl-C 1 -C 6 -alkyl, C 1 -C 5 -hydroxyalkyl, C 1 -C 5 -carboxyalkyl, C 1 -C 5 -alkoxy C 1 -C 5 -alkylcarbonyl, and NR 8 R 9 —C 1 -C 5 -alkylcarbonyl or NR 8 R 9 —C 1 -C 5 -alkyl wherein R 8 and R 9 are independently hydrido, C 1 -C 5 -alkyl
  • R 7 is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, C 1 -C 6 -alkyl, C 3 -C 6 -alkynyl, C 3 -C 6 -alkenyl, C 1 -C 6 -carboxyalkyl and a C 1 -C 6 -hydroxyalkyl group.
  • Z is O or NR 6 .
  • a compound of formula IV as a pharmaceutically acceptable salt is contemplated.
  • a still more preferred group of contemplated compounds for use in a contemplated process correspond in structure to formula V, below;
  • W and Q are independently oxygen (O), NR 6 or sulfur (S), and R 6 is as defined in formula IV;
  • q is zero or one such that when q is zero, Q is absent and the trifluoromethyl group is bonded directly to the depicted phenyl ring.
  • a compound of formula IV as a pharmaceutically acceptable salt is contemplated.
  • ring structure Q including the depicted nitrogen atom is a heterocylic ring that contains 5- or 7-members, preferably 6-members, and can contain zero or one nitrogen atom in addition to that depicted.
  • the members of substituent -A-R-E-Y (or —R-E-Y or -E-Y) are as defined elsewhere in the definition of the members of the substituent -G-A-R-E-Y.
  • substituent -A-R-E-Y (or substituent —R-E-Y or -E-Y) is bonded at the 4-position relative to that depicted nitrogen atom when Q is a 6- or 7-membered ring and at the 3- or 4-position relative to that depicted nitrogen when Q is a 5-membered ring.
  • R 20 , X, Y, Z, m, n, and p of the ring system and g are as before described.
  • an SO 2 -linked R 3 radical is an aryl or heteroaryl group that is a 5- or 6-membered single-ring that is itself substituted with one other single-ringed aryl or heteroaryl group or, with an alkyl or alkoxy group having a chain length of 3 to about 16 carbon atoms (and more preferably a length of up to about 14 carbon atoms), a phenoxy group, a thiophenoxy (C 6 H 5 —S—] group, a phenylazo [C 6 H 5 —N 2 —] group, a N-piperidyl [C 5 H 10 N—] group, a N-piperazyl [NC 4 H 9 N—] group or a benzamido [—NHC(O)C 6 H 5 ] group.
  • the SO 2 -linked single-ringed aryl or heteroaryl R 3 group here is substituted at its own 4-position when a 6-membered ring and at its own 3- or
  • the SO 2 -linked aryl or heteroaryl group of a R 3 radical is preferably itself substituted at the 4-position when a 6-membered ring or the 3- or 4-position when a 5-membered ring.
  • a particularly preferred substituent is a single-ringed aryl or heteroaryl, phenoxy, thiophenoxy, phenylazo, N-piperidyl, N-piperazyl or benzamido group that is unsubstituted or can itself be substituted.
  • Exemplary particularly preferred substituted SO 2 -linked R 3 radicals include 4-(phenyl)phenyl [biphenyl], 4-(4′-methoxyphenyl)-phenyl, 4-(phenoxy)phenyl, 4-(thiophenyl)phenyl [4-(phenylthio)phenyl], 4-(azophenyl)phenyl, 4-[(4′-trifluoromethylthio)phenoxy]phenyl, 4-[(4′-trifluoromethylthio)thiophenyl]phenyl, 4-[(4′-trifluoromethyl)phenoxy]phenyl, 4-[(4′-trifluoromethyl)thiophenyl]phenyl, 4-[(4′-trifluoromethoxy)phenoxy]phenyl, 4-[(4′-trifluoromethoxy)thiophenyl]phenyl, 4-[(4′-phenyl)N-piperidyl]phenyl, 4-[(4′-ace
  • the 1-position of an above-discussed SO 2 -linked aryl or heteroaryl group is the position at which the SO 2 -group is bonded to the ring.
  • the 4- and 3-positions of rings discussed here are numbered from the sites of substituent bonding from the SO 2 -linkage as compared to formalized ring numbering positions used in heteroaryl nomenclature.
  • an R 3 radical including its own substituent has a total length that is greater than a saturated chain of five carbon atoms (a pentyl group), and preferably has a length greater than that of a saturated chain of six carbon atoms (a hexyl group); i.e., a length of about a heptyl chain or longer.
  • An R 3 radical also has a length that is less than that of a saturated chain of about 20 carbon atoms [an icosyl group (icosyl was formerly spelled eicosyl)] and more preferably about 18 carbon atoms (a stearyl group). Most preferably, the length of R 3 is about that of an 8 to about 12 carbon atom chain, even though many more atoms may be present in ring structures or substituents. This length requirement is discussed further below.
  • an R 3 radical (group or moiety) has a length that is greater than that of a pentyl group. Such an R 3 radical also has a length that is less than that of an icosyl (didecyl) group. That is to say that R 3 is a radical having a minimal length longer that a saturated five carbon chain, and preferably greater than a hexyl group, but is shorter than the length of a saturated twenty carbon atom chain, and preferably shorter than an eighteen carbon chain. Most preferably, R 3 has a length greater than that of an octyl group and less than that of a lauryl group.
  • an R 3 group has a minimal length of a hexyl group only when that substituent is comprised of two rings that can be fused or simply covalently linked together by exocyclic bonding.
  • R 3 does not contain two linked or fused rings, e.g., where a R 3 radical includes an alkyl or second, third or fourth ring substituent, R 3 has a length that is greater than that of a hexyl group.
  • Exemplary of such two ring R 3 groups are a 2-naphthyl group or a 2-quinolinyl group (each with a six carbon chain length) and 8-purinyl (with a five carbon atom chain length).
  • radical chain lengths are measured along the longest linear atom chain in the radical, following the skeletal atoms around a ring where necessary.
  • Each atom in the chain e.g. carbon, oxygen, sulfur or nitrogen, is presumed to be carbon for ease in calculation.
  • Such lengths can be readily determined by using published bond angles, bond lengths and atomic radii, as needed, to draw and measure a desired, usually staggered, chain, or by building models using commercially available kits whose bond angles, lengths and atomic radii are in accord with accepted, published values. Radical (substituent) lengths can also be determined somewhat less exactly by assuming that all atoms have bond lengths saturated carbon, that unsaturated bonds have the same lengths as saturated bonds and that bond angles for unsaturated bonds are the same as those for saturated bonds, although the above-mentioned modes of measurement are preferred. For example, a phenyl or pyridyl group has a length of a four carbon chain, as does a propoxy group, whereas a biphenyl group has a length of about an eight carbon chain using such a measurement mode.
  • a R 3 group when rotated about an axis drawn through the SO 2 -bonded 1-position and the 4-position of a 6-membered ring or the SO 2 -bonded position and substituent-bonded 3- or 4-position of a 5-membered ring defines a three-dimensional volume whose widest dimension has the width of about one furanyl ring to about two phenyl rings in a direction transverse to that axis to rotation.
  • a 2-naphthyl substituent or an 8-purinyl substituent is an appropriately sized R 3 group when examined using the above rotational width criterion as well as the before-discussed criterion.
  • a 1-naphthyl group or a 7- or 9-purinyl group is too wide upon rotation and is excluded from being an R 3 group.
  • R 3 radicals such as 4-(phenyl)phenyl [biphenyl], 4-(4′-methoxyphenyl)-phenyl, 4-(phenoxy)phenyl, 4-(thiophenyl)phenyl [4-(phenylthio)phenyl], 4-(azophenyl)phenyl, 4-[(4′-trifluoromethylthio)phenoxy]phenyl, 4-[(4′-trifluoromethylthio)thiophenyl]phenyl, 4-[(4′-trifluoromethyl)phenoxy]phenyl, 4-[(4′-trifluoromethyl)thiophenyl]phenyl, 4-[(4′-trifluoromethoxy)phenoxy]phenyl, 4-[(4′-trifluoromethoxy)thiophenyl]phenyl, 4-[(4′-phenyl)N-piperidyl]phenyl, 4-[(4′-phenyl)N-piperidyl]phenyl
  • substituents can themselves also be substituted in the second ring from the SO 2 group at the meta- or para-position or both with a single atom or a substituent containing a longest chain length that is preferably of up to five atoms, excluding hydrogen.
  • the length of a R 3 radical substituent bonded to the SO 2 group is believed to play a role in the overall activity of a contemplated inhibitor compound against MMP enzymes generally.
  • the length of the R 3 radical group also appears to play a role in the selective activity of an inhibitor compound against particular MMP enzymes.
  • R 3 is a PhR 23 group, wherein Ph is phenyl.
  • the phenyl ring (Ph) of a PhR 23 group is substituted at its para-position (4-position) by an R 23 group that can be another single-ringed aryl or heteroaryl group, a piperidyl group, a piperazinyl group, a phenoxy group, a thiophenoxy [C 6 H 5 —S—) group, a phenylazo [C 6 H 5 —N 2 —] group or a benzamido [—NHC(O)C 6 H 5 ] group.
  • an R 23 substituent is phenoxy and is itself substituted at its own para-position with a moiety that is selected from the group consisting of a halogen, a C 1 -C 4 alkoxy group, a C 1 -C 4 alkyl group, a dimethylamino group, a carboxyl C 1 -C 3 alkylene group, a C 1 -C 4 alkoxy carbonyl C 1 -C 3 alkylene group, a trifluoromethylthio group, a trifluoromethoxy group, a trifluoromethyl group and a carboxamido C 1 -C 3 alkylene group, or is substituted at the meta- and para-positions by a methylenedioxy group. It is to be understood that any R 23 substituent can be substituted with a moiety from the above list. Such substitution at the para-position is preferred.
  • the present invention also contemplates a compound that corresponds in structure to formula VI, below, that is useful in preparing a compound of formulas I-V, as well as as an active MMP-inhibiting compound and as a pro-drug form of an inhibitor.
  • R 20 is (a)—O—R 21 , where R 21 is selected from the group consisting of a hydrido, C 1 -C 6 -alkyl, aryl, ar-C 1 -C 6 -alkyl group and a pharmaceutically acceptable cation, (b)—NH—O—R 22 wherein R 22 is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), carbonyl-C 1 -C 6 -alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide synthesis resin and the like, wherein the trisubstituted silyl group is substituted with C 1 -C 6 -alkyl, aryl, or ar-C 1 -C 6 -alkyl or a mixture thereof, (c)—NH—O—R 14 , where R 14 is hydrido, a pharmaceutically
  • m is zero, 1 or 2;
  • n is zero, 1 or 2;
  • p is zero, 1 or 2;
  • one of X, Y and Z is selected from the group consisting of C(O), NR 6 , O, S, S(O), S(O) 2 and NS(O) 2 R 7 , and the remaining two of X, Y and Z are CR 8 R 9 , and CR 10 R 11 , or
  • n is zero and X, Y and Z together constitute a moiety selected from the group consisting of
  • R 6 and R 6 are independently selected from the group consisting of hydrido, formyl, sulfonic-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxycarbonyl-C 1 -C 6 -alkyl, hydroxycarbonyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkylcarbonyl-C 1 -C 6 -alkyl, R 8 R 9 -aminocarbonyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxycarbonyl-C 1 -C 6 -alkylcarbonyl, hydroxycarbonyl-C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkylcarbonyl-C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonylcarbonyl, hydroxycarbonylcarbonylcarbonyl, C 1 -
  • R 7 is selected from the group consisting of a arylalkyl, aryl, heteroaryl, heterocyclo, C 1 -C 6 -alkyl, C 3 -C 6 -alkynyl, C 3 -C 6 -alkenyl, C 1 -C 6 -carboxyalkyl and a C 1 -C 6 -hydroxyalkyl group;
  • R 8 and R 9 and R 10 and R 11 are independently selected from the group consisting of a hydrido, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkanoyl, aroyl, aryl, ar-C 1 -C 6 -alkyl, heteroaryl, heteroar-C 1 -C 6 -alkyl, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, thiol-C 1 -C 6 -alkyl, C 1 -C 6 -alkylthio-C 1 -C 6 -alkyl, cycloalkyl, cycloalkyl-C 1 -C 6 -alkyl, heterocycloalkyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, aralkoxy-C 1 -C 6 -C 6
  • R 12 and R 12 ′ are independently selected from the group consisting of a hydrido, C 1 -C 6 -alkyl, aryl, ar-C 1 -C 6 -alkyl, heteroaryl, heteroaralkyl, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, thiol-C 1 -C 6 -alkyl, cycloalkyl, cycloalkyl-C 1 -C 6 -alkyl, heterocycloalkyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, aryloxy-C 1 -C 6 -alkyl, amino-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6
  • R 13 is selected from the group consisting of a hydrido, benzyl, phenyl, C 1 -C 6 -alkyl, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl and a C 1 -C 6 -hydroxyalkyl group;
  • R 24 is R 3 as defined in formulas I, III, IV or is the substituent G-A-R-E-Y of formula II (formula VIA).
  • R 24 is R 3 ′, an aryl or heteroaryl group that is substituted with a coupling substituent reactive for coupling with another moiety (formula VIB), such as a nucleophilically displaceable leaving group, D.
  • Exemplary nucleophilically displaceable leaving groups, D include a halo (fluoro, chloro, bromo, or iodo) nitro, azido, phenylsulfoxido, aryloxy, C 1 -C 6 -alkoxy, a C 1 -C 6 -alkylsulfonate or arylsulfonate group and a trisubstituted ammonium group in which the three substituents are independently aryl, ar-C 1 -C 6 -alkyl or C 1 -C 6 -alkyl.
  • Additional coupling substituents include, without limitation, a hydroxyl group and an amino group that can be coupled with carbonyl-containing moieties to form esters, urethanes, carbonates, amides and ureas.
  • a carboxyl coupling substituent can be used to form an ester, thioester or amide.
  • a coupling substituent is useful in converting a coupling substituent-containing aryl or heteroaryl group into a substituent such as a G-A-R-E-Y substituent discussed hereinabove by the formation of a covalent bond.
  • a compound of formula VI can be coupled with another moiety at the R 3 ′ coupling substituent to form a compound whose newly formed R 3 group is that of formulas I, III, IV or -G-A-R-E-Y.
  • Exemplary of such couplings are the nucleophilic displacement to form ethers and thioethers, as well as the formation of ester, amide, urea, carbonate, urethane and the like linkages.
  • a precursor carboxylic acid or ester compound is defined that can be readily transformed into a hydroxamic acid, as is illustrated in several examples hereinafter.
  • R 20 group is —NH—O—R 22
  • R 22 is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), carbonyl-C 1 -C 6 -alkoxy, trisubstituted silyl group, an o-nitrophenyl group, or a peptide synthesis resin and the like
  • a synthetic intermediate is typically defined.
  • a trisubstituted silyl group is substituted with C 1 -C 6 -alkyl, aryl, ar-C 1 -C 6 -alkyl or a mixture thereof, such as a trimethylsilyl, dimethylisopropylsilyl, triethylsilyl, triphenylsilyl, t-butyldiphenylsilyl, diphenylmethylsilyl, a tribenzylsilyl group, and the like.
  • Exemplary trisubstituted silyl protecting groups and their uses are discussed at several places in Greene et al., Protective Groups In Organic Synthesis, 2nd ed., John Wiley & Sons, Inc., New York (1991).
  • a contemplated peptide synthesis resin is solid phase support also known as a so-called Merrifield's Peptide Resin that is adapted for synthesis and selective release of hydroxamic acid derivatives as is commercially available from Sigma Chemical Co., St. Louis, MO.
  • An exemplary peptide synthesis resin so adapted and its use in the synthesis of hydroxamic acid derivatives is discussed in Floyd et al., Tetrahedron Let., 37(44):8048-8048(1996).
  • a 2-tetrahydropyranyl (THP) protecting group is a particularly preferred selectively removable protecting group.
  • a contemplated THP-protected hydroxamate compound of formula VII can be prepared by reacting the carboxylic acid precursor compound of formula VII [where R 20 is —O—R 21 and R 21 is a hydrido group] in water with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine in the presence of N-methylmorpholine, N-hydroxybenzotriazole hydrate and a water-soluble carbodiimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • THP protecting group is readily removable in an aqueous acid solution such as an aqueous mixture of p-toluenesulfonic acid or HCl and acetonitrile or methanol.
  • aqueous acid solution such as an aqueous mixture of p-toluenesulfonic acid or HCl and acetonitrile or methanol.
  • An illustrative THP-protected compound corresponds in structure to formula VIIB, below, wherein m, n, p, g, X, Z. Y, and D are as defined previously.
  • R 20 is —NR 26 R 27 , and R 26 and R 27 are as defined before, an amide compound is defined that can be used as a precursor intermediate and surprisingly as a MMP inhibitor compound.
  • R 26 and R 27 are both preferably hydrido.
  • R group is —NH—O—R 14 , and R 14 is hydrido, or a pharmaceutically acceptable cation
  • an active hydroxamic acid or hydroxamate is defined.
  • R 20 group is —NH—O—R 14 , and R 14 is a C(W)R 25 group as defined before
  • a pro-drug form of the hydroxamic acid is defined that can form a hydroxamic acid or hydroxamate form of the inhibitor in situ.
  • a particularly preferred precursor intermediate to an intermediate compound of formula VI is an intermediate compound of formula VII, below
  • a preferred intermediate corresponds in structure to formula VIIA, below, wherein R 20 , X, Y, Z, m, n, p and D are as defined previously.
  • molecular descriptors can be combined to produce words or phrases that describe structural groups or are combined to describe structural groups. Such descriptors are used in this document. Common illustrative examples include such terms as aralkyl (or arylalkyl), heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, aralkoxyalkoxycarbonyl and the like.
  • aralkyl or arylalkyl
  • heteroaralkyl heterocycloalkyl
  • cycloalkylalkyl aralkoxyalkoxycarbonyl
  • a specific example of a compound encompassed with the latter descriptor aralkoxyalkoxycarbonyl is C 6 H 5 —CH 2 —CH 2 —O—CH 2 —O—(C ⁇ O)— wherein C 6 H 5 — is phenyl.
  • a structural group can have more than one descriptive word or phrase in the art, for example, heteroaryloxyalkylcarbonyl can also be termed heteroaryloxyalkanoyl.
  • heteroaryloxyalkylcarbonyl can also be termed heteroaryloxyalkanoyl.
  • alkyl means a straight-chain or branched-chain alkyl radical containing 1 to about 12 carbon atoms, preferably 1 to about 10 carbon atoms, and more preferably 1 to about 6 carbon atoms.
  • examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like.
  • alkenyl means a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing 2 to about 12 carbon atoms preferably 2 to about 10 carbon atoms, and more preferably, 2 to about 6 carbon atoms.
  • suitable alkenyl radicals include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, decenyl and the like.
  • alkynyl alone or in combination, means a straight-chain hydrocarbon radical having one or more triple bonds and containing 2 to about 12 carbon atoms, preferably 2 to about 10 carbon atoms, and more preferably, 2 to about 6 carbon atoms.
  • alkynyl radicals include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
  • carbonyl or “oxo”, alone or in combination, means a —C( ⁇ O)— group wherein the remaining two bonds (valences) can be independently substituted.
  • carbonyl is also intended to encompass a hydrated carbonyl group —C(OH) 2 —.
  • thiol or “sulfhydryl”, alone or in combination, means a —SH group.
  • thio or “thia”, alone or in combination, means a thiaether group; i.e., an ether group wherein the ether oxygen is replaced by a sulfur atom.
  • amino alone or in combination, means an amine or —NH 2 group whereas the term mono-substituted amino, alone or in combination, means a substituted amine —N(H)(substituent) group wherein one hydrogen atom is replaced with a substituent, and disubstituted amine means a —N(substituent) 2 wherein two hydrogen atoms of the amino group are replaced with independently selected substituent groups.
  • Amines, amino groups and amides are compounds that can be designated as primary (I°), secondary (II°) or tertiary (III°) or unsubstituted, mono-substituted or N,N-disubstituted depending on the degree of substitution of the amino nitrogen.
  • Quaternary amine (ammonium)(IV°) means a nitrogen with four substituents [—N + (substituent) 4 ] that is positively charged and accompanied by a counter ion, whereas N-oxide means one substituent is oxygen and the group is represented as [—N + (substituent) 3 —O ⁇ ]; i.e., the charges are internally compensated.
  • cyano alone or in combination, means a —C-triple bond-N (—C ⁇ N) group.
  • zido alone or in combination, means a —N-triple bond-N (—N ⁇ N) group.
  • hydroxyl alone or in combination, means a —OH group.
  • nitro alone or in combination, means a —NO 2 group.
  • azo alone or in combination, means a —N ⁇ N-group wherein the bonds at the terminal positions can be independently substituted.
  • hydrazino alone or in combination, means a —NH—NH— group wherein the depicted remaining two bonds (valences) can be independently substituted.
  • the hydrogen atoms of the hydrazino group can be replaced, independently, with substituents and the nitrogen atoms can form acid addition salts or be quaternized.
  • sulfonyl alone or in combination, means a —SO 2 — group wherein the depicted remaining two bonds (valences) can be independently substituted.
  • sulfoxido alone or in combination, means a —SO— group wherein the remaining two bonds (valences) can be independently substituted.
  • sulfone alone or in combination, means a —SO 2 — group wherein the depicted remaining two bonds (valences) can be independently substituted.
  • sulfenamide alone or in combination, means a —SON ⁇ group wherein the remaining three depicted bonds (valences) can be independently substituted.
  • sulfide alone or in combination, means a —S— group wherein the remaining two bonds (valences) can be independently substituted.
  • alkoxy alone or in combination, means an alkyl ether radical wherein the term alkyl is as defined above.
  • suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
  • cycloalkyl alone or in combination, means a cyclic alkyl radical that contains 3 to about 8 carbon atoms.
  • cycloalkylalkyl means an alkyl radical as defined above that is substituted by a cycloalkyl radical containing 3 to about 8, preferably 3 to about 6, carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • a heterocyclic (heterocyclo) or heterocyclo portion of a heterocyclocarbonyl, heterocyclooxy-carbonyl, heterocycloalkoxycarbonyl, or heterocycloalkyl group or the like is a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle that contains one or more hetero atoms selected from nitrogen, oxygen and sulphur.
  • Heterocyclo compounds include benzofused heterocyclic compounds such as benzo-1,4-dioxane.
  • Such a moiety can be optionally substituted on one or more ring carbon atoms by halogen, hydroxy, hydroxycarbonyl, alkyl, alkoxy, oxo, and the like, and/or on a secondary nitrogen atom (i.e., —NH—) of the ring by alkyl, aralkoxycarbonyl, alkanoyl, aryl or arylalkyl or on a tertiary nitrogen atom (i.e., ⁇ N—) by oxido and that is attached via a carbon atom.
  • the tertiary nitrogen atom with three substituents can also attached to form a N-oxide [ ⁇ N(O)-] group.
  • aryl alone or in combination, means a 5- or 6-membered carbocyclic aromatic ring-containing moiety or a fused ring system containing two or three rings that have all carbon atoms in the ring; i.e., a carbocyclic aryl radical.
  • exemplary carbocyclic aryl radicals include phenyl, indenyl and naphthyl radicals.
  • heteroaryl alone or in combination means a 5- or 6-membered aromatic ring-containing moiety or a fused ring system (radical) containing two or three rings that have carbon atoms and also one or more heteroatoms in the ring(s) such as sulfur, oxygen and nitrogen.
  • heterocyclic or heteroaryl groups examples include pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyl (e.g., imidazol-4-yl, 1-benzyloxycarbonylimidazol-4-yl, and the like), pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, furyl, tetrahydrofuryl, thienyl, triazolyl, tetrazolyl, oxazolyl, oxadiazoyl, thiazolyl, thiadiazoyl, indolyl (e.g., 2-indolyl, and the like), quinolinyl, (e.g., 2-quinolinyl, 3-quinolinyl, 1-oxido-2-quinolinyl, and the like), isoquinolinyl (e.g.,
  • an aryl or heteroaryl radical is a substituting moiety (group, substituent, or radical), it can itself substituted, the last-named substituent is independently selected from the group consisting of a cyano, perfluoroalkyl, trifluoro-methoxy, trifluoromethylthio, haloalkyl, trifluoromethylalkyl, aralkoxycarbonyl, aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy,
  • amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of an alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl and an alkanoyl group, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring containing zero to two additional heteroatoms that are nitrogen, oxygen or sulfur and which ring itself is (a) unsubstituted or (b) substituted with one or two groups independently selected from the group consisting of an aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalky
  • the carbonylamino nitrogen is (i) unsubstituted, or (ii) is the reacted amine of an amino acid, or (iii) substituted with one or two radicals selected from the group consisting of an alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzofused heterocycloalkyl, benzofused heterocycloalkyl, benzofused cycloalkyl, and an N,N-dialkylsubstituted alkylamino-alkyl group, or (iv) the carboxamido nitrogen and two substituents bonded thereto together form a 5- to 8-membered heterocyclo, heteroaryl or benzofused heterocycloalkyl ring that is itself unsubstituted or substituted with one or two radicals independently selected from the group consisting of an alkyl, alkoxy
  • amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of alkyl, aryl, and heteroaryl, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, and an aminoalkyl group
  • aminoalkyl nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents independently selected from the group consisting of an alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and an alkanoyl group, or (iii) wherein the aminoalkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring.
  • aralkyl alone or in combination, means an alkyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as benzyl, 2-phenylethyl and the like.
  • aralkoxycarbonyl alone or in combination, means a radical of the formula aralkyl-O—C(O)— in which the term “aralkyl” has the significance given above.
  • An example of an aralkoxycarbonyl radical is benzyloxycarbonyl.
  • aryloxy means a radical of the formula aryl-O— in which the term aryl has the significance given above.
  • the phenoxy radical is an exemplary aryloxy radical.
  • heteroarylkyl and “heteroaryloxy” mean radicals structurally similar to aralkyl and aryloxy that are formed from heteroaryl radicals.
  • exemplary radicals include 4-picolinyl and 2-pyrimidinoxy, respectively.
  • alkanoyl or “alkylcarbonyl”, alone or in combination, means an acyl radical derived from an alkanecarboxylic acid, examples of which include formyl, acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like.
  • cycloalkylcarbonyl means an acyl group derived from a monocyclic or bridged cycloalkanecarboxylic acid such as cyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, and the like, or from a benz-fused monocyclic cycloalkanecarboxylic acid that is optionally substituted by, for example, alkanoylamino, such as 1,2,3,4-tetrahydro-2-naphthoyl, 2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl.
  • aralkanoyl or “aralkylcarbonyl” mean an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl and the like.
  • aroyl or “arylcarbonyl” means an acyl radical derived from an aromatic carboxylic acid.
  • radicals include aromatic carboxylic acids, an optionally substituted benzoic or naphthoic acid such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.
  • cycloalkylalkoxycarbonyl means an acyl group of the formula cycloalkylalkyl-O—CO— wherein cycloalkylalkyl has the significance given above.
  • aryloxyalkanoyl means an acyl radical of the formula aryl-O-alkanoyl wherein aryl and alkanoyl have the significance given above.
  • heterocyclooxycarbonyl means an acyl group having the formula heterocyclo-O—CO— wherein heterocyclo is as defined above.
  • heterocycloalkanoyl is an acyl radical of the formula heterocyclo-substituted alkane carboxylic acid wherein heterocyclo has the significance given above.
  • heterocycloalkoxycarbonyl means an acyl radical of the formula heterocyclo-substituted alkane-O—CO— wherein heterocyclo has the significance given above.
  • heteroaryloxycarbonyl means an acyl radical represented by the formula heteroaryl-O—CO— wherein heteroaryl has the significance given above.
  • aminocarbonyl (carboxamide) alone or in combination, means an amino-substituted carbonyl (carbamoyl) group derived from an amine reacted with a carboxylic acid wherein the amino (amido nitrogen) group is unsubstituted (—NH 2 ) or a substituted primary or secondary amino group containing one or two substituents selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like, as recited.
  • a hydroxamate is a N-hydroxycarboxamide.
  • aminoalkanoyl means an acyl group derived from an amino-substituted alkanecarboxylic acid wherein the amino group can be a primary or secondary amino group containing substituents independently selected from hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like.
  • halogen means fluoride, chloride, bromide or iodide.
  • haloalkyl means an alkyl radical having the significance as defined above wherein one or more hydrogens are replaced with a halogen. Examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like.
  • perfluoroalkyl means an alkyl group wherein each hydrogen has been replaced by a fluorine atom.
  • perfluoroalkyl groups in addition to trifluoromethyl above, are perfluorobutyl, perfluoroisopropyl, perfluorododecyl and perfluorodecyl.
  • perfluoroalkoxy alone or in combination, means a perfluoroalkyl ether radical wherein the term perfluoroalkyl is as defined above.
  • perfluoroalkoxy groups in addition to trifluoromethoxy (F 3 C—O—), are perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy and perfluorodecoxy.
  • perfluoroalkylthio alone or in combination, means a perfluoroalkyl thioether radical wherein the term perfluoroalkyl is as defined above.
  • perfluoroalkylthio groups in addition to trifluoromethylthio (F 3 C—S—), are perfluorobutylthio, perfluoroisopropylthio, perfluorododecylthio and perfluorodecylthio.
  • aromatic ring in combinations such as substituted-aromatic ring sulfone or substituted-aromatic ring sulfoxide means aryl or heteroaryl as defined before.
  • compositions include metallic ions and organic ions. More preferred metallic ions include, but are not limited to appropriate alkali metal (Group Ia) salts, alkaline earth metal (Group IIa) salts and other physiological acceptable metal ions. Exemplary ions include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc in their usual valences.
  • Preferred organic ions include protonated tertiary amines and quaternary ammonium cations, including in part, trimethylamine, diethylamine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • Exemplary pharmaceutically acceptable acids include without limitation hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like.
  • M utilized in the reaction schemes that follow represents a leaving group such as halogen, phosphate ester or sulfate ester.
  • Schemes A through C and Schemes 1 through 19 hereinbelow illustrate chemical processes and transformations that can be useful for the preparation of compounds useful in this invention; i.e., compounds of formulas I, II, III, IV and V and similar cyclic inhibitors.
  • compounds of formula VI and formula VII is illustrated.
  • Compounds of formula VI and formula VII can be used as intermediates in the preparation of the compounds of formulas I, II, III, IV and V or pro-drugs or MMP inhibitors.
  • the symbol J independently represents R 20 or other synthetically useful groups such as amides, acid chlorides, mixed anhydrides and the like.
  • the n is 0, 1 or 2 and is preferred to be 1 or 2 in Scheme C.
  • the n of these schemes corresponds to g in formulas VI and VII., and is zero, 1 or 2.
  • the symbol m is 1 or 2.
  • the symbol r is independently 1, 2 or 3.
  • the symbol P represents a protecting group that can also be a member of the group R 6 .
  • positional isomers are illustrated with a bond through the ring in standard fashion.
  • Scheme A shows in step 1 the reduction of a heteraryl compound to a carboxyl derivative.
  • the first product is a hydrogen-containing amine heterocycle when the starting material is aromatic or an R 6 -containing heterocycle when a partially unsaturated heterocycle is the starting material.
  • Compound 2 can be treated in several ways depending on the needs of the chemist.
  • the nitrogen can be protected by preparing, for example, a carbobenzoxy (Z) or tert-butoxycarbonyl derivative.
  • acylations can be carried out by methods well known in the art, especially the art of amino acid and peptide synthesis.
  • the process of acylation with activated carboxyl group- or activated sulfonyl group-containing reagents to prepare contemplated compounds is carried out in the same manner.
  • Examples of such acylating groups are carbonyl azides, halides, anhydrides, mixed anhydrides, carbodiimide derivatives or other less traditional activated ester groups such as the hydroxybenzotriazole derivative.
  • acylations can be run in the presence of base including mild bases such as triethylamine or N-ethylmorpholine if desired.
  • base including mild bases such as triethylamine or N-ethylmorpholine if desired.
  • the preparation of some activated ester reagents and their use to prepare other compounds useful in this invention is discussed below. It should be recalled that the groups constituting P and serving as a selectively removable protecting group can also be included as part of the group R 6 .
  • Step 4 of Scheme A shows the alkylation or acylation of Compound 2 to produce compound 5.
  • the process of acylation and alkylation are as discussed herein.
  • the group J can be changed if desired.
  • An example of such a change is exchange of an ester for a THP-protected hydroxamate conversion of a THP-protected hydroxamate inot a hydroxamate or conversion of an acid into a protected hydroxamate or the like.
  • Steps 3, 7 and 8 show the preparation of sulfur-containing derivatives of the contemplated compounds or intermediates to those compounds.
  • the starting material for the above steps e.g., compounds 2, 5 and 6) can be treated with a base to deprotonate the carbon alpha to the carbonyl function. This anion can be reacted with a sulfur electrophile to produce a sulfone, sulfoxide or sulfide.
  • Such electrophiles can be of the form of, for example, R 24 S—SR 24 , R 24 SO 2 C 1 , R 24 SC 1 , R 24 SOC 1 , R 24 S(O)—SR 24 and the like where R 24 is as defined before or is an aryl or heteroaryl sulfur-containing material containing a coupling substituent, R 3 ′, that can be used to prepare one of the R 24 -containing groups.
  • R 24 is as defined before or is an aryl or heteroaryl sulfur-containing material containing a coupling substituent, R 3 ′, that can be used to prepare one of the R 24 -containing groups.
  • Preparation of the anion requires a base and a strong base may be required such as one of the metal amides, hydrides or alkyls discussed herein.
  • the solvents are nonprotic, and dipolar aprotic solvents are preferred along with an inert atmosphere. Subsequent schemes usually utilize R 3 for the R 24 group for ease of illustration.
  • Scheme A, Steps 6, 9, 10 and 12 independently illustrate the interconversion of groups within J.
  • interconversions include exchange of an ester for hydroxamic acid or hydroxamic acid derivative, conversion of a carboxylic acid into an activated carbonyl derivative or into a hydroxamic acid or hydroxamic acid derivative (pro-drug or protected derivative), or removal of a protecting group from a hydroxamate derivative.
  • the preparation of activated carbonyl compounds their reaction with nucleophiles such as hydroxamic acid, protected hydroxamates or hydroxamic acid pro-drugs is discussed below as is the conversion of protected hydroxamic acid derivatives into hydroxamic acids.
  • Step 6 illustrates the conversion of compound 4 into compound 9, without first being converted into compound 7.
  • Scheme B illustrates an alternate method of preparing contemplated compounds.
  • the reagent shown above the arrow in Step 1 is a reagent with two active groups in addition to the heteroatoms (B) noted before.
  • the particular reagent illustrated was selected to permit a clear illustration of the reaction, but it is also intended to represent reagents that permit the preparation of the heteroatom position, and 5-, 7- and 8-membered ring size compounds. These reagents are readily selected by those skilled in the art.
  • C and C′ in this Step 1 reagent are independently an electophile or a group convertible into an electrophile.
  • groups include halides, sulfonic acid esters, epoxides, thioepoxides, hydroxyl groups, and the like.
  • This reagent is reacted with a nucleophilic anion of a sulfur containing carbonyl compound such as compound 1.
  • the anion is formed by deprotonation of compound 1 and examples of bases suitable for such a deprotonation are discussed below.
  • Treatment with the above electrophilic reagent is carried out under alkylating conditions well known in the art and discussed herein.
  • the product of this reaction can be either Compound 2 or Compound 3; i.e., the reaction can be carried out as a pot or two step process as required.
  • Step 3 illustrates the interconversion of J groups if desired as discussed above for Scheme A.
  • Step 4 uses reagent where C, for example, represents a nucleophile as discussed above and C′ represents an electrophile or a nucleophile such as hydroxyl, thiol or R 6 -amino. It is noted that Cl can be, independently, a nucleophile or an electrophile when m is 2; i.e., the C′ groups are not required to be the same when m is 2. When m is 2, treatment with a second mole of base provides the skilled chemist an alternative preparation of Compound 5.
  • C′ is hydroxyl, thiol, or R 6 -amino and m is 2
  • the person skilled in the art can condense Compound 4 with, for example, an aldehyde or ketone, under reductive conditions or with subsequent reduction to form a contemplated compound.
  • the compound where m is 2 can be made in one step (one pot process) or two steps, thus permitting the chemist the choice of having the reagent(s) be the same (one pot) or different (two step).
  • Scheme B also illustrates the interconversions of the groups within J, the oxidation state of the sulfur and groups on nitrogen; i.e., R 6 groups, to provide the contemplated compounds. These methods and processes are discussed above for the reactions of Scheme A.
  • Scheme C illustrates the nucleophilic displacement of a group D as defined herein. This reaction is carried out in a similar manner to the displacement reactions discussed herein.
  • the choice of oxidation state of the sulfur is made by the person skilled in the art, but sulfoxide or sulfone groups are preferred, and the sulfone is most preferred.
  • the displacement can be carried out either before or after the methylene next to the carbonyl group is reacted to form a Spiro heterocyclic group.
  • Steps 1, 2 and 3 also illustrate that although the nucleophilic displacement can be carried out with one nucleophile (Nu), the product of this reaction can be modified by methods well known in the art and as shown herein to provide the group -A-R-E-Y as defined hereinbefore.
  • D is fluoride.
  • the fluoride leaving group can be directly displaced with the anion of 4-trifluoromethylphenol, 4-trifluoromethoxyphenol, 4-trifluoromethylthiophenol and the like to provide a contemplated compound.
  • This is a one pot process from Compound 4.
  • Other compounds included in -A-R-E-Y can be prepared by displacing the fluoride leaving group with ammonia to provide an amine, which can then be acylated by methods discussed wherein with, for example, 4-trifluoromethylbenzoyl chloride, to form another contemplated product compound.
  • R 6 function can be changed and/or further modified in compounds or at steps in the Schemes as desired or required by the person skilled in the art to prepare the contemplated compounds. Interconversion of dual purpose functional groups such as short or long term protecting groups into other R 6 groups has been mentioned. Many other routine and/or useful conversions, including the preparation of synthetic intermediates, are very well known in the art.
  • a few non-limiting examples of such conversions or reactions include: reductions; nucleophilic displacement/substitution reactions; exchange or preparation of carboxylic or sulfonic acids, amides, esters, acid halides, mixed anhydrides and the like; electrophilic displacement/substitution reactions; oxidations; ring/chain conversions, ring opening reactions, condensation reactions including those involving sulfonyl or carbonyl groups and/or carbon-hydrogen bonds influenced by either or both of those groups.
  • the selection of preparative methods or conversion methods of the contemplated compounds and the order of the reaction(s) is made by the skilled person. It is expected that should a particular sequence or method prove to be undesirable that an alternative will be selected and used. Included is the choice of preparing/adding the groups in a single step using a convergent inhibitor strategy or preparing the final R 6 group following a stepwise strategy.
  • the illustrated reactions are usually carried out at a temperature of between ⁇ 25° C. to solvent reflux under an inert atmosphere such as nitrogen or argon.
  • the solvent or solvent mixture can vary widely depending upon reagents and other conditions and can include polar or dipolar aprotic solvents as listed or mixtures of these solvents. Reactions can be carried out at lower temperatures such as dry ice/acetone or liquid nitrogen temperature if desired to carry out such reactions as metalations or anion formations using strong bases.
  • amines such as triethylamine, pyridine or other non-reactive bases can serve as reagents and/or solvents and/or co-solvents.
  • protecting groups can be used to maintain or retain groups in other parts of a molecule(s) at locations that is(are) not desired reactive centers. Examples of such groups that the skilled person can maintain or retain include, amines, other hydroxyls, thiols, acids and the like.
  • Such protecting groups can include acyl groups, arylalkyl groups, carbamoyl groups, ethers, alkoxyalkyl ethers, cycloalkyloxy ethers, arylalkyl groups, silyl groups including trisubstituted silyl groups, ester groups and the like.
  • Examples of such protecting groups include acetyl, trifluoroacetyl, tetrahydropyran (THP), benzyl, tert-butoxy carbonyl (BOC or TBOC), benzyloxycarbonyl (Z or CBZ), tert-butyldimethylsilyl (TBDMS) or methoxyethoxymethylene (MEM) groups.
  • THP tetrahydropyran
  • BOC or TBOC benzyloxycarbonyl
  • Z or CBZ tert-butyldimethylsilyl
  • MEM methoxyethoxymethylene
  • Bases that can act as reactants, reagents, deprotonating agents, acid scavengers, salt forming reagents, solvents, co-solvents and the like.
  • Bases that can be used include, for example, metal hydroxides such as sodium, potassium, lithium, cesium or magnesium hydroxide, oxides such as those of sodium, potassium, lithium, calcium or magnesium, metal carbonates such as those of sodium, potassium, lithium, cesium, calcium or magnesium, metal bicarbonates such as sodium bicarbonate or potassium bicarbonate, primary (I°), secondary (II°) or tertiary (III°) organic amines such as alkyl amines, arylalkyl amines, alkylarylalkyl amines, heterocyclic amines or heteroaryl amines, ammonium hydroxides or quaternary ammonium hydroxides.
  • such amines can include triethylamine, trimethylamine, diisopropylamine, methyldiisopropylamine, diazabicyclononane, tribenzylamine, dimethylbenzylamine, morpholine, N-methylmorpholine, N,N′-dimethylpiperazine, N-ethylpiperidine, 1,1,5,5-tetramethylpiperidine, dimethylaminopyridine, pyridine, quinoline, tetramethylethylenediamine, and the like.
  • Non-limiting examples of ammonium hydroxides can include ammonium hydroxide, triethylammonium hydroxide, trimethylammonium hydroxide, methyldiiospropylammonium hydroxide, tribenzylammonium hydroxide, dimethylbenzylammonium hydroxide, morpholinium hydroxide, N-methylmorpholinium hydroxide, N,N′-dimethylpiperazinium hydroxide, N-ethylpiperidinium hydroxide, and the like.
  • quaternary ammonium hydroxides can include tetraethylammonium hydroxide, tetramethylammonium hydroxide, dimethyldiiospropyl-ammonium hydroxide, benzylmethyldiisopropylammonium hydroxide, methyldiazabicyclononylammonium hydroxide, methyltribenzylammonium hydroxide, N,N-dimethyl-morpholiniumhydroxide, N,N,N′,N′-tetramethylpiperazinium hydroxide, and N-ethyl-N′-hexylpiperidinium hydroxide and the like.
  • Metal hydrides, amides or alcoholates such as calcium hydride, sodium hydride, potassium hydride, lithium hydride, aluminum hydride, diisobutylaluminum hydride (DIBAL) sodium methoxide, potassium tert-butoxide, calcium ethoxide, magnesium ethoxide, sodium amide, potassium diisopropyl amide and the like can also be suitable reagents.
  • DIBAL diisobutylaluminum hydride
  • Organometallic deprotonating agents such as alkyl or aryl lithium reagents such as methyl lithium, phenyl lithium, tert-butyl lithium, lithium acetylide or butyl lithium, Grignard reagents such as methylmagnesium bromide or methymagnesium chloride, organocadmium reagents such as dimethylcadmium and the like can also serve as bases for causing salt formation or catalyzing the reaction. Quaternary ammonium hydroxides or mixed salts are also useful for aiding phase transfer couplings or serving as phase transfer reagents. Pharmaceutically acceptable bases can be reacted with acids to form contemplated pharmaceutically acceptable salts. It should also be noted that optically active bases can be used to make optically active salts which can be used for optical resolutions.
  • reaction media can comprise a single solvent, mixed solvents of the same or different classes or serve as a reagent in a single or mixed solvent system.
  • the solvents can be protic, non-protic or dipolar aprotic.
  • protic solvents include water, methanol (MeOH), denatured or pure 95% or absolute ethanol, isopropanol and the like.
  • Typical non-protic solvents include acetone, tetrahydrofuran (THF), dioxane, diethyl ether, tert-butylmethyl ether (TBME), aromatics such as xylene, toluene, or benzene, ethyl acetate, methyl acetate, butyl acetate, trichloroethane, methylene chloride, ethylenedichloride (EDC), hexane, heptane, isooctane, cyclohexane and the like.
  • THF tetrahydrofuran
  • TBME tert-butylmethyl ether
  • aromatics such as xylene, toluene, or benzene, ethyl acetate, methyl acetate, butyl acetate, trichloroethane, methylene chloride, ethylenedichloride (EDC), hexane,
  • Dipolar aprotic solvents include compounds such as dimethylformamide (DMF), dimethylacetamide (DMAc), acetonitrile, DMSO, hexamethylphosphorus triamide (HMPA), nitromethane, tetramethylurea, N-methylpyrrolidone and the like.
  • Non-limiting examples of reagents that can be used as solvents or as part of a mixed solvent system include organic or inorganic mono- or multi-protic acids or bases such as hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, triethylamine, morpholine, N-methylmorpholine, piperidine, pyrazine, piperazine, pyridine, potassium hydroxide, sodium hydroxide, alcohols or amines for making esters or amides or thiols for making contemplated products and the like.
  • organic or inorganic mono- or multi-protic acids or bases such as hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, triethylamine, morpholine, N-methylmorpholine, piperidine, pyrazine, piperazine, pyridine, potassium hydroxide, sodium hydroxide, alcohols
  • the preparation of compounds contemplated herein can require the oxidation of nitrogen or sulfur to N-oxide derivatives or sulfoxides or sulfones.
  • Reagents for this process can include, in a non-limiting example, peroxymonosulfate (OXONE®), hydrogen peroxide, meta-chloroperbenzoic acid, perbenzoic acid, peracetic acid, perlactic acid, tert-butyl peroxide, tert-butyl hypochlorite, sodium hydpochlorite, hypochlorous acid, sodium meta-periodate, periodic acid and the like with the weaker agents being most useful for the preparation of sulfones and sulfoxides.
  • Protic, non-protic, dipolar aprotic solvents, either pure or mixed, can be chosen, for example, methanol/water.
  • the oxidation can be carried out at temperature of about ⁇ 780 to about 50° degrees Centigrade, and normally selected from a range ⁇ 10° C. to about 40° C.
  • Sulfoxides are best prepared using one equivalent of oxidizing agent. It can be desirable in the case of more active oxidizing agents, but not required, that the reactions be carried out under an inert gas atmosphere with or without degassed solvents. It should be noted that the oxidation of sulfides to sulfones can be carried out in one step or two steps via the sulfoxide as desired by the chemist.
  • Reduction is a well known process in the art with a useful method being hydrogenation.
  • a metal catalyst such as Rh, Pd, Pt, Ni or the like with or without an additional support such as carbon, barium carbonate and the like.
  • Solvents can be protic or non-protic pure solvents or mixed solvents as required.
  • the reductions can be carried out at atmospheric pressure to a pressure of multiple atmospheres with atmospheric pressure to about 40 pounds per square inch (psi) preferred or very high pressures in special hydrogenation equipment well known in the art.
  • Reductive alkylation of amines or active methylene compounds is also a useful method of preparing compounds.
  • Such alkylations can be carried out under reductive hydrogenation conditions as presented above using, for example, aldehydes or ketones.
  • Hydride transfer reagents such as sodium cyanoborohydride, aluminum hydride, lithium aluminumhydride, borane, sodium borohydride, di-isobutylaluminum hydride and the like are also useful as reagents for reductive alkylation.
  • Acyl groups can be reduced in a similar manner to produce substituted amines.
  • Alternative methods of alkylating carbon or nitrogen are direct alkylation.
  • Such an alkylation can be carried by treatment of an activated carbon containing at least one hydrogen with base to form the corresponding anion, adding an electrophilic reagent and permitting the SN2 reaction to proceed.
  • An amine to be alkylated is treated similarly except that deprotonation may not be required.
  • Electrophiles include halogen derivatives, sulfonate esters, epoxides and the like.
  • Bases and solvents for alkylation reactions are those discussed above. Preferred are bases that are hindered such that competition with the electrophile is minimized. Additional preferred bases are metal hydrides, amide anions or organometallic bases such as n-butyl lithium. The solvents, solvent mixtures or solvent/reagent mixtures discussed are satisfactory but non-protic or dipolar aprotic solvents such as acetone, acetonitrile, DMF and the like are examples of preferred classes.
  • Acids are used in many reactions during various syntheses. For example, removal of the THP protecting group to produce the hydroxamic acid.
  • the acid can be a mono-, di- or tri-protic organic or inorganic acid.
  • acids include hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, hydrobromic acid, hydrofluoric acid, carbonic acid, phosphorus acid, p-toluene sulfonic acid, trifluoromethane sulfonic acid, trifluoroacetic acid, difluoroacetic acid, benzoic acid, methane sulfonic acid, benzene sulfonic acid, 2,6-dimethylbenzene sulfonic acid, trichloroacetic acid, nitrobenzoic acid, dinitrobenzoic acid, trinitrobenzoic acid, and the like.
  • They can also be Lewis acids such as aluminum chloride, borontrifluoride, antimony pentafluoride and the like. Acids in a protic can also be used to hydrolyze esters, amides and the like as well as catalyze exchange reactions.
  • a base such as a salt of an alcohol used as a solvent, for example, sodium methoxide in methanol
  • a base such as a salt of an alcohol used as a solvent, for example, sodium methoxide in methanol
  • exchange can be carried out with a protected hydroxylamine such as tetrahydropyranylhydroxyamine (THPONH 2 ), benzylhydroxylamine (BnONH 2 ), and the like in which case compounds such as shown in Schemes A, B and C that are tetrahydropyranyl (THP) or benzyl (Bn) hydroxamic acid derivatives are the products.
  • THPONH 2 tetrahydropyranylhydroxyamine
  • BnONH 2 benzylhydroxylamine
  • Removal of the protecting groups when desired, for example, following further transformations in another part of the molecule or following storage, is accomplished by standard methods well known in the art such as acid hydrolysis of the THP group as discussed above or reductive removal of the benzyl group with hydrogen and a metal catalyst such as palladium, platinum, palladium on carbon or nickel.
  • R 20 is hydroxyl; i.e., where the intermediate is a carboxylic acid
  • standard coupling reactions can be used.
  • the acid can be converted into an acid chloride, mixed anhydride or activated ester such as hydroxybenzotriazole and treated with hydroxylamine or a protected hydroxylamine in the presence of a non-competitive base to the nitrogen acylated compound.
  • This is the same product as discussed above. Couplings of this nature are well known in the art and especially the art related to peptide and amino acid chemistry.
  • An amide of this invention is prepared by treatment of an acid halide, anhydride, mixed anhydride or active ester with a primary amine, secondary amine or ammonia, or their equivalent. These standard coupling reactions are well known in the art and are discussed elsewhere herein.
  • An alternative method of preparation of amides is by the exchange of, for example, an alkoxycarbonyl (ester) or aminecarbonyl (amide) group for an amine or different amine as required. Ester exchange processes are especially useful when less hindered amines, including ammonia, are used to make the corresponding amides of this invention.
  • amides can be prepared from hydroxamic acids or protected hydroxamic acid compounds by catalytic reductions or in vivo or in vitro enzymatic processes.
  • catalytic reduction of O-benzylhydroxamic acid compounds is known to produce varying ratios of amide and hydroxamic acid depending upon the catalyst used as well as other reaction conditions such as solvent, temperature, hydrogen gas pressure and the like.
  • Compounds contemplated herein can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers, enantiomers, diastereoisomers, as well as in the form of racemic or nonracemic mixtures.
  • a compound can also exist in other isomeric forms such as ortho, meta and para isomers, cis and trans isomers, syn and anti isomers, E and Z isomers, tautomeric isomers, alpha and beta isomers, axial and equatorial isomers and isomers due to hindered rotation.
  • An isomer can exist in equilibrium with another isomer in a mammal or a test system.
  • Such a compound can also exist as an isomeric equilibrium system with a solvent or water, for example, as a hydrated ketone or aldehyde, as is well known in the art. All isomers are included as compounds of this invention.
  • Table 1 through Table 165 show several contemplated aromatic sulfone hydroxamic acid inhibitor compounds or structural formulas that illustrate substituent groups. Each group of compounds is illustrated by a generic formula, or formulae, followed by a series of preferred moieties or groups that constitute various substituents that can be attached at the position clearly shown in the generic structure.
  • the substituent symbols, e.g., R1 and R2 and R3, are as shown in each Table, and are typically not those used before.
  • One or two bonds are shown with those substituents to indicate the respective positions of attachment in the illustrated compound.
  • This system is well known in the chemical communication arts and is widely used in scientific papers and presentations. For example in Table 2, R1 and R2 together with the atoms to which they are bonded is the variable group with the structural entities that can substitute for R1 and R2 together shown in the balance of that table. TABLE 1 1 7 2 8 3 9 4 10 5 11 6 12
  • a contemplated inhibitor compound is used for treating a host mammal such as a mouse, rat, rabbit, dog, horse, primate such as a monkey, chimpanzee or human that has a condition associated with pathological matrix metalloprotease activity.
  • contemplated is use of a contemplated metalloprotease inhibitor compound in the treatment of a disease state that can be affected by the activity of metalloproteases TNF- ⁇ convertase.
  • exemplary of such disease states are the acute phase responses of shock and sepsis, coagulation responses, hemorrhage and cardiovascular effects, fever and inflammation, anorexia and cachexia.
  • a contemplated MMP inhibitor compound in treating a disease condition associated with pathological matrix metalloproteinase activity, can be used in the form of an amine salt derived from an inorganic or organic acid.
  • exemplary salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalene
  • a basic nitrogen-containing group can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibuytl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others to provide enhanced water-solubility. Water or oil-soluble or dispersible products are thereby obtained as desired.
  • the salts are formed by combining the basic compounds with the desired acid.
  • salts can also form salts. Examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases or basic quaternary ammonium salts.
  • the salts can also be used as an aid in the isolation, purification or resolution of the compounds of this invention.
  • Total daily dose administered to a host mammal in single or divided doses can be in amounts, for example, for 0.001 to 30 mg/kg body weight daily and more usually 0.01 to 10 mg.
  • Dosage unit compositions can contain such amounts or submultiples thereof to make up the daily dose.
  • a suitable dose can be administered, in multiple sub-doses per day. Multiple doses per day can also increase the total daily dose, should this be desired by the person prescribing the drug.
  • the dosage regimen for treating a disease condition with a compound and/or composition of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized and whether the compound is administered as part of a drug combination.
  • the dosage regimen actually employed can vary widely and therefore can deviate from the preferred dosage regimen set forth above.
  • a compound of the present invention can be formulated as a pharmaceutical composition. Such a composition can then be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences , Mack Publishing Co., Easton, Pa.; 1975 and Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms , Marcel Decker, New York, N.Y., 1980.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter, synthetic mono- di- or triglycerides, fatty acids and polyethylene glycols that are sold at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • a suitable nonirritating excipient such as cocoa butter, synthetic mono- di- or triglycerides, fatty acids and polyethylene glycols that are sold at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules.
  • the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration.
  • a contemplated aromatic sulfone hydroximate inhibitor compound can be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
  • Such capsules or tablets can contain a controlled-release formulation as can be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
  • the dosage forms can also comprise buffering agents such as sodium citrate, magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings.
  • formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from soerile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration.
  • a contemplated aromatic sulfone hydroximate inhibitor compound can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
  • Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
  • Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • the amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the mammalian host treated and the particular mode of administration.
  • DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
  • EDC 1-ethyl-3-[3-(dimethylamino)-propyl]carbodiimide hydrochloride
  • NMM N-methyl morpholine
  • TsCl toluenesulfonyl chloride
  • THP—O-hydroxylamine O-tetrahydropyran-hydroxylamine and O-tetrahydro-2H-pyran-2-yl-hydroxylamine
  • Part A A solution of 4-(phenoxy)benzenethiol (2.03 g, 10.0 mmol) in DMSO (DMSO; 20 mL) was heated to sixty-five degrees Celsius for 5 hours. The solution remained at ambient temperature for 18 hours. The solution was extracted with ethyl acetate and the combined organic layers were washed with H 2 O and saturated NaCl and dried over magnesium sulfate. Concentration in vacuo provided the disulfide as a yellow oil (2.3 g, quantitative yield).
  • Part B To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF (5 mL) drop-wise over 20 minutes. The solution was stirred overnight (about eighteen hours) at ambient temperature and concentrated in vacuo to yield a light oil. The oil was filtered through silica gel (7:3 ethyl acetate/hexanes) and concentrated in vacuo to give the BOC-piperidine compound (26.2 g, quantitative yield) as a clear, colorless oil.
  • Part C To a solution of diisopropylamine (2.8 mL, 20 mmol in THF (30 mL), cooled to minus seventy-eight degrees Celsius, was added n-butyl lithium (12.5 mL, 20 mmol) drop-wise. After 15 minutes, the BOC-piperidine compound of part B (2.6 g, 10 mmol) in THF (10 mL) was added drop-wise. After 1.5 hours the solution was cooled to minus sixty degrees Celsius and the disulfide of part A (2.0 g, 10 mmol) in THF (7 mL). The solution was stirred at ambient temperature for 2 hours. The solution was diluted with H 2 O and extracted with ethyl acetate.
  • Part D To a solution of the sulfide of part C (1.8 g, 3.95 mmol) in dichloromethane (75 mL) cooled to zero degrees Celsius, was added m-chloroperbenzoic acid (1.7 g, 7.9 mmol). The solution was stirred for 1.5 hours followed by dilution with H 2 O and extraction with dichloromethane. The organic layer was washed with 10 percent Na 2 SO 4 , H 2 O, and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfone as a solid (1.15 g, 59%).
  • Part E To a solution of the sulfone of part D (800 mg, 1.63 mmol) in THF (9 mL) and ethanol (9 mL) was added NaOH (654 mg, 16.3 mmol) in H 2 O (3 mL). The solution was heated at sixty-five degrees Celsius for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in H 2 O. Following acidification with 2N HCl to pH 4, the solution was extracted with ethyl acetate and the organic layer was washed with saturated NaCl and dried over magnesium sulfate. Concentration in vacuo provided the acid as a white foam (790 mg, quantitative yield). Analytical calculated for C 23 H 27 NO 7 S: C, 59.86; H, 5.90; N, 3.04; S, 6.95. Found: C, 59.49; H, 6.37; N, 2.81; S, 6.59.
  • Part F To a solution of the acid of part G (730-mg, 1.58 mmol) in DMF (9 mL) was added HOBT (256 mg, 1.90 mmol) followed by EDC (424 mg, 2.21 mmol), 4-methylmorpholine (0.521 mL, 4.7 mmol) and 50 percent aqueous hydroxylamine (1.04 mL, 15.8 mmol). The solution was stirred for 20 hours and additional N-hydroxybenzotriazole.H 2 O (256 mg), EDC (424 mg) and 50 percent aqueous hydroxylamine (1.04 mL) were added.
  • Part A To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF (5 mL) drop-wise over 20 minutes. The solution was stirred overnight (about eighteen hours) at ambient temperature and concentrated in vacuo to yield a light oil. The oil was filtered through silica gel (ethyl acetate/hexanes) and concentrated in vacuo to give the BOC-piperidine compound as a clear, colorless oil (26.2 g, quantitative yield).
  • Part B A solution of 4-fluorothiophenol (50.29 g, 390 mmol) in DMSO (500 mL) was heated to 65 degrees Celsius for 6 hours. The reaction was quenched into wet ice and the resulting solid was collected by vacuum filtration to provide the disulfide as a white solid (34.4 g, 68.9%).
  • Part C To a solution of the BOC-piperdine compound of part A (16 g, 62 mmol) in THF (300 mL) cooled to minus 50 degrees Celsius was added lithium diisopropylamide (41.33 mL, 74 mmol) and the solution was stirred for 1.5 hours at zero degrees Celsius. To this solution was added the disulfide of part B (15.77 g, 62 mmol), and the resulting solution was stirred at ambient temperature for 20 hours. The reaction was quenched with the addition of H 2 O and the solution was concentrated in vacuo.
  • Part D To a solution of the sulfide of part C (16.5 g, 43 mmol) in dichloromethane (500 mL) cooled to zero degrees Celsius was added 3-chloroperbenzoic acid (18.0 g, 86 mmol) and the solution was stirred for 20 hours. The solution was diluted with H 2 O and extracted with dichloromethane. The organic layer was washed with 10 percent Na 2 SO 3 , H 2 O, and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfone as a solid (10.7 g, 60%).
  • Part E Into a solution of the sulfone of part D (10 g, 24.0 mmol) in ethyl acetate (250 mL) was bubbled HCl gas for 10 minutes followed by stirring at ambient temperature for 4 hours. Concentration in vacuo provided the amine hydrochloride salt as a white solid (7.27 g, 86%).
  • Part F To a solution of the amine hydrochloride salt of part E (5.98 g, 17.0 mmol) in DMF (120 mL) was added potassium carbonate (4.7 g, 34.0 mmol) followed by propargyl bromide (2.02 g, 17.0 mmol) and the solution was stirred for 4 hours at ambient temperature. The solution was partitioned between ethyl acetate and H 2 O, and the organic layer was washed with H 2 O and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the propargyl amine as a yellow oil (5.2 g, 86%).
  • Part G To a solution of the propargyl amine of part F in DMF (15 mL) was added thiophenol (0.80 mL, 7.78 mmol) and CsCO 3 (2.79 g, 8.56 mmol) and the solution was heated to 70 degrees Celsius for 6 hours. The solution was partitioned between ethyl ether and H 2 O. The organic layer was washed with H 2 O and saturated NaCl, and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the S-phenoxyphenyl compound as an oil (1.95 g, 56%).
  • Part H To a solution of the S-phenoxyphenyl of part G (1.81 g, 4.06 mmol) in ethanol (21 mL) and H 2 O (3.5 mL) was added KOH (1.37 g, 24.5 mmol) and the solution was heated to 105 degrees Celsius for 4.5 hours. The solution was acidified to a pH value of 1 with concentrated HCl solution and then concentrated to provide the acid as a yellow residue that was used without additional purification (1.82 g).
  • Part I To a solution of the acid of part H (1.82 g, 4.06 mmol) in acetonitrile (20 mL) was added O-tetrahydro-2H-pyran-2-yl-hydroxylamine (723 mg, 6.17 mmol) and triethylamine (0.67 mL, 4.86 mmol). To this stirring solution was added EDC (1.18 g, 6.17 mmol) and the solution was stirred for 18 hours. The solution was partitioned between H 2 O and ethyl acetate. The organic layer was washed with H 2 O, saturated NaHCO 3 and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the protected hydroxamate as a white solid (1.32 g, 63%).
  • Part J To a solution of the protected hydroxamate of part I (9.65 g, 18.7 mmol) in methanol (148 mL) cooled to zero degrees Celsius was added acetyl chloride (4.0 mL, 56.2 mmol), and the solution was stirred for 45 minutes at ambient temperature. Concentration in vacuo followed by trituration with ethyl ether provided the title compound as a white solid (8.10 g, 94%). MS(CI) MH + calculated for C 21 H 22 N 2 O 4 S 2 : 431, found 431.
  • Part A A solution of 4-(phenoxy)benzenethiol (2.03 g, 10.0 mmol) in DMSO (20 mL) was heated to 65 degrees Celsius for 5 hours. The solution remained at ambient temperature for 18 hours. The solution was extracted with ethyl acetate and the combined organic layers were washed with H 2 O and saturated NaCl, and dried over magnesium sulfate. Concentration in vacuo provided the disulfide as a yellow oil (2.3 g, quantitative yield).
  • Part B To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF (5 mL) dropwise over 20 minutes. The solution was stirred overnight at ambient temperature and concentrated in vacuo to yield a light oil. The oil was filtered through silica gel (ethyl acetate/hexane) and concentrated in vacuo to give the BOC-piperidine compound as a clear, colorless oil (26.2 g, quantitative yield).
  • Part C To a solution of diisopropylamine (2.8 mL, 20 mmol) in THF (30 mL), cooled to minus seventy-eight degrees Celsius, was added n-butyl lithium (12.5 mL, 20 mmol) dropwise. After 15 minutes, the BOC-piperidine compound of Part B (2.6 g, 10 mmol) in THF (10 mL) was added dropwise. After 1.5 hours, the solution was cooled to minus sixty degrees Celsius and the disulfide of Part A (2.0 g, 10 mmol) in THF (7 mL) was added. The solution was stirred at ambient temperature for 2 hours. The solution was diluted with H 2 O and extracted with ethyl acetate.
  • Part D To a solution of the sulfide of
  • Part E Into a solution of the sulfone of
  • Part F To a solution of the amine hydrochloride salt of part E (2.6 g, 6 mmol) and K 2 CO 3 (1.66 g, 12 mmol) in DMF (50 mL) was added propargyl bromide (892 mg, 6 mmol) and the solution was stirred at ambient temperature for 4 hours. The solution was diluted with H 2 O and extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the propargyl amine as a white solid (2.15 g, 82%).
  • Part G To a solution of the propargyl amine of part F (2.15 g, 5 mmol) in THF (30 mL) and ethanol (30 mL) was added NaOH (2.0 g, 50 mmol) and the solution was heated at 65 degrees Celsius for 48 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to a pH value of 5. Vacuum filtration of the resulting precipitate provided the acid as a white solid (2.04 g, quantitative yield).
  • Part H To a solution of the acid of part G (559 mg, 1.4 mmol) in dichloromethane (5 mL) was added triethylamine (0.585 mL, 4.2 mmol) and 50 percent aqueous hydroxylamine (0.925 mL, 14.0 mmol) followed by bromotris(pyrrolidino)phosphonium hexafluourphosphate (PyBroP; 718 mg, 1.54 mmol). The solution was stirred at ambient temperature for 4 hours. The solution was diluted with H 2 O and extracted with dichloromethane. The organic layer was washed with saturated NaCl and dried over magnesium sulfate.
  • Part I To a solution of the hydroxamate of part H (121 mg, 0.292 mmol) in methanol (2 mL) cooled to zero degrees Celsius was added acetyl chloride (0.228 mL, 0.321 mmol) in methanol (1 mL). After stirring at ambient temperature for 30 minutes the solution was concentrated under a stream of N 2 . Trituration with ethyl ether provided the title compound as a white solid (107 mg, 81%). Analytical calculation for C 21 H 22 N 2 O 5 S.HCl.0.3H 2 O: C, 55.27; H, 5.21; N, 6.14. Found: C, 54.90; H, 5.37; N, 6.07.
  • Part A In dry equipment under nitrogen, sodium metal (8.97 g, 0.39 mol) was added to methanol (1000 mL) at two degrees Celsius. The reaction was stirred at ambient temperature for forty five minutes at which time the sodium had dissolved. The solution was chilled to five degrees Celsius and p-fluorothiophenol (41.55 mL, 0.39 mmol) was added, followed by methyl 2-chloroacetate (34.2 mL, 0.39 mol). The reaction was stirred at ambient temperature for four hours, filtered, and concentrated in vacuo to give the sulfide as a clear colorless oil (75.85 g, 97%).
  • Part B To a solution of the sulfide from part A (75.85 g, 0.38 mol) in methanol (1000 mL) were added water (100 mL) and Oxone (720 g, 1.17 mol) at 20 degrees Celsius. An exotherm to 67 degrees Celsius was noted. After two hours, the reaction was filtered and the cake was washed well with methanol. The filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and washed with brine, dried over MgSO 4 , filtered, and concentrated in vacuo to give the sulfone as a crystalline solid (82.74 g, 94%).
  • Part C To a solution of the sulfone from part B (28.5 g, 0.123 mol) in N,N-dimethylacetamide (200 mL) were added potassium carbonate (37.3 g, 0.27 mol), bis-(2-bromoethyl)ether (19.3 mL, 0.147 mol), 4-dimethylaminopyridine (0.75 g, 6 mmol), and tetrabutylammonium bromide (1.98 g, 6 mmol). The reaction was stirred overnight (about 18 hours) at ambient temperature. The reaction was slowly poured into 1N HCl (300 mL), the resultant solid filtered and the cake washed well with hexanes.
  • potassium carbonate 37.3 g, 0.27 mol
  • bis-(2-bromoethyl)ether (19.3 mL, 0.147 mol
  • 4-dimethylaminopyridine (0.75 g, 6 mmol
  • Part E In dry equipment under nitrogen, the carboxylic acid from part D (9.1 g, 31.6 mmol) was dissolved in dry N,N-dimethylformamide (70 mL) and the remaining reagents were added to the solution in the following order: N-hydroxybenzotriazole hydrate (5.1 g, 37.9 mmol), N-methylmorpholine (10.4 mL, 94.8 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (11.5 g, 98 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.48 g, 44.2 mmol).
  • Part B To a slurry of the THP-protected hydroxamate from part A (4.0 g, 7.3 mmol) in dioxane (20 mL) were added a 4N HCl dioxane solution (20 mL) and methanol (20 mL). After fifteen minutes at ambient temperature, the reaction was diluted with ethyl acetate and washed with water, dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The product was recrystallized (acetone/hexanes) to give the title compound as a white solid (2.2 g, 65%).
  • Part A To a solution of the product of Preparative Example II, part E, (14.36 g, 40 mmol) in methanol (50 mL) was added acetic acid (24.5 g, 400 mmol), a portion (about 2 g) of 4-Angstrom molecular sieves, (1-ethoxycyclopropyl)-oxytrimethyl silane (25.8 mL, 148 mmol) and sodium cyanoborohydride (7.05 g, 112 mmol). The solution was heated at reflux for 8 hours. The precipitated solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was diluted with H 2 O (400 mL) and extracted with ethyl acetate.
  • Part B A solution of the cyclopropyl amine of Part A (2.0 g, 5.6 mmol), ethylene glycol phenyl ether (2.8 mL, 23 mmol), and cesium carbonate (7.3 g, 23 mmol) in DMAC (10 mL) was heat at 125-135 degrees Celsius for 18 hours under an atmosphere of nitrogen. The mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, dried over magnesium sulfate, concentrated in vacuo, dissolved in diethyl ether, precipitated as the hydrochloride salt, and dried at 40 degrees Celsius in a vacuum oven.
  • Part C A mixture of the ether of part B (1.8 g, 3.7 mmol) and a 50% NaOH aqueous solution (3.0 g, 37 mmol) in THF (32 mL), EtOH (32 mL), and H 2 O (16 mL) was heated at 60 degrees Celsius under a nitrogen atmosphere for 24 hours. The material was concentrated in vacuo and triturated with diethyl ether to give a solid. The tan solid was dissolved into a mixture of water, ethanol, and THF, precipitated by adjusting the pH to 3 with concentrated hydrochloric acid, concentrated in vacuo, triturated with water, and dried at 50 degrees Celsius in a vacuum oven to give a crude white solid acid (2.3 g).
  • Part D To an ambient temperature solution of acetyl chloride (0.31 mL, 4.4 mmol) in methanol (11 mL) under a nitrogen atmosphere was added the protected hydroxamate of part C (0.80 g, 1.5 mmol). After stirring for 2.5 hours, the precipitate was collected by filtration, washed with diethyl ether, and dried at 45 degrees Celsius in a vacuum oven to afford the title compound as a white solid (0.58 g, 79%): MS MH+ calcd. for C 23 H 28 N 2 O 6 S 461, found 461. Anal. calcd. for C 23 H 28 N 2 O 6 S.1.5 HCl: C, 53.62; H, 5.77; N, 5.44; S, 6.22. Found: C, 53.47; H, 5.79; N, 5.41; S, 6.16.
  • Part A To a solution of the product of Preparative Example II, Part D (30 g, 161 mmol) in dichloromethane (50 mL) cooled to zero degrees Celsius was added trifluroacetic acid (25 mL) and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the trifluoroacetate salt and K 2 CO 3 (3.6 g, 26 mmol) in N,N-dimethylformamide (50 mL) cooled to zero degrees Celsius was added 2-bromoethyl methyl ether (19 mL, 201 mmol), and solution was stirred at ambient temperature for 36 hours.
  • Part B To a solution of methoxyethyl amine (6.0 g, 16.0 mmol) of Part A and powdered K 2 CO 3 (4.44 g, 32 mmol) in N,N-dimethylformamide (30 mL) was added 4-(trifluoromethoxy)phenol (5.72 g, 32 mmol) at ambient temperature and the solution was heated to ninety degrees Celsius for 25 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N NaOH, H 2 O and dried over MgSO 4 . Chromatography on silica eluting with ethyl acetate/hexane provided trifluoromethoxy phenoxyphenyl sulfone as a light yellow gel (7.81 g, 91.5%).
  • Part D To a solution of the acid of Part C (5.64 g, 10.8 mmol), N-methyl morpholine (4.8 mL, 43.1 mmol), 1-hydroxybenzotriazole (4.38 g, 32.4 mmol) and O-tetrahydropyranyl hydroxylamine (2.5 g, 21.6 mmol) in N,N-dimethylformamide (50 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.2 g, 32.4 mmol), and the solution was stirred at ambient temperature for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate.
  • Part E To a solution of 4N HCl in dioxane (28 mL, 110 mmol) was added a solution of the tetrahydropyranyl-protected hydroxamate of Part D (6.65 g, 11.03 mmol) in methanol (3 mL) and dioxane (9 mL) and was stirred at ambient temperature for 3 hours. Concentration in vacuo and trituration with diethyl ether provided the title compound as a white solid (4.79 g, 78.2%). Analytical calculation for C 22 H 25 N 2 O 7 SF 3 .HCl.0.5H 2 O: C, 46.85; H, 4.83; N, 4.97; S, 5.69. Found: C, 46.73; H, 4.57; N, 4.82; S, 5.77.
  • Part A To a suspension of 4-bromopiperidine hydrobromide (107.0 g, 0.436 mol) in tetrahydrofuran (1 L) was slowly added triethylamine (122 mL, 0.872 mol) followed by di-tert-butyl dicarbonate (100 g, 0.458 mol), which was added in several portions. The resulting mixture was stirred at ambient temperature for 22 hours then filtered and concentrated in vacuo. The solids were washed with hexanes and then collected by filtration to give the Boc-piperidine compound as an amber oil (124 g, >100%).
  • Part B To a solution of 4-fluorophenol (50.0 g, 0.390 mol) in acetone (400 mL), degassed with N 2 , was added Cs 2 CO 3 (159 g, 0.488 mol). After degassing the resulting mixture with N 2 for 5 minutes, the Boc-piperidine compound of Part A (85.9 g, 0.325 mol) was added. The resulting mixture was stirred at ambient temperature for 18 hours and then filtered through a pad of Celite®, washing with acetone. The filtrate was concentrated in vacuo to provide the sulfide as a tan residue (98.5 g, 97%).
  • Part C To a solution of the sulfide of Part B (8.00 g, 25.7 mmol) in dichloromethane (90 mL) and methanol (15 mL) was added monoperoxyphthalic acid magnesium salt hexahydrate (19.1 g, 38.6 mmol) in two portions. The resulting mixture was stirred at ambient temperature for 1.5 hours and then filtered. The filtrate was washed with saturated NaHCO 3 and then with saturated NaCl. The combined aqueous layers were extracted with dichloromethane (100 mL). The combined organic layers were dried over Na 2 SO 4 and then concentrated in vacuo.
  • Part D To a solution of sulfone of Part C (7.00 g, 20.4 mmol) in N,N-dimethylformamide (40 mL) was added Cs 2 CO 3 (19.9 g, 61.2 mmol) and ⁇ , ⁇ , ⁇ -trifluoro- ⁇ -cresol (3.97 g, 24.5 mmol). The resulting mixture was heated at eighty degrees Celsius for 16 hours. After cooling to ambient temperature the reaction mixture was concentrated in vacuo. The resulting residue was treated with H 2 O and the solids were collected by filtration. The solids were then washed with hexanes then methanol to provide the biaryl ether as a tan solid (8.60 g, 87%).
  • Part E To a solution of the biaryl ether of Part D (8.59 g, 17.7 mmol) in tetrahydrofuran (100 mL), cooled to zero degrees Celsius, was slowly added lithium bis(trimethylsilyl)amide (22.0 mL, 1.0M in tetrahydrofuran, 22.0 mmol), at such a rate that the temperature of the reaction never exceeded one degree Celsius. The resulting mixture was stirred at zero degrees Celsius for 1 hour then a solution of methyl chloroformate (2.05 mL, 26.6 mmol) in tetrahydrofuran (5.0 mL) was slowly added, at such a rate that the temperature of the reaction mixture never exceeded four degrees Celsius.
  • Part F To a solution of the methyl ester of Part E (7.66 g, 14.1 mmol) in dioxane (30 mL) and methanol (10 mL) was added a solution of 4N HCl in dioxane (10 mL, 40 mmol). After stirring at ambient temperature for 2 hours additional 4N HCl in dioxane (10 mL, 40 mmol) was added. After stirring at ambient temperature for 2.5 hours, the reaction mixture was concentrated in vacuo to provide the amine as an off-white solid (6.80 g, >100%).
  • Part G To a suspension of the amine of Part F (3.00 g, 6.25 mmol) in acetonitrile (20 mL) was added K 2 CO 3 (3.46 g, 25.0 mmol), 4-(2-chloroethyl)morpholine hydrochloride (1.22 g, 6.56 mmol) and a catalytic amount of NaI. The resulting mixture was heated at reflux for 22 hours. After cooling to ambient temperature, the reaction mixture was filtered through a pad of Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuo to provide the morpholinyl ethyl amine as a tan solid (3.45 g, >100%).
  • Part H To a solution of the morpholinyl ethyl amine of Part G (3.45 g, 6.25 mmol) in tetrahydrofuran (60 mL) was added potassium trimethylsilanolate (1.60 g, 12.50 mmol). After stirring at ambient temperature for 25 hours, H 2 O was added. The reaction mixture was then neutralized (pH 7) with 1N HCl. The tetrahydrofuran was removed in vacuo and the resulting precipitate was collected by filtration and washed with diethyl ether to provide the amino acid as an off-white solid (2.87 g, 85%).
  • Part J To a solution of the protected hydroxamate of Part I (2.62 g, 4.08 mmol) in dioxane (9 mL) and methanol (3 mL) was added a solution of 4N HCl in dioxane (10 mL, 40.0 mmol). The resulting mixture was stirred at ambient temperature for 2 hours and then diethyl ether (20 mL) was added. The resulting solids were collected by filtration to give the title compound as an off-white solid (2.31 g, 90%). MS MH + calculated for C 25 H 31 O 6 N 3 SF 3 : 558, found 558.
  • Part A To a solution of the product of Preparative Example VI, Part A, (6.97 g, 19.6 mmol) in DMF (500 mL) was added K 2 CO 3 (3.42 g, 18.0 mmol) and 4-(triflouromethoxy)phenol (3.7 g, 24.8 mmol). The solution was stirred at ninety degrees Celsius for 40 hours. The solution was diluted with H 2 O (600 mL) and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl and dried over MgSO 4 , filtered and concentrated in vacuo to afford the desired diaryl ether as an oil (8.5 g, quantitative). HRMS MH + calculated for C 24 H 26 NSO 6 F 3 : 514.1511. Found 514.1524.
  • Part C To a solution of the hydrochloride salt of Part B (5.0 g, 10.3 mmol) in DMF (80 mL) were added 1-hydroxybenzotriazole (1.65 g, 12.3 mmol), N-methyl morpholine (3.4 mL, 30.9 mmol) and O-tetrahydropyranyl hydroxylamine hydrochloride (1.8 g, 15.4 mmol) followed by 1-3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.60 g, 12.3 mmol). The solution was stirred at ambient temperature for 42 hours.
  • Part D To a solution of tetrahydropyranyl-protected hydroxamate of Part C (5.4 g, 9.2 mmol) in dioxane (80 mL) and methanol (20 mL) was added 4 N HCl/dioxane (50 mL). The reaction was stirred at ambient temperature for 2.5 hours, the solution was concentrated in vacuo. Trituration with diethyl ether afforded the title compound as a white solid (4.02 g, 81%).
  • Part A To a solution of the product of Preparative Example VI, Part A, (5.96 g, 15.0 mmol) in DMF (100 mL) was added K 2 CO 3 (12.34 g, 38.0 mmol) and ⁇ , ⁇ , ⁇ -trifluoromethyl phenol (3.65 g, 22.5 mmol). The solution was stirred ninety degrees Celsius for 28 hours. The solution was diluted with H 2 O (400 mL) and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl and dried over MgSO 4 , filtered and concentrated in vacuo to afford desired aryl ether as an oil (7.54 g, quantitative)
  • Part C To a solution of the hydrochloride salt of Part B (7.60 g, 15.0 mmol) in DMF (100 mL) were added 1-hydroxybenzotriazole (2.44 g, 18.0 mmol), N-methyl morpholine (3.4 mL, 30.9 mmol) and O-tetrahydropyranyl hydroxylamine hydrochloride (2.63 g, 22.5 mmol) followed by 1-3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (4.02 g, 21.0 mmol). The solution was stirred at ambient temperature for 96 hours.
  • Part D To a solution of tetrahydropyranyl-protected hydroxamate of Part C (3.8 g, 6.7 mmol) in dioxane (100 mL) was added 4 N HCl/dioxane (30 mL). The reaction was stirred at ambient temperature for 2 hours, then the solution was concentrated in vacuo. Trituration with diethyl ether afforded the title compound as a white solid (3.33 g, 96%). MS MH + calculated for C 22 H 23 N 2 SO 5 F 3 : 485, found 485.
  • Resin II 50 mg, 0.046 mmol was weighed into an 8 mL glass vial, and a 0.5 M solution of a nucleophile in 1-methyl-2-pyrrolidinone (1 mL) was added to the vessel.
  • a nucleophile in 1-methyl-2-pyrrolidinone 1 mL was added to the vessel.
  • cesium carbonate 148 mg, 0.46 mmol was added, and in the case of substituted piperazine nucleophiles, potassium carbonate (64 mg, 0.46 mmol) was added.
  • the vial was capped and heated to 70 to 155 degrees Celsius for 24-48 hours, then cooled to room temperature.
  • the resin was drained and washed with 1-methyl-2-pyrrolidinone, 1-methyl-2-pyrrolidinone/water (1:1), water, 10% acetic acid/water, methanol, and methylene chloride (3 ⁇ 3 mL each solvent).
  • Resin II (5 g, 0.91 mmol) was weighed into an oven-dried three-necked round bottom flask fitted with a temperature probe, an overhead stirring paddle, and a nitrogen inlet.
  • Anhydrous 1-methyl-2-pyrrolidinone 35 mL was added to the flask followed by ethyl isonipecotate (7.0 mL, 45.5 mmol).
  • the resin slurry was stirred slowly with the overhead stirrer, and the mixture was heated to 80 degrees Celsius with a heating mantle for 65 hours. The flask was thereafter cooled to room temperature.
  • Step 3 Cleavage of Hydroxamic Acids From The Polymer-Support
  • Resin III was treated with a trifluoroacetic acid/water mixture (19:1, 1 mL) for 1 hour at room temperature. During that time, the resin became a deep red color. The resin was then drained and washed with trifluoroacetic acid/water (19:1) and methylene chloride (2 ⁇ 1 mL each solvent), collecting the combined filtrates in a tared vial. The volatiles were removed in vacuo, then a toluene/methylene chloride mixture (2 mL each) was added to the residue. The mixture was again concentrated in vacuo. The product was characterized by electrospray mass spectroscopy.
  • Step 4 Hydrolysis of Polymer-Bound Ester: Preparation of Resin IVa
  • Resin IIIa (5.8 g, 4.5 mmol) was weighed into a three-necked round bottomed flask fitted with an overhead stirring paddle. 1,4-Dioxane was added to the flask, and the resin slurry was stirred for 15 minutes. Then, a 4 M solution of KOH (5 mL, 20 mmol) was added, and the mixture was stirred for 44 hours. The resin was thereafter collected in a sintered-disk glass funnel and washed with dioxane/water (9:1), water, 10% acetic acid/water, methanol and methylene chloride (3 ⁇ 30 mL each solvent).
  • the resin was dried in vacuo to yield 5.64 g of resin IVa as off-white polymer beads.
  • FTIR microscopy showed bands at 1732 and 1704 cm ⁇ 1 and a broad band from 2500-3500 cm ⁇ 1 .
  • the theoretical loading of the polymer-bound acid was 0.84 mmol/g.
  • Part A To a solution of the product of Preparative Example II, part D, (30 g, 161 mmol) in dichloromethane (50 mL) cooled to zero degrees Celsius was added trifluroacetic acid (25 mL) and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the trifluoroacetate salt and K 2 CO 3 (3.6 g, 26 mmol) in N,N-dimethylformamide (50 mL) cooled to zero degrees Celsius was added 2-bromoethyl methyl ether (19 mL, 201 mmol) and solution was stirred at ambient temperature for 36 hours.
  • Part B To a solution of the methoxyethyl amine (6.0 g, 16.0 mmol) of part A and powdered K 2 CO 3 (4.44 g, 32 mmol) in N,N-dimethylformamide (30 mL) was added 4-(trifluoromethoxy)phenol (5.72 g, 32 mmol) at ambient temperature and the solution was heated to ninety degrees Celsius for 25 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N NaOH, H 2 O and dried over MgSO 4 . Chromatography on silica eluting with ethyl acetate/hexane provided trifluoromethoxy phenoxyphenyl sulfone as a light yellow gel (7.81 g, 91.5%).
  • Part D To a suspension of the carboxylic acid of part C (200 mg, 0.397 mmol) in methylene chloride (4 mL) was added oxalyl chloride (101 mg, 0.80 mmol). After 15 minutes at ambient temperature the volatiles were removed under vacuum. The solid residue was resuspended in methylene chloride (4 mL) and gaseous ammonia was bubbled through the suspension. Triethylamine (81 mg, 0.80 mmol) was added and the stream of ammonia gas through the reaction was continued for 1 minute.
  • reaction mixture was stirred for 24 hours, then the resin was drained and washed with 1-methyl-2-pyrrolidinone and methylene chloride (4 ⁇ 3 mL each solvent).
  • the reaction was repeated using the same amounts of reagents described above.
  • the reaction was stirred for 4 hours at zero degrees Celsius after the activating step and ambient temperature for 24 hours following amine solution addition.
  • the resin was drained and washed with 1-methyl-2-pyrrolidinone, 1:1 1-methyl-2-pyrrolidinone/water, water, 1:9 acetic acid/water, methanol and methylene chloride (3 ⁇ 3 mL each solvent).
  • Step 1 Preparation of Resin MT-I.
  • N-hydroxy-4-[[4-(4-trifluoromethoxy-phenoxy)phenyl]sulfonyl]-1-(9-fluorenylmethoxy-carbonyl)-4-piperidinecarboxamide of Example 89 (11.5 mmol) in dimethylformamide (75 mL) were added resin I (Floyd et al., Tetrahedron Lett. 1996, 37, 8045-8048) (7.0 g, 7.67 mmol), pyBOP (8.0 g) and N-methylmorpholine (5.05 mL), and the mixture was stirred with an overhead stirrer 4 days.
  • the resin was filtered and washed with dimethylformamide (3 ⁇ 50 mL), methanol (3 ⁇ 50 mL), dichloromethane (3 ⁇ 50 mL) and ether (3 ⁇ 50 mL). The resin was dried in vacuo to provide resin MT-I.
  • Step 2 Fmoc deprotection of Resin MT-I.
  • Resin MT-I was swelled with dimethylformamide (2 ⁇ 100 mL) and drained.
  • dimethylformamide 2 ⁇ 100 mL
  • Step 3 Preparation of N-hydroxy-4-[[4-(4-trifluoromethoxyphenoxy)phenyl]sulfonyl]-1-(phenylcarbonyl)-4-piperidinecarboxamide from Resin MT-II.
  • Resin MT-II 250 mg
  • dichloromethane 2 mL
  • diisopropyl-ethylamine 165 ⁇ L
  • benzoyl chloride 110 ⁇ L
  • the resin was filtered and washed with dichloromethane (2 ⁇ 10 mL) and methanol (2 ⁇ 10 mL).
  • N-hydroxy-4-[[4-(4-trifluoromethyl-phenoxy)phenyl] sulfonyl]-1-(phenylcarbonyl)-4-piperidinecarboxamide was prepared by the method of Example 91 from N-hydroxy-4-[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-1-(9-fluorenylmethoxycarbonyl)-4-piperidinecarboxamide (the product of Example 90). MS (ES) m/z 549 (M+H) + .
  • Step 1 Boc deprotection of ethyl 4-[[4-(4-trifluoromethoxyphenoxy)phenyl]sulfonyl]-1-[(1,1-dimethylethoxy)carbonyl]piperidinecarboxylate.
  • Step 2 Cbz protection of step 1.
  • the material from step 1 was dissolved in dichloromethane (200 mL). To this solution was added diisopropyl-ethylamine (33.3 mL) and benzyl chloroformate (5.5 mL) and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 2M aqueous hydrochloric acid to a pH value of about 1 and extracted with dichloromethane (2 ⁇ 100 mL). The combined organics were washed with 2M aqueous HCl (1 ⁇ 100 mL) and brine (1 ⁇ 100 mL), dried over magnesium sulfate, filtered and the solvent evaporated to afford a pale yellow oil.
  • Step 3 Hydrolysis of the product of step 2.
  • the material prepared in step 2 was dissolved in tetrahydrofuran (100 mL) and ethanol (50 mL). To this solution was added 1M aqueous sodium hydroxide (50 mL) and 50% aqueous sodium hydroxide (10 mL) and stirred 16 hours. To the solution was added 50% aqueous sodium hydroxide (2 mL) and stirred and additional 24 hours. The tetrahydrofuran and ethanol were evaporated. The pH value of the solution was adjusted to pH about 1 with concentrated hydrochloric acid. The reaction mixture was extracted with ethyl acetate (2 ⁇ 100 mL), washed with brine (1 ⁇ 100 mL), dried over magnesium sulfate, filtered and the solvent evaporated to afford a pale yellow oil.
  • Step 4 Cbz deprotection of step 3.
  • the material prepared in step 3 was dissolved in ethanol (100 mL). This solution was added to 10% palladium on carbon (1.0 g). The solution was placed under 45 psi hydrogen. Additional catalyst was added at 6 hours (1.75 g) and 20 hours (1.0 g 4% Pd/C). After 48 hours the reaction mixture was filtered through a plug of Celite. The filtrate was evaporated and triturated with ether to afford N-(2-tetrahydropyranoxy)-4[[4-(4-trifluoromethoxy-phenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide (4.47 g) as a white solid. MS (ES) m/z 545 (M+H) + .
  • N-(2-tetrahydropyranoxy)-4[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide was prepared by the method of Example 93 starting from ethyl 4-[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-1-[(1,1-dimethylethoxy)carbonyl]piperidinecarboxylate (see Example 90). MS (ES) m/z 529 (M+H) + .
  • hydroxamic acids were prepared by the method of Example 95 using the appropriate acylating agent (electophile) and starting from N-(2-tetrahydropyranoxy)-4[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide, the product of Example 94.
  • Step 1 Hydrolysis of methyl 4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-4-thianecarboxylate.
  • methyl 4-[[4-(4-methoxyphenoxy)-phenyl]sulfonyl]-4-thianecarboxylate dissolved in tetrahydrofuran (150 mL) was added potassium trimethylsilanolate (12.1 g) and stirred 2 hours. Water was added to the reaction mixture and extracted with ethyl acetate (2 ⁇ 100 mL).
  • the pH value of the aqueous layer was adjusted to 2 with 2M hydrochloric acid and extracted with ethyl acetate (2 ⁇ 100 mL). The latter organics were washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated to afford a pale yellow solid (8.20 g).
  • Step 2 Loading on resin.
  • the compound obtained in step 1 (4.0 g, 13.1 mmol) was dissolved in 1-methyl-2-pyrrolidinone (15 mL) and added to a suspension of resin I (6.0 g, 6.6 mmol; Preparative Example XI) in 1-methyl-2-pyrrolidinone (40 mL).
  • pyBOP (6.85 g) and N-methylmorpholine (2.9 mL)
  • the resin was filtered and washed with dimethylformamide (3 ⁇ 50 mL), methanol (3 ⁇ 50 mL), dichloromethane (3 ⁇ 50 mL) and ether (3 ⁇ 50 mL).
  • the resin was dried in vacuo to provide resin MT-III (6.79 g).
  • Step 3 Aryl fluoride displacement of resin MT-III.
  • a suspension of resin MT-III (200 mg, 0.17 mmol), 1-methyl-2-pyrrolidinone (2 mL), cesium carbonate (560 mg) and 4-methoxyphenyl (306 mg) were stirred at 105° C. for 16 hours.
  • the reaction mixture was cooled and the resin filtered.
  • the resin was washed with dimethylformamide (3 ⁇ 5 mL), methanol (3 ⁇ 5 mL), 10% aqueous acetic acid (3 ⁇ 5 mL), methanol (3 ⁇ 5 mL) and dichloromethane (3 ⁇ 5 mL).
  • Example R Alcohol MS (ES) m/z 147 4-trifluoro- 4-trifluoro- 495 (M + NH 4 ) + methoxyphenyl methoxyphenol 148 4-isopropyl- 4-isopropylphenol 453 (M + NH 4 ) + phenyl 149 3-pyridyl 3-hydroxypyridine 395 (M + H) + 150 3,4-dimethoxy- 3,4-dimethoxyphenol 471 (M + NH 4 ) + phenyl 151 4-pyridyl 4-hydroxypyridine 395 (M + H) +
  • Example R Amine MS (ES) m/z 152 4-(4-fluoro- 4-(4-fluorobenzoyl)- 507 (M + H) + benzoyl)piperidyl piperidine 153 4-(2-methoxy- 4-(2-methoxyphenyl)- 491 (M + H) + phenyl)piperidyl piperidine 154 N-cyclopropyl-meth- yl-N-methyl-4-pipe- ridine carboxamide 496 (M + H) + 155 pyrrolidinyl pyrrolidine 371 (M + H) +
  • Step 1 Oxidation of Resin MT-III.
  • a suspension of resin MT-III (2.0 g, 1.72 mmol), m-perbenzoic chloroperbenzoic acid (4.37 g) and dichloromethane 25 mL) was stirred at room temperature for 20 hours.
  • the resin was filtered and washed with dichloromethane (3 ⁇ 25 mL), dimethylformamide (3 ⁇ 25 mL), methanol (3 ⁇ 25 mL), 1M aqueous sodium bicarbonate (2 ⁇ 25 mL), methanol (3 ⁇ 25 mL), dichloromethane (3 ⁇ 25 mL) and ether (3 ⁇ 25 mL).
  • the resin was dried in vacuo to afford resin MT-IV (2.16 g).
  • Step 2 Aryl fluoride displacement of resin MT-IV. N-hydroxy-4-[[4-(4-methoxyphenoxy)-phenyl]sulfonyl]-4-thianecarboxamide 1,1-dioxide was prepared by the method of Example 146 using resin MT-IV in the place of resin MT-III. ES (MS) m/z 473 (M+NH 4 ) + .
  • Example R Alcohol MS (ES) m/z 157 4-trifluoro- 4-trifluoro- 527 (M + NH 4 ) + methoxyphenyl methoxyphenol 158 4-isopropylphenyl 4-isopropylphenol 485 (M + NH 4 ) + 159 3-pyridyl 3-hydroxypyridine 427 (M + H) + 160 4-pyridyl 4-hydroxypyridine 427 (M + H) +
  • Step 1 Aryl fluoride displacement of Resin MT-III.
  • resin MT-III (4.06 g, 3.4 mmol) in 1-methyl-2-pyrrolidinone (40 mL)
  • ethyl isonipecotate (5.25 mL)
  • the cooled reaction mixture was filtered and the resin was washed with methanol (3 ⁇ 25 mL), dichloromethane (1 ⁇ 10 mL) and ether (3 ⁇ 25 mL).
  • the resin was dried in vacuo to afford resin MT-V (4.21 g).
  • Step 2 Hydrolysis of resin MT-V.
