Classifications

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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
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  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
  • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
  • C07C311/17—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
  • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
  • C07C323/46—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms
  • C07C323/49—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms to sulfur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
  • C07D207/48—Sulfur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
  • C07D211/96—Sulfur atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
  • C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
  • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
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  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• This invention is directed to proteinase (protease) inhibitors, and more particularly to thiol sulfonamide inhibitors for matrix metalloproteinases, compositions of proteinase inhibitors, intermediates for the syntheses of proteinase inhibitors, processes for the preparation of proteinase inhibitors and processes for treating pathological conditions associated with pathological matrix metalloproteinase activity .
• Connective tissue, extracellular matrix constituents and basement membranes are required components of all mammals. These components are che 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, proteogiycans, fibronectin and laminin. These biochemicals makeup, or are components of structures, such as skin, bone, teeth, tendon, cartilage, basement membrane, blood vessels, cornea and vitreous humor . 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.
• 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, 72kDa gelatinase, basement membrane collagenase; EC 3.4.24.24), gelatinase B (MMP-9, 92kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11), metalloelastase (MMP-12, HME, human macrophage elastase) and membrane
• MMP is an abbreviation or acronym representing the term Matrix Metalloprotease with the attached numerals providing differentiation between specific members of the MMP group.
• 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 pos -surgical adhesions .
• TNF- ⁇ tumor necrosis factor
• Matrix 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- ⁇ 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 vi tro 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.
• TNF- ⁇ convertase is a metalloproteinase involved in the formation of active TNF- ⁇ .
• TNF- ⁇ convertase inhibits production of active TNF- ⁇ .
• Compounds that inhibit both MMPs activity have been disclosed in IPO International Publication Nos . WO 94/24140, WO 94/02466 and WO 97/20824.
• MMP and TNF- ⁇ convertase inhibiting agents 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)).
• 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 ⁇ -protease inhibitor ( ⁇ -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 ⁇ -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, or collagenase III are 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 in 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.
• Inhibitors of metalloproteases are known. Examples include natural biochemicals such as tissue inhibitor of metalloproteinase (TIMP) , ⁇ 2 ⁇ acroglobulin and their analogs or derivatives. These 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 vi tro 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, W095/12389, WO96/11209 and U.S. 4,595,700.
• MMP metalloprotease
• the present invention is directed to a process for treating a mammal having a condition associated with pathological matrix metalloprotease (MMP) activity, as well as to molecules that particularly inhibit the activity of MMP-13.
• MMP pathological matrix metalloprotease
• one embodiment of the present invention is directed to a process for treating a mammal having a condition associated with pathological matrix metalloprotease activity that comprises administering a metalloprotease inhibitor in an effective amount to a host having such a condition.
• the administered enzyme inhibitor corresponds in structure to one of formulae (I) , (II) or (III) , below
• R 9 group is an alkyl, aryl, alkoxy, cycloalkyl, aryloxy, aralkoxy, aralkyl, aminoalkyl, heteroaryl and N-monosubstituted or N,N-disubstituted aminoalkyl group wherein the substituent (s) on the nitrogen are selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl , alkoxycarbonyl, and alkanoyl, or wherein the nitrogen and two substituents attached thereto form a 5- to 8 -membered heterocyclic or heteroaryl ring.
• a contemplated R-*- group is linked to the SO2 portion of an inhibitor and is an alkyl, cycloalkyl, heterocycloalkyl , aralkanoylalkyl , arylcarbonylalkyl, hydroxyalkyl , alkanoylalkyl , aralkylaryl, aryloxyalkylaryl, aralkoxyaryl , arylazoaryl, arylhydrazinoaryl , haloalkyl, alkylthioaryl , arylthioalkyl , alkylthioaralkyl, aralkylthioalkyl , or aralkylthioaryl group, the sulfoxide or sulfone of any of those thio substituents, alkylthioalkyl, and preferably aryl and heterocyclic (heteroaryl) rings such as aralkyl, heteroaralkyl, aralkoxyalkyl
• aryl (carbocyclic) and heteroaryl substituents of R 1 are themselves unsubstituted or substituted with one or two substituents independently selected from among halo, c l" c 10 a lky_., C-L.C-JI Q alkoxy, nitro, cyano, perfluoroalkyl, trifluoromethylalkyl , hydroxy, thiol, hydroxycarbonyl , aryloxy, arylthio, arylamino, aralkyl, arylcarboxamido, heteroarylcarboxamido, azoaryl, azoheteroaryl , aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, cycloalkylamino, heteroaralkoxy,
• R 2 substituent can be hydrogen (hydrido) , an alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkynylalkyl , alkenylalkyl, thioalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl , alkoxyalkyl, aralkoxyalkyl , aminoalkyl, alkoxyalkoxyalkyl , aryloxyalkyl , hydroxyalkyl , hydroxycarbonylalkyl , hydroxycarbonylaralkyl , or N-monosubstituted or N,N-disubstituted aminoalkyl group wherein the substituent (s) on the nitrogen are selected from the group consisting of alkyl, aralkyl, cycloalkyl and alkanoyl, or wherein R 2 and the nitrogen to which it is bonded and another substituent (i
• R 2 and R 6 or R 2 and R 8 together form a 4- to 8-membered heterocyclo or heteroaryl ring.
• R 3 and R 4 groups are independently selected.
• substituents can be hydrogen (hydrido) , an alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, aryloxyalkyl, aralkoxyalkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl , aralkoxycarbonylalkyl , hydroxycarbonyl , alkoxycarbonyl, perfluoroalkyl , trifluoromethylalkyl, thioalkyl, alkylthioalkyl, arylthioalkyl, aralkylthioalkyl , heteroaralkylthioalkyl , or a sulfoxide or sulfone of any of the thio substituents, aminocarbonyl, aminocarbonylalkyl, N-
• R 5 and R 6 substituents are also independently selected.
• R ⁇ and R 6 substituents can be a substituent that constitutes R 3 and R 4 , or R 6 and R 4 together with atoms to which they are attached form a 4- to 8-membered ring, or R 6 and R 2 together with the atoms to which they are attached form a 5- to 8-membered ring (as above) , or R 6 and R 8 together with the atoms to which they are attached form a 4- to 8-membered ring, or R ⁇ and R 6 together with atom to which they are attached form a 3- to 8-membered ring.
• R 7 and R 8 substituents are also independently selected.
• R 7 and R 8 substituents can also be a substituent that constitutes R-* and R , or R 8 and R 2 together with the atoms to which they are attached form a 6- to 8-membered ring (as above) , or R 7 and R 8 together with the atom to which they are attached form a 3- to 8-membered ring, or R 8 and R 4 together with the atom to which they are attached form a 5- to 8-membered ring (as above) , or R 8 and R 6 together with the atoms to which they are attached form a 4- to 8-membered ring (as above) .
• the present invention is also directed to a more preferred sub-set of molecules of formulas I, II, and III, above.
• x is zero so that the mercapto group is bonded directly to the carbon atom that bears the R 5 and R 6 substituent radicals, which are themselves both hydrido, as is R 3 .
• R 5 and R 6 substituent radicals which are themselves both hydrido, as is R 3 .
• R 2 is other than hydrogen (hydrido) unless R 1 is phenylazophenyl , R 1 is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group containing one 5- or 6 -membered ring; i.e. Rl is not a fused aryl ring or heteroaryl group, and a compound of formula III is a homodimer.
• R 1 is phenylazophenyl
• R 1 is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group containing one 5- or 6 -membered ring; i.e. Rl is not a fused aryl ring or heteroaryl group, and a compound of formula III is a homodimer.
• a contemplated inhibitor compound constitutes another sub-set of the compounds of formulas I, II and III.
• R 3 , R 5 and R 6 are again hydrido
• the S ⁇ 2 ⁇ linked R 1 substituent is a 4 -substituted phenyl group (PhR 11 )
• W is 0.
• Yet another aspect of the invention is directed to a matrix metalloprotease inhibitor corresponding to formula IV, below,
• R 10 is hydrogen (hydrido) or -C(0)-R 5, and R 1 ,
• R 2 , R 3 , R 4 , R 5 , R 6 , R 9 and x are as defined above, and Y represents hydrogen, halogen, alkyl, alkoxy, nitro, cyano, carboxy or amino.
• a benefit of this invention is the provision of a compound and composition effective for inhibiting metalloproteinases, particularly 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.
• An advantage of the invention is the provision of a method for preparing such compositions.
• Another benefit is the provision of a method for treating a pathological condition associated with abnormal matrix metalloproteinase activity.
• Another advantage is the provision of compounds, compositions and methods effective for treating such pathological conditions by selective inhibition of a metalloproteinase, MMP-13, associated with such conditions with minimal side effects resulting from inhibition of other proteinases whose activity is necessary or desirable for normal body function.
• MMP-13 metalloproteinase
• certain thiol sulfonamides 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 thiol sulfonamides are effective for inhibition of collagenase III (MMP-13) , which can be particularly destructive to tissue if present or generated in abnormal quantities or concentrations, and thus exhibit a pathological activity.
• thiol sulfonamides are selective in the inhibition of MMP-13, as well as other MMPs associated with diseased conditions without excessive " inhibition of other collagenases essential to normal bodily function such as tissue turnover and repair. More particularly, it has been found that particularly preferred the thiol sulfonamides of the invention are particularly active in inhibiting of MMP-13, while being selective for MMP-13, in having a limited or minimal effect on MMP-1. This point is discussed in detail hereinafter and is illustrated in several examples.
• One embodiment of the present invention is directed to a process for treating a mammal having a condition associated with pathological matrix metalloprotease activity. That process comprises administering a metalloprotease inhibitor in an effective amount to a host having such a condition.
• the administered enzyme inhibitor corresponds in structure to one of formulas (I), (II) or (III), below
• a contemplated R 9 group is an alkyl, aryl, alkoxy, cycloalkyl, aryloxy, aralkoxy, aralkyl, aminoalkyl, heteroaryl and N-monosubstituted or N,N-disubstituted aminoalkyl group wherein the substituent (s) on the nitrogen are selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl , alkoxycarbonyl , and alkanoyl , or wherein the nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring;
• a contemplated R 1 group is linked to the
• SO2 portion of an inhibitor is an alkyl, cycloalkyl, heterocycloalkyl, aralkanoylalkyl, arylcarbonylalkyl, hydroxyalkyl, alkanoylalkyl , aralkylaryl, aryloxyalkylaryl, aralkoxyaryl , arylazoaryl, arylhydrazinoaryl , haloalkyl, alkylthioaryl, arylthioalkyl , alkylthioaralkyl , aralkylthioalkyl, or aralkylthioaryl group, the sulfoxide or sulfone of any of those thio substituents, alkylthioalkyl, and preferably aryl (carbocyclicaryl) and heteroaryl rings such as aralkyl, heteroaralkyl, aralkoxyalkyl, aryloxyalkyl, as well as a fused
• aryl and heteroaryl substituents of which R 1 can be comprised are unsubstituted or preferably substituted with one (preferably) or two substituents independently selected from among halo, C-L-C-L Q alkyl, C- ⁇ .
• R 2 substituent can be hydrogen (hydrido), an alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkynylalkyl , alkenylalkyl, thioalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, aralkoxyalkyl, aminoalkyl, alkoxyalkoxyalkyl , aryloxyalkyl, hydroxyalkyl, hydroxycarbonylalkyl, hydroxycarbonylaralkyl, or N-monosubstituted or N,N-disubstituted aminoalkyl group wherein the substituent (s) on the nitrogen are selected from the group consisting of alkyl, aralkyl, cycloalkyl and alkanoyl, or wherein R 2 and the nitrogen to which it is bonded and another substituent (i.e., R 2 and R
• R 3 and R 4 groups are independently selected.
• substituents can be hydrogen (hydrido), an alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, aryloxyalkyl, aralkoxyalkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, hydroxycarbonyl , alkoxycarbonyl, perfluoroalkyl , trifluoromethylalkyl, thioalkyl, alkylthioalkyl, arylthioalkyl, aralkylthioalkyl , heteroaralkyl - thioalkyl, or a sulfoxide or sulfone of any of the thio substituents, aminocarbonyl, aminocarbonylalkyl, N-mono
• R 5 and R 6 substituents are also independently selected.
