ZA200202207B - Beta disubstituted metalloprotease inhibitors. - Google Patents

Beta disubstituted metalloprotease inhibitors. Download PDF

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ZA200202207B
ZA200202207B ZA200202207A ZA200202207A ZA200202207B ZA 200202207 B ZA200202207 B ZA 200202207B ZA 200202207 A ZA200202207 A ZA 200202207A ZA 200202207 A ZA200202207 A ZA 200202207A ZA 200202207 B ZA200202207 B ZA 200202207B
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biphenyl
sulfonylamino
methoxy
phenyl
propionic acid
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ZA200202207A
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Stanislaw Pikul
Norman Eugene Ohler
Kelly Michell Solinsky
Neil Gregory Almsted
Biswanath De
Michael George Natchus
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Procter & Gamble
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Description

BETA DISUBSTITUTED METALLOPROTEASE INHIBITORS 3
TECHNICAL FIELD
This invention is directed to compounds that are useful in treating diseases ‘associated with metalloprotease activity, particularly zinc metalloprotease activity. The a invention is also directed to pharmaceutical compositions comprising the compounds, and s to methods of treating metalloprotease-related maladies using the compounds or the pharmaceutical compositions.
BACKGROUND
A number of structurally related metalloproteases effect the breakdown of structural proteins. These metalloproteases often act on the intercellular matrix, and thus are involved in tissue breakdown and remodeling. = Such proteins are referred to as metalloproteases or MPs.
There are several different families of MPs, classified by sequence homology, disclosed in the art. These MPs include Matrix-Metallo Proteases (MMPs); zinc metalloproteases; many of the membrane bound metalloproteases; TNF converting 1s enzymes; angiotensin-converting enzymes (ACEs); disintegrins, including ADAMs (See
Wolfsberg et al, 131 J. Cell Bio. 275-78 October, 1995); and the enkephalinases.
Examples of MPs include human skin fibroblast collagenase, human skin fibroblast gelatinase, human sputum collagenase, aggrecanse and gelatinase, and human stromelysin. Collagenases, stromelysin, aggrecanase and related enzymes are thought to be important in mediating the symptomatology of a number of diseases.
Potential therapeutic indications of MP inhibitors have been discussed in the literature. See, for example, U.S. Patents 5,506,242 (Ciba Geigy Corp.) and 5,403,952 (Merck & Co.); the following PCT published application: WO 96/06074 (British Bio
Tech Ltd.); WO 96/00214 (Ciba Geigy), WO 95/35275 (British Bio Tech Ltd.), WO 3s 95/35276 (British Bio Tech Ltd.), WO 95/33731 (Hoffman-LaRoche), WO 95/33709 (Hoffman-LaRoche), WO 95/32944 (British Bio Tech Ltd.), WO 95/26989 (Merck), WO 9529892 (DuPont Merck), WO 95/24921 (Inst. Opthamology), WO 95/23790 (SmithKline Beecham), WO 95/22966 (Sanofi Winthrop), WO 95/19965 (Glycomed),
WO 95 19956 (British Bio Tech Ltd), WO 95/19957 (British Bio Tech Ltd.), WO
. ~ WO 01/27084 PCT/US00/28194 ' 95/19961 (British Bio Tech Ltd.), WO 95/13289 (Chiroscience Ltd.), WO 95/12603 (Syntex), WO 95/09633 (Florida State Univ.), WO 95/09620 (Florida State Univ.), WO 95/04033 (Celitech), WO 94/25434 (Celltech), WO 94/25435 (Celltech); WO 93/14112 (Merck), WO 94/0019 (Glaxo), WO 93/21942 (British Bio Tech Ltd.), WO 92/22523 s (Res. Corp. Tech Inc), WO 94/10990 (British Bio Tech Ltd.), WO 93/09090 (Yamanouchi); British patents GB 2282598 (Merck) and GB 2268934 (British Bio Tech
Ltd.); published European Patent Applications EP 95/684240 (Hoffman LaRoche), EP 574758 (Hoffman LaRoche) and EP 575844 (Hoffman LaRoche); published Japanese applications JP 08053403 (Fujusowa Pharm. Co. Ltd.) and JP 7304770 (Kanebo Ltd.); 10 and Bird et al., J. Med. Chem., vol. 37, pp. 158-69 (1994).
Examples of potential therapeutic uses of MP inhibitors include rheumatoid arthritis - Mullins, D. E., et al., Biochim. Biophys. Acta. (1983) 695:117-214; osteoarthritis - Henderson, B., et al., Drugs of the Future (1990) 15:495-508; cancer - Yu,
A. E. et al., Matrix Metalloproteinases - Novel Targets for Directed Cancer Therapy, 1s Drugs & Aging, Vol. 11(3), p. 229-244 (Sept. 1997), Chambers, A.F. and Matrisian,
L.M., Review: Changing Views of the Role of Matrix Metalloproteinases in Metastasis, J. of the Nat’l Cancer Inst., Vol. 89(17), p. 1260-1270 (Sept. 1997), Bramhall, S.R., The
Matrix Metalloproteinases and Their Inhibitors in Pancreatic Cancer, Internat’] J. of
Pancreatology, Vol. 4, p. 1101-1109 (May 1998), Nemunaitis, J. et al.,, Combined w Analysis of Studies of the Effects of the Matrix Metalloproteinase Inhibitor Marimastat on Serum Tumor Markers in Advanced Cancer: Selection of a Biologically Active and
Tolerable Dose for Longer-term Studies, Clin. Cancer Res., Vol 4, p. 1101-1109 (May 1998), and Rasmussen, H.S. and McCann, P.P, Matrix Metalloproteinase Inhibition as a
Novel Anticancer Strategy: A Review with Special Focus on Batimastat and Marimastat, »s Pharmacol. Ther., Vol 75(1), p. 69-75 (1997); the metastasis of tumor cells - ibid,
Broadhurst, M. J., et al., European Patent Application 276,436 (published 1987), Reich,
R., et al., Cancer Res., Vol. 48, p. 3307-3312 (1988); multiple sclerosis - Gijbels et al., J.
Clin. Invest, vol. 94, p. 2177-2182 (1994); and various ulcerations or ulcerative conditions of tissue. For example, ulcerative conditions can result in the cornea as the result of alkali bums or as a result of infection by Pseudomonas aeruginosa,
Acanthamoeba, Herpes simplex and vaccinia viruses. Other examples of conditions characterized by undesired metalloprotease activity include periodontal disease, ' epidermolysis bullosa, fever, inflammation and scleritis (e.g., DeCicco et al., World
Patent Publication WO 95/29892 published November 9, 1995).