  • resin MT-V 4M aqueous potassium hydroxide (10 mL) and stirred at room temperature for 5 days.
  • the resin was filtered and washed with methanol (3 ⁇ 25 mL), dichloromethane (3 ⁇ 25 mL) and ether (3 ⁇ 25 mL). The resin was dried in vacuo to afford resin MT-VI.
  • Step 3 Conversion to amide.
  • N-hydroxy-4-[[4-[4-[(3,5-dimethyl-piperidyl)carbonyl]piperidyl]phenyl]sulfonyl]-4-thianecarboxamide was prepared by the method of using cis-2,6-dimethylmorpholine as the amine. MS (ES) m/z 526 (M+H) + .
  • Step 1 Preparation of amine 4-(4-fluorophenyl)methoxy piperidine.
  • Boc-(4-hydroxy)-piperidine (1 g, 4.97 mmol) in 10 mL of dimethyl formamide is added and the reaction mixture is stirred at room temperature for 15 minutes
  • 4-fluoro benzyl bromide (1.4 g, 7.5 mmol) is added and the reaction mixture is stirred at room temperature for 16 hours, then quenched with water and diluted with ethyl acetate. The organic layer was washed with brine, then dried over MgSO 4 , and concentrated in vacuo.
  • Step 2 Preparation of N-hydroxy-4 [[[4-[4-(4-fluorophenyl)methoxy] piperidyl] phenyl]sulfonyl]-1-tetrahydropyrancarboxamide.
  • N-tetrahydropyranoxy-4-fluorophenyl-sulfonyl-1-tetrahydropyrancarboxamide 100 mg, 0.26 mmol
  • DMA a solution of N-tetrahydropyranoxy-4-fluorophenyl-sulfonyl-1-tetrahydropyrancarboxamide
  • cesium carbonate 420 mg, 1.29 mmol
  • N-hydroxy-4[[[4-[3-(4-fluorophenyl)-methoxy]piperidyl]phenyl]sulfonyl]-1-tetrahydro-pyrancarboxamide is prepared by the method of Example 164 starting from Boc-(3-hydroxy)-piperidine in step 1.
  • N-hydroxy-4 [[[4-(4-phenoxy)piperidyl] phenyl]sulfonyl]-1-tetrahydropyrancarboxamide is prepared by the method of Example 164 starting from 4-phenoxypiperidine in step 2.
  • Step 1 A solution of N-tetrahydro-pyranoxy-4-fluorophenylsulfonyl-1-tetrahydro-pyrancarboxamide (1 g, 2.58 mmol), 4-hydroxy-piperidine (392 mg, 3.87 mmol) and cesium carbonate (2.52 g, 7.74 mmol) in 20 mL of NMP is stirred at 100° C. for 48 hours.
  • the reaction mixture is treated with water and neutralized to pH 4 with 5% aqueous HCl.
  • the aqueous layer is extracted twice with ethyl acetate and the combined organic layer is dried using magnesium sulfate and concentrated in vacuo.
  • Step 2 To a solution of alcohol N-tetrahydro-pyranoxy-4[[(4-hydroxypiperidyl)-phenyl]sulfonyl]-1-tetrahydropyrancarboxamide (50 mg, 0.107 mmol) in 2 mL of dichloromethane is added alpha, alpha, alpha-trifluoro-M-tolyl isocyanate (21 mg, 0.112 mmol). The reaction mixture is stirred for 16 hours at room temperature and 21 mg of alpha,alpha,alpha-trifluoro-m-tolyl isocyanate is added. The mixture is stirred 48 hours at room temperature and treated with water.
  • N-hydroxy-4[[4-(4-trifluoromethoxyphenoxy)-phenyl]sulfonyl]-1-[[(2-trifluoromethoxy)phenyl]-sulfonyl-4-piperidinecarboxamide can be prepared using the method of Example 93 starting from 2-trifluoromethoxybenzene sulfonyl chloride.
  • Part A An oven-dried 1.0 liter flask fitted with a thermometer and nitrogen inlet was charged with 55 mL of a 2 M solution of lithium diisopropoylamide in tetrahydrofuran and 50 mL of tetrahydrofuran. The flask was immersed in a dry ice/acetone bath. When the temperature of the solution was less than ⁇ 70 degrees, a solution of N-t-butoxycarbonylpiperidinone (20.0 g, 0.1 mole) in 100 mL tetrahydrofuran was added dropwise, maintaining the temperature less than ⁇ 65 degrees. After complete addition, the flask was stirred with cooling for 20 minutes.
  • Part B A three-necked 15 mL round-bottom flask was charged with the product from Part A (6 g, 18.1 mmol), o-trifluorobenzeneboronic acid (4.94 g, 26 mmol), lithium chloride (2.34 g, 55 mmol), 2 M sodium carbonate (26 mL, 52 mmol) and ethylene glycol dimethyl ether (60 mL). Nitrogen was bubbled through the solution for 10 minutes, then palladium tetrakistriphenylphosphine (1.06 g, 0.92 mmol) was added. The mixture was heated to reflux for 1.5 hours, then cooled to room temperature.
  • Example 203 The title compound of Example 203 (300 mg, 0.92 mmol) was dissolved in methylene chloride (5 mL) in a 15 mL round-bottom flask, and 5 mL of trifluoroacetic acid was added dropwise. After 15 minutes, the solvent was removed in vacuo, and the residue partitioned between 20 mL of ethyl acetate and 20 mL of 2 M sodium carbonate. The organic layer was washed with additional 2 M sodium carbonate, dried over magnesium carbonate and concentrated in vacuo to yield 195 mg of pure product as a colorless oil. Electrospray mass spectroscopy showed m/z 228 (M+H).
  • Part B The product from Part A above (2.24 g, 6.8 mmol) was dissolved in 100 mL methylene chloride, and 100 mL of trifluoroacetic acid was added dropwise. After 15 minutes, the solvent was removed in vacuo, and the residue partitioned between 100 mL of ethyl acetate and 100 mL of 2 M sodium carbonate. The organic layer was washed with additional 2 M sodium carbonate, dried over magnesium carbonate and concentrated in vacuo to yield 1.12 g of pure product as a colorless oil. Electrospray mass spectroscopy showed m/z 230 (M+H).
  • Part A A 2 dram vial was charged with aryl fluoro compound of Preparative Example IV (170 mg, 0.44 mmol), 1 ml of 2-methylpyrrolidinone, cesium carbonate (360 mg, 1.1 mmol) and 0.66 mmol of an amine. A small magnetic stirring bar was added, then the vial was capped and placed in a Pierce Reacti-thermTM at 115 degrees Celsius. The reaction progress was followed by analytical HPLC. When the reaction was greater than 90% complete, the vial was cooled to room temperature. The reaction mixture was diluted with 5 mL of water, then 1.2 mL of 5% hydrogen chloride/water was added dropwise. Then, the entire mixture was poured onto a column of Celite. The column was washed exhaustively with ethyl acetate (30-40 mL) and the filtrate was collected and concentrated to give the crude products.
  • Part B The product from above was dissolved in 2 mL 1,4-dioxane and 2 mL of methanol in a 4 dram vial with a small magnetic stirring bar. A solution of 4 N hydrogen chloride in 1,4-dioxane was carefully added to the reaction, and the mixture was stirred for 2 hours. Then the solvent was removed in vacuo and the residue purified by preparative reversed-phase HPLC.
  • Part A To a solution of the product of Preparative Example IV (2.5 g, 6 mmol) in dimethylformamide (50 mL) was added 4-pentafluroethyloxy phenol (2.0 g, 6 mmol) followed by cesium carbonate (5 g, 12 mmol). The reaction was heated at eighty degrees Celsius for twelve hours. Stripping the dimethylformamide in vacuo afforded a brown solid (5.5 g). The product was dissolvent in ethylacetate (150 ml) and extracted with water, brine and dried over sodium sulfate. The 1 H NMR, MS, and HPLC was consistent with desired compound.
  • Part B To the product of part A, crude THP-protected hydroxamate was disolved in acetonitrile/water (40 ml) was slowly added 10% aq HCl (10 ml). After stirring two hours, the acetonitrile was stripped. The resultant precipitate was collected, giving the title compound as a white solid (2.1 g). The 1 H NMR, MS, and HPLC was consistent with desired compound. This solid was recrystallized from ethylacetate and hexanes (1.8 g). The 1 H NMR, MS, and HPLC was consistent with desired compound. MS (CI) M+H calculated for C 23 H 27 BrNO 6 S: 511, found 511.
  • Part A Phenol (1500 g, 15.9 mol) and 4-chloropyridine hydrochloride (800 g, 7.1 mol) were combined in a melt at 150° C. under a nitrogen atmosphere. After fifteen hours, the reaction was dissolve in 3N sodium hydroxide solution (5400 mL) and extracted with methylene chloride (4 ⁇ ). The organic extracts were combined, washed with 1N sodium hydroxide solution, water and brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The isolated oil was dissolved in hexanes (1000 mL) and cooled to ⁇ 60° C. The precipitate was collected and dried in vacuo to yield 452 g (38%) of the 4-phenoxypyridine as a white solid.
  • Part B A solution of the 4-phenylpyridine from part A (400 g, 2.3 mol) in 1,2-dichloroethane (1250 mL) was cooled in an ice bath under a nitrogen atmosphere and treated with chlorosulfonic acid (400 mL, 6.0 mol). The reaction temperature was held below 12° C. during the addition. The reaction was then heated to 45° C. for 15 hours. The standard work-up procedure afforded 270 grams (40%) of the desired 4-[(pyrid-4-yl)oxy]benzenesulfonic acid.
  • Part C A slurry of the sulfonic acid part B (420 g, 1.5 mol) in acetonitrile (2500 mL) and DMF (40 mL) was warmed to 75° C. under a nitrogen atmosphere and treated with thionyl chloride (243 mL, 3.3 mol) added dropwise over 3 hours. After stirring for one-half hour, the standard work-up procedure afforded 483 grams (100%) of the desired 4-[(pyrid-4-yl)oxy]benzenesulfonyl chloride hydrochloride.
  • Part A A solution of 4-(4-pyridyloxy)-thiophenol (2.0 g, 8.34 mmol) and tert-butylbromoacetate (1.2 mL, 1.6 g, 8.34 mmol) in dry methanol (30 mL) was cooled to zero degrees C. and treated with triethylamine (2.4 mL, 1.8 g, 17.52 mmol). The addition was done at a rate which held the reaction temperature below 10° C. The ice bath was removed and after two hours at ambient temperature, the reaction was concentrated in vacuo.
  • Part B To a solution of the tert-butyl ester of the sulfide acid from part A (2.3 g, 7.25 mmol) in dry anisole (85 mL, 8.1 g, 74.67 mmol) was added trifluoroacetic acid (25.5 mL, 37.7 g, 330.6 mmol). After one-half hour at ambient temperature, the reaction was concentrated in vacuo to 3.7 g of the TFA salt of the sulfide acid suitable for the next step.
  • Part C To a solution of the TFA salt of the acid obtained from part B (2.7 g, 7.19 mmol) in dimethylformamide (10 mL) was added N-hydroxybenzotriazole hydrate (1.5 g, 10.79 mmol), N-methylmorpholine (4.7 mL, 4.4 g, 43.16 mmol), 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (2.5 g, 21.58 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.8 g, 9.35 mmol). After sixteen hours at ambient temperature, the reaction was concentrated in vacuo.
  • Part D To a solution of the THP sulfide hydroxamate from part C (2.1 g, 5.83 mmol) in methanol/water (13 mL/2 mL) was added tetrabutylammonium Oxone (5.8 g, 61.29 mmol). After 2 days at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (6 ⁇ ). The organic extracts were combined, washed with water and brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • Part A A solution of 4-(4-pyridyloxy)-thiophenol (18.0 g, 75.08 mmol) and tert-butylbromoacetate (10.5 mL, 13.9 g, 71.33 mmol) in dry methanol (250 mL) was cooled to 0° C. and treated with triethylamine (22.0 mL, 16.0 g, 157.68 mmol). The addition was done at a rate which held the reaction temperature below 1° C. The ice bath was removed and after one-half hour at ambient temperature, the reaction was concentrated in vacuo.
  • Part B To a solution of the tert-butyl ester of the sulfide acid from part A (221.7 g, 68.37 mmol) in dry anisole (76.5 mL, 76.1 g, 704.12 mmol) was added trifluoroacetic acid (240 mL, 355 g, 3,117 mmol). After one hour at ambient temperature, the reaction was concentrated in vacuo to yield 34.7 g of the TFA salt of the sulfide acid suitable for the next step.
  • Part C To a solution of the TFA salt of the sulfide acid from part B (34.7 g, 68.37 mmol) in dry methanol (100 mL) was added thionyl chloride (7.5 mL, 12.2 g, 102.5 mmol). After twelve hours at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (3 ⁇ ). The organic extracts were combined, washed with water and brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo to yield 18.7 grams of the methyl ester of the sulfide acid suitable for the next step.
  • Part D To a solution of the methyl ester of the sulfide acid obtained from part C (18.7 g, 67.92 mmol) in methylene chloride (325 mL) was added tetrabutylammonium Oxone (193 g, 543.4 mmol). After 2 days at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (9 ⁇ ). The organic extracts were combined, washed with water and brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • Part E To a solution of the methyl ester of the sulfone acid obtained from part D (2.7 g, 8.79 mmol) in dry dimethylformamide (20 mL) was added 18-crown-6 ether (0.5 g, 1.90 mmol) and potassium carbonate (4.9 g, 35.14 mmol). The reaction slurry was treated with bis-(2-bromoethyl)ether (1.1 mL, 2.0 g, 8.79 mmol) and then heated to 60° C. After fifteen hours at 60° C., the reaction was concentrated in vacuo.
  • Part F To a solution of the THP sulfone methyl ester from part E (1.6 g, 4.24 mmol) in dry tetrahydrofuran (20 mL) was added potassium trimethylsilanoate (1.6 g, 12.72 mmol). After five hours at ambient temperature, the reaction was concentrated in vacuo to yield the potassium salt of the THP sulfone acid as a tan solid suitable for use in the next step.
  • Part G To a slurry of the potassium salt of the THP sulfone acid obtained from part F (1.7 g, 4.24 mmol) in dimethylformamide (20 mL) was added N-hydroxybenzotriazole hydrate (1.1 g, 8.48 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.6 g, 8.48 mmol). After heating the reaction mixture at 40° C. for one-half hour, N-methylmorpholine (1.4 mL, 1.3 g, 12.72 mmol) and 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (1.0 g, 8.48 mmol) were added.
  • Part B To a solution of the aniline of part A (1.56 g, 3.85 mmol) in N,N-dimethylformamide (8.0 mL) was added K 2 CO 3 (1.06 g, 7.70 mmol) and 4-(trifluoromethoxy)phenol (0.823 g, 4.62 mmol). The resulting mixture was heated to ninety degrees Celsius for 19 hours. The reaction was cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between H 2 O and diethyl ether. The organic layer was washed with saturated NaCl and dried over Na 2 SO 4 . Concentration in vacuo provided the biaryl ether as a brown oil (2.42 g, >100%).
  • Part D To a suspension of the acid of part C (1.95 g, 3.64 mmol) in N,N-dimethylformamide (15 mL) was added 1-hydroxybenzotriazole (0.596 g, 4.37 mmol), N-methylmorpholine (1.19 mL, 10.92 mmol), 0-(tetrahydropuranyl) hydroxylamine (1.28 g, 10.92 mmol) and 1-3-[(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.977 g, 5.10 mmol). The resulting mixture was stirred at ambient temperature for 16 hours then concentrated in vacuo.
  • Part E To the protected hydroxamate of part D (1.89 g, 3.00 mmol) was added 4N HCl in dioxane (7.50 mL, 30.0 mmol) and methanol (1.22 mL, 30.0 mmol). The resulting mixture was stirred at ambient temperature for 2 hours, then diethyl ether (5 mL) was added and the precipitate was collected by filtration to provide the title compound as a fine white solid (1.56 g, 89%). MS MH + calculated for C 26 H 25 O 6 N 2 S 1 F 3 : 551, found 551.
  • Part B The tetrahydropyranyl ether from Part A was stirred at 110 degrees Celsius for 20 hours in the presence of powdered potassium carbonate (2.07 g, 15 mmol), 4-(trifluoromethoxy)phenol (2.67 mL, 15 mmol), and N,N-dimethyformamide (5 mL). The mixture was diluted with saturated sodium bicarbonate (50 mL) and was extracted with ethyl acetate (150, then 50 mL). The combined organic layers were dried over magnesium sulfate, concentrated, and chromatographed to afford the desired aryl ether as an oil (5.72 g, quantitative).
  • Part C The aryl ether from Part C (1.28 g, 2.1 mmol) was refluxed in the presence of potassium hydroxide (954 mg, 16.8 mmol), ethanol (9 mL), and water (3 mL). After 2 hours, the reaction vessel was cooled to zero degrees Celsius. Concentrated hydrochloric acid was added drop-wise to adjust the pH to 4.0. The acidified reaction was concentrated, azeotroped with acetonitrile, and dried in vacuo, affording the crude carboxylic acid, which was used directly in Part D.
  • Part D The carboxylic acid from Part C was converted to O-tetrahydropyranyl hydroxamate using O-tetrahydropyranyl hydroxylamine (351 mg, 3 mmol), N-methylmorpholine (0.5 mL), N-hydroxybenzotriazole (405 mg, 3 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (573 mg, 3 mmol) in N,N-dimethylformamide (9 mL). The tetrahydropyranyl hydroxamate (855 mg, 60%) was obtained as an oil.
  • Part E The tetrahydropyranyl hydroxamate (855 mg, 1.26 mmol) was dissolved in absolute methanol (10 mL). Acetyl chloride (0.78 mL, 11 mmol) was added over 2-3 minutes. After 4 hours both tetrahydropyranyl groups had been cleaved. The reaction was concentrated, azeotroped with chloroform/acetonitrile, and dried in vacuo affording the title compound as a white foam (676 mg, 98%). MS (EI) MH + calculated for C 21 H 23 F 3 N 2 O 7 S: 505, found 505.
  • Part A To a solution of the compound of example N-tert-butoxycarbonyl-ethyl 4-(4-fluorophenylsulfonyl)-4-piperidinecarboxylate, hydrochloride of Preparative Example II (1.50 g, 3.61 mmol) in N,N-dimethylformamide (10 mL) was added cesium carbonate (2.94 g, 9.03 mmol) and (4-trifluoromethylthio) phenol (1.05 g, 5.41 mmol) and the solution was heated to 100 degrees Celsius for 24 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and dried over sodium sulfate.
  • Part C To a solution of the carboxylic acid of part B (2.0 g, ⁇ 3.61 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (586 mg, 4.33 mmol), 4-methylmorpholine (1.19 mL, 10.8 mmol) and O-tetrahydropyranyl hydroxylamine (634 mg, 5.41 mmol) and the solution was stirred for 30 minutes. The 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (969 mg, 5.05 mmol) was added and the solution was stirred for seven days.
  • Part D To a solution of the protected hydroxamate of part C (1.05 g, 1.60 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1.5 hours. The solution was diluted with ethyl ether and the resulting white precipitate was collected by vacuum filtration to provide the title compound as a white solid (330 mg, 40% yield). MS(CI) MH+calculated for C 19 H 19 N 2 O 5 S 2 F 3 : 477, found 477. HRMS calculated for C 19 H 19 N 2 O 5 S 2 F 3 : 477.0766, found 477.0766. Analytical calculation for C 19 H 19 N 2 O 5 S 2 HCl: C, 44.49; H, 3.93; N, 5.46; Cl, 6.91. Found: C, 44.51; H, 3.90; N, 5.38; Cl, 6.95.
  • Part A To a solution of ethyl N-cyclopropyl-4-(4-fluorophenylsulfonyl]-4-piperidinecarboxylate (Preparative Example VI, Part A) (2.0 g, 5.11 mmol) in dimethylacetamide (10 mL) was added methyl isonipectotate (1.03 mL, 7.66 mmol) and cesium carbonate (4.16 g, 12.78 mmol) and was heated to one hundred ten degrees Celsius for 18 hours. The solution was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an oil (1.81 g, 74%). MS(CI) MH + calculated for C 24 H 34 N 2 O 6 S: 479, found 479.
  • Part C To a solution of the acid of part B (500 mg, 1.08 mmol) in dichloromethane (10 mL) was added 1-hydroxybenzotriazole hydrate (160 mg, 1.19 mmol), triethylamine (0.15 mL, 1.19 mmol) and N-benzylmethylamine (0.33 mL, 2.38 mmol). After thirty minutes the 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added and the solution was stirred for 20 hours at ambient temperature. The solution was diluted with ethyl acetate and washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate) provided the amide as a white solid (480 mg, 78%). MS(CI) MH + calculated for C 31 H 41 N 3 O 5 S: 568, found 568.
  • Part E To a solution of the crude acid of part D ( ⁇ 0.71 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (115 mg, 0.85 mmol), 4-methylmorpholine (0.39 mL) and O-tetrahydropyranyl hydroxylamine (124 mg, 1.06 mmol). After thirty minutes 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (190 mg, 0.99 mmol) was added and the solution was stirred for 18 hours.
  • Part F To a solution of the protected hydroxamate of part E (180 mg, 0.28 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for one hour. Trituration (ethyl ether) and vacuum filtration provided the title compound as a white solid (96.5 mg, 58%). MS(CI) MH + calculated for C 29 H 38 N 4 O 5 S: 555, found 555. HRMS calc. 555.2641, found 555.2644.
  • Part B To a solution of the N-Boc-isonipecotic acid of part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg, 4.45 mmol), 1-hydroxybenzotriazole hydrate (620 mg, 4.59 mmol) 3,5-dimethylpiperdine (0.67 mL, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 21 hours. The solution was concentrated in vacuo.
  • Part C To a solution of the amide of part B (1.20 g, 3.84 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII,
  • Part A (956 mg, 2.56 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.92 g, 8.96 mmol) was added and the solution was heated to one hundred degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an oil (1.53 g, 68%). MS(CI) MH + calculated for C 30 H 47 N 3 O 6 S: 578, found 578.
  • Part E To a solution of the acid of part D (492 mg, 0.84 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (136 mg, 1.01 mmol), 4-methylmorpholine (0.46 mL, 4.20 mmol), and O-tetrahydropyranyl hydroxylamine (147 mg, 1.26 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (225 mg, 1.18 mmol) was added and the solution was stirred for 72 hours at ambient temperature. The solution was partitioned between ethyl acetate and water.
  • Part F To a solution of the protected hydroxamate of part E (514 mg, 0.79 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1.5 hours. The solution was concentrated in vacuo and trituration (ethyl ether) provided the title compound as a white solid (360 mg, 76%). MS(CI) MH+calculated for C 28 H 44 N 4 O 6 S: 565, found 565. HRMS calculated for C 28 H 44 N 4 O 6 S: 565.3060, found 565.3070.
  • Part A A solution of the hydroxamate of Example 233, part F (50 mg, 0.08 mmol) in water (2 mL) was neutralized with saturated sodium bicarbonate. The aqueous solution was extracted with ethyl acetate. Concentration in vacuo provided the hydroxamate free base as an orange solid (35 mg, 75%).
  • Part A To a solution of the N-Boc-isonipecotic acid of Example 233, part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg, 4.45 mmol), 1-hydroxy-benzotriazole hydrate (620 mg, 4.59 mmol), 2-(2-methylaminoethyl)pyridine (0.69 mL, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 21 hours. The solution was concentrated in vacuo.
  • Part B To a solution of the amide of part A (1.0 g, 2.88 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII, Part A (716 mg, 1.92 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.20 g, 6.72 mmol) was added and the solution was heated to one hundred degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as a yellow oil (1.20 g, quantitative yield). MS(CI) MH + calculated for C 31 H 44 N 4 O 6 S: 601, found 601.
  • Part D To a solution of the acid of part C ( ⁇ 2.0 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (324 mg, 2.04 mmol), 4-methylmorpholine (1.1 mL, 10.0 mmol), and O-tetrahydropyranyl hydroxylamine (351 mg, 3.00 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (536 mg, 2.80 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water.
  • Part E To a solution of the protected hydroxamate of part D (160 mg, 0.24 mmol) in dioxane (7 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 30 minutes. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (90 mg, 57%). MS(CI) MH+calculated for C 29 H 37 N 5 O 6 S: 588, found 588. HRMS calculated for C 29 H 37 N 5 O 6 S: 558.2856, found 588.2857.
  • Part A To a solution of the N-Boc-isonipecotic acid of Example 233, part A (1.0 g, 4.37 mmol) in dichloromethane (4 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (752 mg, 4.28 mmol). The solution was cooled to zero degrees Celsius and 4-methylmorpholine (0.47 mL, 4.28 mmol) was added. After two hours aniline (0.39 mL, 4.28 mmol) was added and the solution was stirred for 20 hours at ambient temperature. The solution was concentrated in vacuo.
  • Part B To a solution of the amide of part A (1.48 g, 4.28 mmol) in dichloromethane (5 mL) was added trifluoroacetic (5 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII, Part A (1.06 mg, 2.85 mmol) in dimethylacetamide (10 mL). Cesium carbonate (3.25 g, 9.97 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as a yellow oil (1.74 g, quantitative yield). MS(CI) MH + calculated for C 29 H 39 N 3 O 6 S: 558, found 558.
  • Part D To a solution of the acid of part C (1.60 g, 2.83 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (458 mg, 3.40 mmol), 4-methylmorpholine (1.56 mL, 14.2 mmol), and O-tetrahydropyranyl hydroxylamine (497 mg, 4.24 mmol). After one hour, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (759 mg, 3.96 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water.
  • Part E To a solution of the protected hydroxamate of part D (780 mg, 1.24 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (580 mg, 80%). MS(CI) MH+calculated for C 27 H 36 N 4 O 6 S: 545, found 545. HRMS calculated for C 27 H 36 N 4 O 6 S: 545.2434, found 545.2429.
  • Part A To a solution of the N-Boc-isonipecotic acid of Example 233, part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg, 4.45 mmol), 1-hydroxybenzotriazole hydrate (620 mg, 4.59 mmol), 3-phenyl-1-propylamine (0.72 mL, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 18 hours. The solution was concentrated in vacuo.
  • Part B To a solution of the amide of part A (1.4 g, 4.05 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. The resulting solid was collected by vacuum filtration and washed with ethyl ether. The solid was added to a solution of the compound of Preparative Example VII, Part A (1.01 mg, 2.70 mmol) in dimethylacetamide (10 mL). Cesium carbonate (3.07 g, 9.45 mmol) was added and the solution was heated to one hundred degrees Celsius for 18 hours.
  • Part D To a solution of the acid of part C (1.02 g, 1.68 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (272 mg, 2.02 mmol), 4-methylmorpholine (0.92 mL, 8.4 mmol), and O-tetrahydropyranyl hydroxylamine (295 mg, 2.52 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (451 mg, 2.35 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water.
  • Part E To a solution of the protected hydroxamate of part D (480 mg, 0.72 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for one hour. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (400 mg, 90%). MS(CI) MH + calculated for C 30 H 42 N 4 O 6 S: 587, found 587. Analytical calculation for C 30 H 42 N 4 O 6 S 2HCl :2H 2 O: C, 51.79; H, 6.95; N, 8.05; S, 4.61; Cl, 10.19. Found: C,51.34; H, 6.72; N, 7.82; S, 4.59; Cl, 10.92.
  • Part A To a solution of the N-Boc-isonipecotic acid of Example 233, Part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg, 4.45 mmol), 1-hydroxybenzotriazole hydrate (620 mg, 4.59 mmol) 3,5-dimethylpiperdine (0.67 mL, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 21 hours. The solution was concentrated in vacuo.
  • Part B To a solution of the amide of part A (1.4 g, 4.49 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided a solid that was added directly to a solution of the compound of Preparative Example II, Part D, (1.24 mg, 2.99 mmol) in dimethylacetamide (10 mL). Cesium carbonate (3.42 g, 10.5 mmol) was added and the solution was heated to one hundred degrees Celsius for 20 hours.

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Abstract

A treatment process is disclosed that comprises administering an effective amount of an aromatic sulfone hydroxamic acid that exhibits excellent inhibitory activity of one or more matrix metalloprotease (MMP) enzymes, such as MMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibition at least of MMP-1 to a host having a condition associated with pathological matrix metalloprotease activity. Also disclosed are metalloprotease inhibitor compounds having those selective activities, processes for manufacture of such compounds and pharmaceutical compositions using an inhibitor. A contemplated compound corresponds in structure to formula B, below,
Figure US20040235818A1-20041125-C00001

Description

    CROSS-REFERENCE TO RELATED APPLICATION
  • This is a continuation-in-part of application Ser. No. 09/311,837 filed on May 14, 1999 that was a continuation-in-part of application Ser. No. 09/256,948 filed on Feb. 24, 1999, that was a continuation-in-part of application Ser. No. 09/74497 filed on Nov. 13, 1998.[0001]
    • TECHNICAL FIELD
  • This invention is directed to proteinase (protease) inhibitors, and more particularly to the use of aromatic sulfone hydroxamic acid compounds that, inter alia, are selective inhibitors of matrix metalloproteinases in a process for treating conditions associated with pathological matrix metalloproteinase activity, the selective inhibitors themselves, compositions of proteinase inhibitors, intermediates for the syntheses of proteinase inhibitors, and processes for the preparation of proteinase inhibitors. [0002]
    • BACKGROUND OF THE INVENTION
  • Connective tissue, extracellular matrix constituents and basement membranes are required components of all mammals. These components are the biological materials that provide rigidity, differentiation, attachments and, in some cases, elasticity to biological systems including human beings and other mammals. Connective tissues components include, for example, collagen, elastin, proteoglycans, fibronectin and laminin. Th se biochemicals makeup, or are components of structures, such as skin, bone, teeth, tendon, cartilage, basement membrane, blood vessels, cornea and vitreous humor. [0003]
  • Under normal conditions, connective tissue turnover and/or repair processes are controlled and in equilibrium. The loss of this balance for whatever reason leads to a number of disease states. Inhibition of the enzymes responsible loss of equilibrium provides a control mechanism for this tissue decomposition and, therefore, a treatment for these diseases. [0004]
  • Degradation of connective tissue or connective tissue components is carried out by the action of proteinase enzymes released from resident tissue cells and/or invading inflammatory or tumor cells. A major class of enzymes involved in this function are the zinc metalloproteinases (metalloproteases). [0005]
  • The metalloprotease enzymes are divided into classes with some members having several different names in common use. Examples are: collagenase I (MMP-1, fibroblast collagenase; EC 3.4.24.3); collagenase II (MMP-8, neutrophil collagenase; EC 3.4.24.34), collagenase III (MMP-13), stromelysin 1 (MMP-3; EC 3.4.24.17), stromelysin 2 (MMP-10; EC 3.4.24.22), proteoglycanase, matrilysin (MMP-7), gelatinase A (MMP-2, 72 kDa gelatinase, basement membrane collagenase; EC 3.4.24.24), gelatinase B (MMP-9, 92 kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11), metalloelastase (MMP-12, HME, human macrophage elastase) and membrane MMP (MMP-14). MMP is an abbreviation or acronym representing the term Matrix Metalloprotease with the attached numerals providing differentiation between specific members of the MMP group. [0006]
  • The uncontrolled breakdown of connective tissue by metalloproteases is a feature of many pathological conditions. Examples include rheumatoid arthritis, osteoarthritis, septic arthritis; corneal, epidermal or gastric ulceration; tumor metastasis, invasion or angiogenesis; periodontal disease; proteinuria; Alzheimers Disease; coronary thrombosis and bone disease. Defective injury repair processes also occur. This can produce improper wound healing leading to weak repairs, adhesions and scarring. These latter defects can lead to disfigurement and/or permanent disabilities as with post-surgical adhesions. [0007]
  • Metalloproteases are also involved in the biosynthesis of tumor necrosis factor (TNF), and inhibition of the production or action of TNF and related compounds is an important clinical disease treatment mechanism. TNF-α, for example, is a cytokine that at present is thought to be produced initially as a 28 kD cell-associated molecule. It is released as an active, 17 kD form that can mediate a large number of deleterious effects in vitro and in vivo. For example, TNF can cause and/or contribute to the effects of inflammation, rheumatoid arthritis, autoimmune disease, multiple sclerosis, graft rejection, fibrotic disease, cancer, infectious diseases, malaria, mycobacterial infection, meningitis, fever, psoriasis, cardiovascular/pulmonary effects such as post-ischemic reperfusion injury, congestive heart failure, hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage and acute phase responses like those seen with infections and sepsis and during shock such as septic shock and hemodynamic shock. Chronic release of active TNF can cause cachexia and anorexia. TNF can be lethal, and TNF can help control the growth of tumor cells. [0008]
  • TNF-α convertase is a metalloprotease involved in the formation of soluble TNF-α. Inhibition of TNF-α convertase (TACE) inhibits production of active TNF-α. Compounds that inhibit both MMPs activity and TNF-α production have been disclosed in WIPO International Publication Nos. WO 94/24140, WO 94/02466 and WO 97/20824. Compounds that inhibit MMPs such as collagenase, stromelysin and gelatinase have been shown to inhibit the release of TNF (Gearing et al. [0009] Nature 376, 555-557 (1994), McGeehan et al., Nature 376, 558-561 (1994)). There remains a need for effective MMP inhibitors. There also remains a need for effective TNF-α convertase inhibiting agents.
  • MMPs are involved in other biochemical processes in mammals as well. Included is the control of ovulation, post-partum uterine involution, possibly implantation, cleavage of APP (β-Amyloid Precursor Protein) to the amyloid plaque and inactivation of α[0010] 1-protease inhibitor (α1-PI). Inhibition of these metalloproteases permits the control of fertility and the treatment or prevention of Alzheimers Disease. In addition, increasing and maintaining the levels of an endogenous or administered serine protease inhibitor drug or biochemical such as α1-PI supports the treatment and prevention of diseases such as emphysema, pulmonary diseases, inflammatory diseases and diseases of aging such as loss of skin or organ stretch and resiliency.
  • Inhibition of selected MMPs can also be desirable in other instances. Treatment of cancer and/or inhibition of metastasis and/or inhibition of angiogenesis are examples of approaches to the treatment of diseases wherein the selective inhibition of stromelysin, gelatinase A or B, or collagenase III appear to be the relatively most important enzyme or enzymes to inhibit especially when compared with collagenase I (MMP-1). A drug that does not inhibit collagenase I can have a superior therapeutic profile. Osteoarthritis, another prevalent disease wherein it is believed that cartilage degradation of inflamed joints is at least partially caused by MMP-13 released from cells such as stimulated chrondrocytes, may be best treated by administration of drugs one of whose modes of action is inhibition of MMP-13. See, for example, Mitchell et al., [0011] J. Clin. Invest., 97:761-768 (1996) and Reboul et al., J. Clin. Invest., 97:2011-2019 (1996).
  • Inhibitors of metalloproteases are known. Examples include natural biochemicals such as tissue inhibitors of metalloproteinases (TIMPs), α[0012] 2-macroglobulin and their analogs or derivatives. These endogenous inhibitors are high molecular weight protein molecules that form inactive complexes with metalloproteases. A number of smaller peptide-like compounds that inhibit metalloproteases have been described. Mercaptoamide peptidyl derivatives have shown ACE inhibition in vitro and in vivo. Angiotensin converting enzyme (ACE) aids in the production of angiotensin II, a potent pressor substance in mammals and inhibition of this enzyme leads to the lowering of blood pressure.
  • Thiol group-containing amide or peptidyl amide-based metalloprotease (MMP) inhibitors are known as is shown in, for example, WO95/12389, WO96/11209 and U.S. Pat. No. 4,595,700. Hydroxamate group-containing MMP inhibitors are disclosed in a number of published patent applications such as WO 95/29892, WO 97/24117, WO 97/49679 and EP 0 780 386 that disclose carbon back-boned compounds, and WO 90/05719, WO 93/20047, WO 95/09841 and WO 96/06074 that disclose hydroxamates that have a peptidyl back-bones or peptidomimetic back-bones, as does the article by Schwartz et al., [0013] Progr. Med. Chem., 29:271-334(1992) and those of Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997) and Denis et al., Invest. New Drugs, 15(3): 175-185 (1997).
  • One possible problem associated with known MMP inhibitors is that such compounds often exhibit the same or similar inhibitory effects against each of the MMP enzymes. For example, the peptidomimetic hydroxamate known as batimastat is reported to exhibit IC[0014] 50 values of about 1 to about 20 nanomolar (nM) against each of MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9. Marimastat, another peptidomimetic hydroxamate was reported to be another broad-spectrum MMP inhibitor with an enzyme inhibitory spectrum very similar to batimastat, except that marimastat exhibited an IC50 value against MMP-3 of 230 nM. Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997).
  • Meta analysis of data from Phase I/II studies using marimastat in patients with advanced, rapidly progressive, treatment-refractory solid tumor cancers (colorectal, pancreatic, ovarian, prostate) indicated a dose-related reduction in the rise of cancer-specific antigens used as surrogate markers for biological activity. Although marimastat exhibited some measure of efficacy via these markers, toxic side effects were noted. The most common drug-related toxicity of marimastat in those clinical trials was musculoskeletal pain and stiffness, often commencing in the small joints in the hands, spreading to the arms and shoulder. A short dosing holiday of 1-3 weeks followed by dosage reduction permits treatment to continue. Rasmussen et al., [0015] Pharmacol. Ther., 75(1): 69-75 (1997). It is thought that the lack of specificity of inhibitory effect among the MMPs may be the cause of that effect.
  • International application WO 98/38163, published on Sep. 3, 1998 disclose a large group of hydroxamate inhibitors of MMPs and TACE. The compounds of WO 98/38163 contain one or two substituents adjacent to the hydroxamate functionality and a substituent that can be an aromatic sulfonyl group adjacent to those one or two substituents. [0016]
  • International application WO 98/37877, published on Sep. 3, 1998 discloses compounds that contain a 5- to 7-membered heterocyclic ring adjacent to the hydroxamate functionality and can contain an aromatic sulfonyl group adjacent to the heterocyclic ring. [0017]
  • Although many of the known MMP inhibitors such as batimastat, marimastat and the hydroxamates of WO 98/37877 and WO 98/38163 exhibit a broad spectrum of activity against MMPS, those compounds are not particularly selective in their inhibitory activity. This lack of selectivity may be the cause of the musculoskeletal pain and stiffness observed with their use. In addition, it can be therapeutically advantageous to utilize a medicament that is selective in its activity as compared to a generally active material so that treatment can be more closely tailored to the pathological condition presented by the host mammal. The disclosure that follows describes a process for treating a host mammal having a condition associated with pathological matrix metalloprotease activity that utilizes a compound that selectively inhibits one or more MMPs, while exhibiting less activity against at least MMP-1. [0018]
    • SUMMARY OF THE INVENTION
  • The present invention is directed to a treatment process that comprises administering a contemplated aromatic sulfone hydroxamic acid metalloprotease inhibitor in an effective amount to a host mammal having a condition associated with pathological metalloprotease activity. A contemplated molecule, inter alia, exhibits excellent inhibitory activity of one or more matrix metalloprotease (MMP) enzymes, such as MMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibition at least of MMP-1. By “substantially less” it is meant that a contemplated compound exhibits an IC[0019] 50 value ratio against one or more of MMP-2, MMP-9 or MMP-13 as compared to its IC50 value against MMP-1, e.g., IC50 MMP-2:IC50 MMP-1, that is less than about 1:10, preferably less than about 1:100, and most preferably less than about 1:1000 in the in vitro inhibition assay utilized hereinafter. The invention also contemplates particular compounds that selectively inhibit the activity of one or more of MMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibition at least of MMP-1, as well as a composition containing such a MMP inhibitor as active ingredient. Similarly contemplated are particular compounds such as those of Examples 16, 498, 667, 672 and 684 that selectively inhibit the activity of one or more of MMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibition at least of MMP-7, as well as a composition containing such a MMP inhibitor as active ingredient. The invention further contemplates intermediates in the preparation of a contemplated aromatic sulfone hydroxamic acid molecule and a process for preparing an aromatic sulfone hydroxamic acid molecule.
  • Briefly, one embodiment of the present invention is directed to a treatment process that comprises administering a contemplated aromatic sulfone hydroxamic acid metalloprotease inhibitor that selectively inhibits matrix metalloprotease activity as above in an effective amount to a host mammal having a condition associated with pathological metalloprotease activity. The administered enzyme inhibitor corresponds in structure to formula I, below, or a pharmaceutically acceptable salt thereof: [0020]
    Figure US20040235818A1-20041125-C00002
  • wherein [0021]
  • R[0022] 1 and R2 are both hydrido or R1 and R2 together with the atoms to which they are bonded form a 5- to 8-membered ring containing one, two or three heteroatoms in the ring that are oxygen, sulfur or nitrogen.
  • R[0023] 3 in formula I is an optionally substituted aryl or optionally substituted heteroaryl radical. When R3 is a substituted aryl or heteroaryl radical, a contemplated substituent is selected from the group consisting of an aryl, heteroaryl, aralkyl, heteroaralkyl, aryloxy, arylthio, aralkoxy, heteroaralkoxy, aralkoxyalkyl, aryloxyalkyl, aralkanoylalkyl, arylcarbonylalkyl, aralkylaryl, aryloxyalkylaryl, aralkoxyaryl, arylazoaryl, arylhydrazinoaryl, alkylthioaryl, arylthioalkyl, alkylthioaralkyl, aralkylthioalkyl, an aralkylthioaryl radical, the sulfoxide or sulfone of any of the thio substituents, and a fused ring structure comprising two or more 5- or 6-membered rings selected from the group consisting of aryl, heteroaryl, carbocyclic and heterocyclic.
  • The substituent bonded to the aryl or heteroaryl radical of which the R[0024] 3 radical is comprised itself can be substituted with one or more substituents; i.e., the substituting substituent is optionally substituted. When that aryl or heteroaryl radical is substituted, and the substituting moiety (group, substituent, or radical) is itself substituted, the last-named substituent is independently selected from the group consisting of a cyano, perfluoroalkyl, trifluoromethoxy, trifluoromethylthio, haloalkyl, trifluoromethylalkyl, aralkoxycarbonyl, aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy, aralkylthio, aralkylamino, heterocyclo, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino,
  • wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of an alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl and an alkanoyl group, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring containing zero to two additional heteroatoms that are nitrogen, oxygen or sulfur and which ring itself is (a) unsubstituted or (b) substituted with one or two groups independently selected from the group consisting of an aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzofused heterocycloalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofused heterocycloalkoxy, benzofused cycloalkylcarbonyl, heterocyclo-alkylcarbonyl, and a cycloalkylcarbonyl group, carbonylamino [0025]
  • wherein the carbonylamino nitrogen is (i) unsubstituted, or (ii) is the reacted amine of an amino acid, or (iii) substituted with one or two radicals selected from the group consisting of an alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzofused heterocycloalkyl, benzofused heterocycloalkyl, benzofused cycloalkyl, and an N,N-dialkylsubstituted alkylamino-alkyl group, or (iv) the carboxamido nitrogen and two substituents bonded thereto together form a 5- to 8-membered heterocyclo, heteroaryl or benzofused heterocycloalkyl ring that is itself unsubstituted or substituted with one or two radicals independently selected from the group consisting of an alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl and an amino group, [0026]
  • wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of alkyl, aryl, and heteroaryl, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, and an aminoalkyl group [0027]
  • wherein the aminoalkyl nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents independently selected from the group consisting of an alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and an alkanoyl group, or (iii) wherein the aminoalkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring. [0028]
  • Preferably, the R[0029] 3 substituent is Ph-Q-A-R-E-Y wherein Ph is phenyl substituted at the 4-position relative to the depicted SO2 group, and -Q-A-R-E-Y is a substituent in which Q is a 5- to 7-membered heterocyclic ring containing one or two nitrogen atoms, one of which is bonded the depicted phenyl group, and whose remaining members are defined hereinafter for the substituent G-A-R-E-Y.
  • A compound of formula I is a compound of more general formula A, wherein R[0030] 3, R1 and R2 are as defined before and R20 is defined below.
    Figure US20040235818A1-20041125-C00003
  • The substituent R[0031] 20 is (a) —O—R21, where R21 is selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl group and a pharmaceutically acceptable cation, (b) —NH—O—R22 wherein R22 is a selectively removable protecting group such as a 2-tetrahydropyranyl., benzyl, p-methoxybenzyl (MOZ), carbonyl-C1-C6-alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide synthesis resin and the like, wherein the trisubstituted silyl group is substituted with C1-C6-alkyl, aryl, or ar-C1-C6-alkyl or a mixture thereof, (c) —NH—O—R14, where R14 is hydrido, a pharmaceutically acceptable cation or C(W)R25 where W is O (oxo) or S (thioxo) and R25 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino C1-C6-alkyl group wherein the amino C1-C6-alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or (d) —NR26R27, where R26 and R27 are independently selected from the group consisting of a hydrido, C1-C6-alkyl, amino C1-C6-alkyl, hydroxy C1-C6-alkyl, aryl, ar-C1-C6-alkyl group, or R26 and R27 together with the depicted nitrogen atom form a 5- to 8-membered ring containing zero or one additional heteroatom that is oxygen, nitrogen or sulfur. When used in a contemplated process or method, R20 is —NH—O—R22, as defined above.
  • In preferred practice, R[0032] 1 and R2 together with the atoms to which they are bonded form a 6-membered ring.
  • An R[0033] 3 radical preferably has a length that is greater than that of a pentyl group [a —(CH2)4CH3 chain], more preferably greater than about that of a hexyl group [a —(CH2)5CH3 chain], and most preferably greater than an octyl group [a —(CH2)7CH3 chain]. An R3 radical preferably has a length that is less than that of an icosyl group [a —(CH2)19CH3 chain], and more preferably a length that is less than that of a stearyl group [a —(CH2)17CH3 chain). A preferred R3 group contains two or more 5- or 6-membered rings. A contemplated R3 group, when rotated about an axis drawn through the SO2-bonded 1-position and the substituent-bonded 4-position of a 6-membered ring or the SO2-bonded 1-position and substituent-bonded 3- or 4-position of a 5-membered ring, defines a three-dimensional volume whose widest dimension has the width in a direction transverse to that axis to rotation of about one furanyl ring to about two phenyl rings.
  • It is also preferred that a R[0034] 3 radical be a single-ringed aryl or heteroaryl group that is 5- or 6-membered, and is itself substituted at its own 4-position when a 6-membered ring or at its own 3- or 4-position when a 5-membered ring with an optionally substituted substituent selected from the group consisting of one other single-ringed aryl or heteroaryl group, a C3-C14 alkyl group, a N-piperidyl group, a N-piperazyl group, a phenoxy group, a thiophenoxy group, a 4-thiopyridyl group, a phenylazo group and a benzamido group. The substituent of the 5- or 6-membered aryl or heteroaryl group can itself be substituted as discussed before.
  • A preferred compound for use in a contemplated process has a structure that corresponds to formula II, below, or a pharmaceutically acceptable salt thereof: [0035]
    Figure US20040235818A1-20041125-C00004
  • wherein [0036]
  • R[0037] 14 is hydrido, a pharmaceutically acceptable cation or C(W)R15 where W is O or S and R15 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring;
  • m is zero, 1 or 2; [0038]
  • n is zero, 1 or 2; [0039]
  • p is zero, 1 or 2; [0040]
  • the sum of m+n+p=1, 2, 3 or 4; [0041]
  • (a) one of X, Y and Z is selected from the group consisting of C(O), NR[0042] 6, O, S, S(O), S(O)2 and NS(O)2R7, and the remaining two of X, Y and Z are CR8R9, and CR10R11, or
  • (b) X and Z or Z and Y together constitute a moiety that is selected from the group consisting of NR[0043] 6C(O), NR6S(O), NR6S(O)2, NR6S, NR6O, SS, NR6NR6 and OC(O), with the remaining one of X, Y and Z being CR8R9, or
  • (c) n is zero and X, Y and Z together constitute a moiety selected from the group consisting of [0044]
    Figure US20040235818A1-20041125-C00005
  • wherein wavy lines are bonds to the atoms of the depicted ring; [0045]
  • R[0046] 6 and R6′ are independently selected from the group consisting of hydrido, formyl, sulfonic-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, C1-C6-alkylcarbonyl-C1-C6-alkyl, R8R9-aminocarbonyl-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkylcarbonyl, hydroxycarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkylcarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C1-C6-alkylcarbonylcarbonyl, R8R9-aminocarbonylcarbonyl, C1-C6-alkanoyl, aryl-C1-C6-alkyl, aroyl, bis(C1-C6-alkoxy-C1-C6-alkyl)-C1-C6-alkyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-perfluoroalkyl, C1-C6-trifluoromethylalkyl, C1-C6-perfluoroalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, heteroarycarbonyl, heterocyclocarbonyl, C3-C8-heterocycloalkyl, C3-C8-heterocycloalkylcarbonyl, aryl, C5-C6-heterocyclo, C5-C6-heteroaryl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkoxy-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, arylsulfonyl, C1-C6-alkylsulfonyl, Cs-C6-heteroarylsulfonyl, carboxy-C1-C6-alkyl, C1-C4-alkoxycarbonyl-C1-C6-alkyl, aminocarbonyl, C1-C6-alkyl(R8N)iminocarbonyl, aryl(R8N)iminocarbonyl, C5-C6-heterocyclo(R8N)iminocarbonyl, arylthio-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C3-C6-alkenyl, C1-C4-alkylthio-C3-C6-alkenyl, C5-C6-heteroaryl-C1-C6-alkyl, halo-C1-C6-alkanoyl, hydroxy-C1-C6-alkanoyl, thiol-C1-C6-alkanoyl, C3-C6-alkenyl, C3-C6-alkynyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C5-alkoxycarbonyl, aryloxycarbonyl, NR8R9—(R8)iminomethyl, NR8R9—C1-C5-alkylcarbonyl, hydroxy-C1-C5-alkyl, R8R9-aminocarbonyl, R8R9-aminocarbonyl-C1-C6-alkylcarbonyl, hydroxyaminocarbonyl, R8R9-aminosulfonyl, R8R9-aminosulfon-C1-C6-alkyl, R8R9-amino-C1-C6-alkylsulfonyl and an R8R9-amino-C1-C6-alkyl group;
  • R[0047] 7 is selected from the group consisting of a arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl and a C1-C6-hydroxyalkyl group;
  • R[0048] 8 and R9 and R10 and R11 are independently selected from the group consisting of a hydrido, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroar-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thio]-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aralkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl, or wherein R8 and R9 or R10 and R11 and the carbon to which they are bonded form a carbonyl group, or wherein R8 and R9 or R10 and R11, or R8 and R10 together with the atoms to which they are bonded form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclic or heteroaryl ring containing one or two heteroatoms that are nitrogen, oxygen, or sulfur, with the proviso that only one of R8 and R9 or R10 and R11 is hydroxy;
  • R[0049] 12 and R12′ are independently selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroaralkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aryloxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl;
  • R[0050] 13 is selected from the group consisting of a hydrido, benzyl, phenyl, C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl and a C1-C6-hydroxyalkyl group; and
  • G-A-R-E-Y is a substituent that preferably has a length greater than that of a pentyl group, and more preferably has a length greater than that of a hexyl group. The substituent G-A-R-E-Y preferably has a length that is less than that of an icosyl group, and is more preferably less than that of a stearyl group. In this substituent: [0051]
  • G is an aryl or heteroaryl group; [0052]
  • A is selected from the group consisting of [0053]
  • (1) —O—; [0054]
  • (2) —S—; [0055]
  • (3) —NR[0056] 17—;
  • (4) —CO—N(R[0057] 17) or —N(R17)—CO—, wherein R17 is hydrogen, C1-C4-alkyl, or phenyl;
  • (5) —CO—O— or —O—CO—; [0058]
  • (6) —O—CO—O—; [0059]
  • (7) —HC═CH—; [0060]
  • (8) —NH—CO—NH—; [0061]
  • (9) —C≡C—; [0062]
  • (10) —NH—CO—O— or —O—CO—NH—; [0063]
  • (11) —N═N—; [0064]
  • (12) —NH—NH—; and [0065]
  • (13) —CS—N(R[0066] 18)— or —N(R18)—CS—, wherein
  • R[0067] 18 is hydrogen C1-C4-alkyl, or phenyl; or
  • (14) A is absent and G is bonded directly to R; [0068]
  • R is a moiety selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C[0069] 1-C2-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group, and R is other than alkyl or alkoxyalkyl when A is —O— or —S—;
  • E is selected from the group consisting of [0070]
  • (1) —CO(R[0071] 19)— or —(R19)CO—, wherein R19 is a heterocycloalkyl, or a cycloalkyl group;
  • (2) —CONH— or —HNCO—; and [0072]
  • (3) —CO—; [0073]
  • (4) —SO[0074] 2—R19— or —R19—SO2—;
  • (5) —SO[0075] 2—;
  • (6) —NH—SO[0076] 2— or —SO2—NH—;
  • (7) —S—; [0077]
  • (8) —NH—CO—O— or —O—CO—NH—; or [0078]
  • (9) E is absent and R is bonded directly to Y; and [0079]
  • the moiety Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl, aralkyl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of an alkanoyl, halo, nitro, aralkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy and an amino group wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group. [0080]
  • A particularly preferred compound for use in a contemplated process corresponds in structure to formula III, below, or a pharmaceutically acceptable salt thereof: [0081]
    Figure US20040235818A1-20041125-C00006
  • wherein [0082]
  • m, n, p, X, Z. Y and R[0083] 14 are as defined above for formula II, and the R3 radical that is defined below is a sub-set of the previously discussed G-A-R-E-Y substituents.
  • Thus, R[0084] 3 is a radical that is comprised of a single-ringed aryl or heteroaryl group that is 5- or 6-membered, and is itself substituted at its own 4-position when a 6-membered ring and at its own 3- or 4-position when a 5-membered ring with a substituent selected from the group consisting of a thiophenoxy, 4-chlorophenoxy, 3-chlorophenoxy, 4-methoxyphenoxy, 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluorophenoxy, 4-fluorothiophenoxy, phenoxy, 4-trifluoromethoxy-phenoxy, 4-trifluoromethylphenoxy, 4-(trifluoromethylthio)-phenoxy, 4-(trifluoromethylthio)-thiophenoxy, 4-chloro-3-fluorophenoxy, 4-isopropoxyphenoxy, 4-isopropylphenoxy, (2-methyl-1,3-benzothiazol-5-yl)oxy, 4-(1H-imidazol-1-yl)phenoxy, 4-chloro-3-methylphenoxy, 3-methylphenoxy, 4-ethoxyphenoxy, 3,4-difluorophenoxy, 4-chloro-3-methylphenoxy, 4-fluoro-3-chlorophenoxy, 4-(1H-1,2,4-triazol-1-yl)phenoxy, 3,5-difluorophenoxy, 3,4-dichlorophenoxy, 4-cyclopentylphenoxy, 4-bromo-3-methylphenoxy, 4-bromophenoxy, 4-methylthiophenoxy, 4-phenylphenoxy, 4-benzylphenoxy, 6-quinolinyloxy, 4-amino-3-methylphenoxy, 3-methoxyphenoxy, 5,6,7,8-tetrahydro-2-naphthalenyloxy, 3-hydroxymethylphenoxy, N-piperidyl, N-piperazinyl and a 4-benzyloxyphenoxy group.
  • A more particularly preferred compound for use in a contemplated process has a structure that corresponds to formula IV, below, or a pharmaceutically acceptable salt thereof: [0085]
    Figure US20040235818A1-20041125-C00007
  • wherein R[0086] 3 is as defined above for formula I, more preferably as defined for formula II (wherein this R3 group is the G-A-R-E-Y substituent), and more preferably still as defined for formula III, and
  • Z is selected group the group consisting of O, S, NR[0087] 6, SO, SO2, and NSO2R7,
  • wherein R[0088] 6 is selected from the group consisting of hydrido, C1-C5-alkyl, C1-C5-alkanoyl, benzyl, benzoyl, C3-C5-alkynyl, C3-C5-alkenyl, C1-C3-alkoxy-C1-C4-alkyl, C3-C6-cycloalkyl, heteroaryl-C1-C6-alkyl, C1-C5-hydroxyalkyl, C1-C5-carboxyalkyl, C1-C5-alkoxy C1-C5-alkylcarbonyl, and NR8R9—C1-C5-alkylcarbonyl or NR8R9—C1-C5-alkyl wherein R8 and R9 are independently hydrido, C1-C5-alkyl, C1-C5-alkoxycarbonyl or aryl-C1-C5-alkoxycarbonyl, or NR8R9 together form a heterocyclic ring containing 5- to 8-atoms in the ring; and
  • R[0089] 7 is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl and a C1-C6-hydroxyalkyl group.
  • A still more preferred group of compounds for use in a contemplated process correspond in structure to formula V, below, or a pharmaceutically acceptable salt thereof: [0090]
    Figure US20040235818A1-20041125-C00008
  • wherein [0091]
  • Z is as previously defined in formula IV; [0092]
  • W and Q are independently oxygen (O), NR[0093] 6 or sulfur (S), and R6 is as defined in formula IV; and
  • q is zero or one such that when q is zero, the trifluoromethyl group is bonded directly to the depicted phenyl ring. [0094]
  • Further compounds of formula A are also particularly preferred. One group of these compounds corresponds in structure to formula B (including formulas B, B-A, B-1, B-1A, B-2, B-2A, B-3 and B-3A), formula VIC, and more still particularly to formula VIC-1 and formula VIC-2, and formula VIII, below. In those formulas, ring structure Q is a substituent of the depicted phenyl ring and can itself be substituted. Substituent Q including the depicted nitrogen atom is a heterocylic ring that contains 5- or 7-members, preferably 6-members, and can contain zero or one additional nitrogen atom. The substituents of Q such as A-R-E-Y, R-E-Y and E-Y are as defined before, and such a substituent is bonded at the 4-position relative to that depicted nitrogen atom when Q is a 6- or 7-membered ring and at the 3- or 4-position relative to that depicted nitrogen when Q is a 5-membered ring. The remaining members of such a Q-beraing substituent (e.g., A-R-E-Y) are defined herein for the substituent G-A-R-E-Y. In addition, R[0095] 20, X, Y, Z, m, n, and p of the ring system and g are as before described, with Z preferably being O or NR6.
    Figure US20040235818A1-20041125-C00009
    Figure US20040235818A1-20041125-C00010
  • The compounds of formulas IX, IX-1, IX-2, X, XI, XI-1, XI-2 and XII, below, are more particularly preferred among the compounds of formula VIC, formula VIC-1, formula VIC-2, and formula VIII. In those latter formulas, Z is as before described, with Z preferably being O or NR[0096] 6, and substituent Q is a 6-membered ring, as is shown. The A moiety of the Q ring substituent -A-R-E-Y (e.g. of formula B or B-1) is preferably absent in some embodiments, as in the compounds of formulas XI through XII, whereas both moieties A and R of that substituent group are absent in compounds of formulas 1× through X. The moieties A, R, E and Y of the substituent group -A-R-E-Y are as defined for the substituent group -G-A-R-E-Y.
    Figure US20040235818A1-20041125-C00011
  • When used in a contemplated in a before-described process, a compound of formulas A, B, and I-VI, VI VIC, VIC-1, VIC-2, VIII, IX, IX-1, IX-2, X, XI, XI-1, XI-2 and XII, a R[0097] 20 group is preferably —NH—O—R22 as defined above, and such a compound can also be present as a pharmaceutically acceptable salt. In addition, when so used, g is 2 in formulas B, VIC, VIC-1, VIC-2 and VII. The compounds of formulas A, B, and I-VI, VI VIC, VIC-1, VIC-2, VIII, IX, IX-1, IX-2, X, XI, XI-1, XI-2 and XII and their pharmaceutically acceptable salts are contemplated compounds of this invention.
  • The present invention also contemplates a precursor or intermediate compound that is useful in preparing a compound of formulas I-X. Such an intermediate compound corresponds in structure to formula VI, below: [0098]
    Figure US20040235818A1-20041125-C00012
  • wherein m, n, p, X, Z and Y are as defined above for formula II, g is zero, 1 or 2 and R[0099] 24 is R3 as defined in formulas I, III or IV, is the substituent G-A-R-E-Y of formula II (formula VIA) or is R3′, an aryl or heteroaryl group that is substituted with a coupling substituent reactive for coupling with another moiety (formula VIB), such as a nucleophilically displaceable leaving group, D.
    Figure US20040235818A1-20041125-C00013
  • Exemplary nucleophilically displaceable leaving groups, D, include a halo (fluoro, chloro, bromo, or iodo) nitro, azido, phenylsulfoxido, aryloxy, C[0100] 1-C6-alkoxy, a C1-C6-alkylsulfonate or arylsulfonate group and a trisubstituted ammonium group in which the three substituents are independently aryl, ar-C1-C6-alkyl or C1-C6-alkyl.
  • R[0101] 20 is (a)—O—R21, where R21 is selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl group and a pharmaceutically acceptable cation, (b)—NH—O—R22 wherein R22 is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), carbonyl-C1-C6-alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide synthesis resin and the like, wherein the trisubstituted silyl group is substituted with C1-C6-alkyl, aryl, or ar-C1-C6-alkyl or a mixture thereof, (c)—NH—O—R14, where R14 is hydrido, a pharmaceutically acceptable cation or C(W)R25 where W is O (oxo) or S (thioxo) and R25 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino C1-C6-alkyl group wherein the amino C1-C6-alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or (d) —NR26R27, where R26 and R27 are independently selected from the group consisting of a hydrido, C1-C6-alkyl, amino C1-C6-alkyl, hydroxy C1-C6-alkyl, aryl, ar-C1-C6-alkyl group, or R26 and R27 together with the depicted nitrogen atom form a 5- to 8-membered ring containing zero or one additional heteroatom that is oxygen, nitrogen or sulfur.
  • A particularly preferred precursor intermediate to an intermediate compound of formula VI is an intermediate compound of formula VII [0102]
    Figure US20040235818A1-20041125-C00014
  • wherein m, n, p, g, X, Z, Y, D and R[0103] 20 are as defined above for formula VI.
  • Among the several benefits and advantages of the present invention are the provision of compounds and compositions effective as inhibitors of matrix metalloproteinase activity, the provision of such compounds and compositions that are effective for the inhibition of metalloproteinases implicated in diseases and disorders involving uncontrolled breakdown of connective tissue. [0104]
  • More particularly, a benefit of this invention is the provision of a compound and composition effective for selectively inhibiting certain metalloproteinases, such as one or more of MMP-2, MMP-9 and MMP-13, associated with pathological conditions such as, for example, rheumatoid arthritis osteoarthritis, septic arthritis, corneal, epidermal or gastric ulceration, tumor metastasis, invasion or angiogenesis, periodontal disease, proteinuria, Alzheimer's Disease, coronary thrombosis and bone disease. [0105]
  • An advantage of the invention is the provision of compounds, compositions and methods effective for treating such pathological conditions by selective inhibition of a metalloproteinase such as MMP-2, MMP-9 or MMP-13 associated with such conditions with minimal side effects resulting from inhibition of other metalloproteinases, such as MMP-1, whose activity is necessary or desirable for normal body function. [0106]
  • Yet another advantage of the invention is the provision of a process for preparing such compounds. [0107]
  • Another benefit is the provision of a method for treating a pathological condition associated with abnormal matrix metalloproteinase activity. [0108]
  • A further advantage of the invention is the provision of a process for preparing such compositions. [0109]
  • Still further benefits and advantages of the invention will be apparent to the skilled worker from the disclosure that follows.[0110]
    • DETAILED DESCRIPTION OF THE INVENTION
  • In accordance with the present invention, it has been discovered that certain aromatic sulfone hydroxamic acids (hydroxamates) are effective for inhibition of matrix metalloproteinases (“MMPs”) believed to be associated with uncontrolled or otherwise pathological breakdown of connective tissue. In particular, it has been found that these certain aromatic sulfone hydroxamates are effective for inhibition of one or more enzymes such as MMP-2, MMP-9 and MMP-13, which can be particularly destructive to tissue if present or generated in abnormal quantities or concentrations, and thus exhibit a pathological activity. Included in that pathological activity is the assistance of tumors and tumor cells in the process of penetrating basement membrane, and developing a new or improved blood supply; i.e., angiogenesis. [0111]
  • Moreover, it has been discovered that these aromatic sulfone hydroxamates are selective in the inhibition of one or more of MMP-2, MMP-9 and MMP-13 without excessive inhibition of other collagenases essential to normal bodily function such as tissue turnover and repair. More particularly, it has been found that a contemplated aromatic sulfone hydroxamate of the invention, or a pharmaceutically acceptable salt thereof, is particularly active in inhibiting of one or more of MMP-2, MMP-9 and MMP-13 in an in vitro assay that is predictive of in vivo activity. In addition, while being selective for one or more of MMP-2, MMP-9 and MMP-13, a contemplated aromatic sulfone hydroxamate, or its salt, has a limited or minimal in vitro inhibitory effect on MMP-1. [0112]
  • There is thus a substantial difference in the activity of a compound used in a contemplated process toward one or more of MMP-2, MMP-9 and MMP-13 and MMP-1. This substantial difference is assayed using the in vitro inhibition assay discussed in the examples. A substantial difference in activity corresponds to a compound exhibiting an IC[0113] 50 value against one or more of MMP-2, MMP-9 and MMP-13 that is about 0.1 times that of the compound against MMP-1, and more preferably 0.01 times that against MMP-1 and most preferably 0.001 times that against MMP-1, or more. Indeed, some compounds exhibit selectivity differences measured by IC50 values that exceed the bounds of the assay at the number 100,000-fold. These selectivities are illustrated in the Inhibition Tables hereinafter.
  • Put differently, a contemplated compound can inhibit the activity of MMP-2 compared to MMP-9 or MMP-13 and MMP-1. Similarly, a contemplated compound can inhibit the activity of MMP-13 and MMP-2, while exhibiting less inhibition against MMP-1 and MMP-9. In addition, a contemplated compound can inhibit the activity of a MMP enzyme, while having less of an effect on tumor necrosis factor release. [0114]
  • The advantages of the selectivity of a contemplated compound can be appreciated, without wishing to be bound by theory, by considering the therapeutic uses the compounds. For example, inhibition of MMP-1 is suggested to be undesirable due to its role as a housekeeping enzyme, helping to maintain normal connective tissue turnover and repair. Inhibition of MMP-1 can lead to toxicities or side effects such as such as joint or connective tissue deterioration and pain. On the other hand, MMP-13 has been suggested to be intimately involved in the destruction of joint components in diseases such as osteoarthritis. Thus, potent and selective inhibition of MMP-13 compared with inhibition MMP-1 is highly desirable because a MMP-13 inhibitor can have a positive effect on disease progression in a patient in addition to having an anti-inflammatory effect. [0115]
  • Inhibition of MMP-2 and MMP-9 can be desirable for inhibition of tumor growth, metastasis, invasion and/or angiogenesis. A profile of selective inhibition of MMP-2 and MMP-9 relative to MMP-1 can provide a therapeutic advantage. [0116]
  • Yet another advantage of a contemplated compound is the selectivity with respect to tumor necrosis factor release and/or tumor necrosis factor receptor release that provides the physician with another factor to help select the best drug for a particular patient. While not wishing to be bound by theory, it is believed that there are several factors to this type of selectivity to be considered. [0117]
  • The first is that presence of tumor necrosis factor can be desirable for the control of cancer in the organism, so long as TNF is not present in a toxic excess. Thus, uncontrolled inhibition of release of TNF cad be counterproductive and actually can be considered an adverse side effect even in cancer patients. In addition, selectivity with respect to inhibition of the release of the tumor necrosis factor receptor can also be desirable. The presence of that receptor can be desirable for maintaining a controlled tumor necrosis level in the mammal by binding excess TNF. [0118]
  • A contemplated selective MMP inhibitor compound useful in a contemplated process can be administered to by various routes and provide adequate therapeutic blood levels of enzymatically active inhibitor. A compound can be administered, for example, by the oral (IG, PO) or intravenous (IV) routes. Oral administration is advantageous if the patient is ambulatory, not hospitalized, physically able and sufficiently-responsible to take drug at the required intervals. This is true even if the person is being treated with more than one drug for one or more diseases. On the other hand, IV drug administration is an advantage in a hospital setting wherein the dose and thus the blood levels can well controlled. A contemplated inhibitor can also be formulated for IM administration if desired. This route of administration can be desirable for the administration of prodrugs or regular drug delivery to patients that are either physically weak or have a poor compliance record or require constant drug blood levels. [0119]
  • Thus, in one embodiment, the present invention is directed to a treatment process that comprises administering a contemplated aromatic sulfone hydroxamic acid metalloprotease inhibitor, or a pharmaceutically acceptable salt thereof, in an effective amount to a host mammal having a condition associated with pathological matrix metalloprotease activity. A contemplated aromatic sulfone hydroxamate inhibitor compound useful in such a process inhibits the activity of one or more of MMP-2, MMP-9 and MMP-13, and exhibits substantially less inhibitory activity against at least MMP-1 in the in vitro assay noted above and discussed in detail hereinbelow. An aromatic sulfone hydroxamate inhibitor compound for use in a contemplated process corresponds in structure to formula I, below: [0120]
    Figure US20040235818A1-20041125-C00015
  • wherein [0121]
  • In one embodiment, R[0122] 1 and R2 are both hydrido. In another embodiment, R1 and R2 together with the atoms to which they are bonded form a 5- to 8-membered ring containing one, two or three heteroatoms in the ring that are oxygen, sulfur or nitrogen.
  • It is preferred that R[0123] 1 and R2 together with the atoms to which they are bonded form a five-to eight-membered ring that contains one or two heteroatoms in the ring, although R1 and R2 together with the atoms to which they are bonded form a 5- to 8-membered ring containing one, two or three heteroatoms. The heterocyclic ring can itself also be substituted with up to six C1-C6-alkyl groups or groups that comprise a another 5- to 8-membered carbocyclic or heterocyclic ring, an amino group, or contain one or two oxo (carbonyl) groups.
  • R[0124] 3 in formula I is an optionally substituted aryl or optionally substituted heteroaryl radical. That R3 radical is selected from the group consisting of an aryl, heteroaryl, aralkyl, heteroaralkyl, aralkoxy, heteroaralkoxy, aralkoxyalkyl, aryloxyalkyl, aralkanoylalkyl, arylcarbonylalkyl, aralkylaryl, aryloxyalkylaryl, aralkoxyaryl, arylazoaryl, arylhydrazinoaryl, alkylthioaryl, arylthioalkyl, alkylthioaralkyl, aralkylthioalkyl, an aralkylthioaryl radical, the sulfoxide or sulfone of any of the thio substituents, and a fused ring structure comprising two or more 5- or 6-membered rings selected from the group consisting of aryl, heteroaryl, carbocyclic and heterocyclic.
  • The substituent of which R[0125] 3 is comprised itself is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a cyano, perfluoroalkyl, trifluoromethylalkyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy, aralkylthio, aralkylamino, heterocyclo, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino,
  • wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of an alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl and an alkanoyl group, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring containing zero to two additional heteroatoms that are nitrogen, oxygen or sulfur and which ring itself is (a) unsubstituted or (b) substituted with one or two groups independently selected from the group consisting of an aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzofused heterocycloalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofused heterocycloalkoxy, benzofused cycloalkylcarbonyl, heterocyclo-alkylcarbonyl, and a cycloalkylcarbonyl group, carbonylamino [0126]
  • wherein the carboxamido nitrogen is (i) unsubstituted, or (ii) is the reacted amine of an amino acid, or (iii) substituted with one or two radicals selected from the group consisting of an alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzofused heterocycloalkyl, benzofused heterocycloalkyl, benzofused cycloalkyl, and an N,N-dialkylsubstituted alkylamino-alkyl group, or (iv) the carboxamido nitrogen and two substituents bonded thereto together form a 5- to 8-membered heterocyclo, heteroaryl or benzofused heterocycloalkyl ring that is itself unsubstituted or substituted with one or two radicals independently selected from the group consisting of an alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl and an amino group, [0127]
  • wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of alkyl, aryl, and heteroaryl, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, and an aminoalkyl-group [0128]
  • wherein the aminoalkyl nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents independently selected from the group consisting of an alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and an alkanoyl group, or (iii) wherein the aminoalkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring. A compound of formula I can also be used in the form of a pharmaceutically acceptable salt. [0129]
  • The R[0130] 3 radical has a length that is greater than that of a pentyl group [a —(CH2)4CH3 chain], is more preferably greater than about the length of a hexyl group [a —(CH2)5CH3 chain), and most preferably is greater than about the length of an octyl group [a —(CH2)7CH3 chain]. A R3 group has a length that is less than that of an icosyl group [eicosyl; a —(CH2)19CH3 chain), and more preferably, a length that is less than that of a stearyl group [a —(CH2)17CH3 chain). When rotated about an axis drawn through the SO2-bonded 1-position and the substituent-bonded 4-position of a 6-membered ring or the SO2-bonded 1-position and substituent-bonded 3- or 4-position of a 5-membered ring, a contemplated R3 radical defines a three-dimensional volume whose widest dimension has the width of about one furanyl ring to about two phenyl rings in a direction transverse to that axis to rotation.
  • A compound of formula I is a compound of more general formula A, wherein R[0131] 3, R1 and R2 are as defined before and R20 is defined below.
    Figure US20040235818A1-20041125-C00016
  • The substituent R[0132] 20 is (a)—O—R21, where R21 is selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl group and a pharmaceutically acceptable cation, (b)—NH—O—R22 wherein R22 is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), carbonyl-C1-C6-alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide synthesis resin and the like, wherein the trisubstituted silyl group is substituted with C1-C6-alkyl, aryl, or ar-C1-C6-alkyl or a mixture thereof, (c) —NH—O—R14, where R14 is hydrido, a pharmaceutically acceptable cation or C(W)R25 where W is 0 (oxo) or S (thioxo) and R25 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino C1-C6-alkyl group wherein the amino C1-C6-alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or (d)—NR26R27, where R26 and R27 are independently selected from the group consisting of a hydrido, C1-C6-alkyl, amino C1-C6-alkyl, hydroxy C1-C6-alkyl, aryl, ar-C1-C6-alkyl group, or R26 and R27 together with the depicted nitrogen atom form a 5- to 8-membered ring containing zero or one additional heteroatom that is oxygen, nitrogen or sulfur.
  • Several exemplary R[0133] 1 and R2 groups that together form a contemplated heterocyclic ring are shown in the Tables that follow hereinafter, as well as in the descriptions of those 5- to 8-membered rings and the specific Examples, as are several contemplated aromatic sulfone hydroxamic acid compounds.
  • In more preferred practice, R[0134] 1 and R2 of formula I or formula A together with the atom to which they are bonded form a 5- to 8-membered ring that contains one, two or three heteroatoms. Most preferably, that ring is a 6-membered ring that contains one heteroatom located at the 4-position relative to the position at which the SO2 group is bonded. Other preferred compounds for use in a contemplated process correspond in structure to one or more of formulas II, III, IV or V, which are discussed hereinafter.
  • In one embodiment, a preferred compound used in a contemplated process has a structure that corresponds to formula II, below: [0135]
    Figure US20040235818A1-20041125-C00017
  • wherein [0136]
  • R[0137] 14 is hydrido, a pharmaceutically acceptable cation or C(W)R15 where W is O or S and R15 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring;
  • m is zero, 1 or 2; [0138]
  • n is zero, 1 or 2; [0139]
  • p is zero, 1 or 2; [0140]
  • the sum of m+n+p=1, 2, 3 or 4; [0141]
  • (a) one of X, Y and Z is selected from the group consisting of C(O), NR[0142] 6, O, S, S(O), S(O)2 and NS(O)2R7, and the remaining two of X, Y and Z are CR8R9, and CR10R11, or
  • (b) X and Z or Z and Y together constitute a moiety that is selected from the group consisting of NR[0143] 6C(O), NR6S(O), NR6S(O)2, NR6S, NR6O, SS, NR6NR6 and OC(O), with the remaining one of X, Y and Z being CR8R9, or
  • (c) n is zero and X, Y and Z together constitute a moiety selected from the group consisting of [0144]
    Figure US20040235818A1-20041125-C00018
  • wherein wavy lines are bonds to the atoms of the depicted ring; [0145]
  • R[0146] 6 and R6′ are independently selected from the group consisting of hydrido, formyl, sulfonic-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, C1-C6-alkylcarbonyl-C1-C6-alkyl, R8R9-aminocarbonyl-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkylcarbonyl, hydroxycarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkylcarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C1-C6-alkylcarbonylcarbonyl, R8R9-aminocarbonylcarbonyl, C1-C6-alkanoyl, aryl-C1-C6-alkyl, aroyl, bis(C1-C6-alkoxy-C1-C6-alkyl)-C1-C6-alkyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-perfluoroalkyl, C1-C6-trifluoromethylalkyl, C1-C6-perfluoroalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, heteroarycarbonyl, heterocyclocarbonyl, C3-C8-heterocycloalkyl, C3-C8-heterocycloalkylcarbonyl, aryl, C5-C6-heterocyclo, C5-C6-heteroaryl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkoxy-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, arylsulfonyl, C1-C6-alkylsulfonyl, C5-C6-heteroarylsulfonyl, carboxy-C1-C6-alkyl, C1-C4-alkoxycarbonyl-C1-C6-alkyl, aminocarbonyl, C1-C6-alkyl(R8N)iminocarbonyl, aryl(R8N)iminocarbonyl, C5-C6-heterocyclo(R8N)iminocarbonyl, arylthio-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C3-C6-alkenyl, C1-C4-alkylthio-C3-C6-alkenyl, C5-C6-heteroaryl-C1-C6-alkyl, halo-C1-C6-alkanoyl, hydroxy-C1-C6-alkanoyl, thio]-C1-C6-alkanoyl, C3-C6-alkenyl, C3-C6-alkynyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C5-alkoxycarbonyl, aryloxycarbonyl, NR8R9—(R8)iminomethyl; NR8R9—C1-C5-alkylcarbonyl, hydroxy-C1-C5-alkyl, R8R9-aminocarbonyl, R8R9-aminocarbonyl-C1-C6-alkylcarbonyl, hydroxyaminocarbonyl, R8R9-aminosulfonyl, R8R9-aminosulfon-C1-C6-alkyl, R8R9-amino-C1-C6-alkylsulfonyl and an R8R9-amino-C1-C6-alkyl group;
  • R[0147] 7 is selected from the group consisting of a arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl and a C1-C6-hydroxyalkyl group;
  • R[0148] 8 and R9 and R10 and R11 are independently selected from the group consisting of a hydrido, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroar-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aralkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl, or wherein R8 and R9 or R10 and R11 and the carbon to which they are bonded form a carbonyl group, or wherein R8 and R9 or R10 and R11, or R8 and R10 together with the atoms to which they are bonded form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclic or heteroaryl ring containing one or two heteroatoms that are nitrogen, oxygen, or sulfur, with the proviso that only one of R8 and R9 or R10 and R11 is hydroxy;
  • R[0149] 12 and R12′ are independently selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroaralkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aryloxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl;
  • R[0150] 13 is selected from the group consisting of a hydrido, benzyl, phenyl, C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl and a C1-C6-hydroxyalkyl group; and
  • G-A-R-E-Y is a substituent that preferably as a length greater than that of a pentyl group, and ore preferably has a length greater than that of a hexyl group. The substituent G-A-R-E-Y preferably has a length that is less than that of an icosyl group, and is more preferably less than that of a stearyl group. In this substituent: [0151]
  • G is an aryl or heteroaryl group; [0152]
  • A is selected from the group consisting of [0153]
  • (1) —O—; [0154]
  • (2) —S—; [0155]
  • (3) —NR[0156] 17—;
  • (4) —CO—N(R[0157] 17) or —N(R17)—CO—, wherein R17 is hydrogen, C1-C4-alkyl, or phenyl;
  • (5) —CO—O— or —O—CO—; [0158]
  • (6) —O—CO—O—; [0159]
  • (7) —HC═CH—; [0160]
  • (8) —NH—CO—NH—; [0161]
  • (9) —C≡C—; [0162]
  • (10) —NH—CO—O— or —O—CO—NH—; [0163]
  • (11) —N═N—; [0164]
  • (12) —NH—NH—; and [0165]
  • (13) —CS—N(R[0166] 18)— or —N(R18)—CS—, wherein
  • R[0167] 18 is hydrogen C1-C4-alkyl, or phenyl; or
  • (14) A is absent and G is bonded directly to R; [0168]
  • R is a moiety selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C[0169] 1-C2-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group, and R is other than alkyl or alkoxyalkyl when A is —O— or —S—;
  • E is selected from the group consisting of [0170]
  • (1) —CO(R[0171] 19)— or —(R19)CO—, wherein R19 is a heterocycloalkyl, or a cycloalkyl group;
  • (2) —CONH— or —HNCO—; and [0172]
  • (3) —CO—; [0173]
  • (4) —SO[0174] 2—R19— or —R19—SO2—;
  • (5) —SO[0175] 2—;
  • (6) —NH—SO[0176] 2— or —SO2—NH—;
  • (7) —S—; [0177]
  • (8) —NH—CO—O— or —O—CO—NH—; or [0178]
  • (9) E is absent and R is bonded directly to Y; and [0179]
  • the moiety Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl, aralkyl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of an alkanoyl, halo, nitro, aralkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy and an amino group wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group. [0180]
  • The substituent -G-A-R-E-Y preferably contains two to four carbocyclic or heterocyclic rings, including the aryl or heteroaryl group, G. More preferably, each of those rings is 6-membered. Additional separate preferences for a compound of formula II include: (a) that A is —O— or —S—, (b) R is an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, (c) E is absent, and (d) Y is selected from the group consisting of hydrido, an alkyl, alkoxy, perfluoroalkoxy and a perfluoroalkylthio group. [0181]
  • A more preferred compound for use in a contemplated process has a structure that corresponds to formula III, below: [0182]
    Figure US20040235818A1-20041125-C00019
  • wherein R[0183] 3 is a single-ringed aryl or heteroaryl group that is 5- or 6-membered, and is itself substituted at its own 4-position when a 6-membered ring and at its own 3- or 4-position when a 5-membered ring with a substituent selected from the group consisting of a thiophenoxy, 4-chloro-phenoxy, 3-chlorophenoxy, 4-methoxyphenoxy, 3-benzodioxol-5-yloxy, 3,4-dimethylphenoxy, 4-fluoro-phenoxy, 4-fluorothiophenoxy, phenoxy, 4-trifluoro-methoxyphenoxy, 4-trifluoromethylphenoxy, 4-(trifluoromethylthio)phenoxy, 4-(trifluoromethyl-thio)thiophenoxy, 4-chloro-3-fluorophenoxy, 4-isopropoxyphenoxy, 4-isopropylphenoxy, (2-methyl-1,3-benzothiazol-5-yl)oxy, 4-(1H-imidazol-1-yl)phenoxy, 4-chloro-3-methylphenoxy, 3-methyl-phenoxy, 4-ethoxyphenoxy, 3,4-difluorophenoxy, 4-chloro-3-methylphenoxy, 4-fluoro-3-chlorophenoxy, 4-(1H-1,2,4-triazol-1-yl)phenoxy, 3,5-difluorophenoxy, 3,4-dichlorophenoxy, 4-cyclopentylphenoxy, 4-bromo-3-methylphenoxy, 4-bromophenoxy, 4-methylthiophenoxy, 4-phenylphenoxy, 4-benzylphenoxy, 6-quinolinyloxy, 4-amino-3-methylphenoxy, 3-methoxyphenoxy, 5,6,7,8-tetrahydro-2-naphthalenyloxy, 3-hydroxymethylphenoxy, and a 4-benzyloxyphenoxy group;
  • R[0184] 14 is hydrido, a pharmaceutically acceptable cation or C(W)R15 where W is O or S and R15 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and a C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring;
  • m is zero, 1 or 2; [0185]
  • n is zero, 1 or 2; [0186]
  • p is zero, 1 or 2; [0187]
  • the sum of m+n+p 1, 2, 3 or 4; [0188]
  • (a) one of X, Y and Z is selected from the group consisting of C(O), NR[0189] 6, O, S, S(O), S(O)2 and NS(O)2R7, and the remaining two of X, Y and Z are CR8R9, and CR10R11, or
  • (b) X and Z or Z and Y together constitute a moiety that is selected from the group consisting of NR[0190] 6C(O), NR6S(O), NR6S(O)2, NR6S, NR6O, SS, NR6NR6 and OC(O), with the remaining one of X, Y and Z being CR8R9, or
  • (c) n is zero and X, Y and Z together constitute a moiety selected from the group consisting of [0191]
    Figure US20040235818A1-20041125-C00020
  • wherein wavy lines are bonds to the atoms of the depicted ring; [0192]
  • R[0193] 6 and R6′ are independently selected from the group consisting of hydrido, formyl, sulfonic-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, C1-C6-alkylcarbonyl-C1-C6-alkyl, R8R9-aminocarbonyl-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkylcarbonyl, hydroxycarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkylcarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C1-C6-alkylcarbonylcarbonyl, R8R9-aminocarbonylcarbonyl, C1-C6-alkanoyl, aryl-C1-C6-alkyl, aroyl, bis(C1-C6-alkoxy-C1-C6-alkyl)-C1-C6-alkyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-perfluoroalkyl, C1-C6-trifluoromethylalkyl, C1-C6-perfluoroalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6 alkyl, C3-C6-cycloalkyl, heteroarycarbonyl, heterocyclocarbonyl, C3-C8-heterocycloalkyl, C3-C8-heterocycloalkylcarbonyl, aryl, C5-C6-heterocyclo, C5-C6-heteroaryl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkoxy-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, arylsulfonyl, C1-C6-alkylsulfonyl, C5-C6-heteroarylsulfonyl, carboxy-C1-C6-alkyl, C1-C4-alkoxycarbonyl-C1-C6-alkyl, aminocarbonyl, C1-C6-alkyl(R8N)iminocarbonyl, aryl(R8N)iminocarbonyl, C5-C6-heterocyclo(R8N)iminocarbonyl, arylthio-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C3-C6-alkenyl, C1-C4-alkylthio-C3-C6-alkenyl, C5-C6-heteroaryl-C1-C6-alkyl, halo-C1-C6-alkanoyl, hydroxy-C1-C6-alkanoyl, thiol-C1-C6-alkanoyl, C3-C6-alkenyl, C3-C6-alkynyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C5-alkoxycarbonyl, aryloxycarbonyl, NR8R9—(R8)iminomethyl, NR8R9—C1-C5-alkylcarbonyl, hydroxy-C1-C5-alkyl, R8R9-aminocarbonyl, R8R9-aminocarbonyl-C1-C6-alkylcarbonyl, hydroxyaminocarbonyl, R8R9-aminosulfonyl, R8R9-aminosulfon-C1-C6-alkyl, R8R9-amino-C1-C6-alkylsulfonyl and an R8R9-amino-C1-C6-alkyl group;
  • R[0194] 7 is selected from the group consisting of a arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl and a C1-C6-hydroxyalkyl group;
  • R[0195] 8 and R9 and R10 and R11 are independently selected from the group consisting of a hydrido, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroar-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aralkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl, or wherein R8 and R9 or R10 and R11 and the carbon to which they are bonded form a carbonyl group, or wherein R8 and R9 or R10 and R11, or R8 and R10 together with the atoms to which they are bonded form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclic or heteroaryl ring containing one or two heteroatoms that are nitrogen, oxygen, or sulfur, with the proviso that only one of R8 and R9 or R10 and R11 is hydroxy;
  • R[0196] 12 and R12′ are independently selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroaralkyl, C2-C6-alkynyl, C2-C6-alkenyl, thio]-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aryloxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl; and
  • R[0197] 13 is selected from the group consisting of a hydrido, benzyl, phenyl, C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl and a C1-C6-hydroxyalkyl group. Again, the use of a compound of formula III as a pharmaceutically acceptable salt is also contemplated.
  • Preferences related to a compound of formula III that also apply to a compound of formula II include the following, which are independently preferred: (a) the sum of m+n+p=1 or 2, and more preferably 2; (b) Z is O, S or NR[0198] 6; (c) R6 is selected from the group consisting of C3-C6-cycloalkyl, C1-C6-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C1-C6-alkoxy-C1-C6-alkyl, amino-C1-C6-alkyl, aminosulfonyl, heteroaryl-C1-C6-alkyl, aryloxycarbonyl, and C1-C6-alkoxycarbonyl; and (d) m=n=zero, p=1, and Y is NR6. Another preference for a compound of both of formulas II and III is that R14 be hydrido, or that W of the C(W)R15 pro-drug form be 0 and R15 be a C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, or aryloxy group.
  • A still more preferred compound for use in a contemplated process corresponds in structure to formula IV, below: [0199]
    Figure US20040235818A1-20041125-C00021
  • Here, R[0200] 3 is as defined above as to formulas I, III and more preferably as defined as to formula II (wherein the R3 radical is the substituent G-A-R-E-Y). Most preferably, R3 is as defined in formula III.
  • Z is selected group the group consisting of O, S, NR[0201] 6, SO, SO2, and NSO2R7,
  • wherein R[0202] 6 is selected from the group consisting of hydrido, C1-C5-alkyl, C1-C5-alkanoyl, benzyl, benzoyl, C3-C5-alkynyl, C3-C5-alkenyl, C1-C3-alkoxy-C1-C4-alkyl, C3-C6-cycloalkyl, heteroaryl-C1-C6-alkyl, C1-C5-hydroxyalkyl, C1-C5-carboxyalkyl, C1-C5-alkoxy C1-C5-alkylcarbonyl, and NR8R9—C1-C5-alkylcarbonyl or NR8R9—C1-C5-alkyl wherein R8 and R9 are independently hydrido, C1-C5-alkyl, C1-C5-alkoxycarbonyl or aryl-C1-C5-alkoxycarbonyl, or NR8R9 together form a heterocyclic ring containing 5- to 8-atoms in the ring; and
  • R[0203] 7 is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl and a C1-C6-hydroxyalkyl group. Most preferably, Z is O or NR6. Here too, the use of a compound of formula IV as a pharmaceutically acceptable salt is contemplated.
  • A still more preferred group of contemplated compounds for use in a contemplated process correspond in structure to formula V, below; [0204]
    Figure US20040235818A1-20041125-C00022
  • wherein [0205]
  • Z is as previously defined for formula IV; [0206]
  • W and Q are independently oxygen (O), NR[0207] 6 or sulfur (S), and R6 is as defined in formula IV; and
  • q is zero or one such that when q is zero, Q is absent and the trifluoromethyl group is bonded directly to the depicted phenyl ring. Here again, the use of a compound of formula IV as a pharmaceutically acceptable salt is contemplated. [0208]
  • Further compounds of formula A are also particularly preferred. One group of these compounds corresponds in structure to formula B, formula VIC, and more still particularly to formula VIC-1 and formula VIC-2, and formula VIII, below. In those formulas, ring structure Q including the depicted nitrogen atom is a heterocylic ring that contains 5- or 7-members, preferably 6-members, and can contain zero or one nitrogen atom in addition to that depicted. The members of substituent -A-R-E-Y (or —R-E-Y or -E-Y) are as defined elsewhere in the definition of the members of the substituent -G-A-R-E-Y. Furthermore, substituent -A-R-E-Y (or substituent —R-E-Y or -E-Y) is bonded at the 4-position relative to that depicted nitrogen atom when Q is a 6- or 7-membered ring and at the 3- or 4-position relative to that depicted nitrogen when Q is a 5-membered ring. Still fruther, R[0209] 20, X, Y, Z, m, n, and p of the ring system and g are as before described.
    Figure US20040235818A1-20041125-C00023
    Figure US20040235818A1-20041125-C00024
  • More particularly preferred among the compounds of formula VIC, formula VIC-1, formula VIC-2, and formula VIII, are the compounds of formulas IX, IX-1, IX-2, X, XI, XI-1, XI-2 and XII, below, wherein Z is as before described and the members of substituent group -E-Y and —R-E-Y are as defined for the substituent group -G-A-R-E-Y. [0210]
    Figure US20040235818A1-20041125-C00025
    Figure US20040235818A1-20041125-C00026
  • The use of a compound of formulas A and I-VI, VI VIC, VIC-1, VIC-2, VIII, IX, IX-1, IX-2 and X, or a pharmaceutically acceptable salt of one of those compounds is contemplated in a before-described process. In addition, the compounds of those formulas and their pharmaceutically acceptable salts are contemplated compounds of this invention. [0211]
  • Particularly preferred compounds within the group defined by formula B have the structural formulas shown below: [0212]
    Figure US20040235818A1-20041125-C00027
  • Several particularly preferred compounds whose structures correspond to formulas I through XII are illustrated in the Tables and examples provided hereinafter. [0213]
  • As was noted before, the compounds of formulas I-XII, and their pharmaceutically acceptable salts are themselves contemplated compounds of the invention. [0214]
  • In preferred practice, an SO[0215] 2-linked R3 radical is an aryl or heteroaryl group that is a 5- or 6-membered single-ring that is itself substituted with one other single-ringed aryl or heteroaryl group or, with an alkyl or alkoxy group having a chain length of 3 to about 16 carbon atoms (and more preferably a length of up to about 14 carbon atoms), a phenoxy group, a thiophenoxy (C6H5—S—] group, a phenylazo [C6H5—N2—] group, a N-piperidyl [C5H10N—] group, a N-piperazyl [NC4H9N—] group or a benzamido [—NHC(O)C6H5] group. The SO2-linked single-ringed aryl or heteroaryl R3 group here is substituted at its own 4-position when a 6-membered ring and at its own 3- or 4-position when a 5-membered ring.
  • The SO[0216] 2-linked aryl or heteroaryl group of a R3 radical is preferably itself substituted at the 4-position when a 6-membered ring or the 3- or 4-position when a 5-membered ring. A particularly preferred substituent is a single-ringed aryl or heteroaryl, phenoxy, thiophenoxy, phenylazo, N-piperidyl, N-piperazyl or benzamido group that is unsubstituted or can itself be substituted.
  • The 4- and 3-positions of rings discussed here are numbered from the sites of substituent bonding as compared to formalized ring numbering positions used in heteroaryl nomenclature, as is discussed further hereinbelow. Here, single atoms such as halogen moieties (fluoro, chloro, bromo, or iodo) or substituents that contain one to a chain length of about five atoms other than hydrogen such as phenyl, C[0217] 1-C4 alkyl, trifluoromethyl, trifluoromethoxy, trifluorothiomethyl or carboxyethyl groups are preferred, although longer substituents can be accommodated up to a total length of an icosyl group.
  • Exemplary particularly preferred substituted SO[0218] 2-linked R3 radicals include 4-(phenyl)phenyl [biphenyl], 4-(4′-methoxyphenyl)-phenyl, 4-(phenoxy)phenyl, 4-(thiophenyl)phenyl [4-(phenylthio)phenyl], 4-(azophenyl)phenyl, 4-[(4′-trifluoromethylthio)phenoxy]phenyl, 4-[(4′-trifluoromethylthio)thiophenyl]phenyl, 4-[(4′-trifluoromethyl)phenoxy]phenyl, 4-[(4′-trifluoromethyl)thiophenyl]phenyl, 4-[(4′-trifluoromethoxy)phenoxy]phenyl, 4-[(4′-trifluoromethoxy)thiophenyl]phenyl, 4-[(4′-phenyl)N-piperidyl]phenyl, 4-[(4′-acetyl)N-piperazyl]phenyl and 4-(benzamido)phenyl.