• R 5 and R 6 substituents can be a substituent that constitutes R 3 and R 4 .
• R 6 and R 4 together with atoms to which they are attached form a 4- to 8-membered ring
• R 6 and R 2 together with the atoms to which they are attached form a 5- to 8-membered ring (as above)
• R 6 and R 8 together with the atoms to which they are attached form a 4- to 8-membered ring, or R 5 and R ⁇ together with atom to which they are attached form a 3- to 8-membered ring;
• R 7 and R 8 substituents are also independently selected.
• R 7 and R 8 substituents can also be a substituent that constitutes R 3 and R 4 .
• R s and R 2 together with the atoms to which they are attached form a 6- to 8-membered ring
• R 7 and R 8 together with the atom to which they are attached form a 3- to 8-membered ring
• R 8 and R 4 together with the atom to which they are attached form a 5- to 8-membered ring (as above)
• R 8 and R 6 together with the atoms to which they are attached form a 4- to 8-membered ring (as above) .
• a provision to the above definitions is provided that no carbon atom is geminally substituted with more than one sulfhydryl group.
• starred substituent "R" groups and “x” of formula III are the same as or different from the unstarred "R” groups and "x” .
• R 1 represents an aryl or heteroaryl ring -Cl ⁇ c 10 alkyl, wherein the aryl or heteroaryl ring can optionally be substituted by one or more of the following substituents: C]_-C ] _ Q alkyl, alkoxy, aryloxy, heteroaryloxy, aryl, heteroaryl, aralkoxy, heteroaralkoxy, C]_-C ⁇ _o alkylthio, arylthio, heteroarylthio .
• R 1 represents a single aryl or heteroaryl ring, wherein the single aryl or heteroaryl ring can optionally be substituted by one or more of the following substituents: C_-C alkyl, C ⁇ -Cg alkoxy, arylcarboxamido , heteroarylcarboxamido , arylazo , heteroarylazo, aryloxy, heteroaryloxy, aryl, heteroaryl, aralkoxy, heteroaralkoxy, C ⁇ -Cg alkylthio, arylthio, heteroarylthio in which each ring -containing substituent itself contains a single ring.
• R 1 represents a 6 -membered aryl ring, wherein the aryl ring can optionally be substituted in the para-position (4-position) by one of the following substituents: C ⁇ -Cg alkyl, C ⁇ _-Cg alkoxy, arylcarboxamido, heteroarylcarboxamido, arylazo, heteroarylazo, aryloxy, heteroaryloxy, aryloxy, heteroaryloxy, aryl, heteroaryl, aralkoxy, heteroaralkoxy, C]_-Cg alkylthio, arylthio, heteroarylthio in which each ring-containing substituent itself contains a single ring.
• R 1 represents a 6-membered aryl ring, wherein the aryl ring is substituted in the para- position by C ⁇ -C alkyl, C ⁇ _-Cg alkoxy arylcarboxamido, arylazo, aryloxy, arylthio and aryl in which each ring-containing substituent itself contains a single ring.
• R 1 represents phenyl, wherein the phenyl ring is substituted in the para-position by n-propyl, n-butyl, n-pentyl, n-hexyl, isobutyl, isoamyl, " -ethoxy, n-propyloxy, n-butoxy, n-pentyloxy, n-hexyloxy, isobutoxy, phenoxy, thiophenoxy (phenylthio) , phenyl, azophenyl or benzamido, in which the para-substituted R 1 phenyl substituent can itself optionally contain a meta- or para- substituent, or both containing one atom or a chain of no more than five atoms other than hydrogen.
• R 2 represents hydrogen, C ] _-Cg alkyl, aralkyl, heteroaralkyl, cycloalkylalkyl having 4-8 carbons in the ring and 1-3 carbons in the alkyl chain, heterocycloalkylalkyl in which 4-8 atoms are in the ring, one or two of which atoms can be nitrogen, oxygen or sulfur and in which the alkyl chain contains 1-3 carbons, C1-C5 alkyl substituted by hydroxycarbonyl , amino, mono-substituted amino and di-substituted amino, wherein the substituents on nitrogen are chosen from C ⁇ _C4 alkyl, aralkyl, C5 ⁇ Cg cycloalkyl and C ⁇ -Cg alkanoyl groups, or wherein the two substituents and the nitrogen to which they are attached when taken together form a 5- to 8-membered heterocyclo or heteroaryl ring.
• R 2 represents hydrogen, C ] __Cg alkyl, aralkyl, heteroaralkyl, cycloalkylalkyl having 4-8 carbons in the ring and 1-3 carbons in the alkyl chain, heterocycloalkylalkyl in which 4-8 atoms are in the ring, one or two of which atoms can be nitrogen, oxygen or sulfur and in which the alkyl chain contains 1-3 carbons.
• R 2 represents hydrogen or C ⁇ -Cg alkyl.
• R 2 represents hydrogen, methyl, ethyl, n-propyl, n-butyl, isobutyl.
• R 2 represents carbocyclic aralkyl or heteroaralkyl as discussed above.
• R 2 represents benzyl, 2 -pyridylmethyl , 3 -pyridylmethyl , 4 -pyridylmethyl , 2-thiazolylmethyl , 4 - thiazolylmethyl , 5-thiazolylmethyl .
• R 2 represents cycloalkylalkyl having 4-8 carbons in the ring and 1-3 carbons in the alkyl chain, heterocycloalkylalkyl in which 4-8 atoms are in the ring, one or two of which atoms can be nitrogen, oxygen or sulfur and in which the alkyl chain contains 1-3 carbons.
• R 2 represents cyclopropylmethyl, cyclopentylmethyl , cyclohexyl ethyl .
• R 2 represents alkyl substituted by hydroxycarbonyl, amino, mono- substituted amino and di-substituted amino, wherein the substituents on the amino nitrogen are chosen from C ⁇ -Cg alkyl, aralkyl,
• R 2 represents C1-C5 alkyl substituted by hydroxycarbonyl .
• R 2 represents 5-pentanoic acid, 4-n-butanoic acid, 3-propanoic acid or 2-ethanoic acid.
• R 2 represents hydrido, C ⁇ -C alkyl, C2-C4 alkyl substituted by amino, mono- substituted amino or di-substituted amino, wherein the substituents on nitrogen are chosen from C_-Cg alkyl, aralkyl, C5-C8 cycloalkyl and C]_-Cg alkanoyl, or wherein the two substituents and the nitrogen to which they are attached when taken together form a 5- to 8-membered heterocyclo or heteroaryl ring containing zero or one • additional hetero atoms that are nitrogen, oxygen or sulfur, a C; ⁇ _-C4 alkylaryl or C1-C4 alkylheteroaryl group having a single ring.
• R 2 represents methyl, 2 -aminoethyl ,
• R 3 and R 4 independently represent hydrogen, hydroxycarbonyl, aminocarbonyl, C -Cg alkyl, aralkyl, aryl, heteroaryl, C5-C8 cycloalkyl, heteroaralkyl, cycloalkylalkyl having 4-8 carbons in the ring and 1-3 carbons in the alkyl chain.
• R 3 is hydrido
• R 4 is hydroxycarbonyl, aminocarbonyl or C ⁇ _-C alkyl.
• R 3 and R 4 independently represents hydrogen, aminocarbonyl, methyl.
• R 3 is hydrido and R 4 represents methyl.
• R 3 is hydrido and R 4 represents hydroxycarbonyl or aminocarbonyl .
• R 3 represents hydrido and R 4 represents aminocarbonyl (carbamyl) or methyl.
• R 5 and R 6 Preferences:
• R ⁇ and R6 independently represent hydrogen (hydrido), hydroxycarbonyl, aryl, heteroaryl, C ⁇ _-Cg alkyl .
• R 5 and R 6 are both hydrido .
• R 7 and R 8 Preferences :
• R 7 and R 8 independently represent hydrogen, hydroxycarbonyl, C ] _-Cg alkyl.
• x is preferably zero.
• W is preferably oxygen (0) .
• R 9 represents C]_-Cg alkyl, aryl, C ⁇ _-Cg alkoxy, heteroaryl, amino C ⁇ -Cg alkyl,
• R 9 represents C; ⁇ _-C alkyl, C5-C8 cycloalkyl, aryl, C; ⁇ _-Cg alkoxy, heteroaryl, amino C ⁇ -Cg alkyl, N-monosubstituted amino C ⁇ -C alkyl and N,N-disubstituted amino C ⁇ _-Cg alkyl, wherein the substituents on nitrogen are chosen from C ⁇ -C alkyl, aralkyl, C5-C3 cycloalkyl and C ⁇ _-Cg alkanoyl, or wherein the two substituents and the nitrogen to which they are attached when taken together form a 5- to 8-membered heterocyclo or heteroaryl ring.
• R 9 represents C ⁇ _-Cg alkyl, C3_-C alkoxy, a single-ringed aryl or heteroaryl.
• R 9 represents methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl .
• R 9 represents a 3- to 8-membered cycloalkyl ring .
• R 9 represents cyclohexyl and cyclopentyl .
• R 9 represents aryl or heteroaryl.
• R 9 represents phenyl, 2 -pyridyl, 3 -pyridyl, 4 -pyridyl, thiophene-2-yl , 3 -thiophene-3 -yl .
• R 9 represents C ] _-Cg alkoxy.
• R 9 represents methoxy and ethoxy.
• Starred substituents, R* , and x* are preferably the same as unstarred substituents, R, and x so that a compound of formula III is homodimer.
• R 1 substituent is an aryl or heteroaryl group that is a 5- or 6-membered single-ring, and is itself substituted with one other single-ringed aryl or heteroaryl group or, with an alkyl or alkoxy group containing an umbranched chain of 3 to about 7 carbon atoms, a phenoxy group, a thiophenoxy [C5H5-S-] group, a phenylazido [C H5-N2 ⁇ ] group or a benzamido
• [-NHC (0) CgHs] group The S ⁇ 2 ⁇ linked single-ringed aryl or heteroaryl R 1 group is substituted at its own 4 -position when a 6-membered ring and at its own 3 -position when a 5-membered ring.
• the R 1 group's substituent single-ringed aryl or heteroaryl, phenoxy, thiophenoxy, phenylazo or benzamido group is unsubstituted or can itself be substituted at the 4 -position when a 6-membered ring or the 3 -position when a 5 -membered ring.
• 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.
• single atoms such as halogen moieties or substituents that contain one to a chain of about five atoms other than hydrogen such as C ⁇ -C4 alkyl, C 1 -C4 alkoxy or carboxyethyl groups can be used.
• exemplary substituted SO2- linked R 1 substituents include biphenyl , 4-phenoxyphenyl , 4-thiophenoxyphenyl , 4-butoxyphenyl , 4-pentylphenyl , 4- (4 ' -dimethylaminophenyl) azophenyl, and 2-[(2- pyridyl) -5-thienyl] .
• an R 1 substituent including its own substituent has a total length of greater than a saturated chain of four carbon atoms and less than a saturated chain of about 18 and preferably about 12 carbon atoms, even though many more atoms may be present in ring structures or substituents. This length requirement is discussed further below.
• R 1 radical (group or moiety) has a length greater than that of an butyl group.
• Such an R 1 radical also has a length that is less than that of a stearyl (octadecyl) group. That is to say that a particularly preferred R 1 is a radical having a length greater than that of a saturated four carbon chain, and shorter than that of a saturated eighteen carbon chain, and more preferably, a length greater than that of a pentyl group and less than that of a lauryl group.
• the radical chain lengths are measured along the longest linear atom chain in the radical, and each atom in the chain, e.g. oxygen 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 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 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.
• a particularly preferred R 1 group when rotated about an axis drawn through the S ⁇ 2 ⁇ bonded 1-position and the 4-position of a 6-membered ring or the S ⁇ 2 ⁇ bonded position and substituent-bonded 3- or 5 -position of a 5-membered ring defines a three-dimensional volume whose widest dimension has the width of about one phenyl ring to about three phenyl rings in a direction transverse to that axis to rotation.