In view of the involvement of such metalloproteases in a number of disease s conditions, attempts have been made to prepare inhibitors to these enzymes. A number of such inhibitors are disclosed in the literature. Examples include U.S. Patent No. 5,183,900, issued February 2, 1993 to Galardy; U.S. Patent No. 4,996,358, issued
February 26, 1991 to Handa, et al; U.S. Patent No. 4,771,038, issued September 13, 1988 to Wolanin, et al.; U.S. Patent No. 4,743,587, issued May 10, 1988 to Dickens, et al., oo European Patent Publication No. 575,844, published December 29, 1993 by Broadhurst, et al.; International Patent Publication No. WO 93/09090, published May 13, 1993 by
Isomura, et al.; World Patent Publication 92/17460, published October 15, 1992 by
Markwell et al.; and European Patent Publication No. 498,665, published August 12, 1992 by Beckett, et al. 1 It would be advantageous to inhibit these metalloproteases in treating diseases related to unwanted metalloprotease activity. Though a variety of MP inhibitors have : been prepared, there is a continuing need for potent matrix metalloprotease inhibitors useful in treating diseases associated with metalloprotease activity. :
SUMMARY OF THE INVENTION
The invention provides compounds which are potent inhibitors of metalloproteases and which are effective in treating conditions characterized by excess activity of these enzymes. In particular, the present invention relates to compounds having a structure according to the following Formula (1): 0 R°R®
Ap FAN
R Ss ¢g <Z 0,
R*TSRE
R M
»s wherein: (A) R'is selected from -OH and -NHOH;
(B) R? is selected from hydrogen, hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and halogen; — n= Se (©) R? is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, s aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; (D) R*is -(CR'R”)-X-(CR®R¥)~E-A where: (1) kis from 0 to about 4; (2) lis from O to about 4; (3) eachof R’,R”, R® and R®, when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, and haloalkyl; (4) X is selected from -O-, -S-, -S(0)-, -S(02)-, -N(R’)-, -N(COR’)-, -
N(CO;R’)-, -N(CONR’R?)-, and -N(SO;R®)-, where (i) each R® and R”, when present, is independently selected from hydrogen, alkyl, alkenyl, . 15 alkynyl, hcteroalkyl, haloalkyl, aryl, .arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or (ii) R’ and R’, ) together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; 2 (5) E is selected from a covalent bond, -O-, -S-, -S(O)-, -S(02)-, -NR™)-, -N(COR'%)-, -N(CO;R'%)-, -N(CONR'’R'?)-, and -N(SO,R'®)-, where (i) each R' and R'”, when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or (ii) R' and R'?, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; provided that when / = 0, E is a covalent bond; and (6) (a) A is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or
(b) A, together with R, R7, RE, RY, R’, RY, R' or RY, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ) ring atoms of which from 1 to 3 are heteroatoms; (E) R® is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, s aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
F) RS is selected from alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and hydroxyl; provided that when k > 0, R® is -OH and when k = 0, R® is not -OH; (G) G is selected from -$-, -O-, -N(R'")-, -C(R'")=C(R'")-, -N=C(R'")-, and - 10 N=N-, where each R'' and R'", when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; (H) Z is selected from: (1) cycloalkyl and heterocycloalkyl; ts 2) -L-(CR'R'")a-R" where: (a) ais from O to about 4; ) (b) Lis selected from -C=C-, -CH=CH-, -N=N-, -O-, -S- and -SO»-; (c) each R' and R'?, when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, 20 cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; and (d) R" is selected from hydrogen, aryl, heteroaryl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, heterocycloalkyl and cycloalkyl, and, if L is -C=C- or -CH=CH-, then R" may also be selected from 25 -CON(RMR') where (i) R' and R'* are independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, or (ii) R' and R'¥, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 30 to 8 ring atoms of which from 1 to 3 are heteroatoms; (3) -NR"R" where:
. w WO 01/27084 PCT/US00/28194 (a) R' and RY each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, hetcroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heteroalkyl and -C(0)-Q-(CR'®R'®);-R'” where:
Cl (i) bis from 0 to about 4; s (ii) Q is selected from a covalent bond and -N(R'®)-; and (iii) each R'® and R'®, when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; each R' and R" is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, or
R'7 and R'®, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; or R'® and R"%, together with the nitrogen atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from S to 8 ring atoms of which from 2 to 3 are heteroatoms; or (b) R'* and R'?, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; and
E-M 1 \
MN era—a “) ¢ , Where: (a) E’and M’ are independently selected from -CH- and -N-; 2 (b) Lis selected from -S-, -O-, -N(R*)-, -C(R*)=C(R™")-, -
N=C(R?)-, and -N=N-, where each R*® and R*®, when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; (c) cis from 0 to about 4;
(d) each R" and R'', when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, : cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; (e) A’ is selected from a covalent bond, -O-, -SO4-, -C(O)-, -C(O)N(R?")-, -N(R?")-, and -N(R?")C(O)-; where d is from 0 to 2 and R* is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkyl; and (f) Gis -(CR*?R¥),-R? where e is from 0 to about 4; each R*? and
R*?, when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, alkoxy and aryloxy; and R? is selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; or R* and R%, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 atoms of which 1 to 3 are heteroatoms; or R?° and R?, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 atoms of which 1 to 3 are heteroatoms; or an optical isomer, diastereomer or enantiomer for Formula (I), or a pharmaceutically- acceptable salt, or biohydrolyzable amide, ester, or imide thereof.
This invention also includes optical isomers, diastereomers and enantiomers of the »s formula above, and pharmaceutically-acceptable salts, biohydrolyzable amides, esters, and imides thereof.
The compounds of the present invention are useful for the treatment of diseases and conditions which are characterized by unwanted metalloprotease activity.
Accordingly, the invention further provides pharmaceutical compositions comprising 3 these compounds. The invention still further provides methods of treatment for metalloprotease-related maladies.
. ~WO 01/27084 PCT/US00/28194
DETAILED DESCRIPTION OF THE INVENTION
I. Terms and Definitions:
The following is a list of definitions for terms used herein.
Cee "Acyl" or "carbonyl" is a radical formed by removal of the hydroxy from a s carboxylic acid (i.e., R-C(=Q)-). Preferred acyl groups include (for example) acetyl, formyl, and propionyl. “Alkyl" is a saturated hydrocarbon chain having 1 to 15 carbon atoms, preferably 1 to 10, more preferably 1 to 4 carbon atoms. “Alkene” is a hydrocarbon chain having at least one (preferably only one) carbon-carbon double bond and having 2 to 15 carbon 1 atoms, preferably 2 to 10, more preferably 2 to 4 carbon atoms. “Alkyne” is a hydrocarbon chain having at least one (preferably only one) carbon-carbon triple bond and having 2 to 15 carbon atoms, preferably 2 to 10, more preferably 2 to 4 carbon atoms.
Alkyl, alkene and alkyne chains (referred to collectively as “hydrocarbon chains”) may be straight or branched and may be unsubstituted or substituted. Preferred branched } 1s alkyl, alkene and alkyne chains have one or two branches, preferably one branch.