  • Inasmuch as a contemplated SO[0219] 2-linked aryl or heteroaryl radical of an R3 group is itself preferably substituted with a 6-membered ring, two nomenclature systems are used together herein for ease in understanding substituent positions. The first system uses position numbers for the ring directly bonded to the SO2-group, whereas the second system uses ortho, meta or para for the position of one or more substituents of a 6-membered ring bonded to a SO2-linked aryl or heteroaryl radical. Although ortho, meta and para positional nomenclature is normally not used with aliphatic ring systems, it is believed more readily understood for describing the present compounds when used in conjunction with the numerical system for the first ring bonded to the SO2-group. When a R3 radical is other than a 6-membered ring, substituent positions are numbered from the position of linkage to the aromatic or heteroaromatic ring. Formal chemical nomenclature is used in naming particular compounds.
  • Thus, the 1-position of an above-discussed SO[0220] 2-linked aryl or heteroaryl group is the position at which the SO2-group is bonded to the ring. The 4- and 3-positions of rings discussed here are numbered from the sites of substituent bonding from the SO2-linkage as compared to formalized ring numbering positions used in heteroaryl nomenclature.
  • When examined along its longest chain of atoms, an R[0221] 3 radical including its own substituent has a total length that is greater than a saturated chain of five carbon atoms (a pentyl group), and preferably has a length greater than that of a saturated chain of six carbon atoms (a hexyl group); i.e., a length of about a heptyl chain or longer. An R3 radical also has a length that is less than that of a saturated chain of about 20 carbon atoms [an icosyl group (icosyl was formerly spelled eicosyl)] and more preferably about 18 carbon atoms (a stearyl group). Most preferably, the length of R3 is about that of an 8 to about 12 carbon atom chain, even though many more atoms may be present in ring structures or substituents. This length requirement is discussed further below.
  • Looked at more generally, and aside from specific moieties from which it is constructed, an R[0222] 3 radical (group or moiety) has a length that is greater than that of a pentyl group. Such an R3 radical also has a length that is less than that of an icosyl (didecyl) group. That is to say that R3 is a radical having a minimal length longer that a saturated five carbon chain, and preferably greater than a hexyl group, but is shorter than the length of a saturated twenty carbon atom chain, and preferably shorter than an eighteen carbon chain. Most preferably, R3 has a length greater than that of an octyl group and less than that of a lauryl group.
  • More specifically, an R[0223] 3 group has a minimal length of a hexyl group only when that substituent is comprised of two rings that can be fused or simply covalently linked together by exocyclic bonding. When R3 does not contain two linked or fused rings, e.g., where a R3 radical includes an alkyl or second, third or fourth ring substituent, R3 has a length that is greater than that of a hexyl group. Exemplary of such two ring R3 groups are a 2-naphthyl group or a 2-quinolinyl group (each with a six carbon chain length) and 8-purinyl (with a five carbon atom chain length). Without wishing to be bound by theory, it is believed that the presence of multiple rings in R3 enhances selectivity of the enzyme activity inhibitor profile.
  • The radical chain lengths are measured along the longest linear atom chain in the radical, following the skeletal atoms around a ring where necessary. Each atom in the chain, e.g. carbon, oxygen, sulfur or nitrogen, is presumed to be carbon for ease in calculation. [0224]
  • Such lengths can be readily determined by using published bond angles, bond lengths and atomic radii, as needed, to draw and measure a desired, usually staggered, chain, or by building models using commercially available kits whose bond angles, lengths and atomic radii are in accord with accepted, published values. Radical (substituent) lengths can also be determined somewhat less exactly by assuming that all atoms have bond lengths saturated carbon, that unsaturated bonds have the same lengths as saturated bonds and that bond angles for unsaturated bonds are the same as those for saturated bonds, although the above-mentioned modes of measurement are preferred. For example, a phenyl or pyridyl group has a length of a four carbon chain, as does a propoxy group, whereas a biphenyl group has a length of about an eight carbon chain using such a measurement mode. [0225]
  • In addition, a R[0226] 3 group when rotated about an axis drawn through the SO2-bonded 1-position and the 4-position of a 6-membered ring or the SO2-bonded position and substituent-bonded 3- or 4-position of a 5-membered ring defines a three-dimensional volume whose widest dimension has the width of about one furanyl ring to about two phenyl rings in a direction transverse to that axis to rotation.
  • Thus, a 2-naphthyl substituent or an 8-purinyl substituent is an appropriately sized R[0227] 3 group when examined using the above rotational width criterion as well as the before-discussed criterion. On the other hand, a 1-naphthyl group or a 7- or 9-purinyl group is too wide upon rotation and is excluded from being an R3 group.
  • As a consequence of these length and width requirements, R[0228] 3 radicals such as 4-(phenyl)phenyl [biphenyl], 4-(4′-methoxyphenyl)-phenyl, 4-(phenoxy)phenyl, 4-(thiophenyl)phenyl [4-(phenylthio)phenyl], 4-(azophenyl)phenyl, 4-[(4′-trifluoromethylthio)phenoxy]phenyl, 4-[(4′-trifluoromethylthio)thiophenyl]phenyl, 4-[(4′-trifluoromethyl)phenoxy]phenyl, 4-[(4′-trifluoromethyl)thiophenyl]phenyl, 4-[(4′-trifluoromethoxy)phenoxy]phenyl, 4-[(4′-trifluoromethoxy)thiophenyl]phenyl, 4-[(4′-phenyl)N-piperidyl]phenyl, 4-[(4′-acetyl)N-piperazyl]phenyl and 4-(benzamido)phenyl are particularly preferred R3 radicals. Those substituents can themselves also be substituted in the second ring from the SO2 group at the meta- or para-position or both with a single atom or a substituent containing a longest chain length that is preferably of up to five atoms, excluding hydrogen.
  • Without wishing to be bound by theory, the length of a R[0229] 3 radical substituent bonded to the SO2 group is believed to play a role in the overall activity of a contemplated inhibitor compound against MMP enzymes generally. The length of the R3 radical group also appears to play a role in the selective activity of an inhibitor compound against particular MMP enzymes.
  • In particularly preferred practice, R[0230] 3 is a PhR23 group, wherein Ph is phenyl. The phenyl ring (Ph) of a PhR23 group is substituted at its para-position (4-position) by an R23 group that can be another single-ringed aryl or heteroaryl group, a piperidyl group, a piperazinyl group, a phenoxy group, a thiophenoxy [C6H5—S—) group, a phenylazo [C6H5—N2—] group or a benzamido [—NHC(O)C6H5] group.
  • In one embodiment of a particularly preferred aromatic sulfone hydroxamate inhibitor compound, an R[0231] 23 substituent is phenoxy and is itself substituted at its own para-position with a moiety that is selected from the group consisting of a halogen, a C1-C4 alkoxy group, a C1-C4 alkyl group, a dimethylamino group, a carboxyl C1-C3 alkylene group, a C1-C4 alkoxy carbonyl C1-C3 alkylene group, a trifluoromethylthio group, a trifluoromethoxy group, a trifluoromethyl group and a carboxamido C1-C3 alkylene group, or is substituted at the meta- and para-positions by a methylenedioxy group. It is to be understood that any R23 substituent can be substituted with a moiety from the above list. Such substitution at the para-position is preferred.
  • The present invention also contemplates a compound that corresponds in structure to formula VI, below, that is useful in preparing a compound of formulas I-V, as well as as an active MMP-inhibiting compound and as a pro-drug form of an inhibitor. [0232]
    Figure US20040235818A1-20041125-C00028
  • wherein g is zero, 1 or 2; [0233]
  • R[0234] 20 is (a)—O—R21, where R21 is selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl group and a pharmaceutically acceptable cation, (b)—NH—O—R22 wherein R22 is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), carbonyl-C1-C6-alkoxy, trisubstituted silyl group or o-nitrophenyl group, peptide synthesis resin and the like, wherein the trisubstituted silyl group is substituted with C1-C6-alkyl, aryl, or ar-C1-C6-alkyl or a mixture thereof, (c)—NH—O—R14, where R14 is hydrido, a pharmaceutically acceptable cation or C(W)R25 where W is O (oxo) or S (thioxo) and R25 is selected from the group consisting of an C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl and amino C1-C6-alkyl group wherein the amino C1-C6-alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or (d) —NR26R27, where R26 and R27 are independently selected from the group consisting of a hydrido, C1-C6-alkyl, amino C1-C6-alkyl, hydroxy C1-C6-alkyl, aryl, ar-C1-C6-alkyl group, or R26 and R27 together with the depicted nitrogen atom form a 5- to 7-membered ring containing zero or one additional heteroatom that is oxygen, nitrogen or sulfur;
  • m is zero, 1 or 2; [0235]
  • n is zero, 1 or 2; [0236]
  • p is zero, 1 or 2; [0237]
  • the sum of m+n+p=1, 2, 3 or 4; [0238]
  • (a) one of X, Y and Z is selected from the group consisting of C(O), NR[0239] 6, O, S, S(O), S(O)2 and NS(O)2R7, and the remaining two of X, Y and Z are CR8R9, and CR10R11, or
  • (b) X and Z or Z and Y together constitute a moiety that is selected from the group consisting of NR[0240] 6C(O), NR6S(O), NR6S(O)2, NR6S, NR6O, SS, NR6NR6 and OC(O), with the remaining one of X, Y and Z being CR8R9, or
  • (c) n is zero and X, Y and Z together constitute a moiety selected from the group consisting of [0241]
    Figure US20040235818A1-20041125-C00029
  • wherein wavy lines are bonds to the atoms of the depicted ring; [0242]
  • R[0243] 6 and R6 are independently selected from the group consisting of hydrido, formyl, sulfonic-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, C1-C6-alkylcarbonyl-C1-C6-alkyl, R8R9-aminocarbonyl-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkylcarbonyl, hydroxycarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkylcarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C1-C6-alkylcarbonylcarbonyl, R8R9-aminocarbonylcarbonyl, C1-C6-alkanoyl, aryl-C1-C6-alkyl, aroyl, bis(C1-C6-alkoxy-C1-C6-alkyl)-C1-C6-alkyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-perfluoroalkyl, C1-C6-trifluoromethylalkyl, C1-C6-perfluoroalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, heteroarycarbonyl, heterocyclocarbonyl, C3-C8-heterocycloalkyl, C3-C8-heterocycloalkylcarbonyl, aryl, C5-C6-heterocyclo, C5-C6-heteroaryl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkoxy-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, arylsulfonyl, C1-C6-alkylsulfonyl, C5-C6-heteroarylsulfonyl, carboxy-C1-C6-alkyl, C1-C4-alkoxycarbonyl-C1-C6-alkyl, aminocarbonyl, C1-C6-alkyl(R8N)iminocarbonyl, aryl(R8N)iminocarbonyl, C5-C6-heterocyclo(R8N)iminocarbonyl, arylthio-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C3-C6-alkenyl, C1-C4-alkylthio-C3-C6-alkenyl, C5-C6-heteroaryl-C1-C6-alkyl, halo-C1-C6-alkanoyl, hydroxy-C1-C6-alkanoyl, thio]-C1-C6-alkanoyl, C3-C6-alkenyl, C3-C6-alkynyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C5-alkoxycarbonyl, aryloxycarbonyl, NR8R9—(R8)iminomethyl, NR8R9—C1-C5-alkylcarbonyl, hydroxy-C1-C5-alkyl, R8R9-aminocarbonyl, R8R9-aminocarbonyl-C1-C6-alkylcarbonyl, hydroxyaminocarbonyl, R8R9-aminosulfonyl, R8R9-aminosulfon-C1-C6-alkyl, R8R9-amino-C1-C6-alkylsulfonyl and an R8R9-amino-C1-C6-alkyl group;
  • R[0244] 7 is selected from the group consisting of a arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl and a C1-C6-hydroxyalkyl group;
  • R[0245] 8 and R9 and R10 and R11 are independently selected from the group consisting of a hydrido, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroar-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aralkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl, or wherein R8 and R9 or R10 and R11 and the carbon to which they are bonded form a carbonyl group, or wherein R8 and R9 or R10 and R11, or R8 and R10 together with the atoms to which they are bonded form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclic or heteroaryl ring containing one or two heteroatoms that are nitrogen, oxygen, or sulfur, with the proviso that only one of R8 and R9 or R10 and R11 is hydroxy;
  • R[0246] 12 and R12′ are independently selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroaralkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aryloxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide or sulfone of any said thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl and an amino-C1-C6-alkyl group wherein the aminoalkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl and C1-C6-alkanoyl;
  • R[0247] 13 is selected from the group consisting of a hydrido, benzyl, phenyl, C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl and a C1-C6-hydroxyalkyl group; and
  • R[0248] 24 is R3 as defined in formulas I, III, IV or is the substituent G-A-R-E-Y of formula II (formula VIA). Alternatively, R24 is R3′, an aryl or heteroaryl group that is substituted with a coupling substituent reactive for coupling with another moiety (formula VIB), such as a nucleophilically displaceable leaving group, D.
    Figure US20040235818A1-20041125-C00030
  • Exemplary nucleophilically displaceable leaving groups, D, include a halo (fluoro, chloro, bromo, or iodo) nitro, azido, phenylsulfoxido, aryloxy, C[0249] 1-C6-alkoxy, a C1-C6-alkylsulfonate or arylsulfonate group and a trisubstituted ammonium group in which the three substituents are independently aryl, ar-C1-C6-alkyl or C1-C6-alkyl. Additional coupling substituents include, without limitation, a hydroxyl group and an amino group that can be coupled with carbonyl-containing moieties to form esters, urethanes, carbonates, amides and ureas. Similarly, a carboxyl coupling substituent can be used to form an ester, thioester or amide. Thus, a coupling substituent is useful in converting a coupling substituent-containing aryl or heteroaryl group into a substituent such as a G-A-R-E-Y substituent discussed hereinabove by the formation of a covalent bond.
  • A compound of formula VI can be coupled with another moiety at the R[0250] 3′ coupling substituent to form a compound whose newly formed R3 group is that of formulas I, III, IV or -G-A-R-E-Y. Exemplary of such couplings are the nucleophilic displacement to form ethers and thioethers, as well as the formation of ester, amide, urea, carbonate, urethane and the like linkages.
  • More particularly, where a R[0251] 20 group is —O—R21, with R21 being selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl group and a pharmaceutically acceptable cation, a precursor carboxylic acid or ester compound is defined that can be readily transformed into a hydroxamic acid, as is illustrated in several examples hereinafter.
  • Where a R[0252] 20 group is —NH—O—R22, wherein R22 is a selectively removable protecting group such as a 2-tetrahydropyranyl, benzyl, p-methoxybenzyl (MOZ), carbonyl-C1-C6-alkoxy, trisubstituted silyl group, an o-nitrophenyl group, or a peptide synthesis resin and the like, a synthetic intermediate is typically defined. In these compounds, a trisubstituted silyl group is substituted with C1-C6-alkyl, aryl, ar-C1-C6-alkyl or a mixture thereof, such as a trimethylsilyl, dimethylisopropylsilyl, triethylsilyl, triphenylsilyl, t-butyldiphenylsilyl, diphenylmethylsilyl, a tribenzylsilyl group, and the like. Exemplary trisubstituted silyl protecting groups and their uses are discussed at several places in Greene et al., Protective Groups In Organic Synthesis, 2nd ed., John Wiley & Sons, Inc., New York (1991).
  • A contemplated peptide synthesis resin is solid phase support also known as a so-called Merrifield's Peptide Resin that is adapted for synthesis and selective release of hydroxamic acid derivatives as is commercially available from Sigma Chemical Co., St. Louis, MO. An exemplary peptide synthesis resin so adapted and its use in the synthesis of hydroxamic acid derivatives is discussed in Floyd et al., [0253] Tetrahedron Let., 37(44):8048-8048(1996).
  • A 2-tetrahydropyranyl (THP) protecting group is a particularly preferred selectively removable protecting group. A contemplated THP-protected hydroxamate compound of formula VII can be prepared by reacting the carboxylic acid precursor compound of formula VII [where R[0254] 20 is —O—R21 and R21 is a hydrido group] in water with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine in the presence of N-methylmorpholine, N-hydroxybenzotriazole hydrate and a water-soluble carbodiimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The THP protecting group is readily removable in an aqueous acid solution such as an aqueous mixture of p-toluenesulfonic acid or HCl and acetonitrile or methanol. An illustrative THP-protected compound corresponds in structure to formula VIIB, below, wherein m, n, p, g, X, Z. Y, and D are as defined previously.
  • Where R[0255] 20 is —NR26R27, and R26 and R27 are as defined before, an amide compound is defined that can be used as a precursor intermediate and surprisingly as a MMP inhibitor compound. R26 and R27 are both preferably hydrido.
  • Where a R group is —NH—O—R[0256] 14, and R14 is hydrido, or a pharmaceutically acceptable cation, an active hydroxamic acid or hydroxamate is defined. Where a R20 group is —NH—O—R14, and R14 is a C(W)R25 group as defined before, a pro-drug form of the hydroxamic acid is defined that can form a hydroxamic acid or hydroxamate form of the inhibitor in situ.
  • A particularly preferred precursor intermediate to an intermediate compound of formula VI is an intermediate compound of formula VII, below [0257]
    Figure US20040235818A1-20041125-C00031
  • wherein m, n, p, g, X, Z, Y, D and R[0258] 20 are as defined above for formula VI.
    Figure US20040235818A1-20041125-C00032
  • In regard to a compound of each of formulas VI and VII, the subscript letter “g” is used to show the oxidation state of the sulfur atom. Where g is zero, the sulfur is unoxidized, and the compound depicted is typically the sulfide reaction product of a sulfur-containing synthon as is illustrated in the examples hereinafter. Where g is 1, the sulfur is oxidized to a sulfoxide, whereas when g is 2, the sulfur is oxidized to a sulfone as is also illustrated hereinafter. A compound of formulas VI or VII wherein g is zero or 1 as itself typically an intermediate in the formation of a similar compound wherein g is 2 and the intermediate is a preferred sulfone. [0259]
  • A preferred intermediate corresponds in structure to formula VIIA, below, wherein R[0260] 20, X, Y, Z, m, n, p and D are as defined previously.
    Figure US20040235818A1-20041125-C00033
  • In the written descriptions of molecules and groups, molecular descriptors can be combined to produce words or phrases that describe structural groups or are combined to describe structural groups. Such descriptors are used in this document. Common illustrative examples include such terms as aralkyl (or arylalkyl), heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, aralkoxyalkoxycarbonyl and the like. A specific example of a compound encompassed with the latter descriptor aralkoxyalkoxycarbonyl is C[0261] 6H5—CH2—CH2—O—CH2—O—(C═O)— wherein C6H5— is phenyl. It is also to be noted that a structural group can have more than one descriptive word or phrase in the art, for example, heteroaryloxyalkylcarbonyl can also be termed heteroaryloxyalkanoyl. Such combinations are used herein in the description of the processes, compounds and compositions of this invention and further examples are described below. The following list is not intended to be exhaustive or drawn out but provide illustrative examples of words or phrases (terms) that are used herein.
  • As utilized herein, the term “alkyl”, alone or in combination, means a straight-chain or branched-chain alkyl radical containing 1 to about 12 carbon atoms, preferably 1 to about 10 carbon atoms, and more preferably 1 to about 6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. [0262]
  • The term “alkenyl”, alone or in combination, means a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing 2 to about 12 carbon atoms preferably 2 to about 10 carbon atoms, and more preferably, 2 to about 6 carbon atoms. Examples of suitable alkenyl radicals include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, decenyl and the like. [0263]
  • The term “alkynyl”, alone or in combination, means a straight-chain hydrocarbon radical having one or more triple bonds and containing 2 to about 12 carbon atoms, preferably 2 to about 10 carbon atoms, and more preferably, 2 to about 6 carbon atoms. Examples of alkynyl radicals include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like. [0264]
  • The term “carbonyl” or “oxo”, alone or in combination, means a —C(═O)— group wherein the remaining two bonds (valences) can be independently substituted. The term carbonyl is also intended to encompass a hydrated carbonyl group —C(OH)[0265] 2—.
  • The term “thiol” or “sulfhydryl”, alone or in combination, means a —SH group. The term “thio” or “thia”, alone or in combination, means a thiaether group; i.e., an ether group wherein the ether oxygen is replaced by a sulfur atom. [0266]
  • The term “amino”, alone or in combination, means an amine or —NH[0267] 2 group whereas the term mono-substituted amino, alone or in combination, means a substituted amine —N(H)(substituent) group wherein one hydrogen atom is replaced with a substituent, and disubstituted amine means a —N(substituent)2 wherein two hydrogen atoms of the amino group are replaced with independently selected substituent groups.
  • Amines, amino groups and amides are compounds that can be designated as primary (I°), secondary (II°) or tertiary (III°) or unsubstituted, mono-substituted or N,N-disubstituted depending on the degree of substitution of the amino nitrogen. Quaternary amine (ammonium)(IV°) means a nitrogen with four substituents [—N[0268] +(substituent)4] that is positively charged and accompanied by a counter ion, whereas N-oxide means one substituent is oxygen and the group is represented as [—N+(substituent)3—O−]; i.e., the charges are internally compensated.
  • The term “cyano”, alone or in combination, means a —C-triple bond-N (—C≡N) group. The term “azido”, alone or in combination, means a —N-triple bond-N (—N≡N) group. The term “hydroxyl”, alone or in combination, means a —OH group. The term “nitro”, alone or in combination, means a —NO[0269] 2 group. The term “azo”, alone or in combination, means a —N═N-group wherein the bonds at the terminal positions can be independently substituted.
  • The term “hydrazino”, alone or in combination, means a —NH—NH— group wherein the depicted remaining two bonds (valences) can be independently substituted. The hydrogen atoms of the hydrazino group can be replaced, independently, with substituents and the nitrogen atoms can form acid addition salts or be quaternized. [0270]
  • The term “sulfonyl”, alone or in combination, means a —SO[0271] 2— group wherein the depicted remaining two bonds (valences) can be independently substituted. The term “sulfoxido”, alone or in combination, means a —SO— group wherein the remaining two bonds (valences) can be independently substituted.
  • The term “sulfone”, alone or in combination, means a —SO[0272] 2— group wherein the depicted remaining two bonds (valences) can be independently substituted. The term “sulfenamide”, alone or in combination, means a —SON═ group wherein the remaining three depicted bonds (valences) can be independently substituted. The term “sulfide”, alone or in combination, means a —S— group wherein the remaining two bonds (valences) can be independently substituted.
  • The term “alkoxy”, alone or in combination, means an alkyl ether radical wherein the term alkyl is as defined above. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like. [0273]
  • The term “cycloalkyl”, alone or in combination, means a cyclic alkyl radical that contains 3 to about 8 carbon atoms. The term “cycloalkylalkyl” means an alkyl radical as defined above that is substituted by a cycloalkyl radical containing 3 to about 8, preferably 3 to about 6, carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. [0274]
  • A heterocyclic (heterocyclo) or heterocyclo portion of a heterocyclocarbonyl, heterocyclooxy-carbonyl, heterocycloalkoxycarbonyl, or heterocycloalkyl group or the like is a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle that contains one or more hetero atoms selected from nitrogen, oxygen and sulphur. Heterocyclo compounds include benzofused heterocyclic compounds such as benzo-1,4-dioxane. Such a moiety can be optionally substituted on one or more ring carbon atoms by halogen, hydroxy, hydroxycarbonyl, alkyl, alkoxy, oxo, and the like, and/or on a secondary nitrogen atom (i.e., —NH—) of the ring by alkyl, aralkoxycarbonyl, alkanoyl, aryl or arylalkyl or on a tertiary nitrogen atom (i.e., ═N—) by oxido and that is attached via a carbon atom. The tertiary nitrogen atom with three substituents can also attached to form a N-oxide [═N(O)-] group. [0275]
  • The term “aryl”, alone or in combination, means a 5- or 6-membered carbocyclic aromatic ring-containing moiety or a fused ring system containing two or three rings that have all carbon atoms in the ring; i.e., a carbocyclic aryl radical. Exemplary carbocyclic aryl radicals include phenyl, indenyl and naphthyl radicals. [0276]
  • The term “heteroaryl”, alone or in combination means a 5- or 6-membered aromatic ring-containing moiety or a fused ring system (radical) containing two or three rings that have carbon atoms and also one or more heteroatoms in the ring(s) such as sulfur, oxygen and nitrogen. Examples of such heterocyclic or heteroaryl groups are pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyl (e.g., imidazol-4-yl, 1-benzyloxycarbonylimidazol-4-yl, and the like), pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, furyl, tetrahydrofuryl, thienyl, triazolyl, tetrazolyl, oxazolyl, oxadiazoyl, thiazolyl, thiadiazoyl, indolyl (e.g., 2-indolyl, and the like), quinolinyl, (e.g., 2-quinolinyl, 3-quinolinyl, 1-oxido-2-quinolinyl, and the like), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, and the like), tetrahydroquinolinyl (e.g., 1,2,3,4-tetrahydro-2-quinolyl, and the like), 1,2,3,4-tetrahydroisoquinolinyl (e.g., 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, and the like), quinoxalinyl, β-carbolinyl, 2-benzofurancarbonyl, benzothiophenyl, 1-, 2-, 4- or 5-benzimidazolyl, and the like radicals. [0277]
  • When an aryl or heteroaryl radical is a substituting moiety (group, substituent, or radical), it can itself substituted, the last-named substituent is independently selected from the group consisting of a cyano, perfluoroalkyl, trifluoro-methoxy, trifluoromethylthio, haloalkyl, trifluoromethylalkyl, aralkoxycarbonyl, aryloxycarbonyl, hydroxy, halo, alkyl, alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, aralkyl, aryl, arylcarbonylamino, heteroaryloxy, heteroarylthio, heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, heteroaralkoxy, heteroaralkylthio, aralkoxy, aralkylthio, aralkylamino, heterocyclo, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino, [0278]
  • wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of an alkyl, aryl, heteroaryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, arylcarbonyl, aralkanoyl, heteroarylcarbonyl, heteroaralkanoyl and an alkanoyl group, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring containing zero to two additional heteroatoms that are nitrogen, oxygen or sulfur and which ring itself is (a) unsubstituted or (b) substituted with one or two groups independently selected from the group consisting of an aryl, alkyl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, alkanoyl, cycloalkyl, heterocycloalkyl, alkoxycarbonyl, hydroxyalkyl, trifluoromethyl, benzofused heterocycloalkyl, hydroxyalkoxyalkyl, aralkoxycarbonyl, hydroxycarbonyl, aryloxycarbonyl, benzofused heterocycloalkoxy, benzofused cycloalkylcarbonyl, heterocyclo-alkylcarbonyl, and a cycloalkylcarbonyl group, carbonylamino [0279]
  • wherein the carbonylamino nitrogen is (i) unsubstituted, or (ii) is the reacted amine of an amino acid, or (iii) substituted with one or two radicals selected from the group consisting of an alkyl, hydroxyalkyl, hydroxyheteroaralkyl, cycloalkyl, aralkyl, trifluoromethylalkyl, heterocycloalkyl, benzofused heterocycloalkyl, benzofused heterocycloalkyl, benzofused cycloalkyl, and an N,N-dialkylsubstituted alkylamino-alkyl group, or (iv) the carboxamido nitrogen and two substituents bonded thereto together form a 5- to 8-membered heterocyclo, heteroaryl or benzofused heterocycloalkyl ring that is itself unsubstituted or substituted with one or two radicals independently selected from the group consisting of an alkyl, alkoxycarbonyl, nitro, heterocycloalkyl, hydroxy, hydroxycarbonyl, aryl, aralkyl, heteroaralkyl and an amino group, [0280]
  • wherein the amino nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents that are independently selected from the group consisting of alkyl, aryl, and heteroaryl, or (iii) wherein the amino nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, and an aminoalkyl group [0281]
  • wherein the aminoalkyl nitrogen is (i) unsubstituted, or (ii) substituted with one or two substituents independently selected from the group consisting of an alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and an alkanoyl group, or (iii) wherein the aminoalkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring. [0282]
  • The term “aralkyl”, alone or in combination, means an alkyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as benzyl, 2-phenylethyl and the like. [0283]
  • The term “aralkoxycarbonyl”, alone or in combination, means a radical of the formula aralkyl-O—C(O)— in which the term “aralkyl” has the significance given above. An example of an aralkoxycarbonyl radical is benzyloxycarbonyl. [0284]
  • The term “aryloxy” means a radical of the formula aryl-O— in which the term aryl has the significance given above. The phenoxy radical is an exemplary aryloxy radical. [0285]
  • The terms “heteroaralkyl” and “heteroaryloxy” mean radicals structurally similar to aralkyl and aryloxy that are formed from heteroaryl radicals. Exemplary radicals include 4-picolinyl and 2-pyrimidinoxy, respectively. [0286]
  • The terms “alkanoyl” or “alkylcarbonyl”, alone or in combination, means an acyl radical derived from an alkanecarboxylic acid, examples of which include formyl, acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like. [0287]
  • The term “cycloalkylcarbonyl” means an acyl group derived from a monocyclic or bridged cycloalkanecarboxylic acid such as cyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, and the like, or from a benz-fused monocyclic cycloalkanecarboxylic acid that is optionally substituted by, for example, alkanoylamino, such as 1,2,3,4-tetrahydro-2-naphthoyl, 2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. [0288]
  • The terms “aralkanoyl” or “aralkylcarbonyl” mean an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl and the like. [0289]
  • The terms “aroyl” or “arylcarbonyl” means an acyl radical derived from an aromatic carboxylic acid. Examples of such radicals include aromatic carboxylic acids, an optionally substituted benzoic or naphthoic acid such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like. [0290]
  • The term “cycloalkylalkoxycarbonyl” means an acyl group of the formula cycloalkylalkyl-O—CO— wherein cycloalkylalkyl has the significance given above. The term “aryloxyalkanoyl” means an acyl radical of the formula aryl-O-alkanoyl wherein aryl and alkanoyl have the significance given above. The term “heterocyclooxycarbonyl” means an acyl group having the formula heterocyclo-O—CO— wherein heterocyclo is as defined above. [0291]
  • The term “heterocycloalkanoyl” is an acyl radical of the formula heterocyclo-substituted alkane carboxylic acid wherein heterocyclo has the significance given above. The term “heterocycloalkoxycarbonyl” means an acyl radical of the formula heterocyclo-substituted alkane-O—CO— wherein heterocyclo has the significance given above. The term “heteroaryloxycarbonyl” means an acyl radical represented by the formula heteroaryl-O—CO— wherein heteroaryl has the significance given above. [0292]
  • The term “aminocarbonyl” (carboxamide) alone or in combination, means an amino-substituted carbonyl (carbamoyl) group derived from an amine reacted with a carboxylic acid wherein the amino (amido nitrogen) group is unsubstituted (—NH[0293] 2) or a substituted primary or secondary amino group containing one or two substituents selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like, as recited. A hydroxamate is a N-hydroxycarboxamide.
  • The term “aminoalkanoyl” means an acyl group derived from an amino-substituted alkanecarboxylic acid wherein the amino group can be a primary or secondary amino group containing substituents independently selected from hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like. [0294]
  • The term “halogen” means fluoride, chloride, bromide or iodide. The term “haloalkyl” means an alkyl radical having the significance as defined above wherein one or more hydrogens are replaced with a halogen. Examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like. [0295]
  • The term “perfluoroalkyl” means an alkyl group wherein each hydrogen has been replaced by a fluorine atom. Examples of such perfluoroalkyl groups, in addition to trifluoromethyl above, are perfluorobutyl, perfluoroisopropyl, perfluorododecyl and perfluorodecyl. [0296]
  • The term “perfluoroalkoxy” alone or in combination, means a perfluoroalkyl ether radical wherein the term perfluoroalkyl is as defined above. Examples of such perfluoroalkoxy groups, in addition to trifluoromethoxy (F[0297] 3C—O—), are perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy and perfluorodecoxy.
  • The term “perfluoroalkylthio” alone or in combination, means a perfluoroalkyl thioether radical wherein the term perfluoroalkyl is as defined above. Examples of such perfluoroalkylthio groups, in addition to trifluoromethylthio (F[0298] 3C—S—), are perfluorobutylthio, perfluoroisopropylthio, perfluorododecylthio and perfluorodecylthio.
  • The term “aromatic ring” in combinations such as substituted-aromatic ring sulfone or substituted-aromatic ring sulfoxide means aryl or heteroaryl as defined before. [0299]
  • The term “pharmaceutically acceptable” is used adjectivally herein to mean that the modified noun is appropriate for use in a pharmaceutical product. Pharmaceutically acceptable cations include metallic ions and organic ions. More preferred metallic ions include, but are not limited to appropriate alkali metal (Group Ia) salts, alkaline earth metal (Group IIa) salts and other physiological acceptable metal ions. Exemplary ions include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc in their usual valences. Preferred organic ions include protonated tertiary amines and quaternary ammonium cations, including in part, trimethylamine, diethylamine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Exemplary pharmaceutically acceptable acids include without limitation hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like. [0300]
  • “M” utilized in the reaction schemes that follow represents a leaving group such as halogen, phosphate ester or sulfate ester. [0301]
  • Preparation of Useful Compounds [0302]
  • Schemes A through C and Schemes 1 through 19 hereinbelow illustrate chemical processes and transformations that can be useful for the preparation of compounds useful in this invention; i.e., compounds of formulas I, II, III, IV and V and similar cyclic inhibitors. In addition, the preparation of compounds of formula VI and formula VII is illustrated. Compounds of formula VI and formula VII can be used as intermediates in the preparation of the compounds of formulas I, II, III, IV and V or pro-drugs or MMP inhibitors. [0303]
  • In Schemes A through C, the symbol J independently represents R[0304] 20 or other synthetically useful groups such as amides, acid chlorides, mixed anhydrides and the like. The n is 0, 1 or 2 and is preferred to be 1 or 2 in Scheme C. The n of these schemes corresponds to g in formulas VI and VII., and is zero, 1 or 2. The symbol m is 1 or 2. The symbol r is independently 1, 2 or 3. The symbol P represents a protecting group that can also be a member of the group R6. In Scheme A, for simplicity and clarity of illustration positional isomers are illustrated with a bond through the ring in standard fashion. Later Schemes typically only show one positional isomer but positional isomers are represented by these structures and reactions in a manner consistent with Formula I, II, III, IV, V, VI, VII above. Similarly, the symbol B represents O, S, SO, SO2 and NR6. The symbols C and C′ independently are electrophilic groups or groups capable of participating in a condensation reaction. Here to it should be noted that the six-membered ring is shown for illustrative purposes but the procedures and/or reagents are applicable to and represent combinations the permit the preparation of 5- to 8-membered rings.
  • The structures in Schemes 1 through 19 are also shown with compounds that represent the other compounds of this invention. The aromatic ring in Scheme C is aryl and heteroaryl. The moieties of -A-R-E-Y are as defined before. Reactions illustrated involving a spiroheterocyclic nitrogen atom may not be applicable to those compounds with sulfur or oxygen. [0305]
    Figure US20040235818A1-20041125-C00034
  • Scheme A shows in step 1 the reduction of a heteraryl compound to a carboxyl derivative. Generally, the first product is a hydrogen-containing amine heterocycle when the starting material is aromatic or an R[0306] 6-containing heterocycle when a partially unsaturated heterocycle is the starting material.
  • Compound 2 can be treated in several ways depending on the needs of the chemist. In Step 2, the nitrogen can be protected by preparing, for example, a carbobenzoxy (Z) or tert-butoxycarbonyl derivative. Such acylations can be carried out by methods well known in the art, especially the art of amino acid and peptide synthesis. The process of acylation with activated carboxyl group- or activated sulfonyl group-containing reagents to prepare contemplated compounds is carried out in the same manner. Examples of such acylating groups are carbonyl azides, halides, anhydrides, mixed anhydrides, carbodiimide derivatives or other less traditional activated ester groups such as the hydroxybenzotriazole derivative. These acylations can be run in the presence of base including mild bases such as triethylamine or N-ethylmorpholine if desired. The preparation of some activated ester reagents and their use to prepare other compounds useful in this invention is discussed below. It should be recalled that the groups constituting P and serving as a selectively removable protecting group can also be included as part of the group R[0307] 6.
  • Step 4 of Scheme A shows the alkylation or acylation of Compound 2 to produce compound 5. The process of acylation and alkylation are as discussed herein. In Step 5, the group J can be changed if desired. An example of such a change is exchange of an ester for a THP-protected hydroxamate conversion of a THP-protected hydroxamate inot a hydroxamate or conversion of an acid into a protected hydroxamate or the like. [0308]
  • Steps 3, 7 and 8 show the preparation of sulfur-containing derivatives of the contemplated compounds or intermediates to those compounds. The starting material for the above steps (e.g., compounds 2, 5 and 6) can be treated with a base to deprotonate the carbon alpha to the carbonyl function. This anion can be reacted with a sulfur electrophile to produce a sulfone, sulfoxide or sulfide. Such electrophiles can be of the form of, for example, R[0309] 24S—SR24, R24SO2C1, R24SC1, R24SOC1, R24S(O)—SR24 and the like where R24 is as defined before or is an aryl or heteroaryl sulfur-containing material containing a coupling substituent, R3′, that can be used to prepare one of the R24-containing groups. Preparation of the anion requires a base and a strong base may be required such as one of the metal amides, hydrides or alkyls discussed herein. The solvents are nonprotic, and dipolar aprotic solvents are preferred along with an inert atmosphere. Subsequent schemes usually utilize R3 for the R24 group for ease of illustration.
  • It should be noted that these processes produce sulfides (thio ethers), sulfoxides or sulfones depending on starting material. In addition, the sulfides can be oxidized to sulfoxides or sulfones, and the sulfoxides can be oxidized to their corresponding sulfone derivatives. The choice of position in the synthetic sequence to change the oxidation state of sulfur as well as the decision to change oxidation state is under the control of the chemist skilled in the art. Methods of oxidizing sulfur are discussed hereinbelow. [0310]
  • Scheme A, Steps 6, 9, 10 and 12 independently illustrate the interconversion of groups within J. Examples of such interconversions include exchange of an ester for hydroxamic acid or hydroxamic acid derivative, conversion of a carboxylic acid into an activated carbonyl derivative or into a hydroxamic acid or hydroxamic acid derivative (pro-drug or protected derivative), or removal of a protecting group from a hydroxamate derivative. The preparation of activated carbonyl compounds their reaction with nucleophiles such as hydroxamic acid, protected hydroxamates or hydroxamic acid pro-drugs is discussed below as is the conversion of protected hydroxamic acid derivatives into hydroxamic acids. The preparation of, for example, hydroxybenzotriazole/carbodiimide, derived products is discussed herein. The preparation or hydrolysis of esters, amides, amide derivatives, acid chlorides, acid anhydrides, mixed anhydrides and the like are synthetic methods very well known in the art, and are not discussed in detail herein. Step 6 illustrates the conversion of compound 4 into compound 9, without first being converted into compound 7. [0311]
    Figure US20040235818A1-20041125-C00035
  • Scheme B illustrates an alternate method of preparing contemplated compounds. The reagent shown above the arrow in Step 1 is a reagent with two active groups in addition to the heteroatoms (B) noted before. Here again, the particular reagent illustrated was selected to permit a clear illustration of the reaction, but it is also intended to represent reagents that permit the preparation of the heteroatom position, and 5-, 7- and 8-membered ring size compounds. These reagents are readily selected by those skilled in the art. [0312]
  • C and C′ in this Step 1 reagent are independently an electophile or a group convertible into an electrophile. Such groups include halides, sulfonic acid esters, epoxides, thioepoxides, hydroxyl groups, and the like. This reagent is reacted with a nucleophilic anion of a sulfur containing carbonyl compound such as compound 1. The anion is formed by deprotonation of compound 1 and examples of bases suitable for such a deprotonation are discussed below. Treatment with the above electrophilic reagent is carried out under alkylating conditions well known in the art and discussed herein. The product of this reaction can be either Compound 2 or Compound 3; i.e., the reaction can be carried out as a pot or two step process as required. [0313]
  • Step 3 illustrates the interconversion of J groups if desired as discussed above for Scheme A. Step 4 uses reagent where C, for example, represents a nucleophile as discussed above and C′ represents an electrophile or a nucleophile such as hydroxyl, thiol or R[0314] 6-amino. It is noted that Cl can be, independently, a nucleophile or an electrophile when m is 2; i.e., the C′ groups are not required to be the same when m is 2. When m is 2, treatment with a second mole of base provides the skilled chemist an alternative preparation of Compound 5. When C′ is hydroxyl, thiol, or R6-amino and m is 2, the person skilled in the art can condense Compound 4 with, for example, an aldehyde or ketone, under reductive conditions or with subsequent reduction to form a contemplated compound. As above, the compound where m is 2 can be made in one step (one pot process) or two steps, thus permitting the chemist the choice of having the reagent(s) be the same (one pot) or different (two step).
  • Scheme B also illustrates the interconversions of the groups within J, the oxidation state of the sulfur and groups on nitrogen; i.e., R[0315] 6 groups, to provide the contemplated compounds. These methods and processes are discussed above for the reactions of Scheme A.
    Figure US20040235818A1-20041125-C00036
  • Scheme C illustrates the nucleophilic displacement of a group D as defined herein. This reaction is carried out in a similar manner to the displacement reactions discussed herein. The choice of oxidation state of the sulfur is made by the person skilled in the art, but sulfoxide or sulfone groups are preferred, and the sulfone is most preferred. The displacement can be carried out either before or after the methylene next to the carbonyl group is reacted to form a Spiro heterocyclic group. [0316]
  • Steps 1, 2 and 3 also illustrate that although the nucleophilic displacement can be carried out with one nucleophile (Nu), the product of this reaction can be modified by methods well known in the art and as shown herein to provide the group -A-R-E-Y as defined hereinbefore. [0317]
  • A non-limiting illustration of such a process is provided when D is fluoride. The fluoride leaving group can be directly displaced with the anion of 4-trifluoromethylphenol, 4-trifluoromethoxyphenol, 4-trifluoromethylthiophenol and the like to provide a contemplated compound. This is a one pot process from Compound 4. Other compounds included in -A-R-E-Y can be prepared by displacing the fluoride leaving group with ammonia to provide an amine, which can then be acylated by methods discussed wherein with, for example, 4-trifluoromethylbenzoyl chloride, to form another contemplated product compound. [0318]
  • The R[0319] 6 function can be changed and/or further modified in compounds or at steps in the Schemes as desired or required by the person skilled in the art to prepare the contemplated compounds. Interconversion of dual purpose functional groups such as short or long term protecting groups into other R6 groups has been mentioned. Many other routine and/or useful conversions, including the preparation of synthetic intermediates, are very well known in the art. A few non-limiting examples of such conversions or reactions include: reductions; nucleophilic displacement/substitution reactions; exchange or preparation of carboxylic or sulfonic acids, amides, esters, acid halides, mixed anhydrides and the like; electrophilic displacement/substitution reactions; oxidations; ring/chain conversions, ring opening reactions, condensation reactions including those involving sulfonyl or carbonyl groups and/or carbon-hydrogen bonds influenced by either or both of those groups. The selection of preparative methods or conversion methods of the contemplated compounds and the order of the reaction(s) is made by the skilled person. It is expected that should a particular sequence or method prove to be undesirable that an alternative will be selected and used. Included is the choice of preparing/adding the groups in a single step using a convergent inhibitor strategy or preparing the final R6 group following a stepwise strategy.
  • Thus, in general, the choices of starting material and reaction conditions can vary as is well known to those skilled in the art. Usually, no single set of conditions is limiting because variations can be applied as required. Conditions are also selected as desired to suit a specific purpose such as small scale preparations or large scale preparations. In either case, the use of less safe or less environmentally sound materials or reagents is usually be minimized. Examples of such materials are diazomethane, diethyl ether, heavy metal salts, dimethyl sulfide, chloroform, benzene and the like. [0320]
  • These reactions can be carried out under a dry inert atmosphere such a nitrogen or argon if desired. Selected reactions known to those skilled in the art, can be carried out under a dry atmosphere such as dry air whereas other synthetic steps, for example, aqueous acid or base ester or amide hydrolysis, can be carried out under laboratory air. In addition, some processes of these syntheses can be carried out in a pressure apparatus at pressures above, equal to or below atmospheric pressure. The use of such an apparatus aids in the control of gaseous reagents such as hydrogen, ammonia, trimethylamine, methylamine, oxygen and the like, and can also help prevent the leakage of air or humidity into a reaction in progress. This discussion is not intended to be exhaustive as it is readily noted that additional or alternative methods, conditions, reactions or systems can be identified and used by a chemist of ordinary skill. [0321]
  • The illustrated reactions are usually carried out at a temperature of between −25° C. to solvent reflux under an inert atmosphere such as nitrogen or argon. The solvent or solvent mixture can vary widely depending upon reagents and other conditions and can include polar or dipolar aprotic solvents as listed or mixtures of these solvents. Reactions can be carried out at lower temperatures such as dry ice/acetone or liquid nitrogen temperature if desired to carry out such reactions as metalations or anion formations using strong bases. [0322]
  • In some cases, amines such as triethylamine, pyridine or other non-reactive bases can serve as reagents and/or solvents and/or co-solvents. In some instances, in these reactions and other reactions in these Schemes, protecting groups can be used to maintain or retain groups in other parts of a molecule(s) at locations that is(are) not desired reactive centers. Examples of such groups that the skilled person can maintain or retain include, amines, other hydroxyls, thiols, acids and the like. Such protecting groups can include acyl groups, arylalkyl groups, carbamoyl groups, ethers, alkoxyalkyl ethers, cycloalkyloxy ethers, arylalkyl groups, silyl groups including trisubstituted silyl groups, ester groups and the like. Examples of such protecting groups include acetyl, trifluoroacetyl, tetrahydropyran (THP), benzyl, tert-butoxy carbonyl (BOC or TBOC), benzyloxycarbonyl (Z or CBZ), tert-butyldimethylsilyl (TBDMS) or methoxyethoxymethylene (MEM) groups. The preparation of such protected compounds as well as their removal is well known in the art. The protecting groups can also be used as substituents in the contemplated compounds whose utility is as a drug rather than as a synthetic intermediate. [0323]
  • Many reactions or processes involve bases that can act as reactants, reagents, deprotonating agents, acid scavengers, salt forming reagents, solvents, co-solvents and the like. Bases that can be used include, for example, metal hydroxides such as sodium, potassium, lithium, cesium or magnesium hydroxide, oxides such as those of sodium, potassium, lithium, calcium or magnesium, metal carbonates such as those of sodium, potassium, lithium, cesium, calcium or magnesium, metal bicarbonates such as sodium bicarbonate or potassium bicarbonate, primary (I°), secondary (II°) or tertiary (III°) organic amines such as alkyl amines, arylalkyl amines, alkylarylalkyl amines, heterocyclic amines or heteroaryl amines, ammonium hydroxides or quaternary ammonium hydroxides. As non-limiting examples, such amines can include triethylamine, trimethylamine, diisopropylamine, methyldiisopropylamine, diazabicyclononane, tribenzylamine, dimethylbenzylamine, morpholine, N-methylmorpholine, N,N′-dimethylpiperazine, N-ethylpiperidine, 1,1,5,5-tetramethylpiperidine, dimethylaminopyridine, pyridine, quinoline, tetramethylethylenediamine, and the like. Non-limiting examples of ammonium hydroxides, usually made from amines and water, can include ammonium hydroxide, triethylammonium hydroxide, trimethylammonium hydroxide, methyldiiospropylammonium hydroxide, tribenzylammonium hydroxide, dimethylbenzylammonium hydroxide, morpholinium hydroxide, N-methylmorpholinium hydroxide, N,N′-dimethylpiperazinium hydroxide, N-ethylpiperidinium hydroxide, and the like. As non-limiting examples, quaternary ammonium hydroxides can include tetraethylammonium hydroxide, tetramethylammonium hydroxide, dimethyldiiospropyl-ammonium hydroxide, benzylmethyldiisopropylammonium hydroxide, methyldiazabicyclononylammonium hydroxide, methyltribenzylammonium hydroxide, N,N-dimethyl-morpholiniumhydroxide, N,N,N′,N′-tetramethylpiperazinium hydroxide, and N-ethyl-N′-hexylpiperidinium hydroxide and the like. [0324]
  • Metal hydrides, amides or alcoholates such as calcium hydride, sodium hydride, potassium hydride, lithium hydride, aluminum hydride, diisobutylaluminum hydride (DIBAL) sodium methoxide, potassium tert-butoxide, calcium ethoxide, magnesium ethoxide, sodium amide, potassium diisopropyl amide and the like can also be suitable reagents. Organometallic deprotonating agents such as alkyl or aryl lithium reagents such as methyl lithium, phenyl lithium, tert-butyl lithium, lithium acetylide or butyl lithium, Grignard reagents such as methylmagnesium bromide or methymagnesium chloride, organocadmium reagents such as dimethylcadmium and the like can also serve as bases for causing salt formation or catalyzing the reaction. Quaternary ammonium hydroxides or mixed salts are also useful for aiding phase transfer couplings or serving as phase transfer reagents. Pharmaceutically acceptable bases can be reacted with acids to form contemplated pharmaceutically acceptable salts. It should also be noted that optically active bases can be used to make optically active salts which can be used for optical resolutions. [0325]
  • Generally, reaction media can comprise a single solvent, mixed solvents of the same or different classes or serve as a reagent in a single or mixed solvent system. The solvents can be protic, non-protic or dipolar aprotic. Non-limiting examples of protic solvents include water, methanol (MeOH), denatured or pure 95% or absolute ethanol, isopropanol and the like. Typical non-protic solvents include acetone, tetrahydrofuran (THF), dioxane, diethyl ether, tert-butylmethyl ether (TBME), aromatics such as xylene, toluene, or benzene, ethyl acetate, methyl acetate, butyl acetate, trichloroethane, methylene chloride, ethylenedichloride (EDC), hexane, heptane, isooctane, cyclohexane and the like. Dipolar aprotic solvents include compounds such as dimethylformamide (DMF), dimethylacetamide (DMAc), acetonitrile, DMSO, hexamethylphosphorus triamide (HMPA), nitromethane, tetramethylurea, N-methylpyrrolidone and the like. Non-limiting examples of reagents that can be used as solvents or as part of a mixed solvent system include organic or inorganic mono- or multi-protic acids or bases such as hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, triethylamine, morpholine, N-methylmorpholine, piperidine, pyrazine, piperazine, pyridine, potassium hydroxide, sodium hydroxide, alcohols or amines for making esters or amides or thiols for making contemplated products and the like. [0326]
  • The preparation of compounds contemplated herein can require the oxidation of nitrogen or sulfur to N-oxide derivatives or sulfoxides or sulfones. Reagents for this process can include, in a non-limiting example, peroxymonosulfate (OXONE®), hydrogen peroxide, meta-chloroperbenzoic acid, perbenzoic acid, peracetic acid, perlactic acid, tert-butyl peroxide, tert-butyl hypochlorite, sodium hydpochlorite, hypochlorous acid, sodium meta-periodate, periodic acid and the like with the weaker agents being most useful for the preparation of sulfones and sulfoxides. Protic, non-protic, dipolar aprotic solvents, either pure or mixed, can be chosen, for example, methanol/water. [0327]
  • The oxidation can be carried out at temperature of about −780 to about 50° degrees Centigrade, and normally selected from a range −10° C. to about 40° C. Sulfoxides are best prepared using one equivalent of oxidizing agent. It can be desirable in the case of more active oxidizing agents, but not required, that the reactions be carried out under an inert gas atmosphere with or without degassed solvents. It should be noted that the oxidation of sulfides to sulfones can be carried out in one step or two steps via the sulfoxide as desired by the chemist. [0328]
  • Reduction is a well known process in the art with a useful method being hydrogenation. In such cases (catalytic reduction), there can be a metal catalyst such as Rh, Pd, Pt, Ni or the like with or without an additional support such as carbon, barium carbonate and the like. Solvents can be protic or non-protic pure solvents or mixed solvents as required. The reductions can be carried out at atmospheric pressure to a pressure of multiple atmospheres with atmospheric pressure to about 40 pounds per square inch (psi) preferred or very high pressures in special hydrogenation equipment well known in the art. [0329]
  • Reductive alkylation of amines or active methylene compounds is also a useful method of preparing compounds. Such alkylations can be carried out under reductive hydrogenation conditions as presented above using, for example, aldehydes or ketones. Hydride transfer reagents such as sodium cyanoborohydride, aluminum hydride, lithium aluminumhydride, borane, sodium borohydride, di-isobutylaluminum hydride and the like are also useful as reagents for reductive alkylation. Acyl groups can be reduced in a similar manner to produce substituted amines. [0330]
  • Alternative methods of alkylating carbon or nitrogen are direct alkylation. Such an alkylation, as is well known in the art, can be carried by treatment of an activated carbon containing at least one hydrogen with base to form the corresponding anion, adding an electrophilic reagent and permitting the SN2 reaction to proceed. An amine to be alkylated is treated similarly except that deprotonation may not be required. Electrophiles include halogen derivatives, sulfonate esters, epoxides and the like. [0331]
  • Bases and solvents for alkylation reactions are those discussed above. Preferred are bases that are hindered such that competition with the electrophile is minimized. Additional preferred bases are metal hydrides, amide anions or organometallic bases such as n-butyl lithium. The solvents, solvent mixtures or solvent/reagent mixtures discussed are satisfactory but non-protic or dipolar aprotic solvents such as acetone, acetonitrile, DMF and the like are examples of preferred classes. [0332]
  • Acids are used in many reactions during various syntheses. For example, removal of the THP protecting group to produce the hydroxamic acid. The acid can be a mono-, di- or tri-protic organic or inorganic acid. Examples of acids include hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, hydrobromic acid, hydrofluoric acid, carbonic acid, phosphorus acid, p-toluene sulfonic acid, trifluoromethane sulfonic acid, trifluoroacetic acid, difluoroacetic acid, benzoic acid, methane sulfonic acid, benzene sulfonic acid, 2,6-dimethylbenzene sulfonic acid, trichloroacetic acid, nitrobenzoic acid, dinitrobenzoic acid, trinitrobenzoic acid, and the like. They can also be Lewis acids such as aluminum chloride, borontrifluoride, antimony pentafluoride and the like. Acids in a protic can also be used to hydrolyze esters, amides and the like as well as catalyze exchange reactions. [0333]
  • Conversion of a carboxylic acid protected as an ester or amide into a hydroxamic acid or hydroxamic acid derivative such as an O-arylalkylether or O-cycloalkoxyalkylether group is useful. In the case where hydroxylamine is used, treatment of an ester or amide with one or more equivalents of hydroxylamine hydrochloride at room temperature or above in a solvent or solvents, usually protic or partially protic, such as those listed above can provide a hydroxamic acid directly. This exchange process can be further catalyzed by the addition of additional acid. Alternatively, a base such as a salt of an alcohol used as a solvent, for example, sodium methoxide in methanol, can be used to form hydroxylamine from hydroxylamine hydrochloride in situ which can exchange with an ester or amide. As mentioned above, exchange can be carried out with a protected hydroxylamine such as tetrahydropyranylhydroxyamine (THPONH[0334] 2), benzylhydroxylamine (BnONH2), and the like in which case compounds such as shown in Schemes A, B and C that are tetrahydropyranyl (THP) or benzyl (Bn) hydroxamic acid derivatives are the products. Removal of the protecting groups when desired, for example, following further transformations in another part of the molecule or following storage, is accomplished by standard methods well known in the art such as acid hydrolysis of the THP group as discussed above or reductive removal of the benzyl group with hydrogen and a metal catalyst such as palladium, platinum, palladium on carbon or nickel.
  • In the case where R[0335] 20 is hydroxyl; i.e., where the intermediate is a carboxylic acid, standard coupling reactions can be used. For example, the acid can be converted into an acid chloride, mixed anhydride or activated ester such as hydroxybenzotriazole and treated with hydroxylamine or a protected hydroxylamine in the presence of a non-competitive base to the nitrogen acylated compound. This is the same product as discussed above. Couplings of this nature are well known in the art and especially the art related to peptide and amino acid chemistry.
  • An amide of this invention, whether used as a drug or as a protecting group, is prepared by treatment of an acid halide, anhydride, mixed anhydride or active ester with a primary amine, secondary amine or ammonia, or their equivalent. These standard coupling reactions are well known in the art and are discussed elsewhere herein. An alternative method of preparation of amides is by the exchange of, for example, an alkoxycarbonyl (ester) or aminecarbonyl (amide) group for an amine or different amine as required. Ester exchange processes are especially useful when less hindered amines, including ammonia, are used to make the corresponding amides of this invention. [0336]
  • Further, amides can be prepared from hydroxamic acids or protected hydroxamic acid compounds by catalytic reductions or in vivo or in vitro enzymatic processes. For example, catalytic reduction of O-benzylhydroxamic acid compounds is known to produce varying ratios of amide and hydroxamic acid depending upon the catalyst used as well as other reaction conditions such as solvent, temperature, hydrogen gas pressure and the like. [0337]
  • Compounds contemplated herein can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers, enantiomers, diastereoisomers, as well as in the form of racemic or nonracemic mixtures. A compound can also exist in other isomeric forms such as ortho, meta and para isomers, cis and trans isomers, syn and anti isomers, E and Z isomers, tautomeric isomers, alpha and beta isomers, axial and equatorial isomers and isomers due to hindered rotation. An isomer can exist in equilibrium with another isomer in a mammal or a test system. Such a compound can also exist as an isomeric equilibrium system with a solvent or water, for example, as a hydrated ketone or aldehyde, as is well known in the art. All isomers are included as compounds of this invention. [0338]
  • The chemical reactions described above are generally disclosed in terms of their broadest application to the preparation of the compounds of this invention. Occasionally, the reactions may not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifications known to those skilled in the art, e.g., by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, and the like, or other reactions disclosed herein or otherwise conventional, are applicable to the preparation of the corresponding compounds that are contemplated. [0339]
    Figure US20040235818A1-20041125-C00037
    Figure US20040235818A1-20041125-C00038
    Figure US20040235818A1-20041125-C00039
    Figure US20040235818A1-20041125-C00040
    Figure US20040235818A1-20041125-C00041
    Figure US20040235818A1-20041125-C00042
    Figure US20040235818A1-20041125-C00043
    Figure US20040235818A1-20041125-C00044
    Figure US20040235818A1-20041125-C00045
    Figure US20040235818A1-20041125-C00046
    Figure US20040235818A1-20041125-C00047
    Figure US20040235818A1-20041125-C00048
    Figure US20040235818A1-20041125-C00049
    Figure US20040235818A1-20041125-C00050
    Figure US20040235818A1-20041125-C00051
    Figure US20040235818A1-20041125-C00052
    Figure US20040235818A1-20041125-C00053
    Figure US20040235818A1-20041125-C00054
    Figure US20040235818A1-20041125-C00055
  • Table 1 through Table 165, below, show several contemplated aromatic sulfone hydroxamic acid inhibitor compounds or structural formulas that illustrate substituent groups. Each group of compounds is illustrated by a generic formula, or formulae, followed by a series of preferred moieties or groups that constitute various substituents that can be attached at the position clearly shown in the generic structure. The substituent symbols, e.g., R1 and R2 and R3, are as shown in each Table, and are typically not those used before. One or two bonds (wavy lines) are shown with those substituents to indicate the respective positions of attachment in the illustrated compound. This system is well known in the chemical communication arts and is widely used in scientific papers and presentations. For example in Table 2, R1 and R2 together with the atoms to which they are bonded is the variable group with the structural entities that can substitute for R1 and R2 together shown in the balance of that table. [0340]
    TABLE 1
    Figure US20040235818A1-20041125-C00056
    1
    Figure US20040235818A1-20041125-C00057
         		7
    Figure US20040235818A1-20041125-C00058
    2
    Figure US20040235818A1-20041125-C00059
         		8
    Figure US20040235818A1-20041125-C00060
    3
    Figure US20040235818A1-20041125-C00061
         		9
    Figure US20040235818A1-20041125-C00062
    4
    Figure US20040235818A1-20041125-C00063
         		10 
    Figure US20040235818A1-20041125-C00064
    5
    Figure US20040235818A1-20041125-C00065
         		11 
    Figure US20040235818A1-20041125-C00066
    6
    Figure US20040235818A1-20041125-C00067
         		12 
    Figure US20040235818A1-20041125-C00068
  • [0341]
    TABLE 2
    II
    Figure US20040235818A1-20041125-C00069
    1
    Figure US20040235818A1-20041125-C00070
    2
    Figure US20040235818A1-20041125-C00071
    3
    Figure US20040235818A1-20041125-C00072
    4
    Figure US20040235818A1-20041125-C00073
    5
    Figure US20040235818A1-20041125-C00074
    6
    Figure US20040235818A1-20041125-C00075
    7
    Figure US20040235818A1-20041125-C00076
    8
    Figure US20040235818A1-20041125-C00077
    9
    Figure US20040235818A1-20041125-C00078
    10 
    Figure US20040235818A1-20041125-C00079
    11 
    Figure US20040235818A1-20041125-C00080
    12 
    Figure US20040235818A1-20041125-C00081
  • [0342]
    TABLE 3
    Figure US20040235818A1-20041125-C00082
     1
    Figure US20040235818A1-20041125-C00083
     2
    Figure US20040235818A1-20041125-C00084
     3
    Figure US20040235818A1-20041125-C00085
     4
    Figure US20040235818A1-20041125-C00086
     5
    Figure US20040235818A1-20041125-C00087
     6
    Figure US20040235818A1-20041125-C00088
     7
    Figure US20040235818A1-20041125-C00089
     8
    Figure US20040235818A1-20041125-C00090
     9
    Figure US20040235818A1-20041125-C00091
    10
    Figure US20040235818A1-20041125-C00092
    11
    Figure US20040235818A1-20041125-C00093
    12
    Figure US20040235818A1-20041125-C00094
    13
    Figure US20040235818A1-20041125-C00095
    14
    Figure US20040235818A1-20041125-C00096
    15
    Figure US20040235818A1-20041125-C00097
    16
    Figure US20040235818A1-20041125-C00098
    17
    Figure US20040235818A1-20041125-C00099
    18
    Figure US20040235818A1-20041125-C00100
  • [0343]
    TABLE 4
    Figure US20040235818A1-20041125-C00101
     1
    Figure US20040235818A1-20041125-C00102
     2
    Figure US20040235818A1-20041125-C00103
     3
    Figure US20040235818A1-20041125-C00104
     4
    Figure US20040235818A1-20041125-C00105
     5
    Figure US20040235818A1-20041125-C00106
     6
    Figure US20040235818A1-20041125-C00107
     7
    Figure US20040235818A1-20041125-C00108
     8
    Figure US20040235818A1-20041125-C00109
     9
    Figure US20040235818A1-20041125-C00110
    10
    Figure US20040235818A1-20041125-C00111
    11
    Figure US20040235818A1-20041125-C00112
    12
    Figure US20040235818A1-20041125-C00113
    13
    Figure US20040235818A1-20041125-C00114
    14
    Figure US20040235818A1-20041125-C00115
    15
    Figure US20040235818A1-20041125-C00116
    16
    Figure US20040235818A1-20041125-C00117
    17
    Figure US20040235818A1-20041125-C00118
    18
    Figure US20040235818A1-20041125-C00119
    19
    Figure US20040235818A1-20041125-C00120
    20
    Figure US20040235818A1-20041125-C00121
    21
    Figure US20040235818A1-20041125-C00122
  • [0344]
    TABLE 5
    Figure US20040235818A1-20041125-C00123
     1
    Figure US20040235818A1-20041125-C00124
     2
    Figure US20040235818A1-20041125-C00125
     3
    Figure US20040235818A1-20041125-C00126
     4
    Figure US20040235818A1-20041125-C00127
     5
    Figure US20040235818A1-20041125-C00128
     6
    Figure US20040235818A1-20041125-C00129
     7
    Figure US20040235818A1-20041125-C00130
     8
    Figure US20040235818A1-20041125-C00131
     9
    Figure US20040235818A1-20041125-C00132
    10
    Figure US20040235818A1-20041125-C00133
    11
    Figure US20040235818A1-20041125-C00134
    12
    Figure US20040235818A1-20041125-C00135
    13
    Figure US20040235818A1-20041125-C00136
    14
    Figure US20040235818A1-20041125-C00137
    15
    Figure US20040235818A1-20041125-C00138
    16
    Figure US20040235818A1-20041125-C00139
    17
    Figure US20040235818A1-20041125-C00140
    18
    Figure US20040235818A1-20041125-C00141
    19
    Figure US20040235818A1-20041125-C00142
    20
    Figure US20040235818A1-20041125-C00143
    21
    Figure US20040235818A1-20041125-C00144
    22
    Figure US20040235818A1-20041125-C00145
  • [0345]
    TABLE 6
    Figure US20040235818A1-20041125-C00146
     1
    Figure US20040235818A1-20041125-C00147
     2
    Figure US20040235818A1-20041125-C00148
     3
    Figure US20040235818A1-20041125-C00149
     4
    Figure US20040235818A1-20041125-C00150
     5
    Figure US20040235818A1-20041125-C00151
     6
    Figure US20040235818A1-20041125-C00152
     7
    Figure US20040235818A1-20041125-C00153
     8
    Figure US20040235818A1-20041125-C00154
     9
    Figure US20040235818A1-20041125-C00155
    10
    Figure US20040235818A1-20041125-C00156
    11
    Figure US20040235818A1-20041125-C00157
    12
    Figure US20040235818A1-20041125-C00158
    13
    Figure US20040235818A1-20041125-C00159
    14
    Figure US20040235818A1-20041125-C00160
    15
    Figure US20040235818A1-20041125-C00161
    16
    Figure US20040235818A1-20041125-C00162
    17
    Figure US20040235818A1-20041125-C00163
    18
    Figure US20040235818A1-20041125-C00164
    19
    Figure US20040235818A1-20041125-C00165
    20
    Figure US20040235818A1-20041125-C00166
    21
    Figure US20040235818A1-20041125-C00167
    22
    Figure US20040235818A1-20041125-C00168
    23
    Figure US20040235818A1-20041125-C00169
    24
    Figure US20040235818A1-20041125-C00170
    25
    Figure US20040235818A1-20041125-C00171
    26
    Figure US20040235818A1-20041125-C00172
    27
    Figure US20040235818A1-20041125-C00173
    28
    Figure US20040235818A1-20041125-C00174
    29
    Figure US20040235818A1-20041125-C00175
    30
    Figure US20040235818A1-20041125-C00176
  • [0346]
    TABLE 7
    Figure US20040235818A1-20041125-C00177
     1
    Figure US20040235818A1-20041125-C00178
     2
    Figure US20040235818A1-20041125-C00179
     3
    Figure US20040235818A1-20041125-C00180
     4
    Figure US20040235818A1-20041125-C00181
     5
    Figure US20040235818A1-20041125-C00182
     6
    Figure US20040235818A1-20041125-C00183
     7
    Figure US20040235818A1-20041125-C00184
     8
    Figure US20040235818A1-20041125-C00185
     9
    Figure US20040235818A1-20041125-C00186
    10
    Figure US20040235818A1-20041125-C00187
    11
    Figure US20040235818A1-20041125-C00188
    12
    Figure US20040235818A1-20041125-C00189
    13
    Figure US20040235818A1-20041125-C00190
    14
    Figure US20040235818A1-20041125-C00191
    15
    Figure US20040235818A1-20041125-C00192
    16
    Figure US20040235818A1-20041125-C00193
    17
    Figure US20040235818A1-20041125-C00194
    18
    Figure US20040235818A1-20041125-C00195
    19
    Figure US20040235818A1-20041125-C00196
    20
    Figure US20040235818A1-20041125-C00197
    21
    Figure US20040235818A1-20041125-C00198
  • [0347]
    TABLE 8
    Figure US20040235818A1-20041125-C00199
    1
    Figure US20040235818A1-20041125-C00200
    2
    Figure US20040235818A1-20041125-C00201
    3
    Figure US20040235818A1-20041125-C00202
    4
    Figure US20040235818A1-20041125-C00203
    5
    Figure US20040235818A1-20041125-C00204
    6
    Figure US20040235818A1-20041125-C00205
    7
    Figure US20040235818A1-20041125-C00206
    8
    Figure US20040235818A1-20041125-C00207
    9
    Figure US20040235818A1-20041125-C00208
    10 
    Figure US20040235818A1-20041125-C00209
    11 
    Figure US20040235818A1-20041125-C00210
  • [0348]
    TABLE 9
    Figure US20040235818A1-20041125-C00211
     1
    Figure US20040235818A1-20041125-C00212
     2
    Figure US20040235818A1-20041125-C00213
     3
    Figure US20040235818A1-20041125-C00214
     4
    Figure US20040235818A1-20041125-C00215
     5
    Figure US20040235818A1-20041125-C00216
     6
    Figure US20040235818A1-20041125-C00217
     7
    Figure US20040235818A1-20041125-C00218
     8
    Figure US20040235818A1-20041125-C00219
     9
    Figure US20040235818A1-20041125-C00220
    10
    Figure US20040235818A1-20041125-C00221
    11
    Figure US20040235818A1-20041125-C00222
    12
    Figure US20040235818A1-20041125-C00223
    13
    Figure US20040235818A1-20041125-C00224
    14
    Figure US20040235818A1-20041125-C00225
    15
    Figure US20040235818A1-20041125-C00226
    16
    Figure US20040235818A1-20041125-C00227
    17
    Figure US20040235818A1-20041125-C00228
    18
    Figure US20040235818A1-20041125-C00229
    19
    Figure US20040235818A1-20041125-C00230
    20
    Figure US20040235818A1-20041125-C00231
    21
    Figure US20040235818A1-20041125-C00232
  • [0349]
    TABLE 10
    Figure US20040235818A1-20041125-C00233
     1
    Figure US20040235818A1-20041125-C00234
     2
    Figure US20040235818A1-20041125-C00235
     3
    Figure US20040235818A1-20041125-C00236
     4
    Figure US20040235818A1-20041125-C00237
     5
    Figure US20040235818A1-20041125-C00238
     6
    Figure US20040235818A1-20041125-C00239
     7
    Figure US20040235818A1-20041125-C00240
     8
    Figure US20040235818A1-20041125-C00241
     9
    Figure US20040235818A1-20041125-C00242
    10
    Figure US20040235818A1-20041125-C00243
    11
    Figure US20040235818A1-20041125-C00244
    12
    Figure US20040235818A1-20041125-C00245
    13
    Figure US20040235818A1-20041125-C00246
    14
    Figure US20040235818A1-20041125-C00247
    15
    Figure US20040235818A1-20041125-C00248
    16
    Figure US20040235818A1-20041125-C00249
    17
    Figure US20040235818A1-20041125-C00250
    18
    Figure US20040235818A1-20041125-C00251
  • [0350]
    TABLE 11
    Figure US20040235818A1-20041125-C00252
    Figure US20040235818A1-20041125-C00253
    1
    Figure US20040235818A1-20041125-C00254
    2
    Figure US20040235818A1-20041125-C00255
    3
    Figure US20040235818A1-20041125-C00256
    4
    Figure US20040235818A1-20041125-C00257
    5
    Figure US20040235818A1-20041125-C00258
    6
    Figure US20040235818A1-20041125-C00259
    7
    Figure US20040235818A1-20041125-C00260
    8
    Figure US20040235818A1-20041125-C00261
    9
    Figure US20040235818A1-20041125-C00262
    10
    Figure US20040235818A1-20041125-C00263
    11
    Figure US20040235818A1-20041125-C00264
    12
    Figure US20040235818A1-20041125-C00265
    13
    Figure US20040235818A1-20041125-C00266
    14
    Figure US20040235818A1-20041125-C00267
    15
    Figure US20040235818A1-20041125-C00268
    16
    Figure US20040235818A1-20041125-C00269
    17
    Figure US20040235818A1-20041125-C00270
    18
    Figure US20040235818A1-20041125-C00271
    19
    Figure US20040235818A1-20041125-C00272
    20
    Figure US20040235818A1-20041125-C00273
    21
    Figure US20040235818A1-20041125-C00274
  • [0351]
    TABLE 12
    Figure US20040235818A1-20041125-C00275
    Figure US20040235818A1-20041125-C00276
    1
    Figure US20040235818A1-20041125-C00277
    2
    Figure US20040235818A1-20041125-C00278
    3
    Figure US20040235818A1-20041125-C00279
    4
    Figure US20040235818A1-20041125-C00280
    5
    Figure US20040235818A1-20041125-C00281
    6
    Figure US20040235818A1-20041125-C00282
    7
    Figure US20040235818A1-20041125-C00283
    8
    Figure US20040235818A1-20041125-C00284
    9
    Figure US20040235818A1-20041125-C00285
    10
    Figure US20040235818A1-20041125-C00286
    11
    Figure US20040235818A1-20041125-C00287
    12
    Figure US20040235818A1-20041125-C00288
    13
    Figure US20040235818A1-20041125-C00289
    14
    Figure US20040235818A1-20041125-C00290
    15
    Figure US20040235818A1-20041125-C00291
    16
    Figure US20040235818A1-20041125-C00292
    17
    Figure US20040235818A1-20041125-C00293
    18
    Figure US20040235818A1-20041125-C00294
    19
    Figure US20040235818A1-20041125-C00295
    20
    Figure US20040235818A1-20041125-C00296
    21
    Figure US20040235818A1-20041125-C00297
    22
    Figure US20040235818A1-20041125-C00298
  • [0352]
    TABLE 13
    Figure US20040235818A1-20041125-C00299
    Figure US20040235818A1-20041125-C00300
    1
    Figure US20040235818A1-20041125-C00301
    2
    Figure US20040235818A1-20041125-C00302
    3
    Figure US20040235818A1-20041125-C00303
    4
    Figure US20040235818A1-20041125-C00304
    5
    Figure US20040235818A1-20041125-C00305
    6
    Figure US20040235818A1-20041125-C00306
    7
    Figure US20040235818A1-20041125-C00307
    8
    Figure US20040235818A1-20041125-C00308
    9
    Figure US20040235818A1-20041125-C00309
    10
    Figure US20040235818A1-20041125-C00310
    11
    Figure US20040235818A1-20041125-C00311
    12
    Figure US20040235818A1-20041125-C00312
    13
    Figure US20040235818A1-20041125-C00313
    14
    Figure US20040235818A1-20041125-C00314
    15
    Figure US20040235818A1-20041125-C00315
    16
    Figure US20040235818A1-20041125-C00316
    17
    Figure US20040235818A1-20041125-C00317
    18
    Figure US20040235818A1-20041125-C00318
    19
    Figure US20040235818A1-20041125-C00319
    20
    Figure US20040235818A1-20041125-C00320
    21
    Figure US20040235818A1-20041125-C00321
    22
    Figure US20040235818A1-20041125-C00322
    23
    Figure US20040235818A1-20041125-C00323
    24
    Figure US20040235818A1-20041125-C00324
    25
    Figure US20040235818A1-20041125-C00325
    26
    Figure US20040235818A1-20041125-C00326
    27
    Figure US20040235818A1-20041125-C00327
    28
    Figure US20040235818A1-20041125-C00328
    29
    Figure US20040235818A1-20041125-C00329
    30
    Figure US20040235818A1-20041125-C00330
  • [0353]
    TABLE 14
    Figure US20040235818A1-20041125-C00331
    Figure US20040235818A1-20041125-C00332
    1
    Figure US20040235818A1-20041125-C00333
    2
    Figure US20040235818A1-20041125-C00334
    3
    Figure US20040235818A1-20041125-C00335
    4
    Figure US20040235818A1-20041125-C00336
    5
    Figure US20040235818A1-20041125-C00337
    6
    Figure US20040235818A1-20041125-C00338
    7
    Figure US20040235818A1-20041125-C00339
    8
    Figure US20040235818A1-20041125-C00340
    9
    Figure US20040235818A1-20041125-C00341
    10
    Figure US20040235818A1-20041125-C00342
    11
    Figure US20040235818A1-20041125-C00343
    12
    Figure US20040235818A1-20041125-C00344
    13
    Figure US20040235818A1-20041125-C00345
    14
    Figure US20040235818A1-20041125-C00346
    15
    Figure US20040235818A1-20041125-C00347
    16
    Figure US20040235818A1-20041125-C00348
    17
    Figure US20040235818A1-20041125-C00349
    18
    Figure US20040235818A1-20041125-C00350
    19
    Figure US20040235818A1-20041125-C00351
    20
    Figure US20040235818A1-20041125-C00352
    21
    Figure US20040235818A1-20041125-C00353
  • [0354]
    TABLE 15
    Figure US20040235818A1-20041125-C00354
    Figure US20040235818A1-20041125-C00355
    1
    Figure US20040235818A1-20041125-C00356
    2
    Figure US20040235818A1-20041125-C00357
    3
    Figure US20040235818A1-20041125-C00358
    4
    Figure US20040235818A1-20041125-C00359
    5
    Figure US20040235818A1-20041125-C00360
    6
    Figure US20040235818A1-20041125-C00361
    7
    Figure US20040235818A1-20041125-C00362
    8
    Figure US20040235818A1-20041125-C00363
    9
    Figure US20040235818A1-20041125-C00364
    10
    Figure US20040235818A1-20041125-C00365
    11
    Figure US20040235818A1-20041125-C00366
  • [0355]
    TABLE 16
    Figure US20040235818A1-20041125-C00367
    Figure US20040235818A1-20041125-C00368
    1
    Figure US20040235818A1-20041125-C00369
    2
    Figure US20040235818A1-20041125-C00370
    3
    Figure US20040235818A1-20041125-C00371
    4
    Figure US20040235818A1-20041125-C00372
    5
    Figure US20040235818A1-20041125-C00373
    6
    Figure US20040235818A1-20041125-C00374
    7
    Figure US20040235818A1-20041125-C00375
    8
    Figure US20040235818A1-20041125-C00376
    9
    Figure US20040235818A1-20041125-C00377
    10
    Figure US20040235818A1-20041125-C00378
    11
    Figure US20040235818A1-20041125-C00379
    12
    Figure US20040235818A1-20041125-C00380
    13
    Figure US20040235818A1-20041125-C00381
    14
    Figure US20040235818A1-20041125-C00382
    15
    Figure US20040235818A1-20041125-C00383
    16
    Figure US20040235818A1-20041125-C00384
    17
    Figure US20040235818A1-20041125-C00385
    18
    Figure US20040235818A1-20041125-C00386
    19
    Figure US20040235818A1-20041125-C00387
    20
    Figure US20040235818A1-20041125-C00388
    21
    Figure US20040235818A1-20041125-C00389
  • [0356]
    TABLE 17
    Figure US20040235818A1-20041125-C00390
    Figure US20040235818A1-20041125-C00391
    1
    Figure US20040235818A1-20041125-C00392
    2
    Figure US20040235818A1-20041125-C00393
    3
    Figure US20040235818A1-20041125-C00394
    4
    Figure US20040235818A1-20041125-C00395
    5
    Figure US20040235818A1-20041125-C00396
    6
    Figure US20040235818A1-20041125-C00397
    7
    Figure US20040235818A1-20041125-C00398
    8
    Figure US20040235818A1-20041125-C00399
    9
    Figure US20040235818A1-20041125-C00400
    10
    Figure US20040235818A1-20041125-C00401
    11
    Figure US20040235818A1-20041125-C00402
    12
    Figure US20040235818A1-20041125-C00403
    13
    Figure US20040235818A1-20041125-C00404
    14
    Figure US20040235818A1-20041125-C00405
    15
    Figure US20040235818A1-20041125-C00406
    16
    Figure US20040235818A1-20041125-C00407
    17
    Figure US20040235818A1-20041125-C00408
    18
    Figure US20040235818A1-20041125-C00409
  • [0357]
    TABLE 18
    Figure US20040235818A1-20041125-C00410
    Figure US20040235818A1-20041125-C00411
    1
    Figure US20040235818A1-20041125-C00412
    2
    Figure US20040235818A1-20041125-C00413
    3
    Figure US20040235818A1-20041125-C00414
    4
    Figure US20040235818A1-20041125-C00415
    5
    Figure US20040235818A1-20041125-C00416
    6
    Figure US20040235818A1-20041125-C00417
    7
    Figure US20040235818A1-20041125-C00418
    8
    Figure US20040235818A1-20041125-C00419
    9
    Figure US20040235818A1-20041125-C00420
    10
    Figure US20040235818A1-20041125-C00421
    11
    Figure US20040235818A1-20041125-C00422
    12
    Figure US20040235818A1-20041125-C00423
    13
    Figure US20040235818A1-20041125-C00424
    14
    Figure US20040235818A1-20041125-C00425
    15
    Figure US20040235818A1-20041125-C00426
    16
    Figure US20040235818A1-20041125-C00427
    17
    Figure US20040235818A1-20041125-C00428
    18
    Figure US20040235818A1-20041125-C00429
    19
    Figure US20040235818A1-20041125-C00430
    20
    Figure US20040235818A1-20041125-C00431
    21
    Figure US20040235818A1-20041125-C00432
  • [0358]
    TABLE 19
    Figure US20040235818A1-20041125-C00433
    Figure US20040235818A1-20041125-C00434
    1
    Figure US20040235818A1-20041125-C00435
    2
    Figure US20040235818A1-20041125-C00436
    3
    Figure US20040235818A1-20041125-C00437
    4
    Figure US20040235818A1-20041125-C00438
    5
    Figure US20040235818A1-20041125-C00439
    6
    Figure US20040235818A1-20041125-C00440
    7
    Figure US20040235818A1-20041125-C00441
    8
    Figure US20040235818A1-20041125-C00442
    9
    Figure US20040235818A1-20041125-C00443
    10
    Figure US20040235818A1-20041125-C00444
    11
    Figure US20040235818A1-20041125-C00445
    12
    Figure US20040235818A1-20041125-C00446
    13
    Figure US20040235818A1-20041125-C00447
    14
    Figure US20040235818A1-20041125-C00448
    15
    Figure US20040235818A1-20041125-C00449
    16
    Figure US20040235818A1-20041125-C00450
    17
    Figure US20040235818A1-20041125-C00451
    18
    Figure US20040235818A1-20041125-C00452
    19
    Figure US20040235818A1-20041125-C00453
    20
    Figure US20040235818A1-20041125-C00454
    21
    Figure US20040235818A1-20041125-C00455
    22
    Figure US20040235818A1-20041125-C00456
  • [0359]
    TABLE 20
    Figure US20040235818A1-20041125-C00457
    Figure US20040235818A1-20041125-C00458
    1
    Figure US20040235818A1-20041125-C00459
    2
    Figure US20040235818A1-20041125-C00460
    3
    Figure US20040235818A1-20041125-C00461
    4
    Figure US20040235818A1-20041125-C00462
    5
    Figure US20040235818A1-20041125-C00463
    6
    Figure US20040235818A1-20041125-C00464
    7
    Figure US20040235818A1-20041125-C00465
    8
    Figure US20040235818A1-20041125-C00466
    9
    Figure US20040235818A1-20041125-C00467
    10
    Figure US20040235818A1-20041125-C00468
    11
    Figure US20040235818A1-20041125-C00469
    12
    Figure US20040235818A1-20041125-C00470
    13
    Figure US20040235818A1-20041125-C00471
    14
    Figure US20040235818A1-20041125-C00472
    15
    Figure US20040235818A1-20041125-C00473
    16
    Figure US20040235818A1-20041125-C00474
    17
    Figure US20040235818A1-20041125-C00475
    18
    Figure US20040235818A1-20041125-C00476
    19
    Figure US20040235818A1-20041125-C00477
    20
    Figure US20040235818A1-20041125-C00478
    21
    Figure US20040235818A1-20041125-C00479
    22
    Figure US20040235818A1-20041125-C00480
    23
    Figure US20040235818A1-20041125-C00481
    24
    Figure US20040235818A1-20041125-C00482
    25
    Figure US20040235818A1-20041125-C00483
    26
    Figure US20040235818A1-20041125-C00484
    27
    Figure US20040235818A1-20041125-C00485
    28
    Figure US20040235818A1-20041125-C00486
    29
    Figure US20040235818A1-20041125-C00487
    30
    Figure US20040235818A1-20041125-C00488
  • [0360]
    TABLE 21
    Figure US20040235818A1-20041125-C00489
     1
    Figure US20040235818A1-20041125-C00490
     2
    Figure US20040235818A1-20041125-C00491
     3
    Figure US20040235818A1-20041125-C00492
     4
    Figure US20040235818A1-20041125-C00493
     5
    Figure US20040235818A1-20041125-C00494
     6
    Figure US20040235818A1-20041125-C00495
     7
    Figure US20040235818A1-20041125-C00496
     8
    Figure US20040235818A1-20041125-C00497
     9
    Figure US20040235818A1-20041125-C00498
    10
    Figure US20040235818A1-20041125-C00499
    11
    Figure US20040235818A1-20041125-C00500
    12
    Figure US20040235818A1-20041125-C00501
    13
    Figure US20040235818A1-20041125-C00502
    14
    Figure US20040235818A1-20041125-C00503
    15
    Figure US20040235818A1-20041125-C00504
    16
    Figure US20040235818A1-20041125-C00505
    17
    Figure US20040235818A1-20041125-C00506
    18
    Figure US20040235818A1-20041125-C00507
    19
    Figure US20040235818A1-20041125-C00508
    20
    Figure US20040235818A1-20041125-C00509
    21
    Figure US20040235818A1-20041125-C00510
  • [0361]
    TABLE 22
    Figure US20040235818A1-20041125-C00511
     1
    Figure US20040235818A1-20041125-C00512
     2
    Figure US20040235818A1-20041125-C00513
     3
    Figure US20040235818A1-20041125-C00514
     4
    Figure US20040235818A1-20041125-C00515
     5
    Figure US20040235818A1-20041125-C00516
     6
    Figure US20040235818A1-20041125-C00517
     7
    Figure US20040235818A1-20041125-C00518
     8
    Figure US20040235818A1-20041125-C00519
     9
    Figure US20040235818A1-20041125-C00520
    10
    Figure US20040235818A1-20041125-C00521
    11
    Figure US20040235818A1-20041125-C00522
  • [0362]
    TABLE 23
    Figure US20040235818A1-20041125-C00523
     1
    Figure US20040235818A1-20041125-C00524
     2
    Figure US20040235818A1-20041125-C00525
     3
    Figure US20040235818A1-20041125-C00526
     4
    Figure US20040235818A1-20041125-C00527
     5
    Figure US20040235818A1-20041125-C00528
     6
    Figure US20040235818A1-20041125-C00529
     7
    Figure US20040235818A1-20041125-C00530
     8
    Figure US20040235818A1-20041125-C00531
     9
    Figure US20040235818A1-20041125-C00532
    10
    Figure US20040235818A1-20041125-C00533
    11
    Figure US20040235818A1-20041125-C00534
    12
    Figure US20040235818A1-20041125-C00535
    13
    Figure US20040235818A1-20041125-C00536
    14
    Figure US20040235818A1-20041125-C00537
    15
    Figure US20040235818A1-20041125-C00538
    16