• R 1 substituents such as 4- (phenyl) phenyl [biphenyl] ,
• MMP-13 inhibitor compounds useful in a before- described process has structures depicted by formulas la, Ila and Ilia, below.
• R 4 -containing carbon atom is that of a naturally- occurring amino acid.
• the substituent groups are discussed below for these compounds.
• R 1 group represents a single aryl or heteroaryl ring, wherein the single aryl ring is unsubstituted or can optionally be substituted by one or more of the following substituents: C ] _-Cg alkyl,
• a single-ringed aryl or heteroaryl group is
• 5- or 6-membered is itself preferably substituted at its own 4 -position when a 6-membered ring and at its own 3 -position when a 5 -membered ring with a substituent selected from the group consisting of one other single-ringed aryl or hetroaryl group, an alkyl or alkoxy group containing an umbranched chain of 3 to about 7 carbon atoms, a phenoxy group, a thiophenoxy group, a phenylazo group or a benzamido group .
• R 2 represents hydrido, C -Cg alkyl, C 2 -C 4 alkyl substituted by amino, mono-substituted amino or di-substituted amino, wherein the substituents on nitrogen are chosen from C -Cg alkyl, aralkyl, C5-C8 cycloalkyl and C]_-Cg alkanoyl, or wherein the two
• R 4 group is hydroxyxcarbonyl , aminocarbonyl or C ] _-Cg alkyl.
• W is sulfur or oxygen, but preferably oxygen (0) .
• An R 9 group represents a C ⁇ _-Cg alkyl group
• a most preferred MMP-13 inhibitor sub-set of compounds useful in a before-described process also preferably has the configuration of a naturally- occurring amino acid, and corresponds to the structures depicted by formulas lb, lib and Illb, below.
• R 4 group is C ⁇ -Cg alkyl, and particularly methyl, or aminocarbonyl [-C(0)NH2] .
• An R 2 group is C ] _-Cg alkyl and particularly methyl, a C2-C3 alkyl cycloamino group having five or six atoms in the ring and zero or one additional heteroatom that is oxygen or nitrogen, and ⁇ - ⁇ alkyl single-ringed aryl or heteroaryl, wherein the single heteroaryl ring contains one or two nitrogen atoms.
• Exemplary most preferred substituents in addition to methyl include 2- (4-morpholino) ethyl , 2- (1-piperidino) ethyl, 2- (1-pyrrolidino) ethyl and
• Hydrogen (hydrido) can also be a most preferred R 2 group as is discussed below.
• the sulfonyl group (-SO2-) of a most preferred sub-set of inhibitor compounds is linked to a phenyl group (Ph) , which itself is substituted at the 4-position by a substituent denominated R 11 that together with the phenyl group is referred to as
• PhR 11 A 4 -substituted phenyl group substituent
• R 11 can be C3-C8 alkoxy such as butoxy, C3-C8 alkyl such as pentyl , as well as phenoxy, thiophenoxy (phenylthio) , benzamido, phenylazo or phenyl.
• R 11 6-membered ring-containing substituent group can itself also be substituted in a 3-(meta) or 4- (para-) position, or both, with a halogen (fluorine, chlorine, bromine or iodine), a C1-C4 alkoxy group such as methoxy or isopropoxy, a * C ⁇ -C 4 alkyl group such as methyl, a two or three carbon-containing carboxyl group such as carboxymethyl or carboxyethyl an amine, or a mono- or di-C ⁇ _-C4 alkyl-substituted amine such as dimethyl amino.
• a 3 , 4-methylenedioxy substituent is a contemplated 3 , 4 -substituent , whereas methyl is a contemplated 3 -substituent .
• R 11 ring para substituent has one atom or a longest chain of up to five atoms, excluding hydrogen.
• R 9 represents a C ⁇ -C alkyl group, a C; ] _-C alkoxy group, a single-ringed carbocyclic aryl or heteroaryl group, and more particularly, a phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thiophene-2-yl , 3-thiophene-3-yl, methyl, ethyl, methoxy or ethoxy group .
• R 10 is hydrogen (hydrido) or -C(0)-R 9 ' and R 1 , R 2 , R 3 ,
• R 4 , R 5 , R 6 , R 9 and x are as defined above, and Y represents hydrogen, halogen, alkyl, alkoxy, nitro, cyano , carboxy or amino .
• substituent "R" groups and x are as they have been previously described in regard to formulas Ia-IIIa and Ib-IIIb, respectively, except that R 3 and R 4 are both hydrido in most preferred compounds.
• x is zero so that R 5 and R 6 • and the carbon to which they are bonded are absent, Y is hydrogen, and the sulfur atom bonded to the depicted phenyl ring is linked ortho to the sulfonamide-bearing carbon atom. It is thus seen that particularly preferred and most preferred compounds of formula IV constitute compounds of formulas I and II in which x is one, and the R° and
• R 8 substituents together with the atoms to which they are attached form a 6-membered, aromatic ring.
• a particularly or most preferred R 1 group is a radical having a length greater than that of a saturated four carbon chain, and shorter than that of a saturated eighteen carbon chain.
• the substituent defines a three-dimensional volume whose widest dimension has the width of about one phenyl ring to about three phenyl rings in a direction transverse to that axis to rotation.
• an SO2- linked R 1 substituent is an aryl or heteroaryl group that is a 5- or 6-membered single-ring, and is itself substituted with one other single-ringed aryl or heteroaryl group or, with an alkyl or alkoxy group containing an umbranched chain of 3 to about 7 carbon atoms, a phenoxy group, a thiophenoxy [C H5 ⁇ S-] group, a phenylazido [CgH5-N2 ⁇ ] group or a benzamido [-NHC(O) C 6 H 5 ] group.
• the S0 2 -linked single-ringed aryl or heteroaryl R 1 group is substituted at its own 4 -position when a 6-membered ring and at its own 3 -position when a 5 -membered ring
• R 2 represents hydrido, C ⁇ _-Cg alkyl, 2 - ⁇ alkyl substituted by amino, mono-substituted amino or di-substituted amino, wherein the substituents on nitrogen are chosen from C ] _-Cg alkyl, aralkyl, C 5 -Cg cycloalkyl and C ] _-Cg alkanoyl, or wherein the two substituents and the nitrogen to which they are attached when taken together form a 5- to 8-membered heterocyclo or heteroaryl ring containing zero or one additional hetero atoms that are nitrogen, oxygen or sulfur, a C1-C4 alkylaryl or C ⁇ _-C 4 alkylheteroaryl group having a
• R 3 group is hydrido
• R 4 is hydroxyxcarbonyl , aminocarbonyl or C ⁇ -C alkyl.
• R 3 and R 4 are both hydrido in most preferred compounds .
• An R 9 group represents C ⁇ -Cg alkyl, C ⁇ -Cg alkoxy, a single-ringed carbocyclic aryl or heteroaryl, and more particularly, phenyl, 2 -pyridyl, 3 -pyridyl, -pyridyl, thiophene-2-yl, 3-thiophene- 3-yl, methyl, ethyl, methoxy and ethoxy.
• Particularly preferred and most preferred compounds correspond to formulas IVa, IVb, IVc and IVd that are shown below:
• the compounds described herein are useful in a process described herein in that such compounds can inhibit the activity of MMP-13.
• a particularly preferred compound inhibits the enzyme with an IC5 value of about 1000 nm or less in the in vi tro assay discussed hereinafter.
• a most preferred compound exhibits an IC50 value in that assay of about 20 nm or less, with some compounds exhibiting values of about 1 nm or less.
• IC50 MMP-I/IC50 MMP-13 IC50 MMP-I/IC50 MMP-13
• Inhibition data for several exemplary compounds are provided in a table hereinafter.
• 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.
• xemplary 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 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.
• lower alkyl halides such as methyl, ethyl, propyl , and butyl chloride, bromides, and iodides
• dialkyl sulfates like dimethyl, diethyl, dibuytl, and dia
• the salts are formed by combining the basic compounds with the desired acid.
• 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 .
• 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 sub ultiples 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 useful in the present invention can be formulated as a pharmaceutical composition.
• compositions 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 tran ⁇ dermal 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, Pennsylvania; 1975 and Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980.
• 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.
• 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.
• the compounds 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 sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds 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.
• 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.
• Certain compounds of this invention can serve as prodrugs to other compounds of this invention.
• Prodrugs are drugs that can be chemically converted in vivo or in vi tro by biological systems into an active derivative or derivatives.
• An example from this invention are drugs of formula II (Ila or lib) where the acyl group is hydrolyzed to a compound of formula I (or la or lb) .
• An additional example is where a disulfide of this invention is reduced to its thiol product or, in some cases, converted into an active mixed disulfide. Table 1 through Table 80, below, show several series of compounds useful in this invention.
• R 2 is the variable group with the structural variables that can substitute for R 2 shown in the balance of the table.
• R 2 groups including hydrogen
• Table 43 illustrates a compound with a generic structure containing two variable groups. The groups are R 1 and R 2 .
• this example shows a matrix of 12 Rl groups and 10 R 2 groups (including hydrogen) that represent 120 non- limiting compounds of this invention that can be prepared.
• 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 documen .
• Common illustrative examples include such terms as aralkyl (or arylalkyl), heteroaralkyl, heterocycloalkyl , cycloalkylalkyl, aralkoxyalkoxycarbonyl and the like.
• 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 .
• Such combinations are used above in the description of the 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 further illustrative examples of such words or phrases .
• 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.
• thiol or "sulfhydryl” , alone or in combination, means a -SH group.
• thio or thia
• 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 -NH2 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 - (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 (1°), secondary (II 0 ) or tertiary (III 0 ) or unsubstituted, mono-substituted or di-substituted 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) _-0 " ] ; 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 - O2 group.
• hydrazino alone or in combination, means a - H-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 -SO2- 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.
• 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.
• cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
• aryl alone or in combination, ' means a 5- or 6-membered 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, or a heteroaryl radical containing one or more heteroatoms such as sulfur, oxygen and nitrogen in the ring(s) .
• exemplary carbocyclic aryl radicals include phenyl, indenyl and naphthyl radicals.
• heterocyclic or heteroaryl groups examples include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl , pyrrolyl , imidazolyl (e.g., imidazol-4-yl, l-benzyloxycarbonylimidazol-4-yl , and the like), pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl , furyl, tetrahydrofuryl , thienyl, triazolyl, oxazolyl, oxadiazoyl, thiazolyl, thiadiazoyl, indolyl (e.g., 2-indolyl, and the like), quinolinyl, (e.g., 2-quinolinyl, 3 -quinolinyl, l-oxido-2 -quinolinyl, and the like), isoquinolinyl,
• tetrahydroquinolinyl e.g., 1, 2,3 , 4-tetrahydro-2-quinolyl, and the like
• 1, 2, 3 etrahydroisoquinolinyl (e.g., 1,2,3,4- tetrahydro-1-oxo-isoquinolinyl, and the like)
• An aryl ring group optionally carries one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, nitro and the like, such as phenyl, p-tolyl, 4-methoxyphenyl , 4-(tert- butoxy) phenyl , 4 -fluorophenyl , 4-chlorophenyl , 4- hydroxyphenyl , 1-naphthyl, 2-naphthyl, and the like.
• substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, nitro and the like, such as phenyl, p-tolyl, 4-methoxyphenyl , 4-(tert- butoxy) phenyl , 4 -fluorophenyl , 4-chlorophenyl , 4- hydroxyphenyl , 1-naphthyl, 2-naphthyl, and the like.
• 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 -C(0)-0- aralkyl 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.
• alkanoyl or alkylcarbonyl alone or in combination, means an acyl radical derived from an alkanecarboxylic acid, examples of which include acetyl, propionyl, butyryl , valeryl , 4 -methylvaleryl , and the like.
• cycloalkylcarbonyl means an acyl group derived from a monocyclie or bridged cycloalkanecarboxylic acid such as cyclopropanecarbonyl , cyclohexanecarbonyl , adamantanecarbonyl, and the like, or from a benz- fused monocyclie cycloalkanecarboxylic acid that is optionally substituted by, for example, alkanoylamino, such as 1 , 2 , 3 , 4 - tetrahydro-2- naphthoyl , 2-acetamido-l, 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.