Preferred chains are alkyl. Alkyl, alkene and alkyne hydrocarbon chains each may be unsubstituted or substituted with from 1 to 4 substituents; when substituted, preferred chains are mono-, di-, or tri-substituted. Alkyl, alkene and alkyne hydrocarbon chains each may be substituted with halo, hydroxy, aryloxy (e.g., phenoxy), heteroaryloxy, 2 acyloxy (e.g., acetoxy), carboxy, aryl (e.g, phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amino, amido, acylamino, keto, thioketo, cyano, or any combination thereof. Preferred hydrocarbon groups include methyl, ethyl, propyl, isopropyl, butyl, vinyl, allyl, butenyl, and exomethylenyl.
Also, as referred to herein, a "lower" alkyl, alkene or alkyne moiety (e.g., 2s "lower alkyl”) is a chain comprised of 1 to 6, preferably from 1 to 4, carbon atoms in the case of alkyl and 2 to 6, preferably 2 to 4, carbon atoms in the case of alkene and alkyne. "Alkoxy" is an oxygen radical having a hydrocarbon chain substituent, where the hydrocarbon chain is an alkyl or alkenyl (i.e., -O-alkyl or -O-alkenyl). Preferred alkoxy groups include (for example) methoxy, ethoxy, propoxy and allyloxy.
“Aryl” is an aromatic hydrocarbon ring. Aryl rings are monocyclic or fused bicyclic ring systems. Monocyclic aryl rings contain 6 carbon atoms in the ring. :
Monocyclic aryl rings are also referred to as phenyl rings. Bicyclic aryl rings contain from 8 to 17 carbon atoms, preferably 9 to 12 carbon atoms, in the ring. Bicyclic aryl s rings include ring systems wherein one ring is aryl and the other ring is aryl, cycloalkyl, or heterocycloakyl. Preferred bicyclic aryl rings comprise 5-, 6- or 7- membered rings fused to 5-, 6-, or 7-membered rings. Aryl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Aryl may be substituted with halo, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, io phenyl, aryloxy, alkoxy, heteroalkyloxy, carbamyl, methylenedioxy, heteroaryloxy, or any combination thereof. Preferred aryl rings include naphthyl, tolyl, xylyl, and phenyl.
The most preferred aryl ring radical is phenyl. “Aryloxy” is an oxygen radical having an aryl substituent (i.e., -O-aryl).
Preferred aryloxy groups include (for example) phenoxy, napthyloxy, methoxyphenoxy, is and methylenedioxyphenoxy. “Cycloalky!" is a saturated or unsaturated hydrocarbon ring. Cycloalkyl rings are : not aromatic. Cycloalkyl rings are monocyclic, or are fused, spiro, or bridged bicyclic ring systems. Monocyclic cycloalkyl rings contain from about 3 to about 9 carbon atoms, : preferably from 3 to 7 carbon atoms, in the ring. Bicyclic cycloalkyl rings contain from 7 to 17 carbon atoms, preferably from 7 to 12 carbon atoms, in the ring. Preferred bicyclic cycloalkyl rings comprise 4-, 5-, 6- or 7-membered nngs fused to 5-, 6-, or 7- membered rings. Cycloalkyl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Cycloalkyl may be substituted with halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, 2s heteroaryloxy, or any combination thereof. Preferred cycloalkyl rings include cyclopropyl, cyclopentyl, and cyclohexyl. “Halo" or “halogen” is fluoro, chloro, bromo or iodo. Preferred halo are fluoro, chloro and bromo; more preferred typically are chloro and fluoro. “Haloalkyl" is a straight, branched, or cyclic hydrocarbon substituted with one or 3 more halo substituents. Preferred are C1-Cj haloalkyls; more preferred are Cy-Cg haloalkyls; still more preferred still are C1-C3 haloalkyls. Preferred halo substituents are fluoro and chloro. “Heteroatom” is a nitrogen, sulfur, or oxygen atom. Groups containing more than
Co one heteroatom may contain different heteroatoms. s “Heteroalkyl” is a saturated or unsaturated chain containing carbon and at least one heteroatom, wherein no two heteroatoms are adjacent. Heteroalkyl chains contain from 2 to 15 member atoms (carbon and heteroatoms) in the chain, preferably 2 to 10, more preferably 2 to 5. For example, alkoxy (i.e., -O-alkyl or -O-heteroalky!) radicals are included in heteroalkyl. Heteroalkyl chains may be straight or branched. Preferred 0 branched heteroalkyl have one or two branches, prefcrably one branch. Preferred heteroalkyl arc saturated. Unsaturated heteroalkyl have one or more carbon-carbon double bonds and/or one or more carbon-carbon triple bonds. Preferred unsaturated heteroalkyls have one or two double bonds or one triple bond, more preferably one double bond. Heteroalkyl chains may be unsubstituted or substituted with from 1 to 4 15 substituents. Preferred substituted heteroalkyl are mono-, di-, or tri-substituted.
Heteroalkyl may be substituted with lower alkyl, haloalkyl, halo, hydroxy, aryloxy, heteroaryloxy, acyloxy, carboxy, monocyclic aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amino, acylamino, amido, keto, thioketo, cyano, or any combination thereof. 20 “Heteroaryl” is an aromatic ring containing carbon atoms and from 1 to about 6 heteroatoms in the ring. Heteroaryl rings are monocyclic or fused bicyclic ring systems.
Monocyclic heteroaryl rings contain from about 5 to about 9 member atoms (carbon and heteroatoms), preferably 5 or 6 member atoms, in the ring. Bicyclic heteroaryl rings contain from 8 to 17 member atoms, preferably 8 to 12 member atoms, in the ring. 2s Bicyclic heteroaryl rings include ring systems wherein one ring is heteroaryl and the other ring is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl. Preferred bicyclic heteroaryl ring systems comprise 5-, 6- or 7-membered rings fused to 5-, 6-, or 7- membered rings. Heteroaryl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Heteroaryl may be substituted with halo, cyano, nitro, hydroxy, 3 carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, alkoxy, aryloxy,
heteroaryloxy, or any combination thereof. Preferred heteroaryl rings include, but are not limited to, the following: .
H H H
(0) S N NY N O 0
OU YU UN 2 UY
N N
Furan Thiophene Pyrrole Pyrazole Imidazole Oxazole Isoxazole
H
.S S .S. .N S JO.
N\ J «J NY N 7 Wi NO
N 7 N ~ N-N J
Isothiazole Thiazole 1,2,5-Thiadiazole 1,2,3-Triazole 1,3.4-Thiadiazole Furazan
Ss S N N N
NY vo Cox QQ wa
Nt LN N YN N—N s 1,2,3-Thiadiazole 1,2,4-Thiadiazole Benzotriazole 1,2,4-Triazole Tetrazole .0 le) O. S. .S.