    Figure US20040235818A1-20041125-C00539
    17
    Figure US20040235818A1-20041125-C00540
    18
    Figure US20040235818A1-20041125-C00541
    19
    Figure US20040235818A1-20041125-C00542
    20
    Figure US20040235818A1-20041125-C00543
    21
    Figure US20040235818A1-20041125-C00544
  • [0363]
    TABLE 24
    Figure US20040235818A1-20041125-C00545
     1
    Figure US20040235818A1-20041125-C00546
     2
    Figure US20040235818A1-20041125-C00547
     3
    Figure US20040235818A1-20041125-C00548
     4
    Figure US20040235818A1-20041125-C00549
     5
    Figure US20040235818A1-20041125-C00550
     6
    Figure US20040235818A1-20041125-C00551
     7
    Figure US20040235818A1-20041125-C00552
     8
    Figure US20040235818A1-20041125-C00553
     9
    Figure US20040235818A1-20041125-C00554
    10
    Figure US20040235818A1-20041125-C00555
    11
    Figure US20040235818A1-20041125-C00556
    12
    Figure US20040235818A1-20041125-C00557
    13
    Figure US20040235818A1-20041125-C00558
    14
    Figure US20040235818A1-20041125-C00559
    15
    Figure US20040235818A1-20041125-C00560
    16
    Figure US20040235818A1-20041125-C00561
    17
    Figure US20040235818A1-20041125-C00562
    18
    Figure US20040235818A1-20041125-C00563
  • [0364]
    TABLE 25
    Figure US20040235818A1-20041125-C00564
     1
    Figure US20040235818A1-20041125-C00565
     2
    Figure US20040235818A1-20041125-C00566
     3
    Figure US20040235818A1-20041125-C00567
     4
    Figure US20040235818A1-20041125-C00568
     5
    Figure US20040235818A1-20041125-C00569
     6
    Figure US20040235818A1-20041125-C00570
     7
    Figure US20040235818A1-20041125-C00571
     8
    Figure US20040235818A1-20041125-C00572
     9
    Figure US20040235818A1-20041125-C00573
    10
    Figure US20040235818A1-20041125-C00574
    11
    Figure US20040235818A1-20041125-C00575
    12
    Figure US20040235818A1-20041125-C00576
    13
    Figure US20040235818A1-20041125-C00577
    14
    Figure US20040235818A1-20041125-C00578
    15
    Figure US20040235818A1-20041125-C00579
    16
    Figure US20040235818A1-20041125-C00580
    17
    Figure US20040235818A1-20041125-C00581
    18
    Figure US20040235818A1-20041125-C00582
    19
    Figure US20040235818A1-20041125-C00583
    20
    Figure US20040235818A1-20041125-C00584
    21
    Figure US20040235818A1-20041125-C00585
  • [0365]
    TABLE 26
    Figure US20040235818A1-20041125-C00586
     1
    Figure US20040235818A1-20041125-C00587
     2
    Figure US20040235818A1-20041125-C00588
     3
    Figure US20040235818A1-20041125-C00589
     4
    Figure US20040235818A1-20041125-C00590
     5
    Figure US20040235818A1-20041125-C00591
     6
    Figure US20040235818A1-20041125-C00592
     7
    Figure US20040235818A1-20041125-C00593
     8
    Figure US20040235818A1-20041125-C00594
     9
    Figure US20040235818A1-20041125-C00595
    10
    Figure US20040235818A1-20041125-C00596
    11
    Figure US20040235818A1-20041125-C00597
    12
    Figure US20040235818A1-20041125-C00598
    13
    Figure US20040235818A1-20041125-C00599
    14
    Figure US20040235818A1-20041125-C00600
    15
    Figure US20040235818A1-20041125-C00601
    16
    Figure US20040235818A1-20041125-C00602
    17
    Figure US20040235818A1-20041125-C00603
    18
    Figure US20040235818A1-20041125-C00604
    19
    Figure US20040235818A1-20041125-C00605
    20
    Figure US20040235818A1-20041125-C00606
    21
    Figure US20040235818A1-20041125-C00607
    22
    Figure US20040235818A1-20041125-C00608
  • [0366]
    TABLE 27
    Figure US20040235818A1-20041125-C00609
     1
    Figure US20040235818A1-20041125-C00610
     2
    Figure US20040235818A1-20041125-C00611
     3
    Figure US20040235818A1-20041125-C00612
     4
    Figure US20040235818A1-20041125-C00613
     5
    Figure US20040235818A1-20041125-C00614
     6
    Figure US20040235818A1-20041125-C00615
     7
    Figure US20040235818A1-20041125-C00616
     8
    Figure US20040235818A1-20041125-C00617
     9
    Figure US20040235818A1-20041125-C00618
    10
    Figure US20040235818A1-20041125-C00619
    11
    Figure US20040235818A1-20041125-C00620
    12
    Figure US20040235818A1-20041125-C00621
    13
    Figure US20040235818A1-20041125-C00622
    14
    Figure US20040235818A1-20041125-C00623
    15
    Figure US20040235818A1-20041125-C00624
    16
    Figure US20040235818A1-20041125-C00625
    17
    Figure US20040235818A1-20041125-C00626
    18
    Figure US20040235818A1-20041125-C00627
    19
    Figure US20040235818A1-20041125-C00628
    20
    Figure US20040235818A1-20041125-C00629
    21
    Figure US20040235818A1-20041125-C00630
    22
    Figure US20040235818A1-20041125-C00631
    23
    Figure US20040235818A1-20041125-C00632
    24
    Figure US20040235818A1-20041125-C00633
    25
    Figure US20040235818A1-20041125-C00634
    26
    Figure US20040235818A1-20041125-C00635
    27
    Figure US20040235818A1-20041125-C00636
    28
    Figure US20040235818A1-20041125-C00637
    29
    Figure US20040235818A1-20041125-C00638
    30
    Figure US20040235818A1-20041125-C00639
  • [0367]
    TABLE 28
    Figure US20040235818A1-20041125-C00640
     1
    Figure US20040235818A1-20041125-C00641
     2
    Figure US20040235818A1-20041125-C00642
     3
    Figure US20040235818A1-20041125-C00643
     4
    Figure US20040235818A1-20041125-C00644
     5
    Figure US20040235818A1-20041125-C00645
     6
    Figure US20040235818A1-20041125-C00646
     7
    Figure US20040235818A1-20041125-C00647
     8
    Figure US20040235818A1-20041125-C00648
     9
    Figure US20040235818A1-20041125-C00649
    10
    Figure US20040235818A1-20041125-C00650
    11
    Figure US20040235818A1-20041125-C00651
    12
    Figure US20040235818A1-20041125-C00652
    13
    Figure US20040235818A1-20041125-C00653
    14
    Figure US20040235818A1-20041125-C00654
    15
    Figure US20040235818A1-20041125-C00655
    16
    Figure US20040235818A1-20041125-C00656
    17
    Figure US20040235818A1-20041125-C00657
    18
    Figure US20040235818A1-20041125-C00658
    19
    Figure US20040235818A1-20041125-C00659
    20
    Figure US20040235818A1-20041125-C00660
    21
    Figure US20040235818A1-20041125-C00661
  • [0368]
    TABLE 29
    Figure US20040235818A1-20041125-C00662
     1
    Figure US20040235818A1-20041125-C00663
     2
    Figure US20040235818A1-20041125-C00664
     3
    Figure US20040235818A1-20041125-C00665
     4
    Figure US20040235818A1-20041125-C00666
     5
    Figure US20040235818A1-20041125-C00667
     6
    Figure US20040235818A1-20041125-C00668
     7
    Figure US20040235818A1-20041125-C00669
     8
    Figure US20040235818A1-20041125-C00670
     9
    Figure US20040235818A1-20041125-C00671
    10
    Figure US20040235818A1-20041125-C00672
    11
    Figure US20040235818A1-20041125-C00673
  • [0369]
    TABLE 30
    Figure US20040235818A1-20041125-C00674
     1
    Figure US20040235818A1-20041125-C00675
     2
    Figure US20040235818A1-20041125-C00676
     3
    Figure US20040235818A1-20041125-C00677
     4
    Figure US20040235818A1-20041125-C00678
     5
    Figure US20040235818A1-20041125-C00679
     6
    Figure US20040235818A1-20041125-C00680
     7
    Figure US20040235818A1-20041125-C00681
     8
    Figure US20040235818A1-20041125-C00682
     9
    Figure US20040235818A1-20041125-C00683
    10
    Figure US20040235818A1-20041125-C00684
    11
    Figure US20040235818A1-20041125-C00685
    12
    Figure US20040235818A1-20041125-C00686
    13
    Figure US20040235818A1-20041125-C00687
    14
    Figure US20040235818A1-20041125-C00688
    15
    Figure US20040235818A1-20041125-C00689
    16
    Figure US20040235818A1-20041125-C00690
    17
    Figure US20040235818A1-20041125-C00691
    18
    Figure US20040235818A1-20041125-C00692
  • [0370]
    TABLE 31
    Figure US20040235818A1-20041125-C00693
     1
    Figure US20040235818A1-20041125-C00694
     2
    Figure US20040235818A1-20041125-C00695
     3
    Figure US20040235818A1-20041125-C00696
     4
    Figure US20040235818A1-20041125-C00697
     5
    Figure US20040235818A1-20041125-C00698
     6
    Figure US20040235818A1-20041125-C00699
     7
    Figure US20040235818A1-20041125-C00700
     8
    Figure US20040235818A1-20041125-C00701
     9
    Figure US20040235818A1-20041125-C00702
    10
    Figure US20040235818A1-20041125-C00703
    11
    Figure US20040235818A1-20041125-C00704
    12
    Figure US20040235818A1-20041125-C00705
    13
    Figure US20040235818A1-20041125-C00706
    14
    Figure US20040235818A1-20041125-C00707
    15
    Figure US20040235818A1-20041125-C00708
    16
    Figure US20040235818A1-20041125-C00709
    17
    Figure US20040235818A1-20041125-C00710
    18
    Figure US20040235818A1-20041125-C00711
    19
    Figure US20040235818A1-20041125-C00712
    20
    Figure US20040235818A1-20041125-C00713
    21
    Figure US20040235818A1-20041125-C00714
  • [0371]
    TABLE 32
    Figure US20040235818A1-20041125-C00715
     1
    Figure US20040235818A1-20041125-C00716
     2
    Figure US20040235818A1-20041125-C00717
     3
    Figure US20040235818A1-20041125-C00718
     4
    Figure US20040235818A1-20041125-C00719
     5
    Figure US20040235818A1-20041125-C00720
     6
    Figure US20040235818A1-20041125-C00721
     7
    Figure US20040235818A1-20041125-C00722
     8
    Figure US20040235818A1-20041125-C00723
     9
    Figure US20040235818A1-20041125-C00724
    10
    Figure US20040235818A1-20041125-C00725
    11
    Figure US20040235818A1-20041125-C00726
    12
    Figure US20040235818A1-20041125-C00727
    13
    Figure US20040235818A1-20041125-C00728
    14
    Figure US20040235818A1-20041125-C00729
    15
    Figure US20040235818A1-20041125-C00730
    16
    Figure US20040235818A1-20041125-C00731
    17
    Figure US20040235818A1-20041125-C00732
    18
    Figure US20040235818A1-20041125-C00733
    19
    Figure US20040235818A1-20041125-C00734
    20
    Figure US20040235818A1-20041125-C00735
    21
    Figure US20040235818A1-20041125-C00736
    22
    Figure US20040235818A1-20041125-C00737
  • [0372]
    TABLE 33
    Figure US20040235818A1-20041125-C00738
     1
    Figure US20040235818A1-20041125-C00739
     2
    Figure US20040235818A1-20041125-C00740
     3
    Figure US20040235818A1-20041125-C00741
     4
    Figure US20040235818A1-20041125-C00742
     5
    Figure US20040235818A1-20041125-C00743
     6
    Figure US20040235818A1-20041125-C00744
     7
    Figure US20040235818A1-20041125-C00745
     8
    Figure US20040235818A1-20041125-C00746
     9
    Figure US20040235818A1-20041125-C00747
    10
    Figure US20040235818A1-20041125-C00748
    11
    Figure US20040235818A1-20041125-C00749
    12
    Figure US20040235818A1-20041125-C00750
    13
    Figure US20040235818A1-20041125-C00751
    14
    Figure US20040235818A1-20041125-C00752
    15
    Figure US20040235818A1-20041125-C00753
    16
    Figure US20040235818A1-20041125-C00754
    17
    Figure US20040235818A1-20041125-C00755
    18
    Figure US20040235818A1-20041125-C00756
    19
    Figure US20040235818A1-20041125-C00757
    20
    Figure US20040235818A1-20041125-C00758
    21
    Figure US20040235818A1-20041125-C00759
    22
    Figure US20040235818A1-20041125-C00760
    23
    Figure US20040235818A1-20041125-C00761
    24
    Figure US20040235818A1-20041125-C00762
    25
    Figure US20040235818A1-20041125-C00763
    26
    Figure US20040235818A1-20041125-C00764
    27
    Figure US20040235818A1-20041125-C00765
    28
    Figure US20040235818A1-20041125-C00766
    29
    Figure US20040235818A1-20041125-C00767
    30
    Figure US20040235818A1-20041125-C00768
  • [0373]
    TABLE 34
    Figure US20040235818A1-20041125-C00769
     1
    Figure US20040235818A1-20041125-C00770
     2
    Figure US20040235818A1-20041125-C00771
     3
    Figure US20040235818A1-20041125-C00772
     4
    Figure US20040235818A1-20041125-C00773
     5
    Figure US20040235818A1-20041125-C00774
     6
    Figure US20040235818A1-20041125-C00775
     7
    Figure US20040235818A1-20041125-C00776
     8
    Figure US20040235818A1-20041125-C00777
     9
    Figure US20040235818A1-20041125-C00778
    10
    Figure US20040235818A1-20041125-C00779
    11
    Figure US20040235818A1-20041125-C00780
    12
    Figure US20040235818A1-20041125-C00781
    13
    Figure US20040235818A1-20041125-C00782
    14
    Figure US20040235818A1-20041125-C00783
    15
    Figure US20040235818A1-20041125-C00784
    16
    Figure US20040235818A1-20041125-C00785
    17
    Figure US20040235818A1-20041125-C00786
    18
    Figure US20040235818A1-20041125-C00787
    19
    Figure US20040235818A1-20041125-C00788
    20
    Figure US20040235818A1-20041125-C00789
    21
    Figure US20040235818A1-20041125-C00790
  • [0374]
    TABLE 35
    Figure US20040235818A1-20041125-C00791
    1
    Figure US20040235818A1-20041125-C00792
    2
    Figure US20040235818A1-20041125-C00793
    3
    Figure US20040235818A1-20041125-C00794
    4
    Figure US20040235818A1-20041125-C00795
    5
    Figure US20040235818A1-20041125-C00796
    6
    Figure US20040235818A1-20041125-C00797
    7
    Figure US20040235818A1-20041125-C00798
    8
    Figure US20040235818A1-20041125-C00799
    9
    Figure US20040235818A1-20041125-C00800
    10 
    Figure US20040235818A1-20041125-C00801
    11 
    Figure US20040235818A1-20041125-C00802
  • [0375]
    TABLE 36
    Figure US20040235818A1-20041125-C00803
     1
    Figure US20040235818A1-20041125-C00804
     2
    Figure US20040235818A1-20041125-C00805
     3
    Figure US20040235818A1-20041125-C00806
     4
    Figure US20040235818A1-20041125-C00807
     5
    Figure US20040235818A1-20041125-C00808
     6
    Figure US20040235818A1-20041125-C00809
     7
    Figure US20040235818A1-20041125-C00810
     8
    Figure US20040235818A1-20041125-C00811
     9
    Figure US20040235818A1-20041125-C00812
    10
    Figure US20040235818A1-20041125-C00813
    11
    Figure US20040235818A1-20041125-C00814
    12
    Figure US20040235818A1-20041125-C00815
    13
    Figure US20040235818A1-20041125-C00816
    14
    Figure US20040235818A1-20041125-C00817
    15
    Figure US20040235818A1-20041125-C00818
    16
    Figure US20040235818A1-20041125-C00819
    17
    Figure US20040235818A1-20041125-C00820
    18
    Figure US20040235818A1-20041125-C00821
    19
    Figure US20040235818A1-20041125-C00822
    20
    Figure US20040235818A1-20041125-C00823
    21
    Figure US20040235818A1-20041125-C00824
  • [0376]
    TABLE 37
    Figure US20040235818A1-20041125-C00825
     1
    Figure US20040235818A1-20041125-C00826
     2
    Figure US20040235818A1-20041125-C00827
     3
    Figure US20040235818A1-20041125-C00828
     4
    Figure US20040235818A1-20041125-C00829
     5
    Figure US20040235818A1-20041125-C00830
     6
    Figure US20040235818A1-20041125-C00831
     7
    Figure US20040235818A1-20041125-C00832
     8
    Figure US20040235818A1-20041125-C00833
     9
    Figure US20040235818A1-20041125-C00834
    10
    Figure US20040235818A1-20041125-C00835
    11
    Figure US20040235818A1-20041125-C00836
    12
    Figure US20040235818A1-20041125-C00837
    13
    Figure US20040235818A1-20041125-C00838
    14
    Figure US20040235818A1-20041125-C00839
    15
    Figure US20040235818A1-20041125-C00840
    16
    Figure US20040235818A1-20041125-C00841
    17
    Figure US20040235818A1-20041125-C00842
    18
    Figure US20040235818A1-20041125-C00843
  • [0377]
    TABLE 38
    Figure US20040235818A1-20041125-C00844
     1
    Figure US20040235818A1-20041125-C00845
     2
    Figure US20040235818A1-20041125-C00846
     3
    Figure US20040235818A1-20041125-C00847
     4
    Figure US20040235818A1-20041125-C00848
     5
    Figure US20040235818A1-20041125-C00849
     6
    Figure US20040235818A1-20041125-C00850
     7
    Figure US20040235818A1-20041125-C00851
     8
    Figure US20040235818A1-20041125-C00852
     9
    Figure US20040235818A1-20041125-C00853
    10
    Figure US20040235818A1-20041125-C00854
    11
    Figure US20040235818A1-20041125-C00855
    12
    Figure US20040235818A1-20041125-C00856
    13
    Figure US20040235818A1-20041125-C00857
    14
    Figure US20040235818A1-20041125-C00858
    15
    Figure US20040235818A1-20041125-C00859
    16
    Figure US20040235818A1-20041125-C00860
    17
    Figure US20040235818A1-20041125-C00861
    18
    Figure US20040235818A1-20041125-C00862
    19
    Figure US20040235818A1-20041125-C00863
    20
    Figure US20040235818A1-20041125-C00864
    21
    Figure US20040235818A1-20041125-C00865
  • [0378]
    TABLE 39
    Figure US20040235818A1-20041125-C00866
     1
    Figure US20040235818A1-20041125-C00867
     2
    Figure US20040235818A1-20041125-C00868
     3
    Figure US20040235818A1-20041125-C00869
     4
    Figure US20040235818A1-20041125-C00870
     5
    Figure US20040235818A1-20041125-C00871
     6
    Figure US20040235818A1-20041125-C00872
     7
    Figure US20040235818A1-20041125-C00873
     8
    Figure US20040235818A1-20041125-C00874
     9
    Figure US20040235818A1-20041125-C00875
    10
    Figure US20040235818A1-20041125-C00876
    11
    Figure US20040235818A1-20041125-C00877
    12
    Figure US20040235818A1-20041125-C00878
    13
    Figure US20040235818A1-20041125-C00879
    14
    Figure US20040235818A1-20041125-C00880
    15
    Figure US20040235818A1-20041125-C00881
    16
    Figure US20040235818A1-20041125-C00882
    17
    Figure US20040235818A1-20041125-C00883
    18
    Figure US20040235818A1-20041125-C00884
    19
    Figure US20040235818A1-20041125-C00885
    20
    Figure US20040235818A1-20041125-C00886
    21
    Figure US20040235818A1-20041125-C00887
    22
    Figure US20040235818A1-20041125-C00888
  • [0379]
    TABLE 40
    Figure US20040235818A1-20041125-C00889
     1
    Figure US20040235818A1-20041125-C00890
     2
    Figure US20040235818A1-20041125-C00891
     3
    Figure US20040235818A1-20041125-C00892
     4
    Figure US20040235818A1-20041125-C00893
     5
    Figure US20040235818A1-20041125-C00894
     6
    Figure US20040235818A1-20041125-C00895
     7
    Figure US20040235818A1-20041125-C00896
     8
    Figure US20040235818A1-20041125-C00897
     9
    Figure US20040235818A1-20041125-C00898
    10
    Figure US20040235818A1-20041125-C00899
    11
    Figure US20040235818A1-20041125-C00900
    12
    Figure US20040235818A1-20041125-C00901
    13
    Figure US20040235818A1-20041125-C00902
    14
    Figure US20040235818A1-20041125-C00903
    15
    Figure US20040235818A1-20041125-C00904
    16
    Figure US20040235818A1-20041125-C00905
    17
    Figure US20040235818A1-20041125-C00906
    18
    Figure US20040235818A1-20041125-C00907
    19
    Figure US20040235818A1-20041125-C00908
    20
    Figure US20040235818A1-20041125-C00909
    21
    Figure US20040235818A1-20041125-C00910
    22
    Figure US20040235818A1-20041125-C00911
    23
    Figure US20040235818A1-20041125-C00912
    24
    Figure US20040235818A1-20041125-C00913
    25
    Figure US20040235818A1-20041125-C00914
    26
    Figure US20040235818A1-20041125-C00915
    27
    Figure US20040235818A1-20041125-C00916
    28
    Figure US20040235818A1-20041125-C00917
    29
    Figure US20040235818A1-20041125-C00918
    30
    Figure US20040235818A1-20041125-C00919
  • [0380]
    TABLE 41
    Figure US20040235818A1-20041125-C00920
     1
    Figure US20040235818A1-20041125-C00921
     2
    Figure US20040235818A1-20041125-C00922
     3
    Figure US20040235818A1-20041125-C00923
     4
    Figure US20040235818A1-20041125-C00924
     5
    Figure US20040235818A1-20041125-C00925
     6
    Figure US20040235818A1-20041125-C00926
     7
    Figure US20040235818A1-20041125-C00927
     8
    Figure US20040235818A1-20041125-C00928
     9
    Figure US20040235818A1-20041125-C00929
    10
    Figure US20040235818A1-20041125-C00930
    11
    Figure US20040235818A1-20041125-C00931
    12
    Figure US20040235818A1-20041125-C00932
    13
    Figure US20040235818A1-20041125-C00933
    14
    Figure US20040235818A1-20041125-C00934
    15
    Figure US20040235818A1-20041125-C00935
    16
    Figure US20040235818A1-20041125-C00936
    17
    Figure US20040235818A1-20041125-C00937
    18
    Figure US20040235818A1-20041125-C00938
    19
    Figure US20040235818A1-20041125-C00939
    20
    Figure US20040235818A1-20041125-C00940
    21
    Figure US20040235818A1-20041125-C00941
  • [0381]
    TABLE 42
    Figure US20040235818A1-20041125-C00942
    1
    Figure US20040235818A1-20041125-C00943
    2
    Figure US20040235818A1-20041125-C00944
    3
    Figure US20040235818A1-20041125-C00945
    4
    Figure US20040235818A1-20041125-C00946
    5
    Figure US20040235818A1-20041125-C00947
    6
    Figure US20040235818A1-20041125-C00948
    7
    Figure US20040235818A1-20041125-C00949
    8
    Figure US20040235818A1-20041125-C00950
    9
    Figure US20040235818A1-20041125-C00951
    10 
    Figure US20040235818A1-20041125-C00952
    11 
    Figure US20040235818A1-20041125-C00953
  • [0382]
    TABLE 43
    Figure US20040235818A1-20041125-C00954
     1
    Figure US20040235818A1-20041125-C00955
     2
    Figure US20040235818A1-20041125-C00956
     3
    Figure US20040235818A1-20041125-C00957
     4
    Figure US20040235818A1-20041125-C00958
     5
    Figure US20040235818A1-20041125-C00959
     6
    Figure US20040235818A1-20041125-C00960
     7
    Figure US20040235818A1-20041125-C00961
     8
    Figure US20040235818A1-20041125-C00962
     9
    Figure US20040235818A1-20041125-C00963
    10
    Figure US20040235818A1-20041125-C00964
    11
    Figure US20040235818A1-20041125-C00965
    12
    Figure US20040235818A1-20041125-C00966
    13
    Figure US20040235818A1-20041125-C00967
    14
    Figure US20040235818A1-20041125-C00968
    15
    Figure US20040235818A1-20041125-C00969
    16
    Figure US20040235818A1-20041125-C00970
    17
    Figure US20040235818A1-20041125-C00971
    18
    Figure US20040235818A1-20041125-C00972
    19
    Figure US20040235818A1-20041125-C00973
    20
    Figure US20040235818A1-20041125-C00974
    21
    Figure US20040235818A1-20041125-C00975
  • [0383]
    TABLE 44
    Figure US20040235818A1-20041125-C00976
     1
    Figure US20040235818A1-20041125-C00977
     2
    Figure US20040235818A1-20041125-C00978
     3
    Figure US20040235818A1-20041125-C00979
     4
    Figure US20040235818A1-20041125-C00980
     5
    Figure US20040235818A1-20041125-C00981
     6
    Figure US20040235818A1-20041125-C00982
     7
    Figure US20040235818A1-20041125-C00983
     8
    Figure US20040235818A1-20041125-C00984
     9
    Figure US20040235818A1-20041125-C00985
    10
    Figure US20040235818A1-20041125-C00986
    11
    Figure US20040235818A1-20041125-C00987
    12
    Figure US20040235818A1-20041125-C00988
    13
    Figure US20040235818A1-20041125-C00989
    14
    Figure US20040235818A1-20041125-C00990
    15
    Figure US20040235818A1-20041125-C00991
    16
    Figure US20040235818A1-20041125-C00992
    17
    Figure US20040235818A1-20041125-C00993
    18
    Figure US20040235818A1-20041125-C00994
  • [0384]
    TABLE 45
    Figure US20040235818A1-20041125-C00995
     1
    Figure US20040235818A1-20041125-C00996
     2
    Figure US20040235818A1-20041125-C00997
     3
    Figure US20040235818A1-20041125-C00998
     4
    Figure US20040235818A1-20041125-C00999
     5
    Figure US20040235818A1-20041125-C01000
     6
    Figure US20040235818A1-20041125-C01001
     7
    Figure US20040235818A1-20041125-C01002
     8
    Figure US20040235818A1-20041125-C01003
     9
    Figure US20040235818A1-20041125-C01004
    10
    Figure US20040235818A1-20041125-C01005
    11
    Figure US20040235818A1-20041125-C01006
    12
    Figure US20040235818A1-20041125-C01007
    13
    Figure US20040235818A1-20041125-C01008
    14
    Figure US20040235818A1-20041125-C01009
    15
    Figure US20040235818A1-20041125-C01010
    16
    Figure US20040235818A1-20041125-C01011
    17
    Figure US20040235818A1-20041125-C01012
    18
    Figure US20040235818A1-20041125-C01013
    19
    Figure US20040235818A1-20041125-C01014
    20
    Figure US20040235818A1-20041125-C01015
    21
    Figure US20040235818A1-20041125-C01016
  • [0385]
    TABLE 46
    Figure US20040235818A1-20041125-C01017
     1
    Figure US20040235818A1-20041125-C01018
     2
    Figure US20040235818A1-20041125-C01019
     3
    Figure US20040235818A1-20041125-C01020
     4
    Figure US20040235818A1-20041125-C01021
     5
    Figure US20040235818A1-20041125-C01022
     6
    Figure US20040235818A1-20041125-C01023
     7
    Figure US20040235818A1-20041125-C01024
     8
    Figure US20040235818A1-20041125-C01025
     9
    Figure US20040235818A1-20041125-C01026
    10
    Figure US20040235818A1-20041125-C01027
    11
    Figure US20040235818A1-20041125-C01028
    12
    Figure US20040235818A1-20041125-C01029
    13
    Figure US20040235818A1-20041125-C01030
    14
    Figure US20040235818A1-20041125-C01031
    15
    Figure US20040235818A1-20041125-C01032
    16
    Figure US20040235818A1-20041125-C01033
    17
    Figure US20040235818A1-20041125-C01034
    18
    Figure US20040235818A1-20041125-C01035
    19
    Figure US20040235818A1-20041125-C01036
    20
    Figure US20040235818A1-20041125-C01037
    21
    Figure US20040235818A1-20041125-C01038
    22
    Figure US20040235818A1-20041125-C01039
  • [0386]
    TABLE 47
    Figure US20040235818A1-20041125-C01040
     1
    Figure US20040235818A1-20041125-C01041
     2
    Figure US20040235818A1-20041125-C01042
     3
    Figure US20040235818A1-20041125-C01043
     4
    Figure US20040235818A1-20041125-C01044
     5
    Figure US20040235818A1-20041125-C01045
     6
    Figure US20040235818A1-20041125-C01046
     7
    Figure US20040235818A1-20041125-C01047
     8
    Figure US20040235818A1-20041125-C01048
     9
    Figure US20040235818A1-20041125-C01049
    10
    Figure US20040235818A1-20041125-C01050
    11
    Figure US20040235818A1-20041125-C01051
    12
    Figure US20040235818A1-20041125-C01052
    13
    Figure US20040235818A1-20041125-C01053
    14
    Figure US20040235818A1-20041125-C01054
    15
    Figure US20040235818A1-20041125-C01055
    16
    Figure US20040235818A1-20041125-C01056
    17
    Figure US20040235818A1-20041125-C01057
    18
    Figure US20040235818A1-20041125-C01058
    19
    Figure US20040235818A1-20041125-C01059
    20
    Figure US20040235818A1-20041125-C01060
    21
    Figure US20040235818A1-20041125-C01061
    22
    Figure US20040235818A1-20041125-C01062
    23
    Figure US20040235818A1-20041125-C01063
    24
    Figure US20040235818A1-20041125-C01064
    25
    Figure US20040235818A1-20041125-C01065
    26
    Figure US20040235818A1-20041125-C01066
    27
    Figure US20040235818A1-20041125-C01067
    28
    Figure US20040235818A1-20041125-C01068
    29
    Figure US20040235818A1-20041125-C01069
    30
    Figure US20040235818A1-20041125-C01070
  • [0387]
    TABLE 48
    Figure US20040235818A1-20041125-C01071
     1
    Figure US20040235818A1-20041125-C01072
     2
    Figure US20040235818A1-20041125-C01073
     3
    Figure US20040235818A1-20041125-C01074
     4
    Figure US20040235818A1-20041125-C01075
     5
    Figure US20040235818A1-20041125-C01076
     6
    Figure US20040235818A1-20041125-C01077
     7
    Figure US20040235818A1-20041125-C01078
     8
    Figure US20040235818A1-20041125-C01079
     9
    Figure US20040235818A1-20041125-C01080
    10
    Figure US20040235818A1-20041125-C01081
    11
    Figure US20040235818A1-20041125-C01082
    12
    Figure US20040235818A1-20041125-C01083
    13
    Figure US20040235818A1-20041125-C01084
    14
    Figure US20040235818A1-20041125-C01085
    15
    Figure US20040235818A1-20041125-C01086
    16
    Figure US20040235818A1-20041125-C01087
    17
    Figure US20040235818A1-20041125-C01088
    18
    Figure US20040235818A1-20041125-C01089
    19
    Figure US20040235818A1-20041125-C01090
    20
    Figure US20040235818A1-20041125-C01091
    21
    Figure US20040235818A1-20041125-C01092
  • [0388]
    TABLE 49
    Figure US20040235818A1-20041125-C01093
    1
    Figure US20040235818A1-20041125-C01094
    2
    Figure US20040235818A1-20041125-C01095
    3
    Figure US20040235818A1-20041125-C01096
    4
    Figure US20040235818A1-20041125-C01097
    5
    Figure US20040235818A1-20041125-C01098
    6
    Figure US20040235818A1-20041125-C01099
    7
    Figure US20040235818A1-20041125-C01100
    8
    Figure US20040235818A1-20041125-C01101
    9
    Figure US20040235818A1-20041125-C01102
    10 
    Figure US20040235818A1-20041125-C01103
    11 
    Figure US20040235818A1-20041125-C01104
  • [0389]
    TABLE 50
    Figure US20040235818A1-20041125-C01105
     1
    Figure US20040235818A1-20041125-C01106
     2
    Figure US20040235818A1-20041125-C01107
     3
    Figure US20040235818A1-20041125-C01108
     4
    Figure US20040235818A1-20041125-C01109
     5
    Figure US20040235818A1-20041125-C01110
     6
    Figure US20040235818A1-20041125-C01111
     7
    Figure US20040235818A1-20041125-C01112
     8
    Figure US20040235818A1-20041125-C01113
     9
    Figure US20040235818A1-20041125-C01114
    10
    Figure US20040235818A1-20041125-C01115
    11
    Figure US20040235818A1-20041125-C01116
    12
    Figure US20040235818A1-20041125-C01117
    13
    Figure US20040235818A1-20041125-C01118
    14
    Figure US20040235818A1-20041125-C01119
    15
    Figure US20040235818A1-20041125-C01120
    16
    Figure US20040235818A1-20041125-C01121
    17
    Figure US20040235818A1-20041125-C01122
    18
    Figure US20040235818A1-20041125-C01123
    19
    Figure US20040235818A1-20041125-C01124
    20
    Figure US20040235818A1-20041125-C01125
    21
    Figure US20040235818A1-20041125-C01126
  • [0390]
    TABLE 51
    Figure US20040235818A1-20041125-C01127
    Figure US20040235818A1-20041125-C01128
    Figure US20040235818A1-20041125-C01129
    Figure US20040235818A1-20041125-C01130
    Figure US20040235818A1-20041125-C01131
    Figure US20040235818A1-20041125-C01132
    Figure US20040235818A1-20041125-C01133
    Figure US20040235818A1-20041125-C01134
    Figure US20040235818A1-20041125-C01135
    Figure US20040235818A1-20041125-C01136
    Figure US20040235818A1-20041125-C01137
    Figure US20040235818A1-20041125-C01138
    Figure US20040235818A1-20041125-C01139
    Figure US20040235818A1-20041125-C01140
    Figure US20040235818A1-20041125-C01141
    Figure US20040235818A1-20041125-C01142
    Figure US20040235818A1-20041125-C01143
    Figure US20040235818A1-20041125-C01144
    Figure US20040235818A1-20041125-C01145
  • [0391]
    TABLE 52
    Figure US20040235818A1-20041125-C01146
    Figure US20040235818A1-20041125-C01147
    Figure US20040235818A1-20041125-C01148
    Figure US20040235818A1-20041125-C01149
    Figure US20040235818A1-20041125-C01150
    Figure US20040235818A1-20041125-C01151
    Figure US20040235818A1-20041125-C01152
    Figure US20040235818A1-20041125-C01153
    Figure US20040235818A1-20041125-C01154
    Figure US20040235818A1-20041125-C01155
    Figure US20040235818A1-20041125-C01156
    Figure US20040235818A1-20041125-C01157
    Figure US20040235818A1-20041125-C01158
    Figure US20040235818A1-20041125-C01159
    Figure US20040235818A1-20041125-C01160
    Figure US20040235818A1-20041125-C01161
    Figure US20040235818A1-20041125-C01162
    Figure US20040235818A1-20041125-C01163
    Figure US20040235818A1-20041125-C01164
    Figure US20040235818A1-20041125-C01165
    Figure US20040235818A1-20041125-C01166
    Figure US20040235818A1-20041125-C01167
  • [0392]
    TABLE 53
    Figure US20040235818A1-20041125-C01168
    Figure US20040235818A1-20041125-C01169
    Figure US20040235818A1-20041125-C01170
    Figure US20040235818A1-20041125-C01171
    Figure US20040235818A1-20041125-C01172
    Figure US20040235818A1-20041125-C01173
    Figure US20040235818A1-20041125-C01174
    Figure US20040235818A1-20041125-C01175
    Figure US20040235818A1-20041125-C01176
    Figure US20040235818A1-20041125-C01177
    Figure US20040235818A1-20041125-C01178
    Figure US20040235818A1-20041125-C01179
    Figure US20040235818A1-20041125-C01180
    Figure US20040235818A1-20041125-C01181
    Figure US20040235818A1-20041125-C01182
    Figure US20040235818A1-20041125-C01183
    Figure US20040235818A1-20041125-C01184
    Figure US20040235818A1-20041125-C01185
    Figure US20040235818A1-20041125-C01186
    Figure US20040235818A1-20041125-C01187
    Figure US20040235818A1-20041125-C01188
    Figure US20040235818A1-20041125-C01189
    Figure US20040235818A1-20041125-C01190
  • [0393]
    TABLE 54
    Figure US20040235818A1-20041125-C01191
    Figure US20040235818A1-20041125-C01192
    Figure US20040235818A1-20041125-C01193
    Figure US20040235818A1-20041125-C01194
    Figure US20040235818A1-20041125-C01195
    Figure US20040235818A1-20041125-C01196
    Figure US20040235818A1-20041125-C01197
    Figure US20040235818A1-20041125-C01198
    Figure US20040235818A1-20041125-C01199
    Figure US20040235818A1-20041125-C01200
    Figure US20040235818A1-20041125-C01201
    Figure US20040235818A1-20041125-C01202
    Figure US20040235818A1-20041125-C01203
    Figure US20040235818A1-20041125-C01204
    Figure US20040235818A1-20041125-C01205
    Figure US20040235818A1-20041125-C01206
    Figure US20040235818A1-20041125-C01207
    Figure US20040235818A1-20041125-C01208
    Figure US20040235818A1-20041125-C01209
    Figure US20040235818A1-20041125-C01210
    Figure US20040235818A1-20041125-C01211
    Figure US20040235818A1-20041125-C01212
    Figure US20040235818A1-20041125-C01213
    Figure US20040235818A1-20041125-C01214
    Figure US20040235818A1-20041125-C01215
    Figure US20040235818A1-20041125-C01216
    Figure US20040235818A1-20041125-C01217
    Figure US20040235818A1-20041125-C01218
    Figure US20040235818A1-20041125-C01219
    Figure US20040235818A1-20041125-C01220
    Figure US20040235818A1-20041125-C01221
  • [0394]
    TABLE 55
    Figure US20040235818A1-20041125-C01222
    Figure US20040235818A1-20041125-C01223
    Figure US20040235818A1-20041125-C01224
    Figure US20040235818A1-20041125-C01225
    Figure US20040235818A1-20041125-C01226
    Figure US20040235818A1-20041125-C01227
    Figure US20040235818A1-20041125-C01228
    Figure US20040235818A1-20041125-C01229
    Figure US20040235818A1-20041125-C01230
    Figure US20040235818A1-20041125-C01231
    Figure US20040235818A1-20041125-C01232
    Figure US20040235818A1-20041125-C01233
    Figure US20040235818A1-20041125-C01234
    Figure US20040235818A1-20041125-C01235
    Figure US20040235818A1-20041125-C01236
    Figure US20040235818A1-20041125-C01237
    Figure US20040235818A1-20041125-C01238
    Figure US20040235818A1-20041125-C01239
    Figure US20040235818A1-20041125-C01240
    Figure US20040235818A1-20041125-C01241
    Figure US20040235818A1-20041125-C01242
    Figure US20040235818A1-20041125-C01243
  • [0395]
    TABLE 56
    Figure US20040235818A1-20041125-C01244
    Figure US20040235818A1-20041125-C01245
    Figure US20040235818A1-20041125-C01246
    Figure US20040235818A1-20041125-C01247
    Figure US20040235818A1-20041125-C01248
    Figure US20040235818A1-20041125-C01249
    Figure US20040235818A1-20041125-C01250
    Figure US20040235818A1-20041125-C01251
    Figure US20040235818A1-20041125-C01252
    Figure US20040235818A1-20041125-C01253
    Figure US20040235818A1-20041125-C01254
    Figure US20040235818A1-20041125-C01255
  • [0396]
    TABLE 57
    Figure US20040235818A1-20041125-C01256
    Figure US20040235818A1-20041125-C01257
    Figure US20040235818A1-20041125-C01258
    Figure US20040235818A1-20041125-C01259
    Figure US20040235818A1-20041125-C01260
    Figure US20040235818A1-20041125-C01261
    Figure US20040235818A1-20041125-C01262
    Figure US20040235818A1-20041125-C01263
    Figure US20040235818A1-20041125-C01264
    Figure US20040235818A1-20041125-C01265
    Figure US20040235818A1-20041125-C01266
    Figure US20040235818A1-20041125-C01267
    Figure US20040235818A1-20041125-C01268
    Figure US20040235818A1-20041125-C01269
    Figure US20040235818A1-20041125-C01270
    Figure US20040235818A1-20041125-C01271
    Figure US20040235818A1-20041125-C01272
    Figure US20040235818A1-20041125-C01273
    Figure US20040235818A1-20041125-C01274
    Figure US20040235818A1-20041125-C01275
    Figure US20040235818A1-20041125-C01276
    Figure US20040235818A1-20041125-C01277
  • [0397]
    TABLE 58
    Figure US20040235818A1-20041125-C01278
    Figure US20040235818A1-20041125-C01279
    Figure US20040235818A1-20041125-C01280
    Figure US20040235818A1-20041125-C01281
    Figure US20040235818A1-20041125-C01282
    Figure US20040235818A1-20041125-C01283
    Figure US20040235818A1-20041125-C01284
    Figure US20040235818A1-20041125-C01285
    Figure US20040235818A1-20041125-C01286
    Figure US20040235818A1-20041125-C01287
    Figure US20040235818A1-20041125-C01288
    Figure US20040235818A1-20041125-C01289
    Figure US20040235818A1-20041125-C01290
    Figure US20040235818A1-20041125-C01291
    Figure US20040235818A1-20041125-C01292
    Figure US20040235818A1-20041125-C01293
    Figure US20040235818A1-20041125-C01294
    Figure US20040235818A1-20041125-C01295
    Figure US20040235818A1-20041125-C01296
  • [0398]
    TABLE 59
    Figure US20040235818A1-20041125-C01297
    Figure US20040235818A1-20041125-C01298
    Figure US20040235818A1-20041125-C01299
    Figure US20040235818A1-20041125-C01300
    Figure US20040235818A1-20041125-C01301
    Figure US20040235818A1-20041125-C01302
    Figure US20040235818A1-20041125-C01303
    Figure US20040235818A1-20041125-C01304
    Figure US20040235818A1-20041125-C01305
    Figure US20040235818A1-20041125-C01306
    Figure US20040235818A1-20041125-C01307
    Figure US20040235818A1-20041125-C01308
    Figure US20040235818A1-20041125-C01309
    Figure US20040235818A1-20041125-C01310
    Figure US20040235818A1-20041125-C01311
    Figure US20040235818A1-20041125-C01312
    Figure US20040235818A1-20041125-C01313
    Figure US20040235818A1-20041125-C01314
    Figure US20040235818A1-20041125-C01315
    Figure US20040235818A1-20041125-C01316
    Figure US20040235818A1-20041125-C01317
    Figure US20040235818A1-20041125-C01318
  • [0399]
    TABLE 60
    Figure US20040235818A1-20041125-C01319
    Figure US20040235818A1-20041125-C01320
    Figure US20040235818A1-20041125-C01321
    Figure US20040235818A1-20041125-C01322
    Figure US20040235818A1-20041125-C01323
    Figure US20040235818A1-20041125-C01324
    Figure US20040235818A1-20041125-C01325
    Figure US20040235818A1-20041125-C01326
    Figure US20040235818A1-20041125-C01327
    Figure US20040235818A1-20041125-C01328
    Figure US20040235818A1-20041125-C01329
    Figure US20040235818A1-20041125-C01330
    Figure US20040235818A1-20041125-C01331
    Figure US20040235818A1-20041125-C01332
    Figure US20040235818A1-20041125-C01333
    Figure US20040235818A1-20041125-C01334
    Figure US20040235818A1-20041125-C01335
    Figure US20040235818A1-20041125-C01336
    Figure US20040235818A1-20041125-C01337
    Figure US20040235818A1-20041125-C01338
    Figure US20040235818A1-20041125-C01339
    Figure US20040235818A1-20041125-C01340
    Figure US20040235818A1-20041125-C01341
  • [0400]
    TABLE 61
    Figure US20040235818A1-20041125-C01342
    Figure US20040235818A1-20041125-C01343
    1
    Figure US20040235818A1-20041125-C01344
    2
    Figure US20040235818A1-20041125-C01345
    3
    Figure US20040235818A1-20041125-C01346
    4
    Figure US20040235818A1-20041125-C01347
    5
    Figure US20040235818A1-20041125-C01348
    6
    Figure US20040235818A1-20041125-C01349
    7
    Figure US20040235818A1-20041125-C01350
    8
    Figure US20040235818A1-20041125-C01351
    9
    Figure US20040235818A1-20041125-C01352
    10
    Figure US20040235818A1-20041125-C01353
    11
    Figure US20040235818A1-20041125-C01354
    12
    Figure US20040235818A1-20041125-C01355
    13
    Figure US20040235818A1-20041125-C01356
    14
    Figure US20040235818A1-20041125-C01357
    15
    Figure US20040235818A1-20041125-C01358
    16
    Figure US20040235818A1-20041125-C01359
    17
    Figure US20040235818A1-20041125-C01360
    18
    Figure US20040235818A1-20041125-C01361
    19
    Figure US20040235818A1-20041125-C01362
    20
    Figure US20040235818A1-20041125-C01363
    21
    Figure US20040235818A1-20041125-C01364
    22
    Figure US20040235818A1-20041125-C01365
    23
    Figure US20040235818A1-20041125-C01366
    24
    Figure US20040235818A1-20041125-C01367
    25
    Figure US20040235818A1-20041125-C01368
    26
    Figure US20040235818A1-20041125-C01369
    27
    Figure US20040235818A1-20041125-C01370
    28
    Figure US20040235818A1-20041125-C01371
    29
    Figure US20040235818A1-20041125-C01372
    30
    Figure US20040235818A1-20041125-C01373
  • [0401]
    TABLE 62
    Figure US20040235818A1-20041125-C01374
    Figure US20040235818A1-20041125-C01375
    1
    Figure US20040235818A1-20041125-C01376
    2
    Figure US20040235818A1-20041125-C01377
    3
    Figure US20040235818A1-20041125-C01378
    4
    Figure US20040235818A1-20041125-C01379
    5
    Figure US20040235818A1-20041125-C01380
    6
    Figure US20040235818A1-20041125-C01381
    7
    Figure US20040235818A1-20041125-C01382
    8
    Figure US20040235818A1-20041125-C01383
    9
    Figure US20040235818A1-20041125-C01384
    10
    Figure US20040235818A1-20041125-C01385
    11
    Figure US20040235818A1-20041125-C01386
    12
    Figure US20040235818A1-20041125-C01387
    13
    Figure US20040235818A1-20041125-C01388
    14
    Figure US20040235818A1-20041125-C01389
    15
    Figure US20040235818A1-20041125-C01390
    16
    Figure US20040235818A1-20041125-C01391
    17
    Figure US20040235818A1-20041125-C01392
    18
    Figure US20040235818A1-20041125-C01393
    19
    Figure US20040235818A1-20041125-C01394
    20
    Figure US20040235818A1-20041125-C01395
    21
    Figure US20040235818A1-20041125-C01396
  • [0402]
    TABLE 63
    Figure US20040235818A1-20041125-C01397
    Figure US20040235818A1-20041125-C01398
    1
    Figure US20040235818A1-20041125-C01399
    2
    Figure US20040235818A1-20041125-C01400
    3
    Figure US20040235818A1-20041125-C01401
    4
    Figure US20040235818A1-20041125-C01402
    5
    Figure US20040235818A1-20041125-C01403
    6
    Figure US20040235818A1-20041125-C01404
    7
    Figure US20040235818A1-20041125-C01405
    8
    Figure US20040235818A1-20041125-C01406
    9
    Figure US20040235818A1-20041125-C01407
    10
    Figure US20040235818A1-20041125-C01408
    11
    Figure US20040235818A1-20041125-C01409
  • [0403]
    TABLE 64
    Figure US20040235818A1-20041125-C01410
    Figure US20040235818A1-20041125-C01411
    1
    Figure US20040235818A1-20041125-C01412
    2
    Figure US20040235818A1-20041125-C01413
    3
    Figure US20040235818A1-20041125-C01414
    4
    Figure US20040235818A1-20041125-C01415
    5
    Figure US20040235818A1-20041125-C01416
    6
    Figure US20040235818A1-20041125-C01417
    7
    Figure US20040235818A1-20041125-C01418
    8
    Figure US20040235818A1-20041125-C01419
    9
    Figure US20040235818A1-20041125-C01420
    10
    Figure US20040235818A1-20041125-C01421
    11
    Figure US20040235818A1-20041125-C01422
    12
    Figure US20040235818A1-20041125-C01423
    13
    Figure US20040235818A1-20041125-C01424
    14
    Figure US20040235818A1-20041125-C01425
    15
    Figure US20040235818A1-20041125-C01426
    16
    Figure US20040235818A1-20041125-C01427
    17
    Figure US20040235818A1-20041125-C01428
    18
    Figure US20040235818A1-20041125-C01429
    19
    Figure US20040235818A1-20041125-C01430
    20
    Figure US20040235818A1-20041125-C01431
    21
    Figure US20040235818A1-20041125-C01432
  • [0404]
    TABLE 65
    Figure US20040235818A1-20041125-C01433
    Figure US20040235818A1-20041125-C01434
    1
    Figure US20040235818A1-20041125-C01435
    2
    Figure US20040235818A1-20041125-C01436
    3
    Figure US20040235818A1-20041125-C01437
    4
    Figure US20040235818A1-20041125-C01438
    5
    Figure US20040235818A1-20041125-C01439
    6
    Figure US20040235818A1-20041125-C01440
    7
    Figure US20040235818A1-20041125-C01441
    8
    Figure US20040235818A1-20041125-C01442
    9
    Figure US20040235818A1-20041125-C01443
    10
    Figure US20040235818A1-20041125-C01444
    11
    Figure US20040235818A1-20041125-C01445
    12
    Figure US20040235818A1-20041125-C01446
    13
    Figure US20040235818A1-20041125-C01447
    14
    Figure US20040235818A1-20041125-C01448
    15
    Figure US20040235818A1-20041125-C01449
    16
    Figure US20040235818A1-20041125-C01450
    17
    Figure US20040235818A1-20041125-C01451
    18
    Figure US20040235818A1-20041125-C01452
  • [0405]
    TABLE 66
    Figure US20040235818A1-20041125-C01453
    Figure US20040235818A1-20041125-C01454
    1
    Figure US20040235818A1-20041125-C01455
    2
    Figure US20040235818A1-20041125-C01456
    3
    Figure US20040235818A1-20041125-C01457
    4
    Figure US20040235818A1-20041125-C01458
    5
    Figure US20040235818A1-20041125-C01459
    6
    Figure US20040235818A1-20041125-C01460
    7
    Figure US20040235818A1-20041125-C01461
    8
    Figure US20040235818A1-20041125-C01462
    9
    Figure US20040235818A1-20041125-C01463
    10
    Figure US20040235818A1-20041125-C01464
    11
    Figure US20040235818A1-20041125-C01465
    12
    Figure US20040235818A1-20041125-C01466
    13
    Figure US20040235818A1-20041125-C01467
    14
    Figure US20040235818A1-20041125-C01468
    15
    Figure US20040235818A1-20041125-C01469
    16
    Figure US20040235818A1-20041125-C01470
    17
    Figure US20040235818A1-20041125-C01471
    18
    Figure US20040235818A1-20041125-C01472
    19
    Figure US20040235818A1-20041125-C01473
    20
    Figure US20040235818A1-20041125-C01474
    21
    Figure US20040235818A1-20041125-C01475
  • [0406]
    TABLE 67
    Figure US20040235818A1-20041125-C01476
    Figure US20040235818A1-20041125-C01477
    1
    Figure US20040235818A1-20041125-C01478
    2
    Figure US20040235818A1-20041125-C01479
    3
    Figure US20040235818A1-20041125-C01480
    4
    Figure US20040235818A1-20041125-C01481
    5
    Figure US20040235818A1-20041125-C01482
    6
    Figure US20040235818A1-20041125-C01483
    7
    Figure US20040235818A1-20041125-C01484
    8
    Figure US20040235818A1-20041125-C01485
    9
    Figure US20040235818A1-20041125-C01486
    10
    Figure US20040235818A1-20041125-C01487
    11
    Figure US20040235818A1-20041125-C01488
    12
    Figure US20040235818A1-20041125-C01489
    13
    Figure US20040235818A1-20041125-C01490
    14
    Figure US20040235818A1-20041125-C01491
    15
    Figure US20040235818A1-20041125-C01492
    16
    Figure US20040235818A1-20041125-C01493
    17
    Figure US20040235818A1-20041125-C01494
    18
    Figure US20040235818A1-20041125-C01495
    19
    Figure US20040235818A1-20041125-C01496
    20
    Figure US20040235818A1-20041125-C01497
    21
    Figure US20040235818A1-20041125-C01498
    22
    Figure US20040235818A1-20041125-C01499
  • [0407]
    TABLE 68
    Figure US20040235818A1-20041125-C01500
    Figure US20040235818A1-20041125-C01501
    1
    Figure US20040235818A1-20041125-C01502
    2
    Figure US20040235818A1-20041125-C01503
    3
    Figure US20040235818A1-20041125-C01504
    4
    Figure US20040235818A1-20041125-C01505
    5
    Figure US20040235818A1-20041125-C01506
    6
    Figure US20040235818A1-20041125-C01507
    7
    Figure US20040235818A1-20041125-C01508
    8
    Figure US20040235818A1-20041125-C01509
    9
    Figure US20040235818A1-20041125-C01510
    10
    Figure US20040235818A1-20041125-C01511
    11
    Figure US20040235818A1-20041125-C01512
    12
    Figure US20040235818A1-20041125-C01513
    13
    Figure US20040235818A1-20041125-C01514
    14
    Figure US20040235818A1-20041125-C01515
    15
    Figure US20040235818A1-20041125-C01516
    16
    Figure US20040235818A1-20041125-C01517
    17
    Figure US20040235818A1-20041125-C01518
    18
    Figure US20040235818A1-20041125-C01519
    19
    Figure US20040235818A1-20041125-C01520
    20
    Figure US20040235818A1-20041125-C01521
    21
    Figure US20040235818A1-20041125-C01522
    22
    Figure US20040235818A1-20041125-C01523
    23
    Figure US20040235818A1-20041125-C01524
    24
    Figure US20040235818A1-20041125-C01525
    25
    Figure US20040235818A1-20041125-C01526
    26
    Figure US20040235818A1-20041125-C01527
    27
    Figure US20040235818A1-20041125-C01528
    28
    Figure US20040235818A1-20041125-C01529
    29
    Figure US20040235818A1-20041125-C01530
    30
    Figure US20040235818A1-20041125-C01531
  • [0408]
    TABLE 69
    Figure US20040235818A1-20041125-C01532
    Figure US20040235818A1-20041125-C01533
    1
    Figure US20040235818A1-20041125-C01534
    2
    Figure US20040235818A1-20041125-C01535
    3
    Figure US20040235818A1-20041125-C01536
    4
    Figure US20040235818A1-20041125-C01537
    5
    Figure US20040235818A1-20041125-C01538
    6
    Figure US20040235818A1-20041125-C01539
    7
    Figure US20040235818A1-20041125-C01540
    8
    Figure US20040235818A1-20041125-C01541
    9
    Figure US20040235818A1-20041125-C01542
    10
    Figure US20040235818A1-20041125-C01543
    11
    Figure US20040235818A1-20041125-C01544
    12
    Figure US20040235818A1-20041125-C01545
    13
    Figure US20040235818A1-20041125-C01546
    14
    Figure US20040235818A1-20041125-C01547
    15
    Figure US20040235818A1-20041125-C01548
    16
    Figure US20040235818A1-20041125-C01549
    17
    Figure US20040235818A1-20041125-C01550
    18
    Figure US20040235818A1-20041125-C01551
    19
    Figure US20040235818A1-20041125-C01552
    20
    Figure US20040235818A1-20041125-C01553
    21
    Figure US20040235818A1-20041125-C01554
  • [0409]
    TABLE 70
    Figure US20040235818A1-20041125-C01555
    Figure US20040235818A1-20041125-C01556
    1
    Figure US20040235818A1-20041125-C01557
    2
    Figure US20040235818A1-20041125-C01558
    3
    Figure US20040235818A1-20041125-C01559
    4
    Figure US20040235818A1-20041125-C01560
    5
    Figure US20040235818A1-20041125-C01561
    6
    Figure US20040235818A1-20041125-C01562
    7
    Figure US20040235818A1-20041125-C01563
    8
    Figure US20040235818A1-20041125-C01564
    9
    Figure US20040235818A1-20041125-C01565
    10
    Figure US20040235818A1-20041125-C01566
    11
    Figure US20040235818A1-20041125-C01567
  • [0410]
    TABLE 71
    Figure US20040235818A1-20041125-C01568
     1
    Figure US20040235818A1-20041125-C01569
     2
    Figure US20040235818A1-20041125-C01570
     3
    Figure US20040235818A1-20041125-C01571
     4
    Figure US20040235818A1-20041125-C01572
     5
    Figure US20040235818A1-20041125-C01573
     6
    Figure US20040235818A1-20041125-C01574
     7
    Figure US20040235818A1-20041125-C01575
     8
    Figure US20040235818A1-20041125-C01576
     9
    Figure US20040235818A1-20041125-C01577
    10
    Figure US20040235818A1-20041125-C01578
    11
    Figure US20040235818A1-20041125-C01579
    12
    Figure US20040235818A1-20041125-C01580
    13
    Figure US20040235818A1-20041125-C01581
    14
    Figure US20040235818A1-20041125-C01582
    15
    Figure US20040235818A1-20041125-C01583
    16
    Figure US20040235818A1-20041125-C01584
    17
    Figure US20040235818A1-20041125-C01585
    18
    Figure US20040235818A1-20041125-C01586
    19
    Figure US20040235818A1-20041125-C01587
    20
    Figure US20040235818A1-20041125-C01588
    21
    Figure US20040235818A1-20041125-C01589
  • [0411]
    TABLE 72
    Figure US20040235818A1-20041125-C01590
     1
    Figure US20040235818A1-20041125-C01591
     2
    Figure US20040235818A1-20041125-C01592
     3
    Figure US20040235818A1-20041125-C01593
     4
    Figure US20040235818A1-20041125-C01594
     5
    Figure US20040235818A1-20041125-C01595
     6
    Figure US20040235818A1-20041125-C01596
     7
    Figure US20040235818A1-20041125-C01597
     8
    Figure US20040235818A1-20041125-C01598
     9
    Figure US20040235818A1-20041125-C01599
    10
    Figure US20040235818A1-20041125-C01600
    11
    Figure US20040235818A1-20041125-C01601
    12
    Figure US20040235818A1-20041125-C01602
    13
    Figure US20040235818A1-20041125-C01603
    14
    Figure US20040235818A1-20041125-C01604
    15
    Figure US20040235818A1-20041125-C01605
    16
    Figure US20040235818A1-20041125-C01606
    17
    Figure US20040235818A1-20041125-C01607
    18
    Figure US20040235818A1-20041125-C01608
  • [0412]
    TABLE 73
    Figure US20040235818A1-20041125-C01609
     1
    Figure US20040235818A1-20041125-C01610
     2
    Figure US20040235818A1-20041125-C01611
     3
    Figure US20040235818A1-20041125-C01612
     4
    Figure US20040235818A1-20041125-C01613
     5
    Figure US20040235818A1-20041125-C01614
     6
    Figure US20040235818A1-20041125-C01615
     7
    Figure US20040235818A1-20041125-C01616
     8
    Figure US20040235818A1-20041125-C01617
     9
    Figure US20040235818A1-20041125-C01618
    10
    Figure US20040235818A1-20041125-C01619
    11
    Figure US20040235818A1-20041125-C01620
    12
    Figure US20040235818A1-20041125-C01621
    13
    Figure US20040235818A1-20041125-C01622
    14
    Figure US20040235818A1-20041125-C01623
    15
    Figure US20040235818A1-20041125-C01624
    16
    Figure US20040235818A1-20041125-C01625
    17
    Figure US20040235818A1-20041125-C01626
    18
    Figure US20040235818A1-20041125-C01627
    19
    Figure US20040235818A1-20041125-C01628
    20
    Figure US20040235818A1-20041125-C01629
    21
    Figure US20040235818A1-20041125-C01630
  • [0413]
    TABLE 74
    Figure US20040235818A1-20041125-C01631
     1
    Figure US20040235818A1-20041125-C01632
     2
    Figure US20040235818A1-20041125-C01633
     3
    Figure US20040235818A1-20041125-C01634
     4
    Figure US20040235818A1-20041125-C01635
     5
    Figure US20040235818A1-20041125-C01636
     6
    Figure US20040235818A1-20041125-C01637
     7
    Figure US20040235818A1-20041125-C01638
     8
    Figure US20040235818A1-20041125-C01639
     9
    Figure US20040235818A1-20041125-C01640
    10
    Figure US20040235818A1-20041125-C01641
    11
    Figure US20040235818A1-20041125-C01642
    12
    Figure US20040235818A1-20041125-C01643
    13
    Figure US20040235818A1-20041125-C01644
    14
    Figure US20040235818A1-20041125-C01645
    15
    Figure US20040235818A1-20041125-C01646
    16
    Figure US20040235818A1-20041125-C01647
    17
    Figure US20040235818A1-20041125-C01648
    18
    Figure US20040235818A1-20041125-C01649
    19
    Figure US20040235818A1-20041125-C01650
    20
    Figure US20040235818A1-20041125-C01651
    21
    Figure US20040235818A1-20041125-C01652
    22
    Figure US20040235818A1-20041125-C01653
  • [0414]
    TABLE 75
    Figure US20040235818A1-20041125-C01654
     1
    Figure US20040235818A1-20041125-C01655
     2
    Figure US20040235818A1-20041125-C01656
     3
    Figure US20040235818A1-20041125-C01657
     4
    Figure US20040235818A1-20041125-C01658
     5
    Figure US20040235818A1-20041125-C01659
     6
    Figure US20040235818A1-20041125-C01660
     7
    Figure US20040235818A1-20041125-C01661
     8
    Figure US20040235818A1-20041125-C01662
     9
    Figure US20040235818A1-20041125-C01663
    10
    Figure US20040235818A1-20041125-C01664
    11
    Figure US20040235818A1-20041125-C01665
    12
    Figure US20040235818A1-20041125-C01666
    13
    Figure US20040235818A1-20041125-C01667
    14
    Figure US20040235818A1-20041125-C01668
    15
    Figure US20040235818A1-20041125-C01669
    16
    Figure US20040235818A1-20041125-C01670
    17
    Figure US20040235818A1-20041125-C01671
    18
    Figure US20040235818A1-20041125-C01672
    19
    Figure US20040235818A1-20041125-C01673
    20
    Figure US20040235818A1-20041125-C01674
    21
    Figure US20040235818A1-20041125-C01675
    22
    Figure US20040235818A1-20041125-C01676
    23
    Figure US20040235818A1-20041125-C01677
    24
    Figure US20040235818A1-20041125-C01678
    25
    Figure US20040235818A1-20041125-C01679
    26
    Figure US20040235818A1-20041125-C01680
    27
    Figure US20040235818A1-20041125-C01681
    28
    Figure US20040235818A1-20041125-C01682
    29
    Figure US20040235818A1-20041125-C01683
    30
    Figure US20040235818A1-20041125-C01684
  • [0415]
    TABLE 76
    Figure US20040235818A1-20041125-C01685
     1
    Figure US20040235818A1-20041125-C01686
     2
    Figure US20040235818A1-20041125-C01687
     3
    Figure US20040235818A1-20041125-C01688
     4
    Figure US20040235818A1-20041125-C01689
     5
    Figure US20040235818A1-20041125-C01690
     6
    Figure US20040235818A1-20041125-C01691
     7
    Figure US20040235818A1-20041125-C01692
     8
    Figure US20040235818A1-20041125-C01693
     9
    Figure US20040235818A1-20041125-C01694
    10
    Figure US20040235818A1-20041125-C01695
    11
    Figure US20040235818A1-20041125-C01696
    12
    Figure US20040235818A1-20041125-C01697
    13
    Figure US20040235818A1-20041125-C01698
    14
    Figure US20040235818A1-20041125-C01699
    15
    Figure US20040235818A1-20041125-C01700
    16
    Figure US20040235818A1-20041125-C01701
    17
    Figure US20040235818A1-20041125-C01702
    18
    Figure US20040235818A1-20041125-C01703
    19
    Figure US20040235818A1-20041125-C01704
    20
    Figure US20040235818A1-20041125-C01705
    21
    Figure US20040235818A1-20041125-C01706
  • [0416]
    TABLE 77
    Figure US20040235818A1-20041125-C01707
    1
    Figure US20040235818A1-20041125-C01708
    2
    Figure US20040235818A1-20041125-C01709
    3
    Figure US20040235818A1-20041125-C01710
    4
    Figure US20040235818A1-20041125-C01711
    5
    Figure US20040235818A1-20041125-C01712
    6
    Figure US20040235818A1-20041125-C01713
    7
    Figure US20040235818A1-20041125-C01714
    8
    Figure US20040235818A1-20041125-C01715
    9
    Figure US20040235818A1-20041125-C01716
    10 
    Figure US20040235818A1-20041125-C01717
    11 
    Figure US20040235818A1-20041125-C01718
  • [0417]
    TABLE 78
    Figure US20040235818A1-20041125-C01719
     1
    Figure US20040235818A1-20041125-C01720
     2
    Figure US20040235818A1-20041125-C01721
     3
    Figure US20040235818A1-20041125-C01722
     4
    Figure US20040235818A1-20041125-C01723
     5
    Figure US20040235818A1-20041125-C01724
     6
    Figure US20040235818A1-20041125-C01725
     7
    Figure US20040235818A1-20041125-C01726
     8
    Figure US20040235818A1-20041125-C01727
     9
    Figure US20040235818A1-20041125-C01728
    10
    Figure US20040235818A1-20041125-C01729
    11
    Figure US20040235818A1-20041125-C01730
    12
    Figure US20040235818A1-20041125-C01731
    13
    Figure US20040235818A1-20041125-C01732
    14
    Figure US20040235818A1-20041125-C01733
    15
    Figure US20040235818A1-20041125-C01734
    16
    Figure US20040235818A1-20041125-C01735
    17
    Figure US20040235818A1-20041125-C01736
    18
    Figure US20040235818A1-20041125-C01737
    19
    Figure US20040235818A1-20041125-C01738
    20
    Figure US20040235818A1-20041125-C01739
    21
    Figure US20040235818A1-20041125-C01740
  • [0418]
    TABLE 79
    Figure US20040235818A1-20041125-C01741
     1
    Figure US20040235818A1-20041125-C01742
     2
    Figure US20040235818A1-20041125-C01743
     3
    Figure US20040235818A1-20041125-C01744
     4
    Figure US20040235818A1-20041125-C01745
     5
    Figure US20040235818A1-20041125-C01746
     6
    Figure US20040235818A1-20041125-C01747
     7
    Figure US20040235818A1-20041125-C01748
     8
    Figure US20040235818A1-20041125-C01749
     9
    Figure US20040235818A1-20041125-C01750
    10
    Figure US20040235818A1-20041125-C01751
    11
    Figure US20040235818A1-20041125-C01752
    12
    Figure US20040235818A1-20041125-C01753
    13
    Figure US20040235818A1-20041125-C01754
    14
    Figure US20040235818A1-20041125-C01755
    15
    Figure US20040235818A1-20041125-C01756
    16
    Figure US20040235818A1-20041125-C01757
    17
    Figure US20040235818A1-20041125-C01758
    18
    Figure US20040235818A1-20041125-C01759
  • [0419]
    TABLE 80
    Figure US20040235818A1-20041125-C01760
     1
    Figure US20040235818A1-20041125-C01761
     2
    Figure US20040235818A1-20041125-C01762
     3
    Figure US20040235818A1-20041125-C01763
     4
    Figure US20040235818A1-20041125-C01764
     5
    Figure US20040235818A1-20041125-C01765
     6
    Figure US20040235818A1-20041125-C01766
     7
    Figure US20040235818A1-20041125-C01767
     8
    Figure US20040235818A1-20041125-C01768
     9
    Figure US20040235818A1-20041125-C01769
    10
    Figure US20040235818A1-20041125-C01770
    11
    Figure US20040235818A1-20041125-C01771
    12
    Figure US20040235818A1-20041125-C01772
    13
    Figure US20040235818A1-20041125-C01773
    14
    Figure US20040235818A1-20041125-C01774
    15
    Figure US20040235818A1-20041125-C01775
    16
    Figure US20040235818A1-20041125-C01776
    17
    Figure US20040235818A1-20041125-C01777
    18
    Figure US20040235818A1-20041125-C01778
    19
    Figure US20040235818A1-20041125-C01779
    20
    Figure US20040235818A1-20041125-C01780
    21
    Figure US20040235818A1-20041125-C01781
  • [0420]
    TABLE 81
    Figure US20040235818A1-20041125-C01782
     1
    Figure US20040235818A1-20041125-C01783
     2
    Figure US20040235818A1-20041125-C01784
     3
    Figure US20040235818A1-20041125-C01785
     4
    Figure US20040235818A1-20041125-C01786
     5
    Figure US20040235818A1-20041125-C01787
     6
    Figure US20040235818A1-20041125-C01788
     7
    Figure US20040235818A1-20041125-C01789
     8
    Figure US20040235818A1-20041125-C01790
     9
    Figure US20040235818A1-20041125-C01791
    10
    Figure US20040235818A1-20041125-C01792
    11
    Figure US20040235818A1-20041125-C01793
    12
    Figure US20040235818A1-20041125-C01794
    13
    Figure US20040235818A1-20041125-C01795
    14
    Figure US20040235818A1-20041125-C01796
    15
    Figure US20040235818A1-20041125-C01797
    16
    Figure US20040235818A1-20041125-C01798
    17
    Figure US20040235818A1-20041125-C01799
    18
    Figure US20040235818A1-20041125-C01800
    19
    Figure US20040235818A1-20041125-C01801
    20
    Figure US20040235818A1-20041125-C01802
    21
    Figure US20040235818A1-20041125-C01803
    22
    Figure US20040235818A1-20041125-C01804
  • [0421]
    TABLE 82
    Figure US20040235818A1-20041125-C01805
     1
    Figure US20040235818A1-20041125-C01806
     2
    Figure US20040235818A1-20041125-C01807
     3
    Figure US20040235818A1-20041125-C01808
     4
    Figure US20040235818A1-20041125-C01809
     5
    Figure US20040235818A1-20041125-C01810
     6
    Figure US20040235818A1-20041125-C01811
     7
    Figure US20040235818A1-20041125-C01812
     8
    Figure US20040235818A1-20041125-C01813
     9
    Figure US20040235818A1-20041125-C01814
    10
    Figure US20040235818A1-20041125-C01815
    11
    Figure US20040235818A1-20041125-C01816
    12
    Figure US20040235818A1-20041125-C01817
    13
    Figure US20040235818A1-20041125-C01818
    14
    Figure US20040235818A1-20041125-C01819
    15
    Figure US20040235818A1-20041125-C01820
    16
    Figure US20040235818A1-20041125-C01821
    17
    Figure US20040235818A1-20041125-C01822
    18
    Figure US20040235818A1-20041125-C01823
    19
    Figure US20040235818A1-20041125-C01824
    20
    Figure US20040235818A1-20041125-C01825
    21
    Figure US20040235818A1-20041125-C01826
    22
    Figure US20040235818A1-20041125-C01827
    23
    Figure US20040235818A1-20041125-C01828
    24
    Figure US20040235818A1-20041125-C01829
    25
    Figure US20040235818A1-20041125-C01830
    26
    Figure US20040235818A1-20041125-C01831
    27
    Figure US20040235818A1-20041125-C01832
    28
    Figure US20040235818A1-20041125-C01833
    29
    Figure US20040235818A1-20041125-C01834
    30
    Figure US20040235818A1-20041125-C01835
  • [0422]
    TABLE 83
    Figure US20040235818A1-20041125-C01836
     1
    Figure US20040235818A1-20041125-C01837
     2
    Figure US20040235818A1-20041125-C01838
     3
    Figure US20040235818A1-20041125-C01839
     4
    Figure US20040235818A1-20041125-C01840
     5
    Figure US20040235818A1-20041125-C01841
     6
    Figure US20040235818A1-20041125-C01842
     7
    Figure US20040235818A1-20041125-C01843
     8
    Figure US20040235818A1-20041125-C01844
     9
    Figure US20040235818A1-20041125-C01845
    10
    Figure US20040235818A1-20041125-C01846
    11
    Figure US20040235818A1-20041125-C01847
    12
    Figure US20040235818A1-20041125-C01848
    13
    Figure US20040235818A1-20041125-C01849
    14
    Figure US20040235818A1-20041125-C01850
    15
    Figure US20040235818A1-20041125-C01851
    16
    Figure US20040235818A1-20041125-C01852
    17
    Figure US20040235818A1-20041125-C01853
    18
    Figure US20040235818A1-20041125-C01854
    19
    Figure US20040235818A1-20041125-C01855
    20
    Figure US20040235818A1-20041125-C01856
    21
    Figure US20040235818A1-20041125-C01857
  • [0423]
    TABLE 84
    Figure US20040235818A1-20041125-C01858
    1
    Figure US20040235818A1-20041125-C01859
    2
    Figure US20040235818A1-20041125-C01860
    3
    Figure US20040235818A1-20041125-C01861
    4
    Figure US20040235818A1-20041125-C01862
    5
    Figure US20040235818A1-20041125-C01863
    6
    Figure US20040235818A1-20041125-C01864
    7
    Figure US20040235818A1-20041125-C01865
    8
    Figure US20040235818A1-20041125-C01866
    9
    Figure US20040235818A1-20041125-C01867
    10 
    Figure US20040235818A1-20041125-C01868
    11 
    Figure US20040235818A1-20041125-C01869
  • [0424]
    TABLE 85
    Figure US20040235818A1-20041125-C01870
     1
    Figure US20040235818A1-20041125-C01871
     2
    Figure US20040235818A1-20041125-C01872
     3
    Figure US20040235818A1-20041125-C01873
     4
    Figure US20040235818A1-20041125-C01874
     5
    Figure US20040235818A1-20041125-C01875
     6
    Figure US20040235818A1-20041125-C01876
     7
    Figure US20040235818A1-20041125-C01877
     8
    Figure US20040235818A1-20041125-C01878
     9
    Figure US20040235818A1-20041125-C01879
    10
    Figure US20040235818A1-20041125-C01880
    11
    Figure US20040235818A1-20041125-C01881
    12
    Figure US20040235818A1-20041125-C01882
    13
    Figure US20040235818A1-20041125-C01883
    14
    Figure US20040235818A1-20041125-C01884
    15
    Figure US20040235818A1-20041125-C01885
    16
    Figure US20040235818A1-20041125-C01886
    17
    Figure US20040235818A1-20041125-C01887
    18
    Figure US20040235818A1-20041125-C01888
    19
    Figure US20040235818A1-20041125-C01889
    20
    Figure US20040235818A1-20041125-C01890
    21
    Figure US20040235818A1-20041125-C01891
  • [0425]
    TABLE 86
    Figure US20040235818A1-20041125-C01892
     1
    Figure US20040235818A1-20041125-C01893
     2
    Figure US20040235818A1-20041125-C01894
     3
    Figure US20040235818A1-20041125-C01895
     4
    Figure US20040235818A1-20041125-C01896
     5
    Figure US20040235818A1-20041125-C01897
     6
    Figure US20040235818A1-20041125-C01898
     7
    Figure US20040235818A1-20041125-C01899
     8
    Figure US20040235818A1-20041125-C01900
     9
    Figure US20040235818A1-20041125-C01901
    10
    Figure US20040235818A1-20041125-C01902
    11
    Figure US20040235818A1-20041125-C01903
    12
    Figure US20040235818A1-20041125-C01904
    13
    Figure US20040235818A1-20041125-C01905
    14
    Figure US20040235818A1-20041125-C01906
    15
    Figure US20040235818A1-20041125-C01907
    16
    Figure US20040235818A1-20041125-C01908
    17
    Figure US20040235818A1-20041125-C01909
    18
    Figure US20040235818A1-20041125-C01910
  • [0426]
    TABLE 87
    Figure US20040235818A1-20041125-C01911
     1
    Figure US20040235818A1-20041125-C01912
     2
    Figure US20040235818A1-20041125-C01913
     3
    Figure US20040235818A1-20041125-C01914
     4
    Figure US20040235818A1-20041125-C01915
     5
    Figure US20040235818A1-20041125-C01916
     6
    Figure US20040235818A1-20041125-C01917
     7
    Figure US20040235818A1-20041125-C01918
     8
    Figure US20040235818A1-20041125-C01919
     9
    Figure US20040235818A1-20041125-C01920
    10
    Figure US20040235818A1-20041125-C01921
    11
    Figure US20040235818A1-20041125-C01922
    12
    Figure US20040235818A1-20041125-C01923
    13
    Figure US20040235818A1-20041125-C01924
    14
    Figure US20040235818A1-20041125-C01925
    15
    Figure US20040235818A1-20041125-C01926
    16
    Figure US20040235818A1-20041125-C01927
    17
    Figure US20040235818A1-20041125-C01928
    18
    Figure US20040235818A1-20041125-C01929
    19
    Figure US20040235818A1-20041125-C01930
    20
    Figure US20040235818A1-20041125-C01931
    21
    Figure US20040235818A1-20041125-C01932
  • [0427]
    TABLE 88
    Figure US20040235818A1-20041125-C01933
     1
    Figure US20040235818A1-20041125-C01934
     2
    Figure US20040235818A1-20041125-C01935
     3
    Figure US20040235818A1-20041125-C01936
     4
    Figure US20040235818A1-20041125-C01937
     5
    Figure US20040235818A1-20041125-C01938
     6
    Figure US20040235818A1-20041125-C01939
     7
    Figure US20040235818A1-20041125-C01940
     8
    Figure US20040235818A1-20041125-C01941
     9
    Figure US20040235818A1-20041125-C01942
    10
    Figure US20040235818A1-20041125-C01943
    11
    Figure US20040235818A1-20041125-C01944
    12
    Figure US20040235818A1-20041125-C01945
    13
    Figure US20040235818A1-20041125-C01946
    14
    Figure US20040235818A1-20041125-C01947
    15
    Figure US20040235818A1-20041125-C01948
    16
    Figure US20040235818A1-20041125-C01949
    17
    Figure US20040235818A1-20041125-C01950
    18
    Figure US20040235818A1-20041125-C01951
    19
    Figure US20040235818A1-20041125-C01952
    20
    Figure US20040235818A1-20041125-C01953
    21
    Figure US20040235818A1-20041125-C01954
    22
    Figure US20040235818A1-20041125-C01955
  • [0428]
    TABLE 89
    Figure US20040235818A1-20041125-C01956
     1
    Figure US20040235818A1-20041125-C01957
     2
    Figure US20040235818A1-20041125-C01958
     3
    Figure US20040235818A1-20041125-C01959
     4
    Figure US20040235818A1-20041125-C01960
     5
    Figure US20040235818A1-20041125-C01961
     6
    Figure US20040235818A1-20041125-C01962
     7
    Figure US20040235818A1-20041125-C01963
     8
    Figure US20040235818A1-20041125-C01964
     9
    Figure US20040235818A1-20041125-C01965
    10
    Figure US20040235818A1-20041125-C01966
    11
    Figure US20040235818A1-20041125-C01967
    12
    Figure US20040235818A1-20041125-C01968
    13
    Figure US20040235818A1-20041125-C01969
    14
    Figure US20040235818A1-20041125-C01970
    15
    Figure US20040235818A1-20041125-C01971
    16
    Figure US20040235818A1-20041125-C01972
    17
    Figure US20040235818A1-20041125-C01973
    18
    Figure US20040235818A1-20041125-C01974
    19
    Figure US20040235818A1-20041125-C01975
    20
    Figure US20040235818A1-20041125-C01976
    21
    Figure US20040235818A1-20041125-C01977
    22
    Figure US20040235818A1-20041125-C01978
    23
    Figure US20040235818A1-20041125-C01979
    24
    Figure US20040235818A1-20041125-C01980
    25
    Figure US20040235818A1-20041125-C01981
    26
    Figure US20040235818A1-20041125-C01982
    27
    Figure US20040235818A1-20041125-C01983
    28
    Figure US20040235818A1-20041125-C01984
    29
    Figure US20040235818A1-20041125-C01985
    30
    Figure US20040235818A1-20041125-C01986
  • [0429]
    TABLE 90
    Figure US20040235818A1-20041125-C01987
    1
    Figure US20040235818A1-20041125-C01988
    2
    Figure US20040235818A1-20041125-C01989
    3
    Figure US20040235818A1-20041125-C01990
    4
    Figure US20040235818A1-20041125-C01991
    5
    Figure US20040235818A1-20041125-C01992
    6
    Figure US20040235818A1-20041125-C01993
    7
    Figure US20040235818A1-20041125-C01994
    8
    Figure US20040235818A1-20041125-C01995
    9
    Figure US20040235818A1-20041125-C01996
    10
    Figure US20040235818A1-20041125-C01997
    11
    Figure US20040235818A1-20041125-C01998
    12
    Figure US20040235818A1-20041125-C01999
    13
    Figure US20040235818A1-20041125-C02000
    14
    Figure US20040235818A1-20041125-C02001
    15
    Figure US20040235818A1-20041125-C02002
    16
    Figure US20040235818A1-20041125-C02003
    17
    Figure US20040235818A1-20041125-C02004
    18
    Figure US20040235818A1-20041125-C02005
    19
    Figure US20040235818A1-20041125-C02006
    20
    Figure US20040235818A1-20041125-C02007
    21
    Figure US20040235818A1-20041125-C02008
  • [0430]
    TABLE 91
    Figure US20040235818A1-20041125-C02009
     1
    Figure US20040235818A1-20041125-C02010
     2
    Figure US20040235818A1-20041125-C02011
     3
    Figure US20040235818A1-20041125-C02012
     4
    Figure US20040235818A1-20041125-C02013
     5
    Figure US20040235818A1-20041125-C02014
     6
    Figure US20040235818A1-20041125-C02015
     7
    Figure US20040235818A1-20041125-C02016
     8
    Figure US20040235818A1-20041125-C02017
     9
    Figure US20040235818A1-20041125-C02018
    10
    Figure US20040235818A1-20041125-C02019
    11
    Figure US20040235818A1-20041125-C02020
  • [0431]
    TABLE 92
    Figure US20040235818A1-20041125-C02021
     1
    Figure US20040235818A1-20041125-C02022
     2
    Figure US20040235818A1-20041125-C02023
     3
    Figure US20040235818A1-20041125-C02024
     4
    Figure US20040235818A1-20041125-C02025
     5
    Figure US20040235818A1-20041125-C02026
     6
    Figure US20040235818A1-20041125-C02027
     7
    Figure US20040235818A1-20041125-C02028
     8
    Figure US20040235818A1-20041125-C02029
     9
    Figure US20040235818A1-20041125-C02030
    10
    Figure US20040235818A1-20041125-C02031
    11
    Figure US20040235818A1-20041125-C02032
    12
    Figure US20040235818A1-20041125-C02033
    13
    Figure US20040235818A1-20041125-C02034
    14
    Figure US20040235818A1-20041125-C02035
    15
    Figure US20040235818A1-20041125-C02036
    16
    Figure US20040235818A1-20041125-C02037
    17
    Figure US20040235818A1-20041125-C02038
    18
    Figure US20040235818A1-20041125-C02039
    19
    Figure US20040235818A1-20041125-C02040
    20
    Figure US20040235818A1-20041125-C02041
    21
    Figure US20040235818A1-20041125-C02042
  • [0432]
    TABLE 93
    Figure US20040235818A1-20041125-C02043
     1
    Figure US20040235818A1-20041125-C02044
     2
    Figure US20040235818A1-20041125-C02045
     3
    Figure US20040235818A1-20041125-C02046
     4
    Figure US20040235818A1-20041125-C02047
     5
    Figure US20040235818A1-20041125-C02048
     6
    Figure US20040235818A1-20041125-C02049
     7
    Figure US20040235818A1-20041125-C02050
     8
    Figure US20040235818A1-20041125-C02051
     9
    Figure US20040235818A1-20041125-C02052
    10
    Figure US20040235818A1-20041125-C02053
    11
    Figure US20040235818A1-20041125-C02054
    12
    Figure US20040235818A1-20041125-C02055
    13
    Figure US20040235818A1-20041125-C02056
    14
    Figure US20040235818A1-20041125-C02057
    15
    Figure US20040235818A1-20041125-C02058
    16
    Figure US20040235818A1-20041125-C02059
    17
    Figure US20040235818A1-20041125-C02060
    18
    Figure US20040235818A1-20041125-C02061
  • [0433]
    TABLE 94
    Figure US20040235818A1-20041125-C02062
     1
    Figure US20040235818A1-20041125-C02063
     2
    Figure US20040235818A1-20041125-C02064
     3
    Figure US20040235818A1-20041125-C02065
     4
    Figure US20040235818A1-20041125-C02066
     5
    Figure US20040235818A1-20041125-C02067
     6
    Figure US20040235818A1-20041125-C02068
     7
    Figure US20040235818A1-20041125-C02069
     8
    Figure US20040235818A1-20041125-C02070
     9
    Figure US20040235818A1-20041125-C02071
    10
    Figure US20040235818A1-20041125-C02072
    11
    Figure US20040235818A1-20041125-C02073
    12
    Figure US20040235818A1-20041125-C02074
    13
    Figure US20040235818A1-20041125-C02075
    14
    Figure US20040235818A1-20041125-C02076
    15
    Figure US20040235818A1-20041125-C02077
    16
    Figure US20040235818A1-20041125-C02078
    17
    Figure US20040235818A1-20041125-C02079
    18
    Figure US20040235818A1-20041125-C02080
    19
    Figure US20040235818A1-20041125-C02081
    20
    Figure US20040235818A1-20041125-C02082
    21
    Figure US20040235818A1-20041125-C02083
  • [0434]
    TABLE 95
    Figure US20040235818A1-20041125-C02084
     1
    Figure US20040235818A1-20041125-C02085
     2
    Figure US20040235818A1-20041125-C02086
     3
    Figure US20040235818A1-20041125-C02087
     4
    Figure US20040235818A1-20041125-C02088
     5
    Figure US20040235818A1-20041125-C02089
     6
    Figure US20040235818A1-20041125-C02090
     7
    Figure US20040235818A1-20041125-C02091
     8
    Figure US20040235818A1-20041125-C02092
     9
    Figure US20040235818A1-20041125-C02093
    10
    Figure US20040235818A1-20041125-C02094
    11
    Figure US20040235818A1-20041125-C02095
    12
    Figure US20040235818A1-20041125-C02096
    13
    Figure US20040235818A1-20041125-C02097
    14
    Figure US20040235818A1-20041125-C02098
    15
    Figure US20040235818A1-20041125-C02099
    16
    Figure US20040235818A1-20041125-C02100
    17
    Figure US20040235818A1-20041125-C02101
    18
    Figure US20040235818A1-20041125-C02102
    19
    Figure US20040235818A1-20041125-C02103
    20
    Figure US20040235818A1-20041125-C02104
    21
    Figure US20040235818A1-20041125-C02105
    22
    Figure US20040235818A1-20041125-C02106
  • [0435]
    TABLE 96
    Figure US20040235818A1-20041125-C02107
     1
    Figure US20040235818A1-20041125-C02108
     2
    Figure US20040235818A1-20041125-C02109
     3
    Figure US20040235818A1-20041125-C02110
     4
    Figure US20040235818A1-20041125-C02111
     5
    Figure US20040235818A1-20041125-C02112
     6
    Figure US20040235818A1-20041125-C02113
     7
    Figure US20040235818A1-20041125-C02114
     8
    Figure US20040235818A1-20041125-C02115
     9
    Figure US20040235818A1-20041125-C02116
    10
    Figure US20040235818A1-20041125-C02117
    11
    Figure US20040235818A1-20041125-C02118
    12
    Figure US20040235818A1-20041125-C02119
    13
    Figure US20040235818A1-20041125-C02120
    14
    Figure US20040235818A1-20041125-C02121
    15
    Figure US20040235818A1-20041125-C02122
    16
    Figure US20040235818A1-20041125-C02123
    17
    Figure US20040235818A1-20041125-C02124
    18
    Figure US20040235818A1-20041125-C02125
    19
    Figure US20040235818A1-20041125-C02126
    20
    Figure US20040235818A1-20041125-C02127
    21
    Figure US20040235818A1-20041125-C02128
    22
    Figure US20040235818A1-20041125-C02129
    23
    Figure US20040235818A1-20041125-C02130
    24
    Figure US20040235818A1-20041125-C02131
    25
    Figure US20040235818A1-20041125-C02132
    26
    Figure US20040235818A1-20041125-C02133
    27
    Figure US20040235818A1-20041125-C02134
    28
    Figure US20040235818A1-20041125-C02135
    29
    Figure US20040235818A1-20041125-C02136
    30
    Figure US20040235818A1-20041125-C02137
  • [0436]
    TABLE 97
    Figure US20040235818A1-20041125-C02138
     1
    Figure US20040235818A1-20041125-C02139
     2
    Figure US20040235818A1-20041125-C02140
     3
    Figure US20040235818A1-20041125-C02141
     4
    Figure US20040235818A1-20041125-C02142
     5
    Figure US20040235818A1-20041125-C02143
     6
    Figure US20040235818A1-20041125-C02144
     7
    Figure US20040235818A1-20041125-C02145
     8
    Figure US20040235818A1-20041125-C02146
     9
    Figure US20040235818A1-20041125-C02147
    10
    Figure US20040235818A1-20041125-C02148
    11
    Figure US20040235818A1-20041125-C02149
    12
    Figure US20040235818A1-20041125-C02150
    13
    Figure US20040235818A1-20041125-C02151
    14
    Figure US20040235818A1-20041125-C02152
    15
    Figure US20040235818A1-20041125-C02153
    16
    Figure US20040235818A1-20041125-C02154
    17
    Figure US20040235818A1-20041125-C02155
    18
    Figure US20040235818A1-20041125-C02156
    19
    Figure US20040235818A1-20041125-C02157
    20
    Figure US20040235818A1-20041125-C02158
    21
    Figure US20040235818A1-20041125-C02159
  • [0437]
    TABLE 98
    Figure US20040235818A1-20041125-C02160
     1
    Figure US20040235818A1-20041125-C02161
     2
    Figure US20040235818A1-20041125-C02162
     3
    Figure US20040235818A1-20041125-C02163
     4
    Figure US20040235818A1-20041125-C02164
     5
    Figure US20040235818A1-20041125-C02165
     6
    Figure US20040235818A1-20041125-C02166
     7
    Figure US20040235818A1-20041125-C02167
     8
    Figure US20040235818A1-20041125-C02168
     9
    Figure US20040235818A1-20041125-C02169
    10
    Figure US20040235818A1-20041125-C02170
    11
    Figure US20040235818A1-20041125-C02171
  • [0438]
    TABLE 99
    Figure US20040235818A1-20041125-C02172
     1
    Figure US20040235818A1-20041125-C02173
     2
    Figure US20040235818A1-20041125-C02174
     3
    Figure US20040235818A1-20041125-C02175
     4
    Figure US20040235818A1-20041125-C02176
     5
    Figure US20040235818A1-20041125-C02177
     6
    Figure US20040235818A1-20041125-C02178
     7
    Figure US20040235818A1-20041125-C02179
     8
    Figure US20040235818A1-20041125-C02180
     9
    Figure US20040235818A1-20041125-C02181
    10
    Figure US20040235818A1-20041125-C02182
    11
    Figure US20040235818A1-20041125-C02183
    12
    Figure US20040235818A1-20041125-C02184
    13
    Figure US20040235818A1-20041125-C02185
    14
    Figure US20040235818A1-20041125-C02186
    15
    Figure US20040235818A1-20041125-C02187
    16
    Figure US20040235818A1-20041125-C02188
    17
    Figure US20040235818A1-20041125-C02189
    18
    Figure US20040235818A1-20041125-C02190
    19
    Figure US20040235818A1-20041125-C02191
    20
    Figure US20040235818A1-20041125-C02192
    21
    Figure US20040235818A1-20041125-C02193
  • [0439]
    TABLE 100
    Figure US20040235818A1-20041125-C02194
     1
    Figure US20040235818A1-20041125-C02195
     2
    Figure US20040235818A1-20041125-C02196
     3
    Figure US20040235818A1-20041125-C02197
     4
    Figure US20040235818A1-20041125-C02198
     5
    Figure US20040235818A1-20041125-C02199
     6
    Figure US20040235818A1-20041125-C02200
     7
    Figure US20040235818A1-20041125-C02201
     8
    Figure US20040235818A1-20041125-C02202
     9
    Figure US20040235818A1-20041125-C02203
    10
    Figure US20040235818A1-20041125-C02204
    11
    Figure US20040235818A1-20041125-C02205
    12
    Figure US20040235818A1-20041125-C02206
    13
    Figure US20040235818A1-20041125-C02207
    14
    Figure US20040235818A1-20041125-C02208
    15
    Figure US20040235818A1-20041125-C02209
    16
    Figure US20040235818A1-20041125-C02210
    17
    Figure US20040235818A1-20041125-C02211
    18
    Figure US20040235818A1-20041125-C02212
  • [0440]
    TABLE 101
    Figure US20040235818A1-20041125-C02213
    Figure US20040235818A1-20041125-C02214
    1
    Figure US20040235818A1-20041125-C02215
    2
    Figure US20040235818A1-20041125-C02216
    3
    Figure US20040235818A1-20041125-C02217
    4
    Figure US20040235818A1-20041125-C02218
    5
    Figure US20040235818A1-20041125-C02219
    6
    Figure US20040235818A1-20041125-C02220
    7
    Figure US20040235818A1-20041125-C02221
    8
    Figure US20040235818A1-20041125-C02222
    9
    Figure US20040235818A1-20041125-C02223
    10
    Figure US20040235818A1-20041125-C02224
    11
    Figure US20040235818A1-20041125-C02225
    12
    Figure US20040235818A1-20041125-C02226
    13
    Figure US20040235818A1-20041125-C02227
    14
    Figure US20040235818A1-20041125-C02228
    15
    Figure US20040235818A1-20041125-C02229
    16
    Figure US20040235818A1-20041125-C02230
    17
    Figure US20040235818A1-20041125-C02231
    18
    Figure US20040235818A1-20041125-C02232
    19
    Figure US20040235818A1-20041125-C02233
    20
    Figure US20040235818A1-20041125-C02234
    21
    Figure US20040235818A1-20041125-C02235
  • [0441]
    TABLE 102
    Figure US20040235818A1-20041125-C02236
    Figure US20040235818A1-20041125-C02237
    1
    Figure US20040235818A1-20041125-C02238
    2
    Figure US20040235818A1-20041125-C02239
    3
    Figure US20040235818A1-20041125-C02240
    4
    Figure US20040235818A1-20041125-C02241
    5
    Figure US20040235818A1-20041125-C02242
    6
    Figure US20040235818A1-20041125-C02243
    7
    Figure US20040235818A1-20041125-C02244
    8
    Figure US20040235818A1-20041125-C02245
    9
    Figure US20040235818A1-20041125-C02246
    10
    Figure US20040235818A1-20041125-C02247
    11
    Figure US20040235818A1-20041125-C02248
    12
    Figure US20040235818A1-20041125-C02249
    13
    Figure US20040235818A1-20041125-C02250
    14
    Figure US20040235818A1-20041125-C02251
    15
    Figure US20040235818A1-20041125-C02252
    16
    Figure US20040235818A1-20041125-C02253
    17
    Figure US20040235818A1-20041125-C02254
    18
    Figure US20040235818A1-20041125-C02255
    19
    Figure US20040235818A1-20041125-C02256
    20
    Figure US20040235818A1-20041125-C02257
    21
    Figure US20040235818A1-20041125-C02258
    22
    Figure US20040235818A1-20041125-C02259
  • [0442]
    TABLE 103
    Figure US20040235818A1-20041125-C02260
    Figure US20040235818A1-20041125-C02261
    1
    Figure US20040235818A1-20041125-C02262
    2
    Figure US20040235818A1-20041125-C02263
    3
    Figure US20040235818A1-20041125-C02264
    4
    Figure US20040235818A1-20041125-C02265
    5
    Figure US20040235818A1-20041125-C02266
    6
    Figure US20040235818A1-20041125-C02267
    7
    Figure US20040235818A1-20041125-C02268
    8
    Figure US20040235818A1-20041125-C02269
    9
    Figure US20040235818A1-20041125-C02270
    10
    Figure US20040235818A1-20041125-C02271
    11
    Figure US20040235818A1-20041125-C02272
    12
    Figure US20040235818A1-20041125-C02273
    13
    Figure US20040235818A1-20041125-C02274
    14
    Figure US20040235818A1-20041125-C02275
    15
    Figure US20040235818A1-20041125-C02276
    16
    Figure US20040235818A1-20041125-C02277
    17
    Figure US20040235818A1-20041125-C02278
    18
    Figure US20040235818A1-20041125-C02279
    19
    Figure US20040235818A1-20041125-C02280
    20
    Figure US20040235818A1-20041125-C02281
    21
    Figure US20040235818A1-20041125-C02282
    22
    Figure US20040235818A1-20041125-C02283
    23
    Figure US20040235818A1-20041125-C02284
    24
    Figure US20040235818A1-20041125-C02285
    25
    Figure US20040235818A1-20041125-C02286
    26
    Figure US20040235818A1-20041125-C02287
    27
    Figure US20040235818A1-20041125-C02288
    28
    Figure US20040235818A1-20041125-C02289
    29
    Figure US20040235818A1-20041125-C02290
    30
    Figure US20040235818A1-20041125-C02291
  • [0443]
    TABLE 104
    Figure US20040235818A1-20041125-C02292
    Figure US20040235818A1-20041125-C02293
    1
    Figure US20040235818A1-20041125-C02294
    2
    Figure US20040235818A1-20041125-C02295
    3
    Figure US20040235818A1-20041125-C02296
    4
    Figure US20040235818A1-20041125-C02297
    5
    Figure US20040235818A1-20041125-C02298
    6
    Figure US20040235818A1-20041125-C02299
    7
    Figure US20040235818A1-20041125-C02300
    8
    Figure US20040235818A1-20041125-C02301
    9
    Figure US20040235818A1-20041125-C02302
    10
    Figure US20040235818A1-20041125-C02303
    11
    Figure US20040235818A1-20041125-C02304
    12
    Figure US20040235818A1-20041125-C02305
    13
    Figure US20040235818A1-20041125-C02306
    14
    Figure US20040235818A1-20041125-C02307
    15
    Figure US20040235818A1-20041125-C02308
    16
    Figure US20040235818A1-20041125-C02309
    17
    Figure US20040235818A1-20041125-C02310
    18
    Figure US20040235818A1-20041125-C02311
    19
    Figure US20040235818A1-20041125-C02312
    20
    Figure US20040235818A1-20041125-C02313
    21
    Figure US20040235818A1-20041125-C02314
  • [0444]
    TABLE 105
    Figure US20040235818A1-20041125-C02315
    Figure US20040235818A1-20041125-C02316
    1
    Figure US20040235818A1-20041125-C02317
    2
    Figure US20040235818A1-20041125-C02318
    3
    Figure US20040235818A1-20041125-C02319
    4
    Figure US20040235818A1-20041125-C02320
    5
    Figure US20040235818A1-20041125-C02321
    6
    Figure US20040235818A1-20041125-C02322
    7
    Figure US20040235818A1-20041125-C02323
    8
    Figure US20040235818A1-20041125-C02324
    9
    Figure US20040235818A1-20041125-C02325
    10
    Figure US20040235818A1-20041125-C02326
    11
    Figure US20040235818A1-20041125-C02327
  • [0445]
    TABLE 106
    Figure US20040235818A1-20041125-C02328
    Figure US20040235818A1-20041125-C02329
    1
    Figure US20040235818A1-20041125-C02330
    2
    Figure US20040235818A1-20041125-C02331
    3
    Figure US20040235818A1-20041125-C02332
    4
    Figure US20040235818A1-20041125-C02333
    5
    Figure US20040235818A1-20041125-C02334
    6
    Figure US20040235818A1-20041125-C02335
    7
    Figure US20040235818A1-20041125-C02336
    8
    Figure US20040235818A1-20041125-C02337
    9
    Figure US20040235818A1-20041125-C02338
    10
    Figure US20040235818A1-20041125-C02339
    11
    Figure US20040235818A1-20041125-C02340
    12
    Figure US20040235818A1-20041125-C02341
    13
    Figure US20040235818A1-20041125-C02342
    14
    Figure US20040235818A1-20041125-C02343
    15
    Figure US20040235818A1-20041125-C02344
    16
    Figure US20040235818A1-20041125-C02345
    17
    Figure US20040235818A1-20041125-C02346
    18
    Figure US20040235818A1-20041125-C02347
    19
    Figure US20040235818A1-20041125-C02348
    20
    Figure US20040235818A1-20041125-C02349
    21
    Figure US20040235818A1-20041125-C02350
  • [0446]
    TABLE 107
    Figure US20040235818A1-20041125-C02351
    Figure US20040235818A1-20041125-C02352
    1
    Figure US20040235818A1-20041125-C02353
    2
    Figure US20040235818A1-20041125-C02354
    3
    Figure US20040235818A1-20041125-C02355
    4
    Figure US20040235818A1-20041125-C02356
    5
    Figure US20040235818A1-20041125-C02357
    6
    Figure US20040235818A1-20041125-C02358
    7
    Figure US20040235818A1-20041125-C02359
    8
    Figure US20040235818A1-20041125-C02360
    9
    Figure US20040235818A1-20041125-C02361
    10
    Figure US20040235818A1-20041125-C02362
    11
    Figure US20040235818A1-20041125-C02363
    12
    Figure US20040235818A1-20041125-C02364
    13
    Figure US20040235818A1-20041125-C02365
    14
    Figure US20040235818A1-20041125-C02366
    15
    Figure US20040235818A1-20041125-C02367
    16
    Figure US20040235818A1-20041125-C02368
    17
    Figure US20040235818A1-20041125-C02369
    18
    Figure US20040235818A1-20041125-C02370
  • [0447]
    TABLE 108
    Figure US20040235818A1-20041125-C02371