• heterocyclic (heterocyclo) or heterocycloalkyl portion of a heterocyclocarbonyl , heterocyclooxycarbonyl, heterocycloalkoxycarbonyl, or heterocycloalkyl group or the like is a saturated or partially unsaturated monocyclie, bicyclic or tricyclic heterocycle that contains one or more hetero atoms selected from nitrogen, oxygen and sulphur.
• cycloalkylalkoxycarbonyl means an acyl group of the formula cycloalkylalkyl -0-C0- 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-0-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 alone or in combination, means an amino-substituted carbonyl (carbamoyl) group derived from an amino-substituted carboxylic acid (carboxamide) wherein the amino group can be a primary or secondary amino (amido nitrogen) group containing substituents selected from hydrogen, and alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like.
• 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 .
• aromatic ring in combinations such as substituted-aromatic ring sulfonamide, substituted-aromatic ring sulfinamide or substituted- aromatic ring sulfenamide means aryl or heteroaryl as defined above.
• M utilized in the reaction Schemes that follow represents a leaving group such as halogen, phosphate ester or sulfate ester.
• 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.
• some processes of this invention 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. It 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.
• Step 1 in Scheme 1 illustrates conversion of a hydroxyl group into compound 2 with an activated carbon-M bond via hydroxyl activation or replacement to provide intermediates useful as electrophilic reagents or, when M is -SH, a product of this invention of formula I is formed.
• M usually represents leaving groups such as halides (Cl, Br, I) , fluorides (aromatic) or sulfate esters such as tosylate (OTs) , mesylate (OMs) , triflate (OTs) and . the like, or epoxides .
• the preparations of epoxides, sulfate esters or organic halides are well known in the art.
• M can also represent groups such as -SH (thiol) or, following treatment of a thiol with base or with a pre -formed salt, an -S " group.
• the non-thiols are prepared from the alcohols by standard methods such as treatment with HCl , HBr, thionyl chloride or bromide, phosphorus trihalide, phosphorus pentahalide, trifluoromethylsulfonyl chloride, tosylchloride or methanesulfonyl chloride and the like.
• reaction are usually carried out at a temperature of about -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.
• amines such as triethyl amine, 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.
• 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.
• protecting groups include acetyl, trifluoroacetyl , tetrahydropyran (THP) , Benzyl, tert-butoxy carbonyl (BOC or TBOC) , benzyloxycarbonyl (Z or CBZ) , tert- butyldimethyl ⁇ ilyl (TBDMS) or methoxyethoxymethylene (MEM) groups .
• THP tetrahydropyran
• BOC or TBOC Benzyl, tert-butoxy carbonyl
• Z or CBZ benzyloxycarbonyl
• MEM methoxyethoxymethylene
• the preparation of such protected compounds as well as their removal is well known in the art .
• the second step in Scheme 1 illustrates preparation of a sulfonamide 2. Sulfamidation reactions are conveniently carried out by reacting an amine with, for example, a sulfonyl chloride or sulfonic anhydride.
• a suitable solvent or mixture of solvents includes aprotic or dipolar aprotic solvents as defined below with examples being acetone, ethylene chloride DMF, THF, tert-butylmethylether (tBME) or mixtures of such solvents.
• aprotic or dipolar aprotic solvents as defined below with examples being acetone, ethylene chloride DMF, THF, tert-butylmethylether (tBME) or mixtures of such solvents.
• tBME tert-butylmethylether
• a base for the scavenging of acid is usually also present with non- limiting examples being triethyl amine, pyridine, DBU, N-ethyl morpholine (NEM) , sodium carbonate and the like.
• the sulfonyl chlorides are well know in the art and are commercially available or can be prepared by the reaction of a suitable organometallic reagent with sulfuryl chloride or sulfur dioxide followed by oxidation with a halogen such as chlorine.
• Grignard and alkyl lithium reagents are desirable organometallic reagents.
• thiols can be oxidized to sulfonyl chlorides using chlorine and/or chlorine with water.
• Sulfonic acids are available by the oxidation of thiols, reaction of sulfur derivatives with organometallic reagents and the like and can be converted into sulfonyl chlorides by treatment with thionyl chloride, PCI5 and the like. They are also commercially available.
• 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 (1°), secondary (11°) or tertiary (III 0 ) organic amines such as alkyl amines, arylalkyl amines, alkylarylalkyl amines, heterocyclic amines or heteroaryl amines, ammonium hydroxides or quaternary ammonium hydroxides.
• 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
• such amines can include triethylamine, trimethylamine, diisopropylamine , methyldiisopropylamine , diazabicyclononane , tribenzylamine , dimethylbenzylamine, morpholine, N-methylmorpholine, N,N' -dimethylpiperazine, N-ethylpiperidine, 1,1,5,5- tetramethylpiperidine, dimethyla inopyridine, pyridine, quinoline, tetramethylethylenediamine, diazabicyclononane and the like.
• Non- limiting examples of ammonium hydroxides can include ammonium hydroxide, triethyl ammonium hydroxide, trimethyl ammonium hydroxide, methyldiiospropyl ammonium hydroxide, tribenzyl ammonium hydroxide, dimethylbenzyl ammonium hydroxide, morpholinium hydroxide, N- ethylmorpholinium hydroxide, N,N' -dimethylpiperazinium hydroxide,
• quaternary ammonium hydroxides can include tetraethyl ammonium hydroxide, tetramethyl ammonium hydroxide, dimethyldiiospropyl ammonium hydroxide, benzymethyldiisopropyl ammonium hydroxide, methyldiazabicyclononyl ammonium hydroxide, methyltribenzyl ammonium hydroxide, N,N-dimethylmorpholinium hydroxide, N,N, N' ,N' -tetramethylpiperazenium 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 hydrice (DIBAL) sodium ethoxide, potassium tert-butoxide, calcium ethoxide, magnesium ethoxide, sodium amide, potassium diisopropyl amide and the like can also be suitable reagents.
• DIBAL diisobutylaluminum hydrice
• 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, organocadium reagents such as dimethylcadium 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 and be reacted with acids to form pharmaceutically acceptable salts of this invention.
• reaction media can consist of 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, tetrahydrofurane (THF) , dioxane, diethylether, 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 tetrahydrofurane
• TBME tert-butylmethyl ether
• aromatics such as xylene, toluene, or benzene, ethyl acetate, methyl acetate, butyl acetate, trichloroethane, methylene chloride, ethylenedichloride (ED
• Dipolar aprotic solvents include compounds such as dimethylformamide (DMF) , dimethylacetamide (DMAc) , acetonitrile, DMSO, hexamethylphosphorus triamide (HMPA) , nitromethane, tetramethylurea, N-methylpyrrolidone and the like.
• reagents that might 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,
• Step 4 of Scheme 1 is sulfamidation of compound 1 where R 2 can be hydrogen or as otherwise defined.
• R 2 can be hydrogen or as otherwise defined.
• the process of sulfamidation is discussed above in reference to Step 2.
• the product is the alcohol 4.
• Scheme 1 shows in Step 5 the direct conversion of an alcohol such as compound 4 into a contemplated sulfur-containing compound, 5.
• a descriptive term for this process is activated azo coupling.
• the process can be carried out by reacting a phosphine such as triphenyl phosphine and an azo compound such as diisopropylaziodicarboxylate (DIAD) or diethylazodicarboxylate (DEAD) , a starting alcohol and a thiolcarboxylic acid or dithiocarboxylic acid.
• the reaction is usually carried out under an inert atmosphere such as nitrogen or argon at about -40°C to about 50 °C in an inert solvent such as methylene chloride, THF or the others listed above.
• Compound 5 can be hydrolyzed to form compound 8 in Scheme 1 or compounds 15 or 16 as shown in Scheme 4.
• Compound 8 is a compound of formula I. This hydrolysis can be carried out with bases such as a metal hydroxide (LiOH, NaOH, KOH) , carbonate (Na 2 C0 3 , K 2 C0 3 ) or a bicarbonate (NaHCC ⁇ ) .
• bases such as a metal hydroxide (LiOH, NaOH, KOH) , carbonate (Na 2 C0 3 , K 2 C0 3 ) or a bicarbonate (NaHCC ⁇ ) .
• hydrolytic reagents suitable for this reaction include alkoxides such as sodium methoxide, potassium ethoxide and the like, a thiolate such as sodium thiophenolate , potassium methanethiolate and the like or by hydrolytic exchange with an amine or ammonia. These reactions can be carried out under an inert atmosphere such as helium, nitrogen or argon at temperatures of from about -50°C to about 100°C. Temperatures from about 0°C to about 60°C are preferred.
• Solvents, pure or mixed include water, alcohols especially for alcoholate hydrolysis or dipolar aprotic solvents such as acetonitrile, DMSO or DMF .
• Amine exchanges can occur under conditions as discussed above.
• the amine can serve if desired as the solvent or a co-solvent as, for example, when diethylamine, morpholine, dimethyl amine (in a pressure system) or piperidine, are used as exchange agents.
• the preparation of compound 8 from compound 5 can also be carried out using reductive processes if desired.
• Useful reducing agents may include lithium aluminum hydride, aluminum hydride, DIBAL, potassium borohydride, sodium borohydride, lithium borohydride or a metal catalyzed hydrogenation with a system such as the employing a Rosen und catalyst .
• Reductions of the hydride type are usually carried out at between 80°C and -80°C in non-polar aprotic solvents such as THF or ethers whereas hydrogenations with hydrogen gas require containers (hydrogenation bottles, Parr bombs, pressure kettles and the like) with protic or non-protic solvents or solvent mixtures at temperatures of between -20°C to 100°C.
• Conversion of compound 3 in Scheme 1 into the sulfur-containing compound 5 illustrates displacement of an electrophile by a nucleophile; i.e., the conversion of a intermediate containing our activated leaving group M or a derivative into a sulfur compound of this invention.
• This method of synthesis is commonly called bimolecular nucleophilic substitution.
• Solvolysis or SNi reactions are also possible and, if desired, can be used to provide electrophilic substitutions to produce alcohols, ethers, amines, carboxylate esters and the like.
• the reagents that provide the above compounds via SNi ractions are water, alcohols, amines and carboxylic acids.
• the nucleophilic displacement (SN2) reaction can be used in Step 3 wherein group M is displaced by a thiol compound or the salt of a thiol compound to produce compounds of formula I (compound 8) or formula II (compound 5) directly or a compound of formula I via conversion of II into I.
• the diagramatically reverse procedure; i.e., synthesis of a compound of formula I followed by its conversion into a compound of formula II or formula III can also be accomplished.
• Either compounds of formula I or of formula II can be direct or non-direct intermediates in the preparation of compounds III (e.g. compound 6) .
• a thiolate or other anion can be obtained from a preformed salt such as sodium sulfide or sodium thiolacetate or it can be formed in situ via addition of a base to an acid such as hydrogen sulfide or thiolacetic acid.
• bases and solvents are discussed above.
• Preferred bases are those that are hindered or tertiary such that competition with a sulfur anion as a nucleophile in a two stage reaction is minimized, e.g., triethylamine, pyridine, DBU, DMAP and the like.
• a strong inorganic base or organometallic base can be used if desired.
• solvents, solvent mixtures or solvent/reagent mixtures discussed above are satisfactory but non-protic or dipolar aprotic solvents such as acetone, acetonitrile, DMF, acetonitrile and the like are examples of a preferred class.
• Bases can also be used as solvents as well as reagents. Mixtures of the above solvents or with a solvent and a base such as pyridine or triethylamine are also useful. These reactions are usually carried out under an inert atmosphere (nitrogen, argon) at temperatures varying from between about -10°C to about 80 °C. In many cases, room temperature is preferred due to cost or simplicity.
• Such a derivative can be an activated carbonyl compounds prepared using reagents well know in the art including the peptide and protein synthesis and amino acid coupling or conjugation art.