NCD i { N CN NUN
LN N—N N-N N-N \Y 1,2,4-Oxadiazole 1,3,4-Oxadiazole 1,2,3,4-Oxatriazole 1,2,3,4-Thiatriazole 1.2.3,5-Thiatriazole
Od N. NJ N. Oo
NTN “N [ °N i °N :
Ly ZN = No? 1,2,3,5-Oxatriazole 1,2,3-Triazine 1,2,4-Triazine 1,2,4,5-Tetrazine Dibenzofuran
N. ~~ N y
SN SNOONTSN SN NF
J Y
= = = N= N. 2N xN
Pyridine Pyridazine Pyrimidine Pyrazine 1,3,5-Triazine Indolizine Indole
H H N
Cow C0 CO C0 CO / /
Isoindole Benzofuran Benzothiophene 1H-Indazole Purine Quinoline
N
N
N S 0)
N ? ? NH
H N N
Benzimidazole Benzthiazole Benzoxazole Carbazole 2,3-Dihydro-1H-Isoindole
Ee eleclesioetooloe = Z ZN ZN NE INF
Isoquinoline Cinnoline Phthalazine Quinazoline Quinoxaline 1,8-Napthypyridine (J coo Co Og
N N N o O
Pteridine Acridine Phenazine 1,2-Benzisothiazoline Benzylsultam sedisuicasioeles
Z CO 0 CO CD
Coumarin indoline Phenoxazine 2H-Chromene 3H-Indole 0) Oo H oY CO oy coo Co 0 7 S
Chromone Chroman 4H-3,1-benzoxazine Phenothiazine Phthalan s “Heteroaryloxy” is an oxygen radical having a heteroaryl substituent (i.e., -O- heteroaryl). Preferred heteroaryloxy groups include (for example) pyridyloxy, furanyloxy, (thiophene)oxy, (oxazole)oxy, (thiazole)oxy, (isoxazole)oxy, pyrmidinyloxy, pyrazinyloxy, and benzothiazolyloxy. “Heterocycloalkyl" is a saturated or unsaturated ring containing carbon atoms and from 1 to about 4 (preferably 1 to 3) heteroatoms in the ring. Heterocycloalky! rings are not aromatic. Heterocycloalkyl rings are monocyclic, or are fused, bridged, or spiro bicyclic ring systems. Monocyclic heterocycloalkyl rings contain from about 3 to about 9 member atoms (carbon and heteroatoms), preferably from 5 to 7 member atoms, in the ring. Bicyclic heterocycloalkyl rings contain from 7 to 17 member atoms, preferably 7 to 1s 12 member atoms, in the ring. Bicyclic heterocycloalkyl rings contain from about 7 to about 17 ring atoms, preferably from 7 to 12 ring atoms. Bicyclic heterocycloalkyl rings may be fused, spiro, or bridged ring systems. Preferred bicyclic heterocycloalkyl rings comprise 5-, 6- or 7-membered rings fused to 5-, 6-, or 7- membered rings. Heterocycloalkyl rings may be unsubstituted or substituted with from 1 0 to 4 substituents on the ring. Heterocycloalkyl may be substituted with halo, cyano, hydroxy, carboxy, keto, thioketo, amino, acylamino, acyl, amido, alkyl, heteroalkyl,
haloalkyl, phenyl, alkoxy, aryloxy or any combination thereof. Preferred substituents on heterocycloalkyl include halo and haloalkyl. Preferred heterocycloalkyl rings include, but are not limited to, the following:
H 0) o NH 0 N C ) po Dw FO DS
Oxirane Aziridine Oxetane Azetidine Tetrahydrofuran Pyrrolidine 1 4-Oxathiane 0 S, S 0, Q,
C > (Cs C > B Iw 0) S s 1,3-Dioxolane 1,2-Dithiolane 1,3-Dithiolane 4,5-Dihydroisoxazole 2,3-Dihydroisoxazole
H
H H
Od dog
N
Z N NJ x-N
H hexahydro-Pyridazine 4,5-Dihydropyrazole Imidazolidine 2H-Pyrrole 4H-Quinolizine
H
WOO OQ
FO b
Pyrazolidine 2H-Pyran 3,4-Dihydro-2H-pyran Tetrahydropyran 1,3-Dioxane )
H o N © Z>0 lo)
UU JL
N N N N
5,6-dihydro-4H-1,3-oxazine Piperidine Morpholine 4H-1,3-Oxazine 6H-1,3-Oxazine
H H s 0) N Oi C s 0) N () & 3 Ny
Cepham Piperazine Hexahydroazepine 1,3-Dithiane 1,4-Dioxane Penem
H H H
N 0) N O N O : i “YT (YF
N
C ) C ) Ch Th Lh Cs
S
S 0 lo} NH, 0 1,4-Dithiane Thiomorpholine Uracil Thymine Cytosine Thiolane
As used herein, "mammalian metalloprotease" refers to the proteases disclosed in the "Background" section of this application. The compounds of the present invention are preferably active against "mammalian metalloproteases”, including any metal-
I containing (preferably zinc-containing) enzyme found in animal, preferably mammalian, s sources capable of catalyzing the breakdown of collagen, gelatin or proteoglycan under suitable assay conditions. Appropriate assay conditions can be found, for example, in
U.S. Patent No. 4,743,587, which references the procedure of Cawston, et al., Anal.
Biochem. (1979) 99:340-345; usc of a synthetic substrate is described by Weingarten, H., et al., Biochem. Biophy. Res. Comm. (1984) 139:1184-1187. See also Knight, C.G. et 0 al, “A Novel Coumarin-Labelled Peptide for Sensitive Continuous Assays of the Matrix
Metalloproteases”, FEBS Letters, Vol. 296, pp. 263-266 (1992). Any standard method for analyzing the breakdown of these structural proteins can, of course, be used. The present compounds arc more preferably active against metalloprotease enzymes that are zinc-containing proteases which are similar in structure to, for example, human 1s stromelysin or skin fibroblast collagenase. The ability of candidate compounds to inhibit metalloprotease activity can, of course, be tested in the assays described above. Isolated metalloprotease enzymes can be used to confirm the inhibiting activity of the invention compounds, or crude extracts which contain the range of enzymes capable of tissue breakdown can be used. “Spirocycle” is an alkyl or heteroalkyl diradical substituent of alkyl or heteroalkyl wherein said diradical substituent is attached geminally and wherein said diradical substituent forms a ring, said ring containing 4 to 8 member atoms (carbon or heteroatom), preferably 5 or 6 member atoms.
While alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl groups may be ;s substituted with hydroxy, amino, and amido groups as stated above, the following are not envisioned in the invention: 1. Enols (OH attached to a carbon-carbon double bond). 2. Amino groups attached to a carbon-carbon double bond (except for vinylogous amides).
3. More than one hydroxy, amino, or amido attached to a single carbon (except where two nitrogen atoms are attached to a single carbon atom and all three . atoms are member atoms within a heterocycloalkyl ning). 4. Hydroxy, amino, or amido attached to a carbon that also has a halogen attached to it.