    Figure US20040235818A1-20041125-C02372
    1
    Figure US20040235818A1-20041125-C02373
    2
    Figure US20040235818A1-20041125-C02374
    3
    Figure US20040235818A1-20041125-C02375
    4
    Figure US20040235818A1-20041125-C02376
    5
    Figure US20040235818A1-20041125-C02377
    6
    Figure US20040235818A1-20041125-C02378
    7
    Figure US20040235818A1-20041125-C02379
    8
    Figure US20040235818A1-20041125-C02380
    9
    Figure US20040235818A1-20041125-C02381
    10
    Figure US20040235818A1-20041125-C02382
    11
    Figure US20040235818A1-20041125-C02383
    12
    Figure US20040235818A1-20041125-C02384
    13
    Figure US20040235818A1-20041125-C02385
    14
    Figure US20040235818A1-20041125-C02386
    15
    Figure US20040235818A1-20041125-C02387
    16
    Figure US20040235818A1-20041125-C02388
    17
    Figure US20040235818A1-20041125-C02389
    18
    Figure US20040235818A1-20041125-C02390
    19
    Figure US20040235818A1-20041125-C02391
    20
    Figure US20040235818A1-20041125-C02392
    21
    Figure US20040235818A1-20041125-C02393
  • [0448]
    TABLE 109
    Figure US20040235818A1-20041125-C02394
    Figure US20040235818A1-20041125-C02395
    1
    Figure US20040235818A1-20041125-C02396
    2
    Figure US20040235818A1-20041125-C02397
    3
    Figure US20040235818A1-20041125-C02398
    4
    Figure US20040235818A1-20041125-C02399
    5
    Figure US20040235818A1-20041125-C02400
    6
    Figure US20040235818A1-20041125-C02401
    7
    Figure US20040235818A1-20041125-C02402
    8
    Figure US20040235818A1-20041125-C02403
    9
    Figure US20040235818A1-20041125-C02404
    10
    Figure US20040235818A1-20041125-C02405
    11
    Figure US20040235818A1-20041125-C02406
    12
    Figure US20040235818A1-20041125-C02407
    13
    Figure US20040235818A1-20041125-C02408
    14
    Figure US20040235818A1-20041125-C02409
    15
    Figure US20040235818A1-20041125-C02410
    16
    Figure US20040235818A1-20041125-C02411
    17
    Figure US20040235818A1-20041125-C02412
    18
    Figure US20040235818A1-20041125-C02413
    19
    Figure US20040235818A1-20041125-C02414
    20
    Figure US20040235818A1-20041125-C02415
    21
    Figure US20040235818A1-20041125-C02416
    22
    Figure US20040235818A1-20041125-C02417
  • [0449]
    TABLE 110
    Figure US20040235818A1-20041125-C02418
    Figure US20040235818A1-20041125-C02419
    1
    Figure US20040235818A1-20041125-C02420
    2
    Figure US20040235818A1-20041125-C02421
    3
    Figure US20040235818A1-20041125-C02422
    4
    Figure US20040235818A1-20041125-C02423
    5
    Figure US20040235818A1-20041125-C02424
    6
    Figure US20040235818A1-20041125-C02425
    7
    Figure US20040235818A1-20041125-C02426
    8
    Figure US20040235818A1-20041125-C02427
    9
    Figure US20040235818A1-20041125-C02428
    10
    Figure US20040235818A1-20041125-C02429
    11
    Figure US20040235818A1-20041125-C02430
    12
    Figure US20040235818A1-20041125-C02431
    13
    Figure US20040235818A1-20041125-C02432
    14
    Figure US20040235818A1-20041125-C02433
    15
    Figure US20040235818A1-20041125-C02434
    16
    Figure US20040235818A1-20041125-C02435
    17
    Figure US20040235818A1-20041125-C02436
    18
    Figure US20040235818A1-20041125-C02437
    19
    Figure US20040235818A1-20041125-C02438
    20
    Figure US20040235818A1-20041125-C02439
    21
    Figure US20040235818A1-20041125-C02440
    22
    Figure US20040235818A1-20041125-C02441
    23
    Figure US20040235818A1-20041125-C02442
    24
    Figure US20040235818A1-20041125-C02443
    25
    Figure US20040235818A1-20041125-C02444
    26
    Figure US20040235818A1-20041125-C02445
    27
    Figure US20040235818A1-20041125-C02446
    28
    Figure US20040235818A1-20041125-C02447
    29
    Figure US20040235818A1-20041125-C02448
    30
    Figure US20040235818A1-20041125-C02449
  • [0450]
    TABLE 111
    Figure US20040235818A1-20041125-C02450
     1
    Figure US20040235818A1-20041125-C02451
     2
    Figure US20040235818A1-20041125-C02452
     3
    Figure US20040235818A1-20041125-C02453
     4
    Figure US20040235818A1-20041125-C02454
     5
    Figure US20040235818A1-20041125-C02455
     6
    Figure US20040235818A1-20041125-C02456
     7
    Figure US20040235818A1-20041125-C02457
     8
    Figure US20040235818A1-20041125-C02458
     9
    Figure US20040235818A1-20041125-C02459
    10
    Figure US20040235818A1-20041125-C02460
    11
    Figure US20040235818A1-20041125-C02461
    12
    Figure US20040235818A1-20041125-C02462
    13
    Figure US20040235818A1-20041125-C02463
    14
    Figure US20040235818A1-20041125-C02464
    15
    Figure US20040235818A1-20041125-C02465
    16
    Figure US20040235818A1-20041125-C02466
    17
    Figure US20040235818A1-20041125-C02467
    18
    Figure US20040235818A1-20041125-C02468
    19
    Figure US20040235818A1-20041125-C02469
    20
    Figure US20040235818A1-20041125-C02470
    21
    Figure US20040235818A1-20041125-C02471
  • [0451]
    TABLE 112
    Figure US20040235818A1-20041125-C02472
    1
    Figure US20040235818A1-20041125-C02473
    2
    Figure US20040235818A1-20041125-C02474
    3
    Figure US20040235818A1-20041125-C02475
    4
    Figure US20040235818A1-20041125-C02476
    5
    Figure US20040235818A1-20041125-C02477
    6
    Figure US20040235818A1-20041125-C02478
    7
    Figure US20040235818A1-20041125-C02479
    8
    Figure US20040235818A1-20041125-C02480
    9
    Figure US20040235818A1-20041125-C02481
    10 
    Figure US20040235818A1-20041125-C02482
    11 
    Figure US20040235818A1-20041125-C02483
  • [0452]
    TABLE 113
    Figure US20040235818A1-20041125-C02484
     1
    Figure US20040235818A1-20041125-C02485
     2
    Figure US20040235818A1-20041125-C02486
     3
    Figure US20040235818A1-20041125-C02487
     4
    Figure US20040235818A1-20041125-C02488
     5
    Figure US20040235818A1-20041125-C02489
     6
    Figure US20040235818A1-20041125-C02490
     7
    Figure US20040235818A1-20041125-C02491
     8
    Figure US20040235818A1-20041125-C02492
     9
    Figure US20040235818A1-20041125-C02493
    10
    Figure US20040235818A1-20041125-C02494
    11
    Figure US20040235818A1-20041125-C02495
    12
    Figure US20040235818A1-20041125-C02496
    13
    Figure US20040235818A1-20041125-C02497
    14
    Figure US20040235818A1-20041125-C02498
    15
    Figure US20040235818A1-20041125-C02499
    16
    Figure US20040235818A1-20041125-C02500
    17
    Figure US20040235818A1-20041125-C02501
    18
    Figure US20040235818A1-20041125-C02502
    19
    Figure US20040235818A1-20041125-C02503
    20
    Figure US20040235818A1-20041125-C02504
    21
    Figure US20040235818A1-20041125-C02505
  • [0453]
    TABLE 114
    Figure US20040235818A1-20041125-C02506
     1
    Figure US20040235818A1-20041125-C02507
     2
    Figure US20040235818A1-20041125-C02508
     3
    Figure US20040235818A1-20041125-C02509
     4
    Figure US20040235818A1-20041125-C02510
     5
    Figure US20040235818A1-20041125-C02511
     6
    Figure US20040235818A1-20041125-C02512
     7
    Figure US20040235818A1-20041125-C02513
     8
    Figure US20040235818A1-20041125-C02514
     9
    Figure US20040235818A1-20041125-C02515
    10
    Figure US20040235818A1-20041125-C02516
    11
    Figure US20040235818A1-20041125-C02517
    12
    Figure US20040235818A1-20041125-C02518
    13
    Figure US20040235818A1-20041125-C02519
    14
    Figure US20040235818A1-20041125-C02520
    15
    Figure US20040235818A1-20041125-C02521
    16
    Figure US20040235818A1-20041125-C02522
    17
    Figure US20040235818A1-20041125-C02523
    18
    Figure US20040235818A1-20041125-C02524
  • [0454]
    TABLE 115
    Figure US20040235818A1-20041125-C02525
     1
    Figure US20040235818A1-20041125-C02526
     2
    Figure US20040235818A1-20041125-C02527
     3
    Figure US20040235818A1-20041125-C02528
     4
    Figure US20040235818A1-20041125-C02529
     5
    Figure US20040235818A1-20041125-C02530
     6
    Figure US20040235818A1-20041125-C02531
     7
    Figure US20040235818A1-20041125-C02532
     8
    Figure US20040235818A1-20041125-C02533
     9
    Figure US20040235818A1-20041125-C02534
    10
    Figure US20040235818A1-20041125-C02535
    11
    Figure US20040235818A1-20041125-C02536
    12
    Figure US20040235818A1-20041125-C02537
    13
    Figure US20040235818A1-20041125-C02538
    14
    Figure US20040235818A1-20041125-C02539
    15
    Figure US20040235818A1-20041125-C02540
    16
    Figure US20040235818A1-20041125-C02541
    17
    Figure US20040235818A1-20041125-C02542
    18
    Figure US20040235818A1-20041125-C02543
    19
    Figure US20040235818A1-20041125-C02544
    20
    Figure US20040235818A1-20041125-C02545
    21
    Figure US20040235818A1-20041125-C02546
  • [0455]
    TABLE 116
    Figure US20040235818A1-20041125-C02547
     1
    Figure US20040235818A1-20041125-C02548
     2
    Figure US20040235818A1-20041125-C02549
     3
    Figure US20040235818A1-20041125-C02550
     4
    Figure US20040235818A1-20041125-C02551
     5
    Figure US20040235818A1-20041125-C02552
     6
    Figure US20040235818A1-20041125-C02553
     7
    Figure US20040235818A1-20041125-C02554
     8
    Figure US20040235818A1-20041125-C02555
     9
    Figure US20040235818A1-20041125-C02556
    10
    Figure US20040235818A1-20041125-C02557
    11
    Figure US20040235818A1-20041125-C02558
    12
    Figure US20040235818A1-20041125-C02559
    13
    Figure US20040235818A1-20041125-C02560
    14
    Figure US20040235818A1-20041125-C02561
    15
    Figure US20040235818A1-20041125-C02562
    16
    Figure US20040235818A1-20041125-C02563
    17
    Figure US20040235818A1-20041125-C02564
    18
    Figure US20040235818A1-20041125-C02565
    19
    Figure US20040235818A1-20041125-C02566
    20
    Figure US20040235818A1-20041125-C02567
    21
    Figure US20040235818A1-20041125-C02568
    22
    Figure US20040235818A1-20041125-C02569
  • [0456]
    TABLE 117
    Figure US20040235818A1-20041125-C02570
     1
    Figure US20040235818A1-20041125-C02571
     2
    Figure US20040235818A1-20041125-C02572
     3
    Figure US20040235818A1-20041125-C02573
     4
    Figure US20040235818A1-20041125-C02574
     5
    Figure US20040235818A1-20041125-C02575
     6
    Figure US20040235818A1-20041125-C02576
     7
    Figure US20040235818A1-20041125-C02577
     8
    Figure US20040235818A1-20041125-C02578
     9
    Figure US20040235818A1-20041125-C02579
    10
    Figure US20040235818A1-20041125-C02580
    11
    Figure US20040235818A1-20041125-C02581
    12
    Figure US20040235818A1-20041125-C02582
    13
    Figure US20040235818A1-20041125-C02583
    14
    Figure US20040235818A1-20041125-C02584
    15
    Figure US20040235818A1-20041125-C02585
    16
    Figure US20040235818A1-20041125-C02586
    17
    Figure US20040235818A1-20041125-C02587
    18
    Figure US20040235818A1-20041125-C02588
    19
    Figure US20040235818A1-20041125-C02589
    20
    Figure US20040235818A1-20041125-C02590
    21
    Figure US20040235818A1-20041125-C02591
    22
    Figure US20040235818A1-20041125-C02592
    23
    Figure US20040235818A1-20041125-C02593
    24
    Figure US20040235818A1-20041125-C02594
    25
    Figure US20040235818A1-20041125-C02595
    26
    Figure US20040235818A1-20041125-C02596
    27
    Figure US20040235818A1-20041125-C02597
    28
    Figure US20040235818A1-20041125-C02598
    29
    Figure US20040235818A1-20041125-C02599
    30
    Figure US20040235818A1-20041125-C02600
  • [0457]
    TABLE 118
    Figure US20040235818A1-20041125-C02601
    1
    Figure US20040235818A1-20041125-C02602
    2
    Figure US20040235818A1-20041125-C02603
    3
    Figure US20040235818A1-20041125-C02604
    4
    Figure US20040235818A1-20041125-C02605
    5
    Figure US20040235818A1-20041125-C02606
    6
    Figure US20040235818A1-20041125-C02607
    7
    Figure US20040235818A1-20041125-C02608
    8
    Figure US20040235818A1-20041125-C02609
    9
    Figure US20040235818A1-20041125-C02610
    10 
    Figure US20040235818A1-20041125-C02611
    11 
    Figure US20040235818A1-20041125-C02612
  • [0458]
    TABLE 119
    Figure US20040235818A1-20041125-C02613
     1
    Figure US20040235818A1-20041125-C02614
     2
    Figure US20040235818A1-20041125-C02615
     3
    Figure US20040235818A1-20041125-C02616
     4
    Figure US20040235818A1-20041125-C02617
     5
    Figure US20040235818A1-20041125-C02618
     6
    Figure US20040235818A1-20041125-C02619
     7
    Figure US20040235818A1-20041125-C02620
     8
    Figure US20040235818A1-20041125-C02621
     9
    Figure US20040235818A1-20041125-C02622
    10
    Figure US20040235818A1-20041125-C02623
    11
    Figure US20040235818A1-20041125-C02624
    12
    Figure US20040235818A1-20041125-C02625
    13
    Figure US20040235818A1-20041125-C02626
    14
    Figure US20040235818A1-20041125-C02627
    15
    Figure US20040235818A1-20041125-C02628
    16
    Figure US20040235818A1-20041125-C02629
    17
    Figure US20040235818A1-20041125-C02630
    18
    Figure US20040235818A1-20041125-C02631
    19
    Figure US20040235818A1-20041125-C02632
    20
    Figure US20040235818A1-20041125-C02633
    21
    Figure US20040235818A1-20041125-C02634
  • [0459]
    TABLE 120
    Figure US20040235818A1-20041125-C02635
     1
    Figure US20040235818A1-20041125-C02636
     2
    Figure US20040235818A1-20041125-C02637
     3
    Figure US20040235818A1-20041125-C02638
     4
    Figure US20040235818A1-20041125-C02639
     5
    Figure US20040235818A1-20041125-C02640
     6
    Figure US20040235818A1-20041125-C02641
     7
    Figure US20040235818A1-20041125-C02642
     8
    Figure US20040235818A1-20041125-C02643
     9
    Figure US20040235818A1-20041125-C02644
    10
    Figure US20040235818A1-20041125-C02645
    11
    Figure US20040235818A1-20041125-C02646
    12
    Figure US20040235818A1-20041125-C02647
    13
    Figure US20040235818A1-20041125-C02648
    14
    Figure US20040235818A1-20041125-C02649
    15
    Figure US20040235818A1-20041125-C02650
    16
    Figure US20040235818A1-20041125-C02651
    17
    Figure US20040235818A1-20041125-C02652
    18
    Figure US20040235818A1-20041125-C02653
  • [0460]
    TABLE 121
    Figure US20040235818A1-20041125-C02654
     1
    Figure US20040235818A1-20041125-C02655
     2
    Figure US20040235818A1-20041125-C02656
     3
    Figure US20040235818A1-20041125-C02657
     4
    Figure US20040235818A1-20041125-C02658
     5
    Figure US20040235818A1-20041125-C02659
     6
    Figure US20040235818A1-20041125-C02660
     7
    Figure US20040235818A1-20041125-C02661
     8
    Figure US20040235818A1-20041125-C02662
     9
    Figure US20040235818A1-20041125-C02663
    10
    Figure US20040235818A1-20041125-C02664
    11
    Figure US20040235818A1-20041125-C02665
    12
    Figure US20040235818A1-20041125-C02666
    13
    Figure US20040235818A1-20041125-C02667
    14
    Figure US20040235818A1-20041125-C02668
    15
    Figure US20040235818A1-20041125-C02669
    16
    Figure US20040235818A1-20041125-C02670
    17
    Figure US20040235818A1-20041125-C02671
    18
    Figure US20040235818A1-20041125-C02672
    19
    Figure US20040235818A1-20041125-C02673
    20
    Figure US20040235818A1-20041125-C02674
    21
    Figure US20040235818A1-20041125-C02675
  • [0461]
    TABLE 122
    Figure US20040235818A1-20041125-C02676
     1
    Figure US20040235818A1-20041125-C02677
     2
    Figure US20040235818A1-20041125-C02678
     3
    Figure US20040235818A1-20041125-C02679
     4
    Figure US20040235818A1-20041125-C02680
     5
    Figure US20040235818A1-20041125-C02681
     6
    Figure US20040235818A1-20041125-C02682
     7
    Figure US20040235818A1-20041125-C02683
     8
    Figure US20040235818A1-20041125-C02684
     9
    Figure US20040235818A1-20041125-C02685
    10
    Figure US20040235818A1-20041125-C02686
    11
    Figure US20040235818A1-20041125-C02687
    12
    Figure US20040235818A1-20041125-C02688
    13
    Figure US20040235818A1-20041125-C02689
    14
    Figure US20040235818A1-20041125-C02690
    15
    Figure US20040235818A1-20041125-C02691
    16
    Figure US20040235818A1-20041125-C02692
    17
    Figure US20040235818A1-20041125-C02693
    18
    Figure US20040235818A1-20041125-C02694
    19
    Figure US20040235818A1-20041125-C02695
    20
    Figure US20040235818A1-20041125-C02696
    21
    Figure US20040235818A1-20041125-C02697
    22
    Figure US20040235818A1-20041125-C02698
  • [0462]
    TABLE 123
    Figure US20040235818A1-20041125-C02699
     1
    Figure US20040235818A1-20041125-C02700
     2
    Figure US20040235818A1-20041125-C02701
     3
    Figure US20040235818A1-20041125-C02702
     4
    Figure US20040235818A1-20041125-C02703
     5
    Figure US20040235818A1-20041125-C02704
     6
    Figure US20040235818A1-20041125-C02705
     7
    Figure US20040235818A1-20041125-C02706
     8
    Figure US20040235818A1-20041125-C02707
     9
    Figure US20040235818A1-20041125-C02708
    10
    Figure US20040235818A1-20041125-C02709
    11
    Figure US20040235818A1-20041125-C02710
    12
    Figure US20040235818A1-20041125-C02711
    13
    Figure US20040235818A1-20041125-C02712
    14
    Figure US20040235818A1-20041125-C02713
    15
    Figure US20040235818A1-20041125-C02714
    16
    Figure US20040235818A1-20041125-C02715
    17
    Figure US20040235818A1-20041125-C02716
    18
    Figure US20040235818A1-20041125-C02717
    19
    Figure US20040235818A1-20041125-C02718
    20
    Figure US20040235818A1-20041125-C02719
    21
    Figure US20040235818A1-20041125-C02720
    22
    Figure US20040235818A1-20041125-C02721
    23
    Figure US20040235818A1-20041125-C02722
    24
    Figure US20040235818A1-20041125-C02723
    25
    Figure US20040235818A1-20041125-C02724
    26
    Figure US20040235818A1-20041125-C02725
    27
    Figure US20040235818A1-20041125-C02726
    28
    Figure US20040235818A1-20041125-C02727
    29
    Figure US20040235818A1-20041125-C02728
    30
    Figure US20040235818A1-20041125-C02729
  • [0463]
    TABLE 124
    Figure US20040235818A1-20041125-C02730
     1
    Figure US20040235818A1-20041125-C02731
     2
    Figure US20040235818A1-20041125-C02732
     3
    Figure US20040235818A1-20041125-C02733
     4
    Figure US20040235818A1-20041125-C02734
     5
    Figure US20040235818A1-20041125-C02735
     6
    Figure US20040235818A1-20041125-C02736
     7
    Figure US20040235818A1-20041125-C02737
     8
    Figure US20040235818A1-20041125-C02738
     9
    Figure US20040235818A1-20041125-C02739
    10
    Figure US20040235818A1-20041125-C02740
    11
    Figure US20040235818A1-20041125-C02741
    12
    Figure US20040235818A1-20041125-C02742
    13
    Figure US20040235818A1-20041125-C02743
    14
    Figure US20040235818A1-20041125-C02744
    15
    Figure US20040235818A1-20041125-C02745
    16
    Figure US20040235818A1-20041125-C02746
    17
    Figure US20040235818A1-20041125-C02747
    18
    Figure US20040235818A1-20041125-C02748
    19
    Figure US20040235818A1-20041125-C02749
    20
    Figure US20040235818A1-20041125-C02750
    21
    Figure US20040235818A1-20041125-C02751
  • [0464]
    TABLE 125
    Figure US20040235818A1-20041125-C02752
    1
    Figure US20040235818A1-20041125-C02753
    2
    Figure US20040235818A1-20041125-C02754
    3
    Figure US20040235818A1-20041125-C02755
    4
    Figure US20040235818A1-20041125-C02756
    5
    Figure US20040235818A1-20041125-C02757
    6
    Figure US20040235818A1-20041125-C02758
    7
    Figure US20040235818A1-20041125-C02759
    8
    Figure US20040235818A1-20041125-C02760
    9
    Figure US20040235818A1-20041125-C02761
    10 
    Figure US20040235818A1-20041125-C02762
    11 
    Figure US20040235818A1-20041125-C02763
  • [0465]
    TABLE 126
    Figure US20040235818A1-20041125-C02764
     1
    Figure US20040235818A1-20041125-C02765
     2
    Figure US20040235818A1-20041125-C02766
     3
    Figure US20040235818A1-20041125-C02767
     4
    Figure US20040235818A1-20041125-C02768
     5
    Figure US20040235818A1-20041125-C02769
     6
    Figure US20040235818A1-20041125-C02770
     7
    Figure US20040235818A1-20041125-C02771
     8
    Figure US20040235818A1-20041125-C02772
     9
    Figure US20040235818A1-20041125-C02773
    10
    Figure US20040235818A1-20041125-C02774
    11
    Figure US20040235818A1-20041125-C02775
    12
    Figure US20040235818A1-20041125-C02776
    13
    Figure US20040235818A1-20041125-C02777
    14
    Figure US20040235818A1-20041125-C02778
    15
    Figure US20040235818A1-20041125-C02779
    16
    Figure US20040235818A1-20041125-C02780
    17
    Figure US20040235818A1-20041125-C02781
    18
    Figure US20040235818A1-20041125-C02782
    19
    Figure US20040235818A1-20041125-C02783
    20
    Figure US20040235818A1-20041125-C02784
    21
    Figure US20040235818A1-20041125-C02785
  • [0466]
    TABLE 127
    Figure US20040235818A1-20041125-C02786
     1
    Figure US20040235818A1-20041125-C02787
     2
    Figure US20040235818A1-20041125-C02788
     3
    Figure US20040235818A1-20041125-C02789
     4
    Figure US20040235818A1-20041125-C02790
     5
    Figure US20040235818A1-20041125-C02791
     6
    Figure US20040235818A1-20041125-C02792
     7
    Figure US20040235818A1-20041125-C02793
     8
    Figure US20040235818A1-20041125-C02794
     9
    Figure US20040235818A1-20041125-C02795
    10
    Figure US20040235818A1-20041125-C02796
    11
    Figure US20040235818A1-20041125-C02797
    12
    Figure US20040235818A1-20041125-C02798
    13
    Figure US20040235818A1-20041125-C02799
    14
    Figure US20040235818A1-20041125-C02800
    15
    Figure US20040235818A1-20041125-C02801
    16
    Figure US20040235818A1-20041125-C02802
    17
    Figure US20040235818A1-20041125-C02803
    18
    Figure US20040235818A1-20041125-C02804
    19
    Figure US20040235818A1-20041125-C02805
    20
    Figure US20040235818A1-20041125-C02806
    21
    Figure US20040235818A1-20041125-C02807
  • [0467]
    TABLE 128
    Figure US20040235818A1-20041125-C02808
     1
    Figure US20040235818A1-20041125-C02809
     2
    Figure US20040235818A1-20041125-C02810
     3
    Figure US20040235818A1-20041125-C02811
     4
    Figure US20040235818A1-20041125-C02812
     5
    Figure US20040235818A1-20041125-C02813
     6
    Figure US20040235818A1-20041125-C02814
     7
    Figure US20040235818A1-20041125-C02815
     8
    Figure US20040235818A1-20041125-C02816
     9
    Figure US20040235818A1-20041125-C02817
    10
    Figure US20040235818A1-20041125-C02818
    11
    Figure US20040235818A1-20041125-C02819
    12
    Figure US20040235818A1-20041125-C02820
    13
    Figure US20040235818A1-20041125-C02821
    14
    Figure US20040235818A1-20041125-C02822
    15
    Figure US20040235818A1-20041125-C02823
    16
    Figure US20040235818A1-20041125-C02824
    17
    Figure US20040235818A1-20041125-C02825
    18
    Figure US20040235818A1-20041125-C02826
    19
    Figure US20040235818A1-20041125-C02827
    20
    Figure US20040235818A1-20041125-C02828
    21
    Figure US20040235818A1-20041125-C02829
  • [0468]
    TABLE 129
    Figure US20040235818A1-20041125-C02830
    1
    Figure US20040235818A1-20041125-C02831
         		14
    Figure US20040235818A1-20041125-C02832
    2
    Figure US20040235818A1-20041125-C02833
         		15
    Figure US20040235818A1-20041125-C02834
    3
    Figure US20040235818A1-20041125-C02835
         		16
    Figure US20040235818A1-20041125-C02836
    4
    Figure US20040235818A1-20041125-C02837
         		17
    Figure US20040235818A1-20041125-C02838
    5
    Figure US20040235818A1-20041125-C02839
         		18
    Figure US20040235818A1-20041125-C02840
    6
    Figure US20040235818A1-20041125-C02841
         		19
    Figure US20040235818A1-20041125-C02842
    7
    Figure US20040235818A1-20041125-C02843
         		20
    Figure US20040235818A1-20041125-C02844
    8
    Figure US20040235818A1-20041125-C02845
         		21
    Figure US20040235818A1-20041125-C02846
    9
    Figure US20040235818A1-20041125-C02847
         		22
    Figure US20040235818A1-20041125-C02848
    10 
    Figure US20040235818A1-20041125-C02849
         		23
    Figure US20040235818A1-20041125-C02850
    11 
    Figure US20040235818A1-20041125-C02851
         		24
    Figure US20040235818A1-20041125-C02852
    12 
    Figure US20040235818A1-20041125-C02853
         		25
    Figure US20040235818A1-20041125-C02854
    13 
    Figure US20040235818A1-20041125-C02855
         		26
    Figure US20040235818A1-20041125-C02856
  • [0469]
    TABLE 130
    Figure US20040235818A1-20041125-C02857
    1
    Figure US20040235818A1-20041125-C02858
         		14
    Figure US20040235818A1-20041125-C02859
    2
    Figure US20040235818A1-20041125-C02860
         		15
    Figure US20040235818A1-20041125-C02861
    3
    Figure US20040235818A1-20041125-C02862
         		16
    Figure US20040235818A1-20041125-C02863
    4
    Figure US20040235818A1-20041125-C02864
         		17
    Figure US20040235818A1-20041125-C02865
    5
    Figure US20040235818A1-20041125-C02866
         		18
    Figure US20040235818A1-20041125-C02867
    6
    Figure US20040235818A1-20041125-C02868
         		19
    Figure US20040235818A1-20041125-C02869
    7
    Figure US20040235818A1-20041125-C02870
         		20
    Figure US20040235818A1-20041125-C02871
    8
    Figure US20040235818A1-20041125-C02872
         		21
    Figure US20040235818A1-20041125-C02873
    9
    Figure US20040235818A1-20041125-C02874
         		22
    Figure US20040235818A1-20041125-C02875
    10 
    Figure US20040235818A1-20041125-C02876
         		23
    Figure US20040235818A1-20041125-C02877
    11 
    Figure US20040235818A1-20041125-C02878
         		24
    Figure US20040235818A1-20041125-C02879
    12 
    Figure US20040235818A1-20041125-C02880
         		25
    Figure US20040235818A1-20041125-C02881
    13 
    Figure US20040235818A1-20041125-C02882
         		26
    Figure US20040235818A1-20041125-C02883
  • [0470]
    TABLE 131
    Figure US20040235818A1-20041125-C02884
    Figure US20040235818A1-20041125-C02885
    1
    Figure US20040235818A1-20041125-C02886
         		14
    Figure US20040235818A1-20041125-C02887
    2
    Figure US20040235818A1-20041125-C02888
         		15
    Figure US20040235818A1-20041125-C02889
    3
    Figure US20040235818A1-20041125-C02890
         		16
    Figure US20040235818A1-20041125-C02891
    4
    Figure US20040235818A1-20041125-C02892
         		17
    Figure US20040235818A1-20041125-C02893
    5
    Figure US20040235818A1-20041125-C02894
         		18
    Figure US20040235818A1-20041125-C02895
    6
    Figure US20040235818A1-20041125-C02896
         		19
    Figure US20040235818A1-20041125-C02897
    7
    Figure US20040235818A1-20041125-C02898
         		20
    Figure US20040235818A1-20041125-C02899
    8
    Figure US20040235818A1-20041125-C02900
         		21
    Figure US20040235818A1-20041125-C02901
    9
    Figure US20040235818A1-20041125-C02902
         		22
    Figure US20040235818A1-20041125-C02903
    10
    Figure US20040235818A1-20041125-C02904
         		23
    Figure US20040235818A1-20041125-C02905
    11
    Figure US20040235818A1-20041125-C02906
         		24
    Figure US20040235818A1-20041125-C02907
    12
    Figure US20040235818A1-20041125-C02908
         		25
    Figure US20040235818A1-20041125-C02909
    13
    Figure US20040235818A1-20041125-C02910
         		26
    Figure US20040235818A1-20041125-C02911
  • [0471]
    TABLE 132
    Figure US20040235818A1-20041125-C02912
    Figure US20040235818A1-20041125-C02913
    1
    Figure US20040235818A1-20041125-C02914
         		14
    Figure US20040235818A1-20041125-C02915
    2
    Figure US20040235818A1-20041125-C02916
         		15
    Figure US20040235818A1-20041125-C02917
    3
    Figure US20040235818A1-20041125-C02918
         		16
    Figure US20040235818A1-20041125-C02919
    4
    Figure US20040235818A1-20041125-C02920
         		17
    Figure US20040235818A1-20041125-C02921
    5
    Figure US20040235818A1-20041125-C02922
         		18
    Figure US20040235818A1-20041125-C02923
    6
    Figure US20040235818A1-20041125-C02924
         		19
    Figure US20040235818A1-20041125-C02925
    7
    Figure US20040235818A1-20041125-C02926
         		20
    Figure US20040235818A1-20041125-C02927
    8
    Figure US20040235818A1-20041125-C02928
         		21
    Figure US20040235818A1-20041125-C02929
    9
    Figure US20040235818A1-20041125-C02930
         		22
    Figure US20040235818A1-20041125-C02931
    10
    Figure US20040235818A1-20041125-C02932
         		23
    Figure US20040235818A1-20041125-C02933
    11
    Figure US20040235818A1-20041125-C02934
         		24
    Figure US20040235818A1-20041125-C02935
    12
    Figure US20040235818A1-20041125-C02936
         		25
    Figure US20040235818A1-20041125-C02937
    13
    Figure US20040235818A1-20041125-C02938
         		26
    Figure US20040235818A1-20041125-C02939
  • [0472]
    TABLE 133
    Figure US20040235818A1-20041125-C02940
    Figure US20040235818A1-20041125-C02941
    1
    Figure US20040235818A1-20041125-C02942
         		14
    Figure US20040235818A1-20041125-C02943
    2
    Figure US20040235818A1-20041125-C02944
         		15
    Figure US20040235818A1-20041125-C02945
    3
    Figure US20040235818A1-20041125-C02946
         		16
    Figure US20040235818A1-20041125-C02947
    4
    Figure US20040235818A1-20041125-C02948
         		17
    Figure US20040235818A1-20041125-C02949
    5
    Figure US20040235818A1-20041125-C02950
         		18
    Figure US20040235818A1-20041125-C02951
    6
    Figure US20040235818A1-20041125-C02952
         		19
    Figure US20040235818A1-20041125-C02953
    7
    Figure US20040235818A1-20041125-C02954
         		20
    Figure US20040235818A1-20041125-C02955
    8
    Figure US20040235818A1-20041125-C02956
         		21
    Figure US20040235818A1-20041125-C02957
    9
    Figure US20040235818A1-20041125-C02958
         		22
    Figure US20040235818A1-20041125-C02959
    10
    Figure US20040235818A1-20041125-C02960
         		23
    Figure US20040235818A1-20041125-C02961
    11
    Figure US20040235818A1-20041125-C02962
         		24
    Figure US20040235818A1-20041125-C02963
    12
    Figure US20040235818A1-20041125-C02964
         		25
    Figure US20040235818A1-20041125-C02965
    13
    Figure US20040235818A1-20041125-C02966
         		26
    Figure US20040235818A1-20041125-C02967
  • [0473]
    TABLE 134
    Figure US20040235818A1-20041125-C02968
    Figure US20040235818A1-20041125-C02969
    1
    Figure US20040235818A1-20041125-C02970
         		14
    Figure US20040235818A1-20041125-C02971
    2
    Figure US20040235818A1-20041125-C02972
         		15
    Figure US20040235818A1-20041125-C02973
    3
    Figure US20040235818A1-20041125-C02974
         		16
    Figure US20040235818A1-20041125-C02975
    4
    Figure US20040235818A1-20041125-C02976
         		17
    Figure US20040235818A1-20041125-C02977
    5
    Figure US20040235818A1-20041125-C02978
         		18
    Figure US20040235818A1-20041125-C02979
    6
    Figure US20040235818A1-20041125-C02980
         		19
    Figure US20040235818A1-20041125-C02981
    7
    Figure US20040235818A1-20041125-C02982
         		20
    Figure US20040235818A1-20041125-C02983
    8
    Figure US20040235818A1-20041125-C02984
         		21
    Figure US20040235818A1-20041125-C02985
    9
    Figure US20040235818A1-20041125-C02986
         		22
    Figure US20040235818A1-20041125-C02987
    10
    Figure US20040235818A1-20041125-C02988
         		23
    Figure US20040235818A1-20041125-C02989
    11
    Figure US20040235818A1-20041125-C02990
         		24
    Figure US20040235818A1-20041125-C02991
    12
    Figure US20040235818A1-20041125-C02992
         		25
    Figure US20040235818A1-20041125-C02993
    13
    Figure US20040235818A1-20041125-C02994
         		26
    Figure US20040235818A1-20041125-C02995
  • [0474]
    TABLE 135
    Figure US20040235818A1-20041125-C02996
    Figure US20040235818A1-20041125-C02997
    1
    Figure US20040235818A1-20041125-C02998
    2
    Figure US20040235818A1-20041125-C02999
    3
    Figure US20040235818A1-20041125-C03000
    4
    Figure US20040235818A1-20041125-C03001
    5
    Figure US20040235818A1-20041125-C03002
    6
    Figure US20040235818A1-20041125-C03003
    7
    Figure US20040235818A1-20041125-C03004
    8
    Figure US20040235818A1-20041125-C03005
    9
    Figure US20040235818A1-20041125-C03006
    10
    Figure US20040235818A1-20041125-C03007
    11
    Figure US20040235818A1-20041125-C03008
    12
    Figure US20040235818A1-20041125-C03009
    13
    Figure US20040235818A1-20041125-C03010
    14
    Figure US20040235818A1-20041125-C03011
    15
    Figure US20040235818A1-20041125-C03012
    16
    Figure US20040235818A1-20041125-C03013
  • [0475]
    TABLE 136
    Figure US20040235818A1-20041125-C03014
    Figure US20040235818A1-20041125-C03015
    1
    Figure US20040235818A1-20041125-C03016
    2
    Figure US20040235818A1-20041125-C03017
    3
    Figure US20040235818A1-20041125-C03018
    4
    Figure US20040235818A1-20041125-C03019
    5
    Figure US20040235818A1-20041125-C03020
    6
    Figure US20040235818A1-20041125-C03021
    7
    Figure US20040235818A1-20041125-C03022
    8
    Figure US20040235818A1-20041125-C03023
    9
    Figure US20040235818A1-20041125-C03024
    10
    Figure US20040235818A1-20041125-C03025
    11
    Figure US20040235818A1-20041125-C03026
    12
    Figure US20040235818A1-20041125-C03027
    13
    Figure US20040235818A1-20041125-C03028
    14
    Figure US20040235818A1-20041125-C03029
    15
    Figure US20040235818A1-20041125-C03030
    16
    Figure US20040235818A1-20041125-C03031
  • [0476]
    TABLE 137
    Figure US20040235818A1-20041125-C03032
    Figure US20040235818A1-20041125-C03033
    1
    Figure US20040235818A1-20041125-C03034
    2
    Figure US20040235818A1-20041125-C03035
    3
    Figure US20040235818A1-20041125-C03036
    4
    Figure US20040235818A1-20041125-C03037
    5
    Figure US20040235818A1-20041125-C03038
    6
    Figure US20040235818A1-20041125-C03039
    7
    Figure US20040235818A1-20041125-C03040
    8
    Figure US20040235818A1-20041125-C03041
    9
    Figure US20040235818A1-20041125-C03042
    10
    Figure US20040235818A1-20041125-C03043
    11
    Figure US20040235818A1-20041125-C03044
    12
    Figure US20040235818A1-20041125-C03045
    13
    Figure US20040235818A1-20041125-C03046
    14
    Figure US20040235818A1-20041125-C03047
    15
    Figure US20040235818A1-20041125-C03048
    16
    Figure US20040235818A1-20041125-C03049
  • [0477]
    TABLE 138
    Figure US20040235818A1-20041125-C03050
    Figure US20040235818A1-20041125-C03051
    1
    Figure US20040235818A1-20041125-C03052
    2
    Figure US20040235818A1-20041125-C03053
    3
    Figure US20040235818A1-20041125-C03054
    4
    Figure US20040235818A1-20041125-C03055
    5
    Figure US20040235818A1-20041125-C03056
    6
    Figure US20040235818A1-20041125-C03057
    7
    Figure US20040235818A1-20041125-C03058
    8
    Figure US20040235818A1-20041125-C03059
    9
    Figure US20040235818A1-20041125-C03060
    10
    Figure US20040235818A1-20041125-C03061
    11
    Figure US20040235818A1-20041125-C03062
    12
    Figure US20040235818A1-20041125-C03063
    13
    Figure US20040235818A1-20041125-C03064
    14
    Figure US20040235818A1-20041125-C03065
    15
    Figure US20040235818A1-20041125-C03066
    16
    Figure US20040235818A1-20041125-C03067
  • [0478]
    TABLE 139
    Figure US20040235818A1-20041125-C03068
    Figure US20040235818A1-20041125-C03069
    1
    Figure US20040235818A1-20041125-C03070
    2
    Figure US20040235818A1-20041125-C03071
    3
    Figure US20040235818A1-20041125-C03072
    4
    Figure US20040235818A1-20041125-C03073
    5
    Figure US20040235818A1-20041125-C03074
    6
    Figure US20040235818A1-20041125-C03075
    7
    Figure US20040235818A1-20041125-C03076
    8
    Figure US20040235818A1-20041125-C03077
    9
    Figure US20040235818A1-20041125-C03078
    10
    Figure US20040235818A1-20041125-C03079
    11
    Figure US20040235818A1-20041125-C03080
    12
    Figure US20040235818A1-20041125-C03081
    13
    Figure US20040235818A1-20041125-C03082
    14
    Figure US20040235818A1-20041125-C03083
    15
    Figure US20040235818A1-20041125-C03084
    16
    Figure US20040235818A1-20041125-C03085
  • [0479]
    TABLE 140
    Figure US20040235818A1-20041125-C03086
    Figure US20040235818A1-20041125-C03087
    1
    Figure US20040235818A1-20041125-C03088
    2
    Figure US20040235818A1-20041125-C03089
    3
    Figure US20040235818A1-20041125-C03090
    4
    Figure US20040235818A1-20041125-C03091
    5
    Figure US20040235818A1-20041125-C03092
    6
    Figure US20040235818A1-20041125-C03093
    7
    Figure US20040235818A1-20041125-C03094
    8
    Figure US20040235818A1-20041125-C03095
    9
    Figure US20040235818A1-20041125-C03096
    10
    Figure US20040235818A1-20041125-C03097
    11
    Figure US20040235818A1-20041125-C03098
    12
    Figure US20040235818A1-20041125-C03099
    13
    Figure US20040235818A1-20041125-C03100
    14
    Figure US20040235818A1-20041125-C03101
    15
    Figure US20040235818A1-20041125-C03102
    16
    Figure US20040235818A1-20041125-C03103
  • [0480]
    TABLE 141
    Figure US20040235818A1-20041125-C03104
    Figure US20040235818A1-20041125-C03105
    1
    Figure US20040235818A1-20041125-C03106
    2
    Figure US20040235818A1-20041125-C03107
    3
    Figure US20040235818A1-20041125-C03108
    4
    Figure US20040235818A1-20041125-C03109
    5
    Figure US20040235818A1-20041125-C03110
    6
    Figure US20040235818A1-20041125-C03111
    7
    Figure US20040235818A1-20041125-C03112
    8
    Figure US20040235818A1-20041125-C03113
    9
    Figure US20040235818A1-20041125-C03114
    10
    Figure US20040235818A1-20041125-C03115
    11
    Figure US20040235818A1-20041125-C03116
    12
    Figure US20040235818A1-20041125-C03117
    13
    Figure US20040235818A1-20041125-C03118
    14
    Figure US20040235818A1-20041125-C03119
    15
    Figure US20040235818A1-20041125-C03120
    16
    Figure US20040235818A1-20041125-C03121
  • [0481]
    TABLE 142
    Figure US20040235818A1-20041125-C03122
    Figure US20040235818A1-20041125-C03123
    1
    Figure US20040235818A1-20041125-C03124
    2
    Figure US20040235818A1-20041125-C03125
    3
    Figure US20040235818A1-20041125-C03126
    4
    Figure US20040235818A1-20041125-C03127
    5
    Figure US20040235818A1-20041125-C03128
    6
    Figure US20040235818A1-20041125-C03129
    7
    Figure US20040235818A1-20041125-C03130
    8
    Figure US20040235818A1-20041125-C03131
    9
    Figure US20040235818A1-20041125-C03132
    10
    Figure US20040235818A1-20041125-C03133
    11
    Figure US20040235818A1-20041125-C03134
    12
    Figure US20040235818A1-20041125-C03135
    13
    Figure US20040235818A1-20041125-C03136
    14
    Figure US20040235818A1-20041125-C03137
    15
    Figure US20040235818A1-20041125-C03138
    16
    Figure US20040235818A1-20041125-C03139
  • [0482]
    TABLE 143
    Figure US20040235818A1-20041125-C03140
    Figure US20040235818A1-20041125-C03141
    1
    Figure US20040235818A1-20041125-C03142
    2
    Figure US20040235818A1-20041125-C03143
    3
    Figure US20040235818A1-20041125-C03144
    4
    Figure US20040235818A1-20041125-C03145
    5
    Figure US20040235818A1-20041125-C03146
    6
    Figure US20040235818A1-20041125-C03147
    7
    Figure US20040235818A1-20041125-C03148
    8
    Figure US20040235818A1-20041125-C03149
    9
    Figure US20040235818A1-20041125-C03150
    10
    Figure US20040235818A1-20041125-C03151
    11
    Figure US20040235818A1-20041125-C03152
    12
    Figure US20040235818A1-20041125-C03153
  • [0483]
    TABLE 144
    Figure US20040235818A1-20041125-C03154
    Figure US20040235818A1-20041125-C03155
    1
    Figure US20040235818A1-20041125-C03156
    2
    Figure US20040235818A1-20041125-C03157
    3
    Figure US20040235818A1-20041125-C03158
    4
    Figure US20040235818A1-20041125-C03159
    5
    Figure US20040235818A1-20041125-C03160
    6
    Figure US20040235818A1-20041125-C03161
    7
    Figure US20040235818A1-20041125-C03162
    8
    Figure US20040235818A1-20041125-C03163
    9
    Figure US20040235818A1-20041125-C03164
    10
    Figure US20040235818A1-20041125-C03165
    11
    Figure US20040235818A1-20041125-C03166
    12
    Figure US20040235818A1-20041125-C03167
  • [0484]
    TABLE 145
    Figure US20040235818A1-20041125-C03168
    Figure US20040235818A1-20041125-C03169
    1
    Figure US20040235818A1-20041125-C03170
    2
    Figure US20040235818A1-20041125-C03171
    3
    Figure US20040235818A1-20041125-C03172
    4
    Figure US20040235818A1-20041125-C03173
    5
    Figure US20040235818A1-20041125-C03174
    6
    Figure US20040235818A1-20041125-C03175
    7
    Figure US20040235818A1-20041125-C03176
    8
    Figure US20040235818A1-20041125-C03177
    9
    Figure US20040235818A1-20041125-C03178
    10
    Figure US20040235818A1-20041125-C03179
    11
    Figure US20040235818A1-20041125-C03180
    12
    Figure US20040235818A1-20041125-C03181
  • [0485]
    TABLE 146
    Figure US20040235818A1-20041125-C03182
    Figure US20040235818A1-20041125-C03183
    1
    Figure US20040235818A1-20041125-C03184
    2
    Figure US20040235818A1-20041125-C03185
    3
    Figure US20040235818A1-20041125-C03186
    4
    Figure US20040235818A1-20041125-C03187
    5
    Figure US20040235818A1-20041125-C03188
    6
    Figure US20040235818A1-20041125-C03189
    7
    Figure US20040235818A1-20041125-C03190
    8
    Figure US20040235818A1-20041125-C03191
    9
    Figure US20040235818A1-20041125-C03192
    10
    Figure US20040235818A1-20041125-C03193
    11
    Figure US20040235818A1-20041125-C03194
    12
    Figure US20040235818A1-20041125-C03195
  • [0486]
    TABLE 147
    Figure US20040235818A1-20041125-C03196
    Figure US20040235818A1-20041125-C03197
    1
    Figure US20040235818A1-20041125-C03198
    2
    Figure US20040235818A1-20041125-C03199
    3
    Figure US20040235818A1-20041125-C03200
    4
    Figure US20040235818A1-20041125-C03201
    5
    Figure US20040235818A1-20041125-C03202
    6
    Figure US20040235818A1-20041125-C03203
    7
    Figure US20040235818A1-20041125-C03204
    8
    Figure US20040235818A1-20041125-C03205
    9
    Figure US20040235818A1-20041125-C03206
    10
    Figure US20040235818A1-20041125-C03207
    11
    Figure US20040235818A1-20041125-C03208
    12
    Figure US20040235818A1-20041125-C03209
  • [0487]
    TABLE 148
    Figure US20040235818A1-20041125-C03210
    Figure US20040235818A1-20041125-C03211
    1
    Figure US20040235818A1-20041125-C03212
    2
    Figure US20040235818A1-20041125-C03213
    3
    Figure US20040235818A1-20041125-C03214
    4
    Figure US20040235818A1-20041125-C03215
    5
    Figure US20040235818A1-20041125-C03216
    6
    Figure US20040235818A1-20041125-C03217
    7
    Figure US20040235818A1-20041125-C03218
    8
    Figure US20040235818A1-20041125-C03219
    9
    Figure US20040235818A1-20041125-C03220
    10
    Figure US20040235818A1-20041125-C03221
    11
    Figure US20040235818A1-20041125-C03222
    12
    Figure US20040235818A1-20041125-C03223
  • [0488]
    TABLE 149
    Figure US20040235818A1-20041125-C03224
    Figure US20040235818A1-20041125-C03225
    1
    Figure US20040235818A1-20041125-C03226
    2
    Figure US20040235818A1-20041125-C03227
    3
    Figure US20040235818A1-20041125-C03228
    4
    Figure US20040235818A1-20041125-C03229
    5
    Figure US20040235818A1-20041125-C03230
    6
    Figure US20040235818A1-20041125-C03231
    7
    Figure US20040235818A1-20041125-C03232
    8
    Figure US20040235818A1-20041125-C03233
    9
    Figure US20040235818A1-20041125-C03234
    10
    Figure US20040235818A1-20041125-C03235
    11
    Figure US20040235818A1-20041125-C03236
    12
    Figure US20040235818A1-20041125-C03237
  • [0489]
    TABLE 150
    Figure US20040235818A1-20041125-C03238
    Figure US20040235818A1-20041125-C03239
    1
    Figure US20040235818A1-20041125-C03240
    2
    Figure US20040235818A1-20041125-C03241
    3
    Figure US20040235818A1-20041125-C03242
    4
    Figure US20040235818A1-20041125-C03243
    5
    Figure US20040235818A1-20041125-C03244
    6
    Figure US20040235818A1-20041125-C03245
    7
    Figure US20040235818A1-20041125-C03246
    8
    Figure US20040235818A1-20041125-C03247
    9
    Figure US20040235818A1-20041125-C03248
    10
    Figure US20040235818A1-20041125-C03249
    11
    Figure US20040235818A1-20041125-C03250
    12
    Figure US20040235818A1-20041125-C03251
  • [0490]
    TABLE 151
    Figure US20040235818A1-20041125-C03252
     1
    Figure US20040235818A1-20041125-C03253
         		22
    Figure US20040235818A1-20041125-C03254
     2
    Figure US20040235818A1-20041125-C03255
         		23
    Figure US20040235818A1-20041125-C03256
     3
    Figure US20040235818A1-20041125-C03257
         		24
    Figure US20040235818A1-20041125-C03258
     4
    Figure US20040235818A1-20041125-C03259
         		25
    Figure US20040235818A1-20041125-C03260
     5
    Figure US20040235818A1-20041125-C03261
         		26
    Figure US20040235818A1-20041125-C03262
     6
    Figure US20040235818A1-20041125-C03263
         		27
    Figure US20040235818A1-20041125-C03264
     7
    Figure US20040235818A1-20041125-C03265
         		28
    Figure US20040235818A1-20041125-C03266
     8
    Figure US20040235818A1-20041125-C03267
         		29
    Figure US20040235818A1-20041125-C03268
     9
    Figure US20040235818A1-20041125-C03269
         		30
    Figure US20040235818A1-20041125-C03270
    10
    Figure US20040235818A1-20041125-C03271
         		31
    Figure US20040235818A1-20041125-C03272
    11
    Figure US20040235818A1-20041125-C03273
         		32
    Figure US20040235818A1-20041125-C03274
    12
    Figure US20040235818A1-20041125-C03275
         		33
    Figure US20040235818A1-20041125-C03276
    13
    Figure US20040235818A1-20041125-C03277
         		34
    Figure US20040235818A1-20041125-C03278
    14
    Figure US20040235818A1-20041125-C03279
         		35
    Figure US20040235818A1-20041125-C03280
    15
    Figure US20040235818A1-20041125-C03281
         		36
    Figure US20040235818A1-20041125-C03282
    16
    Figure US20040235818A1-20041125-C03283
         		37
    Figure US20040235818A1-20041125-C03284
    17
    Figure US20040235818A1-20041125-C03285
         		38
    Figure US20040235818A1-20041125-C03286
    18
    Figure US20040235818A1-20041125-C03287
         		39
    Figure US20040235818A1-20041125-C03288
    19
    Figure US20040235818A1-20041125-C03289
         		40
    Figure US20040235818A1-20041125-C03290
    20
    Figure US20040235818A1-20041125-C03291
         		41
    Figure US20040235818A1-20041125-C03292
    21
    Figure US20040235818A1-20041125-C03293
         		42
    Figure US20040235818A1-20041125-C03294
  • [0491]
    TABLE 152
    Figure US20040235818A1-20041125-C03295
    43
    Figure US20040235818A1-20041125-C03296
         		70
    Figure US20040235818A1-20041125-C03297
    44
    Figure US20040235818A1-20041125-C03298
         		71
    Figure US20040235818A1-20041125-C03299
    45
    Figure US20040235818A1-20041125-C03300
         		72
    Figure US20040235818A1-20041125-C03301
    46
    Figure US20040235818A1-20041125-C03302
         		73
    Figure US20040235818A1-20041125-C03303
    47
    Figure US20040235818A1-20041125-C03304
         		74
    Figure US20040235818A1-20041125-C03305
    48
    Figure US20040235818A1-20041125-C03306
         		75
    Figure US20040235818A1-20041125-C03307
    49
    Figure US20040235818A1-20041125-C03308
         		76
    Figure US20040235818A1-20041125-C03309
    50
    Figure US20040235818A1-20041125-C03310
         		78
    Figure US20040235818A1-20041125-C03311
    51
    Figure US20040235818A1-20041125-C03312
         		79
    Figure US20040235818A1-20041125-C03313
    52
    Figure US20040235818A1-20041125-C03314
         		80
    Figure US20040235818A1-20041125-C03315
    53
    Figure US20040235818A1-20041125-C03316
         		81
    Figure US20040235818A1-20041125-C03317
    54
    Figure US20040235818A1-20041125-C03318
         		82
    Figure US20040235818A1-20041125-C03319
    55
    Figure US20040235818A1-20041125-C03320
         		83
    Figure US20040235818A1-20041125-C03321
    56
    Figure US20040235818A1-20041125-C03322
         		84
    Figure US20040235818A1-20041125-C03323
    57
    Figure US20040235818A1-20041125-C03324
         		85
    Figure US20040235818A1-20041125-C03325
    58
    Figure US20040235818A1-20041125-C03326
         		86
    Figure US20040235818A1-20041125-C03327
    59
    Figure US20040235818A1-20041125-C03328
         		87
    Figure US20040235818A1-20041125-C03329
    60
    Figure US20040235818A1-20041125-C03330
         		88
    Figure US20040235818A1-20041125-C03331
    61
    Figure US20040235818A1-20041125-C03332
         		89
    Figure US20040235818A1-20041125-C03333
    62
    Figure US20040235818A1-20041125-C03334
         		90
    Figure US20040235818A1-20041125-C03335
    63
    Figure US20040235818A1-20041125-C03336
         		91
    Figure US20040235818A1-20041125-C03337
    64
    Figure US20040235818A1-20041125-C03338
         		92
    Figure US20040235818A1-20041125-C03339
    65
    Figure US20040235818A1-20041125-C03340
         		93
    Figure US20040235818A1-20041125-C03341
    66
    Figure US20040235818A1-20041125-C03342
         		94
    Figure US20040235818A1-20041125-C03343
    67
    Figure US20040235818A1-20041125-C03344
         		95
    Figure US20040235818A1-20041125-C03345
    68
    Figure US20040235818A1-20041125-C03346
         		96
    Figure US20040235818A1-20041125-C03347
    69
    Figure US20040235818A1-20041125-C03348
  • [0492]
    TABLE 153
    Figure US20040235818A1-20041125-C03349
     97
    Figure US20040235818A1-20041125-C03350
         		112
    Figure US20040235818A1-20041125-C03351
     98
    Figure US20040235818A1-20041125-C03352
         		113
    Figure US20040235818A1-20041125-C03353
     99
    Figure US20040235818A1-20041125-C03354
         		114
    Figure US20040235818A1-20041125-C03355
    100
    Figure US20040235818A1-20041125-C03356
         		115
    Figure US20040235818A1-20041125-C03357
    101
    Figure US20040235818A1-20041125-C03358
         		116
    Figure US20040235818A1-20041125-C03359
    102
    Figure US20040235818A1-20041125-C03360
         		117
    Figure US20040235818A1-20041125-C03361
    103
    Figure US20040235818A1-20041125-C03362
         		118
    Figure US20040235818A1-20041125-C03363
    104
    Figure US20040235818A1-20041125-C03364
         		119
    Figure US20040235818A1-20041125-C03365
    105
    Figure US20040235818A1-20041125-C03366
         		120
    Figure US20040235818A1-20041125-C03367
    106
    Figure US20040235818A1-20041125-C03368
         		121
    Figure US20040235818A1-20041125-C03369
    107
    Figure US20040235818A1-20041125-C03370
         		122
    Figure US20040235818A1-20041125-C03371
    108
    Figure US20040235818A1-20041125-C03372
         		123
    Figure US20040235818A1-20041125-C03373
    109
    Figure US20040235818A1-20041125-C03374
         		124
    Figure US20040235818A1-20041125-C03375
    110
    Figure US20040235818A1-20041125-C03376
         		125
    Figure US20040235818A1-20041125-C03377
    111
    Figure US20040235818A1-20041125-C03378
         		126
    Figure US20040235818A1-20041125-C03379
  • [0493]
    TABLE 154
    Figure US20040235818A1-20041125-C03380
    127
    Figure US20040235818A1-20041125-C03381
         		142
    Figure US20040235818A1-20041125-C03382
    128
    Figure US20040235818A1-20041125-C03383
         		143
    Figure US20040235818A1-20041125-C03384
    129
    Figure US20040235818A1-20041125-C03385
         		144
    Figure US20040235818A1-20041125-C03386
    130
    Figure US20040235818A1-20041125-C03387
         		145
    Figure US20040235818A1-20041125-C03388
    131
    Figure US20040235818A1-20041125-C03389
         		146
    Figure US20040235818A1-20041125-C03390
    132
    Figure US20040235818A1-20041125-C03391
         		147
    Figure US20040235818A1-20041125-C03392
    133
    Figure US20040235818A1-20041125-C03393
         		148
    Figure US20040235818A1-20041125-C03394
    134
    Figure US20040235818A1-20041125-C03395
         		149
    Figure US20040235818A1-20041125-C03396
    135
    Figure US20040235818A1-20041125-C03397
         		150
    Figure US20040235818A1-20041125-C03398
    136
    Figure US20040235818A1-20041125-C03399
         		151
    Figure US20040235818A1-20041125-C03400
    137
    Figure US20040235818A1-20041125-C03401
         		152
    Figure US20040235818A1-20041125-C03402
    138
    Figure US20040235818A1-20041125-C03403
         		153
    Figure US20040235818A1-20041125-C03404
    139
    Figure US20040235818A1-20041125-C03405
         		154
    Figure US20040235818A1-20041125-C03406
    140
    Figure US20040235818A1-20041125-C03407
         		155
    Figure US20040235818A1-20041125-C03408
    141
    Figure US20040235818A1-20041125-C03409
         		156
    Figure US20040235818A1-20041125-C03410
  • [0494]
    TABLE 155
    Figure US20040235818A1-20041125-C03411
    157
    Figure US20040235818A1-20041125-C03412
         		165
    Figure US20040235818A1-20041125-C03413
    158
    Figure US20040235818A1-20041125-C03414
         		166
    Figure US20040235818A1-20041125-C03415
    159
    Figure US20040235818A1-20041125-C03416
         		167
    Figure US20040235818A1-20041125-C03417
    160
    Figure US20040235818A1-20041125-C03418
         		168
    Figure US20040235818A1-20041125-C03419
    161
    Figure US20040235818A1-20041125-C03420
         		169
    Figure US20040235818A1-20041125-C03421
    162
    Figure US20040235818A1-20041125-C03422
         		170
    Figure US20040235818A1-20041125-C03423
    163
    Figure US20040235818A1-20041125-C03424
         		171
    Figure US20040235818A1-20041125-C03425
    164
    Figure US20040235818A1-20041125-C03426
         		172
    Figure US20040235818A1-20041125-C03427
  • [0495]
    TABLE 156
    Figure US20040235818A1-20041125-C03428
     1
    Figure US20040235818A1-20041125-C03429
         		22
    Figure US20040235818A1-20041125-C03430
     2
    Figure US20040235818A1-20041125-C03431
         		23
    Figure US20040235818A1-20041125-C03432
     3
    Figure US20040235818A1-20041125-C03433
         		24
    Figure US20040235818A1-20041125-C03434
     4
    Figure US20040235818A1-20041125-C03435
         		25
    Figure US20040235818A1-20041125-C03436
     5
    Figure US20040235818A1-20041125-C03437
         		26
    Figure US20040235818A1-20041125-C03438
     6
    Figure US20040235818A1-20041125-C03439
         		27
    Figure US20040235818A1-20041125-C03440
     7
    Figure US20040235818A1-20041125-C03441
         		28
    Figure US20040235818A1-20041125-C03442
     8
    Figure US20040235818A1-20041125-C03443
         		29
    Figure US20040235818A1-20041125-C03444
     9
    Figure US20040235818A1-20041125-C03445
         		30
    Figure US20040235818A1-20041125-C03446
    10
    Figure US20040235818A1-20041125-C03447
         		31
    Figure US20040235818A1-20041125-C03448
    11
    Figure US20040235818A1-20041125-C03449
         		32
    Figure US20040235818A1-20041125-C03450
    12
    Figure US20040235818A1-20041125-C03451
         		33
    Figure US20040235818A1-20041125-C03452
    13
    Figure US20040235818A1-20041125-C03453
         		34
    Figure US20040235818A1-20041125-C03454
    14
    Figure US20040235818A1-20041125-C03455
         		35
    Figure US20040235818A1-20041125-C03456
    15
    Figure US20040235818A1-20041125-C03457
         		36
    Figure US20040235818A1-20041125-C03458
    16
    Figure US20040235818A1-20041125-C03459
         		37
    Figure US20040235818A1-20041125-C03460
    17
    Figure US20040235818A1-20041125-C03461
         		38
    Figure US20040235818A1-20041125-C03462
    18
    Figure US20040235818A1-20041125-C03463
         		39
    Figure US20040235818A1-20041125-C03464
    19
    Figure US20040235818A1-20041125-C03465
         		40
    Figure US20040235818A1-20041125-C03466
    20
    Figure US20040235818A1-20041125-C03467
         		41
    Figure US20040235818A1-20041125-C03468
    21
    Figure US20040235818A1-20041125-C03469
         		42
    Figure US20040235818A1-20041125-C03470
  • [0496]
    TABLE 157
    Figure US20040235818A1-20041125-C03471
    43
    Figure US20040235818A1-20041125-C03472
         		70
    Figure US20040235818A1-20041125-C03473
    44
    Figure US20040235818A1-20041125-C03474
         		71
    Figure US20040235818A1-20041125-C03475
    45
    Figure US20040235818A1-20041125-C03476
         		72
    Figure US20040235818A1-20041125-C03477
    46
    Figure US20040235818A1-20041125-C03478
         		73
    Figure US20040235818A1-20041125-C03479
    47
    Figure US20040235818A1-20041125-C03480
         		74
    Figure US20040235818A1-20041125-C03481
    48
    Figure US20040235818A1-20041125-C03482
         		75
    Figure US20040235818A1-20041125-C03483
    49
    Figure US20040235818A1-20041125-C03484
         		76
    Figure US20040235818A1-20041125-C03485
    50
    Figure US20040235818A1-20041125-C03486
         		78
    Figure US20040235818A1-20041125-C03487
    51
    Figure US20040235818A1-20041125-C03488
         		79
    Figure US20040235818A1-20041125-C03489
    52
    Figure US20040235818A1-20041125-C03490
         		80
    Figure US20040235818A1-20041125-C03491
    53
    Figure US20040235818A1-20041125-C03492
         		81
    Figure US20040235818A1-20041125-C03493
    54
    Figure US20040235818A1-20041125-C03494
         		82
    Figure US20040235818A1-20041125-C03495
    55
    Figure US20040235818A1-20041125-C03496
         		83
    Figure US20040235818A1-20041125-C03497
    56
    Figure US20040235818A1-20041125-C03498
         		84
    Figure US20040235818A1-20041125-C03499
    57
    Figure US20040235818A1-20041125-C03500
         		85
    Figure US20040235818A1-20041125-C03501
    58
    Figure US20040235818A1-20041125-C03502
         		86
    Figure US20040235818A1-20041125-C03503
    59
    Figure US20040235818A1-20041125-C03504
         		87
    Figure US20040235818A1-20041125-C03505
    60
    Figure US20040235818A1-20041125-C03506
         		88
    Figure US20040235818A1-20041125-C03507
    61
    Figure US20040235818A1-20041125-C03508
         		89
    Figure US20040235818A1-20041125-C03509
    62
    Figure US20040235818A1-20041125-C03510
         		90
    Figure US20040235818A1-20041125-C03511
    63
    Figure US20040235818A1-20041125-C03512
         		91
    Figure US20040235818A1-20041125-C03513
    64
    Figure US20040235818A1-20041125-C03514
         		92
    Figure US20040235818A1-20041125-C03515
    65
    Figure US20040235818A1-20041125-C03516
         		93
    Figure US20040235818A1-20041125-C03517
    66
    Figure US20040235818A1-20041125-C03518
         		94
    Figure US20040235818A1-20041125-C03519
    67
    Figure US20040235818A1-20041125-C03520
         		95
    Figure US20040235818A1-20041125-C03521
    68
    Figure US20040235818A1-20041125-C03522
         		96
    Figure US20040235818A1-20041125-C03523
    69
    Figure US20040235818A1-20041125-C03524
  • [0497]
    TABLE 158
    Figure US20040235818A1-20041125-C03525
     97
    Figure US20040235818A1-20041125-C03526
         		112
    Figure US20040235818A1-20041125-C03527
     98
    Figure US20040235818A1-20041125-C03528
         		113
    Figure US20040235818A1-20041125-C03529
     99
    Figure US20040235818A1-20041125-C03530
         		114
    Figure US20040235818A1-20041125-C03531
    100
    Figure US20040235818A1-20041125-C03532
         		115
    Figure US20040235818A1-20041125-C03533
    101
    Figure US20040235818A1-20041125-C03534
         		116
    Figure US20040235818A1-20041125-C03535
    102
    Figure US20040235818A1-20041125-C03536
         		117
    Figure US20040235818A1-20041125-C03537
    103
    Figure US20040235818A1-20041125-C03538
         		118
    Figure US20040235818A1-20041125-C03539
    104
    Figure US20040235818A1-20041125-C03540
         		119
    Figure US20040235818A1-20041125-C03541
    105
    Figure US20040235818A1-20041125-C03542
         		120
    Figure US20040235818A1-20041125-C03543
    106
    Figure US20040235818A1-20041125-C03544
         		121
    Figure US20040235818A1-20041125-C03545
    107
    Figure US20040235818A1-20041125-C03546
         		122
    Figure US20040235818A1-20041125-C03547
    108
    Figure US20040235818A1-20041125-C03548
         		123
    Figure US20040235818A1-20041125-C03549
    109
    Figure US20040235818A1-20041125-C03550
         		124
    Figure US20040235818A1-20041125-C03551
    110
    Figure US20040235818A1-20041125-C03552
         		125
    Figure US20040235818A1-20041125-C03553
    111
    Figure US20040235818A1-20041125-C03554
         		126
    Figure US20040235818A1-20041125-C03555
  • [0498]
    TABLE 159
    Figure US20040235818A1-20041125-C03556
    127
    Figure US20040235818A1-20041125-C03557
         		142
    Figure US20040235818A1-20041125-C03558
    128
    Figure US20040235818A1-20041125-C03559
         		143
    Figure US20040235818A1-20041125-C03560
    129
    Figure US20040235818A1-20041125-C03561
         		144
    Figure US20040235818A1-20041125-C03562
    130
    Figure US20040235818A1-20041125-C03563
         		145
    Figure US20040235818A1-20041125-C03564
    131
    Figure US20040235818A1-20041125-C03565
         		146
    Figure US20040235818A1-20041125-C03566
    132
    Figure US20040235818A1-20041125-C03567
         		147
    Figure US20040235818A1-20041125-C03568
    133
    Figure US20040235818A1-20041125-C03569
         		148
    Figure US20040235818A1-20041125-C03570
    134
    Figure US20040235818A1-20041125-C03571
         		149
    Figure US20040235818A1-20041125-C03572
    135
    Figure US20040235818A1-20041125-C03573
         		150
    Figure US20040235818A1-20041125-C03574
    136
    Figure US20040235818A1-20041125-C03575
         		151
    Figure US20040235818A1-20041125-C03576
    137
    Figure US20040235818A1-20041125-C03577
         		152
    Figure US20040235818A1-20041125-C03578
    138
    Figure US20040235818A1-20041125-C03579
         		153
    Figure US20040235818A1-20041125-C03580
    139
    Figure US20040235818A1-20041125-C03581
         		154
    Figure US20040235818A1-20041125-C03582
    140
    Figure US20040235818A1-20041125-C03583
         		155
    Figure US20040235818A1-20041125-C03584
    141
    Figure US20040235818A1-20041125-C03585
         		156
    Figure US20040235818A1-20041125-C03586
  • [0499]
    TABLE 160
    Figure US20040235818A1-20041125-C03587
    157
    Figure US20040235818A1-20041125-C03588
         		165
    Figure US20040235818A1-20041125-C03589
    158
    Figure US20040235818A1-20041125-C03590
         		166
    Figure US20040235818A1-20041125-C03591
    159
    Figure US20040235818A1-20041125-C03592
         		167
    Figure US20040235818A1-20041125-C03593
    160
    Figure US20040235818A1-20041125-C03594
         		168
    Figure US20040235818A1-20041125-C03595
    161
    Figure US20040235818A1-20041125-C03596
         		169
    Figure US20040235818A1-20041125-C03597
    162
    Figure US20040235818A1-20041125-C03598
         		170
    Figure US20040235818A1-20041125-C03599
    163
    Figure US20040235818A1-20041125-C03600
         		171
    Figure US20040235818A1-20041125-C03601
    164
    Figure US20040235818A1-20041125-C03602
         		172
    Figure US20040235818A1-20041125-C03603
  • [0500]
    TABLE 161
    Figure US20040235818A1-20041125-C03604
    1
    Figure US20040235818A1-20041125-C03605
    2
    Figure US20040235818A1-20041125-C03606
    3
    Figure US20040235818A1-20041125-C03607
    4
    Figure US20040235818A1-20041125-C03608
    5
    Figure US20040235818A1-20041125-C03609
    6
    Figure US20040235818A1-20041125-C03610
    7
    Figure US20040235818A1-20041125-C03611
    8
    Figure US20040235818A1-20041125-C03612
    9
    Figure US20040235818A1-20041125-C03613
    10
    Figure US20040235818A1-20041125-C03614
    11
    Figure US20040235818A1-20041125-C03615
    12
    Figure US20040235818A1-20041125-C03616
    13
    Figure US20040235818A1-20041125-C03617
    14
    Figure US20040235818A1-20041125-C03618
    15
    Figure US20040235818A1-20041125-C03619
    16
    Figure US20040235818A1-20041125-C03620
    17
    Figure US20040235818A1-20041125-C03621
    18
    Figure US20040235818A1-20041125-C03622
    19
    Figure US20040235818A1-20041125-C03623
    20
    Figure US20040235818A1-20041125-C03624
    21
    Figure US20040235818A1-20041125-C03625
    22
    Figure US20040235818A1-20041125-C03626
    23
    Figure US20040235818A1-20041125-C03627
    24
    Figure US20040235818A1-20041125-C03628
    25
    Figure US20040235818A1-20041125-C03629
    26
    Figure US20040235818A1-20041125-C03630
    27
    Figure US20040235818A1-20041125-C03631
    28
    Figure US20040235818A1-20041125-C03632
    29
    Figure US20040235818A1-20041125-C03633
    30
    Figure US20040235818A1-20041125-C03634
    31
    Figure US20040235818A1-20041125-C03635
    32
    Figure US20040235818A1-20041125-C03636
    33
    Figure US20040235818A1-20041125-C03637
    34
    Figure US20040235818A1-20041125-C03638
    35
    Figure US20040235818A1-20041125-C03639
    36
    Figure US20040235818A1-20041125-C03640
    37
    Figure US20040235818A1-20041125-C03641
    38
    Figure US20040235818A1-20041125-C03642
    39
    Figure US20040235818A1-20041125-C03643
    40
    Figure US20040235818A1-20041125-C03644
    41
    Figure US20040235818A1-20041125-C03645
    42
    Figure US20040235818A1-20041125-C03646
  • [0501]
    TABLE 162
    Figure US20040235818A1-20041125-C03647
    43
    Figure US20040235818A1-20041125-C03648
    44
    Figure US20040235818A1-20041125-C03649
    45
    Figure US20040235818A1-20041125-C03650
    46
    Figure US20040235818A1-20041125-C03651
    47
    Figure US20040235818A1-20041125-C03652
    48
    Figure US20040235818A1-20041125-C03653
    49
    Figure US20040235818A1-20041125-C03654
    50
    Figure US20040235818A1-20041125-C03655
    51
    Figure US20040235818A1-20041125-C03656
    52
    Figure US20040235818A1-20041125-C03657
    53
    Figure US20040235818A1-20041125-C03658
    54
    Figure US20040235818A1-20041125-C03659
    55
    Figure US20040235818A1-20041125-C03660
    56
    Figure US20040235818A1-20041125-C03661
    57
    Figure US20040235818A1-20041125-C03662
    58
    Figure US20040235818A1-20041125-C03663
    59
    Figure US20040235818A1-20041125-C03664
    60
    Figure US20040235818A1-20041125-C03665
    61
    Figure US20040235818A1-20041125-C03666
    62
    Figure US20040235818A1-20041125-C03667
    63
    Figure US20040235818A1-20041125-C03668
    64
    Figure US20040235818A1-20041125-C03669
    65
    Figure US20040235818A1-20041125-C03670
    66
    Figure US20040235818A1-20041125-C03671
    67
    Figure US20040235818A1-20041125-C03672
    68
    Figure US20040235818A1-20041125-C03673
    69
    Figure US20040235818A1-20041125-C03674
    70
    Figure US20040235818A1-20041125-C03675
    71
    Figure US20040235818A1-20041125-C03676
    72
    Figure US20040235818A1-20041125-C03677
    73
    Figure US20040235818A1-20041125-C03678
    74
    Figure US20040235818A1-20041125-C03679
    75
    Figure US20040235818A1-20041125-C03680
    76
    Figure US20040235818A1-20041125-C03681
    78
    Figure US20040235818A1-20041125-C03682
    79
    Figure US20040235818A1-20041125-C03683
    80
    Figure US20040235818A1-20041125-C03684
    81
    Figure US20040235818A1-20041125-C03685
    82
    Figure US20040235818A1-20041125-C03686
    83
    Figure US20040235818A1-20041125-C03687
    84
    Figure US20040235818A1-20041125-C03688
    85
    Figure US20040235818A1-20041125-C03689
    86
    Figure US20040235818A1-20041125-C03690
    87
    Figure US20040235818A1-20041125-C03691
    88
    Figure US20040235818A1-20041125-C03692
    89
    Figure US20040235818A1-20041125-C03693
    95
    Figure US20040235818A1-20041125-C03694
    90
    Figure US20040235818A1-20041125-C03695
    91
    Figure US20040235818A1-20041125-C03696
    92
    Figure US20040235818A1-20041125-C03697
    93
    Figure US20040235818A1-20041125-C03698
    94
    Figure US20040235818A1-20041125-C03699
    96
    Figure US20040235818A1-20041125-C03700
  • [0502]
    TABLE 163
    Figure US20040235818A1-20041125-C03701
    97
    Figure US20040235818A1-20041125-C03702
    98
    Figure US20040235818A1-20041125-C03703
    99
    Figure US20040235818A1-20041125-C03704
    100
    Figure US20040235818A1-20041125-C03705
    101
    Figure US20040235818A1-20041125-C03706
    102
    Figure US20040235818A1-20041125-C03707
    103
    Figure US20040235818A1-20041125-C03708
    104
    Figure US20040235818A1-20041125-C03709
    105
    Figure US20040235818A1-20041125-C03710
    106
    Figure US20040235818A1-20041125-C03711
    107
    Figure US20040235818A1-20041125-C03712
    108
    Figure US20040235818A1-20041125-C03713
    109
    Figure US20040235818A1-20041125-C03714
    110
    Figure US20040235818A1-20041125-C03715
    111
    Figure US20040235818A1-20041125-C03716
    112
    Figure US20040235818A1-20041125-C03717
    113
    Figure US20040235818A1-20041125-C03718
    114
    Figure US20040235818A1-20041125-C03719
    115
    Figure US20040235818A1-20041125-C03720
    116
    Figure US20040235818A1-20041125-C03721
    117
    Figure US20040235818A1-20041125-C03722
    118
    Figure US20040235818A1-20041125-C03723
    119
    Figure US20040235818A1-20041125-C03724
    120
    Figure US20040235818A1-20041125-C03725
    121
    Figure US20040235818A1-20041125-C03726
    122
    Figure US20040235818A1-20041125-C03727
    123
    Figure US20040235818A1-20041125-C03728
    124
    Figure US20040235818A1-20041125-C03729
    125
    Figure US20040235818A1-20041125-C03730
    126
    Figure US20040235818A1-20041125-C03731
  • [0503]
    TABLE 164
    Figure US20040235818A1-20041125-C03732
    127
    Figure US20040235818A1-20041125-C03733
    128
    Figure US20040235818A1-20041125-C03734
    129
    Figure US20040235818A1-20041125-C03735
    130
    Figure US20040235818A1-20041125-C03736
    131
    Figure US20040235818A1-20041125-C03737
    132
    Figure US20040235818A1-20041125-C03738
    133
    Figure US20040235818A1-20041125-C03739
    134
    Figure US20040235818A1-20041125-C03740
    135
    Figure US20040235818A1-20041125-C03741
    136
    Figure US20040235818A1-20041125-C03742
    137
    Figure US20040235818A1-20041125-C03743
    138
    Figure US20040235818A1-20041125-C03744
    139
    Figure US20040235818A1-20041125-C03745
    140
    Figure US20040235818A1-20041125-C03746
    141
    Figure US20040235818A1-20041125-C03747
    142
    Figure US20040235818A1-20041125-C03748
    143
    Figure US20040235818A1-20041125-C03749
    144
    Figure US20040235818A1-20041125-C03750
    145
    Figure US20040235818A1-20041125-C03751
    146
    Figure US20040235818A1-20041125-C03752
    147
    Figure US20040235818A1-20041125-C03753
    148
    Figure US20040235818A1-20041125-C03754
    149
    Figure US20040235818A1-20041125-C03755
    150
    Figure US20040235818A1-20041125-C03756
    151
    Figure US20040235818A1-20041125-C03757
    152
    Figure US20040235818A1-20041125-C03758
    153
    Figure US20040235818A1-20041125-C03759
    154
    Figure US20040235818A1-20041125-C03760
    155
    Figure US20040235818A1-20041125-C03761
    156
    Figure US20040235818A1-20041125-C03762
  • [0504]
    TABLE 165
    Figure US20040235818A1-20041125-C03763
    157
    Figure US20040235818A1-20041125-C03764
    158
    Figure US20040235818A1-20041125-C03765
    159
    Figure US20040235818A1-20041125-C03766
    160
    Figure US20040235818A1-20041125-C03767
    161
    Figure US20040235818A1-20041125-C03768
    162
    Figure US20040235818A1-20041125-C03769
    163
    Figure US20040235818A1-20041125-C03770
    164
    Figure US20040235818A1-20041125-C03771
    165
    Figure US20040235818A1-20041125-C03772
    166
    Figure US20040235818A1-20041125-C03773
    167
    Figure US20040235818A1-20041125-C03774
    168
    Figure US20040235818A1-20041125-C03775
    169
    Figure US20040235818A1-20041125-C03776
    170
    Figure US20040235818A1-20041125-C03777
    171
    Figure US20040235818A1-20041125-C03778
    172
    Figure US20040235818A1-20041125-C03779
  • Treatment Method [0505]
  • A contemplated inhibitor compound is used for treating a host mammal such as a mouse, rat, rabbit, dog, horse, primate such as a monkey, chimpanzee or human that has a condition associated with pathological matrix metalloprotease activity. [0506]
  • Also contemplated is use of a contemplated metalloprotease inhibitor compound in the treatment of a disease state that can be affected by the activity of metalloproteases TNF-α convertase. Exemplary of such disease states are the acute phase responses of shock and sepsis, coagulation responses, hemorrhage and cardiovascular effects, fever and inflammation, anorexia and cachexia. [0507]
  • In treating a disease condition associated with pathological matrix metalloproteinase activity, a contemplated MMP inhibitor compound can be used in the form of an amine salt derived from an inorganic or organic acid. Exemplary salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate. [0508]
  • Also, a basic nitrogen-containing group can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibuytl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others to provide enhanced water-solubility. Water or oil-soluble or dispersible products are thereby obtained as desired. The salts are formed by combining the basic compounds with the desired acid. [0509]
  • Other compounds useful in this invention that are acids can also form salts. Examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases or basic quaternary ammonium salts. [0510]
  • In some cases, the salts can also be used as an aid in the isolation, purification or resolution of the compounds of this invention. [0511]
  • Total daily dose administered to a host mammal in single or divided doses can be in amounts, for example, for 0.001 to 30 mg/kg body weight daily and more usually 0.01 to 10 mg. Dosage unit compositions can contain such amounts or submultiples thereof to make up the daily dose. A suitable dose can be administered, in multiple sub-doses per day. Multiple doses per day can also increase the total daily dose, should this be desired by the person prescribing the drug. [0512]
  • The dosage regimen for treating a disease condition with a compound and/or composition of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed can vary widely and therefore can deviate from the preferred dosage regimen set forth above. [0513]
  • A compound of the present invention can be formulated as a pharmaceutical composition. Such a composition can then be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Formulation of drugs is discussed in, for example, Hoover, John E., [0514] Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.; 1975 and Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980.
  • Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Dimethyl acetamide, surfactants including ionic and non-ionic detergents, polyethylene glycols can be used. Mixtures of solvents and wetting agents such as those discussed above are also useful. [0515]
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter, synthetic mono- di- or triglycerides, fatty acids and polyethylene glycols that are sold at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug. [0516]
  • Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, a contemplated aromatic sulfone hydroximate inhibitor compound can be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain a controlled-release formulation as can be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents such as sodium citrate, magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings. [0517]
  • For therapeutic purposes, formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from soerile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. A contemplated aromatic sulfone hydroximate inhibitor compound can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. [0518]
  • Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents. [0519]
  • The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the mammalian host treated and the particular mode of administration. [0520]
    • BEST MODE FOR CARRYING OUT THE INVENTION
  • Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limiting of the remainder of the disclosure in any way whatsoever. [0521]
  • Abbreviations are often used for reagents and solvents in the specific examples that follow. Those abbreviations and their meanings are as follows: [0522]
  • BOC=t-butoxycarbonyl [0523]
  • DEAD=diethyl azodicarboxylate [0524]
  • DMF=dimethylformamide [0525]
  • DMPU=1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone [0526]
  • EtOAc=ethyl acetate [0527]
  • EDC=1-ethyl-3-[3-(dimethylamino)-propyl]carbodiimide hydrochloride [0528]
  • Et[0529] 2O=diethyl ether
  • HOBT=1-hydroxybenzotriazole [0530]
  • MeOH=methanol [0531]
  • MeCl[0532] 2=methylene chloride
  • MsCl=methanesulfonyl chloride [0533]
  • NMM=N-methyl morpholine [0534]
  • THF=tetrahydrofruan [0535]
  • TsCl=toluenesulfonyl chloride [0536]
  • THP—O-hydroxylamine=O-tetrahydropyran-hydroxylamine and O-tetrahydro-2H-pyran-2-yl-hydroxylamine [0537]
  • The preparation of compounds useful in the synthesis of compounds of the invention are provided herein below in Preparative Examples I through XI. [0538]
    • PREPARATIVE EXAMPLE I Preparation of 1,1-dimethylethyl ester 4-[(hydroxyamino)-carbonyl]-4-[(phenoxyphenyl)-sulfonyl]-1-piperidinecarboxylic acid
  • [0539]
    Figure US20040235818A1-20041125-C03780
  • Part A: A solution of 4-(phenoxy)benzenethiol (2.03 g, 10.0 mmol) in DMSO (DMSO; 20 mL) was heated to sixty-five degrees Celsius for 5 hours. The solution remained at ambient temperature for 18 hours. The solution was extracted with ethyl acetate and the combined organic layers were washed with H[0540] 2O and saturated NaCl and dried over magnesium sulfate. Concentration in vacuo provided the disulfide as a yellow oil (2.3 g, quantitative yield).
  • Part B: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF (5 mL) drop-wise over 20 minutes. The solution was stirred overnight (about eighteen hours) at ambient temperature and concentrated in vacuo to yield a light oil. The oil was filtered through silica gel (7:3 ethyl acetate/hexanes) and concentrated in vacuo to give the BOC-piperidine compound (26.2 g, quantitative yield) as a clear, colorless oil. [0541]
  • Part C: To a solution of diisopropylamine (2.8 mL, 20 mmol in THF (30 mL), cooled to minus seventy-eight degrees Celsius, was added n-butyl lithium (12.5 mL, 20 mmol) drop-wise. After 15 minutes, the BOC-piperidine compound of part B (2.6 g, 10 mmol) in THF (10 mL) was added drop-wise. After 1.5 hours the solution was cooled to minus sixty degrees Celsius and the disulfide of part A (2.0 g, 10 mmol) in THF (7 mL). The solution was stirred at ambient temperature for 2 hours. The solution was diluted with H[0542] 2O and extracted with ethyl acetate. The organic layer was washed with H2O and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfide as an oil (1.8 g, 40%).
  • Part D: To a solution of the sulfide of part C (1.8 g, 3.95 mmol) in dichloromethane (75 mL) cooled to zero degrees Celsius, was added m-chloroperbenzoic acid (1.7 g, 7.9 mmol). The solution was stirred for 1.5 hours followed by dilution with H[0543] 2O and extraction with dichloromethane. The organic layer was washed with 10 percent Na2SO4, H2O, and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfone as a solid (1.15 g, 59%).
  • Part E: To a solution of the sulfone of part D (800 mg, 1.63 mmol) in THF (9 mL) and ethanol (9 mL) was added NaOH (654 mg, 16.3 mmol) in H[0544] 2O (3 mL). The solution was heated at sixty-five degrees Celsius for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in H2O. Following acidification with 2N HCl to pH 4, the solution was extracted with ethyl acetate and the organic layer was washed with saturated NaCl and dried over magnesium sulfate. Concentration in vacuo provided the acid as a white foam (790 mg, quantitative yield). Analytical calculated for C23H27NO7S: C, 59.86; H, 5.90; N, 3.04; S, 6.95. Found: C, 59.49; H, 6.37; N, 2.81; S, 6.59.
  • Part F: To a solution of the acid of part G (730-mg, 1.58 mmol) in DMF (9 mL) was added HOBT (256 mg, 1.90 mmol) followed by EDC (424 mg, 2.21 mmol), 4-methylmorpholine (0.521 mL, 4.7 mmol) and 50 percent aqueous hydroxylamine (1.04 mL, 15.8 mmol). The solution was stirred for 20 hours and additional N-hydroxybenzotriazole.H[0545] 2O (256 mg), EDC (424 mg) and 50 percent aqueous hydroxylamine (1.04 mL) were added. After an additional 24 hours of stirring the solution was diluted with H2O and extracted with ethyl acetate and the organic layer was washed with saturated NaCl and dried over magnesium sulfate. Reverse phase chromatography (on silica, acetonitrile/H2O) provided the title compound as a white solid (460 mg, 61%). HPLC purity: >99%. Analytical calculated for C23H28N2O7S: C, 57.97; H, 5.92; N, 5.88; S, 6.73. Found: C, 57.95; H, 6.02; N, 5.81; S, 6.85.
    • PREPARATIVE EXAMPLE II Preparation of N-hydroxy-4-[[4-(phenylthio)phenyl]sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide, monohydrochloride
  • [0546]
    Figure US20040235818A1-20041125-C03781
  • Part A: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF (5 mL) drop-wise over 20 minutes. The solution was stirred overnight (about eighteen hours) at ambient temperature and concentrated in vacuo to yield a light oil. The oil was filtered through silica gel (ethyl acetate/hexanes) and concentrated in vacuo to give the BOC-piperidine compound as a clear, colorless oil (26.2 g, quantitative yield). [0547]
  • Part B: A solution of 4-fluorothiophenol (50.29 g, 390 mmol) in DMSO (500 mL) was heated to 65 degrees Celsius for 6 hours. The reaction was quenched into wet ice and the resulting solid was collected by vacuum filtration to provide the disulfide as a white solid (34.4 g, 68.9%). [0548]
  • Part C: To a solution of the BOC-piperdine compound of part A (16 g, 62 mmol) in THF (300 mL) cooled to minus 50 degrees Celsius was added lithium diisopropylamide (41.33 mL, 74 mmol) and the solution was stirred for 1.5 hours at zero degrees Celsius. To this solution was added the disulfide of part B (15.77 g, 62 mmol), and the resulting solution was stirred at ambient temperature for 20 hours. The reaction was quenched with the addition of H[0549] 2O and the solution was concentrated in vacuo. The aqueous residue was extracted with ethyl acetate and the organic layer was washed with 0.5N KOH, H2O, and saturated NaCl. Chromatography (on silica, hexane/ethyl acetate) provided the sulfide as an oil (18.0 g, 75%).
  • Part D: To a solution of the sulfide of part C (16.5 g, 43 mmol) in dichloromethane (500 mL) cooled to zero degrees Celsius was added 3-chloroperbenzoic acid (18.0 g, 86 mmol) and the solution was stirred for 20 hours. The solution was diluted with H[0550] 2O and extracted with dichloromethane. The organic layer was washed with 10 percent Na2SO3, H2O, and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfone as a solid (10.7 g, 60%).
  • Part E: Into a solution of the sulfone of part D (10 g, 24.0 mmol) in ethyl acetate (250 mL) was bubbled HCl gas for 10 minutes followed by stirring at ambient temperature for 4 hours. Concentration in vacuo provided the amine hydrochloride salt as a white solid (7.27 g, 86%). [0551]
  • Part F: To a solution of the amine hydrochloride salt of part E (5.98 g, 17.0 mmol) in DMF (120 mL) was added potassium carbonate (4.7 g, 34.0 mmol) followed by propargyl bromide (2.02 g, 17.0 mmol) and the solution was stirred for 4 hours at ambient temperature. The solution was partitioned between ethyl acetate and H[0552] 2O, and the organic layer was washed with H2O and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the propargyl amine as a yellow oil (5.2 g, 86%).
  • Part G: To a solution of the propargyl amine of part F in DMF (15 mL) was added thiophenol (0.80 mL, 7.78 mmol) and CsCO[0553] 3 (2.79 g, 8.56 mmol) and the solution was heated to 70 degrees Celsius for 6 hours. The solution was partitioned between ethyl ether and H2O. The organic layer was washed with H2O and saturated NaCl, and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the S-phenoxyphenyl compound as an oil (1.95 g, 56%).
  • Part H: To a solution of the S-phenoxyphenyl of part G (1.81 g, 4.06 mmol) in ethanol (21 mL) and H[0554] 2O (3.5 mL) was added KOH (1.37 g, 24.5 mmol) and the solution was heated to 105 degrees Celsius for 4.5 hours. The solution was acidified to a pH value of 1 with concentrated HCl solution and then concentrated to provide the acid as a yellow residue that was used without additional purification (1.82 g).
  • Part I: To a solution of the acid of part H (1.82 g, 4.06 mmol) in acetonitrile (20 mL) was added O-tetrahydro-2H-pyran-2-yl-hydroxylamine (723 mg, 6.17 mmol) and triethylamine (0.67 mL, 4.86 mmol). To this stirring solution was added EDC (1.18 g, 6.17 mmol) and the solution was stirred for 18 hours. The solution was partitioned between H[0555] 2O and ethyl acetate. The organic layer was washed with H2O, saturated NaHCO3 and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the protected hydroxamate as a white solid (1.32 g, 63%).
  • Part J: To a solution of the protected hydroxamate of part I (9.65 g, 18.7 mmol) in methanol (148 mL) cooled to zero degrees Celsius was added acetyl chloride (4.0 mL, 56.2 mmol), and the solution was stirred for 45 minutes at ambient temperature. Concentration in vacuo followed by trituration with ethyl ether provided the title compound as a white solid (8.10 g, 94%). MS(CI) MH[0556] + calculated for C21H22N2O4S2: 431, found 431.
    • PREPARATIVE EXAMPLE III Preparation of N-hydroxy-4-[(4-phenoxyphenyl)sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide, monohydrochloride
  • [0557]
    Figure US20040235818A1-20041125-C03782
  • Part A: A solution of 4-(phenoxy)benzenethiol (2.03 g, 10.0 mmol) in DMSO (20 mL) was heated to 65 degrees Celsius for 5 hours. The solution remained at ambient temperature for 18 hours. The solution was extracted with ethyl acetate and the combined organic layers were washed with H[0558] 2O and saturated NaCl, and dried over magnesium sulfate. Concentration in vacuo provided the disulfide as a yellow oil (2.3 g, quantitative yield).
  • Part B: To a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in THF (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in THF (5 mL) dropwise over 20 minutes. The solution was stirred overnight at ambient temperature and concentrated in vacuo to yield a light oil. The oil was filtered through silica gel (ethyl acetate/hexane) and concentrated in vacuo to give the BOC-piperidine compound as a clear, colorless oil (26.2 g, quantitative yield). [0559]
  • Part C: To a solution of diisopropylamine (2.8 mL, 20 mmol) in THF (30 mL), cooled to minus seventy-eight degrees Celsius, was added n-butyl lithium (12.5 mL, 20 mmol) dropwise. After 15 minutes, the BOC-piperidine compound of Part B (2.6 g, 10 mmol) in THF (10 mL) was added dropwise. After 1.5 hours, the solution was cooled to minus sixty degrees Celsius and the disulfide of Part A (2.0 g, 10 mmol) in THF (7 mL) was added. The solution was stirred at ambient temperature for 2 hours. The solution was diluted with H[0560] 2O and extracted with ethyl acetate. The organic layer was washed with H2O and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfide as an oil (1.8 g, 40%).
  • Part D: To a solution of the sulfide of [0561]
  • Part C (1.8 g, 3.95 mmol) in dichloromethane (75 mL) cooled to zero degrees Celsius, was added m-chloroperbenzoic acid (1.7 g, 7.9 mmol). The solution was stirred for 1.5 hours followed by dilution with H[0562] 2O and extraction with dichloromethane. The organic layer was washed with 10 percent Na2SO4, H2O, and saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfone as a solid (1.15 g, 59%).
  • Part E: Into a solution of the sulfone of [0563]
  • Part D (3.56 g, 7.0 mmol) in ethyl acetate (100 mL) cooled to zero degrees Celsius was bubbled HCl gas for 5 minutes. Concentration in vacuo followed by trituration with ethyl ether provided the amine hydrochloride salt as a white solid (3.5 g, quantitative yield). MS(CI) MH[0564] + calculated for C20H23NO5S: 390, found 390.
  • Part F: To a solution of the amine hydrochloride salt of part E (2.6 g, 6 mmol) and K[0565] 2CO3 (1.66 g, 12 mmol) in DMF (50 mL) was added propargyl bromide (892 mg, 6 mmol) and the solution was stirred at ambient temperature for 4 hours. The solution was diluted with H2O and extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the propargyl amine as a white solid (2.15 g, 82%).
  • Part G: To a solution of the propargyl amine of part F (2.15 g, 5 mmol) in THF (30 mL) and ethanol (30 mL) was added NaOH (2.0 g, 50 mmol) and the solution was heated at 65 degrees Celsius for 48 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to a pH value of 5. Vacuum filtration of the resulting precipitate provided the acid as a white solid (2.04 g, quantitative yield). [0566]
  • Part H: To a solution of the acid of part G (559 mg, 1.4 mmol) in dichloromethane (5 mL) was added triethylamine (0.585 mL, 4.2 mmol) and 50 percent aqueous hydroxylamine (0.925 mL, 14.0 mmol) followed by bromotris(pyrrolidino)phosphonium hexafluourphosphate (PyBroP; 718 mg, 1.54 mmol). The solution was stirred at ambient temperature for 4 hours. The solution was diluted with H[0567] 2O and extracted with dichloromethane. The organic layer was washed with saturated NaCl and dried over magnesium sulfate. Reverse phase chromatography (on silica, acetonitrile/H2O) provided the hydroxamate as a white solid (140 mg, 25%). Analytical calculation for C21H22N2O5S: C, 60.85; H, 5.37; N, 6.76; S, 7.74. Found: C, 60.47; H, 5.35; N, 6.61; S, 7.46.
  • Part I: To a solution of the hydroxamate of part H (121 mg, 0.292 mmol) in methanol (2 mL) cooled to zero degrees Celsius was added acetyl chloride (0.228 mL, 0.321 mmol) in methanol (1 mL). After stirring at ambient temperature for 30 minutes the solution was concentrated under a stream of N[0568] 2. Trituration with ethyl ether provided the title compound as a white solid (107 mg, 81%). Analytical calculation for C21H22N2O5S.HCl.0.3H2O: C, 55.27; H, 5.21; N, 6.14. Found: C, 54.90; H, 5.37; N, 6.07.