• reagents examples include thionyl chloride, oxalyl chloride, phosphorus oxychloride, HOBT (hydroxybenzotriazole) , isobutylchloroformate, carbodimide, azodicarboxylate compounds an the like all of which are well known and established in the art.
• Reduction of the disulfide to the corresponding thiol can be carried out by, for example, treatment with hydride reagents such as lithium aluminum hydride, aluminum hydride, DIBAL, metal borohydrides
• the aminoalcohol compound 7 in Scheme 2 illustrates a special case example of compound 1 wherein R 2 is hydrogen.
• This series of reactions -using, for example, compound 7, permits sulfamidation by processes discussed above wherein one skilled in the art can produce examples of compound 4 where R 2 is hydrogen.
• This intermediate or product can then be alkylated or otherwise substituted to produce compound 4 wherein R 2 is other than hydrogen.
• Alkylating agents include compounds that contain groups that can be displaced by a nucleophile such as a sulfamic acid salt.
• This anion can be reacted in an SN2 manner with an intermediate or reagent containing a group that can be displaced with such displaceable groups including such non-limiting examples as epoxide, chloride, bromide, iodide, tosylate, mesylate, triflate, mesylate and the like.
• reagents or intermediates examples include benzyl bromide, methyl iodide, n-butyl chloride, isoamyl tosylate, N-chloroethylmorpholine, N-bromoethylpiperidine and the like.
• the anion can also be reacted (acylated) with a carbonyl compound in an addition-elimination sequence to provide a N-carbonyl compound.
• acylated compounds might be reduced to desired intermediates or serve as protecting groups or both.
• the anion can be formed with the bases listed and discussed above if the affects of sulfamide structure on pKa are accommodated.
• Sodium carbonate, potassium carbonate, potassium methoxide or DMAP represent bases sufficiently strong that they can be used to deprotonate a sulfonamide such as 4.
• a strong base such as an organometallic base under argon in a aprotic solvent is desirable.
• the reactions are normally carried out under an inert atmosphere at temperatures of from about 0°C to about 100°C using either protic or ' dipolar aprotic solvents or with solvent mixtures.
• the solvent mixtures can include reagents such as amine bases that can also serve as part of a solvent mixture.
• An alkylation or acylation reactions involving salt formation are examples of the type reaction wherein a non-participating group such as a hydroxly group hydroxyl group on compound 4 can be protected if desired by the skilled chemist.
• a second process that can be used to place an R 2 group a sulfonamide with at least one hydrogen atom is reductive amination.
• Treatment of compound 4 containing an active hydrogen on the nitrogen of the sulfamide with an aldehyde or ketone and a reducing agent such as LiAlH4 , NaCNBH4 , LiBH4 • AIH4 or hydrogen in the presence of controlled activity metal catalyst may provide compounds with a R 2 group.
• An intermediate in this reductive process can be an sulfimine, sulfimine derivative or a tautomer thereof.
• the reducing agent can be present in the initial reaction or the intermediate can be subsquently reduced, i.e., the intermdiate carbonyl - sulfamide compound can be isolatable or it may be reduced further directly.
• a sulfamide salt can also add to a carbonyl group (acylation) of an ester, amide, anhydride, acid halide, mixed anhydride or similar compound and then be reduced.
• Step 4 in Scheme 2 involves the hydroxyl conversion step discussed in with regards to Step 1 in Scheme 1.
• protection of a non- reactive group can be desirable.
• the sulfamide can be alkylated or reductively alkylated to introduce the R 2 group (Step 5) if such is desired.
• Scheme 2 also illustrates the conversion of compound 4 into compound 5, compound 4 into compound 9 and compound 9 into compound 3.
• the former conversion is discussed above per Scheme 1.
• the preparation of Compound 9 illustrates the preparation of a sulfonamide compound where R 2 is hydrogen and M is a leaving group (activated intermediate) .
• hydroxyl conversion process is well discussed above under Step 1 of Scheme 1.
• protection of groups that one does not wish to participate in a reaction or process can be useful.
• reagents that convert hydroxyl groups into halide type leaving groups is preferred.
• agents include hydrogen bromide, hydrogen chloride, hydrogen iodide, hydrobromic acid, hydrochloric acid or hydriodic acid.
• Agents that can convert a sulfonamide nitrogen-hydrogen bond into a nitrogen-halogen bond such as sodium hypochlorite can serve as a method of protecting the sulfonamide from further substitution on nitrogen.
• the halogen is removable when desired by reduction.
• compound 9 can be alkylated or acylated by processes as discussed for Step 2 in this Scheme to provide compound 3.
• Compound 3 can be converted into a compound of this invention of formula I or formula II (compound 5) via a nucleophilic or electrophilic substitution process as illustrated in Step 6. These processes and reactions are discussed above.
• Protic solvents can include water wherein the reagent is usually an amine hydroxide such as ammonium hydroxide, benzylamine hydroxide and the like. Amine hydroxides are discussed above . Solvents that can react with amines such as ethyl acetate or acetone are not to be used. A pressure containment system or a low temperature system can be used for gaseous amines such as ammonia, methyl amine ethyl amine and the like. For example, reactions with or in ammonia can be run in liquid ammonia at a temperature of about -33°C. The SN2 reaction can also be carried out with an metal - amine salt such as sodium amide, calcium amide, potassium metylamide and the like.
• an amine hydroxide such as ammonium hydroxide, benzylamine hydroxide and the like. Amine hydroxides are discussed above . Solvents that can react with amines such as ethyl acetate or acetone
• Compound 7 represents compounds where R 2 is hydrogen whereas compound 11 represents compounds wherein R 2 is any other group described earlier in this specification.
• Step 3 in this sequence illustrates conversion of the unprotected alcohol group into the sulfur compound 12, which can then be converted into 5, which is a sulfonamide of this invention if formula II.
• Step 5 shows conversion of the M- ' substituted carbinol 10 into the sulfur compound 13 via a before-discussed activated azo procedure as in Step 3.
• Compound 13 can then be treated in Step 6 as with Step 1 to convert the M-carbon bond in compound 13 into a carbon-nitrogen bond to produce compounds
• R 2 is either hydrogen (compound 14) or not hydrogen (compound 12) .
• this product is compound 14 and R 2 is hydrogen, it can be converted into compound 12 by alkylation or reductive alkylation processes of Step 7 using the methods of Step 2.
• Scheme 4 presents an alternative synthetic route to the compounds of this invention such as compounds 5, 15 or 16.
• the amine R 2 NH2 is reacted with a sulfonamide forming reagent such as a sulfonyl chloride under sulfamidation conditions to provide a sulfonamide.
• the sulfonamide can have two hydrogen atoms on the nitrogen of the sulfonamide group or it can have one nitrogen-carbon bond valence be occupied by a group R 2 .
• the sulfonamide can be alkylated (Step 3) by processes discussed above using compound 13 as the electrophile .
• Compound 13 was prepared in Scheme 3.
• the product of this alkylation is compound 5, which is a sulfur compound of formula II of this invention. Hydrolysis of compound 5 can provide compund 16, which is a compound of formula I discussed above.
• Step three displays the same process as Step 1 except that the amine is replaced by ammonia to provide an unsubstituted sulfonamide.
• This unsubstituted sulfonamide can be alkylated with, for example, compound 13 or compound 10, to produce sulfonamide compound 14 or sulfonamide compound 4.
• -Alkylation of compound 14 by procedures illustrated above provides compound 5.
• Hydrolysis of compound 14 (Step 5) can produce compound 15 which is a compound of this invention of formula I .
• Step 3 or Step 2 is provided by the procedure of Example 44.
• the amine can be R 2 NH2 with R 2 being methyl followed by post sulfamidation alkylation with 2- iodobenzylchloride to produce a dialkylated sulfonamide that is subsequently converted into a thiol compound of this invention of formula IV.
• the inverse procedures can be carried out wherein the product of reaction with iodobenzylchloride or iodobenzylamine is the first sulfonamide that is then alkylated with methyl iodide. Conversion of this intermediate into the sulfur-containing product uses a cobalt complex with thiourea followed by reduction with sodium cyanoborohydride . This process is a useful alternative for the synthesis of aromatic sulfur compounds.
• Scheme 5 presents the preparation of the product of Example 41C.
• the carbinol amine a was treated with the sulfonyl chloride b under sulfa idation conditions to produce sulfonamide compound c.
• the reaction was carried out under nitrogen in THF and water as co-solvents and with triethylamine as the base to act a the product hydrochloric acid scavenger.
• the reaction temperature was about 0°C in an ice bath.
• the sulfonamide c in which R 2 is H was alkylated with methyl iodide to produce the product d wherein R 2 is methyl .
• the solvent for this reaction was DMF with potassium carbonate base being suspended/dissolved therein under an atmosphere of -nitrogen.
• the reaction mixture including the methyl iodide was maintained at room temperature .
• This alcohol was then converted via the activated azo coupling procedure into the sulfur compound f, which is a compound, useful in a process of this invention.
• This reaction was carried out at 0°C in THF under nitrogen.
• the reagents triphenylphosphine and diethyldiazodicarboxylate were dissolved in the THF and thiolacetic acid was added.
• the reaction was permitted to proceed for about one hour to yield compound f which is the product of Example 4IB.
• Hydrolysis of compound f with sodium methoxide in methanol at room temperature for about one half hour provide compound g which is also the product of Example 41C.
• Optically active compound isomers as well as mixed or non-optically active compound isomers are specifically intended to be included in this discussion.
• isomers are RS isomers, enantiomers, diastereomers , racemates, cis isomers, trans isomers, E isomers, Z isomers, syn- isomers, anti- isomers, tauto ers and the like.
• Aryl, heterocyclo or heteroaryl tautomers, heteroatom isomers and ortho, meta or para substitution isomers are also included as isomers.
• Step 4 Sulfamidation Sulfamidation
• Step 5 Activated Step 2 Alkylation/
• Step 2 Step 3 Alkylation Alkylation
• Part A To a solution of (10.0 g, 133 mmol) 2R-amino-l-propanol in 120 mL of acetone and 50 mL of water, was added 35.8 mL of triethylamine. After cooling in an ice bath, 23.5 g (133 mmol) of 3- chloro propanesulfonyl chloride was slowly added over
• Part B To a solution of 4.13 g (20 mmol) of product from part A in (25 mL) of anhydrous acetonitrile, was added (4.4 g, 40 mmol) of triethylamine followed by (3.3 g, 30 mmol) of benzenethiol. After stirring at room temperature for
• Example 7 Preparation of N- (2-mercaptoethyl ) -N- (phenylmethyl) -4-methoxybenzenesulfonamide .
• Part B To a solution of 2.0 g (6.2 mmol of product from Part A and 1.79g (6.8 mmol) of t ⁇ phenylphosphine in 31 mL of anhydrous THF at 0 C, was added 1.35 mL (6.8 mmol) of dnsopropylazodi- carboxylate, followed by 0.50 mL (6.8 mmol) of thiolacetic acid.
• Part C To a suspension of 0.57 g (1.5 mmol) of product from Part B above in 4 mL of anhydrous methanol, was added 1.2 mL (5.4 mmol) of 25 weight % sodium methoxide m methanol. After 30 minutes, the solution was cooled in ice and 2% hydrochloric acid added. Ethyl acetate was added and the organic layer separated and washed with saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and stripped to affor ⁇ 0.5 g of crude material.
• Example 8 Preparation of N- (2-mercaptoethyl) -N- pentyl-4-methoxybenzenesulfonamide .
• Part A To a solution of 2.0 g (8.6 mmol) of N- (2-hydroxyethyl) -4-methoxybenzenesulfonamide from Example 1 in 20 mL of anhydrous DMF, was added 3.58 g (25.9 mmol) of powdered potassium carbonate and then 1.96 g (13 mmol) of 1-bromopentane . After 24 hours, ethyl acetate and water was added, the organic layer separated and washed 3xs with brine, dried with sodium sulfate, filtered and stripped to afford 2.3 g of crude product.