A "pharmaceutically-acceptable salt" is a cationic salt formed at any acidic (e.g., hydroxamic or carboxylic acid) group, or an anionic salt formed at any basic (e.g., amino) group. Many such salts are known in the art, as described in World
Patent Publication 87/05297, Johnston et al, published September 11, 1987 incorporated by reference herein. Preferred cationic salts include the alkali metal salts (such as sodium and potassium), and alkaline earth metal salts (such as magnesium and calcium) and organic salts. Preferred anionic salts include the halides (such as chloride salts), sulfonates, carboxylates, phosphates, and the like.
Such salts are well understood by the skilled artisan, and the skilled artisan is © 1s able to prepare any number of salts given the knowledge in the art. Furthermore, it is recognized that the skilled artisan may prefer one salt over another for reasons of . solubility, stability, formulation ease and the like. Determination and optimization of such salts is within the purview of the skilled artisan's practice.
A "biohydrolyzable amide" is an amide of a hydroxamic acid-containing (i.e., 20 Rin Formula (I) is -NHOH) metalioprotease inhibitor that does not interfere with the inhibitory activity of the compound, or that is readily converted in vivo by an animal, preferably a mammal, more preferably a human subject, to yield an active metalloprotease inhibitor. Examples of such amide derivatives are alkoxyamides, where the hydroxyl hydrogen of the hydroxamic acid of Formula (I) is replaced by an alkyl 2s moiety, and acyloxyamides, where the hydroxyl hydrogen is replaced by an acyl moiety (i.e., R-C(=0)-).
A "biohydrolyzable hydroxy imide" is an imide of a hydroxamic acid- containing metalloprotease inhibitor that does not interfere with the metalloprotease inhibitory activity of these compounds, or that is readily converted in vivo by an 3 animal, preferably a mammal, more preferably a human subject to yield an active metalloprotease inhibitor. Examples of such imide derivatives are those where the amino hydrogen of the hydroxamic acid of Formula (I) is replaced by an acyl moiety (i.e.,
R-C(=0)-).
A "biohydrolyzable ester" is an ester of a carboxylic acid-containing (i.e., R'in
I _Formula (I) is -OH) metalloprotease inhibitor that does not interfere with the s metalloprotease inhibitory activity of these compounds or that is readily converted by an animal to yield an active metalloprotease inhibitor. Such esters include lower alkyl esters, lower acyloxy-alkyl esters (such as acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxyethyl esters), lactonyl esters (such as phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters io (such as methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters and alkyl acylamino alky! esters (such as acetamidomethy! esters).
A "solvate" is a complex formed by the combination of a solute (e.g., a metalloprotease inhibitor) and a solvent (e.g., water). See J. Honig et al., The Van 1s Nostrand Chemist's Dictionary, p. 650 (1953). Pharmaceutically-acceptable solvents used according to this invention include those that do not interfere with the biological activity of the metalloprotease inhibitor (e.g., water, ethanol, acetic acid, N,N- dimethylformamide and others known or readily determined by the skilled artisan).
The terms "optical isomer”, "stereoisomer", and "diastercomer" have the 2 standard art recognized meanings (see, e.g., Hawley's Condensed Chemical
Dictionary, 11th Ed.). The illustration of specific protected forms and other derivatives of the compounds of the instant invention is not intended to be limiting.
The application of other useful protecting groups, salt forms, etc. is within the ability of the skilled artisan. » II. Compounds:
The subject invention involves compounds of Formula (I): 0 R°R®
A A
R S G Zz 0;
R*TSR®
R M where R!, R%, R®, R*, R®, R®, G and Z have the meanings described above. The following provides a description of particularly preferred moieties, but is not intended to limit the : scope of the claims.
R'is selected from -OH and -NHOH; preferably -OH.
R? is selected from hydrogen, hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and halogen; preferably hydrogen or alkyl, more preferably hydrogen.
R3 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; preferably hydrogen or alkyl, more preferably hydrogen.
R* is -(CR’R”)i-X-(CR®R¥*)-E-A. Each of k and / is independently selected from 0, 1, 2, 3 or 4; preferably kis 0, 1, 2 or 3; preferably /is 0, 1 or 2. Each of R",R", R}, and
R¥ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen and haloalkyl; preferably all are 1s hydrogen.
X is selected from -O-, -S-, -S(0)-, -S(O2)-, -N(R®)-, -N(COR®)-, N(CO:R%-, -
N(CONR’R’)-, and -N(SO;R%)-, where each R® and R’ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl (preferably each R® and R” is hydrogen), or (ii) R® and R” together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms. Preferably X is -O-, -S-, -N(SO:R?), -N(COR?), -
NCO,R®), where R’ is preferably lower alkyl or aryl.
E is selected from a covalent bond, -O-, -S-, -S(0), -S(02)-, -N(R'%)-, -N(COR'%)-, 2» -N(COR')-, -N(CONR'®R'")-, and -N(SO;R')-, where (i) each R'® and R'" is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl (preferably each R' and R'" is hydrogen), or (ii) R'" and R'" together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from S to 8 ring atoms of which from 1 to 3 are heteroatoms. Preferably, E is covalent bond, -O-, -S-, -N(SO;R'%)-, -N(COR'%, or -N(COR'%)-, where R'? is preferably lower alkyl or aryl. When /= 0, E is a covalent bond.
A is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; preferably A is s alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.
R’ is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; preferably hydrogen or lower alkyl; more preferably hydrogen.
R® is selected from alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, 0 heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and hydroxyl; preferably aryl, heteroaryl or hydroxyl. When k> 0, R® is -OH and when k = 0, R® is not -OH.
G is selected from -S-, -O-, -N(R")-, -C(R"")=C(R'")-, -N=C(R'")-, and -N=N-; in a preferred embodiment, G is -S- or -C(R'")=C(R'")-. Each R"' and R'"" is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, 1s and heterocycloalkyl; preferably at least one of R'' and R'Y is hydrogen, more preferably both are hydrogen.
Z is selected from cycloalkyl and heterocycloalkyl; -L-(CR'’R'%),-R"; -NRPR';
E-M' ;
Pe. CRPR}- A=G and c .
When Z is cycloalkyl or heterocycloalkyl, preferred is where Z is an optionally substituted piperidine or piperazine.
When Z is -L-(CR'R'),-R", ais 0, 1, 2, 3 or 4, preferably 0 or 1. L is selected from -C=C-, -CH=CH-, -N=N-, -O-, -S- and -S(0)-; preferred is where L is -C=C-, -
CH=CH-, -N=N-, -O- or -S-; more preferred is where L is -C=C-, -CH=CH-, or -N=N-.
Fach R'? and R'? is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, »s heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; preferably each R'? is hydrogen and each R'? is independently hydrogen or lower alkyl. R" is selected from aryl, heteroaryl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, heterocycloalkyl and cycloalkyl; preferably R" is aryl, heteroaryl, heterocycloalkyl or cycloalkyl. However, if L is -C=C- or -CH=CH-, then R'® may also be selected from -
C(O)NR'“R' where (i) R' and R' are independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalky], ; or (ii) R' and R', together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 (preferably 5 or 6) ring s atoms of which from 1 to 3 (preferably 1 or 2) are heteroatoms.