    • PREPARATIVE EXAMPLE IV Preparation of 4-[(4-fluorophenyl)sulfonyl]tetrahydro-N-[(tetrahydro-2H-pyran-2-yl)oxy]-2H-pyran-4-carboxamide
  • [0569]
    Figure US20040235818A1-20041125-C03783
  • Part A: In dry equipment under nitrogen, sodium metal (8.97 g, 0.39 mol) was added to methanol (1000 mL) at two degrees Celsius. The reaction was stirred at ambient temperature for forty five minutes at which time the sodium had dissolved. The solution was chilled to five degrees Celsius and p-fluorothiophenol (41.55 mL, 0.39 mmol) was added, followed by methyl 2-chloroacetate (34.2 mL, 0.39 mol). The reaction was stirred at ambient temperature for four hours, filtered, and concentrated in vacuo to give the sulfide as a clear colorless oil (75.85 g, 97%). [0570]
  • Part B: To a solution of the sulfide from part A (75.85 g, 0.38 mol) in methanol (1000 mL) were added water (100 mL) and Oxone (720 g, 1.17 mol) at 20 degrees Celsius. An exotherm to 67 degrees Celsius was noted. After two hours, the reaction was filtered and the cake was washed well with methanol. The filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and washed with brine, dried over MgSO[0571] 4, filtered, and concentrated in vacuo to give the sulfone as a crystalline solid (82.74 g, 94%).
  • Part C: To a solution of the sulfone from part B (28.5 g, 0.123 mol) in N,N-dimethylacetamide (200 mL) were added potassium carbonate (37.3 g, 0.27 mol), bis-(2-bromoethyl)ether (19.3 mL, 0.147 mol), 4-dimethylaminopyridine (0.75 g, 6 mmol), and tetrabutylammonium bromide (1.98 g, 6 mmol). The reaction was stirred overnight (about 18 hours) at ambient temperature. The reaction was slowly poured into 1N HCl (300 mL), the resultant solid filtered and the cake washed well with hexanes. The solid was recrystallized from ethyl acetate/hexanes to give the pyran compound as a beige solid (28.74 g, 77%). MS (ES+) MH+ calculated for C[0572] 13H15O5S1F1: 303, found 303.
  • Part D: In dry equipment under nitrogen, the pyran compound from part C (8.0 g, 26.5 mmol) was dissolved in dry tetrahydrofuran (250 mL) and a solution of potassium trimethylsilonate (10.2 g, 79.5 mmol) in dry tetrahydrofuran (15 mL) was added at ambient temperature. After ninety minutes, water (100 mL) was added and the solution concentrated in vacuo. The residue was taken up in water and extracted with ethyl acetate to remove unreacted starting material. The aqueous solution was treated with 6N HCl until pH=1. The slurry was extracted with ethyl acetate and the combined extracts washed with water, dried over Na[0573] 2SO4, filtered, and concentrated in vacuo. The residue was heated in diethyl ether, the solid filtered and dried to give the carboxylic acid as a crystalline solid (5.78 g, 76%). HRMS (ES−) M-H calculated for C12H13O5 S1F1: 287.04, found 287.04.
  • Part E: In dry equipment under nitrogen, the carboxylic acid from part D (9.1 g, 31.6 mmol) was dissolved in dry N,N-dimethylformamide (70 mL) and the remaining reagents were added to the solution in the following order: N-hydroxybenzotriazole hydrate (5.1 g, 37.9 mmol), N-methylmorpholine (10.4 mL, 94.8 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (11.5 g, 98 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.48 g, 44.2 mmol). After three hours at ambient temperature, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, 5% KHSO[0574] 4, saturated NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate/hexanes) provided the title compound as a crystalline solid (9.7 g, 80%). HRMS (ES+) MH+ calculated for C17H22NO6 S1F1: 388.12, found 388.12.
    • PREPARATIVE EXAMPLE V Preparation of tetrahydro-N-hydroxy-4-[[4-[4-trifluoromethoxy)-phenoxy)phenyl]sulfonyl]-2H-pyran-4-carboxamide
  • [0575]
    Figure US20040235818A1-20041125-C03784
  • Part A: To a solution of the title compound of Preparative Example IV (3.1 g, 8 mmol) in N,N-dimethylacetamide (20 mL) were added cesium carbonate (8.8 g, 27 mmol) and p-(trifluoromethoxy)phenol (2.1 mL, 16 mmol). The slurry was stirred at 95 degrees Celsius for nineteen hours. The reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over Na[0576] 2SO4, filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate/hexanes) provided the substituted THP-protected hydroxamate as a white foam (4.2 g, 96%). HRMS (ES+) MH+ calculated for C24H26N1O8S1F3: 546.14, found 546.14.
  • Part B: To a slurry of the THP-protected hydroxamate from part A (4.0 g, 7.3 mmol) in dioxane (20 mL) were added a 4N HCl dioxane solution (20 mL) and methanol (20 mL). After fifteen minutes at ambient temperature, the reaction was diluted with ethyl acetate and washed with water, dried over Na[0577] 2SO4, filtered, and concentrated in vacuo. The product was recrystallized (acetone/hexanes) to give the title compound as a white solid (2.2 g, 65%). HRMS (ES+) M+NH4 + calculated for C19H18N1O7S1F3: 479.11, found 479.11.
    • PREPARATIVE EXAMPLE VI Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-(2-phenoxy-ethoxy)phenyl]sulfonyl]-4-piperidine carboxamide, monohydrochloride
  • [0578]
    Figure US20040235818A1-20041125-C03785
  • Part A: To a solution of the product of Preparative Example II, part E, (14.36 g, 40 mmol) in methanol (50 mL) was added acetic acid (24.5 g, 400 mmol), a portion (about 2 g) of 4-Angstrom molecular sieves, (1-ethoxycyclopropyl)-oxytrimethyl silane (25.8 mL, 148 mmol) and sodium cyanoborohydride (7.05 g, 112 mmol). The solution was heated at reflux for 8 hours. The precipitated solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was diluted with H[0579] 2O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO4, filtered and concentrated in vacuo. The solid was filtered, washed with H2O/diethyl ether to give the desired cyclopropyl amine {ethyl 4-[(4-fluorophenyl-sulfonyl)]-1-cyclopropyl-4-piperidinecarboxylate} as a white solid (11.83 g, 81.5%). MS MH30 calculated for C17H22NO4SF: 356, found: 356.
  • Part B: A solution of the cyclopropyl amine of Part A (2.0 g, 5.6 mmol), ethylene glycol phenyl ether (2.8 mL, 23 mmol), and cesium carbonate (7.3 g, 23 mmol) in DMAC (10 mL) was heat at 125-135 degrees Celsius for 18 hours under an atmosphere of nitrogen. The mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, dried over magnesium sulfate, concentrated in vacuo, dissolved in diethyl ether, precipitated as the hydrochloride salt, and dried at 40 degrees Celsius in a vacuum oven. The solid was dissolved into a mixture of water, acetonitrile, and ethanol and then the pH was adjusted to 12 with 1N NaOH solution. The mixture was concentrated in vacuo to remove ethanol and acetonitrile. The solid was isolated by filtration, washed with water, and dried at 50 degrees Celsius in a vacuum oven to afford the ether as a white solid (1.8 g, 68%): MS+ calcd. for C[0580] 25H31NO6S 474, found 474. Anal. calcd. for C25H31NO6S: C, 63.40; H, 6.60; N, 2.96; S, 6.77. Found: C, 63.35; H, 6.59; N, 2.99; S, 6.61.
  • Part C: A mixture of the ether of part B (1.8 g, 3.7 mmol) and a 50% NaOH aqueous solution (3.0 g, 37 mmol) in THF (32 mL), EtOH (32 mL), and H[0581] 2O (16 mL) was heated at 60 degrees Celsius under a nitrogen atmosphere for 24 hours. The material was concentrated in vacuo and triturated with diethyl ether to give a solid. The tan solid was dissolved into a mixture of water, ethanol, and THF, precipitated by adjusting the pH to 3 with concentrated hydrochloric acid, concentrated in vacuo, triturated with water, and dried at 50 degrees Celsius in a vacuum oven to give a crude white solid acid (2.3 g).
  • A mixture of the crude white solid acid (2.3 g), N-hydroxybenzotriazole (1.9 g, 14 mmol), 4-methylmorpholine (1.6 mL, 14 mmol), O-tetrahydro-2H-pyran-2-yl-hydroxylamine (1.1 g, 9.4 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.7 g, 14 mmol) in DMF (90 mL) was stirred at ambient temperature under a nitrogen atmosphere for 2 days. The mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The organic layer was washed with 1N NaOH solution, water, and brine, dried over magnesium sulfate, concentrated in vacuo, and purification by flash chromatography (20:80 to 40:60 ethyl acetate/toluene) to afford the protected hydroxamate as a white solid: (0.43 g, 21%): MS MH+ calcd. for C[0582] 28H36N2O7S 545, found 545. Anal. calcd. for C28H36N2O7S: C, 61.74; H, 6.66; N, 5.14; S, 5.89. Found: C, 61.72; H, 6.75; N, 5.06; S, 5.91.
  • Additional compound was isolated by acidifying the aqueous layer to pH of 3, collecting the solid by filtration, and drying to give a white solid (0.80 g). [0583]
  • Part D: To an ambient temperature solution of acetyl chloride (0.31 mL, 4.4 mmol) in methanol (11 mL) under a nitrogen atmosphere was added the protected hydroxamate of part C (0.80 g, 1.5 mmol). After stirring for 2.5 hours, the precipitate was collected by filtration, washed with diethyl ether, and dried at 45 degrees Celsius in a vacuum oven to afford the title compound as a white solid (0.58 g, 79%): MS MH+ calcd. for C[0584] 23H28N2O6S 461, found 461. Anal. calcd. for C23H28N2O6S.1.5 HCl: C, 53.62; H, 5.77; N, 5.44; S, 6.22. Found: C, 53.47; H, 5.79; N, 5.41; S, 6.16.
    • PREPARATIVE EXAMPLE VII Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoro-methoxy)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride
  • [0585]
    Figure US20040235818A1-20041125-C03786
  • Part A: To a solution of the product of Preparative Example II, Part D (30 g, 161 mmol) in dichloromethane (50 mL) cooled to zero degrees Celsius was added trifluroacetic acid (25 mL) and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the trifluoroacetate salt and K[0586] 2CO3 (3.6 g, 26 mmol) in N,N-dimethylformamide (50 mL) cooled to zero degrees Celsius was added 2-bromoethyl methyl ether (19 mL, 201 mmol), and solution was stirred at ambient temperature for 36 hours. Then, N,N-dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over MgSO4. Concentration in vacuo provided the methoxyethyl amine as a light yellow gel (26.03 g, 86.8%).
  • Part B: To a solution of methoxyethyl amine (6.0 g, 16.0 mmol) of Part A and powdered K[0587] 2CO3 (4.44 g, 32 mmol) in N,N-dimethylformamide (30 mL) was added 4-(trifluoromethoxy)phenol (5.72 g, 32 mmol) at ambient temperature and the solution was heated to ninety degrees Celsius for 25 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N NaOH, H2O and dried over MgSO4. Chromatography on silica eluting with ethyl acetate/hexane provided trifluoromethoxy phenoxyphenyl sulfone as a light yellow gel (7.81 g, 91.5%).
  • Part C: To a solution of trifluoromethoxy phenoxyphenyl sulfone of Part B (7.81 g, 14.7 mmol) in ethanol (14 mL) and tetrahydrofuran (14 mL) was added NaOH (5.88 g, 147 mmol) in H[0588] 2O (28 mL) from an addition funnel at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with ether and acidified to pH=2. Vacuum filtration of white precipitation provided the acid as a white solid (5.64 g, 73.3%).
  • Part D: To a solution of the acid of Part C (5.64 g, 10.8 mmol), N-methyl morpholine (4.8 mL, 43.1 mmol), 1-hydroxybenzotriazole (4.38 g, 32.4 mmol) and O-tetrahydropyranyl hydroxylamine (2.5 g, 21.6 mmol) in N,N-dimethylformamide (50 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.2 g, 32.4 mmol), and the solution was stirred at ambient temperature for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO[0589] 3, H2O and dried over MgSO4. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the tetrahydropyranyl-protected hydroxamate as a white foam (6.65 g, quantitative yield).
  • Part E: To a solution of 4N HCl in dioxane (28 mL, 110 mmol) was added a solution of the tetrahydropyranyl-protected hydroxamate of Part D (6.65 g, 11.03 mmol) in methanol (3 mL) and dioxane (9 mL) and was stirred at ambient temperature for 3 hours. Concentration in vacuo and trituration with diethyl ether provided the title compound as a white solid (4.79 g, 78.2%). Analytical calculation for C[0590] 22H25N2O7SF3.HCl.0.5H2O: C, 46.85; H, 4.83; N, 4.97; S, 5.69. Found: C, 46.73; H, 4.57; N, 4.82; S, 5.77.
    • PREPARATIVE EXAMPLE VIII Preparation of N-hydroxy-1-[2-(4-morpholinyl)-ethyl]-4-[[4-[4-(trifluoromethyl)phenoxy]-phenyl] sulfonyl]-4-piperidinecarboxamide, dihydrochloride
  • [0591]
    Figure US20040235818A1-20041125-C03787
  • Part A: To a suspension of 4-bromopiperidine hydrobromide (107.0 g, 0.436 mol) in tetrahydrofuran (1 L) was slowly added triethylamine (122 mL, 0.872 mol) followed by di-tert-butyl dicarbonate (100 g, 0.458 mol), which was added in several portions. The resulting mixture was stirred at ambient temperature for 22 hours then filtered and concentrated in vacuo. The solids were washed with hexanes and then collected by filtration to give the Boc-piperidine compound as an amber oil (124 g, >100%). [0592]
  • Part B: To a solution of 4-fluorophenol (50.0 g, 0.390 mol) in acetone (400 mL), degassed with N[0593] 2, was added Cs2CO3 (159 g, 0.488 mol). After degassing the resulting mixture with N2 for 5 minutes, the Boc-piperidine compound of Part A (85.9 g, 0.325 mol) was added. The resulting mixture was stirred at ambient temperature for 18 hours and then filtered through a pad of Celite®, washing with acetone. The filtrate was concentrated in vacuo to provide the sulfide as a tan residue (98.5 g, 97%).
  • Part C: To a solution of the sulfide of Part B (8.00 g, 25.7 mmol) in dichloromethane (90 mL) and methanol (15 mL) was added monoperoxyphthalic acid magnesium salt hexahydrate (19.1 g, 38.6 mmol) in two portions. The resulting mixture was stirred at ambient temperature for 1.5 hours and then filtered. The filtrate was washed with saturated NaHCO[0594] 3 and then with saturated NaCl. The combined aqueous layers were extracted with dichloromethane (100 mL). The combined organic layers were dried over Na2SO4 and then concentrated in vacuo. The resulting solids were washed with hexanes then dissolved in dichloromethane and filtered through a pad of Celite®, washing with dichloromethane. The filtrate was concentrated in vacuo and recrystallization from ethyl acetate provided the sulfone as a white crystalline solid (4.45 g, 50%).
  • Part D: To a solution of sulfone of Part C (7.00 g, 20.4 mmol) in N,N-dimethylformamide (40 mL) was added Cs[0595] 2CO3 (19.9 g, 61.2 mmol) and α,α,α-trifluoro-α-cresol (3.97 g, 24.5 mmol). The resulting mixture was heated at eighty degrees Celsius for 16 hours. After cooling to ambient temperature the reaction mixture was concentrated in vacuo. The resulting residue was treated with H2O and the solids were collected by filtration. The solids were then washed with hexanes then methanol to provide the biaryl ether as a tan solid (8.60 g, 87%).
  • Part E: To a solution of the biaryl ether of Part D (8.59 g, 17.7 mmol) in tetrahydrofuran (100 mL), cooled to zero degrees Celsius, was slowly added lithium bis(trimethylsilyl)amide (22.0 mL, 1.0M in tetrahydrofuran, 22.0 mmol), at such a rate that the temperature of the reaction never exceeded one degree Celsius. The resulting mixture was stirred at zero degrees Celsius for 1 hour then a solution of methyl chloroformate (2.05 mL, 26.6 mmol) in tetrahydrofuran (5.0 mL) was slowly added, at such a rate that the temperature of the reaction mixture never exceeded four degrees Celsius. After the addition was complete, the mixture was slowly permitted to warm to ambient temperature. Saturated NH[0596] 4Cl (50 mL) was added and the tetrahydrofuran was removed in vacuo. Water (50 mL) was added to the residue which was then extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl and dried over Na2SO4. Recrystallization from methanol provided the methyl ester as a pale yellow crystalline solid (7.66 g, 80%).
  • Part F: To a solution of the methyl ester of Part E (7.66 g, 14.1 mmol) in dioxane (30 mL) and methanol (10 mL) was added a solution of 4N HCl in dioxane (10 mL, 40 mmol). After stirring at ambient temperature for 2 hours additional 4N HCl in dioxane (10 mL, 40 mmol) was added. After stirring at ambient temperature for 2.5 hours, the reaction mixture was concentrated in vacuo to provide the amine as an off-white solid (6.80 g, >100%). [0597]
  • Part G: To a suspension of the amine of Part F (3.00 g, 6.25 mmol) in acetonitrile (20 mL) was added K[0598] 2CO3 (3.46 g, 25.0 mmol), 4-(2-chloroethyl)morpholine hydrochloride (1.22 g, 6.56 mmol) and a catalytic amount of NaI. The resulting mixture was heated at reflux for 22 hours. After cooling to ambient temperature, the reaction mixture was filtered through a pad of Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuo to provide the morpholinyl ethyl amine as a tan solid (3.45 g, >100%).
  • Part H: To a solution of the morpholinyl ethyl amine of Part G (3.45 g, 6.25 mmol) in tetrahydrofuran (60 mL) was added potassium trimethylsilanolate (1.60 g, 12.50 mmol). After stirring at ambient temperature for 25 hours, H[0599] 2O was added. The reaction mixture was then neutralized (pH 7) with 1N HCl. The tetrahydrofuran was removed in vacuo and the resulting precipitate was collected by filtration and washed with diethyl ether to provide the amino acid as an off-white solid (2.87 g, 85%).
  • Part I: To a suspension of the amino acid of [0600]
  • Part H (2.87 g, 5.29 mmol) in dichloromethane (25 mL) was added N-methylmorpholine (1.74 mL, 15.9 mmol), 0-(tetrahydropuranyl) hydroxylamine (0.682 g, 5.82 mmol) and PyBroP® (2.96 g, 6.35 mmol). After stirring at ambient temperature for 19 hours additional N-methylmorpholine (0.872 mL, 7.94 mmol), O-(tetrahydropuranyl) hydroxylamine (0.310 g, 2.65 mmol) and PyBroP® (1.48 g, 3.17 mmol) were added. The resulting mixture was stirred at ambient temperature for 3 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate and H[0601] 2O. The organic layers were washed with saturated NaCl and dried over Na2SO4. Chromatography (on silica, methanol/chloroform) provided the protected hydroxamate as an off-white solid (2.62 g, 77%).
  • Part J: To a solution of the protected hydroxamate of Part I (2.62 g, 4.08 mmol) in dioxane (9 mL) and methanol (3 mL) was added a solution of 4N HCl in dioxane (10 mL, 40.0 mmol). The resulting mixture was stirred at ambient temperature for 2 hours and then diethyl ether (20 mL) was added. The resulting solids were collected by filtration to give the title compound as an off-white solid (2.31 g, 90%). MS MH[0602] + calculated for C25H31O6N3SF3: 558, found 558.
    • PREPARATIVE EXAMPLE IX Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]-phenyl]sulfonyl]-4-piperidine-carboxamide, monohydrochloride
  • [0603]
    Figure US20040235818A1-20041125-C03788
  • Part A: To a solution of the product of Preparative Example VI, Part A, (6.97 g, 19.6 mmol) in DMF (500 mL) was added K[0604] 2CO3 (3.42 g, 18.0 mmol) and 4-(triflouromethoxy)phenol (3.7 g, 24.8 mmol). The solution was stirred at ninety degrees Celsius for 40 hours. The solution was diluted with H2O (600 mL) and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl and dried over MgSO4, filtered and concentrated in vacuo to afford the desired diaryl ether as an oil (8.5 g, quantitative). HRMS MH+ calculated for C24H26NSO6F3: 514.1511. Found 514.1524.
  • Part B: To a solution of diaryl ether from Part A (8.4 g, 16.4 mmol) in ethanol (50 mL) and tetrahydrofuran (50 mL) was added a solution of NaOH (6.54 g, 164 mmol) in water (20 mL) and the solution was heated at sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo to remove most of organic solvents and the aqueous residue was acidified to pH=4.0. The resulting precipitate was filtered to give the desired filtered to give the hydrochloride salt as a white solid (5.01 g, 63%). HRMS MH[0605] + calculated for C22H22NSO6F3: 486.1198, found 486.1200.
  • Part C: To a solution of the hydrochloride salt of Part B (5.0 g, 10.3 mmol) in DMF (80 mL) were added 1-hydroxybenzotriazole (1.65 g, 12.3 mmol), N-methyl morpholine (3.4 mL, 30.9 mmol) and O-tetrahydropyranyl hydroxylamine hydrochloride (1.8 g, 15.4 mmol) followed by 1-3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.60 g, 12.3 mmol). The solution was stirred at ambient temperature for 42 hours. The solution was diluted with H[0606] 2O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO4, filtered and concentrated in vacuo. Chromatography on silica gel, eluting with 30% ethyl acetate/hexane provided the desired tetrahydropyranyl-protected hydroxamate as a white solid (5.41 g, 89%).
  • Part D: To a solution of tetrahydropyranyl-protected hydroxamate of Part C (5.4 g, 9.2 mmol) in dioxane (80 mL) and methanol (20 mL) was added 4 N HCl/dioxane (50 mL). The reaction was stirred at ambient temperature for 2.5 hours, the solution was concentrated in vacuo. Trituration with diethyl ether afforded the title compound as a white solid (4.02 g, 81%). HRMS MH[0607] + calculated for C22H23N2SO6F3: 501.1307, found 501.1324.
    • PREPARATIVE EXAMPLE X Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethyl) phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride
  • [0608]
    Figure US20040235818A1-20041125-C03789
  • Part A: To a solution of the product of Preparative Example VI, Part A, (5.96 g, 15.0 mmol) in DMF (100 mL) was added K[0609] 2CO3 (12.34 g, 38.0 mmol) and α,α,α-trifluoromethyl phenol (3.65 g, 22.5 mmol). The solution was stirred ninety degrees Celsius for 28 hours. The solution was diluted with H2O (400 mL) and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl and dried over MgSO4, filtered and concentrated in vacuo to afford desired aryl ether as an oil (7.54 g, quantitative)
  • Part B: To a solution of aryl ether from Part A (7.54 g, 15.0 mmol) in ethanol (40 mL) and tetrahydrofuran (40 mL) was added a solution of NaOH (6.06 g, 151.0 mmol) in water (20 mL) and the solution was heated at sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH=2.0. The resulting precipitate was filtered to give the desired hydrochloride salt as a white solid (7.98 g, quantitative). MS MH[0610] + calculated for C22H22NSO5F3: 470, found 470.
  • Part C: To a solution of the hydrochloride salt of Part B (7.60 g, 15.0 mmol) in DMF (100 mL) were added 1-hydroxybenzotriazole (2.44 g, 18.0 mmol), N-methyl morpholine (3.4 mL, 30.9 mmol) and O-tetrahydropyranyl hydroxylamine hydrochloride (2.63 g, 22.5 mmol) followed by 1-3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (4.02 g, 21.0 mmol). The solution was stirred at ambient temperature for 96 hours. The solution was diluted with H[0611] 2O (400 mL) and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO4, filtered and concentrated in vacuo. Chromatography on silica eluting with 30% ethyl acetate/hexane provided the desired tetrahydropyranyl-protected hydroxamate as a white solid (5.93 g, 69%).
  • Part D: To a solution of tetrahydropyranyl-protected hydroxamate of Part C (3.8 g, 6.7 mmol) in dioxane (100 mL) was added 4 N HCl/dioxane (30 mL). The reaction was stirred at ambient temperature for 2 hours, then the solution was concentrated in vacuo. Trituration with diethyl ether afforded the title compound as a white solid (3.33 g, 96%). MS MH[0612] + calculated for C22H23N2SO5F3: 485, found 485.
    • PREPARATIVE EXAMPLE XI Preparation of Resin II
  • Step 1: Attachment of Compound of [0613]
    • PREPARATIVE EXAMPLE IV TO RESIN I
  • A 500 mL round-bottomed flask was charged with of resin I [Floyd et al., [0614] Tetrahedron Lett. 1996, 37, 8045-8048] (8.08 g, 9.7 mmol) and 1-methyl-2-pyrrolidinone (50 mL). A magnetic stirring bar was added, and the resin slurry slowly stirred. A separate solution of the compound of Part D, Preparative Example IV (5.58 g, 19.4 mmol) in 1-methyl-2-pyrrolidinone (35 mL) was added to the slurry followed by addition of benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (10.1 g, 19.4 mmol) in one portion. Once the hexafluorophosphate salt had dissolved, 4-methylmorpholine (4.26 mL, 39 mmol) was added dropwise. The reaction slurry was stirred at room temperature for 24 hours, then the resin was collected in a sintered-disc funnel and washed with N,N-dimethylformamide, methanol, methylene chloride and diethyl ether (3×30 mL each solvent). The resin was dried in vacuo to yield 10.99 g polymer-bound hydroxymate as a tan polymeric solid. Theoretical loading on polymer was 0.91 mmol/g. FTIR microscopy showed bands at 1693 and 3326 cm−1 indicative of the hydroxamate carbonyl and nitrogen-hydrogen stretches, respectively.
  • Step 2: Preparation of Resin III: [0615]
  • Reaction of Resin II With Nucleophiles [0616]
  • Resin II (50 mg, 0.046 mmol) was weighed into an 8 mL glass vial, and a 0.5 M solution of a nucleophile in 1-methyl-2-pyrrolidinone (1 mL) was added to the vessel. In the case of phenol and thiophenol nucleophiles, cesium carbonate (148 mg, 0.46 mmol) was added, and in the case of substituted piperazine nucleophiles, potassium carbonate (64 mg, 0.46 mmol) was added. The vial was capped and heated to 70 to 155 degrees Celsius for 24-48 hours, then cooled to room temperature. The resin was drained and washed with 1-methyl-2-pyrrolidinone, 1-methyl-2-pyrrolidinone/water (1:1), water, 10% acetic acid/water, methanol, and methylene chloride (3×3 mL each solvent). [0617]
  • Large Scale Preparation of Resin IIIa: [0618]
  • Resin II (5 g, 0.91 mmol) was weighed into an oven-dried three-necked round bottom flask fitted with a temperature probe, an overhead stirring paddle, and a nitrogen inlet. Anhydrous 1-methyl-2-pyrrolidinone (35 mL) was added to the flask followed by ethyl isonipecotate (7.0 mL, 45.5 mmol). The resin slurry was stirred slowly with the overhead stirrer, and the mixture was heated to 80 degrees Celsius with a heating mantle for 65 hours. The flask was thereafter cooled to room temperature. [0619]
  • The resin was collected in a sintered-disk glass funnel and washed with N,N-dimethylformamide, methanol and methylene chloride (3×30 mL each solvent). The resin was dried in vacuo to provide 5.86 g of resin IIIa as off-white resin beads. The theoretical loading of the polymer was 0.81 mmol/g. TFA cleavage performed on 50 mg of resin IIIa as described in step 3 yielded 10.4 mg of off-white solid spectroscopically indistinguishable from a known sample. [0620]
  • Step 3: Cleavage of Hydroxamic Acids From The Polymer-Support [0621]
  • Resin III was treated with a trifluoroacetic acid/water mixture (19:1, 1 mL) for 1 hour at room temperature. During that time, the resin became a deep red color. The resin was then drained and washed with trifluoroacetic acid/water (19:1) and methylene chloride (2×1 mL each solvent), collecting the combined filtrates in a tared vial. The volatiles were removed in vacuo, then a toluene/methylene chloride mixture (2 mL each) was added to the residue. The mixture was again concentrated in vacuo. The product was characterized by electrospray mass spectroscopy. [0622]
  • Step 4: Hydrolysis of Polymer-Bound Ester: Preparation of Resin IVa [0623]
  • Resin IIIa (5.8 g, 4.5 mmol) was weighed into a three-necked round bottomed flask fitted with an overhead stirring paddle. 1,4-Dioxane was added to the flask, and the resin slurry was stirred for 15 minutes. Then, a 4 M solution of KOH (5 mL, 20 mmol) was added, and the mixture was stirred for 44 hours. The resin was thereafter collected in a sintered-disk glass funnel and washed with dioxane/water (9:1), water, 10% acetic acid/water, methanol and methylene chloride (3×30 mL each solvent). The resin was dried in vacuo to yield 5.64 g of resin IVa as off-white polymer beads. FTIR microscopy showed bands at 1732 and 1704 cm[0624] −1 and a broad band from 2500-3500 cm−1. The theoretical loading of the polymer-bound acid was 0.84 mmol/g.
    • EXAMPLE 1 Preparation of 1-(2-methoxyethyl)-4-[[4-[4-(trifluoromethoxy) phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide
  • [0625]
    Figure US20040235818A1-20041125-C03790
  • Part A: To a solution of the product of Preparative Example II, part D, (30 g, 161 mmol) in dichloromethane (50 mL) cooled to zero degrees Celsius was added trifluroacetic acid (25 mL) and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the trifluoroacetate salt and K[0626] 2CO3 (3.6 g, 26 mmol) in N,N-dimethylformamide (50 mL) cooled to zero degrees Celsius was added 2-bromoethyl methyl ether (19 mL, 201 mmol) and solution was stirred at ambient temperature for 36 hours. Then N,N-dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over MgSO4. Concentration in vacuo provided the methoxyethyl amine as a light yellow gel (26.03 g, 86.8%).
  • Part B: To a solution of the methoxyethyl amine (6.0 g, 16.0 mmol) of part A and powdered K[0627] 2CO3 (4.44 g, 32 mmol) in N,N-dimethylformamide (30 mL) was added 4-(trifluoromethoxy)phenol (5.72 g, 32 mmol) at ambient temperature and the solution was heated to ninety degrees Celsius for 25 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N NaOH, H2O and dried over MgSO4. Chromatography on silica eluting with ethyl acetate/hexane provided trifluoromethoxy phenoxyphenyl sulfone as a light yellow gel (7.81 g, 91.5%).
  • Part C: To a solution of trifluoromethoxy phenoxyphenyl sulfone of part B (7.81 g, 14.7 mmol) in ethanol (14 mL) and tetrahydrofuran (14 mL) was added NaOH (5.88 g, 147 mmol) in H[0628] 2O (28 mL) from an addition funnel at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with ether and acidified to pH=2. Vacuum filtration of the white precipitation provided the carboxylic acid as a white solid (5.64 g, 73.3%).
  • Part D: To a suspension of the carboxylic acid of part C (200 mg, 0.397 mmol) in methylene chloride (4 mL) was added oxalyl chloride (101 mg, 0.80 mmol). After 15 minutes at ambient temperature the volatiles were removed under vacuum. The solid residue was resuspended in methylene chloride (4 mL) and gaseous ammonia was bubbled through the suspension. Triethylamine (81 mg, 0.80 mmol) was added and the stream of ammonia gas through the reaction was continued for 1 minute. Concentration afforded a solid which was chromatographed (reverse phase C[0629] 18 silica eluting with a gradient of 30% acetonitrile/water to 100% acetonitrile) to afford the desired primary amide as a colorless powder (6 mg, 3 mg). MS MH+ calculated for C22H25N2 F3O6S: 503, found 503. HRMS M+ calculated for C22H25N2 F3O6S: 503.1464, found 503.1472.
    • EXAMPLE 2 Preparation of 4-[(4-phenylthiophenyl) sulfonyl]-1-(2-propynyl)-4-piperidinecarboxamide
  • [0630]
    Figure US20040235818A1-20041125-C03791
  • A mixture of the acid from Preparative Example II, part H, (1.29 g, 2.85 mMol), N-hydroxybenzotriazole (1.15 g, 8.54 mMol), 4-methylmorpholine (0.94 mL, 14 mMol), concentrated NH[0631] 4OH (3 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.64 g, 8.54 mMol) in DMF (25 mL) was stirred at ambient temperature for 20 hours. The mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3, water, and brine, dried over magnesium sulfate, and concentrated in vacuo. Chromatography (on silica, MeOH/CHCl3) afford the title amide as a white solid (0.143 g, 12%). Analytical calculation for C21H22N2O3S2: C, 60.84; H, 5.35; N, 6.76; S, 15.47. Found: C, 60.74; H, 5.31; N, 6.74; S, 15.43.
    • EXAMPLES 3-58
  • The following compounds were prepared by parallel synthesis (resin based synthesis, automated synthesis) using parallel synthesis from Resin IVa as described previously in Preparative Example XI the following compounds were prepared: [0632]
    Figure US20040235818A1-20041125-C03792
    MS
    Example Amine R (M + H)
    3 3,5-Dimethylpiperidine
    Figure US20040235818A1-20041125-C03793
         		508
    4 N-Methylpropargylamine
    Figure US20040235818A1-20041125-C03794
         		464
    5 N-Methylallylamine
    Figure US20040235818A1-20041125-C03795
         		466
    6 1-(1-phenylethyl)- piperazine
    Figure US20040235818A1-20041125-C03796
         		585
    7 1-(2-phenylethyl)- piperazine
    Figure US20040235818A1-20041125-C03797
         		585
    8 1-(2-chlorophenyl)- piperazine
    Figure US20040235818A1-20041125-C03798
         		591
    9 1-(4-methoxyphenyl)-2- methylpiperazine
    Figure US20040235818A1-20041125-C03799
         		585
    10 1-(5-Chloro-2- methylphenyl)piperazine
    Figure US20040235818A1-20041125-C03800
         		605
    11 1-(2-methoxyphenyl)- piperazine
    Figure US20040235818A1-20041125-C03801
         		587
    12 1-Acetylpiperazine
    Figure US20040235818A1-20041125-C03802
         		523
    13 1-(2,4-Dimethylphenyl)- piperazine
    Figure US20040235818A1-20041125-C03803
         		585
    14 N-(2-hydroxyethyl)- piperazine
    Figure US20040235818A1-20041125-C03804
         		525
    15 1-(Ethoxy- carbonylmethyl)- piperazine
    Figure US20040235818A1-20041125-C03805
         		567
    16 1-(2-Fluorophenyl)- piperazine
    Figure US20040235818A1-20041125-C03806
         		575
    17 1-(2-Furoyl)-piperazine
    Figure US20040235818A1-20041125-C03807
         		575
    18 1-(Cyclopentyl)- piperazine
    Figure US20040235818A1-20041125-C03808
         		549
    19 1-(2-Propyl)-piperazine
    Figure US20040235818A1-20041125-C03809
         		523
    20 N-(2-(1-Piperazino)- acetyl)pyrrolidine
    Figure US20040235818A1-20041125-C03810
         		592
    21 1-(3-Dimethyl- aminopropyl)- piperazine
    Figure US20040235818A1-20041125-C03811
         		566
    22 1-(2-Methoxyethyl)- piperazine
    Figure US20040235818A1-20041125-C03812
         		539
    23 1-(2-Dimethyl- aminoethyl)- piperazine
    Figure US20040235818A1-20041125-C03813
         		552
    24 1-(2-Ethoxyphenyl)- piperazine
    Figure US20040235818A1-20041125-C03814
         		601
    25 1-(4-Fluorphenyl)- piperazine
    Figure US20040235818A1-20041125-C03815
         		575
    26 1-(2-Pyridyl)-piperazine
    Figure US20040235818A1-20041125-C03816
         		558
    27 2-(1-piperazinyl)- pyrimidine
    Figure US20040235818A1-20041125-C03817
         		559
    28 4-Piperazino- acetophenone
    Figure US20040235818A1-20041125-C03818
         		599
    29 1-(4-Nitrophenyl)- piperazine
    Figure US20040235818A1-20041125-C03819
         		602
    30 1-(3,5-Dichloropyrid-4- yl)piperazine
    Figure US20040235818A1-20041125-C03820
         		626
    31 4-(2-Methoxyphenyl)- piperidine
    Figure US20040235818A1-20041125-C03821
         		586
    32 N-[2-Nitro-4- (trifluoromethyl)- phenyl]piperazine
    Figure US20040235818A1-20041125-C03822
         		670
    33 1-[3-(Trifluormethyl)- pyrid-2-yl]- piperazine
    Figure US20040235818A1-20041125-C03823
         		626
    34 cis-3,5-Dimethyl- morpholine
    Figure US20040235818A1-20041125-C03824
         		510
    35 N-Propylcyclopropane- methylamine
    Figure US20040235818A1-20041125-C03825
         		508
    36 1-(2,4-Difluorphenyl)- piperazine
    Figure US20040235818A1-20041125-C03826
         		593
    37 1-(4-Pyridyl)- piperazine
    Figure US20040235818A1-20041125-C03827
         		558
    38 1-(4-Trifluoromethyl- phenyl)-piperazine
    Figure US20040235818A1-20041125-C03828
         		625
    39 1-Allylpiperazine
    Figure US20040235818A1-20041125-C03829
         		521
    40 1-(2-Pyrazinyl)- piperazine
    Figure US20040235818A1-20041125-C03830
         		559
    41 1-[3-Chloro-5- (trifluoromethyl)pyrid- 2-yl)]piperazine
    Figure US20040235818A1-20041125-C03831
         		660
    42 1-(2-(4-Morpholino)- ethyl)piperazine
    Figure US20040235818A1-20041125-C03832
         		594
    43 3-Chlorophenyl- piperazine
    Figure US20040235818A1-20041125-C03833
         		591
    44 4-(Hydroxymethyl)- piperidine
    Figure US20040235818A1-20041125-C03834
         		510
    45 Diisobutylamine
    Figure US20040235818A1-20041125-C03835
         		524
    46 cis-2,6-Dimethyl- piperazine
    Figure US20040235818A1-20041125-C03836
         		509
    47 3-Methylpiperidine
    Figure US20040235818A1-20041125-C03837
         		494
    48 N,N-Diallylamine
    Figure US20040235818A1-20041125-C03838
         		492
    49 1-[4-(Trifluormethyl)- 2-pyrimidyl]- piperazine
    Figure US20040235818A1-20041125-C03839
         		627
    50 1-[4-(Trifluormethyl)- 2-pyridyl]- piperazine
    Figure US20040235818A1-20041125-C03840
         		626
    51 N,N,N′-Trimethyl- ethylenediamine
    Figure US20040235818A1-20041125-C03841
         		497
    52 (4-Ethylaminomethyl)- pyridine
    Figure US20040235818A1-20041125-C03842
         		531
    53 Methyl-cyclopropylamine
    Figure US20040235818A1-20041125-C03843
         		466
    54 3,5-Dimethyl-piperidine
    Figure US20040235818A1-20041125-C03844
         		508
    55 3,5-Dimethyl-piperidine
    Figure US20040235818A1-20041125-C03845
         		508
    56 Isobutylamine
    Figure US20040235818A1-20041125-C03846
         		468
    57 Propylamine
    Figure US20040235818A1-20041125-C03847
         		454
    58 N-Methyl- isobutylamine
    Figure US20040235818A1-20041125-C03848
         		482
    • EXAMPLES 59-78
  • Step 5: Preparation of Resin V [0633]
  • Into a fritted reaction vessel was weighed resin IVa (100 mg, 0.083 mmol), and the vessel was capped under nitrogen and cooled to zero degrees Celsius. A 1.0 M solution of 2-chloro-4,6-dimethoxy-1,3,5-triazine in methylene chloride (0.4 mL, 0.4 mmol) was added followed by a 1.0 M solution of N-methylmorpholine in methylene chloride (0.6 mL, 0.6 mmol.) The solutions were stirred for 4 hours at zero degrees Celsius and warmed to ambient temperature. A 0.7 M solution of the appropriate amine to be reacted in methylene chloride (0.4 mL, 0.28 mmol) was added and the reaction mixture stirred for 24 hours. The reaction mixture was stirred for 24 hours, then the resin was drained and washed with 1-methyl-2-pyrrolidinone and methylene chloride (4×3 mL each solvent). The reaction was repeated using the same amounts of reagents described above. The reaction was stirred for 4 hours at zero degrees Celsius after the activating step and ambient temperature for 24 hours following amine solution addition. After 24 hours, the resin was drained and washed with 1-methyl-2-pyrrolidinone, 1:1 1-methyl-2-pyrrolidinone/water, water, 1:9 acetic acid/water, methanol and methylene chloride (3×3 mL each solvent). [0634]
  • The following hydroxamic acids were synthesized using the indicated polymer-bound acid and the indicated amine in Step 5 followed by release from the polymer using Step 3, before: [0635]
    Figure US20040235818A1-20041125-C03849
    Example Amine R MS (M + H)
    59 Aniline
    Figure US20040235818A1-20041125-C03850
         		488
    60 N-Methylaniline
    Figure US20040235818A1-20041125-C03851
         		502
    61 4-(Trifluoromethyl)- aniline
    Figure US20040235818A1-20041125-C03852
         		556
    62 4-Aminopyridine
    Figure US20040235818A1-20041125-C03853
         		489
    63 2-(Trifluoromethoxy)- aniline
    Figure US20040235818A1-20041125-C03854
         		572
    64 2-Chloroaniline
    Figure US20040235818A1-20041125-C03855
         		522
    65 2-Fluoroaniline
    Figure US20040235818A1-20041125-C03856
         		506
    66 o-Anisole
    Figure US20040235818A1-20041125-C03857
         		518
    67 2-(Methylamino)- pyridine
    Figure US20040235818A1-20041125-C03858
         		503
    68 3-(Trifluoromethoxy)- aniline
    Figure US20040235818A1-20041125-C03859
         		572
    69 3-(Trifluoromethyl)- aniline
    Figure US20040235818A1-20041125-C03860
         		556
    70 3-Chloroaniline
    Figure US20040235818A1-20041125-C03861
         		522
    71 3-Fluoroaniline
    Figure US20040235818A1-20041125-C03862
         		506
    72 m-Anisole
    Figure US20040235818A1-20041125-C03863
         		518
    73 4-(Trifluoromethoxy)- aniline
    Figure US20040235818A1-20041125-C03864
         		572
    74 4-Aminopyrmidine
    Figure US20040235818A1-20041125-C03865
         		490
    75 4-Fluoroaniline
    Figure US20040235818A1-20041125-C03866
         		506
    76 p-Anisole
    Figure US20040235818A1-20041125-C03867
         		518
    77 N,N-Dimethyl-1,3- phenylenediamine
    Figure US20040235818A1-20041125-C03868
         		531
    78 N,N-Dimethyl-p- phenylenediamine
    Figure US20040235818A1-20041125-C03869
         		531
    • EXAMPLES 79-88
  • Step 12: Further Synthesis of Resin III. [0636]
  • Into a 8 mL glass vial was placed resin II (200 mg, 0.18 mmol) and cesium carbonate (0.98 g mg, 3 mmol) (no cesium carbonate used with piperidine and pyrrolidine nucleophiles). One mL of a 1.8 M solution of the amine nucleophile to be reacted in 1-methyl-2-pyrrolidinone (1.8 mmol) was added and the vial was capped and heated to 100 degrees Celsius for 30 hours. Then the vessel was cooled to room temperature, and the resin was drained and washed with 1-methyl-2-pyrrolidinone, 1:1 1-methyl-2-pyrrolidinone/water, water, 1:9 acetic acid/water, methanol and methylene chloride (3×3 mL each solvent). [0637]
  • The following hydroxamic acids were synthesized from Resin III using Step 11 with the indicated amines, followed by release from the polymer using the reaction conditions in Step 3. [0638]
    Figure US20040235818A1-20041125-C03870
    Example Amine R MS (M + H)
    79 1-(2-Methoxyphenyl)- piperidine
    Figure US20040235818A1-20041125-C03871
         		475
    80 4-(4-Methoxybenzoyl)- piperidine
    Figure US20040235818A1-20041125-C03872
         		503
    81 Pyrrolidine
    Figure US20040235818A1-20041125-C03873
         		355
    82 1-(4-Methoxyphenyl)-2- piperazine
    Figure US20040235818A1-20041125-C03874
         		490
    83 1-(2-Fluorophenyl)- piperazine
    Figure US20040235818A1-20041125-C03875
         		464
    84 1-(2,4- Diemthylphenyl)- piperiazine
    Figure US20040235818A1-20041125-C03876
         		474
    85 1-(2-Methoxyphenyl- piperazine
    Figure US20040235818A1-20041125-C03877
         		476
    86 1-(4-Trifluoromethyl- phenyl)piperazine
    Figure US20040235818A1-20041125-C03878
         		514
    87 1-(2,4- Difluorophenyl)- piperazine
    Figure US20040235818A1-20041125-C03879
         		482
    88 1-(2-Chlorphenyl)- piperazine
    Figure US20040235818A1-20041125-C03880
         		480
    • EXAMPLE 89 Preparation of N-hydroxy-4 [[4-(4-trifluoromethoxyphenoxy)phenyl] sulfonyl]-1-(9-fluorenylmethoxy-carbonyl)-4-piperidinecarboxamide
  • [0639]
    Figure US20040235818A1-20041125-C03881
  • To a solution of 4-[[4-(4-trifluoromethoxy-phenoxy)phenyl]sulfonyl]-1-[(1,1diemthylethoxy)-carbonyl]piperidinecarboxylic acid (6.25 g, 11.5 mmol) prepared using techniques discussed elsewhere herein was added 50% trifluoroacetic acid solution in dichloromethane (100 mL) and stirred 1 hour at room temperature. The solvent was evaporated to afford 9.91 g of an oil. The oil was dissolved in acetonitrile (50 mL) and water (50 mL). To the solution was added sodium carbonate to a pH-9-10 followed by a solution of N-(9-fluorenylmethoxy-carbonyloxy)succinimide (3.88 g, 11.5 mmol) in acetone (25 mL). The pH value of the solution was adjusted to 9-10 with sodium carbonate. The reaction mixture was stirred 16 hours. To the reaction mixture was added 2M aqueous hydrochloric acid to a pH value of about 3. The solution was extracted with dichloromethane (3×100 mL). The combined organics were dried over magnesium sulfate, filtered and the solvent evaporated to afford N-hydroxy-4 [[4-(4-trifluoromethoxyphenoxy)phenyl] sulfonyl]-1-(9-fluorenylmethoxycarbonyl)-4-piperidinecarboxamide (8.15 g) as a yellow oil. MS (ES) m/z 668 (M+H)[0640] +.
    • EXAMPLE 90 Preparation of N-hydroxy-4 [[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-1-(9-fluorenylmethoxycarbonyl)-4-piperidinecarboxamide
  • [0641]
    Figure US20040235818A1-20041125-C03882
  • Using the method of Example 89, N-hydroxy-4-[[4-(4-trifluoromethyl-phenoxy)phenyl] sulfonyl]-1-(9-fluorenyl-methoxycarbonyl)-4-piperidinecarboxamide was prepared from 4-[[4-(4-trifluoromethylphenoxy)-phenyl]-sulfonyl]-1-[(1,1-dimethylethoxy)carbonyl]-piperidinecarboxylic acid, which itself was prepared using techniques discussed elsewhere herein. MS (ES) m/z 652 (M+H)[0642] +.
    • EXAMPLE 91 Preparation of N-hydroxy-4-[[4-(4-trifluoromethoxyphenoxy)phenyl] sulfonyl]-1-(phenylcarbonyl)-4-piperidinecarboxamide
  • [0643]
    Figure US20040235818A1-20041125-C03883
  • Step 1: Preparation of Resin MT-I. To a solution of N-hydroxy-4-[[4-(4-trifluoromethoxy-phenoxy)phenyl]sulfonyl]-1-(9-fluorenylmethoxy-carbonyl)-4-piperidinecarboxamide of Example 89 (11.5 mmol) in dimethylformamide (75 mL) were added resin I (Floyd et al., [0644] Tetrahedron Lett. 1996, 37, 8045-8048) (7.0 g, 7.67 mmol), pyBOP (8.0 g) and N-methylmorpholine (5.05 mL), and the mixture was stirred with an overhead stirrer 4 days. The resin was filtered and washed with dimethylformamide (3×50 mL), methanol (3×50 mL), dichloromethane (3×50 mL) and ether (3×50 mL). The resin was dried in vacuo to provide resin MT-I.
  • Step 2: Fmoc deprotection of Resin MT-I. Resin MT-I was swelled with dimethylformamide (2×100 mL) and drained. To swollen resin MT-1, was added a 20% solution of piperidine in dimethylformamide (100 mL). After 1 hour, the resin was drained and retreated with 20% piperidine in dimethylformamide (100 mL). After 15 minutes the resin was filtered and washed with dimethylformamide (3×100 mL), methanol (3×100 mL), dichloromethane (3×100 mL) and ether (3×100 mL). The resin was dried in vacuo to afford resin MT-II (7.23 g). [0645]
  • Step 3: Preparation of N-hydroxy-4-[[4-(4-trifluoromethoxyphenoxy)phenyl]sulfonyl]-1-(phenylcarbonyl)-4-piperidinecarboxamide from Resin MT-II. To a suspension of resin MT-II (250 mg) in dichloromethane (2 mL) was added diisopropyl-ethylamine (165 μL) and benzoyl chloride (110 μL) and agitated 3 hours. The resin was filtered and washed with dichloromethane (2×10 mL) and methanol (2×10 mL). To the resin was added a solution of 95% trifluoroacetic acid in water and agitated for 1 hour. The resin was drained and washed with methanol (1×2 mL) and dichloromethane (1×2 mL). The filtrate was evaporated. The residue was purified by RPHPLC to afford N-hydroxy-4-[[4-(4-trifluoromethoxy-phenoxy)phenyl]sulfonyl]-1-(phenylcarbonyl)-4-piperidinecarboxamide (9.8 mg) as a solid. MS (ES) m/z 565 (M+H)[0646] +.
    • EXAMPLE 92 Preparation of N-hydroxy-4-[[4-(4-trifluoromethylphenoxy)phenyl] sulfonyl]-1-(phenylcarbonyl)-4-piperidinecarboxamide
  • [0647]
    Figure US20040235818A1-20041125-C03884
  • N-hydroxy-4-[[4-(4-trifluoromethyl-phenoxy)phenyl] sulfonyl]-1-(phenylcarbonyl)-4-piperidinecarboxamide was prepared by the method of Example 91 from N-hydroxy-4-[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-1-(9-fluorenylmethoxycarbonyl)-4-piperidinecarboxamide (the product of Example 90). MS (ES) m/z 549 (M+H)[0648] +.
    • EXAMPLE 93 Preparation of N-(2-tetrahydropyranoxy) -4-[[4-(4-trifluoromethoxyphenoxy)-phenyl]sulfonyl]-4-piperidinecarboxamide
  • [0649]
    Figure US20040235818A1-20041125-C03885
  • Step 1: Boc deprotection of ethyl 4-[[4-(4-trifluoromethoxyphenoxy)phenyl]sulfonyl]-1-[(1,1-dimethylethoxy)carbonyl]piperidinecarboxylate. To a solution of ethyl 4-[[4-(4-trifluoromethoxy-phenoxy)phenyl]sulfonyl]-1-[(1,1-dimethylethoxy)-carbonyl]piperidinecarboxylate (12.58 g, 19.1 mmol; see Example 89) in dichloromethane (50 mL) was added trifluoroacetic acid (50 mL) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated to afford a pale yellow oil. [0650]
  • Step 2: Cbz protection of step 1. The material from step 1 was dissolved in dichloromethane (200 mL). To this solution was added diisopropyl-ethylamine (33.3 mL) and benzyl chloroformate (5.5 mL) and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 2M aqueous hydrochloric acid to a pH value of about 1 and extracted with dichloromethane (2×100 mL). The combined organics were washed with 2M aqueous HCl (1×100 mL) and brine (1×100 mL), dried over magnesium sulfate, filtered and the solvent evaporated to afford a pale yellow oil. [0651]
  • Step 3: Hydrolysis of the product of step 2. The material prepared in step 2 was dissolved in tetrahydrofuran (100 mL) and ethanol (50 mL). To this solution was added 1M aqueous sodium hydroxide (50 mL) and 50% aqueous sodium hydroxide (10 mL) and stirred 16 hours. To the solution was added 50% aqueous sodium hydroxide (2 mL) and stirred and additional 24 hours. The tetrahydrofuran and ethanol were evaporated. The pH value of the solution was adjusted to pH about 1 with concentrated hydrochloric acid. The reaction mixture was extracted with ethyl acetate (2×100 mL), washed with brine (1×100 mL), dried over magnesium sulfate, filtered and the solvent evaporated to afford a pale yellow oil. [0652]
  • Step 4: Cbz deprotection of step 3. The material prepared in step 3 was dissolved in ethanol (100 mL). This solution was added to 10% palladium on carbon (1.0 g). The solution was placed under 45 psi hydrogen. Additional catalyst was added at 6 hours (1.75 g) and 20 hours (1.0 g 4% Pd/C). After 48 hours the reaction mixture was filtered through a plug of Celite. The filtrate was evaporated and triturated with ether to afford N-(2-tetrahydropyranoxy)-4[[4-(4-trifluoromethoxy-phenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide (4.47 g) as a white solid. MS (ES) m/z 545 (M+H)[0653] +.
    • EXAMPLE 94 Preparation of N-(2-tetrahydro-pyranoxy)-4[[4-(4-trifluoromethyl-phenoxy)phenyl]sulfonyl]-4-piperidine-carboxamide
  • [0654]
    Figure US20040235818A1-20041125-C03886
  • N-(2-tetrahydropyranoxy)-4[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide was prepared by the method of Example 93 starting from ethyl 4-[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-1-[(1,1-dimethylethoxy)carbonyl]piperidinecarboxylate (see Example 90). MS (ES) m/z 529 (M+H)[0655] +.
    • EXAMPLE 95 Preparation of N-hydroxy-4-[[4-(4-trifluoromethylphenoxy)phenyl] sulfonyl]-1-(2-fluorophenyl-carbonyl)-4-piperidinecarboxamide
  • [0656]
    Figure US20040235818A1-20041125-C03887
  • To a solution of N-(2-tetrahydropyranoxy)-4 [[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide, the product of Example 94, (50 mg) dissolved in dichloromethane (2.5 mL) was added PS-NMM (135 mg, Argonaut) and 2-fluorobenzoyl chloride (12.1 μL) and stirred for 2 hours. To the reaction mixture was added PS-trisamine (50 mg, Argonaut) and the mixture was stirred 1 hour. The reaction mixture was filtered and washed with dichloromethane (2×2 mL) and methanol (1×2 mL). The combined organics were evaporated to afford N-hydroxy-4[[4-(4-trifluoromethylphenoxy)phenyl]-sulfonyl]-1-(2-fluorophenylcarbonyl)-4-piperidinecarboxamide (53.5 mg) as a white solid. MS (ES) m/z 583 (M+H)[0657] +.
    • EXAMPLES 96-124
  • The following hydroxamic acids were prepared by the method of Example 95 using the appropriate acylating agent. [0658]
    Figure US20040235818A1-20041125-C03888
    MS (ES)
    Example R Acylating Agent m/z
    96 3-fluorophenyl 3-fluorobenzoyl 583 (M + H)+
    chloride
    97 4-fluorophenyl 4-fluorobenzoyl 583 (M + H)+
    chloride
    98 2-trifluoro- 2-trifluoromethyl- 633 (M + H)+
    methylphenyl benzoyl chloride
    99 3-trifluoro- 3-trifluoro- 633 (M + H)+
    methylphenyl methylbenzoyl
    chloride
    100 phenylmethyl phenylacetyl chloride 579 (M + H)+
    101 2-tolyl 2-toluoyl chloride 579 (M + H)+
    102 4-tolyl 4-toluoyl chloride 579 (M + H)+
    103 4-methoxy- methyl 4- 623 (M + H)+
    carbonylphenyl chlorocarbonyl
    benzoate
    104 4-methoxyphenyl 4-anisoyl chloride 595 (M + H)+
    105 2-thienyl 2-thiophenecarbonyl 571 (M + H)+
    chloride
    106 2-furyl 2-furoyl chloride 555 (M + H)+
    107 3-pyridyl nicotinoyl chloride 566 (M + H)+
    108 4-pyridyl isonicotinoyl 566 (M + H)+
    chloride
    109 c-propyl cyclopropanecarbonyl 529 (M + H)+
    chloride
    110 trichloromethyl trichloroacetic 622 (M + H)+
    anhydride
    111 trifluoromethyl trifluoroacetic 574 (M + H)+
    anhydride
    112 pentafluorophenyl pentafluorobenzoyl 655 (M + H)+
    chloride
    113 4-nitrophenyl 4-nitrobenzoyl 610 (M + H)+
    chloride
    114 4-trifluoro- 4-trifluoromethyl- 633 (M + H)+
    methylphenyl benzoyl chloride
    115 4-trifluoro- 4-trifluoromethoxy- 649 (M + H)+
    methoxyphenyl benzoyl chloride
    116 4-methoxy- 4-methoxyphenyl- 609 (M + H)+
    phenylmethyl acetyl chloride
    117 3-methoxyphenyl 3-anisoyl chloride 595 (M + H)+
    118 2-methoxyphenyl 2-anisoyl chloride 595 (M + H)+
    119 3,5- 3,5-dimethoxybenzoyl 625 (M + H)+
    dimethoxyphenyl chloride
    120 3,4- 3,4-dimethoxybenzoyl 625 (M + H)+
    dimethoxyphenyl chloride
    121 2,5- 2,5-difluorobenzoyl 601 (M + H)+
    difluorophenyl chloride
    122 methoxy- methyl malonyl 561 (M + H)+
    carbonylmethyl chloride
    123 4-dimethyl- 4-dimethylamino- 608 (M + H)+
    aminophenyl benzoyl chloride
    124 1,1-dimethylethyl pivaloyl chloride 545 (M + H)+
    • EXAMPLES 125-138
  • The following hydroxamic acids were prepared by the method of Example of 95 using the appropriate isocyanate as the acylating agent. [0659]
    Figure US20040235818A1-20041125-C03889
    Ex- MS (ES)
    ample RNCO Isocyanate m/z
    125
    Figure US20040235818A1-20041125-C03890
         		Phenyl isocyanate 580 (M + H)
    126
    Figure US20040235818A1-20041125-C03891
         		4-Fluorophenyl isocyanate 598 (M + H)
    127
    Figure US20040235818A1-20041125-C03892
         		4-Methoxybenzyl isocyanate 624 (M + H)
    128
    Figure US20040235818A1-20041125-C03893
         		Ethyl isocyanate 532 (M + H)
    129
    Figure US20040235818A1-20041125-C03894
         		3-Trifluoromethyl phenyl isocyanate 648 (M + H)
    130
    Figure US20040235818A1-20041125-C03895
         		3-Isocyanate propionic acid 576 (M + H)
    131
    Figure US20040235818A1-20041125-C03896
         		3-Pyridyl isocyanate 581 (M + H)
    132
    Figure US20040235818A1-20041125-C03897
         		4-Chlorophenyl isocyanate 614 (M + H)
    133
    Figure US20040235818A1-20041125-C03898
         		3-Fluorophenyl isocyanate 598 (M + H)
    134
    Figure US20040235818A1-20041125-C03899
         		4-Acetylphenyl isocyanate 622 (M + H)
    135
    Figure US20040235818A1-20041125-C03900
         		2-Fluorophenyl isocyanate 598 (M + H)
    136
    Figure US20040235818A1-20041125-C03901
         		4-(Methylthio) phenyl isocyanate 626 (M + H)
    137
    Figure US20040235818A1-20041125-C03902
         		Benzyl isocyanate 594 (M + H)
    138
    Figure US20040235818A1-20041125-C03903
         		3-Cyanophenyl isocyanate 605 (M + H)
    • EXAMPLES 140-143
  • The following hydroxamic acids were prepared by the method of Example 95 using the appropriate acylating agent (electophile) and starting from N-(2-tetrahydropyranoxy)-4[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide, the product of Example 94. [0660]
    Figure US20040235818A1-20041125-C03904
    Ex-
    am- MS
    ple R Electrophile (ES) m/z
    140
    Figure US20040235818A1-20041125-C03905
         		4-trifluoro- methoxybenzoyl chloride 633 (M + H)+
    141
    Figure US20040235818A1-20041125-C03906
         		4-trifluoromethyl- phenyl isocyantate 632 (M + H)+
    142
    Figure US20040235818A1-20041125-C03907
         		4-trifluoro- methylphenyl thioisocyanate 648 (M + H)+
    143
    Figure US20040235818A1-20041125-C03908
         		4-trifluoromethyl- benzenesulfonyl chloride 653 (M + H)+
    • EXAMPLE 144 Preparation of N-hydroxy-4[[4-(4-trifluoromethylphenoxy)phenyl] sulfonyl]-1-(4-aminophenylcarbonyl)-4-piperidinecarboxamide
  • [0661]
    Figure US20040235818A1-20041125-C03909
  • A solution of N-hydroxy-4[[4-(4-trifluoromethylphenoxy)phenyl]sulfonyl]-1-(4-nitrophenylcarbonyl)-4-piperidinecarboxamide, the product of Example 113, (56.0 mg) dissolved in acetic acid (2.5 mL) was added to 4% palladium on carbon (20 mg) and placed under 43 psi hydrogen gas for 2.5 h. The reaction mixture was filtered through a pad of celite. The solvent was evaporated to afford N-hydroxy-4-[[4-(4-trifluoromethylphenoxy)phenyl] sulfonyl]-1-(4-aminophenylcarbonyl)-4-piperidinecarboxamide (50.2 mg) as a pale yellow solid. MS (ES) m/z 580 (M+H)[0662] +.
    • EXAMPLE 145 Preparation of N-hydroxy-4[[4-(4-trifluoromethylphenoxy)phenyl]-sulfonyl]-1-(4-carboxyphenylcarbonyl)-4-piperidinecarboxamide
  • [0663]
    Figure US20040235818A1-20041125-C03910
  • To a solution of the product of Example 103 (57 mg) dissolved in tetrahydrofuran (1 mL) and ethanol (1 mL) was added 1M aqueous sodium hydroxide solution (1 mL) plus 50% aqueous sodium hydroxide (50 μL) and the reaction mixture was stirred 2 hours. The pH value of the reaction mixture was adjusted to 1 with 6M hydrochloric acid. The solution was extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered and the solvent evaporated. The residue was purified by RPHPLC to afford the acid N-hydroxy-4[[4-(4-trifluoromethyl-phenoxy)phenyl]sulfonyl]-1-(4-carboxyphenylcarbonyl)-4-piperidinecarboxamide (12.8 mg). MS (ES) m/z 631 (M+NH[0664] 4)+.
    • EXAMPLE 146 Preparation of N-hydroxy-4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-4-thianecarboxamide
  • [0665]
    Figure US20040235818A1-20041125-C03911
  • Step 1: Hydrolysis of methyl 4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-4-thianecarboxylate. To a solution of methyl 4-[[4-(4-methoxyphenoxy)-phenyl]sulfonyl]-4-thianecarboxylate (10.0 g, 31 mmol) dissolved in tetrahydrofuran (150 mL) was added potassium trimethylsilanolate (12.1 g) and stirred 2 hours. Water was added to the reaction mixture and extracted with ethyl acetate (2×100 mL). The pH value of the aqueous layer was adjusted to 2 with 2M hydrochloric acid and extracted with ethyl acetate (2×100 mL). The latter organics were washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated to afford a pale yellow solid (8.20 g). [0666]
  • Step 2: Loading on resin. The compound obtained in step 1 (4.0 g, 13.1 mmol) was dissolved in 1-methyl-2-pyrrolidinone (15 mL) and added to a suspension of resin I (6.0 g, 6.6 mmol; Preparative Example XI) in 1-methyl-2-pyrrolidinone (40 mL). To this solution were added pyBOP (6.85 g) and N-methylmorpholine (2.9 mL), and the mixture was stirred with overhead stirring 16 hours. The resin was filtered and washed with dimethylformamide (3×50 mL), methanol (3×50 mL), dichloromethane (3×50 mL) and ether (3×50 mL). The resin was dried in vacuo to provide resin MT-III (6.79 g). [0667]
  • Step 3: Aryl fluoride displacement of resin MT-III. A suspension of resin MT-III (200 mg, 0.17 mmol), 1-methyl-2-pyrrolidinone (2 mL), cesium carbonate (560 mg) and 4-methoxyphenyl (306 mg) were stirred at 105° C. for 16 hours. The reaction mixture was cooled and the resin filtered. The resin was washed with dimethylformamide (3×5 mL), methanol (3×5 mL), 10% aqueous acetic acid (3×5 mL), methanol (3×5 mL) and dichloromethane (3×5 mL). To the resin was added 95% aqueous trifluoroacetic acid and the reaction mixture was agitated for 1 hour. The resin was drained and washed with dichloromethane (2×1 mL). The solvent was evaporated. The residue was purified by RPHPLC to provide N-hydroxy-4-[[4-(4-methoxy-phenoxy)phenyl]sulfonyl]-4-thianecarboxamide (17.9 mg) as a pale yellow oil. [0668]
    • EXAMPLES 147-151
  • The following hydroxamic acids were prepared by the method of Example 146 using the appropriate alcohol. [0669]
    Figure US20040235818A1-20041125-C03912
    Example R Alcohol MS (ES) m/z
    147 4-trifluoro- 4-trifluoro- 495 (M + NH4)+
    methoxyphenyl methoxyphenol
    148 4-isopropyl- 4-isopropylphenol 453 (M + NH4)+
    phenyl
    149 3-pyridyl 3-hydroxypyridine 395 (M + H)+
    150 3,4-dimethoxy- 3,4-dimethoxyphenol 471 (M + NH4)+
    phenyl
    151 4-pyridyl 4-hydroxypyridine 395 (M + H)+
    • EXAMPLES 152-155
  • The following hydroxamic acids were prepared by the method of Example 146 using the appropriate amine. [0670]
    Figure US20040235818A1-20041125-C03913
    Example R Amine MS (ES) m/z
    152 4-(4-fluoro- 4-(4-fluorobenzoyl)- 507 (M + H)+
    benzoyl)piperidyl piperidine
    153 4-(2-methoxy- 4-(2-methoxyphenyl)- 491 (M + H)+
    phenyl)piperidyl piperidine
    154
    Figure US20040235818A1-20041125-C03914
         		N-cyclopropyl-meth- yl-N-methyl-4-pipe- ridine carboxamide 496 (M + H)+
    155 pyrrolidinyl pyrrolidine 371 (M + H)+
    • Example 156 Preparation of N-hydroxy-4-[[4-(4-methoxyphenoxy)phenyl]sulfonyl]-4-thianecarboxamide-1,1-dioxide
  • [0671]
    Figure US20040235818A1-20041125-C03915
  • Step 1: Oxidation of Resin MT-III. A suspension of resin MT-III (2.0 g, 1.72 mmol), m-perbenzoic chloroperbenzoic acid (4.37 g) and dichloromethane 25 mL) was stirred at room temperature for 20 hours. The resin was filtered and washed with dichloromethane (3×25 mL), dimethylformamide (3×25 mL), methanol (3×25 mL), 1M aqueous sodium bicarbonate (2×25 mL), methanol (3×25 mL), dichloromethane (3×25 mL) and ether (3×25 mL). The resin was dried in vacuo to afford resin MT-IV (2.16 g). [0672]
  • Step 2: Aryl fluoride displacement of resin MT-IV. N-hydroxy-4-[[4-(4-methoxyphenoxy)-phenyl]sulfonyl]-4-thianecarboxamide 1,1-dioxide was prepared by the method of Example 146 using resin MT-IV in the place of resin MT-III. ES (MS) m/z 473 (M+NH[0673] 4)+.
    • EXAMPLES 156-160
  • The following hydroxamic acids were prepared by the method of Example 156 using the appropriate alcohol. [0674]
    Figure US20040235818A1-20041125-C03916
    Example R Alcohol MS (ES) m/z
    157 4-trifluoro- 4-trifluoro- 527 (M + NH4)+
    methoxyphenyl methoxyphenol
    158 4-isopropylphenyl 4-isopropylphenol 485 (M + NH4)+
    159 3-pyridyl 3-hydroxypyridine 427 (M + H)+
    160 4-pyridyl 4-hydroxypyridine 427 (M + H)+
    • EXAMPLE 161
  • The following hydroxamic acids were prepared by the method of Example 156 using the appropriate amine. [0675]
    Figure US20040235818A1-20041125-C03917
    Example R Amine MS (ES) m/z
    161 4-(4-fluorobenzoyl) 4-(4-fluoro- 539 (M + H)+
    piperidyl benzoyl)-
    piperidine
    • Example 162 Preparation of N-hydroxy-4-[[4-[4-[(3,5-dimethylpiperidyl)carbonyl]-piperidyl]phenyl]sulfonyl]-4-thianecarboxamide
  • [0676]
    Figure US20040235818A1-20041125-C03918
  • Step 1: Aryl fluoride displacement of Resin MT-III. To a suspension of resin MT-III (4.06 g, 3.4 mmol) in 1-methyl-2-pyrrolidinone (40 mL) was added ethyl isonipecotate (5.25 mL), and the mixture was heated to 100° C. for 16 hours. The cooled reaction mixture was filtered and the resin was washed with methanol (3×25 mL), dichloromethane (1×10 mL) and ether (3×25 mL). The resin was dried in vacuo to afford resin MT-V (4.21 g). [0677]
  • Step 2: Hydrolysis of resin MT-V. To a suspension of resin MT-V (4.13 g) in tetrahydrofuran (20 mL) was added 4M aqueous potassium hydroxide (10 mL) and stirred at room temperature for 5 days. The resin was filtered and washed with methanol (3×25 mL), dichloromethane (3×25 mL) and ether (3×25 mL). The resin was dried in vacuo to afford resin MT-VI. [0678]
  • Step 3: Conversion to amide. To a suspension of resin MT-VI (268 mg) in 1-methyl-2-pyrrolidinone (2 mL) were added 3,5-dimethyl-piperidine (299 μL), pyBOP (587 mg) and diisopropylethyl amine (393 μL), and mixture was stirred 40 hours. The resin was filtered and washed with dimethylformamide (3×2 mL), methanol (3×2 mL), 10% aqueous acetic acid (3×2 mL), methanol (3×2 mL), dichloromethane (3×2 mL) and glacial acetic acid (1×2 mL). The resin was treated with 95% aqueous trifluoroacetic acid (2 mL) and agitated 1 hour. The resin was washed with dichloromethane (2 mL) and methanol (2 mL). The filtrate was evaporated. The residue was purified by RPHPLC to afford N-hydroxy-4-[[4-[4-[(3,5-dimethylpiperidyl)carbonyl]piperidyl] phenyl]sulfonyl]-4-thianecarboxamide (7.5 mg) MS (ES) m/z 524 (M+H)[0679] +.
    • EXAMPLE 163 Preparation of N-hydroxy-4-[[4-[4-[(3,5-dimethylpiperidyl)carbonyl]-piperidyl]phenyl]sulfonyl]-4-thianecarboxamide
  • N-hydroxy-4-[[4-[4-[(3,5-dimethyl-piperidyl)carbonyl]piperidyl]phenyl]sulfonyl]-4-thianecarboxamide was prepared by the method of using cis-2,6-dimethylmorpholine as the amine. MS (ES) m/z 526 (M+H)[0680] +.
    • EXAMPLE 164 N-hydroxy-4[[[4-[4-(4-fluorophenyl)-methoxy]piperidyl]phenyl]sulfonyl]-1-tetrahydropyrancarboxamide
  • [0681]
    Figure US20040235818A1-20041125-C03919
  • Step 1: Preparation of amine 4-(4-fluorophenyl)methoxy piperidine. Ninety-five percent dry sodium hydride is weighted in a 25 mL vial. Boc-(4-hydroxy)-piperidine (1 g, 4.97 mmol) in 10 mL of dimethyl formamide is added and the reaction mixture is stirred at room temperature for 15 minutes 4-fluoro benzyl bromide (1.4 g, 7.5 mmol) is added and the reaction mixture is stirred at room temperature for 16 hours, then quenched with water and diluted with ethyl acetate. The organic layer was washed with brine, then dried over MgSO[0682] 4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:10. The Boc-protected amine is dissolved in 3 mL of dichloromethane and 3 mL of trifluoroacetic acid and the reaction mixture is stirred at room temperature for 16 hours and the solvent is evaporated to give 1.8 g of 4-(4-fluorophenyl)-methoxy piperidine. MS: M+H=210.1319.
  • Step 2: Preparation of N-hydroxy-4 [[[4-[4-(4-fluorophenyl)methoxy] piperidyl] phenyl]sulfonyl]-1-tetrahydropyrancarboxamide. To a solution of N-tetrahydropyranoxy-4-fluorophenyl-sulfonyl-1-tetrahydropyrancarboxamide (100 mg, 0.26 mmol) in 1.5 mL of DMA are added the amine from step 1 (0.52 mmol, 2 eq.) and cesium carbonate (420 mg, 1.29 mmol). The reaction mixture is stirred at 100° C. for 48 hours. The reaction is treated with water and filtered through Celite eluting with dichloromethane. The solvent was evaporated and the residue is dissolved in 2 mL of 4M HCl in dioxane. The mixture is stirred at room temperature for 1 hour and 1 mL of methanol is added. After stirring 15 minutes at room temperature, the solvent is evaporated and the residue was purified by RPHPLC eluting with 10% to 90% acetonitrile/water to give N-hydroxy-4-[[[4-[4-(4-fluorophenyl)methoxy]piperidyl]phenyl]sulfonyl]-1-tetrahydropyrancarboxamide. MS: M+H=493.1792. [0683]
    • EXAMPLES 165-181
  • The following hydroxamic acids were synthesized by the procedure of Example 164: [0684]
    Figure US20040235818A1-20041125-C03920
    HI
    Ex- Halide starting RES MS
    ample material R M + H
    165 benzyl bromide
    Figure US20040235818A1-20041125-C03921
         		475.1913
    166 ethyl iodide
    Figure US20040235818A1-20041125-C03922
         		413.1764
    167 4-fluoro benzyl bromide
    Figure US20040235818A1-20041125-C03923
         		493.1792
    168 iodopropane
    Figure US20040235818A1-20041125-C03924
         		427.1918
    169 3,5-dimethyl benzyl bromide
    Figure US20040235818A1-20041125-C03925
         		144.1391
    170 4-chloro benzyl bromide
    Figure US20040235818A1-20041125-C03926
         		509.1515
    171 3-methyl benzyl bromide
    Figure US20040235818A1-20041125-C03927
         		489.2059
    172 4-methyl benzyl bromide
    Figure US20040235818A1-20041125-C03928
         		489.2074
    173 3-trifluoro- methoxy benzyl bromide
    Figure US20040235818A1-20041125-C03929
         		559.1738
    174 2-trifluoro- methyl benzyl bromide
    Figure US20040235818A1-20041125-C03930
         		543.1780
    175 4-trifluoro- methoxy benzyl bromide
    Figure US20040235818A1-20041125-C03931
         		559.1730
    176 3,4-dichloro- benzyl bromide
    Figure US20040235818A1-20041125-C03932
         		543.1155
    177 3-trifluoro- methyl benzyl bromide
    Figure US20040235818A1-20041125-C03933
         		543.1779
    178 3,5-dimethoxy- benzyl bromide
    Figure US20040235818A1-20041125-C03934
         		535.2120
    179 3,4-difluoro- benzyl bromide
    Figure US20040235818A1-20041125-C03935
         		511.1705
    180 4-cyano- benzyl bromide
    Figure US20040235818A1-20041125-C03936
         		500.1835
    181 2-phenyl benzyl bromide
    Figure US20040235818A1-20041125-C03937
         		551.2196
    • Example 182 N-hydroxy-4-[[[4-[3-(4-fluorophenyl)-methoxy]piperidyl] phenyl]sulfonyl]-1-tetrahydropyrancarboxamide
  • [0685]
    Figure US20040235818A1-20041125-C03938
  • N-hydroxy-4[[[4-[3-(4-fluorophenyl)-methoxy]piperidyl]phenyl]sulfonyl]-1-tetrahydro-pyrancarboxamide is prepared by the method of Example 164 starting from Boc-(3-hydroxy)-piperidine in step 1. [0686]
    • Examples 183-184
  • The following hydroxamic acids were synthesized using a procedure similar to that of Example 182: [0687]
    Figure US20040235818A1-20041125-C03939
    Halide
    starting
    Example material R HI RES MS
    183 4-fluroro benzyl bromide
    Figure US20040235818A1-20041125-C03940
         		M + H =475.1913
    184 benzyl bromide
    Figure US20040235818A1-20041125-C03941
         		M + H =551.2196
    • Example 185 N-hydroxy-4[[[4-(4-phenoxy)-piperidyl]phenyl]sulfonyl]-1-tetrahydropyrancarboxamide
  • [0688]
    Figure US20040235818A1-20041125-C03942
  • N-hydroxy-4 [[[4-(4-phenoxy)piperidyl] phenyl]sulfonyl]-1-tetrahydropyrancarboxamide is prepared by the method of Example 164 starting from 4-phenoxypiperidine in step 2. [0689]
    • Examples 186-187
  • The following hydroxamic acids were synthesized using a procedure similar to that of Example 185: [0690]
    Figure US20040235818A1-20041125-C03943
    Ex-
    ample Amine starting material R HI RES MS
    186 187
    Figure US20040235818A1-20041125-C03944
         		H 3,5-di- methyl M + H = 461.1749 M + H = 489.2065
    • Example 188 Preparation of N-hydroxy-4[[[4-[(3-trifluoromethyl)phenylcarbamoxy]-piperidyl]phenyl]sulfonyl]-1-tetrahydropyrancarboxamide
  • [0691]
    Figure US20040235818A1-20041125-C03945
  • Step 1: A solution of N-tetrahydro-pyranoxy-4-fluorophenylsulfonyl-1-tetrahydro-pyrancarboxamide (1 g, 2.58 mmol), 4-hydroxy-piperidine (392 mg, 3.87 mmol) and cesium carbonate (2.52 g, 7.74 mmol) in 20 mL of NMP is stirred at 100° C. for 48 hours. The reaction mixture is treated with water and neutralized to pH 4 with 5% aqueous HCl. The aqueous layer is extracted twice with ethyl acetate and the combined organic layer is dried using magnesium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:10 to give N-tetrahydropyranoxy-4-[[(4-hydroxypiperidyl) phenyl] sulfonyl]-1-tetrahydropyrancarboxamide. MS: M+Na=491.2. [0692]
  • Step 2: To a solution of alcohol N-tetrahydro-pyranoxy-4[[(4-hydroxypiperidyl)-phenyl]sulfonyl]-1-tetrahydropyrancarboxamide (50 mg, 0.107 mmol) in 2 mL of dichloromethane is added alpha, alpha, alpha-trifluoro-M-tolyl isocyanate (21 mg, 0.112 mmol). The reaction mixture is stirred for 16 hours at room temperature and 21 mg of alpha,alpha,alpha-trifluoro-m-tolyl isocyanate is added. The mixture is stirred 48 hours at room temperature and treated with water. The solvent is evaporated and the residue is dissolved in 2 mL of 4M HCl in dioxane. The mixture is stirred at room temperature for 1 hour and 1 mL of methanol is added. After stirring 15 minutes at room temperature the solvent is evaporated and the residue was purified by RPHPLC eluting with 10% to 90% acetonitrile/water to give N-hydroxy-4-[[[4-[(3-trifluoromethyl)phenyl-carbamoxy]piperidyl]phenyl]sulfonyl]-1-tetrahydropyrancarboxamide. MS: M+Na=594.1. [0693]
    • EXAMPLES 189-191
  • The following hydroxamic acids were synthesized using a procedure similar to that of Example 188: [0694]
    Figure US20040235818A1-20041125-C03946
    Example Isocyanate starting material R MS
    189 alpha,alpha,alpha-tri- fluoro-M-tolyl isocyanate
    Figure US20040235818A1-20041125-C03947
         		M + Na = 594.1
    190 4-ethoxyphenyl isocyanate
    Figure US20040235818A1-20041125-C03948
         		M + Na = 570.2
    191 4-fluorophenyl isocyanate
    Figure US20040235818A1-20041125-C03949
         		M + H = 522.1742
    • Example 192 Preparation of N-hydroxy-4[[4-(4-trifluoromethoxyphenoxy)-phenyl]-sulfonyl]-1-[[(2-trifluoromethoxy)-phenyl]-sulfonyl-4-piperidinecarboxamide
  • [0695]
    Figure US20040235818A1-20041125-C03950
  • N-hydroxy-4[[4-(4-trifluoromethoxyphenoxy)-phenyl]sulfonyl]-1-[[(2-trifluoromethoxy)phenyl]-sulfonyl-4-piperidinecarboxamide can be prepared using the method of Example 93 starting from 2-trifluoromethoxybenzene sulfonyl chloride. [0696]
    • EXAMPLES 193-197
  • The following hydroxamic acids were synthesized using a procedure similar to that of Example 192: [0697]
    Figure US20040235818A1-20041125-C03951
    Sulfonyl chloride
    Example starting material R MS
    193 2-trifluoro- methoxybenzene sulfonyl chloride
    Figure US20040235818A1-20041125-C03952
         		M + NH4 =702.1003
    194 benzene sulfonyl chloride
    Figure US20040235818A1-20041125-C03953
         		M + NH4 =618.1216
    195 alpha- toluenesulfonyl chloride
    Figure US20040235818A1-20041125-C03954
         		M + NH4 =632.1337
    196 3-trifluoro- methylbenzene sulfonyl chloride
    Figure US20040235818A1-20041125-C03955
         		M + NH4 =686.1027
    197 3-trifluoro- methane sulfonyl chloride
    Figure US20040235818A1-20041125-C03956
         		M − H =591.1
    • EXAMPLE: 198
  • [0698]
    Figure US20040235818A1-20041125-C03957
  • N-hydroxy-4[[4-(4-trifluoromethoxyphenoxy)-phenyl]sulfonyl]-1-(N-methylthiourea)-4-piperidinecarboxamide was prepared by the method of Example 192 starting with methyl isothiocyanate. M+H=77. [0699]
    • EXAMPLES 199-202
  • The following hydroxamic acids were synthesized using the procedure of Example 198: [0700]
    Figure US20040235818A1-20041125-C03958
    Sulfonyl chloride MS
    Example starting material R M + H
    199 2-morpholinoethyl isothiocyanate
    Figure US20040235818A1-20041125-C03959
         		633.1643
    200 2-piperidinoethyl isothiocyanate
    Figure US20040235818A1-20041125-C03960
         		653.1694
    201 pyridine-3- isothiocyanate
    Figure US20040235818A1-20041125-C03961
         		597.1094
    202 4-dimethylaminophenyl isothiocyanate
    Figure US20040235818A1-20041125-C03962
         		639.1526
    • EXAMPLE 203 Preparation of 1,1-dimethylethyl-3,6-dihydro-4-[2-(trifluoromethyl)phenyl]-[(2H)-pyridinecarboxylate
  • [0701]
    Figure US20040235818A1-20041125-C03963
  • Part A: An oven-dried 1.0 liter flask fitted with a thermometer and nitrogen inlet was charged with 55 mL of a 2 M solution of lithium diisopropoylamide in tetrahydrofuran and 50 mL of tetrahydrofuran. The flask was immersed in a dry ice/acetone bath. When the temperature of the solution was less than −70 degrees, a solution of N-t-butoxycarbonylpiperidinone (20.0 g, 0.1 mole) in 100 mL tetrahydrofuran was added dropwise, maintaining the temperature less than −65 degrees. After complete addition, the flask was stirred with cooling for 20 minutes. Then a solution of N-trifluoromethanesulfonimide (38.2 g, 0.107 mole) was added drop-wise maintaining the temperature less than −65 degrees. After complete addition, the dry ice/acetone bath was swapped with an ice/water bath. The reaction was stirred overnight (about eighteen hours), slowly warming to room temperature. After 16 hours, the solvent was removed in vacuo, and the residue was purified by column chromatography on neutral alumina, yielding 26.53 g of product as a yellow oil. Electrospray mass spectroscopy showed m/z 332 (M+H). [0702]
  • Part B: A three-necked 15 mL round-bottom flask was charged with the product from Part A (6 g, 18.1 mmol), o-trifluorobenzeneboronic acid (4.94 g, 26 mmol), lithium chloride (2.34 g, 55 mmol), 2 M sodium carbonate (26 mL, 52 mmol) and ethylene glycol dimethyl ether (60 mL). Nitrogen was bubbled through the solution for 10 minutes, then palladium tetrakistriphenylphosphine (1.06 g, 0.92 mmol) was added. The mixture was heated to reflux for 1.5 hours, then cooled to room temperature. The solvent was removed in vacuo, then the residue was partitioned between 100 mL of methylene chloride and 100 mL of 2 M sodium carbonate with 3 mL concentrated ammonium hydroxide. The aqueous layer was extracted with an additional 100 mL methylene chloride, then the combined organic layers were dried over magnesium sulfate and concentrated to give 8.42 g of crude product as a dark brown oil. Purification via flash column chromatography (10% ethyl acetate3/hexanes) yielded 2.76 g of pure product as a yellow oil. Electrospray mass spectroscopy showed m/z 328 (M+H). [0703]
    • EXAMPLE 204 Preparation of 1,2,3,6-tetrahydro-4-[2-trifluoromethyl)phenyl]pyridine
  • [0704]
    Figure US20040235818A1-20041125-C03964
  • The title compound of Example 203 (300 mg, 0.92 mmol) was dissolved in methylene chloride (5 mL) in a 15 mL round-bottom flask, and 5 mL of trifluoroacetic acid was added dropwise. After 15 minutes, the solvent was removed in vacuo, and the residue partitioned between 20 mL of ethyl acetate and 20 mL of 2 M sodium carbonate. The organic layer was washed with additional 2 M sodium carbonate, dried over magnesium carbonate and concentrated in vacuo to yield 195 mg of pure product as a colorless oil. Electrospray mass spectroscopy showed m/z 228 (M+H). [0705]
    • EXAMPLE 205 Preparation of 4-[2-(trifluoromethyl) phenyl]piperidine
  • [0706]
    Figure US20040235818A1-20041125-C03965
  • Part A: A solution of the title compound of Example 203 (2.3 g, 7 mmol) in 20 mL ethanol was added to a hydrogenation flask containing 1 g of 4% palladium on carbon (0.38 mmol). The mixture was placed under 100 PSI hydrogen and heated to 50 degrees Celsius for 5 hours. Then the mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated in vacuo to give 2.27 g of pure product as a colorless oil. Electrospray mass spectroscopy showed m/z 330 (M+H). [0707]
  • Part B: The product from Part A above (2.24 g, 6.8 mmol) was dissolved in 100 mL methylene chloride, and 100 mL of trifluoroacetic acid was added dropwise. After 15 minutes, the solvent was removed in vacuo, and the residue partitioned between 100 mL of ethyl acetate and 100 mL of 2 M sodium carbonate. The organic layer was washed with additional 2 M sodium carbonate, dried over magnesium carbonate and concentrated in vacuo to yield 1.12 g of pure product as a colorless oil. Electrospray mass spectroscopy showed m/z 230 (M+H). [0708]
    • EXAMPLE 206 General Description for Preparation of Hydroxamic Acids via Aryl Fluoride Displacement with Amines.
  • Part A: A 2 dram vial was charged with aryl fluoro compound of Preparative Example IV (170 mg, 0.44 mmol), 1 ml of 2-methylpyrrolidinone, cesium carbonate (360 mg, 1.1 mmol) and 0.66 mmol of an amine. A small magnetic stirring bar was added, then the vial was capped and placed in a Pierce Reacti-therm™ at 115 degrees Celsius. The reaction progress was followed by analytical HPLC. When the reaction was greater than 90% complete, the vial was cooled to room temperature. The reaction mixture was diluted with 5 mL of water, then 1.2 mL of 5% hydrogen chloride/water was added dropwise. Then, the entire mixture was poured onto a column of Celite. The column was washed exhaustively with ethyl acetate (30-40 mL) and the filtrate was collected and concentrated to give the crude products. [0709]
  • Part B: The product from above was dissolved in 2 mL 1,4-dioxane and 2 mL of methanol in a 4 dram vial with a small magnetic stirring bar. A solution of 4 N hydrogen chloride in 1,4-dioxane was carefully added to the reaction, and the mixture was stirred for 2 hours. Then the solvent was removed in vacuo and the residue purified by preparative reversed-phase HPLC. [0710]
    • EXAMPLES 207-214
  • The following hydroxamic acids were prepared using the method described above in Example 106 with the indicated amine as the starting material. [0711]
    Figure US20040235818A1-20041125-C03966
    m/z from
    electrospray
    mass
    Example amine R spectroscopy
    207 Product of Example 205
    Figure US20040235818A1-20041125-C03967
         		513.3 (M + H)
    208 Product of Example 204
    Figure US20040235818A1-20041125-C03968
         		511.2 (M + H)
    209 piperidine
    Figure US20040235818A1-20041125-C03969
         		369.2 (M + H)
    210 tetrahydro- piperidine
    Figure US20040235818A1-20041125-C03970
         		367.2 (M + H)
    211 4-(2-keto- benzimid- azolinyl)- piperidine
    Figure US20040235818A1-20041125-C03971
         		501 (M + H)
    212 hexamethyl- eneimine
    Figure US20040235818A1-20041125-C03972
         		383.2 (M + H)
    213 1-methylhomo- piperazine
    Figure US20040235818A1-20041125-C03973
         		398.2 (M + H)
    214 1,3,3-trimethyl- 6-azabicyclo- [3.2.1]octane
    Figure US20040235818A1-20041125-C03974
         		437.3 (M + H)
    • EXAMPLES 215-223
  • Using the procedures outlined in Examples 203, 204, 206 and other methods outlined above, the following analogs are made from the indicated boronic acid: [0712]
    Figure US20040235818A1-20041125-C03975
    Example Boronic acid R
    215
    Figure US20040235818A1-20041125-C03976
    Figure US20040235818A1-20041125-C03977
    216
    Figure US20040235818A1-20041125-C03978
    Figure US20040235818A1-20041125-C03979
    217
    Figure US20040235818A1-20041125-C03980
    Figure US20040235818A1-20041125-C03981
    218
    Figure US20040235818A1-20041125-C03982
    Figure US20040235818A1-20041125-C03983
    219
    Figure US20040235818A1-20041125-C03984
    Figure US20040235818A1-20041125-C03985
    220
    Figure US20040235818A1-20041125-C03986
    Figure US20040235818A1-20041125-C03987
    221
    Figure US20040235818A1-20041125-C03988
    Figure US20040235818A1-20041125-C03989
    222
    Figure US20040235818A1-20041125-C03990
    Figure US20040235818A1-20041125-C03991
    223
    Figure US20040235818A1-20041125-C03992
    Figure US20040235818A1-20041125-C03993
    • EXAMPLE 224 Preparation of Tetrahydro-N-hydroxy-4-[[4-(pentaflourooxy)phenyl]sulfonyl]-2H-thiopyran-4-carboxamide
  • [0713]
    Figure US20040235818A1-20041125-C03994
  • Part A: To a solution of the product of Preparative Example IV (2.5 g, 6 mmol) in dimethylformamide (50 mL) was added 4-pentafluroethyloxy phenol (2.0 g, 6 mmol) followed by cesium carbonate (5 g, 12 mmol). The reaction was heated at eighty degrees Celsius for twelve hours. Stripping the dimethylformamide in vacuo afforded a brown solid (5.5 g). The product was dissolvent in ethylacetate (150 ml) and extracted with water, brine and dried over sodium sulfate. The [0714] 1H NMR, MS, and HPLC was consistent with desired compound.
  • Part B: To the product of part A, crude THP-protected hydroxamate was disolved in acetonitrile/water (40 ml) was slowly added 10% aq HCl (10 ml). After stirring two hours, the acetonitrile was stripped. The resultant precipitate was collected, giving the title compound as a white solid (2.1 g). The [0715] 1H NMR, MS, and HPLC was consistent with desired compound. This solid was recrystallized from ethylacetate and hexanes (1.8 g). The 1H NMR, MS, and HPLC was consistent with desired compound. MS (CI) M+H calculated for C23H27BrNO6S: 511, found 511.
    • EXAMPLE 225 Preparation of Tetrahydro-4-[[4-(pentaflourooxy)phenyl]sulfonyl]-2H-thiopyran-4-carboxamide
  • [0716]
    Figure US20040235818A1-20041125-C03995
  • Part A. The product of Preparative Example V (2.5 g) was dissolved in methanol (60 mL). To this solution ammonium formate (3 g) was added, followed by Pd on charcoal 20% catalyst. The mixture was heated to reflux for 24 hour. After complete reaction the mixture was cooled filtered through a plug of Celite and the solvent removed under reduced pressure to give pure amide (1.7 g). The [0717] 1H NMR, MS, and HPLC was consistent with desired compound. MS (CI) M+H calculated for C23H27BrNO6S: 445, found 445.
    • EXAMPLE 226 Preparation of 4-(4-pyridyloxy) thiophenol hydrochloride
  • [0718]
    Figure US20040235818A1-20041125-C03996
  • Part A: Phenol (1500 g, 15.9 mol) and 4-chloropyridine hydrochloride (800 g, 7.1 mol) were combined in a melt at 150° C. under a nitrogen atmosphere. After fifteen hours, the reaction was dissolve in 3N sodium hydroxide solution (5400 mL) and extracted with methylene chloride (4×). The organic extracts were combined, washed with 1N sodium hydroxide solution, water and brine, dried over Na[0719] 2SO4, filtered, and concentrated in vacuo. The isolated oil was dissolved in hexanes (1000 mL) and cooled to −60° C. The precipitate was collected and dried in vacuo to yield 452 g (38%) of the 4-phenoxypyridine as a white solid.
  • Part B: A solution of the 4-phenylpyridine from part A (400 g, 2.3 mol) in 1,2-dichloroethane (1250 mL) was cooled in an ice bath under a nitrogen atmosphere and treated with chlorosulfonic acid (400 mL, 6.0 mol). The reaction temperature was held below 12° C. during the addition. The reaction was then heated to 45° C. for 15 hours. The standard work-up procedure afforded 270 grams (40%) of the desired 4-[(pyrid-4-yl)oxy]benzenesulfonic acid. [0720]
  • Part C: A slurry of the sulfonic acid part B (420 g, 1.5 mol) in acetonitrile (2500 mL) and DMF (40 mL) was warmed to 75° C. under a nitrogen atmosphere and treated with thionyl chloride (243 mL, 3.3 mol) added dropwise over 3 hours. After stirring for one-half hour, the standard work-up procedure afforded 483 grams (100%) of the desired 4-[(pyrid-4-yl)oxy]benzenesulfonyl chloride hydrochloride. [0721]
  • Part D: A solution of triphenylphosphine (65.6 g, 250.28 mmol) in dry methylene chloride (240 mL) was cooled to zero degrees C. in an ice-water bath, then treated with dimethylformamide (3.4 mL, 3.2 g, 43.40 mmol). The reaction mixture was then treated with the sulfonyl chloride from part C (25.5 g, 83.43 mmol), added as a solid over one-half hour. After two hours in the ice bath, the reaction was treated with 1 N aqueous hydrochloric acid solution (150 mL) and stirred vigorously for one hour. The layers were separated and the aqueous layer was extracted with methylene chloride (1×). The aqueous layer was concentrated in vacuo to yield 17.9 grams (90%) of the 4-(4-pyridyloxy)thiophenol hydrochloride as a tan solid, m/z=204 (M+H). [0722]
    • EXAMPLE 227 Preparation of
  • [0723]
    Figure US20040235818A1-20041125-C03997
  • Part A: A solution of 4-(4-pyridyloxy)-thiophenol (2.0 g, 8.34 mmol) and tert-butylbromoacetate (1.2 mL, 1.6 g, 8.34 mmol) in dry methanol (30 mL) was cooled to zero degrees C. and treated with triethylamine (2.4 mL, 1.8 g, 17.52 mmol). The addition was done at a rate which held the reaction temperature below 10° C. The ice bath was removed and after two hours at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The organic extracts were combined, washed with water and brine, dried over Na[0724] 2SO4, filtered, and concentrated in vacuo to yield 2.3 grams of the tert-butyl ester of the sulfide acid suitable for the next step.