• Part A To a solution of 3.0 g (12 mmol) of N- (2-hydroxy-lR-methylethyl) -4- methoxybenzenesulfonamide from Example 3 in 40 mL of anhydrous DMF, was added 5.1 g (37 mmol) of powdered potassium carbonate, followed by 2.0 mL (2.5 g, 18 mmol) of 1-bromobutane. After 66 hours, and additional 2.5 g (18 mmol) of powdered potassium carbonate and 1.0 mL (1.3 g, 9 mmol) of 1-bromobutane were added, and the reaction heated at 40°C.
• Part B To a solution of 2.8 g (9 mmol) of " N- (2-hydroxy-lR-methylethyl) -N-butyl-d- methoxybenzenesulfonamide from Part A and 2.7 g (10 mmol) of triphenylphosphine in 50 mL of anhydrous THF at 0°C, was added 1.6 mL (1.8 g, 10 mmol) of diethylazodicarboxylate, followed after 5 mm. by 0.7 mL (0.8 g, 10 mM) of thiolacetic acid.
• Part C To a solution of 2.0 g (6 mmol) of the product from Part B in 50 mL of anhydrous methanol, was added 0.5 g (21 mmol) of sodium metal. After 1 hour, the reaction was cooled, IN HC1 solution was added, followed by ethyl acetate and water, the organic layer was separated and washed with saturated sodium bicarbonate solution and brine, dried with magnesium sulfate, filtered and concentrated to afford 1.6 g of crude product.
• Part A To a solution of 10.04 g (43 mmol) of N- (2-hydroxyethyl) -4-methoxybenzenesulfonamide from Example 1 in 85 mL of anhydrous DMF, was added 17.8 g (128 mmol) of powdered potassium carbonate and then 8.2 g (48 mmol) of benzyl bromide. After 24 hours, ethyl acetate and water was added, the oragnic layer separated and washed 3xs with brine, dried with sodium sulfate, filtered and stripped to afford 14.3 g of crude product.
• Part B To a solution of 4.0 g (12.4 mmol) of N- (2-hydroxyethyl) -N- (phenylmethyl) -4- methoxybenzenesulfonamide from Part A in 6 mL of anhydrous methylene chloride and 6 mL of anhydrous dimethyl sulfoxide, was added 17.1 mL of triethylamine, the solution cooled in an ice bath and 7.9 g (50 mmol) of sulfur trioxide/pyridme complex m 38 mL of DMSO was added over 15 minutes.
• Part C To 8.3 mL (25 mmol) of 3M methyl magnesium bromide in diethyl ether at 0C under nitrogen, was added a solution of 4g (12.4 mmol) of crude N- (2-propanal) -4-methoxybenzenesulfonamide from Part B in 10 mL of anhydrous tetrahydrofura . After 1 hour at room temperature, the reaction was cooled in ice and quenched by the addition of saturated ammonium chloride solution, extracted with ethyl acetate, washed with 5% KHS04, brine, dried and stripped to afford 4.0 g of crude material.
• Part E To a solution of 0.43 g (1.1 mmol) of the product of Part D in 5 mL of anhydrous methanol, was added 0.9 mL (3.9 mmol) of 25 wt % sodium methoxide/methanol . After 15 hours at room temperature, an additional 0.9 mL of sodium methoxide/methanol was added.
• Example 11 Preparation of N- (2-mercapto-lR- methylethyl) -N-methyl-4-methoxybenzenesulfonamide .
• Part A To a solution of 3.0 g (12.2 mmol) of N- (2-hydroxy-lR-methylethyl) -4- methoxybenzenesulfonamide from example 3, in 20 mL of anhydrous DMF, was added 5.06 g (36.7 mmol) of powdered potassium carbonate, and then 1.1 L (17.7 mmol) of methyl iodide. After stirring at room temperature for 48 hours, ethyl acetate and water was added, the layers separated and the organic layer washed 3xs with brine, dried with sodium sulfate, filtered and stripped to afford 2.83 g of crude material.
• Part D To a solution of 1.77 g (5.58 mmol) of product from Part C in 20 mL of anhydrous methanol, was added 4.6 mL (20 mmol) of a 25 weight % solution of sodium methoxide in methanol.
• Example 12 Preparation of N- ( 2-mercapto-lR- methylethyl) -N- (phenylmethyl ) -4- methoxybenzenesulfonamide .
• Part A To a solution of 5.0 g (20mmol) of N- (2-hydroxy-lR-methylethyl) -4-methoxybenzene- sulfonamide from Example 3 in 40 mL of anhydrous DMF, was added 8.5 g (61 mmol) of powdered potassium carbonate, followed by 3.2 mL (4.5 g, 27 mmol) of benzyl bromide. After 16 hours, the reaction was concentrated in vacuo, ethyl acetate and water were added, the organic layer was separated and washed 3xs with brine, dried with magnesium sulfate, filtered and concentrated to afford 7.1 g of crude product.
• Part B To a solution of 4.1 g (12 mmol) of N- (2-hydroxy-lR-methylethyl) -N- (phenylmethyl) -4- methoxybenzenesulfonamide from Part A and 3.6 g (14 mmole) of triphenylphosphine in 80 mL of anhydrous THF at 0°C, was added 2.1 mL (2.4 g, 14 mmol) of diethylazodicarboxylate, followed after 5 min. by 1.0 mL (1.0 g, 14 mM) of thiolacetic acid.
• Part C To a solution of 4.3 g (11 mmol) of product from Part B in 100 L of anhydrous methanol, was added 0.9 g (40 mmol) of sodium metal. After 1 hour, the reaction was cooled, IN HC1 solution was added, followed by ethyl acetate and water, the organic layer was separated and washed with saturated sodium bicarbonate solution and brine, dried with magnesium sulfate, filtered and concentrated to afford 3.5 g of crude product.
• Example 13 Preparation of N- ( 2-mercapto-lS- methylethyl) -N- (phenylmethyl) -4- methoxybenzenesulfonamide .
• Part A To a solution of 15.5 mL (15.0 g, 200 mmol) of (S) -(+) -2-amino-l-propanol in 70 mL of THF and 18 mL of water, was added 36 mL (259 mmol) of triethylamine. After cooling in an ice bath, a solution of 37.1 g (179 mmol) of 4- methoxybenzenesulfonyl chloride in 30 mL of tetrahydrofuran was slowly added over 15 minutes.
• Part B To a solution of 5.0 g (20 mmol) of N- (2-hydroxy-lS-methylethyl) 4- methoxybenzenesulfonamide from part A in 40 mL of anhydrous DMF, was added 8.5 g (61 mmol) of powdered potassium carbonate, followed by 3.2 mL (4.5 g, 27 mmol) of benzyl bromide. After 64 hours, the reaction was concentrated in vacuo, ethyl acetate and water were added, the organic layer was separated and washed 3xs with brine, dried with magnesium sulfate, filtered and concentrated to afford 7.0 g of crude product.
• Part C To a solution of 4.2 g (12.5 mmol) of N- (2-hydroxy-lS-methylethyl ) -N- (phenylmethyl) -4- methoxybenzenesulfonamide from Part B and 3.6 g (14 mmole) of triphenylphosphine in 50 mL of anhydrous THF at 0°C, was added 2.2 mL (13.8 mmol) of diethylazodicarboxylate, followed after 5 min . by 1.0 L (13.8 mmol) of thiolacetic acid.
• Part D To a solution of 3.8 g (9.7 mmol) of product from Part C in 20 mL of anhydrous methanol, was added 7.9 mL (34.8 mmol) of a 25 weight % solution of sodium methoxide in methanol.
• Part A To a solution of 3.0 g (12.2 mmol) " •of N- (2-hydroxy-lR-methylethyl) -4-methoxybenzene- sulfonamide from example 3, in 20 mL of anhydrous DMF, was added 5.06 g (36.7 mmol) of powdered potassium carbonate, and then 2.0 mL (18.3 mmol) of isobutyl bromide. After stirring at room temperature for 72 hours, ethyl acetate and water was added, the layers separated and the organic layer washed 3xs with brine, dried with sodium sulfate, filtered and stripped to afford 3.35 g of crude material.
• Part C To a solution of 0.73 g (2.0 mmol) of product from Part B in 10 mL of anhydrous methanol, was added 1.7 mL (7.3 mmol) of a 25 weight % solution of sodium methoxide in methanol. After 0.5 hour, the reaction was quenched with IN HC1 solution, followed by ethyl acetate and water, the organic layer was separated and washed with saturated sodium bicarbonate solution and brine, dried with magnesium sulfate, filtered and concentrated to afford 10.6 g of crude product. This was chromatographed on lOOg of silica gel to afford 182 mg of pure product, identified as
• Part A To a solution of 2.69 g (9.36 mmol) of N- (2-hydroxy-lR-methylethyl) -4- (n-butoxy) benzenesulfonamide from example 4 and 2.7 g (10.3 mmol) of triphenylphosphine in 37 mL of anhydrous THF at 0 C C, was added 1.6 mL (10.3 mmol) of diethylazodi- carboxylate, followed after 5 minutes by 0.75 mL (10.3 mmol) of thiolacetic acid.
• Part B To a solution of 1.59 g (4.6 mmol) of product from Part A in 18 mL of anhydrous methanol, was added 3.8 mL (16.6 mmol) of a 25 weight % solution of sodium methoxide m methanol.
• Part A To a solution of 2.58 g (10.5 mmol) of N- (2-hydroxy-lR-methylethyl ) -4-methoxybenzene- sulfonamide from example 3 and 3.03 g (11.6 mmol) of triphenylphosphine in 40 mL of anhydrous THF at 0°C, was added 1.8 mL (11.6 mmol) of diethylazodi- carboxylate, followed after 5 minutes by 0.83 L (11.6 mmol) of thiolacetic acid.
• Example 17 Preparation of N- (2- ⁇ nercapto-lR- methyle hyl ) -N-phenylmethyl) -4- (n- butoxy) benzenesulfonamide .
• Part A To a solution of 3.52 g (12.3 mmol) of N- (2-hydroxy-lR-methylethyl) -4- (n- butoxy) enzenesulfonamide from example 4 in 25 mL of anhydrous DMF, was added 5.07 g (36.8 mmol) of powdered potassium carbonate, followed by 1.9 mL (2.7 g, 15.9 mmol) of benzyl bromide. After 63 hours, the reaction was concentrated in vacuo, ethyl acetate and water were added, the organic layer was separated and washed 3xs with brine, dried with magnesium sulfate, filtered and concentrated to afford the crude product.
• Part C To a solution of 0.99 g (2.3 mmol) of product from Part B in 10 L of anhydrous methanol, was added 1.9 mL (8.2 mmol) of a 25 weight % solution of sodium methoxide in methanol. After 0.5 hour, the reaction was quenched with IN HC1 solution, followed by ethyl acetate and water, the organic layer was separated and washed with saturated sodium bicarbonate solution and brine, dried with magnesium sulfate, filtered and concentrated to afford 0.75 g of pure product, identified as N-(2- mercapto-lR-methylethyl) -N-phenylmethyl) -4- (nbutoxy) benzenesulfonamide .
• the solid was washed with hexane (400 mL) , filtered and dried to provide sulfonyl chloride (2823g) .
• the hexane wash was concentrated and the resulting solid washed with 400 mL hexane to provide additional sulfonyl chloride (464g) .
• the total yield was 3287g (95.5% based upon 1,3- benzodioxole) .
• Example 20 Preparation of N- (2-mercapto-lR- methylethyl) -N-methyl-5- (1, 3-benzod ⁇ oxol-5- yl) sulfonamide .
• Part A To a solution of 5.4 g (72 mmol) of (R) -2-amino-l-propanol in 25 mL of tetrahydrofuran ana 10 mL of water, was added 13 mL (93 mmol) of triethylamine. The solution was cooled in an ice bath and a solution of 13.3 g (60 mmol) of 1,3- benzod ⁇ oxole-5-sulfonyl chloride in 20 mL of tetrahydrofuran was added over 20 minutes.
• Part B To a solution of 2.6 g (10 mmol) of - (2-hydroxy-lR-methylethyl) -5- (1, 3-benzod ⁇ oxol-5- yl) sulfonamide from Part A, in 15 mL of anhydrous DMF, was added 4.15 g (30 mmol) of powdered potassium carbonate, and then 1.25 mL (20 mmol) of methyl iodide. After stirring at room temperature for 17 hours, ethyl acetate and water was added, the layers separated and the organic layer washed 3xs with brine, dried with sodium sulfate, filtered and stripped to afford 2.8 g of crude material.