When Z is -NR""R", R'® and R" each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heteroalkyl, and -C(0)-Q-(CR'*R'¢),-R""; preferably R'® and R'>' are independently selected from hydrogen, alkyl, aryl and -C(0)-Q-(CR'*R'®*),-R"". When R"’ and/or R'¥ is -C(0)-Q- ww (CR'R'®),-R", bis 0, 1,2, 3 or 4; b is preferably 0 or 1. Q is selected from a covalent bond and -NR'®-; Q is preferably a covalent bond. Each R'® and R'® is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; preferably each R'® is hydrogen and each R'® is independently hydrogen or lower alkyl. R'” and R'® each is 1s independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalky! (preferably one is aryl); or R'" and R®, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 (preferably S or 6) ring atoms of which from 1 to 3 (preferably 1 or 2) are heteroatoms; preferably R'7 is alkyl, aryl, heteroaryl, cycloalkyl! or heterocycloalkyl. Alternatively, R" and R'S, together with the nitrogen atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 (preferably S or 6) ring atoms of which from 1 to 3 (preferably 1 or 2) are heteroatoms. Most preferred is where R'is hydrogen or lower alkyl and R'is -C(0)-Q-(CR'®R'®),-R!” where Q is a covalent bond, = 0, and R" 2s isaryl
Alternatively, R'> and R'¥’, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 (preferably 5 or 6) ring atoms of which from 1 to 3 (preferably 1 or 2) are heteroatoms.
E-M
THE
AN re CRPR")- A—G
When Z 1s ¢ (referred to herein as Formula (A)), E'
So and M’ are independently selected from -CH- and -N-; preferred is where E' is -CH and
M’ is -CH. L' is selected from -S-, -O-, -N(R?®)-, -C(R®*)=C(R*®)-,-N=C(R*®)-, and -
N=N-; preferably L is -C(R?®)=C(R**)-. R* and R*” each is independently selected from s hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; preferably hydrogen or lower alkyl. cis 0, 1, 2, 3 or 4, preferably 0 or 1. Each R" and R" is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; preferably each R'® is hydrogen and each R' is independently hydrogen or 0 lower alkyl. A’ is selected from a covalent bond, -O-, -SO,-, -C(O)-, -C(O)N(R?Y-, -
N(R?")-, and -N(R*)C(O)-; preferably A’ is -O- or -S-. dis 0, 1 or 2. R*' is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkyl; R?' is preferably lower alkyl or aryl. G' is -(CR?R*).-
R%. eis 0, 1, 2, 3 or 4, preferably 0 or 1. Each R?2 and R% is independently selected is from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, alkoxy and aryloxy; preferably each RZ is hydrogen and each R* is independently hydrogen or lower alkyl. R? is selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; preferably R2 is lower alkyl or aryl. Alternatively, R? 2» and R?®, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 (preferably 5 or 6) atoms of which 1 to 3 (preferably 1 or 2) are heteroatoms. Alternatively, R?® and R?, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 (preferably 5 or 6) atoms of which 1 to 3 (preferably 1 or 2) are 2s heteroatoms.
Most preferred compounds are those where Z is -NR"R" or
E-M
JA re. cROR”} A—G
Preferred sub-genuses of compounds are those carboxylic acid-containing compounds having a structure according to the following Formula (II) or Formula (111)
OHH
OHH i 7 \
A WEN org io Nez
H XE
Ac A dan {a1 s whereRS, X, k, I, E, A, G, and Z are as described with respect to Formula (I).
IIL. Compound Preparation
The compounds of the invention can be prepared using a variety of procedures.
The starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available. Particularly preferred syntheses are described in the following general reaction schemes. (The R groups used to illustrate the reaction schemes do not necessarily correlate to the respective R groups used to describe the various aspects of the Formula I compounds. That is, for example, :
R! in Formula (I) does not represent the same moiety as R, here). Specific examples for making the compounds of the present invention are set forth in Section VIII, below. : 1s Scheme \ Be NB Nn
OA -_— OA _— ~ -— 0 OH “R2
S1a Sib Sic
Rr? rR?
WHz | $0, So, aay —_— Ho JA —_— Ho
Or? Oo Og?
S1d Ste Sif
In Scheme 1, the aldehyde S1a is a commercially available material. Its synthetic utility has widely been recognized and several conditions have been developed for its stereoselective reactions with nucleophiles. This way, various aryl or alkyl R' groups can 2 be introduced to form alcohols S1b, and the syn/anti stereochmistry can be controlled depending on the reaction conditions. The newly formed hydroxyl group of Sib can, in turn, be functionalized by a wide variety of alkylating agents using methods well known to the skilled artisan to introduce substituent R%. The product S1c can then be converted to the target carboxylic acid using methods well documented in the chemical literature.
Thus, the Boc and the acetonide protective groups of Slc can be removed under acidic
Rn “conditions to obtain the aminoalcohol Sid. The amino group of this intermediate can s selectively be derivatized by an appropriate aryl sulfonyl chloride using standard Shott and Bouman conditions to give sulfonamide Sle. Further elaboration of the aryl group rR’ may be performed at this stage using, for example, the Suzuki coupling method. Finally, the alcohol function is converted to the carboxylic acid using standard oxidation methods to produce the target molecule S1f.
If desired, the carboxylic acid functionality in compounds of type SIf can be converted to the hydroxamic acid by coupling with hydroxylamine using a mixed anhydride method or by forming of an intermediate acid chloride.
Scheme 2 eal) — AD aa
S2a © S2b © S2c 0 OH 0 0 X.gt
Sad S2e Saf
Re a _o HO [lo] X.g1 [o] Xp
S2g S2h
In Scheme 2, the commercially available epoxy-alcobol S2a is converted to the aziridine ester S2e using known methodology (Zwanenburg et. al., Rec. Trav. Chim. Pay.
Bas 1992, 111, 1). First, the alcohol 1s oxidized and the resulting carboxylic acids S2b is esterified to give the epoxyester S2¢. The epoxide ring of S2¢ can then be opened in the reaction with sodium azide in the presence of ammonium chloride to give the azido- » alcohol S2d as a mixture of regioisomers. The aziridine S2e, which can be obtained from
S2d upon treatment with triphenylphosphine, has been shown in chemical literature to be a highly versatile electrophile capable of undergoing ring opening reactions with various sulfur-, oxygen- and nitrogen-based nucleophiles. For example, thiols react with S2e under the catalysis of boron trifluoride etherate to give functionalized amino-acid S2f
(X=S) in very good yields. Similarily, oxygen or nitrogen functionalized amino-acids S2f (X=0 or N) can be prepared through acetic acid or azide addition, respectively : (Legtersen, I. et. al., Rec. Trav. Chim. Pay. Bas 1992, 111, 59). The free amino group can then be derivatized with various sulfonyl chlorides to give sulfonamide esters S2g. If s necessary, a more complex aryl sulfonyl group can be introduced in a sequence of several synthetic steps. Finally, the ester function is converted to the carboxylic acid using one of the standard hydrolysis methods to produce the target molecule S2h.