  • Part B: To a solution of the tert-butyl ester of the sulfide acid from part A (2.3 g, 7.25 mmol) in dry anisole (85 mL, 8.1 g, 74.67 mmol) was added trifluoroacetic acid (25.5 mL, 37.7 g, 330.6 mmol). After one-half hour at ambient temperature, the reaction was concentrated in vacuo to 3.7 g of the TFA salt of the sulfide acid suitable for the next step. [0725]
  • Part C: To a solution of the TFA salt of the acid obtained from part B (2.7 g, 7.19 mmol) in dimethylformamide (10 mL) was added N-hydroxybenzotriazole hydrate (1.5 g, 10.79 mmol), N-methylmorpholine (4.7 mL, 4.4 g, 43.16 mmol), 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (2.5 g, 21.58 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.8 g, 9.35 mmol). After sixteen hours at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The organic extracts were combined, washed with brine, dried over Na[0726] 2SO4, filtered, and concentrated in vacuo. Chromatography (on silica, methanol-ethyl acetate/hexanes) afforded 2.1 g (81%) of the THP sulfide hydroxamate as a dry, white foam, m/z=361 (M+H).
  • Part D: To a solution of the THP sulfide hydroxamate from part C (2.1 g, 5.83 mmol) in methanol/water (13 mL/2 mL) was added tetrabutylammonium Oxone (5.8 g, 61.29 mmol). After 2 days at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (6×). The organic extracts were combined, washed with water and brine, dried over Na[0727] 2SO4, filtered, and concentrated in vacuo. Chromatography (on silica, methanol-ethyl acetate/hexanes) afforded 0.9 g (40%) of the THP sulfone hydroxamate as a dry, white foam, m/z=393 (M+H).
  • Part E: To a slurry of the THP sulfone hydroxamate from part D (0.9 g, 2.29 mmol) in methanol (0.6 mL) was added 4N HCl dioxane solution (6 mL). After one hour at ambient temperature, the reaction mixture was slowly poured into diethyl ether (200 mL). Filtration afforded 0.6 grams (78%) of the title compound as a white solid, m/z=309 (M+H). [0728]
    • EXAMPLE 228 Preparation of
  • [0729]
    Figure US20040235818A1-20041125-C03998
  • Part A: A solution of 4-(4-pyridyloxy)-thiophenol (18.0 g, 75.08 mmol) and tert-butylbromoacetate (10.5 mL, 13.9 g, 71.33 mmol) in dry methanol (250 mL) was cooled to 0° C. and treated with triethylamine (22.0 mL, 16.0 g, 157.68 mmol). The addition was done at a rate which held the reaction temperature below 1° C. The ice bath was removed and after one-half hour at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The organic extracts were combined, washed with water and brine, dried over Na[0730] 2SO4, filtered, and concentrated in vacuo to yield 21.7 grams of the tert-butyl ester of the sulfide acid suitable for the next step.
  • Part B: To a solution of the tert-butyl ester of the sulfide acid from part A (221.7 g, 68.37 mmol) in dry anisole (76.5 mL, 76.1 g, 704.12 mmol) was added trifluoroacetic acid (240 mL, 355 g, 3,117 mmol). After one hour at ambient temperature, the reaction was concentrated in vacuo to yield 34.7 g of the TFA salt of the sulfide acid suitable for the next step. [0731]
  • Part C: To a solution of the TFA salt of the sulfide acid from part B (34.7 g, 68.37 mmol) in dry methanol (100 mL) was added thionyl chloride (7.5 mL, 12.2 g, 102.5 mmol). After twelve hours at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The organic extracts were combined, washed with water and brine, dried over Na[0732] 2SO4, filtered, and concentrated in vacuo to yield 18.7 grams of the methyl ester of the sulfide acid suitable for the next step.
  • Part D: To a solution of the methyl ester of the sulfide acid obtained from part C (18.7 g, 67.92 mmol) in methylene chloride (325 mL) was added tetrabutylammonium Oxone (193 g, 543.4 mmol). After 2 days at ambient temperature, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (9×). The organic extracts were combined, washed with water and brine, dried over Na[0733] 2SO4, filtered, and concentrated in vacuo. Chromatography (on silica, methanol-ethyl acetate/hexanes) afforded 7.3 g (35%) of the methyl ester of the sulfone acid as a dry, white foam, m/z=308 (M+H).
  • Part E: To a solution of the methyl ester of the sulfone acid obtained from part D (2.7 g, 8.79 mmol) in dry dimethylformamide (20 mL) was added 18-crown-6 ether (0.5 g, 1.90 mmol) and potassium carbonate (4.9 g, 35.14 mmol). The reaction slurry was treated with bis-(2-bromoethyl)ether (1.1 mL, 2.0 g, 8.79 mmol) and then heated to 60° C. After fifteen hours at 60° C., the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The organic extracts were combined, washed with brine (3×), dried over Na[0734] 2SO4, filtered, and concentrated in vacuo. Chromatography (on silica, NH3-methanol-ethyl acetate/hexanes) afforded 1.6 g (48%) of the THP sulfone methyl ester as a tan solid, m/z=378 (M+H).
  • Part F: To a solution of the THP sulfone methyl ester from part E (1.6 g, 4.24 mmol) in dry tetrahydrofuran (20 mL) was added potassium trimethylsilanoate (1.6 g, 12.72 mmol). After five hours at ambient temperature, the reaction was concentrated in vacuo to yield the potassium salt of the THP sulfone acid as a tan solid suitable for use in the next step. [0735]
  • Part G: To a slurry of the potassium salt of the THP sulfone acid obtained from part F (1.7 g, 4.24 mmol) in dimethylformamide (20 mL) was added N-hydroxybenzotriazole hydrate (1.1 g, 8.48 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.6 g, 8.48 mmol). After heating the reaction mixture at 40° C. for one-half hour, N-methylmorpholine (1.4 mL, 1.3 g, 12.72 mmol) and 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (1.0 g, 8.48 mmol) were added. After heating at 45° C. for 15 hours, the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and 10% potassium carbonate, the layers were separated and the aqueous layer was extracted with ethyl acetate (13×). The organic extracts were combined, washed with water and brine (3×), dried over Na[0736] 2SO4, filtered, and concentrated in vacuo. Chromatography (on silica, (2M ammonia in methanol-ethyl acetate)/hexanes) afforded 0.7 g (35%) of the THP-protected THP sulfone hydroxamate as a dry, white foam, m/z=463 (M+H).
  • Part H: To a slurry of the THP-protected THP sulfone hydroxamate from part G (0.7 g, 1.43 mmol) in methanol (0.4 mL) was added 4N HCl dioxane solution (4 mL). After thirty minutes at ambient temperature, the reaction mixture was slowly poured into diethyl ether (200 mL) and stirred for fifteen minutes. Filtration afforded 0.5 grams (83%) of the title compound as the HCl salt, m/z=379 (M+H). [0737]
    • EXAMPLE 229 Preparation of N-hydroxy-1-(4-methyl-phenyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide monohydrochloride
  • [0738]
    Figure US20040235818A1-20041125-C03999
  • Part A: To a suspension of ethyl 4-(4-fluorophenylsulfonyl]-4-piperidinecarboxylate, hydrochloride Preparative Example II (2.56 g, 7.28 mmol) in H[0739] 2O (50 mL) was added 1.25N NaOH (pH=9.0). The aqueous layer was extracted with diethyl ether (2×75 mL). The combined organic layers were washed with saturated NaCl and dried over Na2SO4. Concentration in vacuo provided the free amine as an off-white solid (1.72 g). To a solution of the free amine (1.70 g, 5.39 mmol) in toluene (25 mL) was added Cs2CO3 (2.34 g, 7.19 mmol) and a solution of 4-bromotoluene (0.877 g, 5.13 mmol) in toluene (5 mL). This was followed by the addition of tris(dibenzyldeneacetone)dipallidium (O) (0.047 g, 0.0513 mmol) and BINAP (0.096 g, 0.154 mmol). The resulting mixture was then heated to one hundred degress Celsius for 17 hours. After cooling to ambient temperature, the reaction mixture was filtered through a pad of Celite®, washing with ethyl acetate and the filtrate was concentrated in vacuo. Chromatography (on silica, ethyl acetate/hexane) provided the aniline as a yellow oil (1.59 g, 76%).
  • Part B: To a solution of the aniline of part A (1.56 g, 3.85 mmol) in N,N-dimethylformamide (8.0 mL) was added K[0740] 2CO3 (1.06 g, 7.70 mmol) and 4-(trifluoromethoxy)phenol (0.823 g, 4.62 mmol). The resulting mixture was heated to ninety degrees Celsius for 19 hours. The reaction was cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between H2O and diethyl ether. The organic layer was washed with saturated NaCl and dried over Na2SO4. Concentration in vacuo provided the biaryl ether as a brown oil (2.42 g, >100%).
  • Part C: To a solution of the biaryl ether of part B (2.42 g, 3.85 mmol) in tetrahydrofuran (10 mL) and H[0741] 2O (10 mL) was added NaOH (1.54 g, 38.50 mmol) in H2O (5.0 mL). The mixture was heated to sixty degrees Celsius for 6 hours then cooled to ambient temperature. The mixture was then acidified (pH=7) with 1N HCl. The solids were collected by vacuum filtration, then suspended in acetonitrile and concentrated in vacuo to give the acid as a tan solid (1.95 g, 95%).
  • Part D: To a suspension of the acid of part C (1.95 g, 3.64 mmol) in N,N-dimethylformamide (15 mL) was added 1-hydroxybenzotriazole (0.596 g, 4.37 mmol), N-methylmorpholine (1.19 mL, 10.92 mmol), 0-(tetrahydropuranyl) hydroxylamine (1.28 g, 10.92 mmol) and 1-3-[(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.977 g, 5.10 mmol). The resulting mixture was stirred at ambient temperature for 16 hours then concentrated in vacuo. The residue was partitioned between H[0742] 2O and ethyl acetate. The combined organic layers were washed with H2O, saturated NaHCO3, saturated NaCl and dried over Na2SO4. Chromatography (on silica, methanol/ethyl acetate) provided the protected hydroxamate as a pale-yellow foam (1.90 g, 83%).
  • Part E: To the protected hydroxamate of part D (1.89 g, 3.00 mmol) was added 4N HCl in dioxane (7.50 mL, 30.0 mmol) and methanol (1.22 mL, 30.0 mmol). The resulting mixture was stirred at ambient temperature for 2 hours, then diethyl ether (5 mL) was added and the precipitate was collected by filtration to provide the title compound as a fine white solid (1.56 g, 89%). MS MH[0743] + calculated for C26H25O6N2S1F3: 551, found 551.
    • EXAMPLE 230 Preparation of N-hydroxy-1-(2-hydroxyethyl)-4-[4-(4-trifluoro-methoxyphenoxy)phenyl]sulfonyl]-4-piperidinecarboxamide, hydrochloride
  • [0744]
    Figure US20040235818A1-20041125-C04000
  • Part A: Ethyl 4-(4-fluorophenylsulfonyl]-4-piperidinecarboxylate, hydrochloride (3.95 g, 11.3 mmol) Preparative Example II, powdered potassium carbonate (3.45 g, 25 mmol), and N,N-dimethylformamide (11.3 mL) were combined. 2-(2-Bromoethoxy)tetrahydro-2H-pyran (1.85 mL, 12 mmol) was added and the mixture was stirred for 48 hours at ambient temperature. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (100 mL, then 50 mL). The combined organic layers were dried over magnesium sulfate, concentrated, and chromatographed to afford the desired tetrahydropyranyl ether as an oil (4.44 g, 88%) [0745]
  • Part B: The tetrahydropyranyl ether from Part A was stirred at 110 degrees Celsius for 20 hours in the presence of powdered potassium carbonate (2.07 g, 15 mmol), 4-(trifluoromethoxy)phenol (2.67 mL, 15 mmol), and N,N-dimethyformamide (5 mL). The mixture was diluted with saturated sodium bicarbonate (50 mL) and was extracted with ethyl acetate (150, then 50 mL). The combined organic layers were dried over magnesium sulfate, concentrated, and chromatographed to afford the desired aryl ether as an oil (5.72 g, quantitative). [0746]
  • Part C: The aryl ether from Part C (1.28 g, 2.1 mmol) was refluxed in the presence of potassium hydroxide (954 mg, 16.8 mmol), ethanol (9 mL), and water (3 mL). After 2 hours, the reaction vessel was cooled to zero degrees Celsius. Concentrated hydrochloric acid was added drop-wise to adjust the pH to 4.0. The acidified reaction was concentrated, azeotroped with acetonitrile, and dried in vacuo, affording the crude carboxylic acid, which was used directly in Part D. [0747]
  • Part D: The carboxylic acid from Part C was converted to O-tetrahydropyranyl hydroxamate using O-tetrahydropyranyl hydroxylamine (351 mg, 3 mmol), N-methylmorpholine (0.5 mL), N-hydroxybenzotriazole (405 mg, 3 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (573 mg, 3 mmol) in N,N-dimethylformamide (9 mL). The tetrahydropyranyl hydroxamate (855 mg, 60%) was obtained as an oil. [0748]
  • Part E: The tetrahydropyranyl hydroxamate (855 mg, 1.26 mmol) was dissolved in absolute methanol (10 mL). Acetyl chloride (0.78 mL, 11 mmol) was added over 2-3 minutes. After 4 hours both tetrahydropyranyl groups had been cleaved. The reaction was concentrated, azeotroped with chloroform/acetonitrile, and dried in vacuo affording the title compound as a white foam (676 mg, 98%). MS (EI) MH[0749] + calculated for C21H23F3N2O7S: 505, found 505.
    • EXAMPLE 231 Preparation of N-hydroxy-4-[[4-[4-[(trifluoromethyl)thio]phenoxy]phenyl]-sulfonyl]-4-piperidinecarboxamide, monohydrochloride
  • [0750]
    Figure US20040235818A1-20041125-C04001
  • Part A: To a solution of the compound of example N-tert-butoxycarbonyl-ethyl 4-(4-fluorophenylsulfonyl)-4-piperidinecarboxylate, hydrochloride of Preparative Example II (1.50 g, 3.61 mmol) in N,N-dimethylformamide (10 mL) was added cesium carbonate (2.94 g, 9.03 mmol) and (4-trifluoromethylthio) phenol (1.05 g, 5.41 mmol) and the solution was heated to 100 degrees Celsius for 24 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and dried over sodium sulfate. Filtration through silica gel (ethyl acetate) provided the phenoxyphenol compound as an oil (2.35 g, quantitative yield). MS(CI) MH[0751] + calculated for C26H30NO7S2F3: 590, found 590.
  • Part B: To a solution of phenoxyphenol compound of part A (2.35 g, <3.61 mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) was added sodium hydroxide (1.44 g, 36.1 mmol) in water (5 mL). The solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated under a stream of nitrogen to remove the solvents and the residue was dissolved in water and acidified to pH=1 with 10% hydrochloric acid. The solution was extracted with ethyl acetate and washed with saturated sodium chloride and dried over magnesium sulfate. Concentration in vacuo provided the carboxylic acid as an oil (2.0 g, quantitative yield). [0752]
  • Part C: To a solution of the carboxylic acid of part B (2.0 g, <3.61 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (586 mg, 4.33 mmol), 4-methylmorpholine (1.19 mL, 10.8 mmol) and O-tetrahydropyranyl hydroxylamine (634 mg, 5.41 mmol) and the solution was stirred for 30 minutes. The 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (969 mg, 5.05 mmol) was added and the solution was stirred for seven days. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the protected hydroxamate as a clear, colorless oil (1.07 g, 45% yield). MS(CI) MNa[0753] + calculated for C29H35N2O8S2F3: 683, found 683.
  • Part D: To a solution of the protected hydroxamate of part C (1.05 g, 1.60 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1.5 hours. The solution was diluted with ethyl ether and the resulting white precipitate was collected by vacuum filtration to provide the title compound as a white solid (330 mg, 40% yield). MS(CI) MH+calculated for C[0754] 19H19N2O5S2F3: 477, found 477. HRMS calculated for C19H19N2O5S2F3: 477.0766, found 477.0766. Analytical calculation for C19H19N2O5S2 HCl: C, 44.49; H, 3.93; N, 5.46; Cl, 6.91. Found: C, 44.51; H, 3.90; N, 5.38; Cl, 6.95.
    • EXAMPLE 232 Preparation of 1-[4-[[1-cyclopropyl-4-[(hydroxyamino)carbonyl]-4-piperidinyl] sulfonyl]phenyl]-N-methyl-N-(phenylmethyl)-4-piperidinecarboxamide, monohydrochloride
  • [0755]
    Figure US20040235818A1-20041125-C04002
  • Part A: To a solution of ethyl N-cyclopropyl-4-(4-fluorophenylsulfonyl]-4-piperidinecarboxylate (Preparative Example VI, Part A) (2.0 g, 5.11 mmol) in dimethylacetamide (10 mL) was added methyl isonipectotate (1.03 mL, 7.66 mmol) and cesium carbonate (4.16 g, 12.78 mmol) and was heated to one hundred ten degrees Celsius for 18 hours. The solution was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an oil (1.81 g, 74%). MS(CI) MH[0756] + calculated for C24H34N2O6S: 479, found 479.
  • Part B: To a solution of the phenylamine of part A (1.79 g, 3.74 mmol) in tetrahydrofuran (20 mL) was added potassium trimethylsilanoate (960 mg, 7.49 mmol) and the resulting solution was stirred for 18 hours at ambient temperature. The solution was concentrated in vacuo and the residue was dissolved into water. The solution was acidified with 3N hydrochloric acid to pH=3. The resulting precipitate was collected and washed with ethyl ether to provide the acid as a light yellow solid (1.09 g, 63%). MS(CI) MH[0757] + calculated for C23H32N2O6S: 465, found 465.
  • Part C: To a solution of the acid of part B (500 mg, 1.08 mmol) in dichloromethane (10 mL) was added 1-hydroxybenzotriazole hydrate (160 mg, 1.19 mmol), triethylamine (0.15 mL, 1.19 mmol) and N-benzylmethylamine (0.33 mL, 2.38 mmol). After thirty minutes the 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added and the solution was stirred for 20 hours at ambient temperature. The solution was diluted with ethyl acetate and washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate) provided the amide as a white solid (480 mg, 78%). MS(CI) MH[0758] + calculated for C31H41N3O5S: 568, found 568.
  • Part D: To a solution of the amide of part C (400 mg, 0.71 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added sodium hydroxide (282 mg, 7.1 mmol) in water (3 mL). The solution was heated to sixty degrees Celsius for 24 hours. The solution was concentrated under a stream of nitrogen and the residue was diluted with water and acidified with 3N hydrochloric acid to pH=2. The solution was concentrated to provide the acid as a crude white solid which is used in the next step without further purification. MS(CI) MH[0759] + calculated for C29H37N5O5S: 540, found 540.
  • Part E: To a solution of the crude acid of part D (<0.71 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (115 mg, 0.85 mmol), 4-methylmorpholine (0.39 mL) and O-tetrahydropyranyl hydroxylamine (124 mg, 1.06 mmol). After thirty minutes 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (190 mg, 0.99 mmol) was added and the solution was stirred for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate) provided the protected hydroxamate as an oil (184 mg, 41%). MS(CI) MH[0760] + calculated for C34H46N4O6S: 0.639, found 639.
  • Part F: To a solution of the protected hydroxamate of part E (180 mg, 0.28 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for one hour. Trituration (ethyl ether) and vacuum filtration provided the title compound as a white solid (96.5 mg, 58%). MS(CI) MH[0761] + calculated for C29H38N4O5S: 555, found 555. HRMS calc. 555.2641, found 555.2644.
    • EXAMPLE 233 Preparation of 4-[[4-[4-[(3,5-dimethyl-1-piperidinyl)carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidinecarboxamide, monohydrochloride
  • [0762]
    Figure US20040235818A1-20041125-C04003
  • Part A: To a solution of isonipecotic acid (5.8 g, 44.9 mmol) in water (200 mL) was added sodium carbonate (4.62 g, 44.9 mmol) followed by the drop-wise addition of di-tert-butyl-dicarbonate (10.1 g, 46.3 mmol) in dioxane (40 mL). After four hours the solvent was concentrated in vacuo and the solution was extracted with ethyl ether. The aqueous layer was acidified with 3N hydrochloric acid to pH=2. The solution was extracted with ethyl ether and the organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Concentration in vacuo provided N-Boc-isonipecotic acid as a white solid (9.34 g, 90%). [0763]
  • Part B: To a solution of the N-Boc-isonipecotic acid of part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg, 4.45 mmol), 1-hydroxybenzotriazole hydrate (620 mg, 4.59 mmol) 3,5-dimethylpiperdine (0.67 mL, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 21 hours. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated aqueous sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a clear colorless oil (1.21 g, 89%). [0764]
  • Part C: To a solution of the amide of part B (1.20 g, 3.84 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII, [0765]
  • Part A (956 mg, 2.56 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.92 g, 8.96 mmol) was added and the solution was heated to one hundred degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an oil (1.53 g, 68%). MS(CI) MH[0766] + calculated for C30H47N3O6S: 578, found 578.
  • Part D: To a solution of the phenylamine of part C (1.5 g, 2.6 mmol) in ethanol (9 mL) and tetrahydrofuran (9 mL) was added sodium hydroxide (1.02 g, 26 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=3 with 3N hydrochloric acid. Vacuum filtration provided the acid as a beige solid (500 mg, 33%). MS(CI) MH+calculated for C[0767] 28H43N3O6S: 550, found 550.
  • Part E: To a solution of the acid of part D (492 mg, 0.84 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (136 mg, 1.01 mmol), 4-methylmorpholine (0.46 mL, 4.20 mmol), and O-tetrahydropyranyl hydroxylamine (147 mg, 1.26 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (225 mg, 1.18 mmol) was added and the solution was stirred for 72 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the protected hydroxamate as an oil (524 mg, 96%). MS(CI) MH[0768] + calculated for C33H51N4O7S: 649, found 649.
  • Part F: To a solution of the protected hydroxamate of part E (514 mg, 0.79 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1.5 hours. The solution was concentrated in vacuo and trituration (ethyl ether) provided the title compound as a white solid (360 mg, 76%). MS(CI) MH+calculated for C[0769] 28H44N4O6S: 565, found 565. HRMS calculated for C28H44N4O6S: 565.3060, found 565.3070. Analytical calculation for C28H44N4O6S 2 HCl:2H2O: C, 49.92; H, 7.48; N, 8.32; S, 4.76; Cl, 10.52. Found: C, 49.41; H, 7.55; N, 7.85; S, 4.53; Cl, 10.78.
    • EXAMPLE 234 Preparation of 4-[[4-[4-[(3,5-dimethyl-1-piperidinyl)carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidinecarboxamide
  • [0770]
    Figure US20040235818A1-20041125-C04004
  • Part A: A solution of the hydroxamate of Example 233, part F (50 mg, 0.08 mmol) in water (2 mL) was neutralized with saturated sodium bicarbonate. The aqueous solution was extracted with ethyl acetate. Concentration in vacuo provided the hydroxamate free base as an orange solid (35 mg, 75%). [0771]
    • EXAMPLE 235 Preparation of 1-[4-[[4[(hydroxyamino)-carbonyl]-1-(2-methoxyethyl)-4-piperidinyl]sulfonyl]phenyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-4-piperidine-carboxamide, dihydrochloride
  • [0772]
    Figure US20040235818A1-20041125-C04005
  • Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg, 4.45 mmol), 1-hydroxy-benzotriazole hydrate (620 mg, 4.59 mmol), 2-(2-methylaminoethyl)pyridine (0.69 mL, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 21 hours. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a clear colorless oil (1.03 g, 68%). MS(CI) MH[0773] + calculated for C19H29N3O3: 348, found 348.
  • Part B: To a solution of the amide of part A (1.0 g, 2.88 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII, Part A (716 mg, 1.92 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.20 g, 6.72 mmol) was added and the solution was heated to one hundred degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as a yellow oil (1.20 g, quantitative yield). MS(CI) MH[0774] + calculated for C31H44N4O6S: 601, found 601.
  • Part C: To a solution of the phenylamine of part B (1.20 g, 2.00 mmol) in ethanol (8 mL) and tetrahydrofuran (8 mL) was added sodium hydroxide (800 mg, 20 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid. Concentration in vacuo provided the crude acid as an oil. MS(CI) MH[0775] + calculated for C29H40N4O6S: 573, found 573.
  • Part D: To a solution of the acid of part C (<2.0 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (324 mg, 2.04 mmol), 4-methylmorpholine (1.1 mL, 10.0 mmol), and O-tetrahydropyranyl hydroxylamine (351 mg, 3.00 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (536 mg, 2.80 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Reverse phase chromatography (on silica, acetonitrile/water) provided the protected hydroxamate as an oil (170 mg, 13% yield over two steps). MS(CI) MH[0776] + calculated for C34H49N5O7S: 672, found 672.
  • Part E: To a solution of the protected hydroxamate of part D (160 mg, 0.24 mmol) in dioxane (7 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 30 minutes. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (90 mg, 57%). MS(CI) MH+calculated for C[0777] 29H37N5O6S: 588, found 588. HRMS calculated for C29H37N5O6S: 558.2856, found 588.2857.
    • EXAMPLE 236 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-[(phenylamino)-carbonyl]-1-piperidinyl]phenyl]-sulfonyl]-4-piperidinecarboxamide monohydrochloride)
  • [0778]
    Figure US20040235818A1-20041125-C04006
  • Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, part A (1.0 g, 4.37 mmol) in dichloromethane (4 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (752 mg, 4.28 mmol). The solution was cooled to zero degrees Celsius and 4-methylmorpholine (0.47 mL, 4.28 mmol) was added. After two hours aniline (0.39 mL, 4.28 mmol) was added and the solution was stirred for 20 hours at ambient temperature. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a pink solid (1.48 g, quantitative yield). [0779]
  • Part B: To a solution of the amide of part A (1.48 g, 4.28 mmol) in dichloromethane (5 mL) was added trifluoroacetic (5 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII, Part A (1.06 mg, 2.85 mmol) in dimethylacetamide (10 mL). Cesium carbonate (3.25 g, 9.97 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as a yellow oil (1.74 g, quantitative yield). MS(CI) MH[0780] + calculated for C29H39N3O6S: 558, found 558.
  • Part C: To a solution of the phenylamine of part B (1.74 g, 2.85 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (1.14 g, 28.5 mmol) in water (7 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid producing a solid. Vacuum filtration provided the acid as a beige solid (1.62 g, quantitative yield). MS(CI) MH[0781] + calculated for C27H35N3O6S: 530, found 530.
  • Part D: To a solution of the acid of part C (1.60 g, 2.83 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (458 mg, 3.40 mmol), 4-methylmorpholine (1.56 mL, 14.2 mmol), and O-tetrahydropyranyl hydroxylamine (497 mg, 4.24 mmol). After one hour, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (759 mg, 3.96 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as a yellow oil (790 mg, 44%). MS(CI) MH[0782] + calculated for C32H44N4O7S: 629, found 629.
  • Part E: To a solution of the protected hydroxamate of part D (780 mg, 1.24 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (580 mg, 80%). MS(CI) MH+calculated for C[0783] 27H36N4O6S: 545, found 545. HRMS calculated for C27H36N4O6S: 545.2434, found 545.2429.
    • EXAMPLE 237 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-[[(3-phenyl-propyl)amino]carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-4-piperidine-carboxamide, monohydrochloride
  • [0784]
    Figure US20040235818A1-20041125-C04007
  • Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg, 4.45 mmol), 1-hydroxybenzotriazole hydrate (620 mg, 4.59 mmol), 3-phenyl-1-propylamine (0.72 mL, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 18 hours. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a yellow oil (1.4 g, 93%). [0785]
  • Part B: To a solution of the amide of part A (1.4 g, 4.05 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. The resulting solid was collected by vacuum filtration and washed with ethyl ether. The solid was added to a solution of the compound of Preparative Example VII, Part A (1.01 mg, 2.70 mmol) in dimethylacetamide (10 mL). Cesium carbonate (3.07 g, 9.45 mmol) was added and the solution was heated to one hundred degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an orange oil (1.71 g, quantitative yield). MS(CI) MH[0786] + calculated for C32H45N3O6S: 600, found 600.
  • Part C: To a solution of the phenylamine of part B (1.70 g, 2.70 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (1.08 g, 27.0 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid producing a solid. Vacuum filtration provided the acid as a white solid (1.15 g, 75%). MS(CI) MH[0787] + calculated for C30H41N3O6S: 572, found 572.
  • Part D: To a solution of the acid of part C (1.02 g, 1.68 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (272 mg, 2.02 mmol), 4-methylmorpholine (0.92 mL, 8.4 mmol), and O-tetrahydropyranyl hydroxylamine (295 mg, 2.52 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (451 mg, 2.35 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as an oil (490 mg, 41%). MS(CI) MH[0788] + calculated for C35H50N4O7S: 671, found 671.
  • Part E: To a solution of the protected hydroxamate of part D (480 mg, 0.72 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for one hour. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (400 mg, 90%). MS(CI) MH[0789] + calculated for C30H42N4O6S: 587, found 587. Analytical calculation for C30H42N4O6S 2HCl :2H2O: C, 51.79; H, 6.95; N, 8.05; S, 4.61; Cl, 10.19. Found: C,51.34; H, 6.72; N, 7.82; S, 4.59; Cl, 10.92.
    • EXAMPLE 238 Preparation of rel-4-[[4-[4-[[(3R,5R)-3,5-dimethyl-1-piperidinyl]carbonyl]-1-piperidinyl]phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide, monohydrochloride
  • [0790]
    Figure US20040235818A1-20041125-C04008
  • Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, Part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg, 4.45 mmol), 1-hydroxybenzotriazole hydrate (620 mg, 4.59 mmol) 3,5-dimethylpiperdine (0.67 mL, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 21 hours. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a clear colorless oil (1.4 g, quantitative yield). [0791]
  • Part B: To a solution of the amide of part A (1.4 g, 4.49 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided a solid that was added directly to a solution of the compound of Preparative Example II, Part D, (1.24 mg, 2.99 mmol) in dimethylacetamide (10 mL). Cesium carbonate (3.42 g, 10.5 mmol) was added and the solution was heated to one hundred degrees Celsius for 20 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as a yellow solid (1.90 g, quantitative yield). MS(CI) MH[0792] + calculated for C32H49N3O7S: 620, found 620.
  • Part C: To a solution of the phenylamine of part B (1.9 g, 3.0 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (1.2 g, 30 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid. The solution was extracted with ethyl acetate and washed with 1M hydrochloric acid and saturated sodium chloride and dried over magnesium sulfate. Concentration in vacuo provided the acid as a yellow oil (1.9 g, quantitative yield). MS(CI) MH[0793] + calculated for C30H45N3O7S: 592, found 592.
  • Part D: To a solution of the acid of part C (1.87 g, 3.00 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (486 mg, 3.6 mmol), 4-methylmorpholine (1.65 mL, 15 mmol), and O-tetrahydropyranyl hydroxylamine (526 mg, 4.5 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (805 mg, 4.2 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the protected hydroxamate as an oil (1.63 g, 79%). [0794]
  • Part E: To a solution of the protected hydroxamate of part D (1.61 g, 2.33 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 45 minutes. The solution was concentrated in vacuo and trituration (ethyl ether) a white solid. Reverse phase chromatography (on silica, acetonitrile/water(hydrochloric acid)) produced fractions A, B, C and D. Concentration in vacuo of fraction A provided the title compound as a white solid (59 mg). MS(CI) MH[0795] + calculated for C25H38N4O5S: 507, found 507.
    • EXAMPLE 239 Preparation of rel-1,1-dimethylethyl 4-[[4-[4-[[(3R,5R)-3,5-dimethyl-1-piperidinyl]carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-4-[(hydroxyamino)-carbonyl]-1-piperidinecarboxylate
  • [0796]
    Figure US20040235818A1-20041125-C04009
  • Part A: From the reverse phase chromatography of Example 238, Part E, fraction C was concentrated in vacuo to provide the title compound as a white solid (49 mg). MS(CI) MH[0797] + calculated for C30H46N4O7S: 607, found 607.
    • EXAMPLE 240 Preparation of rel-4-[[4-[4-[[(3R,5S)-3,5-dimethyl-1-piperidinyl]carbonyl]-1-piperidinyl]phenyl]sulfonyl]-N-hydroxy-4-piperidinecarboxamide, monohydrochloride
  • [0798]
    Figure US20040235818A1-20041125-C04010
  • Part A: From the reverse phase chromatography of Example 238, Part E, fraction B was concentrated in vacuo to provide the title compound as a white solid (198 mg). MS(CI) MH[0799] + calculated for C25H38N4O5S: 507, found 507.
    • EXAMPLE 241 Preparation of rel-1,1-dimethylethyl 4-[[4-[4-[[(3R,5S)-3,5-dimethyl-1-piperidinyl]carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-4-[(hydroxyamino)-carbonyl]-1-piperidinecarboxylate
  • [0800]
    Figure US20040235818A1-20041125-C04011
  • Part A: From the reverse phase chromatography of Example 238, Part E, fraction D was concentrated in vacuo to provide the title compound as a white solid (242 mg). MS(CI) MH+calculated for C[0801] 30H46N4O7S: 607, found 607.
    • EXAMPLE 242 Preparation of 4-[[4-[4-[[(2,3-dihydro-1H-inden-2-yl)amino]carbonyl]-1-piperidinyl]phenyl]sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidine-carboxamide, monohydrochloride
  • [0802]
    Figure US20040235818A1-20041125-C04012
  • Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, Part A (1.0 g, 4.37 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (853 mg, 4.45 mmol), 1-hydroxybenzotriazole hydrate (620 mg, 4.59 mmol) 2-aminoindane hydrochloride (853 mg, 5.03 mmol) and diisopropylethylamine (1.67 mL, 9.61 mmol) and was stirred for 21 hours. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a white solid (1.35 g, 90%). [0803]
  • Part B: To a solution of the amide of part A (1.35 g, 3.92 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided a solid which was added directly to a solution of the title compound of Preparative Example VII, Part A, (976 mg, 2.61 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.97 g, 9.14 mmol) was added and the solution was heated to one hundred degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an orange oil (1.65 g, quantitative yield). MS(CI) MH[0804] + calculated for C32H43N3O6S: 598, found 598.
  • Part C: To a solution of the phenylamine of part B (1.60 g, 2.61 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (1.04 g, 26 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 18 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=3 with 3N hydrochloric acid. Vacuum filtration provided the acid as a beige solid (1.06 g, 71%). MS(CI) MH[0805] + calculated for C30H39N3O6S: 570, found 570.
  • Part D: To a solution of the acid of part E (1.0 g, 1.65 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (267 mg, 1.98 mmol), 4-methylmorpholine (0.91 mL, 8.25 mmol), and O-tetrahydropyranyl hydroxylamine (289 mg, 2.48 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (443 mg, 2.31 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate, methanol) provided the protected hydroxamate as an oil (575 mg, 52%). MS(CI) MH[0806] + calculated for C35H48N4O7S: 669, found 669.
  • Part E: To a solution of the protected hydroxamate of part D (565 mg, 0.85 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1.5 hours. The solution was concentrated in vacuo and trituration (ethyl ether) provided the title compound as a white solid (450 mg, 86%). MS(CI) MH[0807] + calculated for C30H40N4O6S: 585, found 585. HRMS calculated for C30H40N4O6S: 585.2747, found 585.2776. Analytical calculation for C30H40N4O6S 2HCl :2H2O: C, 51.94; H, 6.68; N, 8.08; S, 4.62; Cl, 10.22. Found: C, 51.66; H, 6.25; N, 7.80; S, 4.73; Cl, 10.33.
    • EXAMPLE 243 Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-[(phenylamino)carbonyl]-1-piperidinyl]phenyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride
  • [0808]
    Figure US20040235818A1-20041125-C04013
  • Part A: To a solution of the product of Example 232, Part B (562 mg, 1.12 mmol) in dichloromethane (3 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (164 mg, 0.93 mmol) and 4-methylmorpholine (0.21 mL, 1.87 mmol). The solution was stirred for 45 minutes and aniline (0.085 mL, 0.93 mmol) was added. The solution was stirred for 72 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as an oil (434 mg, 86%). MS(CI) MH+calculated for C[0809] 29H37N3O5S: 540, found 540.
  • Part B: To a solution of the amide of part A (425 mg, 0.79 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added sodium hydroxide (315 mg, 7.89 mmol) in water (2 mL) and the solution was heated to sixty degrees Celsius for 18 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid producing a solid. Vacuum filtration provided the acid as a beige solid (261 mg, 60%). MS(CI) MH[0810] + calculated for C27H33N3O5S: 512, found 512.
  • Part C: To a solution of the acid of part B (245 mg, 0.45 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (73 mg, 0.54 mmol), 4-methylmorpholine (0.25 mL, 2.25 mmol), and O-tetrahydropyranyl hydroxylamine (79 mg, 0.68 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (121 mg, 0.63 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate) provided the protected hydroxamate as a yellow oil (242 mg, 88%). MS(CI) MH[0811] + calculated for C32H42N4O6S: 611, found 611.
  • Part D: To a solution of the protected hydroxamate of part C (235 mg, 0.38 mmol) in dioxane (5 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (114 mg, 53%). MS(CI) MH[0812] + calculated for C27H34N4O5S: 527, found 527. HRMS calculated for C27H34N4O5S: 527.2328, found 527.2339.
    • EXAMPLE 244 Preparation of 1-[4-[[4-[(hydroxyamino)-carbonyl]-1-(2-methoxyethyl)-4-piperidinyl]-sulfonyl]phenyl]-N-methyl-N-phenyl-4-piperidinecarboxamide, monohydrate
  • [0813]
    Figure US20040235818A1-20041125-C04014
  • Part A: To a solution of the N-Boc-isonipecotic acid of Example 233, Part A (500 mg, 2.18 mmol) in dichloromethane (2 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (319 mg, 1.82 mmol). The solution was cooled to zero degrees Celsius and 4-methylmorpholine (0.20 mL, 1.82 mmol) was added. After two hours, N-methylaniline (0.20 mL, 1.82 mmol) was added and the solution was stirred for 20 hours at ambient temperature. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a pink solid (445 mg, 77%). [0814]
  • Part B: To a solution of the amide of part A (440 g, 1.38 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII, Part A (344 mg, 0.92 mmol) in dimethylacetamide (10 mL). Cesium carbonate (1.05 g, 3.22 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as a yellow oil (440 mg, 84%). [0815]
  • Part C: To a solution of the phenylamine of part B (440 mg, 0.77 mmol) in ethanol (7 mL) and tetrahydrofuran (7 mL) was added sodium hydroxide (308 mg, 7.7 mmol) in water (3 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid producing a solid. Vacuum filtration provided the acid as a yellow solid and carried on to the next step without additional purification. [0816]
  • Part D: To a solution of the acid of part C (<0.77 mmol) in N,N-dimethylformamide (10 mL) was added-1-hydroxybenzotriazole hydrate (125 mg, 0.92 mmol), 4-methylmorpholine (0.43 mL, 3.85 mmol), and O-tetrahydropyranyl hydroxylamine (135 mg, 1.16 mmol). After one hour, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (207 mg, 1.08 mmol) was added and the solution was stirred for 24 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as a yellow oil (150 mg, 30%). MS(CI) MH[0817] + calculated for C33H46N4O7S: 643, found 643.
  • Part E: To a solution of the protected hydroxamate of part D (150 mg, 0.23 mmol) in dioxane (2 mL) was added 4M hydrochloric acid in dioxane (3 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a yellow solid (75 mg, 55%). MS(CI) MH[0818] + calculated for C28H38N4O6S: 559, found 559. HRMS calculated for C28H38N4O6S: 559.2590, found 559.2613.
    • EXAMPLE 245 Preparation of 1-acetyl-N-hydroxy-4-[[4-[4-[(phenylamino)carbonyl]-1-piperidinyl]phenyl]sulfonyl]-4-piperidinecarboxamide
  • [0819]
    Figure US20040235818A1-20041125-C04015
  • Part A: To a solution of the N-Boc-amide of Preparative Example III, Part B, (6.9 g, 11.4 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the product of Preparative Example II, Part D (3.15 g, 7.6 mmol) in dimethylacetamide (30 mL). Cesium carbonate (8.65 g, 26.6 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as a tan solid (3.92 g, 86%). [0820]
  • Part B: To a solution of the phenylamine of part A (3.90 g, 6.51 mmol) in methanol (20 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 3 hours. Concentration in vacuo followed by trituration (ethyl ether) provided the amine hydrochloride salt as a yellow solid (3.25 g, 93%). [0821]
  • Part C: To a solution of the amine hydrochloride salt of part B (500 mg, 0.93 mmol) in dichloromethane (5 mL) was added triethylamine (0.40 mL, 2.79 mmol) followed by acetyl chloride (0.07 mL, 1.02 mmol). The solution was stirred for 3 hours. The solution was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the acylated compound as an oil (390 mg, 77%). MS(CI) MH[0822] + calculated for C28H35N3O6S: 542, found 542.
  • Part D: To a solution of the acylated compound of part C (390 mg, 0.72 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added sodium hydroxide (58 mg, 1.44 mmol) in water (1 mL) and the solution was heated to sixty degrees Celsius for 3 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid. The solution was extracted with ethyl acetate and washed with water and saturated sodium chloride and dried over magnesium sulfate. Concentration in vacuo provided the acid as a white solid (137 mg, 37%). MS(CI) MH[0823] + calculated for C26H31N3O6S: 514, found 514.
  • Part E: To a solution of the acid of part D (137 mg, 0.27 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added 1-hydroxybenzotriazole hydrate (44 mg, 0.32 mmol), 4-methylmorpholine (0.10 mL, 1.08 mmol), and O-tetrahydropyranyl hydroxylamine (47 mg, 0.41 mmol). After one hour 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (72 mg, 0.38 mmol) was added and the solution was stirred for 24 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as a white solid (140 mg, 85%). MS(CI) MH[0824] + calculated for C31H40N4O7S: 613, found 613.
  • Part F: To a solution of the protected hydroxamate of part E (130 mg, 0.21 mmol) in dioxane (2 mL) was added 4M hydrochloric acid in dioxane (3 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a yellow solid (51 mg, 48%). MS(CI) MH[0825] + calculated for C26H32N4O6S: 528, found 528.
    • EXAMPLE 246 Preparation of 4-[[4-[4-[(2,3-dihydro-1H-indol-1-yl)carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-N-hydroxy-1-(2-methoxyethyl)-4-piperidinecarboxamide, monohydrate
  • [0826]
    Figure US20040235818A1-20041125-C04016
  • Part A: To a solution of the N-Boc-isonipecotic acid of Preparative Example I, Part B (750 mg, 3.27 mmol) in dichloromethane (3 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (564 mg, 3.21 mmol). The solution was cooled to zero degrees Celsius and 4-methylmorpholine (0.35 mL, 3.21 mmol) was added. After two hours, indoline (0.36 mL, 3.21 mmol) was added and the solution was stirred for 22 hours at ambient temperature. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a pink solid (940 mg, 89%). [0827]
  • Part B: To a solution of the amide of part A (935 g, 2.83 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the compound of Preparative Example VII, Part A, (705 mg, 1.89 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.15 g, 6.61 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an orange oil (893 mg, 81%). MS(CI) MH[0828] + calculated for C31H41N3O6S: 584, found 584.
  • Part C: To a solution of the phenylamine of part B (885 g, 1.52 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (607 mg, 15.2 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid producing a solid. Vacuum filtration provided the acid as a beige solid (475 g, 53%). MS(CI) MH[0829] + calculated for C29H37N3O6S: 556, found 556.
  • Part D: To a solution of the acid of part C (465 g, 0.79 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (128 mg, 0.95 mmol), 4-methylmorpholine (0.43 mL, 3.95 mmol), and O-tetrahydropyranyl hydroxylamine (139 mg, 1.18 mmol). After one hour, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (212 mg, 1.10 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as a yellow oil (305 mg, 60%). MS(CI) MH[0830] + calculated for C34H46N4O7S: 655, found 655.
  • Part E: To a solution of the protected hydroxamate of part D (300 mg, 0.46 mmol) in dioxane (5 mL) was added 4M hydrochloric acid in dioxane (5 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (260 mg, 94%). MS(CI) MH[0831] +calculated for C29H34N4O6S: 571, found 571.
    • EXAMPLE 247 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-[[(phenylmethyl) amino]carbonyl]-1-piperidinyl]phenyl]-sulfonyl]-4-piperidinecarboxamide, monohydrochloride
  • [0832]
    Figure US20040235818A1-20041125-C04017
  • Part A: To a solution of the N-Boc-isonipecotic acid of Preparative Example I, Part B, (750 mg, 3.27 mmol) in dichloromethane (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (640 mg, 3.34 mmol), 1-hydroxybenzotriazole hydrate (463 mg, 3.43 mmol) and diisopropylethylamine (1.25 mL, 7.19 mmol). After thirty minutes, benzylamine (0.41 mL, 3.76 mmol) was added and the solution was stirred for 22 hours at ambient temperature. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as an oil (320 mg, 31%). [0833]
  • Part B: To a solution of the amide of part A (320 g, 1.0 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the product of Preparative Example II, Part D, (288 mg, 0.77 mmol) in dimethylacetamide (10 mL). Cesium carbonate (878 g, 2.7 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an orange oil (367 mg, 83%). MS(CI) MH[0834] + calculated for C30H41N3O6S: 572, found 572.
  • Part C: To a solution of the phenylamine of part B (367 g, 0.64 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was added sodium hydroxide (257 mg, 6.4 mmol) in water (2 mL) and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid producing a solid. Vacuum filtration provided the acid as a beige solid (415 g, quantitative yield). MS(CI) MH[0835] +calculated for C28H37N3O6S: 544, found 544.
  • Part D: To a solution of the acid of part C (415 g, <0.64 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (104 mg, 0.77 mmol), 4-methylmorpholine (0.35 mL, 3.20 mmol), and O-tetrahydropyranyl hydroxylamine (112 mg, 0.96 mmol). After one hour, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (172 mg, 0.90 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as a yellow oil (9 mg, 2%). MS(CI) MH[0836] + calculated for C33H46N4O7S: 643, found 643.
  • Part E: To a solution of the protected hydroxamate of part D (9 mg, 0.014 mmol) in dioxane (1 mL) was added 4M hydrochloric acid in dioxane (1 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (2.5 mg, 30%). MS(CI) MH[0837] + calculated for C28H34N4O6S: 559, found 559.
    • EXAMPLE 248 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-[[[4-(trifluoromethoxy)-phenyl]amino]carbonyl]-1-piperidinyl]-phenyl]sulfonyl]-4-piperidine-carboxamide, monohydrochloride
  • [0838]
    Figure US20040235818A1-20041125-C04018
  • Part A: To a solution of the N-Boc-isonipecotic acid of Preparative Example I, Part B, (750 mg, 3.27 mmol) in dichloromethane (3 mL) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (564 mg, 3.21 mmol). The solution was cooled to zero degrees Celsius and 4-methylmorpholine (0.35 mL, 3.21 mmol) was added. After two hours, 4-(trifluoromethoxy)aniline (0.43 mL, 3.21 mmol) was added and the solution was stirred for 22 hours at ambient temperature. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a pink solid (1.16 g, 93%). [0839]
  • Part B: To a solution of the amide of part A (1.16 g, 2.99 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the product of Preparative Example VII, [0840]
  • Part A (743 mg, 1.99 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.26 g, 6.90 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an orange oil (1.38 g, quantitative yield). MS(CI) MH[0841] + calculated for C30H38N3O7SF3: 642, found 642.
  • Part C: To a solution of the phenylamine of part B (1.38 g, 2.00 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (800 mg, 20 mmol) in water (5 mL), and the solution was heated to sixty degrees Celsius for 20 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid producing a solid. Vacuum filtration provided the acid as a beige solid (536 g, 41%). MS(CI) MH[0842] + calculated for C28H34N3O7SF3: 614, found 614.
  • Part D: To a solution of the acid of part C (536 g, 0.83 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (134 mg, 0.99 mmol), 4-methylmorpholine (0.46 mL, 4.15 mmol), and O-tetrahydropyranyl hydroxylamine (145 mg, 1.24 mmol). After one hour 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (223 mg, 1.16 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as a yellow oil (287 mg, 48%). MS(CI) MH[0843] + calculated for C33H43N4O8SF3: 713, found 713.
  • Part E: To a solution of the protected hydroxamate of part D (280 mg, 0.39 mmol) in dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (228 mg, 88%). MS(CI) MH[0844] + calculated for C28H35N4O7SF3: 629, found 629.
    • EXAMPLE 249 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-[[[3-(trifluoro-methoxy)phenyl]amino]carbonyl]-1-piperidinyl]phenyl]sulfonyl]-4-piperidinecarboxamide, monohydrochloride
  • [0845]
    Figure US20040235818A1-20041125-C04019
  • Part A: To a solution of the N-Boc-isonipecotic acid of Preparative Example I, Part B, (750 mg, 3.27 mmol) in dichloromethane (3 mL) was ,added 2-chloro-4,6-dimethoxy-1,3,5-triazine (564 mg, 3.21 mmol). The solution was cooled to zero degrees Celsius and 4-methylmorpholine (0.35 mL, 3.21 mmol) was added. After two hours 3-(trifluoromethoxy)-aniline (0.43 mL, 3.21 mmol) was added and the solution was stirred for 22 hours at ambient temperature. The solution was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the amide as a pink solid (1.20 g, 97%). [0846]
  • Part B: To a solution of the amide of part A (1.20 g, 3.10 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in dioxane (10 mL) and the solution was stirred for 1 hour. Concentration in vacuo provided an oil which was added directly to a solution of the product of Preparative Example VII, Part A, (770 mg, 2.06 mmol) in dimethylacetamide (10 mL). Cesium carbonate (2.34 g, 7.21 mmol) was added and the solution was heated to one hundred ten degrees Celsius for 18 hours. The solution was partitioned between ethyl acetate and water and the organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Concentration in vacuo provided the phenylamine as an orange oil (1.72 g, quantitative yield). MS(CI) MH[0847] + calculated for C30H38N3O7SF3: 642, found 642.
  • Part C: To a solution of the phenylamine of part B (1.72 g, <2.06 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium hydroxide (824 mg, 20.6 mmol) in water (5 mL) and the solution was heated to sixty degrees Celsius for 18 hours. The solution was concentrated and the residue was diluted with water and acidified to pH=1 with 3N hydrochloric acid. Concentration in vacuo provided the acid as a crude brown oil which was used in the next step without additional purification. [0848]
  • Part D: To a solution of the acid of part C (<2.06 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole hydrate (334 mg, 2.47 mmol), 4-methylmorpholine (1.13 mL, 10.3 mmol), and O-tetrahydropyranyl hydroxylamine (361 mg, 3.09 mmol). After one hour, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (553 mg, 2.88 mmol) was added and the solution was stirred for 18 hours at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromatography (on silica, ethyl acetate/methanol) provided the protected hydroxamate as a yellow oil (64 mg, 4% for 2 steps). MS(CI) MH[0849] + calculated for C33H43N4O8SF3: 713, found 713.
  • Part E: To a solution of the protected hydroxamate of part-D (63 mg, 0.089 mmol) in dioxane (5 mL) was added 4M hydrochloric acid in dioxane (5 mL) and the solution was stirred for two hours. The resulting solid was collected by vacuum filtration. Washing with ethyl ether provided the title compound as a white solid (48 mg, 81%). MS(CI) MH[0850] + calculated for C28H35N4O7SF3: 629, found 629.
    • EXAMPLE 250 Preparation of 1-(2-ethoxyethyl)-N-hydroxy-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide monohydrochloride
  • [0851]
    Figure US20040235818A1-20041125-C04020
  • Part A: To a solution of the product of Preparative Example II, Part D, (1.0 g, 2.4 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL) and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the amine trifluoroacetate salt and potassium carbonate (0.99 g, 7.2 mmol) in N,N-dimethylformamide (5 mL) was added 2-bromoethyl ethyl ether (0.33 mL, 2.87 mmol) and the solution was stirred at ambient temperature for 36 hours. Then N,N-dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. Concentration in vacuo provided the ethoxyl ethyl amine as a light yellow gel (0.68 g, 65.4%). [0852]
  • Part B: To a solution of ethoxyl ethyl amine (0.68 g, 1.56 mmol) of part A and powdered potassium carbonate (0.43 g, 3.1 mmol) in N,N-dimethylformamide (5 mL) was added 4-(trifluoromethoxy)phenol (0.4 mL, 3.08 mmol) at ambient temperature and the solution was heated to ninety degrees Celsius for 25 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N sodium hydroxide, water and dried over magnesium sulfate. Chromatography on silica eluting with ethyl acetate/hexane provided the desired trifluoromethoxy phenoxyphenyl sulfone as a light yellow gel (1.0 g, quantitative). [0853]
  • Part C: To a solution of trifluoromethoxy phenoxyphenyl sulfone of Part B (1.0 g, 1.72 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was added sodium hydroxide (0.688 g, 17.2 mmol) in water (4 mL) at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and diluted with water. The aqueous layer was extracted with ether and acidified to pH=2. Vacuum filtration of the white precipitate provided the acid as a white solid (0.94 g, quantitative yield). [0854]
  • Part D: To a solution of the acid of part C (0.94 g, 1.86 mmol), N-methyl morpholine (0.61 mL, 5.55 mmol), 1-hydroxybenzotriazole (0.76 g, 5.59 mmol) and O-tetrahydropyranyl hydroxylamine (0.33 g, 2.7 mmol) in N,N-dimethylformamide (40 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.06 g, 5.59 mmol) and the solution was stirred at ambient temperature for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous Sodium bicarbonate, water and dried over magnesium sulfate. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the tetrahydropyranyl amide as a white foam (0.74 g, 66.1%). [0855]
  • Part E: To a solution of 4N hydrochloric acid (3 mL, 12 mmol)) in dioxane was added a solution of the tetrahydropyranyl amide of part D (0.74 g, 1.2 mmol) in methanol (0.4 ml) and dioxane (1.2 mL) and was stirred at ambient temperature for 3 hours. Filtration of precipitation gave the title compound as white solid (0.217 g, 32.9%). Analytical calculation for C[0856] 22H25N2O7SF3.HCl.0.5H2O: C, 46.85; H, 4.83; N, 4.97; S, 5.69. Found: C, 46.73; H, 4.57; N, 4.82; S, 5.77.
    • EXAMPLE 251 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoro-methoxy)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide monomethane-sulfonate (salt)
  • [0857]
    Figure US20040235818A1-20041125-C04021
  • Part A: To the ethanol solution of the product of Preparative Example VII, Part D, (0.3 g, 0.5 mmol) was added methane sulfonic acid (0.042 mL, 0.65 mmol). After two hours stirring at room temperature the solution was cooled to zero degree Celsius. Filtration of the precipitate gave the title compound as a white crystalline solid (0.105 g, 35%). Analytical calculation for C[0858] 22H25N2O7SF3. CH4O3S. H2O: C, 43.67; H, 4.94; N, 4.43. Found: C, 43.96; H, 4.62; N, 4.47.
    • EXAMPLE 252 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoro-methoxy)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide
  • [0859]
    Figure US20040235818A1-20041125-C04022
  • Part A: The title compound of Preparative Example VII (15 g, 27 mmol) was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution, water, brine and dried over magnesium sulfate. Concentration in vacuo and recrystallization from hot toluene gave the title compound as white crystals (13.14 g, 93.9%). Analytical calculation for C[0860] 22H25N2O7SF3: C, 50.96; H, 4.86; N, 5.40; S, 6.18. Found: C, 51.33; H, 5.11; N, 5.29; S, 6.50.
    • EXAMPLE 253 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(trifluoro-methoxy)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide mono(4-methyl-benzenesulfonate) (salt)
  • [0861]
    Figure US20040235818A1-20041125-C04023
  • Part A: To the ethanol solution of Preparative Example VII (8 g, 13.32 mmol) was added p-toluenesulfonic acid (2.9 g, 15.24 mmol) and the solution was stirred at ambient temperature for 6 hours. Evaporation of the solvent and recrystallization from hot ethanol gave the title compound as white crystals (6.58 g, 71.8%). Analytical calculation for C[0862] 22H25N2O7SF3.C7H8SO3: C, 50.43; H, 4.82; N, 4.06; S, 9.28. Found: C, 50.36; H, 4.95; N, 4.00; S, 9.47.
    • EXAMPLE 254 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide sulfate (2:1) (salt)
  • [0863]
    Figure US20040235818A1-20041125-C04024
  • Part A: To a solution of Preparative Example VII (0.35 g, 0.58 mmol) in ethanol (1.5 mL) was added sulfuric acid (17 ?L, 0.32 mmol) and the solution was stirred at ambient temperature for 6 hours. Evaporation of solvent and recrystallization from hot acetonitrile gave the title compound as a white powder (180 mg, 54.6%). Analytical calculation for C[0864] 22H25N2O7SF3.0.7H2SO4: C, 45.00; H, 4.53; N, 4.77; S, 9.28. Found: C, 44.77; H, 4.97; N, 4.41; S, 9.19.
    • EXAMPLE 255 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide phosphate (1:1) (salt)
  • [0865]
    Figure US20040235818A1-20041125-C04025
  • Part A: To the ethyl acetate solution (4 mL) of Example 252 (0.5 g, 0.9 mmol) was added concentrated phosphoric acid (85%, 0.1248 g, 1.08 mmol) and solution was stirred at ambient temperature for 2 hours. Evaporation of the solvent and recrystallization from hot ethanol gave the title compound as a white powder (0.4917 g, 82.7%). Analytical calculation for C[0866] 22H25N2O7SF3.H3PO4.H2O: C, 41.64; H, 4.77; N, 4.42. Found: C, 41.14; H, 4.64; N, 4.25.
    • EXAMPLE 256 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide monoacetate (salt)
  • [0867]
    Figure US20040235818A1-20041125-C04026
  • Part A: To a solution of Example 252 (0.5 g, 0.9 mmol) in ethyl acetate (5 mL) was added concentrated acetic acid (63.7 mg, 1.08 mmol) and solution was stirred at ambient temperature for 2 hours. Evaporation of the solvent and recrystallization from hot ethyl acetate gave the title compound as a white crystalline solid (0.4635 g, 83.0%). Analytical calculation for C[0868] 22H25N2O7SF3.0.7C2H4O2: C, 50.14; H, 5.00; N, 5.00; S, 5.72. Found: C, 50.47; H, 5.09; N, 5.00; S, 6.13.
    • EXAMPLE 257 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide 2-hydroxy-1,2,3-propanetri-carboxylate (3:1) (salt)
  • [0869]
    Figure US20040235818A1-20041125-C04027
  • Part A: To a solution of Example 252 (0.3 g, 0.578 mmol) in ethyl acetate (5 mL) was added citric acid (41 mg, 0.21 mmol) and the solution was stirred at ambient temperature for 2 hours. Evaporation of the solvent and recrystallization from hot ethanol gave the title compound as a white crystalline solid (0.181 g, 53.7%). Analytical calculation for C[0870] 22H25N2O7SF3.(⅓)C6H9O7. 0.9H2O: C, 48.34; H, 4.99; N, 4.70; S, 5.38. Found: C, 48.42; H, 4.99; N, 4.70; S, 5.38.
    • EXAMPLE 258 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide monobenzenesulfonate (salt)
  • [0871]
    Figure US20040235818A1-20041125-C04028
  • Part A: To a solution of Preparative Example VII, Part D (0.4 g, 0.66 mmol) in ethanol (2.5 mL) was added benzene sulfonic acid (0.11 g, 0.69 mmol) and the solution was stirred at ambient temperature for 3 hours. Evaporation of the solvent and recrystallization from hot ethanol at minus 20 degrees Celsius gave the title compound as white crystals (0.28 g, 64.3%). Analytical calculation for C[0872] 22H25N207SF3.C6H6SO3.0.2H2O: C, 49.44; H, 4.65; N, 4.12; S, 9.43. Found: C, 49.18; H, 4.67; N, 4.08; S, 9.75.
    • EXAMPLE 259 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide (2R,3R)-2,3-dihydroxy-butanedioate (2:1) (salt)
  • [0873]
    Figure US20040235818A1-20041125-C04029
  • Part A: To a solution of Example 252 (0.3 g, 0.578 mmol) in ethyl acetate (5 mL) was added tartaric acid (48 mg, 0.3 mmol) and solution was stirred at ambient temperature for 2 hours. Evaporation of the solvent and recrystallization from hot ethanol at zero degrees Celsius gave the title compound as a white solid (0.2 g, 58.3%). Analytical calculation for C[0874] 22H25N2O7SF3.0.5C4H6O6. 1.25H2O: C, 46.79; H, 4.99; N, 4.55; S, 5.20. Found: C, 47.17; H, 5.20; N, 4.07; S, 5.03
    • Example 260 Preparation of N-hydroxy-1-(2-methoxy-ethyl)-4-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]-4-piperidine-carboxamide phosphate (3:1) (salt)
  • [0875]
    Figure US20040235818A1-20041125-C04030
  • Part A: To a solution of Example 252 (0.5 g, 0.9 mmol) in ethyl acetate (5 mL) was added phosphoric acid (37 mg, 0.32 mmol) and solution was stirred at ambient temperature for 2 hours. Evaporation of the solvent and recrystallization from hot ethanol at zero degrees Celsius gave the title compound as a white solid (0.312 g, 59%). Analytical calculation for C[0876] 22H25N207SF3.0.33H3PO4. 0.5H2O: C, 47.18; H, 4.86; N, 5.00. Found: C, 47.15; H, 4.73; N, 4.90.
    • EXAMPLE 261 Preparation of N-hydroxy-1-[2-(1H-imidazol-1-yl)ethyl]-4-[[4-[4-(trifluoromethoxy)phenoxy]phenyl] sulfonyl]-4-piperidinecarboxamide, dihydrochloride
  • [0877]
    Figure US20040235818A1-20041125-C04031
  • Part A: The aryl ether from Example 230, Part B (3.12 g, 5.2 mmol) was dissolved in absolute methanol (50 mL). Acetyl chloride (2.1 mL, 30 mmol) was added over 1 minute. The reaction was stirred for 4 hours, concentrated, azeotroped with chloroform/acetonitrile, and dried in vacuo, affording the desired hydroxyethyl compound as a white solid (2.75 g, 96%). The desired hydroxyethyl product was characterized by NMR spectroscopy. [0878]
  • Part B: To the dichloromethane solution of the hydroxyethyl compound of Part A (1 g, 1.9 mmol) was added thionyl chloride (3.8 mmol) and reaction solution was stirred at ambient temperature for 12 hours. Concentration in vacuo provided the chloride as a light yellow gel. To the solution of the chloride and potassium carbonate (0.54 g, 3.8 mmol) in N,N-dimethylformamide (5 mL) was added imidazole (0.4 g, 5.7 mmol) and solution was stirred at ambient temperature for 12 hours. Then N,N-dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the imidazole ethyl ester as a light yellow gel (0.82 g, 75.2%). [0879]
  • Part C: To a solution of imidazole ethyl ester of part A (0.82 g, 1.44 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was added sodium hydroxide (0.57 g, 14.4 mmol) in water (6 mL) at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in acetonitrile. Concentrated hydrochloric acid was used to acidify the residue to pH=1 and concentration in vacuo gave the carboxylic acid as the product. To a solution of the carboxylic-acid, N-methyl morpholine (0.62 mL, 5.7 mmol), 1-hydroxybenzotriazole (0.59 g, 4.3 mmol) and O-tetrahydropyranyl hydroxylamine (0.34 g, 2.9 mmol) in N,N-dimethylformamide (30 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.83 g, 5.7 mmol) and the solution was stirred at ambient temperature for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous Sodium bicarbonate, water and dried over magnesium sulfate. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the tetrahydropyranyl amide as a white foam (0.27 g, 29.7%). [0880]
  • Part D: To a solution of 4N hydrochloric acid in dioxane (2 mL, 8 mmol)) was added a solution of the tetrahydropyranyl amide of part B (0.27 g, 0.45 mmol) in methanol (1 ml) and 1,4-dioxane (3 mL) and was stirred at ambient temperature for 3 hours. Evaporation of solvent and trituration with ethyl ether gave the title compound as a white solid (0.179 g, 67%). Analytical calculation for C[0881] 24H25N4O6SF3.2HCl.1.25H2O: C, 44.35; H, 4.57; N, 8.62. Found: C, 44.57; H, 4.36; N, 7.95.
    • EXAMPLE 262 Preparation of N-hydroxy-1-(2-methoxyethyl)-4-[[4-[4-(1H-1,2,4-triazol-1-yl)phenoxy]phenyl]sulfonyl]-4-piperidinecarboxamide trihydrochloride
  • [0882]
    Figure US20040235818A1-20041125-C04032
  • Part A: To a solution of the product of Preparative Example II, Part D, (1.5 g, 3.6 mmol) and powdered potassium carbonate (0.99 g, 7.2 mmol) in N,N-dimethylformamide (10 mL) was added 4-(1,2,4-triazole-1-yl)phenol (0.87 g, 5.4 mmol) at ambient temperature and the solution was heated to ninety degrees Celsius for 32 hours. Solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N sodium hydroxide, water and dried over magnesium sulfate. Chromatography on silica eluting with ethyl acetate/hexane provided the N-Boc diaryl ether as a light yellow gel (0.907 g, 44.5%). [0883]
  • Part B: To a solution of N-Boc diaryl ether of part A (0.907 g, 1.6 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL) and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the amine trifluoroacetate salt and potassium carbonate (0.44 g, 3.2 mmol) in N,N-dimethylformamide (5 mL) was added 2-bromoethyl methyl ether (0.36 mL, 3.8 mmol) and solution was stirred at ambient temperature for 36 hours. The N,N-dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. Concentration in vacuo provided the methoxyl ethyl amine as a light yellow gel (0.82 g, 91%). [0884]
  • Part C: To a solution of the methoxyl ethyl amine of part B (0.80 g, 1.4 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was added sodium hydroxide (0.56 g, 14 mmol) in water (6 mL) at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in acetonitrile. Concentrated hydrochloric acid was used to acidify the residue until the pH=1 and concentration in vacuo gave the carboxylic acid as product. To a solution of the carboxylic acid, N-methyl morpholine (0.92 mL, 8.4 mmol), 1-hydroxybenzotriazole (0.57 g, 4.3 mmol) and O-tetrahydropyranyl hydroxylamine (0.34 g, 2.9 mmol) in N,N-dimethylformamide (30 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.80 g, 4.2 mmol) and the solution was stirred at ambient temperature for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and dried over magnesium sulfate. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the tetrahydropyranyl amide as a white foam (0.39 g, 47.6%). [0885]
  • Part D: To a solution of 4N hydrochloric acid in dioxane (1.6 mL, 6.4 mmol)) was added a solution of the tetrahydropyranyl amide of part C (0.39 g, 0.66 mmol) in methanol (2 ml) and dioxane (6 mL) and was stirred at ambient temperature for 3 hours. Evaporation of the solvent and trituration with ethyl ether gave the title compound as a white solid (0.34 g, 83%). ESI MS calculated for C[0886] 23H27N5O6S: 501, found 501.
    • EXAMPLE 263 Preparation of 1-(2-methoxyethyl)-4-[[4-[4-(trifluoromethoxy)phenoxy]phenyl]-sulfonyl]-4-piperidinecarboxamide monohydrochloride
  • [0887]
    Figure US20040235818A1-20041125-C04033
  • Part A: To a methanol solution of the product of Example 253 (1.0 g, 1.4 mmol) and 20% palladium on carbon (1.5 g) was added ammonium formate (2.4 g, 38 mmol) and reaction solution was heated to reflux for 72 hours. The reaction solution was filtered through Celite and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated aqueous Sodium bicarbonate, water and dried over magnesium sulfate. Concentration in vacuo and chromatography on a C-18 reverse phase column eluting with acetonitrile/water with hydrochloric acid provided the title compound as a white powder (181 mg, 23.2%). Analytical calculation for C[0888] 22H25N2O6SF3.HCl: C, 49.03; H, 4.86; N, 5.20. Found: C, 48.80; H, 4.93; N, 5.29.
    • EXAMPLE 264 Preparation of N-hydroxy-1-[3-(4-morpholinyl)propyl]-4-[[4-[4-(trifluoromethoxy)phenoxy]phenyl] sulfonyl]-4-piperidinecarboxamide dihydrochloride
  • [0889]
    Figure US20040235818A1-20041125-C04034
  • Part A: To a solution of the product of Preparative Example II, Part D, (15 g, 36 mmol) and powdered potassium carbonate (10 g, 72 mmol) in N,N-dimethylformamide (200 mL) was added 4-(trifluoromethoxy)phenol (19.3 mL, 72 mmol) at ambient temperature and the solution was heated to ninety degrees Celsius for 25 hours. The solution was concentrated under high vacuum and residue was dissolved in ethyl acetate. The organic layer was washed with 1N sodium hydroxide, water and dried over magnesium sulfate. Chromatography on silica eluting with ethyl acetate/hexane provided trifluoromethoxy phenoxyphenyl sulfone as a light yellow gel (20 g, quantitative). [0890]
  • Part B: To a solution of trifluoromethoxyl phenoxyphenyl sulfone (1.0 g, 1.75 mmol) of part A in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL) and the solution was stirred at ambient temperature for 1 hour. Concentration in vacuo provided the amine trifluoroacetate salt as a light yellow gel. To the solution of the amine trifluoroacetate salt and potassium carbonate (0.48 g, 3.5 mmol) in N,N-dimethylformamide (10 mL) was added morpholino propyl chloride (0.68 g, 3.5 mmol) and solution was stirred at 40 degree Celsius for 36 hours. The N,N-dimethylformamide was evaporated under high vacuum and the residue was diluted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. Concentration in vacuo provided the morpholino propyl amine as a light yellow gel (1 g, quantitative yield). [0891]
  • Part C: To a solution of morpholino propyl amine of part B (1 g, 1.6 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was added sodium hydroxide (0.67 g, 16 mmol) in water (6 mL) at ambient temperature. The solution was then heated to sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the residue was dissolved in acetonitrile. Concentrated hydrochloric acid was used to acidify the residue to pH=1 and concentration in vacuo gave the carboxylic acid as the product. To a solution of the carboxylic acid, N-methyl morpholine (0.18 mL, 4.8 mmol), 1-hydroxybenzotriazole (0.45 g, 3.2 mmol) and O-tetrahydropyranyl hydroxylamine (0.3 g, 2.5 mmol) in N,N-dimethylformamide (30 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.64 g, 3.2 mmol) and the solution was stirred at ambient temperature for 24 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous Sodium bicarbonate, water and dried over magnesium sulfate. Concentration in vacuo and chromatography on silica eluting with ethyl acetate/hexane provided the tetrahydropyranyl amide as a white foam (0.56 g, 50%). [0892]
  • Part D: To a solution of 4N hydrogen chloride in dioxane (2 mL, 8 mmol)) was added a solution of the tetrahydropyranyl amide of part C (0.56 g, 0.83 mmol) in methanol (3 ml) and dioxane (8 mL) and was stirred at ambient temperature for 3 hours. Evaporation of solvent and tritration with ethyl ether gave the title compound as a white solid (0.476 g, 86.5%). Analytical calculation for C[0893] 26H32N3O7SF3.2HCl: C, 47.28; H, 5.19; N, 6.36; S, 4.85. Found: C, 46.86; H, 5.35; N, 6.29; S, 5.09.
    • EXAMPLE 265 Preparation of N-hydroxy-1-(1H-imidazol-2-ylmethyl)-4-[[4-[4-(trifluoromethyl)phenoxy] phenyl]-sulfonyl]-4-piperidinecarboxamide dihydrochloride
  • [0894]
    Figure US20040235818A1-20041125-C04035
  • Part A: To a suspension of the hydrochloride salt from Preparative Example VIII, Part F, (0.988 g, 21.6 mmol) and 2-imidazolecarboxaldehyde (315 mg, 3.28 mmol) in methanol (5 mL) at room temperature was added borane-pyridine complex (0.41 mL, 3.28 mmol). After 18 hours the reaction was concentrated under a stream of nitrogen. Saturated aqueous sodium bicarbonate was then added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water and brine and dried over sodium sulfate. Concentration gave a residue which was purified on silica gel eluting with ammonia-saturated methanol/methylene chloride (3/97) to afford the desired 4(5)-imidazole derivative (1.04 g, 89.7%) as a yellow solid. MS MH[0895] + calculated for C25H26N3O5SF3: 538, found 538.
  • Part B: A solution of sodium hydroxide (766 mg, 19.2 mmol) in water (5 mL) was added to a solution of the 4(5)-imidazole derivative of Part A (1.03 g, 1.92 mmol) in tetrahydrofuran (5 mL) and ethanol (5 mL) and the resulting solution was stirred at ambient temperature for 66 hours. The solution was concentrated in vacuo to afford a residue which was treated with 2 N aqueous hydrochloric acid (14.4 mL, 28.8 mmol). Concentration afforded the desired carboxylic acid as a yellow foam which was used directly without purification. [0896]
  • Part C: To a solution of the carboxylic acid of [0897]
  • Part B in dimethylformamide (15 mL) was added sequentially N-methylmorpholine (1.16 g, 11.5 mmol), N-hydroxybenzotriazole (311 mg, 2.30 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (478 mg, 2.50 mmol), and O-tetrahydropyranyl hydroxylamine (303 mg, 2.6 mmol). After 16 hours at ambient temperature the reaction was warmed to 51 degrees Celsius for 2 hours and then concentrated in vacuo. Water was added and the mixture was extracted sequentially with ethyl acetate and with methylene chloride. The combined organic extracts were washed with brine and dried over sodium sulfate. Concentration gave a residue which was chromatographed on silica gel eluting with ammonia-saturated methanol/methylene chloride (7/93) to afford the desired tetrahydropyranyl-protected hydroxamate (0.50 g, 43%) as an off-white foam. MS MH+calculated for C[0898] 28H31F3N4O6S: 609, found 609.
  • Part D: To a solution of tetrahydropyranyl-protected hydroxamate of part C (500 mg, 0.82 mmol) in methanol (1 mL) and 1,4-dioxane (5 mL) was added 4 N hydrogen chloride/dioxane (2.5 mL). After stirring at ambient temperature for 1 hours, the solution was concentrated in vacuo. Trituration with diethyl ether provided the title compound as a white solid (490 mg, quantitative yield). HRMS MH+ calculated for C[0899] 23H23N4SO5F3: 525. Found: 525. MS MH+ calculated for C23H23F3N4O5S: 525, found 525.
    • EXAMPLE 266 Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]-phenyl]sulfonyl]-4-piperidinecarboxamide
  • [0900]
    Figure US20040235818A1-20041125-C04036
  • To a solution of the product of Preparative Example IX (2.08 g, 4.0 mmol) in warm water (200 mL) was added sodium bicarbonate to pH=8 and the solution was stirred for 1 hour. The resulting white solid was isolated by filtration, washed with water and dried at 40° C. for 48 hours to afford the title compound as a white solid (1.82 g, 94%). Analytical calculation for C[0901] 22H23N2SF3O5:H2O, 52.50; H, 5.01; N, 5.57; S, 6.38. Found: C, 52.24; H, 4.65; N, 5.46; S, 6.75.
    • EXAMPLE 267 Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]-phenyl]sulfonyl]-4-piperidinecarboxamide mono(4-methylbenzenesulfonate) (salt)
  • [0902]
    Figure US20040235818A1-20041125-C04037
  • To a solution of the product of Example 266 (550 mg, 1.10 mmol) in ethanol (5 mL) was added p-toluenesulfonic acid (240 mg, 1.26 mmol) and the reaction was then stirred for 3.5 hour. The resulting white solid was isolated by filtration, washed with ethanol and dried at 40° C. for 48 hours to afford the title compound as a white solid (633 mg, 86%). Recrystallized from methanol/water afforded the title compound as analytically pure material. Analytical Calculation for C[0903] 29H31N2S2F3O9: 51.78; H, 4.64; N, 4.16. Found: C, 51.44; H, 4.32; N, 4.18.
    • EXAMPLE 268 Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]-phenyl]sulfonyl]-4-piperidinecarbox-amide monomethanesulfonate (salt)
  • [0904]
    Figure US20040235818A1-20041125-C04038
  • To a solution of the product of Example 266 (550 mg, 1.13 mmol) in ethanol (5 mL) was added methane sulfonic acid (82 μL) and the reaction was then stirred for 3.5 hours. Concentration in vacuo afforded the title compound as a solid (640 mg, 97%). Recrystallization from methanol afforded analytically pure title compound. Analytical Calculation for C[0905] 23H27N2S2F3O9: 46.30; H, 4.56; N, 4.70, S, 10.75. Found: C, 46.10; H, 4.71; N, 4.65; S, 10.99.
    • EXAMPLE 269 Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethylphenoxy]-phenyl]sulfonyl]-4-piperidinecarboxamide
  • [0906]
    Figure US20040235818A1-20041125-C04039
  • To a solution of the product of Preparative Example X (2.15 g, 4.0 mmol) in warm water (200 mL) was added sodium bicarbonate to pH=8. The solution was stirred for 1 hour. The resulting white solid was isolated by filtration, washed with water and dried at 40 degrees Celsius for 48 hours to afford the titled compound as a white solid (1.96 g, 98%). Analytical Calculation for C[0907] 22H23N2SF3O5:2H2O: C, 51.26; H, 5.24; N, 5.44; S, 6.21. Found: C, 50.58; H, 4.72; N, 5.33; S, 6.04.
    • EXAMPLE 270 Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethylphenoxy]-phenyl]sulfonyl]-4-piperidinecarboxamide mono(4-methylbenzenesulfonate)(salt)
  • [0908]
    Figure US20040235818A1-20041125-C04040
  • To a solution of the product of Example 269 (550 mg, 1.13 mmol) in ethanol (5 mL) was added p-toluenesulfonic acid (248 mg, 1.26 mmol) and the solution was stirred for 3.5 hours. The resulting white solid was isolated by filtration, washed with ethanol and dried at 40° C. for 48 hours to afford the title compound as a white solid (705 mg, 95%). Recrystallized from methanol afforded analytically pure material. Analytical Calculation for C[0909] 29H31N2S2F308: C, 53.04; H, 4.76; N, 4.27; S, 9.77 Found: C, 52.94; H, 4.46; N, 4.30; S, 9.99.
    • EXAMPLE 271 Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[4-(trifluoromethylphenoxy]-phenyl]sulfonyl]-4-piperidinecarbox-amide monomethanesulfonate (salt)
  • [0910]
    Figure US20040235818A1-20041125-C04041
  • To a solution of the product of Example 269 (550 mg, 1.13 mmol) in ethanol (5 mL) was added methane sulfonic acid (79 μL) and the reaction was stirred for 3.5 hours. Concentration in vacuo gave the title compound as a solid (569 mg, 87%). Analytical Calculation for C[0911] 23H27N2S2F308: C, 47.58; H, 4.69; N, 4.82. Found: C, 47.15; H, 4.18; N, 4.74.
    • EXAMPLE 272 Preparation of 1-acetyl-N-hydroxy-4-[[4-[4-(trifluoromethoxy)phenoxy]-phenyl]sulfonyl]-4-piperidinecarboxamide
  • [0912]
    Figure US20040235818A1-20041125-C04042
  • Part A: To a solution of the product of Preparative Example II, Part D (33.2 g, 80.0 mmol) in dimethylformamide (150 mL) was added cesium carbonate (65.2-g, 200 mmol) and 4-(trifluromethoxy)phenol (21.4 g, 120 mmol). The solution was mechanically stirred at sixty degrees Celsius for 24 hours. The solution was then diluted with water (1 L) and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo. Chromatography on silica gel eluting with 20% ethyl acetate/hexane provided the desired diaryl sulfide as a white solid (45.0 g, quantitative yield). [0913]
  • Part B: To a solution of the diaryl sulfide from part A (24 g, 42.8 mmol) in ethanol (80 mL) and tetrahydrofuran (80 mL) was added a solution of NaOH (14.8 g, 370 mmol) in water (100 mL) and the solution was heated at sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH 5.0 and extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo to give the desired carboxylic acid as a white foam (23.0 g, quantitative yield) [0914]
  • Part C: To a solution of carboxylic acid of part B (22.8 g, 43.0 mmol) in ethyl acetate (400 mL) cooled to zero degrees Celsius was bubbled gaseous Hydrogen chloride for 20 minutes. The reaction was stirred at this temperature for 2.5 hours. The solution was then concentrated in vacuo to afford the desired hydrochloride salt as a white foam (21.0 g, quantitative yield). [0915]
  • Part D: To a solution of the hydrochloride salt of part C (17.0 g, 35.0 mmol) in acetone (125 mL) and water (125 mL) was added triethyl amine (24 mL, 175 mmol). The reaction was cooled to zero degrees Celsius and acetyl chloride (3.73 mL, 53.0 mmol) was added. The solution was then stirred at ambient temperature for 18 hours. Concentration in vacuo gave a residue which was acidified with aqueous hydrochloric acid to pH 1.0 and then extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo to give the desired methanesulfonamide as a white solid (17.0 g, quantitative yield). [0916]
  • Part E: To a solution of the methanesulfonamide of part D (14.4 g, 29.6 mmol) in dimethylformamide (250 mL) was added 1-hydroxybenzotriazole (4.8 g, 35.5 mmol), N-methyl morpholine (12.3 mL, 88.8 mmol) and O-tetrahydropyranyl hydroxylamine (5.2 g, 44.4 mmol) followed by 1-3-(dimethylamino) propyl]-3-ethyl carbodiimide hydrochloride (7.99 g, 41.4 mmol). The solution was stirred at ambient temperature for 18 hours. The solution was diluted with water (500 mL) and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo. Chromatography on a C[0917] 18 reverse phase column eluting with acetonitrile/water provided the desired tetrahydropyranyl-protected hydroxamate as a white solid (12.0 g, 71%).
  • Part F: To a solution of tetrahydropyranyl-protected hydroxamate of part E (12.0 g, 20.5 mmol) in dioxane (250 mL) and methanol (50 mL) was added 4 N hydrogen chloride/dioxane (51 mL). After stirring at ambient temperature for 3.5 hours the solution was concentrated in vacuo. Trituration with diethyl ether and filtration provided the title compound as a white solid (8.84 g, 85%). HRMS MH[0918] + calculated for C21H21N2SO7F3: 503502.1021. Found 502.0979.
    • EXAMPLE 273 Preparation of N-hydroxy-1-(methyl sulfonyl)-4-[[4-[4-sulfonyl]-(trifluoromethoxy) phenoxy] phenyl]-4-piperidinecarboxamide
  • [0919]
    Figure US20040235818A1-20041125-C04043
  • Part A: To a solution of the product of Preparative Example II, Part D, (33.2 g, 80.0 mmol) in dimethylformamide (150 mL) was added cesium carbonate (65.2 gm, 200.0 mmol) and 4-(trifluromethoxy)phenol (21.4 g, 120 mmol). The solution was mechanically stirred at sixty degrees Celsius for 24 hours. The solution was then diluted with water (1 L) and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo. Chromatography on silica gel eluting with 20% ethyl acetate/hexane provided the desired diaryl sulfide as a white solid (45.0 gm, quantitative yield). [0920]
  • Part B: To a solution of the diaryl sulfide from part A (21 g, 37.0 mmol) in ethanol (80 mL) and tetrahydrofuran (80 mL) was added a solution of NaOH (14.8 g, 370 mmol) in water (75 mL) and the solution was heated at sixty degrees Celsius for 18 hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH=5.0, and then extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo to give the desired carboxylic acid as a white foam (19.3 g, 97%) [0921]
  • Part C: To a solution of carboxylic acid of part B (19.3 g, 37.0 mmol) in ethyl acetate (400 mL) cooled to zero degrees Celsius was bubbled gaseous hydrogen chloride for 30 minutes. The reaction was stirred at this temperature for 2.5 hours. The solution was then concentrated in vacuo to afford the desired hydrochloride salt as a white foam (15.8 g, 93%). [0922]
  • Part D: To a solution of the hydrochloride salt of part C (15.8 g, 33.0 mmol) in acetone (100 mL) and water (100 mL) was added triethyl amine (23 mL, 164 mmol). The reaction was cooled to zero degrees Celsius and methanesulfonyl chloride (5.1 mL, 66.0 mmol) was added. The solution was stirred at ambient temperature for 18 hours. The reaction was concentrated in vacuo and acidified with aqueous hydrochloric acid to pH 1.0. The aqueous residue was extracted ethyl acetate. The organic extract was washed with water, saturated sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo to give the desired carboxylic acid methanesulfonamide as a white solid (17.6 gm, quantitative yield). [0923]
  • Part E: To a solution of the methanesulfonamide of part D (18 g, 35.0 mmol) in dimethylformamide (150 mL) was added 1-hydroxybenzotriazole (5.66 gm, 42.0 mmol), N-methyl morpholine (14.0 mL, 105.0 mmol) and O-tetrahydropyranyl hydroxylamine (6.1 g, 52 mmol) followed by 1-3-(dimethylamino) propyl]-3-ethyl carbodiimide hydrochloride (9.4 gm, 49.0 mmol). The solution was stirred at ambient temperature for 18 hours. The solution was diluted with water (500 mL) and extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium chloride and dried over magnesium sulfate, then filtered and concentrated in vacuo. Chromatography on a C[0924] 18 reverse phase column eluting with acetonitrile/water provided desired tetrahydropyranyl-protected hydroxamate as a white solid (8.17 g, 41%).
  • Part F: To a solution of tetrahydropyranyl-protected hydroxamate of part E (8.17 g, 13.0 mmol) in dioxane (100 mL) and methanol (100 mL) was added 4 N hydrogen chloride/dioxane (50 mL). After stirring at ambient temperature for 3.5 hours the solution was concentrated in vacuo. Trituration with diethyl ether provided the title compound as a white solid (6.83 g, 92%). MS MH[0925] + calculated for C20H21NS2O8F: 539. Found 539.