• Part D To a solution of 1.86 g (5.6 mmol) of product from Part C in 20 mL of anhydrous methanol, was added 4.6 mL (20 mmol) of a 25 weight % solution of sodium methoxide in methanol.
• Example 21 Preparation of N- (2-mercapto-lR- methylethyl) -N- (phenylmethyl) -5- (1, 3-benzod ⁇ oxol-5- yl ) sulfonamide .
• Part A To a solution of 5.4 g (72 mmol) of (R) -2-amino-l-propanol in 25 mL of tetrahydrofuran and 10 mL of water, was added 13 mL (93 mmol) of triethylamine. The solution was cooled in an ice -.bath and a solution of 13.3 g (60 mmol) of 1,3- benzodioxole-5-sulfonyl chloride in 20 L of tetrahydrofuran was added over 20 minutes.
• Part B To a solution of 2.5 g (9.6 mmol) of N- (2-hydroxy-lR-methylethyl) -5- (1, 3-benzodioxol-5- yl) sulfonamide from Part A, in 20 mL of anhydrous DMF, was added 3.99 g (29 mmol) of powdered potassium carbonate, and then 1.5 mL (12.5 mmol) of benzyl bromide. After stirring at room temperature for 17 hours, ethyl acetate and water was added, the layers separated and the organic layer washed 3xs with brine, dried with sodium sulfate, filtered and stripped to afford 3.15 g of crude material.
• Example 23 Preparation of N-(1R- mercaptomethyl) propyl -N-methyl-4- (n- butoxy) benzenesulfonamide .
• Part A To a solution of 3.91 g (44 mmol) of (R) -2-amino-l-butanol in 20 mL of tetrahydrofuran and 5 mL of water, was added 9.5 mL (68 mmol) of triethylamine. The solution was cooled in an ice bath and a solution of 9.85 g (40 mmol) of 4-(n- butoxybenzene) sulfonyl chloride in 10 mL of tetrahydrofuran was added over 10 minutes.
• Part B To a solution of 3.0 g (9.85 mmol) of N- (lR-hydroxymethyl)propyl-4- (n-butoxy) benzenesulfonamide from Part A, in 12 mL of anhydrous DMF, was added 4.1 g (30 mmol) of powdered potassium carbonate, and then 1.2 mL (20 mmol) of methyl iodide. After stirring at room temperature for 21 hours, ethyl acetate and water was added, the layers separated and the organic layer washed 3xs with brine, dried with sodium sulfate, filtered and stripped to afford 2.9 g of crude material .
• Part D To a solution of 2.12 g (5.7 mmol) of product from Part C in 23 mL of anhydrous methanol, was added 4.7 mL (20.4 mmol) of a 25 weight % solution of sodium methoxide in methanol .
• Example 24 Preparation of N- (2 -hydroxy-1R- methylethyl) -N- (propyn-3yl) -4- (n- butoxybenzene) sulfonamide .
• Part A To a solution of 2.0 g (7 mmol) of N- ( 2 -hydroxy-1R- ethylethyl) -4- (n-butoxy) benzenesulfonamide from example 4, in 10 mL of anhydrous DMF, was added 2.9 g (21 mmol) of powdered potassium carbonate, and then 1.6 mL of an 80 wt. % solution of propargyl bromide in toluene (15 mmol) . After stirring at room temperature for 24 hours, ethyl acetate and water was added, the layers separated and the organic layer washed 3xs with brine, dried with sodium sulfate, filtered and stripped to afford 2.31 g of crude material.
• Example 25 Preparation of N- (mercapto-lR- methylethyl) -N- (propyn-3 -yl) -4- (n- butoxybenzene) sulfonamide disulfide.
• Part A To a solution of 4.11 g (12.6 mmol) of N- (2-hydr ⁇ xy-lR-methylethyl) -N- (propyn-3 - yl) -4 - (n-butoxybenzene) sulfonamide and 3.64 g (13.9 mmol) of triphenylphosphine in 50 mL of anhydrous THF at 0°C, was added 2.2 mL (13.9 mmol) of diethylazodicarboxylate, followed after 5 minutes by 1.0 L (13.9 mmol) of thiolacetic acid.
• Part B To a solution of 1.1 g (2.9 mmol) of product from Part A in 7 mL of anhydrous methanol, was added 7.4 L of 30% aqueous ammonia. After 1 hour, the reaction was quenched with IN HCl solution, followed by diethyl ether and water, the organic layer was separated and washed with saturated sodium bicarbonate solution and brine, dried with magnesium sulfate, filtered and concentrated to afford 0.90 g of crude product.
• Part A To a solution of 4.5 g (52 mmol) of racemic 3-pyrrolidinol in 20 mL of tetrahydrofuran and 5 mL of water, was added 10 mL of triethylamine.
• Part C To a solution of 1.05 g (3.3 mmol) of product from Part C in 6 mL of anhydrous methanol, was added 8.6 L of 30% aqueous ammonia. After 1 hour, the reaction was quenched with IN HCl solution, followed by ethyl acetate and water, the organic layer was separated and washed with saturated sodium bicarbonate solution and brine, dried with magnesium sulfate, filtered and concentrated to afford 0.74 g of crude product.
• Example 27 Preparation of l-[(4- methoxyphenyl) sulfonyl] -3 -hydroxypiperidine .
• OCH 3 Part A To a solution of 10.27 g (89 mmol) of D,L-proline in 100 mL of water and 60 L of acetone, was added 40 mL (287 mmol) of triethylamine. After cooling in an ice bath, 17.6 g (85 mmol) of 4- (methoxybenzene) sulfonyl chloride was slowly added. After stirring at room temperature for 13 hours, the acetone was stripped, the aqueous layer extracted twice with toluene, then acidified with 25 mL of 6N hydrochloric acid and extracted with ethyl acetate.
• Part B To a solution of 4.00 g (14 mmol) of 1- [ (4-methoxyphenyl) sulfonyl] -2- carboxypyrrolidine from part A in 50 mL of anhydrous tetrahydrofuran at 0 C under a nitrogen atmosphere, was slowly added over 15 minutes, 20 mL (20 mmol) of a 1M solution of lithium aluminum hydride in diethyl ether. After stirring at room temperature for 2 hours, the solution was cooled in an ice bath, and quenched by the slow sequential addition of 0.8 mL of water, 0.8 mL of 10% sodium hydroxide and 2.4 mL of water.
• Part D To a solution of 1.5 g (4.6 mmol) of product from Part C in 10 L of anhydrous methanol, was added 3.7 mL (16.4 mmol) of a 25 weight % solution of sodium ethoxide in methanol. After 0.5 hour, the reaction was quenched with IN HCl solution, followed by ethyl acetate and water, the organic layer was separated and washed with saturated sodium bicarbonate solution and brine, dried with magnesium sulfate, filtered and concentrated to afford 0.9 g of crude product.
• Example 29 Preparation of Racemic N- [1- (mercaptomethyl) -3-methylbutyl] -N- (phenylmethyl) -4- methoxybenzenesulfonamide .
• Part A To a solution of 10.0 g (76.2 mmol) of D,L-leucine in 85 mL of water and 50 L of acetone, was added 30 mL (215 mmol) of triethylamine. This solution was cooled in an ice bath, and a solution of 15.0 g (72.7 mmol) of 4 - methoxybenzenesulfonyl chloride in 50 mL of acetone was slowly added over a 30 minute period.
• Part D To a solution of 3.2 g (7.9 mmol) of the product from part C in 30 mL of anhydrous tetrahydrofuran at 0 C under a nitrogen atmosphere, was slowly added over 15 minutes, 7.9 mL (7.9 mmol) of a 1M solution of lithium aluminum hydride in diethyl ether. After stirring at room temperature for 1 hour, the solution was cooled in an ice bath, and quenched by the slow sequential addition of 0.3 mL of water, 0.3 L of 10% sodium hydroxide and 0.9 L of water. The resulting suspension was filtered through celite and the celite washed with ethyl acetate.
• Part F To a solution of 2.0 g (4.6 mmol) of product from Part E in 10 mL of anhydrous methanol, was added 3.7 mL (16.4 mmol) of a 25 weight % solution of sodium methoxide in methanol.
• Part A To a solution of 20.0 g (170 mmol) of D-valine in 170 mL of water and 95 mL of acetone, was added 50 mL (360 mmol) of triethylamine. This solution was cooled in an ice bath, and a solution of 35.2 g (170 mmol) of 4-methoxybenzenesulfonyl chloride in 75 mL of acetone was slowly added over a 20 minute period.
• Part B To a solution of 35.04 g (122 mmol) of product from part A in 125 mL of anhydrous methanol at 0 C, was slowly added 10.0 mL (137 mmol) of thionyl chloride over 15 minutes. The solution was then stirred for 14 hours at room temperature, concentrated, ethyl acetate added, washed with water, saturated sodium bicarbonate, brine, dried with sodium sulfate, filtered and stripped to afford 37.1 g of crude material.
• Example 31 Preparation of N- [ (lR-mercaptomethyl) -2- methylpropyl] -4 -methoxy-N- (phenylmethyl ) benzenesulfonamide .
• Part B To a solution of 6.3 g (20mmol) of product from Part A in 60 mL of anhydrous THF at 0°C under nitrogen, was added 16.1 mL (0.6 g, 16 mmol) of a 1.0 M solution of lithium aluminum hydride in diethyl ether.
• Part D To a solution of 4.7 g (11 mmol) of product from Part C in 100 mL of anhydrous methanol, was added 1.0 g (41 mmol) of sodium metal. After 1 hour, the reaction was quenched using dry ice, ethyl acetate and 5% potassium hydrogen sulfate solution were added, the organic layer was separated and washed with saturated sodium bicarbonate solution and brine, dried with magnesium sulfate, filtered and concentrated to afford the crude product.
• Part A To a solution of 10.0 g (85 mmol) of L-valine in 85 mL of water and 50 mL of acetone, was added 25 mL (180 mmol) of triethylamine. This solution was cooled in an ice bath, and a solution of 17.6 g (85 mmol) of 4-methoxybenzenesulfonyl chloride in 35 mL of acetone was slowly added over a 20 minute period.
• Part B To a solution of 18.9 g (65.8 mmol) of product from part A in 60 mL of anhydrous methanol at 0 C, was slowly added 6.0 L (83 mmol) of thionyl chloride over 15 minutes. The solution was then stirred for 14 hours at room temperature, concentrated, ethyl acetate added, washed with water, saturated sodium bicarbonate, brine, dried with sodium sulfate, filtered and stripped to afford the crude material .
• Example 33 Preparation of N- [( IS -mercaptomethyl ' , methylpropyl] -4 -methoxy-N- (phenylmethyl ) benzenesulfonamide .
• Part B To a solution of 4.88 g (12.5 mmol) of product from Part A in 50 mL of anhydrous THF at 0°C under nitrogen, was added 12.5 mL (12.5 mmol) of a 1.0 M solution of lithium aluminum hydride in diethyl ether.
• Part C To a solution of 3.94 g (10.8 mmol) of N- [ (lS-hydroxymethyl) -2-methylpropyl] -N- (phenylmethyl) -4-methoxybenzenesulfonamide from Part B and 3.12 g (11.9 mmole) of triphenylphosphine in 50 mL of anhydrous THF at 0°C, was added 1. mL (2.1 g,
• Part D To a solution of 2.7 g (6.4 mmol) of product from Part C in 20 mL of anhydrous methanol, was added 5.3 mL (23 mmol) of 25 weight % sodium methoxide in methanol solution. After 0.5 hour, the reaction was quenched with IN hydrochloric acid, ethyl acetate added and washed with 5% potassium hydrogen sulfate solution, saturated sodium bicarbonate solution and brine, dried with magnesium sulfate, filtered and concentrated to afford 2.05 g of crude product.
• Example 34 Preparation of N- (2-mercaptoethyl) -N- (phenylmethyl) -4- (n-butoxy) benzenesulfonamide .