If desired, the ester functionality in compounds of type S2g can be converted to the hydroxamic acid by reaction with hydroxylamine under alkaline conditions.
Scheme 3
EN Phy Phy a Ae SNC
Nr rx” rr” s3a S3b S3c
OH OH
_ oy LL Sa
HO” TR! HO“ R' . s3d S3e
In Scheme 3, well known Evans chemistry is utilized to establish absolute and relative stereochemistry of chiral centers of the target aminoalcohol S3d. Thus, the oxazolidinone bromoacetate S3a is reacted with a selected aldehyde to obtain a 1s bromoalcohol S3b with very high stereoselectivity. In the following step, standard conditions of Sn2 substitution are applied and the bromide atom is replaced by azide to give an intermediate S3c. Hydrolysis of the oxazolidinone group can be performed utilizing conditions well described in the chemical literature to produce a key intermediate aminoacid S3d. The free amino group of S3d can then be denvatized with various sulfonyl chlorides to give the target inhibitors S3e. If necessary, a more complex aryl sulfonyl groups can be introduced in a sequence of several synthetic steps. If desired, the carboxylic acid functionality in compounds of type S3e can be converted to the hydroxamic acid by coupling with hydroxylamine using a mixed anhydride method or by forming of an intermediate acid chloride.
These steps may be varied to increase yield of desired product. The skilled artisan will recognize the judicious choice of reactants, solvents, and temperatures is an important component in any successful synthesis. Determination of optimal conditions, etc. is routine. Thus, the skilled artisan can make a variety of compounds using the guidance of the schemes above. - : It is recognized that the skilled artisan in the art of organic chemistry can readily s carry out standard manipulations of organic compounds without further direction; that is, it is well within the scope and practice of the skilled artisan to carry out such manipulations. These include, but are not limited to, reduction of carbonyl compounds to their corresponding alcohols, oxidations of hydroxyls and the like, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterification and w saponification and the like. Examples of these manipulations are discussed in standard texts such as March, Advanced Organic Chemistry (Wiley), Carey and Sundberg,
Advanced Organic Chemistry (Vol. 2) and other art that the skilled artisan is aware of.
The skilled artisan will also readily appreciate that certain reactions are best carried out when another potentially reactive functionality on the molecule is masked or 1s protected, thus avoiding any undesirable side reactions and/or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations can be found for example in T. Greene, Protecting Groups in Organic » Synthesis. Of course, amino acids used as starting materials with reactive side chains are preferably blocked to prevent undesired side reactions.
The compounds of the invention may have one or more chiral centers. As a result, one may selectively prepare one optical isomer, including diastereomer and enantiomer, over another, for example by chiral starting materials, catalysts or solvents, or may »s prepare both stereoisomers or both optical isomers, including diastereomers and enantiomers at once (a racemic mixture). Since the compounds of the invention may exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers, or stereoisomers may be separated using known methods, such as chiral salts, chiral chromatography and the like.
In addition, it is recognized that one optical isomer, including diastereomer and enantiomer, or stereoisomer may have favorable properties over the other. Thus when disclosing and claiming the invention, when one racemic mixture is disclosed, it is clearly contemplated that both optical isomers, including diastereomers and enantiomers, or : stereoisomers substantially free of the other are disclosed and claimed as well.
IV. Methods of Use: s Metalloproteases (MPs) found in the body operate, in part, by breaking down the extracellular matrix, which comprises extracellular proteins and glycoproteins. Inhibitors of metalloproteases are useful in treating diseases caused, at least in part, by the breakdown of such proteins and glycoproteins. These proteins and glycoproteins play an important role in maintaining the size, shape, structure and stability of tissue in the body.
Thus, MPs are intimately involved in tissue remodeling.
As a result of this activity, MPs have been said to be active in many disorders involving either the: (1) breakdown of tissues including opthalmic diseases; degenerative diseases, such as arthritis, multiple sclerosis and the like; and metastasis or mobility of tissues in the body; or (2) remodeling of tissues including cardiac disease, fibrotic 1s disease, scarring, benign hyperplasia, and the like.
The compounds of the present invention prevent or treat disorders, diseases and/or unwanted conditions that are characterized by unwanted or elevated activity by MPs. For example, the compounds can be used to inhibit MPs which: 1. destroy structural proteins (i.e. the proteins that maintain tissue stability and structure); 2. interfere in inter/intracellular signaling, including those implicated in cytokine up- regulation, and/or cytokine processing and/or inflammation, tissue degradation and other maladies [Mohler KM, et al, Nature 370 (1994) 218-220, Gearing AJH, et al, Nature 370 (1994) 555-557 McGeehan GM, et al, Nature 370 (1994) 558- 561]; and 3. facilitate processes which are undesired in the subject being treated, for example, the processes of sperm maturation, egg fertilization and the like.
As used herein, an "MP related disorder” or "MP related disease" is one that involves unwanted or elevated MP activity in the biological manifestation of the disease 3 or disorder; in the biological cascade leading to the disorder; or as a symptom of the disorder. This "involvement" of the MP includes:
X . WO 01/27084 PCT/US00/28194 1. The unwanted or elevated MP activity as a "cause" of the disorder or biological : manifestation, whether the activity is elevated genetically, by infection, by autoimmunity, trauma, biomechanical causes, lifestyle [e.g. obesity) or by some other cause; oo 5 2. The MP as part of the observable manifestation of the disease or disorder. That is, the disease or disorder is measurable in terms of the increased MP activity. From a clinical standpoint, unwanted or elevated MP levels indicate the disease; however, MPs need not be the "hallmark" of the disease or disorder; or 3. The unwanted or elevated MP activity is part of the biochemical or cellular cascade that results or relates to the disease or disorder. In this respect, inhibition of the MP activity interrupts the cascade, and thus controls the disease.
The term “treatment” is used herein to mean that, at a minimum, administration of a compound of the present invention mitigates a disease associated with unwanted or eleveated MP activity in a mammalian subject, preferably in humans. Thus, the term 1s “treatment” includes: preventing an MP-mediated disease from occurring in a mammal, particularly when the mammal is predisposed to acquiring the disease, but has not yet been diagnosed with the disease; inhibiting the MP-mediated disease; and/or alleviating the MP-mediated disease. Insofar as the methods of the present invention are directed to preventing disease states associated with unwanted MP activity, it is understood that the term “prevent” does not require that the disease state be completely thwarted. (See
Webster's Ninth Collegiate Dictionary.) Rather, as used herein, the term preventing refers to the ability of the skilled artisan to identify a population that is susceptible to MP- related disorders, such that administration of the compounds of the present invention may occur prior to onset of the disease. The term does not imply that the disease state be 2s completely avoided. For example, osteoarthritis (OA) is the most common rhueumatological disease with some joint changes radiologically detectable in 80% of people over 55 years of age. Fife, R.S., “A Short History of Osteoarthritis”,
Osteoarthritis: Diagnosis and Medical/Surgical Management, R.W. Moskowitz, D.S.