  • The following compounds were prepared by parallel synthesis (resin based synthesis, automated synthesis) procedures utilizing reactions such as acylation and nucleophilic displacement: [0926]
    • EXAMPLE 274
  • [0927]
    Figure US20040235818A1-20041125-C04044
    • EXAMPLE 275
  • [0928]
    Figure US20040235818A1-20041125-C04045
    • EXAMPLE 276
  • [0929]
    Figure US20040235818A1-20041125-C04046
    • EXAMPLES: 277-315
  • [0930]
    Figure US20040235818A1-20041125-C04047
    MS (ES)
    Example R1R2NH Amine m/z
    277
    Figure US20040235818A1-20041125-C04048
         		Ethyl amine 592 (M + H)
    278
    Figure US20040235818A1-20041125-C04049
         		3-(Aminomethyl) pyridine 655 (M + H)
    279
    Figure US20040235818A1-20041125-C04050
         		Imidazole 615 (M + H)
    280
    Figure US20040235818A1-20041125-C04051
         		3-Amino-1-propanol 622 (M + H)
    281
    Figure US20040235818A1-20041125-C04052
         		Histamine 658 (M + H)
    282
    Figure US20040235818A1-20041125-C04053
         		2-Thiophene methyl amine 660 (M + H)
    283
    Figure US20040235818A1-20041125-C04054
         		Morpholine 634 (M + H)
    284
    Figure US20040235818A1-20041125-C04055
         		2-(Aminomethyl) pyridine 655 (M + H)
    285
    Figure US20040235818A1-20041125-C04056
         		4-(Aminomethyl) pyridine 655 (M + H)
    286
    Figure US20040235818A1-20041125-C04057
         		Ethanolamine 608 (M + H)
    287
    Figure US20040235818A1-20041125-C04058
         		N,N,N-Trimethyl ethylenediamine 649 (M + H)
    288
    Figure US20040235818A1-20041125-C04059
         		1-Methylpiperazine 647 (M + H)
    289
    Figure US20040235818A1-20041125-C04060
         		N,N-Dimethyl ethylenediamine 635 (M + H)
    290
    Figure US20040235818A1-20041125-C04061
         		Piperazine 633 (M + H)
    291
    Figure US20040235818A1-20041125-C04062
         		Thiomorpholine 650 (M + H)
    292
    Figure US20040235818A1-20041125-C04063
         		N-Propylcyclopropne methylamine 660 (M + H)
    293
    Figure US20040235818A1-20041125-C04064
         		(Aminomethyl) cyclopropane 618 (M + H)
    294
    Figure US20040235818A1-20041125-C04065
         		Dimethylamine 592 (M + H)
    295
    Figure US20040235818A1-20041125-C04066
         		Diethylamine 620 (M + H)
    296
    Figure US20040235818A1-20041125-C04067
         		Piperidine 632 (M + H)
    297
    Figure US20040235818A1-20041125-C04068
         		(R)-(−)-2- Pyrrolidine methanol 648 (M + H)
    298
    Figure US20040235818A1-20041125-C04069
         		Pyrrolidine 618 (M + H)
    299
    Figure US20040235818A1-20041125-C04070
         		1-(2-(2- Hydroxyethoxy) ethyl)piperazine 721 (M + H)
    300
    Figure US20040235818A1-20041125-C04071
         		Isonipecotamide 675 (M + H)
    301
    Figure US20040235818A1-20041125-C04072
         		2-(2-Aminoethoxy) ethanol 652 (M + H)
    302
    Figure US20040235818A1-20041125-C04073
         		3,3′-Iminobis(N,N- dimethylpropylamine) 734 (M + H)
    303
    Figure US20040235818A1-20041125-C04074
         		Bis(2-Methoxy ethyl)amine 680 (M + H)
    304
    Figure US20040235818A1-20041125-C04075
         		4-Hydroxy piperidine 648 (M + H)
    305
    Figure US20040235818A1-20041125-C04076
         		N-(Carboethoxy methylpiperazine 719 (M + H)
    306
    Figure US20040235818A1-20041125-C04077
         		1-(2-Morpholinoethyl) piperazine 746 (M + H)
    307
    Figure US20040235818A1-20041125-C04078
         		1-(2-Methoxyethyl) piperazine 691 (M + H)
    308
    Figure US20040235818A1-20041125-C04079
         		1-(2- Dimethylaminoethyl) piperazine 704 (M + H)
    309
    Figure US20040235818A1-20041125-C04080
         		2-Methoxyethylamine 622 (M + H)
    310
    Figure US20040235818A1-20041125-C04081
         		2,2,2-Trifluoroethyl amine 646 (M + H)
    311
    Figure US20040235818A1-20041125-C04082
         		1,2,4-Triazole 616 (M + H)
    312
    Figure US20040235818A1-20041125-C04083
         		Methoxyamine 594 (M + H)
    313
    Figure US20040235818A1-20041125-C04084
         		Ethyl isonipecotate 704 (M + H)
    314
    Figure US20040235818A1-20041125-C04085
         		2-Pyrrolidinone 632 (M + H)
    315
    Figure US20040235818A1-20041125-C04086
         		Isonipecotic acid 676 (M + H)
    • EXAMPLES: 316-332
  • [0931]
    Example R1R2NH Amine MS (ES) m/z
    316
    Figure US20040235818A1-20041125-C04087
         		3-(Aminomethyl) pyridine 593 (M + H)
    317
    Figure US20040235818A1-20041125-C04088
         		Imidazole 553 (M + H)
    318
    Figure US20040235818A1-20041125-C04089
         		Piperidine 570 (M + H)
    319
    Figure US20040235818A1-20041125-C04090
         		Morpholine 572 (M + H)
    320
    Figure US20040235818A1-20041125-C04091
         		2-(Aminomethyl) pyridine 593 (M + H)
    321
    Figure US20040235818A1-20041125-C04092
         		Ethanolamine 546 (M + H)
    322
    Figure US20040235818A1-20041125-C04093
         		2,2,2-Trifluoro ethylamine 584 (M + H)
    323
    Figure US20040235818A1-20041125-C04094
         		N,N,N-Trimethyl ethylenediamine 587 (M + H)
    324
    Figure US20040235818A1-20041125-C04095
         		1-Methylpiperazine 585 (M + H)
    325
    Figure US20040235818A1-20041125-C04096
         		4-(Aminomethyl) pyridine 593 (M + H)
    326
    Figure US20040235818A1-20041125-C04097
         		Pyrrolidine 556 (M + H)
    327
    Figure US20040235818A1-20041125-C04098
         		Bis(2-Methoxy ethyl)amine 618 (M + H)
    328
    Figure US20040235818A1-20041125-C04099
         		Piperazine 571 (M + H)
    329
    Figure US20040235818A1-20041125-C04100
         		4-(Ethylamino methyl)pyridine 621 (M + H)
    330
    Figure US20040235818A1-20041125-C04101
         		1-(2-Methoxy ethyl)pyridine 629 (M + H)
    331
    Figure US20040235818A1-20041125-C04102
         		N- Propylcyclopropane methylamine 598 (M + H)
    332
    Figure US20040235818A1-20041125-C04103
         		2-Methoxyethylamine 560 (M + H)
    • EXAMPLES: 333-347
  • [0932]
    Example R1R2NH Amine MS (ES) m/z
    333
    Figure US20040235818A1-20041125-C04104
         		3-(Aminomethyl) pyridine 635 (M + H)
    334
    Figure US20040235818A1-20041125-C04105
         		Piperidine 612 (M + H)
    335
    Figure US20040235818A1-20041125-C04106
         		Morpholine 614 (M + H)
    336
    Figure US20040235818A1-20041125-C04107
         		2-(Aminomethyl) pyridine 635 (M + H)
    337
    Figure US20040235818A1-20041125-C04108
         		Ethanolamine 588 (M + H)
    338
    Figure US20040235818A1-20041125-C04109
         		N,N,N-Trimethyl ethylenediamine 629 (M + H)
    339
    Figure US20040235818A1-20041125-C04110
         		1-Methylpiperazine 627 (M + H)
    340
    Figure US20040235818A1-20041125-C04111
         		4-(Aminomethyl) pyridine 636 (M + H)
    341
    Figure US20040235818A1-20041125-C04112
         		Pyrrolidine 598 (M + H)
    342
    Figure US20040235818A1-20041125-C04113
         		Bis(2-Methoxy ethyl)amine 660 (M + H)
    343
    Figure US20040235818A1-20041125-C04114
         		Piperazine 613 (M + H)
    344
    Figure US20040235818A1-20041125-C04115
         		4-(Ethylamino methyl)pyridine 663 (M + H)
    345
    Figure US20040235818A1-20041125-C04116
         		1-(2-Methoxy ethyl)pyridine 671 (M + H)
    346
    Figure US20040235818A1-20041125-C04117
         		N-Propylcyclopropane methylamine 640 (M + H)
    347
    Figure US20040235818A1-20041125-C04118
         		2-Methoxyethylamine 602 (M + H)
    • EXAMPLES 348-942
  • The following compounds were prepared in a manner similar to that used in the preceding examples. In the tables that follow, a generic structure is shown above the table with substituent groups being illustrated in the table along with available mass spectral data. [0933]
    Figure US20040235818A1-20041125-C04119
    Example R K MS (ES) m/z
    348
    Figure US20040235818A1-20041125-C04120
    Figure US20040235818A1-20041125-C04121
    349
    Figure US20040235818A1-20041125-C04122
    Figure US20040235818A1-20041125-C04123
         		499.1131
    350
    Figure US20040235818A1-20041125-C04124
    Figure US20040235818A1-20041125-C04125
         		583
    351
    Figure US20040235818A1-20041125-C04126
    Figure US20040235818A1-20041125-C04127
         		580.1366
    352
    Figure US20040235818A1-20041125-C04128
    Figure US20040235818A1-20041125-C04129
         		538.1282
    353
    Figure US20040235818A1-20041125-C04130
    Figure US20040235818A1-20041125-C04131
         		610
    354
    Figure US20040235818A1-20041125-C04132
    Figure US20040235818A1-20041125-C04133
    355
    Figure US20040235818A1-20041125-C04134
    Figure US20040235818A1-20041125-C04135
         		648
    356
    Figure US20040235818A1-20041125-C04136
    Figure US20040235818A1-20041125-C04137
    357
    Figure US20040235818A1-20041125-C04138
    Figure US20040235818A1-20041125-C04139
         		610
    358
    Figure US20040235818A1-20041125-C04140
    Figure US20040235818A1-20041125-C04141
    359
    Figure US20040235818A1-20041125-C04142
    Figure US20040235818A1-20041125-C04143
         		648
    360
    Figure US20040235818A1-20041125-C04144
    Figure US20040235818A1-20041125-C04145
    361
    Figure US20040235818A1-20041125-C04146
    Figure US20040235818A1-20041125-C04147
         		616
    362
    Figure US20040235818A1-20041125-C04148
    Figure US20040235818A1-20041125-C04149
         		614
    363
    Figure US20040235818A1-20041125-C04150
    Figure US20040235818A1-20041125-C04151
         		616
    364
    Figure US20040235818A1-20041125-C04152
    Figure US20040235818A1-20041125-C04153
         		648
    365
    Figure US20040235818A1-20041125-C04154
    Figure US20040235818A1-20041125-C04155
         		614
    366
    Figure US20040235818A1-20041125-C04156
    Figure US20040235818A1-20041125-C04157
         		648
    367
    Figure US20040235818A1-20041125-C04158
    Figure US20040235818A1-20041125-C04159
    368
    Figure US20040235818A1-20041125-C04160
    Figure US20040235818A1-20041125-C04161
    369
    Figure US20040235818A1-20041125-C04162
    Figure US20040235818A1-20041125-C04163
    370
    Figure US20040235818A1-20041125-C04164
    Figure US20040235818A1-20041125-C04165
    371
    Figure US20040235818A1-20041125-C04166
    Figure US20040235818A1-20041125-C04167
    372
    Figure US20040235818A1-20041125-C04168
    Figure US20040235818A1-20041125-C04169
         		539.1201
    373
    Figure US20040235818A1-20041125-C04170
    Figure US20040235818A1-20041125-C04171
    374
    Figure US20040235818A1-20041125-C04172
    Figure US20040235818A1-20041125-C04173
         		567.1120
    375
    Figure US20040235818A1-20041125-C04174
    Figure US20040235818A1-20041125-C04175
         		590.1174
    376
    Figure US20040235818A1-20041125-C04176
    Figure US20040235818A1-20041125-C04177
    378
    Figure US20040235818A1-20041125-C04178
    Figure US20040235818A1-20041125-C04179
         		474.1567
    379
    Figure US20040235818A1-20041125-C04180
    Figure US20040235818A1-20041125-C04181
         		555
    380
    Figure US20040235818A1-20041125-C04182
    Figure US20040235818A1-20041125-C04183
         		537.1412
    381
    Figure US20040235818A1-20041125-C04184
    Figure US20040235818A1-20041125-C04185
         		523
    382
    Figure US20040235818A1-20041125-C04186
    Figure US20040235818A1-20041125-C04187
    383
    Figure US20040235818A1-20041125-C04188
    Figure US20040235818A1-20041125-C04189
    384
    Figure US20040235818A1-20041125-C04190
    Figure US20040235818A1-20041125-C04191
         		547.1279
    385
    Figure US20040235818A1-20041125-C04192
    Figure US20040235818A1-20041125-C04193
    386
    Figure US20040235818A1-20041125-C04194
    Figure US20040235818A1-20041125-C04195
         		555.1516
    387
    Figure US20040235818A1-20041125-C04196
    Figure US20040235818A1-20041125-C04197
         		607.1061
    388
    Figure US20040235818A1-20041125-C04198
    Figure US20040235818A1-20041125-C04199
    389
    Figure US20040235818A1-20041125-C04200
    Figure US20040235818A1-20041125-C04201
         		516
    390
    Figure US20040235818A1-20041125-C04202
    Figure US20040235818A1-20041125-C04203
         		539
    391
    Figure US20040235818A1-20041125-C04204
    Figure US20040235818A1-20041125-C04205
         		538.1272
    392
    Figure US20040235818A1-20041125-C04206
    Figure US20040235818A1-20041125-C04207
         		538.1252
    393
    Figure US20040235818A1-20041125-C04208
    Figure US20040235818A1-20041125-C04209
    394
    Figure US20040235818A1-20041125-C04210
    Figure US20040235818A1-20041125-C04211
    395
    Figure US20040235818A1-20041125-C04212
    Figure US20040235818A1-20041125-C04213
         		522.1351
    396
    Figure US20040235818A1-20041125-C04214
    Figure US20040235818A1-20041125-C04215
         		582.2245
    397
    Figure US20040235818A1-20041125-C04216
    Figure US20040235818A1-20041125-C04217
         		532.2280
    398
    Figure US20040235818A1-20041125-C04218
    Figure US20040235818A1-20041125-C04219
    399
    Figure US20040235818A1-20041125-C04220
    Figure US20040235818A1-20041125-C04221
         		528
    400
    Figure US20040235818A1-20041125-C04222
    Figure US20040235818A1-20041125-C04223
    401
    Figure US20040235818A1-20041125-C04224
    Figure US20040235818A1-20041125-C04225
         		515.3344
    402
    Figure US20040235818A1-20041125-C04226
    Figure US20040235818A1-20041125-C04227
         		582.2266
    403
    Figure US20040235818A1-20041125-C04228
    Figure US20040235818A1-20041125-C04229
    404
    Figure US20040235818A1-20041125-C04230
    Figure US20040235818A1-20041125-C04231
         		550
    405
    Figure US20040235818A1-20041125-C04232
    Figure US20040235818A1-20041125-C04233
         		550
    406
    Figure US20040235818A1-20041125-C04234
    Figure US20040235818A1-20041125-C04235
         		555
    407
    Figure US20040235818A1-20041125-C04236
    Figure US20040235818A1-20041125-C04237
    408
    Figure US20040235818A1-20041125-C04238
    Figure US20040235818A1-20041125-C04239
         		600.2162
    409
    Figure US20040235818A1-20041125-C04240
    Figure US20040235818A1-20041125-C04241
         		548
    410
    Figure US20040235818A1-20041125-C04242
    Figure US20040235818A1-20041125-C04243
    411
    Figure US20040235818A1-20041125-C04244
    Figure US20040235818A1-20041125-C04245
    412
    Figure US20040235818A1-20041125-C04246
    Figure US20040235818A1-20041125-C04247
         		502
    413
    Figure US20040235818A1-20041125-C04248
    Figure US20040235818A1-20041125-C04249
         		529
    414
    Figure US20040235818A1-20041125-C04250
    Figure US20040235818A1-20041125-C04251
         		600.2141
    415
    Figure US20040235818A1-20041125-C04252
    Figure US20040235818A1-20041125-C04253
         		600
    416
    Figure US20040235818A1-20041125-C04254
    Figure US20040235818A1-20041125-C04255
         		489
    417
    Figure US20040235818A1-20041125-C04256
    Figure US20040235818A1-20041125-C04257
         		530
    418
    Figure US20040235818A1-20041125-C04258
    Figure US20040235818A1-20041125-C04259
         		598.2200
    419
    Figure US20040235818A1-20041125-C04260
    Figure US20040235818A1-20041125-C04261
         		548.2013
    420
    Figure US20040235818A1-20041125-C04262
    Figure US20040235818A1-20041125-C04263
         		569.2259
    421
    Figure US20040235818A1-20041125-C04264
    Figure US20040235818A1-20041125-C04265
         		570.2186
    422
    Figure US20040235818A1-20041125-C04266
    Figure US20040235818A1-20041125-C04267
         		635.2185
    423
    Figure US20040235818A1-20041125-C04268
    Figure US20040235818A1-20041125-C04269
         		636.2104
    424
    Figure US20040235818A1-20041125-C04270
    Figure US20040235818A1-20041125-C04271
         		586.2059
    425
    Figure US20040235818A1-20041125-C04272
    Figure US20040235818A1-20041125-C04273
         		562.1957
    426
    Figure US20040235818A1-20041125-C04274
    Figure US20040235818A1-20041125-C04275
         		585.1968
    427
    Figure US20040235818A1-20041125-C04276
    Figure US20040235818A1-20041125-C04277
         		586.1936
    428
    Figure US20040235818A1-20041125-C04278
    Figure US20040235818A1-20041125-C04279
         		637.2137
    429
    Figure US20040235818A1-20041125-C04280
    Figure US20040235818A1-20041125-C04281
         		638.2072
    430
    Figure US20040235818A1-20041125-C04282
    Figure US20040235818A1-20041125-C04283
         		637.2146
    431
    Figure US20040235818A1-20041125-C04284
    Figure US20040235818A1-20041125-C04285
         		638.2075
    432
    Figure US20040235818A1-20041125-C04286
    Figure US20040235818A1-20041125-C04287
         		602.1731
    433
    Figure US20040235818A1-20041125-C04288
    Figure US20040235818A1-20041125-C04289
         		654.1921
    434
    Figure US20040235818A1-20041125-C04290
    Figure US20040235818A1-20041125-C04291
         		654.1932
    435
    Figure US20040235818A1-20041125-C04292
    Figure US20040235818A1-20041125-C04293
         		636
    436
    Figure US20040235818A1-20041125-C04294
    Figure US20040235818A1-20041125-C04295
         		596
    437
    Figure US20040235818A1-20041125-C04296
         		—H 502
    438
    Figure US20040235818A1-20041125-C04297
    Figure US20040235818A1-20041125-C04298
         		579
    439
    Figure US20040235818A1-20041125-C04299
    Figure US20040235818A1-20041125-C04300
         		411.1211
    440
    Figure US20040235818A1-20041125-C04301
    Figure US20040235818A1-20041125-C04302
         		480
    441
    Figure US20040235818A1-20041125-C04303
    Figure US20040235818A1-20041125-C04304
         		542
    442
    Figure US20040235818A1-20041125-C04305
    Figure US20040235818A1-20041125-C04306
         		540
    443
    Figure US20040235818A1-20041125-C04307
         		—H 440
    444
    Figure US20040235818A1-20041125-C04308
    Figure US20040235818A1-20041125-C04309
         		518
    445
    Figure US20040235818A1-20041125-C04310
    Figure US20040235818A1-20041125-C04311
         		566
    446
    Figure US20040235818A1-20041125-C04312
    Figure US20040235818A1-20041125-C04313
         		618
    447
    Figure US20040235818A1-20041125-C04314
    Figure US20040235818A1-20041125-C04315
         		616
    448
    Figure US20040235818A1-20041125-C04316
    Figure US20040235818A1-20041125-C04317
         		550.2387
    449
    Figure US20040235818A1-20041125-C04318
    Figure US20040235818A1-20041125-C04319
         		616
    450
    Figure US20040235818A1-20041125-C04320
    Figure US20040235818A1-20041125-C04321
    451
    Figure US20040235818A1-20041125-C04322
    Figure US20040235818A1-20041125-C04323
         		580.1370
    452
    Figure US20040235818A1-20041125-C04324
    Figure US20040235818A1-20041125-C04325
    453
    Figure US20040235818A1-20041125-C04326
    Figure US20040235818A1-20041125-C04327
    454
    Figure US20040235818A1-20041125-C04328
    Figure US20040235818A1-20041125-C04329
         		614
    455
    Figure US20040235818A1-20041125-C04330
    Figure US20040235818A1-20041125-C04331
         		456
    456
    Figure US20040235818A1-20041125-C04332
    Figure US20040235818A1-20041125-C04333
         		585
    457
    Figure US20040235818A1-20041125-C04334
    Figure US20040235818A1-20041125-C04335
         		463
    458
    Figure US20040235818A1-20041125-C04336
    Figure US20040235818A1-20041125-C04337
         		549
    459
    Figure US20040235818A1-20041125-C04338
    Figure US20040235818A1-20041125-C04339
         		532
    460
    Figure US20040235818A1-20041125-C04340
         		—H 574
    461
    Figure US20040235818A1-20041125-C04341
    Figure US20040235818A1-20041125-C04342
         		564
    462
    Figure US20040235818A1-20041125-C04343
    Figure US20040235818A1-20041125-C04344
         		616
    463
    Figure US20040235818A1-20041125-C04345
    Figure US20040235818A1-20041125-C04346
         		598
    464
    Figure US20040235818A1-20041125-C04347
    Figure US20040235818A1-20041125-C04348
         		514
  • [0934]
    Figure US20040235818A1-20041125-C04349
    Example R MS (ES) m/z
    465
    Figure US20040235818A1-20041125-C04350
         		505.1746
    466
    Figure US20040235818A1-20041125-C04351
         		551 (+Na)
    467
    Figure US20040235818A1-20041125-C04352
    468
    Figure US20040235818A1-20041125-C04353
         		463.1704
    469
    Figure US20040235818A1-20041125-C04354
         		486
    470
    Figure US20040235818A1-20041125-C04355
         		503
    471
    Figure US20040235818A1-20041125-C04356
         		537
    472
    Figure US20040235818A1-20041125-C04357
         		533.2348
    473
    Figure US20040235818A1-20041125-C04358
         		499.2304
    474
    Figure US20040235818A1-20041125-C04359
         		504
    475
    Figure US20040235818A1-20041125-C04360
    476
    Figure US20040235818A1-20041125-C04361
         		532.2522
    477
    Figure US20040235818A1-20041125-C04362
    478
    Figure US20040235818A1-20041125-C04363
    479
    Figure US20040235818A1-20041125-C04364
         		539.0842
    480
    Figure US20040235818A1-20041125-C04365
         		545.1595
    481
    Figure US20040235818A1-20041125-C04366
         		574.1483
    482
    Figure US20040235818A1-20041125-C04367
         		503.2238
    483
    Figure US20040235818A1-20041125-C04368
         		515.2234
    484
    Figure US20040235818A1-20041125-C04369
         		417
    485
    Figure US20040235818A1-20041125-C04370
         		475.1910
    486
    Figure US20040235818A1-20041125-C04371
         		383
    487
    Figure US20040235818A1-20041125-C04372
         		460
    488
    Figure US20040235818A1-20041125-C04373
         		438
    489
    Figure US20040235818A1-20041125-C04374
         		452
    490
    Figure US20040235818A1-20041125-C04375
         		474
    491
    Figure US20040235818A1-20041125-C04376
         		476
    492
    Figure US20040235818A1-20041125-C04377
         		383
    493
    Figure US20040235818A1-20041125-C04378
         		472
    494
    Figure US20040235818A1-20041125-C04379
         		472
    495
    Figure US20040235818A1-20041125-C04380
         		383
    496
    Figure US20040235818A1-20041125-C04381
         		383
    497
    Figure US20040235818A1-20041125-C04382
         		517
    498
    Figure US20040235818A1-20041125-C04383
    499
    Figure US20040235818A1-20041125-C04384
         		503
    500
    Figure US20040235818A1-20041125-C04385
         		521
    501
    Figure US20040235818A1-20041125-C04386
         		571
    502
    Figure US20040235818A1-20041125-C04387
         		571
    503
    Figure US20040235818A1-20041125-C04388
         		571
    504
    Figure US20040235818A1-20041125-C04389
         		489.2059
    505
    Figure US20040235818A1-20041125-C04390
         		507.1987
    506
    Figure US20040235818A1-20041125-C04391
         		557
    507
    Figure US20040235818A1-20041125-C04392
         		557
    508
    Figure US20040235818A1-20041125-C04393
         		557
    509
    Figure US20040235818A1-20041125-C04394
         		503.2226
    510
    Figure US20040235818A1-20041125-C04395
         		521.2122
    511
    Figure US20040235818A1-20041125-C04396
         		571.2056
    512
    Figure US20040235818A1-20041125-C04397
         		571.2054
    513
    Figure US20040235818A1-20041125-C04398
         		571.1464
    514
    Figure US20040235818A1-20041125-C04399
         		379.0964
    515
    Figure US20040235818A1-20041125-C04400
         		504.1831
    516
    Figure US20040235818A1-20041125-C04401
         		532.2105
    517
    Figure US20040235818A1-20041125-C04402
         		470.1935
    518
    Figure US20040235818A1-20041125-C04403
         		576.2355
    519
    Figure US20040235818A1-20041125-C04404
         		596.2033
    520
    Figure US20040235818A1-20041125-C04405
         		518.1945
    521
    Figure US20040235818A1-20041125-C04406
         		538.1372
    522
    Figure US20040235818A1-20041125-C04407
         		519
    523
    Figure US20040235818A1-20041125-C04408
         		560
    524
    Figure US20040235818A1-20041125-C04409
         		399
    525
    Figure US20040235818A1-20041125-C04410
         		413
    526
    Figure US20040235818A1-20041125-C04411
         		493
    527
    Figure US20040235818A1-20041125-C04412
         		581
    528
    Figure US20040235818A1-20041125-C04413
         		343.1742
    529
    Figure US20040235818A1-20041125-C04414
         		399.1597
    530
    Figure US20040235818A1-20041125-C04415
         		483
    531
    Figure US20040235818A1-20041125-C04416
         		501
    532
    Figure US20040235818A1-20041125-C04417
         		551
    533
    Figure US20040235818A1-20041125-C04418
         		407
    534
    Figure US20040235818A1-20041125-C04419
         		515
    535
    Figure US20040235818A1-20041125-C04420
         		460
    536
    Figure US20040235818A1-20041125-C04421
         		460
    537
    Figure US20040235818A1-20041125-C04422
         		464
    538
    Figure US20040235818A1-20041125-C04423
         		460
    539
    Figure US20040235818A1-20041125-C04424
         		412
    540
    Figure US20040235818A1-20041125-C04425
         		495.4984
    541
    Figure US20040235818A1-20041125-C04426
         		479.1416
    542
    Figure US20040235818A1-20041125-C04427
         		572.2800
    543
    Figure US20040235818A1-20041125-C04428
         		539.2017
    544
    Figure US20040235818A1-20041125-C04429
         		489.2049
    545
    Figure US20040235818A1-20041125-C04430
         		497
    546
    Figure US20040235818A1-20041125-C04431
         		506
    547
    Figure US20040235818A1-20041125-C04432
         		479
    548
    Figure US20040235818A1-20041125-C04433
         		524
    549
    Figure US20040235818A1-20041125-C04434
         		542
    550
    Figure US20040235818A1-20041125-C04435
         		520
    551
    Figure US20040235818A1-20041125-C04436
         		520
    552
    Figure US20040235818A1-20041125-C04437
         		506
    553
    Figure US20040235818A1-20041125-C04438
         		476
    554
    Figure US20040235818A1-20041125-C04439
         		547.2525
    555
    Figure US20040235818A1-20041125-C04440
         		561.2692
    556
    Figure US20040235818A1-20041125-C04441
         		561.2679
    557
    Figure US20040235818A1-20041125-C04442
         		576.2184
    558
    Figure US20040235818A1-20041125-C04443
         		511.1755
    559
    Figure US20040235818A1-20041125-C04444
         		500.1830
    560
    Figure US20040235818A1-20041125-C04445
         		500.1888
    561
    Figure US20040235818A1-20041125-C04446
         		577.1650
    562
    Figure US20040235818A1-20041125-C04447
         		413.1750
    563
    Figure US20040235818A1-20041125-C04448
         		427.1903
    564
    Figure US20040235818A1-20041125-C04449
         		385.1457
    565
    Figure US20040235818A1-20041125-C04450
         		637.2067
    566
    Figure US20040235818A1-20041125-C04451
         		532.2448
    567
    Figure US20040235818A1-20041125-C04452
         		529.1631
    568
    Figure US20040235818A1-20041125-C04453
         		529.1603
    569
    Figure US20040235818A1-20041125-C04454
         		574.1478
    570
    Figure US20040235818A1-20041125-C04455
         		597.0849
    571
    Figure US20040235818A1-20041125-C04456
         		574.1473
    572
    Figure US20040235818A1-20041125-C04457
         		513.1228
    573
    Figure US20040235818A1-20041125-C04458
         		509.1536
    574
    Figure US20040235818A1-20041125-C04459
         		509.1529
    575
    Figure US20040235818A1-20041125-C04460
         		493.1803
    576
    Figure US20040235818A1-20041125-C04461
         		493.1838
    577
    Figure US20040235818A1-20041125-C04462
         		476.1847
    578
    Figure US20040235818A1-20041125-C04463
         		476.1865
    579
    Figure US20040235818A1-20041125-C04464
         		553.1057
    580
    Figure US20040235818A1-20041125-C04465
         		476.1879
    581
    Figure US20040235818A1-20041125-C04466
         		489.2076
    582
    Figure US20040235818A1-20041125-C04467
         		507.2016
    583
    Figure US20040235818A1-20041125-C04468
    584
    Figure US20040235818A1-20041125-C04469
    585
    Figure US20040235818A1-20041125-C04470
         		415.1559
    586
    Figure US20040235818A1-20041125-C04471
         		401.1399
    587
    Figure US20040235818A1-20041125-C04472
         		443
    588
    Figure US20040235818A1-20041125-C04473
         		477
    589
    Figure US20040235818A1-20041125-C04474
         		515
    590
    Figure US20040235818A1-20041125-C04475
         		538
    591
    Figure US20040235818A1-20041125-C04476
         		452
    592
    Figure US20040235818A1-20041125-C04477
         		466
    593
    Figure US20040235818A1-20041125-C04478
         		472
    594
    Figure US20040235818A1-20041125-C04479
         		502
    595
    Figure US20040235818A1-20041125-C04480
         		556
    596
    Figure US20040235818A1-20041125-C04481
         		457
    597
    Figure US20040235818A1-20041125-C04482
    598
    Figure US20040235818A1-20041125-C04483
         		415.1911
    599
    Figure US20040235818A1-20041125-C04484
         		471
    600
    Figure US20040235818A1-20041125-C04485
         		575.2777
    601
    Figure US20040235818A1-20041125-C04486
         		575
    602
    Figure US20040235818A1-20041125-C04487
         		589.2947
    603
    Figure US20040235818A1-20041125-C04488
         		589.2914
    604
    Figure US20040235818A1-20041125-C04489
         		601.2936
    605
    Figure US20040235818A1-20041125-C04490
         		587.2808
    606
    Figure US20040235818A1-20041125-C04491
         		551.2225
    607
    Figure US20040235818A1-20041125-C04492
         		587.2048
    608
    Figure US20040235818A1-20041125-C04493
         		619.2098
    609
    Figure US20040235818A1-20041125-C04494
         		687.1978
    610
    Figure US20040235818A1-20041125-C04495
         		857.2070
    611
    Figure US20040235818A1-20041125-C04496
         		719.2024
    612
    Figure US20040235818A1-20041125-C04497
         		401.1746
    613
    Figure US20040235818A1-20041125-C04498
         		581.2323
    614
    Figure US20040235818A1-20041125-C04499
         		511.1900
    615
    Figure US20040235818A1-20041125-C04500
         		495.1368
    616
    Figure US20040235818A1-20041125-C04501
         		521.1980
    617
    Figure US20040235818A1-20041125-C04502
         		529.0962
    618
    Figure US20040235818A1-20041125-C04503
         		505.2031
    619
    Figure US20040235818A1-20041125-C04504
         		475.1898
    620
    Figure US20040235818A1-20041125-C04505
         		529.1604
    621
    Figure US20040235818A1-20041125-C04506
         		456.1761
    622
    Figure US20040235818A1-20041125-C04507
         		398.1751
    623
    Figure US20040235818A1-20041125-C04508
         		414.1690
    624
    Figure US20040235818A1-20041125-C04509
         		434.1651
    629
    Figure US20040235818A1-20041125-C04510
         		510
    634
    Figure US20040235818A1-20041125-C04511
         		483.1992
    635
    Figure US20040235818A1-20041125-C04512
         		425
    636
    Figure US20040235818A1-20041125-C04513
         		507.1910
    637
    Figure US20040235818A1-20041125-C04514
         		489.2064
    638
    Figure US20040235818A1-20041125-C04515
         		511.1910
    639
    Figure US20040235818A1-20041125-C04516
         		521.1962
    640
    Figure US20040235818A1-20041125-C04517
         		505.2006
    641
    Figure US20040235818A1-20041125-C04518
         		513.1277
    642
    Figure US20040235818A1-20041125-C04519
         		517.2410
    643
    Figure US20040235818A1-20041125-C04520
         		519.2190
    644
    Figure US20040235818A1-20041125-C04521
         		505
    645
    Figure US20040235818A1-20041125-C04522
         		428.1821
    646
    Figure US20040235818A1-20041125-C04523
         		428
    647
    Figure US20040235818A1-20041125-C04524
         		503
    648
    Figure US20040235818A1-20041125-C04525
         		506.1830
    649
    Figure US20040235818A1-20041125-C04526
         		524
    650
    Figure US20040235818A1-20041125-C04527
         		524.1531
    651
    Figure US20040235818A1-20041125-C04528
         		490.1912
    652
    Figure US20040235818A1-20041125-C04529
         		487
    653
    Figure US20040235818A1-20041125-C04530
         		487
    654
    Figure US20040235818A1-20041125-C04531
         		491
    655
    Figure US20040235818A1-20041125-C04532
         		503
    656
    Figure US20040235818A1-20041125-C04533
         		473
    658
    Figure US20040235818A1-20041125-C04534
    659
    Figure US20040235818A1-20041125-C04535
    665
    Figure US20040235818A1-20041125-C04536
         		510.1353
    666
    Figure US20040235818A1-20041125-C04537
         		541.1815
    667
    Figure US20040235818A1-20041125-C04538
         		475
    668
    Figure US20040235818A1-20041125-C04539
         		510.1366
    669
    Figure US20040235818A1-20041125-C04540
         		510.1358
    670
    Figure US20040235818A1-20041125-C04541
    671
    Figure US20040235818A1-20041125-C04542
         		524
    672
    Figure US20040235818A1-20041125-C04543
         		535
    673
    Figure US20040235818A1-20041125-C04544
         		594
    674
    Figure US20040235818A1-20041125-C04545
         		524
    675
    Figure US20040235818A1-20041125-C04546
         		578
    676
    Figure US20040235818A1-20041125-C04547
         		578
    677
    Figure US20040235818A1-20041125-C04548
         		578
    678
    Figure US20040235818A1-20041125-C04549
         		540
    679
    Figure US20040235818A1-20041125-C04550
         		594
    680
    Figure US20040235818A1-20041125-C04551
         		555
    681
    Figure US20040235818A1-20041125-C04552
         		528
    682
    Figure US20040235818A1-20041125-C04553
         		528
    683
    Figure US20040235818A1-20041125-C04554
         		570
    684
    Figure US20040235818A1-20041125-C04555
         		514
    685
    Figure US20040235818A1-20041125-C04556
         		516
    686
    Figure US20040235818A1-20041125-C04557
         		384.1593
    688
    Figure US20040235818A1-20041125-C04558
         		527.1658 (M + NH4)
    690
    Figure US20040235818A1-20041125-C04559
         		535
    691
    Figure US20040235818A1-20041125-C04560
         		568
    692
    Figure US20040235818A1-20041125-C04561
         		423.1946
    693
    Figure US20040235818A1-20041125-C04562
         		441.2080
    694
    Figure US20040235818A1-20041125-C04563
         		506.1857
    695
    Figure US20040235818A1-20041125-C04564
         		530.1565
    696
    Figure US20040235818A1-20041125-C04565
         		540
    697
    Figure US20040235818A1-20041125-C04566
         		592.1401
    698
    Figure US20040235818A1-20041125-C04567
         		554.1659
    699
    Figure US20040235818A1-20041125-C04568
         		608.1355
    706
    Figure US20040235818A1-20041125-C04569
         		490.1929
    707
    Figure US20040235818A1-20041125-C04570
         		491
    708
    Figure US20040235818A1-20041125-C04571
    714
    Figure US20040235818A1-20041125-C04572
         		560.1568
    720
    Figure US20040235818A1-20041125-C04573
         		459.1987
    721
    Figure US20040235818A1-20041125-C04574
         		508.2019
    722
    Figure US20040235818A1-20041125-C04575
         		480.1700
    723
    Figure US20040235818A1-20041125-C04576
         		441.2053
    724
    Figure US20040235818A1-20041125-C04577
         		509
    725
    Figure US20040235818A1-20041125-C04578
         		557
    726
    Figure US20040235818A1-20041125-C04579
         		557
    727
    Figure US20040235818A1-20041125-C04580
         		541
    728
    Figure US20040235818A1-20041125-C04581
         		491
    729
    Figure US20040235818A1-20041125-C04582
         		541
    730
    Figure US20040235818A1-20041125-C04583
         		501
    731
    Figure US20040235818A1-20041125-C04584
         		509
    732
    Figure US20040235818A1-20041125-C04585
         		501
    733
    Figure US20040235818A1-20041125-C04586
         		501
    734
    Figure US20040235818A1-20041125-C04587
         		517
    735
    Figure US20040235818A1-20041125-C04588
         		521
    736
    Figure US20040235818A1-20041125-C04589
         		505
    737
    Figure US20040235818A1-20041125-C04590
         		501
    738
    Figure US20040235818A1-20041125-C04591
         		559
    740
    Figure US20040235818A1-20041125-C04592
    741
    Figure US20040235818A1-20041125-C04593
    752
    Figure US20040235818A1-20041125-C04594
         		572
    755
    Figure US20040235818A1-20041125-C04595
         		467
    756
    Figure US20040235818A1-20041125-C04596
         		453
    757
    Figure US20040235818A1-20041125-C04597
         		453
    758
    Figure US20040235818A1-20041125-C04598
         		451
    759
    Figure US20040235818A1-20041125-C04599
         		451
    760
    Figure US20040235818A1-20041125-C04600
         		488
    761
    Figure US20040235818A1-20041125-C04601
         		451
    781
    Figure US20040235818A1-20041125-C04602
         		444
    782
    Figure US20040235818A1-20041125-C04603
         		444
    784
    Figure US20040235818A1-20041125-C04604
    786
    Figure US20040235818A1-20041125-C04605
         		499
    787
    Figure US20040235818A1-20041125-C04606
         		499
    788
    Figure US20040235818A1-20041125-C04607
         		515
    789
    Figure US20040235818A1-20041125-C04608
         		529
    790
    Figure US20040235818A1-20041125-C04609
         		516
    791
    Figure US20040235818A1-20041125-C04610
         		517
    793
    Figure US20040235818A1-20041125-C04611
    794
    Figure US20040235818A1-20041125-C04612
    796
    Figure US20040235818A1-20041125-C04613
         		517
    797
    Figure US20040235818A1-20041125-C04614
    798
    Figure US20040235818A1-20041125-C04615
    799
    Figure US20040235818A1-20041125-C04616
    802
    Figure US20040235818A1-20041125-C04617
    807
    Figure US20040235818A1-20041125-C04618
    811
    Figure US20040235818A1-20041125-C04619
    815
    Figure US20040235818A1-20041125-C04620
    816
    Figure US20040235818A1-20041125-C04621
    822
    Figure US20040235818A1-20041125-C04622
    823
    Figure US20040235818A1-20041125-C04623
    825
    Figure US20040235818A1-20041125-C04624
    826
    Figure US20040235818A1-20041125-C04625
    827
    Figure US20040235818A1-20041125-C04626
    828
    Figure US20040235818A1-20041125-C04627
    829
    Figure US20040235818A1-20041125-C04628
    830
    Figure US20040235818A1-20041125-C04629
    831
    Figure US20040235818A1-20041125-C04630
    832
    Figure US20040235818A1-20041125-C04631
    833
    Figure US20040235818A1-20041125-C04632
    834
    Figure US20040235818A1-20041125-C04633
    835
    Figure US20040235818A1-20041125-C04634
    836
    Figure US20040235818A1-20041125-C04635
    838
    Figure US20040235818A1-20041125-C04636
    841
    Figure US20040235818A1-20041125-C04637
    842
    Figure US20040235818A1-20041125-C04638
    844
    Figure US20040235818A1-20041125-C04639
    845
    Figure US20040235818A1-20041125-C04640
    846
    Figure US20040235818A1-20041125-C04641
    847
    Figure US20040235818A1-20041125-C04642
    848
    Figure US20040235818A1-20041125-C04643
    850
    Figure US20040235818A1-20041125-C04644
    851
    Figure US20040235818A1-20041125-C04645
    852
    Figure US20040235818A1-20041125-C04646
    853
    Figure US20040235818A1-20041125-C04647
    854
    Figure US20040235818A1-20041125-C04648
    856
    Figure US20040235818A1-20041125-C04649
    857
    Figure US20040235818A1-20041125-C04650
    858
    Figure US20040235818A1-20041125-C04651
    859
    Figure US20040235818A1-20041125-C04652
    860
    Figure US20040235818A1-20041125-C04653
    861
    Figure US20040235818A1-20041125-C04654
    862
    Figure US20040235818A1-20041125-C04655
    863
    Figure US20040235818A1-20041125-C04656
    864
    Figure US20040235818A1-20041125-C04657
    867
    Figure US20040235818A1-20041125-C04658
    868
    Figure US20040235818A1-20041125-C04659
    869
    Figure US20040235818A1-20041125-C04660
    872
    Figure US20040235818A1-20041125-C04661
    873
    Figure US20040235818A1-20041125-C04662
    877
    Figure US20040235818A1-20041125-C04663
    878
    Figure US20040235818A1-20041125-C04664
    881
    Figure US20040235818A1-20041125-C04665
    882
    Figure US20040235818A1-20041125-C04666
    883
    Figure US20040235818A1-20041125-C04667
    884
    Figure US20040235818A1-20041125-C04668
    885
    Figure US20040235818A1-20041125-C04669
    886
    Figure US20040235818A1-20041125-C04670
    887
    Figure US20040235818A1-20041125-C04671
    888
    Figure US20040235818A1-20041125-C04672
    889
    Figure US20040235818A1-20041125-C04673
    890
    Figure US20040235818A1-20041125-C04674
    891
    Figure US20040235818A1-20041125-C04675
    892
    Figure US20040235818A1-20041125-C04676
    893
    Figure US20040235818A1-20041125-C04677
    894
    Figure US20040235818A1-20041125-C04678
    895
    Figure US20040235818A1-20041125-C04679
    899
    Figure US20040235818A1-20041125-C04680
    901
    Figure US20040235818A1-20041125-C04681
    902
    Figure US20040235818A1-20041125-C04682
    905
    Figure US20040235818A1-20041125-C04683
    906
    Figure US20040235818A1-20041125-C04684
    909
    Figure US20040235818A1-20041125-C04685
    910
    Figure US20040235818A1-20041125-C04686
    911
    Figure US20040235818A1-20041125-C04687
    912
    Figure US20040235818A1-20041125-C04688
    913
    Figure US20040235818A1-20041125-C04689
    914
    Figure US20040235818A1-20041125-C04690
    915
    Figure US20040235818A1-20041125-C04691
    916
    Figure US20040235818A1-20041125-C04692
    920
    Figure US20040235818A1-20041125-C04693
    921
    Figure US20040235818A1-20041125-C04694
    922
    Figure US20040235818A1-20041125-C04695
    924
    Figure US20040235818A1-20041125-C04696
    926
    Figure US20040235818A1-20041125-C04697
    931
    Figure US20040235818A1-20041125-C04698
    932
    Figure US20040235818A1-20041125-C04699
    939
    Figure US20040235818A1-20041125-C04700
  • [0935]
    Figure US20040235818A1-20041125-C04701
    Example R K MS
    940
    Figure US20040235818A1-20041125-C04702
    Figure US20040235818A1-20041125-C04703
    941
    Figure US20040235818A1-20041125-C04704
    Figure US20040235818A1-20041125-C04705
    942
    Figure US20040235818A1-20041125-C04706
    Figure US20040235818A1-20041125-C04707
    • Example 943 In Vitro Metalloprotease Inhibition
  • The compounds prepared in the manner described in the Examples above were assayed for activity by an in vitro assay. Following the procedures of Knight et al., [0936] FEBS Lett. 296(3):263 (1992). Briefly, 4-aminophenylmercuric acetate (APMA) or trypsin-activated MMPs were incubated with various concentrations of the inhibitor compound at room temperature for 5 minutes.
  • More specifically, recombinant human [0937]
  • MMP-13, MMP-1, MMP-2 and MMP-9 enzymes were prepared in laboratories of the assignee following usual laboratory procedures. MMP-13 from a full length cDNA clone was expressed as a proenzyme using a baculovirus as discussed in V. A. Luckow, Insect Cell Expression Technology, pages 183-218, in [0938] Protein Engineering: Principles and Practice, J. L. Cleland et al eds., Wiley-Liss, Inc., (1996). See, also, Luckow et al., J. Virol., 67:4566-4579 (1993); .O'Reilly et al., Baculovirus Expression Vectors: A Laboratory Manual, W. H. Freeman and Company, New York, (1992); and King et al., The Baculovirus Expression System: A Laboratory Guide, Chapman & Hall, London (1992) for further details on use of baculovirus expression systems. The expressed enzyme was purified first over a heparin agarose column and then over a chelating zinc chloride column. The proenzyme was activated by APMA for use in the assay.
  • MMP-1 expressed in transfected HT-1080 cells was provided by Dr. Harold Welgus of Washington University, St. Louis, Mo. The enzyme was also activated using APMA and was then purified over a hydroxamic acid column. Dr. Welgus also provided transfected HT-1080 cells that expressed MMP-9. Transfected cells that expressed MMP-2 were provided by Dr. Gregory Goldberg, also of Washington University. Studies carried out using MMP-2 in the presence of 0.02% 2-mercaptoethanol are shown in the table below with an asterisk. Studies with MMP-7 were carried out at pH 7.5 in the presence of 0.02% 2-mercaptoethanol using conditions otherwise similar to those used for the other enzymes. The enzyme was obtaind from a hMMP-7-expressing [0939] E. coli clone that was a gift of Dr. Steven Shapiro of Washington University, St. Louis, Mo. Further specifics for preparation and use of these enzymes can be found in the scientific literature describing these enzymes. See, for example, Enzyme Nomenclature, Academic Press, San Diego, Calif. (1992) and the citations therein, and Frije et al., J. Biol. Chem., 26(24): 16766-16773 (1994). The enzyme substrate is a methoxycoumarin-containing polypeptide having the following sequence:
  • MCA-ProLeuGlyLeuDpaAlaArgNH[0940] 2, wherein MCA is methoxycoumarin and Dpa is 3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl alanine. This substrate is commercially available from Baychem as product M-1895.
  • The buffer used for assays contained 100 mM Tris-HCl, 100 mM NaCl, 10 mM CaCl[0941] 2 and 0.05 percent polyethyleneglycol (23) lauryl ether at a pH value of 7.5. Assays were carried out at room temperature, and dimethyl sulfoxide (DMSO) at a final concentration of 1 percent was used to dissolve inhibitor compound.
  • The assayed inhibitor compound in [0942]
  • DMSO/buffer solution was compared to an equal amount of DMSO/buffer with no inhibitor as control using Microfluor White Plates (Dynatech). The inhibitor or control solution was maintained in the plate for 10 minutes and the substrate was added to provide a final concentration of 4 μM. [0943]
  • In the absence of inhibitor activity, a fluorogenic peptide was cleaved at the gly-leu peptide bond, separating the highly fluorogenic peptide from a 2,4-dinitrophenyl quencher, resulting in an increase of fluorescence intensity (excitation at 328 nm/emission at 415 nm). Inhibition was measured as a reduction in fluorescent intensity as a function of inhibitor concentration, using a Perkin Elmer L550 plate reader. The IC[0944] 50 values were calculated from those values. The results are set forth in the Inhibition Table A, below, reported in terms of IC50 to three significant figures, where appropriate.
    Inhibition Table A (nM)
    Example MMP-13 MMP-2 MMP-1
    Number IC50(nM) IC50(nM) IC50(nM)
    1 22.7 8.5 >10,000
    2 5,500 6,000 >10,000
    8 15.6 2,900 >10,000
    9 15.6 2,900 >10,000
    10 18.1 >10,000 >10,000
    11 18.0 4,500 >10,000
    12 50.0 2,500 >10,000
    13 12.2 5,600 >10,000
    14 40.0 6,000 >10,000
    15 37.0 2,700 >10,000
    16 6.70 1,400 >10,000
    17 31.6 3,500 >10,000
    18 45.0 >10,000 >10,000
    19 28.0 5,500 >10,000
    20 42.5 4,800 >10,000
    21 70.0 7,000 >10,000
    22 >10,000 >10,000 >10,000
    23 90.0 10,000 >10,000
    24 23.5 4,500 >10,000
    25 6.00 1,600 >10,000
    26 10.7 3,600 >10,000
    27 6.40 1,600 >10,000
    28 6.70 700 >10,000
    29 4.00 445 >10,000
    32 10.0 800 >10,000
    33 20.0 4,500 >10,000
    34 18.1 >10,000 >10,000
    35 30.0 9,000 >10,000
    36 15.8 2,100 >10,000
    37 30.0 1,750 >10,000
    38 67.4 6,000 67.4
    39 19.3 3,700 >10,000
    40 26.8 900 >10,000
    41 70.0 5,400 >10,000
    42 82.5 >10,000 >10,000
    43 17.9 5,000 >10,000
    44 19.0 1,050 >10,000
    45 360 5,000 >10,000
    46 80.0 5,700 >10,000
    47 11.4 6,000 >10,000
    48 27.0 3,200 >10,000
    49 20.0 6,500 >10,000
    51 370 7,000 >10,000
    52 90.0 1,900 >10,000
    53 28.9 1,400 >10,000
    54 40.0 5,700 >10,000
    55 10.0 >10,000 >10,000
    56 55.0 3,500 >10,000
    57 80.0 2,700 >10,000
    58 22.0 4,000 >10,000
    59 4.00 530 >10,000
    60 13.9 3,700 >10,000
    61 7.00 1,500 >10,000
    62 14.0 690 >10,000
    63 20.0 2,900 >10,000
    64 19.3 770 >10,000
    65 5.00 195 >10,000
    66 8.00 240 >10,000
    68 13.0 1,800 >10,000
    69 18.1 3,500 >10,000
    70 10.6 700 >10,000
    71 7.70 270 >10,000
    72 13.0 800 >10,000
    73 15.4 2,000 >10,000
    74 9.00 80.0 >10,000
    75 11.5 500 >10,000
    76 9.00 250 >10,000
    77 75.0 3,400 >10,000
    78 11.7 730 >10,000
    79 20.0 2,000 >10,000
    80 4.10 562 >10,000
    81 60.0 158 >10,000
    82 6.70 490 >10,000
    83 2.70 21.1 3,100
    84 28.6 1,400 >10,000
    85 130 370 >10,000
    86 0.6 12.1 >10,000
    87 4.00 15.5 >10,000
    88 9.00 40.0 >10,000
    91 0.3 <0.1 >10,000
    92 0.8 0.1 >10,000
    95 0.3 <0.1 3,600
    96 0.4 0.1 7,300
    97 0.6 <0.1 >10,000
    98 1.70 0.2 >10,000
    99 1.00 <0.1 >10,000
    100 0.5 <0.1 6,000
    101 1.10 0.8 >10,000
    102 0.6 0.2 >10,000
    103 1.80 0.3 >10,000
    104 0.25 0.2 10,000
    105 1.10 0.3 10,000
    106 0.2 0.15 >10,000
    106 0.1 <0.1 8,200
    108 0.2 <0.1 5,000
    109 0.3 <0.1 >10,000
    110 0.6 0.2 >10,000
    111 0.8 0.15 >10,000
    112 0.5 <0.1 >10,000
    113 0.3 <0.1 >10,000
    114 0.4 <0.1 >10,000
    115 0.1 <0.1 >10,000
    116 0.3 <0.1 >10,000
    117 0.2 0.1 >10,000
    118 0.2 <0.1 >10,000
    119 0.3 0.3 >10,000
    120 0.4 0.1 >10,000
    121 0.2 0.1 5,000
    122 0.2 <0.1 3,000
    123 0.7 <0.1 >10,000
    124 <0.1 <0.1 >10,000
    125 0.4 <0.1 >10,000
    126 0.7 <0.1 >10,000
    127 2.90 0.2 >10,000
    128 0.1 <0.1 3,400
    129 37.2 3.00 >10,000
    130 0.5 0.3 1,600
    131 0.2 <0.1 8,000
    132 0.5 <0.1 >10,000
    133 1.40 0.3 >10,000
    134 1.80 0.3 >10,000
    135 0.6 0.3 10,000
    136 0.9 <0.1 >10,000
    137 0.8 0.1 10,000
    138 3.90 0.25 >10,000
    140 11.4 0.8 >10,000
    141 20.0 9.00 >10,000
    142 12.6 10.0 >10,000
    143 22.0 14.5 >10,000
    144 0.4 0.2 10,000
    145 0.4 0.2 3,700
    146 0.2 0.3 3,000
    147 0.4 0.2 7,700
    148 2.50 3.70 >10,000
    149 15.8 13.8 480
    150 175 175 >10,000
    151 270 290 >10,000
    152 2.00 59.0 >10,000
    153 50.0 5,000 >10,000
    154 18.0 3,700 >10,000
    155 130 240 >10,000
    156 2.20 0.45 >10,000
    157 0.5 0.2 >10,000
    160 300 90.0 >10,000
    161 32.6 900 >10,000
    162 27.8 7,000 >10,000
    163 44.5 2,500 >10,000
    164 3.50 440 >10,000
    165 3.00 48.5 >10,000
    166 32.7 240 >10,000
    168 50.0 285 >10,000
    169 20.0 175 >10,000
    170 2.40 200 >10,000
    171 5.40 186 >10,000
    172 3.80 160 >10,000
    173 6.70 330 3,400
    174 23.5 800 >10,000
    175 2.50 290 >10,000
    176 4.00 250 >10,000
    177 8.80 520 10,000
    178 18.1 325 >10,000
    179 20.6 170 >10,000
    180 1.10 41.8 >10,000
    181 190 2,300 >10,000
    183 300 1,500 >10,000
    184 480 1,500 >10,000
    185 2.20 32.6 >10,000
    187 10.0 600 >10,000
    188 7.0 235 >10,000
    189 7.00 235 >10,000
    190 4.70 136 >10,000
    191 3.50 25.1 >10,000
    193 3.50 0.15 >10,000
    194 0.3 <0.1 >7,300
    195 1.00 0.2 >10,000
    196 1.60 <0.1 >10,000
    197 2.70 <0.1 >10,000
    198 0.375 0.25 7,300
    199 0.2 <0.1 3,000
    200 0.2 <0.1 3,000
    201 0.3 0.2 >10,000
    202 0.4 0.2 >10,000
    207 28.8 900 >10,000
    208 110 1,000 >10,000
    209 50.0 130 >10,000
    210 5.40 4.50 4,000
    211 11.4 1,200 >10,000
    212 160 240 >10,000
    213 1,400 2,700 >10,000
    214 4,900 3,500 >10,000
    224 <0.1 <0.1 4,500
    225 180 41.8 >10,000
    227 28.8 21.7 >10,000
    228 2,448 2,000 >10,000
    229 0.18 0.1 >10,000
    231 0.2 0.1 >10,000
    233 43.5 2,050 >10,000
    235 235 5,300 >10,000
    236 9.00 400 >10,000
    237 13.0 1,900 >10,000
    238 80.0 10,000 >10,000
    239 9.00 8,300 >10,000
    240 76.9 10,000 >10,000
    241 4.80 >10,000 >10,000
    242 42.5 1,500 >10,000
    243 11.3 420 >10,000
    244 67.4 4,400 >10,000
    245 20.0 800 >10,000
    246 32.7 2,700 >10,000
    247 34.5 1,600 >10,000
    248 2.29 270 >10,000
    249 13.0 235 >10,000
    251 <0.1 <0.1 5,840
    252 <0.1 <0.1 3,933.33
    253 <0.1, 3,400 <0.1
    0.15
    256 0.2 0.1 3,200
    257 0.2 0.1 4,100
    258 0.2 0.1 >10,000
    260 0.1 <0.1 5,300
    261 <0.1 <0.1 3,700
    262 1.50 0.9 >10,000
    264 0.2 <0.1 4,500
    265 0.2 1.30, >10,000
    <0.1
    266 0.1 <0.1 5,500
    267 0.2 0.15 10,000
    268 <0.1, 4,000 <0.1
    0.2
    269 0.2 <0.1 >10,000
    270 1.00 1.00 >10,000
    271 0.3 0.17 >10,000
    272 0.2 0.1 3,600
    273 0.3 0.1 >10,000
    274 160 >10,000 >10,000
    275 70.0 >10,000 >10,000
    276 37.3 >10,000 >10,000
    277 70.0 >10,000 >10,000
    278 19.3 >10,000 >10,000
    279 20.0 7,300 >10,000
    280 90.0 >10,000 >10,000
    281 105 >10,000 >10,000
    282 14.8 9,000 >10,000
    283 13.8 >10,000 >10,000
    284 130 >10,000 >10,000
    285 19.3 9,000 >10,000
    286 60.0 >10,000 >10,000
    287 150 >10,000 >10,000
    288 35.0 >10,000 >10,000
    289 50.0 >10,000 >10,000
    290 50.0 >10,000 >10,000
    292 100 >10,000 >10,000
    293 63.1 >10,000 >10,000
    294 59.1 >10,000 >1,000
    295 50.0 >10,000 >10,000
    296 50.0 >10,000 >10,000
    297 34.9 >10,000 >10,000
    298 40.0 >10,000 >10,000
    299 30.6 9,000 >10,000
    300 37.3 >10,000 >10,000
    301 90.0 >10,000 >10,000
    302 175 >10,000 >10,000
    303 115 >10,000 >10,000
    304 30.6 7,000 >10,000
    305 28.6 >10,000 >10,000
    306 60.0 >10,000 >10,000
    307 40.0 >10,000 >10,000
    308 40.0 10,000 >10,000
    309 48.5 >10,000 >10,000
    310 60.0 10,000 >10,000
    311 120 >10,000 >10,000
    312 200 >10,000 >10,000
    313 77.0 >10,000 >10,000
    314 65.0 >10,000 >10,000
    315 420 >10,000 >10,000
    316 0.4 0.2 >10,000
    317 1.40 0.4 >10,000
    318 0.3 0.1 >10,000
    319 0.5 0.2 >10,000
    320 12.1 4.00 >10,000
    321 0.5 0.3 >10,000
    322 0.3 0.3 >10,000
    323 1.30 0.4 >10,000
    324 0.7 0.4 >10,000
    325 0.9 0.2 >10,000
    326 0.6 0.45 >10,000
    327 0.9 0.3 >10,000
    328 0.35 0.4 >10,000
    329 0.9 0.4 >10,000
    330 0.5 0.7 >10,000
    331 0.7 0.2 >10,000
    332 2.10 0.4 >10,000
    333 0.8 0.2 >10,000
    334 0.7 0.3 >10,000
    335 0.9 0.15 >10,000
    336 1.00 <0.1 >10,000
    337 2.70 0.2 >10,000
    338 1.90 0.2 >10,000
    339 1.00 0.3 >10,000
    340 0.3 <0.1 >10,000
    341 0.6 0.2 >10,000
    342 4.00 0.3 >10,000
    343 1.70 0.8 >10,000
    344 2.90 0.65 >10,000
    346 1.20 0.2 >10,000
    347 3.00 0.7 >10,000
    348 16.5 0.8 >10,000
    349 0.2 <0.1 2600
    350 0.1 <0.1 6000
    351 — — —
    352 1.4 0.3 >10,000
    353 0.3 <0.1 >10,000
    354 1.6 15.4
    355 0.4 <0.1 7000
    356 2.4 32.6
    357 0.3 0.1 >10,000
    358 — — —
    359 34.9 12.2 >10,000
    360 10.0 5.6
    361 0.5 <0.1 5000
    362 2.7 <0.1 >10,000
    363 0.4 0.2 8800
    364 1.0 0.2 >10,000
    365 0.3 0.1 >10,000
    366 13.0 2.5 >10,000
    367 — — —
    368 0.5 7.0
    369 3.3 5.4
    370
    371 11.1 400
    372 — — —
    373 3.0 80.0
    374 3.3 4.0 >10,000
    375 16.9 15.6 >10,000
    376 5.5 230
    378 1.7 0.3 200
    379 0.3 0.1 >10,000
    380 — — —
    381 — — —
    382 11.4 260
    383 3.0 700 >10,000
    384 — — —
    385 — — —
    386 0.4 0.2 2100
    387 — — —
    388 50.0 430
    389 1.7 16.1 >10,000
    390 — — —
    391 0.1 <0.1 5400
    392 0.2 0.1 >10,000
    393 4.5 427 >10,000
    394 0.5 8.0
    395 0.9 0.5 >10,000
    396 4.8 330 >10,000
    397 4.4 70.0 >10,000
    398 7.0 70.0 >10,000
    399 1.2 0.3 >10,000
    400 23.5 520
    401 16.9 195 >10,000
    402 15.8 340 >10,000
    403 55.3 4.0 >10,000
    404 0.5 0.25 >10,000
    405
    406
    407 1.2 0.1 >10,000
    408 25.1 800 >10,000
    409 22.4 275 >10,000
    410 0.6 0.25 >10,000
    411 0.2 <0.1 >10,000
    412 0.4 0.2 6400
    413 1.1 0.3 8000
    414 50.5 1500 >10,000
    415 50.4 246 >10,000
    416 0.4 0.2 3000
    417 0.7 4.5 >10,000
    418 7.0 1400 >10,000
    419 4.2 400 >10,000
    420 — — —
    421 — — —
    422 — — —
    423 — — —
    424 5.5 80.0 >10,000
    425 20.0 1000 >10,000
    426 — — —
    427 — — —
    428 — — —
    429 — — —
    430 — — —
    431 — — —
    432 13.9 100 >10,000
    433 450 3500 >10,000
    434 190 3700 >10,000
    435 5.9 1500 >10,000
    436 1.8 330 >10,000
    437 18.1 800 >10,000
    438 1.4 160 >10,000
    439 1070 1600 >10,000
    440 26.8 240 >10,000
    441 6.0 420 >10,000
    442 10.0 211 >10,000
    443 90.0 2200 >10,000
    444 — — —
    445 90.0 1200 >10,000
    446 270 7000 >10,000
    447 23.9 155 >10,000
    448 2.4 540 >10,000
    449 — — —
    450 — — —
    451 0.3 0.1 3700
    452 <0.1 <0.1
    453 0.4 35.0 >10,000
    454 2.1 100 >10,000
    455 6.3 26.8 >10,000
    456 — — —
    457 1800 2700 >10,000
    458 210 2100 >10,000
    459 136 3100 >10,000
    460 4.0 200 >10,000
    461 20.0 145 >10,000
    462 2.9 80.0 >10,000
    463 16.9 210 >10,000
    464 120 400 >10,000
    465 80 370 >10,000
    466 9.4 60 >10,000
    467 27.0 140 >10,000
    468 — — —
    469 0.8 12.0 >10,000
    470 140 2000 >10,000
    471 2400 >10,000 >10,000
    472 4.0 200 >10,000
    473 160 3300 >10,000
    474 12.1 300 >10,000
    475 27.1 500 >10,000
    476 25.4 140 >10,000
    477 11.3 160 >10,000
    478 16.4 306 >10,000
    479 5.0 60.0 >10,000
    480 18.6 155 >10,000
    481 50.0 1400 >10,000
    482 6.0 4.0 >10,000
    483 32.6 10.6 >10,000
    484 240 100 >10,000
    485 8.0 4.2 >10,000
    486 5400 4000 >10,000
    487 140 800 >10,000
    488 140 370 >10,000
    489 770 1900 >10,000
    490 61.0 3000 >10,000
    491 >10,000 >10,000 >10,000
    492 6100 >10,000 >10,000
    493 >10,000 >10,000 >10,000
    494 650 3300 >10,000
    495 14.5 21.1 >10,000
    496 30.7 200 >10,000
    497 50.0 8000 >10,000
    499 0.9 19.3 >10,000
    500 3.0 22.0 >10,000
    501 2.5 180 >10,000
    502 14.0 63 >10,000
    503 10.0 50.0 >10,000
    504 6.3 220 >10,000
    505 14.0 72.0 >10,000
    506 5.0 400 >10,000
    507 15.8 210 >10,000
    508 19.3 210 >10,000
    509 520 >10,000 >10,000
    510 7700 >10,000 >10,000
    511 9000 6000 >10,000
    512 7700 >10,000 >10,000
    513 7700 >10,000 >10,000
    514 1.0 0.6 5,000
    515 8.0 27.0 >10,000
    516 14.8 300 >10,000
    517 14.0 1100 >10,000
    518 11.4 350 >10,000
    519 45.4 1300 >10,000
    520 22.5 250 >10,000
    521 3.5 50.0 >10,000
    522 2.4 94.0 >10,000
    523 2.4 190 >10,000
    524 2700 6400 >10,000
    525 290 700 >10,000
    526 >10,000 >10,000 >10,000
    527 6700 9000 >10,000
    528 7700 >10,000 >10,000
    529 8800 >10,000 >10,000
    530 20.0 60.7 >10,000
    531 13.0 10.0 >10,000
    532 10.0 150 >10,000
    533 60.0 150 >10,000
    534 30.0 480 >10,000
    535 1.9 35.0 >10,000
    536 7.7 88.0 >10,000
    537 70.0 55.0 5200
    538 80.0 370 >10,000
    539 270 350 >10,000
    540 11.4 500 >10,000
    541 0.7 2.0 >10,000
    542 — — —
    543 33.7 5400 >10,000
    544 35.0 3100 >10,000
    545 7.7 120 >10,000
    546 2.7 18.6 >10,000
    547 5.0 64.7 >10,000
    548 40.0 800 >10,000
    549 55.3 2900 >10,000
    550 20.0 2000 >10,000
    551 9.0 140 >10,000
    552 12.8 140 >10,000
    553 12.8 50.0 >10,000
    554 3.7 140 >10,000
    555 3.7 220 >10,000
    556 4.5 170 >10,000
    557 16.9 200 >10,000
    558 4.5 66.4 >10,000
    559 7.2 80.0 >10,000
    560 4.5 306 >10,000
    561 6.0 500 >10,000
    562 1200 6300 >10,000
    563 70.0 235 >10,000
    564 150 550 >10,000
    565 5.5 700 >10,000
    566 15.8 57.1 >10,000
    567 5.0 87.7 >10,000
    568 120 4600 >10,000
    569 16.9 87.7 >10,000
    570 290 >10,000 >10,000
    571 28.6 140 >10,000
    572 37.2 3000 >10,000
    573 11.4 235 >10,000
    574 10.6 220 >10,000
    575 10.7 110 >10,000
    576 8.8 78.0 >10,000
    577 107 2200 >10,000
    578 160 2000 >10,000
    579 2.7 100 >10,000
    580 37.2 700 >10,000
    581 27.0 480 >10,000
    582 30.0 1800 >10,000
    583 70.0 4700 >10,000
    584 2700 3500 >10,000
    585 1400 3500 >10,000
    586 >10,000 >10,000 >10,000
    587 1.8 1.0 >10,000
    588 — — —
    589 70.0 >10,000 >10,000
    590 121 80.0 >10,000
    591 70.0 730 >10,000
    592 57.0 690 >10,000
    593 420 650 >10,000
    594 570 650 >10,000
    595 270 425 >10,000
    596 1.1 10.6 >10,000
    597 670 700 >10,000
    598 25.4 145 >10,000
    600 9.0 600 >10,000
    601 9.0 1300 >10,000
    602 70.0 3000 >10,000
    603 15.8 2300 >10,000
    604 20.0 2500 >10,000
    605 10.6 2000 >10,000
    606 3.0 77.0 >10,000
    607 2.9 220 >10,000
    608 3.0 250 >10,000
    609 30.6 2800 >10,000
    610 425 1300 >10,000
    611 139 1800 >10,000
    612 290 2200 >10,000
    613 8.0 30.7 >10,000
    614 22.0 25.4 >10,000
    615 3.1 11.0 >10,000
    616 4.0 3.7 >10,000
    617 7.0 5.7 >10,000
    618 — — —
    619 4.3 5.7 >10,000
    620 27.8 225 >10,000
    621 120 1500 >10,000
    622 500 1600 >10,000
    623 350 1400 >10,000
    624 120 940 >10,000
    634 4.4 60.7 >10,000
    635 13.9 260 >10,000
    636 3.0 8.0 >10,000
    637 3.8 22 >10,000
    638 — — —
    639 1.5 1.5 9400
    640 4.2 15.8 >10,000
    641 4.0 13.7 >10,000
    642 2.2 1.1 >10,000
    643 1.8 1.2 6000
    644 1.6 3.3 8800
    645 370 1200 >10,000
    646 — 7800 >10,000
    647 6.0 160 >10,000
    648 25.8 110 >10,000
    649 130 1400 >10,000
    650 14.7 1200 >10,000
    651 13.7 60 >10,000
    652 0.4 82.0 >10,000
    653 0.8 160 >10,000
    654 3.2 35.0 >10,000
    655 37.3 1400 >10,000
    656 3.1 120 >10,000
    658 12.2 1000 >10,000
    659 1.0 3.7 >10,000
    665 2.3 29.2 >10,000
    666 48.4 330 >10,000
    667 30 135 >10,000
    668 2.0 25.8 >10,000
    669 4.3 22.7 >10,000
    670
    671 6.0 130 >10,000
    672 6.7 60 >10,000
    673 14.8 455 >10,000
    674 8.0 110 >10,000
    675 13.0 88 6000
    676 7.7 90 >10,000
    677 7.0 34.7 >10,000
    678 5.0 50 >10,000
    679
    680
    681
    682
    683 11.3 290 >10,000
    684 60 1450 >10,000
    685 3/0 34.7 >10,000
    686 4200 3700 >10,000
    688 17.6 110 >10,000
    690 7.3 41.8 >10,000
    691 10.0 130 >10,000
    692 10.0 22.7 >10,000
    693 210 1900 >10,000
    694 3.1 23.2 >10,000
    695 2.0 22.7 >10,000
    696 10.0 140 >10,000
    697 18.1 1500 >10,000
    698 16.9 700 >10,000
    699 50.0 455 >10,000
    705 44.5 1100 >10,000
    706 4.3 40 >10,000
    707 2.3 9.0 >10,000
    708 114 3000 >10,000
    714 28.8 420 >10,000
    720 4.5 36.9 >10,000
    724 28.6 300 >10,000
    725 25.1 210 >10,000
    726 15.8 250 >10,000
    727 34.9 240 >10,000
    728 9.4 106 >10,000
    729 14.8 240 >10,000
    730 37 3000 >10,000
    731 1.9 35 >10,000
    732 3.1 590 >10,000
    733 1.6 270 >10,000
    734 6.0 3300 >10,000
    735 9.0 800 >10,000
    736 0.9 145 >10,000
    737 3.0 1280 >10,000
    738 22.0 270 >10,000
    740 61 175 >10,000
    741 50 125 >10,000
    752 14.8 271 >10,000
    755 2.2 20 >10,000
    756 7.0 28.8 >10,000
    757 3.3 28.8 >10,000
    758 5.0 34.7 >10,000
    759 3.0 60.8 >10,000
    760 6.0 25.4 >10,000
    761 5.0 41.8 >10,000
    769 5.0 0.7 >10,000
    770 270 485 >10,000
    771 500 10,000 >10,000
    772 350 4200 >10,000
    773 6.0 2.7 >10,000
    774 — — —
    775 120 270 >10,000
    776 3.0 10.0 >10,000
    777 2.5 6.5 >10,000
    778 3.3 12 >10,000
    779 40 210 >10,000
    780 17.5 80 >10,000
    781 800 5100 >10,000
    782 21.1 100 >10,000
    784 6.0 4500 >10,000
    786 3.7 700 >10,000
    787 1.2 175 >10,000
    788 3.0 445 >10,000
    789 12.2 3700 >10,000
    790 4.5 700 >10,000
    791 2.0 700 >10,000
    793 4.0 23.5 >10,000
    794 1500 2900 >10,000
    796 5.7 130 >10,000
    797 4.0 175 >10,000
    798 20.0 210 >10,000
    799 10.6 43.5 >10,000
    802 2.3 10,000 >10,000
    807 200 1400 >10,000
    811 14.8 110 >10,000
    815 140 1400 >10,000
    816 1200 >10,000 >10,000
    820 29.0 1400 >10,000
    821 4.0 10.0 >10,000
    822 10.0 210 >10,000
    823 7.0 505 >10,000
    825 11.3 70.0 >10,000
    826 40.0 650 ND
    827 10.0 540 >10,000
    828 1.5 12.8 ND
    829 6.0 22.0 ND
    830 17.9 2100 >10,000
    831 2.3 170 >10,000
    832 18.1 2000 >10,000
    833 11.0 1750 >10,000
    834 150 780 ND
    835 6.0 20.0 >10,000
    836 135 4200 ND
    838 3.0 70.0 >10,000
    841 285 1900 ND
    842 5.5 45.4 >10,000
    844 5.0 4700 >10,000
    845 28.6 2000 ND
    846 4.5 186 >10,000
    847 20.0 1800 ND
    848 — — ND
    850 4.5 150 >10,000
    851 3.7 42.5 ND
    852 25.0 3000 ND
    853 15.8 120 ND
    854 40.0 3300 ND
    856 1.2 250 ND
    857 1.3 120 ND
    858 3.7 600 >10,000
    859 5.5 440 ND
    860 2.7 1500 >10,000
    861 2.0 34.9 ND
    862 1.7 40.0 ND
    863 — — ND
    864 — — ND
    867 16.5 10,000 >10,000
    868 — — ND
    869 2.0 76.9 ND
    870 305 6000 ND
    • Example 944 In Vivo Angiogenesis Assay
  • The study of angiogenesis depends on a reliable and reproducible model for the stimulation and inhibition of a neovascular response. The corneal micropocket assay provides such a model of angiogenesis in the cornea of a mouse. See, [0945] A Model of Angiogenesis in the Mouse Cornea; Kenyon, BM, et al., Investigative Ophthalmology & Visual Science, July 1996, Vol. 37, No. 8.
  • In this assay, uniformLy sized Hydron pellets containing bFGF and sucralfate were prepared and surgically implanted into the stroma mouse cornea adjacent to the temporal limbus. The pellets were formed by making a suspension of 20 μL sterile saline containing 10 μg recombinant bFGF, 10 mg of sucralfate and 10 μL of 12 percent Hydron in ethanol. The slurry was then deposited on a 10×10 mm piece of sterile nylon mesh. After drying, the nylon fibers of the mesh were separated to release the pellets. [0946]
  • The corneal pocket is made by anesthetizing a 7 week old C57B1/6 female mouse, then proptosing the eye with a jeweler's forceps. Using a dissecting microscope, a central, intrastromal linear keratotomy of approximately 0.6 mm in length is performed with a #15 surgical blade, parallel to the insertion of the lateral rectus muscle. Using a modified cataract knife, a lamellar micropocket is dissected toward the temporal limbus. The pocket is extended to within 1.0 mm of the temporal limbus. A single pellet was placed on the corneal surface at the base of the pocket with a jeweler's forceps. The pellet was then advanced to the temporal end of the pocket. Antibiotic ointment was then applied to the eye. [0947]
  • Mice were dosed on a daily basis for the duration of the assay. Dosing of the animals was based on bioavailability and overall potency of the compound. an exemplary dose was 10 or 50 mg/kg (mpk) bid, po. Neovascularization of the corneal stroma begins at about day three and was permitted to continue under the influence of the assayed compound until day five. At day five, the degree of angiogenic inhibition was scored by viewing the neovascular progression with a slit lamp microscope. [0948]
  • The mice were anesthetized and the studied eye was once again proptosed. The maximum vessel length of neovascularization, extending from the limbal vascular plexus toward the pellet was measured. In addition, the contiguous circumferential zone of neovascularization was measured as clock hours, where 30 degrees of arc equals one clock hour. The area of angiogenesis was calculated as follows. [0949] area = ( 0.4 × clock   hours × 3.14 × vessel   length   ( in   mm ) ) 2
    Figure US20040235818A1-20041125-M00001
  • Five to six mice were utilized for each compound in each study. The studied mice were thereafter compared to control mice and the difference in the area of neovascularization was recorded as an averaged value. Each group of mice so studied constitutes an “n” value of one, so that “n” values greater than one represent multiple studies whose averaged result is provided in the table. A contemplated compound typically exhibits about 25 to about 75 percent inhibition, whereas the vehicle control exhibits zero percent inhibition. [0950]
    • EXAMPLE 350 In Vivo PC-3 Tumor Reduction
  • PC-3 human pancreatic cancer eclls (ATCC CRL 1435) were grown to 90% confluence in F12/MEM (Gibco) containing 7% FBS (Gibco). Cells were mechanically harvested using a rubber scraper, and then washed twice with cold medium. The resulting cells were resuspended in cold medium with 30% matrigel (Collaborative Research) and the cell-containing medium was maintained on ice until used. [0951]
  • Balb/c nu/nu mice at 7-9 weeks of age were anesthetized with avertin [2,2,2-tribromethanol/t-amyl alcohol (1 g/l mL) diluted 1:60 into phosphate-buffered sline] and 3-5×10[0952] 6 of the above cells in 0.2 mL of medium were injected into the left flank of each mouse. Cells were injected in the morning, whereas dosing with an inhibitor began at 6 PM. The animals were gavaged BID from day zero (cell injection day) to day 25-30, at which time the animals were euthanized and tumors weighed.
  • Compounds were dosed at 10 mg/mL in 0.5% methylcellulose/0.1% polysorbate 80 to provide a 50 mg/kg (mpk) dose twice each day, or diluted to provide a 10 mg/kg (mpk) dose twice each day. Tumor measurements began on day 7 and continued every third or fourth day until completion of the study. Groups of ten mice were used in each study and nine to ten survived. Each group of mice so studied constitutes an “n” value of one, so that “n” values greater than one represent multiple studies whose averaged result is provided in the table. [0953]
    • EXAMPLE 945 Tumor Necrosis Factor Assays
  • Cell Culture. [0954]
  • The cells used in the assay are the human moncytic line U-937 (ATCC CRL-1593). The cells are grown in RPMI w/10% FCS and PSG supplement (R-10) and are not permitted to overgrow. The assay is carried out as follows: [0955]
  • 1. Count, then harvest cells by centrifugation. Resuspend the pellet in R-10 supplement to a concentration of 1.540×10[0956] 6 cells/mL.
  • 2. Add test compound in 65 μL R-10 to the appropriate wells of a 96-well flat bottom tissue culture plate. The initial dilution from a DMSO stock (0.100 mM compound) provides a 400 μM solution, from which five additional three-fold serial dilutions are made. Each dilution of 65 μl (in triplicate) yields final compound test concentrations of 100 μM, 33.3 μM, 11.1 μM, 3.7 μM, 1.2 μM and 0.4 μM. [0957]
  • 3. The counted, washed and resuspended cells (200,000 cells/well) in 130 μL are added to the wells. [0958]
  • 4. Incubation is for 45 minutes to one hour at 37° C. in 5% CO[0959] 2 in a water saturated container.
  • 5. R-10 (65 uL)containing 160 ng/mL PMA (Sigma) is added to each well. [0960]
  • 6. The test system is incubated at 37° C. in 5% CO[0961] 2 overnight (18-20 hours) under 100% humidity.
  • 7. Supernatant, 150 μL, is carefully removed from each well for use in the ELISA assay. [0962]
  • 8. For toxicity, a 50 μL aliquot of working solution containg 5 mL R-10, 5 mL MTS solution [CellTiter 96 AQueous One Solution Cell Proliferation Assay Cat.#G358/0,1 (Promega Biotech)] and 250 ul PMS solution are added to each well containing the remaining supernatant and cells and the cells incubated at 37° C. in 5% CO[0963] 2 until the color develops. The system is excited at 570 nm and read at 630 nm.
  • TNF Receptor II ELISA Assay [0964]
  • 1. Plate 100 μL/well 2 μg/mL mouse anti-human TNFrII antibody (R&D Systems #MAB226) in 1×PBS (pH 7.1, Gibco) on NUNC-Immuno Maxisorb plate. Incubate the plate at 4° C. overnight (about 18-20 hours). [0965]
  • 2. Wash the plate with PBS-Tween (1×PBS w/0.05% Tween). [0966]
  • 3. Add 200 μL 5% BSA in PBS and block at 37° C. in a water saturated atmosphere for 2 hours. [0967]
  • 4. Wash the plate with PBS-Tween. [0968]
  • 5. Add sample and controls (100 μl of each) to each well. The standards are 0, 50, 100, 200, 300 and 500 μg recombinant human TNFrII (R&D Systems #226-B2) in 100 μL 0.5% BSA in PBS. The assay is linear to between 400-500 pg of standard. [0969]
  • 6. Incubate at 37° C. in a saturated atmosphere for 1.5 hours. [0970]
  • 7. Wash the plate with PBS-Tween. [0971]
  • 8. Add 100 μL goat anti-human TNFrII polyclonal (1.5 μg/mL R&D Systems #AB226-PB in 0.5% BSA in PBS). [0972]
  • 9. Incubate at 37° C. in a saturated atmosphere for 1 hour. [0973]
  • 10. Wash the plate with PBS-Tween. [0974]
  • 11. Add 100 μL anti-goat IgG-peroxidase (1:50,000 in 0.5% BSA in PBS, Sigma #A5420). [0975]

Claims (49)

1-66. (canceled).
67. A compound or a pharmaceutically acceptable salt thereof, wherein:
the compound corresponds in structure to the following formula:
Figure US20040235818A1-20041125-C04708
R14 is selected from the group consisting of hydrogen and C(W)R25;
W is selected from the group consisting of O and S;
R25 is selected from the group consisting of C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, aryl-C1-C6-alkoxy, aryl-C1-C6-alkyl, heteroaryl, and amino C1-C6-alkyl, wherein:
the amino C1-C6-alkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryl-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl, or
the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring;
g is zero, 1, or 2;
m is zero, 1, or 2;
n is zero, 1, or 2;
p is zero, 1, or 2;
the sum of m+n+p=1,2,3, or 4; as to X, Y, and Z:
(a) one of X, Y, and Z is selected from the group consisting of C(O), S, S(O), S(O)2, and NS(O)2R7, and the remaining two of X, Y, and Z are CR8R9, and CR10R11, or
(b) X and Z, or Z and Y together constitute a moiety selected from the group consisting of NR6C(O), NR6S(O), NR6S(O)2, NR6S, NR60, SS, NR6NR6, and OC(O), with the remaining one of X and Y being CR8R9, or
(c) n is zero and X, Y, and Z together constitute a moiety selected from the group consisting of:
Figure US20040235818A1-20041125-C04709
wherein wavy lines are bonds to the atoms of the depicted ring;
R6 and R6′ are independently selected from the group consisting of hydrogen, formyl, sulfonic-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, C1-C6-alkylcarbonyl-C1-C6-alkyl, R8R9-aminocarbonyl-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkylcarbonyl, hydroxycarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkylcarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C1-C6-alkylcarbonylcarbonyl, R8R9-aminocarbonylcarbonyl, C1-C6-alkanoyl, aryl-C1-C6-alkyl, aroyl, bis(C1-C6-alkoxy-C1-C6-alkyl)-C1-C6-alkyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-perfluoroalkyl, C1-C6-trifluoromethylalkyl, C1-C6-perfluoroalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, heteroarylcarbonyl, heterocyclocarbonyl, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkylcarbonyl, aryl, 5- to 6-membered heterocyclo, 5- to 6-membered heteroaryl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkoxy-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, arylsulfonyl, C1-C6-alkylsulfonyl, 5- to 6-membered heteroarylsulfonyl, carboxy-C1-C6-alkyl, C1-C4-alkoxycarbonyl-C1-C6-alkyl, aminocarbonyl, C1-C6-alkyl(R8N)iminocarbonyl, aryl(R8N)iminocarbonyl, 5- to 6-membered heterocyclo(R8N)iminocarbonyl, arylthio-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C3-C6-alkenyl, C1-C4-alkylthio-C3-C6-alkenyl, 5- to 6-membered heteroaryl-C1-C6-alkyl, halo-C1-C6-alkanoyl, hydroxy-C1-C6-alkanoyl, thiol-C1-C6-alkanoyl, C3-C6-alkenyl, C3-C6-alkynyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C5-alkoxycarbonyl, aryloxycarbonyl, NR8R9—(R8)iminomethyl, NR8R9—C1-C5-alkylcarbonyl, hydroxy-C1-C5-alkyl, R8R9-aminocarbonyl, R8R9-aminocarbonyl-C1-C6-alkylcarbonyl, hydroxyaminocarbonyl, R8R9-aminosulfonyl, R8R9-aminosulfon-C1-C6-alkyl, R8R9-amino-C1-C6-alkylsulfonyl, and R8R9-amino-C1-C6-alkyl;
R7 is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl, and C1-C6-hydroxyalkyl;
as to R8:
R8 is selected from the group consisting of hydrogen, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, arylalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-C6-alkylsulfinyl-C1-C6-alkyl, arylsulfinyl-C1-C6-alkyl, heteroarylsulfinyl-C1-C6-alkyl, C1-C6-alkylsulfonyl-C1-C6-alkyl, arylsulfonyl-C1-C6-alkyl, heteroarylsulfonyl-C1-C6-alkyl, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein:
the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl, or
R8 and R9, together with the carbon to which they are bonded, form a carbonyl group, or
R8 and R9 or R8 and R10, together with the atom(s) to which they are bonded, form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
as to R9:
R9 is selected from the group consisting of hydrogen, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, arylalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-C6-alkylsulfinyl-C1-C6-alkyl, arylsulfinyl-C1-C6-alkyl, heteroarylsulfinyl-C1-C6-alkyl, C1-C6-alkylsulfonyl-C1-C6-alkyl, arylsulfonyl-C1-C6-alkyl, heteroarylsulfonyl-C1-C6-alkyl, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein:
the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl, or
R8 and R9, together with the carbon to which they are bonded, form a carbonyl group, a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
as to R10:
R10 is selected from the group consisting of hydrogen, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, arylalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-C6-alkylsulfinyl-C1-C6-alkyl, arylsulfinyl-C1-C6-alkyl, heteroarylsulfinyl-C1-C6-alkyl, C1-C6-alkylsulfonyl-C1-C6-alkyl, arylsulfonyl-C1-C6-alkyl, heteroarylsulfonyl-C1-C6-alkyl, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein:
the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl,
R10 and R11, together with the carbon to which they are bonded, form a carbonyl group, or
R10 and R11 or R8 and R10, together with the atom(s) to which they are bonded, form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
as to R11:
R11 is selected from the group consisting of hydrogen, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, arylalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-C6-alkylsulfinyl-C1-C6-alkyl, arylsulfinyl-C1-C6-alkyl, heteroarylsulfinyl-C1-C6-alkyl, C1-C6-alkylsulfonyl-C1-C6-alkyl, arylsulfonyl-C1-C6-alkyl, heteroarylsulfonyl-C1-C6-alkyl, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein:
the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl, or
R10 and R11, together with the carbon to which they are bonded, form a carbonyl group, a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
only one of R8 and R9 or R10 and R11 is hydroxy;
R12 and R12′ are independently selected from the group consisting of hydrogen, C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroarylalkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aryloxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-C6-alkylsulfinyl-C1-C6-alkyl, arylsulfinyl-C1-C6-alkyl, heteroarylsulfinyl-C1-C6-alkyl, C1-C6-alkylsulfonyl-C1-C6-alkyl, arylsulfonyl-C1-C6-alkyl, heteroarylsulfonyl-C1-C6-alkyl, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein:
the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl;
R13 is selected from the group consisting of hydrogen, benzyl, phenyl, C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, and C1-C6-hydroxyalkyl;
Q is a 5- to 7-membered heterocyclic ring (other than piperazinyl) containing one or two nitrogen atoms;
A is selected from the group consisting of:
(1)—O—,
(2) —S—,
(3) —NR17—,
(4) —CO—N(R17),
(5) —N(R17)—CO—,
(6) —CO—O—,
(7) —O—CO—,
(8) —O—CO—O—,
(9) —HC═CH—,
(10) —NH—CO—NH—,
(11) —C≡C—,
(12)—NH—CO—O—,
(13) —O—CO—NH—,
(14) —N═N—,
(15) —NH—NH—,
(16) —CS—N(R17)—,
(17) —N(R17)—CS—, and
(18) a bond;
R17 is selected from the group consisting of hydrogen, C1-C4-alkyl, and phenyl;
R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocyclothioalkyl, wherein:
the aryl, heteroaryl, cycloalkyl, or heterocyclo is optionally substituted with up to two substituents independently selected from the group consisting of halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C1-C2-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl;
R is other than alkyl or alkoxyalkyl when A is —O— or —S—;
E is selected from the group consisting of:
(1) —CO(R19)—,
(2) —(R19)CO—,
(3) —CONH—,
(4) —HNCO—,
(5) —CO—,
(6) —SO2—R19—,
(7) —R19—SO2—,
(8) —SO2—,
(9)—NH—SO2—,
(10) —SO2—NH—,
(11) —S—,
(12) —NH—CO—O—,
(13) —O—CO—NH—, and
(14) a bond;
R19 is selected from the group consisting of heterocycloalkyl and cycloalkyl; and
Y2 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein:
the aryl, heteroaryl, aralkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkanoyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy, and amino, wherein:
the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and arylalkyl.
68. A compound or salt according to claim 67, wherein g is 2.
69. A compound or salt according to claim 68, wherein A-R-E-Y2 is bonded at the 4-position of Q relative to the phenyl-bonded nitrogen of Q when Q is a 6- or 7-membered ring, and at the 3- or 4-position of Q relative to the phenyl-bonded nitrogen of Q when Q is a 5-membered ring.
70. A compound or salt according to claim 69, wherein R14 is hydrogen.
71. A compound or salt according to claim 69, wherein:
R14 is C(W)R25;
W is O; and
R25 is selected from the group consisting of C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, and aryloxy.
72. A compound or salt according to claim 69, wherein A is selected from the group consisting of —O— and —S—.
73. A compound or salt according to claim 69, wherein R is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocyclo.
74. A compound or salt according to claim 69, wherein the compound corresponds in structure to formula B-1A:
Figure US20040235818A1-20041125-C04710
75. A compound or salt according to claim 69, wherein Q is a 5-membered ring.
76. A compound or salt according to claim 69, wherein Q is a 7-membered ring.
77. A compound or salt according to claim 69, wherein Q is a 6-membered ring.
78. A compound or salt according to claim 77, wherein the compound corresponds in structure to the following formula:
Figure US20040235818A1-20041125-C04711
79. A compound or salt according to claim 78, wherein:
the compound corresponds in structure to the following formula:
Figure US20040235818A1-20041125-C04712
Z is selected from the group consisting of C(O), S, S(O), S(O)2, and NS(O)2R7.
80. A compound or salt according to claim 79, wherein R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, and cycloalkylthioalkyl, wherein:
the aryl, heteroaryl, or cycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C1-C2-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl.
81. A compound or salt according to claim 80, wherein R is selected from the group consisting of aryl, heteroaryl, and cycloalkyl.
82. A compound or salt according to claim 79, wherein Z is S.
83. A compound or salt according to claim 68, wherein the compound corresponds in structure to the formula:
Figure US20040235818A1-20041125-C04713
84. A compound or salt according to claim 83, wherein R-E-Y2 is bonded at the 4-position of Q relative to the phenyl-bonded nitrogen of Q when Q is a 6- or 7-membered ring, and at the 3- or 4-position of Q relative to the phenyl-bonded nitrogen of Q when Q is a 5-membered ring.
85. A compound or salt according to claim 84, wherein:
the compound corresponds in structure to formula XI-1:
Figure US20040235818A1-20041125-C04714
Z is selected from the group consisting of C(O), S, S(O), S(O)2, and NS(O)2R7.
86. A compound or a pharmaceutically acceptable salt thereof, wherein:
the compound corresponds in structure to the following formula:
Figure US20040235818A1-20041125-C04715
R14 is selected from the group consisting of hydrogen and C(W)R25;
W is selected from the group consisting of O and S;
R25 is selected from the group consisting of C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, aryl-C1-C6-alkoxy, aryl-C1-C6-alkyl, heteroaryl, and amino C1-C6-alkyl, wherein:
the amino C1-C6-alkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryl-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl, or
the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring;
g is zero, 1, or 2;
m is zero, 1, or 2;
n is zero, 1, or 2;
p is zero, 1, or 2;
the sum of m+n+p=1, 2, 3, or 4;
as to X, Y, and Z:
(a) one of X, Y, and Z is selected from the group consisting of C(O), S, S(O), S(O)2, and NS(O)2R7, and the remaining two of X, Y, and Z are CR8R9, and CR10R11, or
(b) X and Z, or Z and Y together constitute a moiety selected from the group consisting of NR6C(O), NR6S(O), NR6S(O)2, NR6S, NR60, SS, NR6NR6, and OC(O), with the remaining one of X and Y being CR8R9, or
(c) n is zero and X, Y, and Z together constitute a moiety selected from the group consisting of:
Figure US20040235818A1-20041125-C04716
wherein wavy lines are bonds to the atoms of the depicted ring;
R6 and R6 are independently selected from the group consisting of hydrogen, formyl, sulfonic-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, C1-C6-alkylcarbonyl-C1-C6-alkyl, R8R9-aminocarbonyl-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkylcarbonyl, hydroxycarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkylcarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C1-C6-alkylcarbonylcarbonyl, R8R9-aminocarbonylcarbonyl, C1-C6-alkanoyl, aryl-C1-C6-alkyl, aroyl, bis(C1-C6-alkoxy-C1-C6-alkyl)-C1-C6-alkyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-perfluoroalkyl, C1-C6-trifluoromethylalkyl, C1-C6-perfluoroalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, heteroarylcarbonyl, heterocyclocarbonyl, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkylcarbonyl, aryl, 5- to 6-membered heterocyclo, 5- to 6-membered heteroaryl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkoxy-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, arylsulfonyl, C1-C6-alkylsulfonyl, 5- to 6-membered heteroarylsulfonyl, carboxy-C1-C6-alkyl, C1-C4-alkoxycarbonyl-C1-C6-alkyl, aminocarbonyl, C1-C6-alkyl(R8N)iminocarbonyl, aryl(R8N)iminocarbonyl, 5- to 6-membered heterocyclo(R8N)iminocarbonyl, arylthio-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C3-C6-alkenyl, C1-C4-alkylthio-C3-C6-alkenyl, 5- to 6-membered heteroaryl-C1-C6-alkyl, halo-C1-C6-alkanoyl, hydroxy-C1-C6-alkanoyl, thiol-C1-C6-alkanoyl, C3-C6-alkenyl, C3-C6-alkynyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C5-alkoxycarbonyl, aryloxycarbonyl, NR8R9—(R8)iminomethyl, NR8R9—C1-C5-alkylcarbonyl, hydroxy-C1-C5-alkyl, R8R9-aminocarbonyl, R8R9-aminocarbonyl-C1-C6-alkylcarbonyl, hydroxyaminocarbonyl, R8R9-aminosulfonyl, R8R9-aminosulfon-C1-C6-alkyl, R8R9-amino-C1-C6-alkylsulfonyl, and R8R9-amino-C1-C6-alkyl;
R7 is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl, and C1-C6-hydroxyalkyl;
as to R8:
R8 is selected from the group consisting of hydrogen, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, arylalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-C6-alkylsulfinyl-C1-C6-alkyl, arylsulfinyl-C1-C6-alkyl, heteroarylsulfinyl-C1-C6-alkyl, C1-C6-alkylsulfonyl-C1-C6-alkyl, arylsulfonyl-C1-C6-alkyl, heteroarylsulfonyl-C1-C6-alkyl, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein:
the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl, or
R8 and R9, together with the carbon to which they are bonded, form a carbonyl group, or
R8 and R9 or R8 and R10, together with the atom(s) to which they are bonded, form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
as to R9:
R9 is selected from the group consisting of hydrogen, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol -C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, arylalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-C6-alkylsulfinyl-C1-C6-alkyl, arylsulfinyl-C1-C6-alkyl, heteroarylsulfinyl-C1-C6-alkyl, C1-C6-alkylsulfonyl-C1-C6-alkyl, arylsulfonyl-C1-C6-alkyl, heteroarylsulfonyl-C1-C6-alkyl, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein:
the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl, or
R8 and R9, together with the carbon to which they are bonded, form a carbonyl group, a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
as to R10:
R10 is selected from the group consisting of hydrogen, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, arylalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-C6-alkylsulfinyl-C1-C6-alkyl, arylsulfinyl-C1-C6-alkyl, heteroarylsulfinyl-C1-C6-alkyl, C1-C6-alkylsulfonyl-C1-C6-alkyl, arylsulfonyl-C1-C6-alkyl, heteroarylsulfonyl-C1-C6-alkyl, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein:
the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl,
R10 and R11, together with the carbon to which they are bonded, form a carbonyl group, or
R10 and R11 or R8 and R10, together with the atom(s) to which they are bonded, form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
as to R11:
R11 is selected from the group consisting of hydrogen, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, arylalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-C6-alkylsulfinyl-C1-C6-alkyl, arylsulfinyl-C1-C6-alkyl, heteroarylsulfinyl-C1-C6-alkyl, C1-C6-alkylsulfonyl-C1-C6-alkyl, arylsulfonyl-C1-C6-alkyl, heteroarylsulfonyl-C1-C6-alkyl, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein:
the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl, or
R10 and R11, together with the carbon to which they are bonded, form a carbonyl group, a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclo or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;
only one of R8 and R9 or R10 and R11 is hydroxy;
R12 and R12 are independently selected from the group consisting of hydrogen, C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroarylalkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocyclo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aryloxy-C1-C6-alkyl, amino-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C1-C6-alkylsulfinyl-C1-C6-alkyl, arylsulfinyl-C1-C6-alkyl, heteroarylsulfinyl-C1-C6-alkyl, C1-C6-alkylsulfonyl-C1-C6-alkyl, arylsulfonyl-C1-C6-alkyl, heteroarylsulfonyl-C1-C6-alkyl, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein:
the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl;
R13 is selected from the group consisting of hydrogen, benzyl, phenyl, C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, and C1-C6-hydroxyalkyl;
Q is a 5- to 7-membered heterocyclic ring (other than piperazinyl) containing one or two nitrogen atoms;
E is selected from the group consisting of:
(1) —CO(R19)—,
(2) —(R19)CO—,
(3) —CONH—,
(4) —HNCO—,
(5) —CO—,
(6) —SO2—R19—,
(7) —R19—SO2—,
(8) —SO2—,
(9) —NH—SO2—,
(10) —SO2—NH—,
(11) —S—,
(12) —NH—CO—O—,
(13) —O—CO—NH—, and
(14) a bond;
R19 is selected from the group consisting of heterocycloalkyl and cycloalkyl; and
Y2 is selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocyclo, heterocycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein:
the aryl, heteroaryl, aralkyl, heterocyclo, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkyl, alkanoyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy, and amino, wherein:
the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and arylalkyl.
87. A compound or salt according to claim 86, wherein g is 2.
88. A compound or salt according to claim 87, wherein the compound corresponds in structure to the following formula:
Figure US20040235818A1-20041125-C04717
89. A compound or salt according to claim 87, wherein:
the compound corresponds in structure to formula IX-2:
Figure US20040235818A1-20041125-C04718
Z is selected from the group consisting of C(O), S, S(O), S(O)2, and NS(O)2R7.
90. A compound or salt according to claim 87, wherein E-Y2 is bonded at the 4-position of Q relative to the phenyl-bonded nitrogen of Q when Q is a 6- or 7-membered ring, and at the 3- or 4-position of Q relative to the phenyl-bonded nitrogen of Q when Q is a 5-membered ring.
91. A compound or salt according to claim 90, wherein Y2 is selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein:
the aryl, heteroaryl, aralkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkanoyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy, and amino, wherein:
the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and arylalkyl.
92. A compound or salt according to claim 90, wherein R14 is hydrogen.
93. A compound or salt according to claim 90, wherein:
R14 is C(W)R25;
W is O; and
R25 is selected from the group consisting of C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-Cs-cycloalkyl-C1-C6-alkyl, and aryloxy.
94. A compound or salt according to claim 90, wherein the compound corresponds in structure to formula B-3A:
Figure US20040235818A1-20041125-C04719
95. A compound or salt according to claim 90, wherein Q is a 5-membered ring.
96. A compound or salt according to claim 90, wherein Q is a 7-membered ring.
97. A compound or salt according to claim 90, wherein Q is a 6-membered ring.
98. A compound or salt according to claim 97, wherein the compound corresponds in structure to the following formula:
Figure US20040235818A1-20041125-C04720
99. A compound or salt according to claim 98, wherein:
the compound corresponds in structure to formula IX-1:
Figure US20040235818A1-20041125-C04721
Z is selected from the group consisting of C(O), S, S(O), S(O)2, and NS(O)2R7.
100. A compound or salt according to claim 99, wherein Y2 is selected from the group consisting of alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein:
the aryl, heteroaryl, aralkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkanoyl, halo, nitro, arylalkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy, and amino, wherein:
the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and arylalkyl.
101. A compound or salt according to claim 99, wherein Z is S.
102. A compound or salt according to claim 101, wherein the compound corresponds in structure to the formula:
Figure US20040235818A1-20041125-C04722
103. A method for treating a pathological condition in a mammal, wherein:
the condition is treatable by inhibiting matrix metalloprotease activity;
the method comprises administering a compound or a pharmaceutically acceptable salt thereof to the mammal in an amount that is effective to treat the condition;
the compound corresponds in structure to a compound recited in claim 68; and
the compound or salt inhibits the activity of one or more of MMP-2, MMP-9, and MMP-13, while exhibiting substantially less inhibitory activity against MMP-1.
104. A method according to claim 103, wherein A is a bond.
105. A method according to claim 103, wherein the pathological condition is selected from the group consisting of rheumatoid arthritis, osteoarthritis, septic arthritis, corneal, epidermal or gastric ulceration, tumor metastasis, invasion or angiogenesis, periodontal disease, proteinuria, Alzheimer's disease, coronary thrombosis, and bone disease.
106. A method according to claim 105, wherein the pathological condition is osteoarthritis.
107. A method according to claim 103, wherein the compound or salt is administered a plurality of times.
108. A method for treating a pathological condition in a mammal, wherein:
the condition is treatable by inhibiting matrix metalloprotease activity;
the method comprises administering a compound or a pharmaceutically acceptable salt thereof to the mammal in an amount that is effective to treat the condition;
the compound corresponds in structure to a compound recited in claim 87; and
the compound or salt inhibits the activity of one or more of MMP-2, MMP-9, and MMP-13, while exhibiting substantially less inhibitory activity against MMP-1.
109. A method according to claim 108, wherein the pathological condition is selected from the group consisting of rheumatoid arthritis, osteoarthritis, septic arthritis, corneal, epidermal or gastric ulceration, tumor metastasis, invasion or angiogenesis, periodontal disease, proteinuria, Alzheimer's disease, coronary thrombosis, and bone disease.
110. A method according to claim 109, wherein the pathological condition is osteoarthritis.
111. A method according to claim 108, wherein the compound or salt is administered a plurality of times.
112. A pharmaceutical composition that comprises a compound or salt according to claim 68 dissolved or dispersed in a pharmaceutically acceptable carrier.
113. A pharmaceutical composition according to claim 112, wherein A is a bond.
114. A pharmaceutical composition that comprises a compound or salt according to claim 87 dissolved or dispersed in a pharmaceutically acceptable carrier.
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