• Part A To a solution of 15.11 g (55 mmol) of N- (2-hydroxyethyl) -4- (n-butoxy) benzenesulfonamide from Example 2 in 100 mL of anhydrous DMF, was added 22.9 g (165 mmol) of powdered potassium carbonate and then 10.3 g (60 mmol) of benzyl bromide. After 16 hours, ethyl acetate and water was added, the oragnic layer separated and washed 3xs with brine, dried with sodium sulfate, filtered and stripped to afford 20.7 g of crude product.
• Part B To a solution of 3.0 g (8.2 mmol) of N- (2-hydroxyethyl) -N- (phenylmethyl) -4- (n-butoxy) - benzenesulfonamide from Part A and 2.38 g (9.1 mmol) of triphenylphosphine in 40 mL of anhydrous THF at 0 C, was added 1.4 mL (9.1 mmol) of diisopropylazo- dicarboxylate, followed by 0.65 mL (9.1 mmol) of thiolacetic acid.
• Part C To a suspension of 1.7 g (4.1 mmol) of product from Part B above in 20 mL of anhydrous methanol, was added 3.3 mL (14.6 mmol) of 25 weight % sodium methoxide in methanol. After 30 minutes, the solution was cooled in ice and 2% hydrochloric acid added.
• Example 36 Preparation of N- (2 -hydroxy- 1R- methylethyl) -N-methyl-4 - hydroxybenzenesulfonamide .
• Part A To a solution of 7.4 L (95.1 mmol) of (R) -(-) -2-amino-l-propanol in 31 mL of THF and 9 L of water, was added 17.2 mL (123 mmol) of triethylamine. After cooling in an ice bath, a solution of 24.4 g (86.5 mmol) of 4- (benzyloxy) - benzenesulfonyl chloride in 40 mL of tetrahydrofuran was slowly added over 15 minutes.
• Part B To a solution of 18.25 g (56.8 mmol) of the product from Part A in 100 L of anhydrous DMF, was added 23.5 g (170 mmol) of powdered potassium carbonate and then 24.2 g (170 mmol) of methyl iodide.
• Example 37 Preparation of N- (2-mercapto-lR- methylethyl) -N-methyl-4- (n- propyloxy) benzenesulfonamide .
• Part A To a solution of 1.50 g (6.11 mmol) of N- (2-hydroxy-lR-methylethyl) -4 -hydroxybenzenesulfonamide from example 36, in 10 mL of anhydrous DMF, was added 2.53 g (18.3 mmol) of powdered potassium carbonate, and then 0.85 mL (9.3 mmol) of bromopropane .
• Part B To a solution of 1.70 g (5.9 mmol) of product from Part A and 1.70 g (6.5 mmol) of triphenylphosphine in 23 mL of anhydrous THF at 0°C, was added 1.0 mL (6.5 mmol) of diethylazodicarboxylate , followed after 5 minutes by
• Part C To a solution of 1.02 g (2.95 mmol) of product from Part B in 10 mL of anhydrous methanol, was added 2.4 L (10.5 mmol) of a 25 weight % solution of sodium methoxide in methanol.
• Example 38 Preparation of N- (2 -mercapto-lR- methylethyl) -N-methyl -4 -ethoxybenzenesulfonamide .
• Part A To a solution of 1.50 g (6.11 mmol) of N- (2 -hydroxy-IR-methylethyl) -4- hydroxybenzenesulfonamide from example 36, in 10 mL of anhydrous DMF, was added 2.53 g (18.3 mmol) of powdered potassium carbonate, and then 0.70 mL (9.2 mmol) of bro oethane.
• Part C To a solution of 1.53 g (4.62 mmol) of product from Part B in 20 mL of anhydrous methanol, was added 3.8 mL (16.6 mmol) of a 25 weight % solution of sodium methoxide in methanol.
• Example 39 Preparation of N- (2 -mercapto- IR- methylethyl) -N-methyl-4- (n- pentyloxy) benzenesulfonamide .
• Part A To a solution of 1.50 g (6.11 mmol) of N- (2 -hydroxy- IR-methylethyl) -4- hydroxybenzenesulfonamide from example 36 in 10 mL of anhydrous DMF, was added 2.53 g (18.3 mmol) of powdered potassium carbonate, and then 1.13 mL (9.2 mmol) of 1-bromopentane .
• Part C To a solution of 1.48 g (3.96 mmol) of product from Part B in 15 mL of anhydrous methanol, was added 3.3 mL (14 mmol) of a 25 weight % solution of sodium methoxide in methanol.
• Example 40 Preparation of N- (2 -mercapto-lR- ethylethyl) -N-methyl-4- (phenoxy) benzenesulfonamide .
• Part A To a solution of 5.02 g (66.8 mmol) of (R) -(-) -2-amino-l-propanol in 28 mL of THF and 7 mL of water, was added 14.0 mL (100 mmol) of triethylamine. After cooling in an ice bath, 11.7 g (60 mmol) of 4-fluorobenzenesulfonyl chloride was slowly added over 10 minutes.
• Part B To a solution of 5.14 g (22.0 mmol) of N- (2-hydroxy-lR-methylethyl) -4-fluorobenzene- sulfonamide from Part A in 40 mL of anhydrous DMF, was added 9.12 g (66.1 mmol) of powdered potassium carbonate, and then 4.2 mL (66 mmol) of methyl iodide.
• Part C To a solution of 3.00 g (12.1 mmol) of the product from Part B in 25 mL of anhydrous DMF, was added 5.02 g (36.4 mmol) of powdered potassium carbonate, and then 2.3 g (24.3 mmol) of phenol. The reaction mixture was heated to 100 C for 48 hours, cooled and tert-butylmethyl ether and water added. The organic layer was separated and washed with 10% sodium hydroxide, brine, dried with sodium sulfate, filtered and stripped to afford 3.0 g of crude material.
• Part E To a solution of 0.76 g (2.05 mmol) of product from Part D in 5 mL of anhydrous methanol, was added 1.8 mL (7.4 mmol) of a 25 weight % solution of sodium methoxide in methanol. After 0.5 hour, the reaction was quenched with IN HCl solution, followed by ethyl acetate and water, the organic layer was separated and washed with saturated sodium bicarbonate solution and brine, dried with magnesium sulfate, filtered and concentrated to afford the crude product. This was chromatographed on 100 g of silica gel using 100% methylene chloride to provide the pure
• Example 41 Preparation of N- (2-mercapto-lR- ethylethyl) -N-methyl-4 - (thiophenyl) benzenesulfonamide .
• Part A To a solution of 1.72 g (6.95 mmol) of N- (2 -hydroxy- IR-methylethyl) -N-methyl-4- fluorobenzenesulfonamide from Example 40, part B, in 10 mL of anhydrous DMF, was added 7.03 g (21.5 mmol) of cesium carbonate, and then 1.0 mL (1.07 g, 9.73 mmol) of thiophenol. The reaction mixture was heated to 70 C for 15 hours, cooled and ethyl acetate and water added. The organic layer was separated and washed 3xs with brine, dried with sodium sulfate, filtered and stripped to afford 2.5 g of crude material.
• Part C To a solution of 1.0 g (2.53 mmol) of product from Part B in 10 mL of anhydrous methanol, was added 2.1 mL (9.1 mmol) of a 25 weight % solution of sodium methoxide in methanol. After 0.5 hour, the reaction was quenched with IN HCl solution, followed by ethyl acetate and water, the organic layer was separated and washed with saturated sodium bicarbonate solution and brine, dried with magnesium sulfate, filtered and concentrated to afford the crude product.
• Part A To a solution of 1.97 g (26.2 mmol) of (R) -(-) -2-amino-l-propanol in 10 mL of THF and 3.5 mL of water, was added 4.5 mL (32 mmol) of triethylamine. After cooling in an ice bath, 5.44 g (20.9 mmol) of 2 - (pyrid-2-yl) thiophene-5-sulfonyl chloride was slowly added over 10 minutes.
• Part B To a solution of 0. 4 g (3.15 mmol) of product from Part A in 10 mL of anhydrous DMF, was added 1.31 g (9.45 mmol) of powdered potassium carbonate, and then 0.60 mL (9.5 mmol) of methyl iodide. After stirring at room temperature for 24 hours, ethyl acetate and water was added, the layers separated and the organic layer washed 3xs with brine, dried with sodium sulfate, filtered and stripped to afford 0.93 g of the desired N-(2- hydroxy- IR-methylethyl) -N-methyl-2- (pyrid-2- yl) thiophene-5 -sul onamide .
• Example 43 Preparation of N- (2 -mercapto- 1 , 1- dimethylethyi) -N- (phenylmethyl) -4- methoxybenzenesulfonamide .
• Part A To a solution of 4.47 g (50 mmol) of 2-amino-2-methyl-l-propanol in 20 mL of THF and 5 mL of water, was added 10 mL (72 mmol) of triethylamine. After cooling in an ice bath, 9.0 g (44 mmol) of 4 -methoxybenzenesulfonyl chloride was slowly added over 10 minutes.
• Part B To a solution of 3.12 g (12 mmol) of product from Part A in 25 mL of anhydrous DMF, was added 5.0 g (36 mmol) of powdered potassium carbonate, and then 2.2 L (18 mmol) of benzyl bromide. After stirring at room temperature for 17 hours, ethyl acetate and water was added, the layers separated and the organic layer washed 3xs with brine, dried with sodium sulfate, filtered and stripped to afford 3.2 g of crude product.
• Part D To a solution of 0.60 g (1.47 mmol) of product from Part C in 10 L of anhydrous methanol, was added 1.2 mL (5.3 mmol) of a 25 weight percent solution of sodium methoxide in methanol.
• Example 44 Preparation of N-[(2- mercaptophenyl) methyl] -N-methyl-4 - methoxybenzenesulfonamide.
• Part B To a solution of 6.32 g (25.0 mmol) of 2 -iodobenzyl chloride in 40 mL of anhydrous DMF, was added 5.04 g (25.0 mmol) of the product from Part A, and then 10.4 g (75.3 mmol) of powdered potassium carbonate was added. After stirring at room temperature for 5 hours, ethyl acetate and water were added, the organic layer separated and washed 3xs with brine, dried with sodium sulfate, filtered and stripped to afford 10.6 g of crude product.
• Part C To a mixture of 834 mg (2.0 mmol) of the product from Part B, 236 mg (3.1 mmol) of thiourea and 55 mg (0.10 mmol) of bis(tri-n- butylphosphine) -nickel (II) chloride under a nitrogen atmosphere at room temperature, was added 1 mL of anhydrous DMF, and then 16 mg (0.25 mmol) of sodium cyanoborohydride . The reaction was then warmed to 65 C for 15 hours, cooled to room temperature and 2.0 mL (5 mmol) of 2.5 N sodium hydroxide solution added.
• Example 45 Preparation of N- (2-mercapto-lR- methylethyl) -N- [2- (4 - orpholino) ethyl] -4- (n- butoxy) benzenesulfonamide .
• Part A To a solution of 2.87 g (10 mmol) of N- (2-hydroxy- IR-methylethyl) -4- (n-butoxy) benzenesulfonamide from Example 4 in (10 ml) of anhydrous DMF, was added 4.14 g (30 mmol) of powdered potassium carbonate and then 2.04 g (11 mmol) of 4- (2 -Chloroethyl) morpholine hydrochloride.
• Part B To a solution of 1.5 g (3.74 mmol) of product from Part A and 983 mg (3.74 mmol) of triphenylphosphine in 15 ml of anhydrous THF at room temperature was added 0.588 mL (3.74 mmol) of diethyl azodicarboxylate, followed by 0.8 mL (11.22 mmol) of thiolacetic acid.
• Part C To a suspension of 0.63 g (1.7 mmol) of product from Part B in 20 mL of anhydrous methanol, was added 0.5 mL (2.3 mmol) of 25 wt . % sodium methoxide in methanol.
• Example 46 Preparation of N- (2-mercapto-lR- methylethyl) -N- [2- (1-piperidino) ethyl] -4- (n- butoxy) benzenesulfonamide .

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