Howell, V.M. Goldberg and H.J. Mankin Eds., p 11-14 (1992). A common risk factor 3 that increases the incidence of OA is traumatic injury of the joint. Surgical removal of the meniscus following knee injury increases the risk of radiographically detectable OA and this risk increases with time. Roos, H et al. “Knee Osteoarthritis After Menisectomy:
Prevalence of Radiographic Changes After Twenty-one Years, Compared with Matched
Controls.” Arthritis Rheum., Vol. 41, pp 687-693; Roos, H et al. “Osteoarthritis of the
Knee After Injury to the Anterior Cruciate Ligament or Meniscus: The Influence of Time s and Age.” Osteoarthritis Cartilege., Vol. 3, pp 261-267 (1995). Thus, this patient population is identifiable and could receive administration of a compound of the present invention before progression of the disease. Thus, progression of OA in such individuals would be “prevented”.
Advantageously, many MPs are not distributed evenly throughout the body. io Thus, the distribution of MPs expressed in various tissues are often specific to those tissues. For example, the distribution of metalloproteases implicated in the breakdown of tissues in the joints is not the same as the distribution of metalloproteases found in other tissues. Though not essential for activity or efficacy, certain diseases, disorders, and unwanted conditions preferably are treated with compounds that act on specific MPs 1s found in the affected tissues or regions of the body. For example, a compound which displays a higher degree of affinity and inhibition for an MP found in the joints (e.g. chondrocytes) would be preferred for treatment of a disease, disorder, or unwanted condition found there than other compounds which are less specific.
In addition, certain inhibitors are more bioavailable to certain tissues than others. 2 Choosing an MP inhibitor which is more bioavailable to a certain tissue and which acts on the specific MPs found in that tissue, provides for specific treatment of the disease, disorder, or unwanted condition. For example, compounds of this invention vary in their ability to penetrate into the central nervous system. Thus, compounds may be selected to produce effects mediated through MPs found specifically outside the central nervous system.
Determination of the specificity of an inhibitor of a specific MP is within the skill of the artisan in that field. Appropriate assay conditions can be found in the literature.
Specifically, assays are known for stromelysin and collagenase. For example, U.S. Pat.
No. 4,743,587 references the procedure of Cawston, et al., Anal Biochem (1979) 99:340- 3 345. See also, Knight, C.G. et al., “A Novel Coumarin-Labelled Peptide for Sensitive
Continuous Assays of the Matrix Metalloproteases”, FEBS Letters, Vol. 296, pp. 263-266
(1992). The use of a synthetic substrate in an assay is descnibed by Weingarten, H. et al., ) Biochem Biophy Res Comm (1984) 139:1184-1187. Any standard method for analyzing the breakdown of structural proteins by MPs can, of course, be used. The ability of compounds of the invention to inhibit metalloprotease activity can be tested in the assays ) s found in the literature, or variations thereof. Isolated metalloprotease enzymes can be used to confirm the inhibiting activity of the invention compounds, or crude extracts which contain the range of enzymes capable of tissue breakdown can be used.
The compounds of this invention are also useful for prophylactic or acute treatment. They are administered in any way the skilled artisan in the fields of medicine or pharmacology would desire. It is immediately apparent to the skilled artisan that preferred routes of administration will depend upon the disease state being treated and the dosage form chosen. Preferred routes for systemic administration include administration perorally or parenterally.
However, the skilled artisan will readily appreciate the advantage of administering 1s the MP inhibitor directly to the affected area for many diseases, disorders, or unwanted ) conditions. For example, it may be advantageous to administer MP inhibitors directly to the area of the disease, disorder, or unwanted condition such as in the area affected by surgical trauma (e. g., angioplasty), scarring, burning (e.g., topical to the skin), or for opthalmic and periodontal indications.
Because the remodeling of bone involves MPs, the compounds of the invention are useful in preventing prosthesis loosening. It is known in the art that over time prostheses loosen, become painful, and may result in further bone injury, thus demanding replacement. The need for replacement of such prostheses includes those such as in joint replacements (for example hip, knee and shoulder replacements), dental prosthesis, » including dentures, bridges and prosthesis secured to the maxilla and/or mandible.
MPs are also active in remodeling of the cardiovascular system (for example, in congestive heart failure). It has been suggested that one of the reasons angioplasty has a higher than expected long term failure rate (reclosure over time) is that MP activity is not desired or is elevated in response io what may be recognized by the body as "injury" to 3 the basement membrane of the vessel. Thus regulation of MP activity in indications such as dilated cardiomyopathy, congestive heart failure, atherosclerosis, plaque rupture,
reperfusion injury, ischemia, chronic obstructive pulmonary disease, angioplasty restenosis and aortic aneurysm may increase long term success of any other treatment, or . may be a treatment in itself.
In skin care, MPs are implicated in the remodeling or "turnover" of skin. As a s result, the regulation of MPs improves treatment of skin conditions including but not limited to, wrinkle repair, regulation and prevention and repair of ultraviolet induced skin damage. Such a treatment includes prophylactic treatment or treatment before the physiological manifestations are obvious. For example, the MP may be applied as a pre- exposure treatment to prevent ultaviolet damage and/or during or after exposure to jo prevent or minimize post-exposure damage. In addition, MPs are implicated in skin disorders and diseases related to abnormal tissues that result from abnormal turnover, which includes metalloprotease activity, such as epidermolysis bullosa, psoriasis, scleroderma and atopic dermatitis. The compounds of the invention are also useful for treating the consequences of "normal" injury to the skin including scarring or 1s "contraction" of tissue, for example, following burns. MP inhibition is also useful in surgical procedures involving the skin for prevention of scarring, and promotion of . normal tissue growth including in such applications as limb reattachment and refractory surgery (whether by laser or incision).
In addition, MPs are related to disorders involving irregular remodeling of other » tissues, such as bone, for example, in otosclerosis and/or osteoporosis, or for specific organs, such as in liver cirrhosis and fibrotic lung disease. Similarly, in diseases such as multiple sclerosis, MPs may be involved in the irregular modeling of blood brain barrier and/or myelin sheaths of nervous tissue. Thus, regulating MP activity may be used as a strategy in treating, preventing, and controlling such diseases. 2 MPs are also thought to be involved in many infections, including cytomegalovirus (CMV); retinitis; HIV, and the resulting syndrome, AIDS.
MPs may also be involved in extra vascularization where surrounding tissue needs to be broken down to allow new blood vessels such as in angiofibroma and hemangioma.
Since MPs break down the extracellular matrix, it is contemplated that inhibitors wo of these enzymes can be used as birth control agents, for example in preventing ovulation,
in preventing penetration of the sperm into and through the extracellular milieu of the : ovum, implantation of the fertilized ovum and in preventing sperm maturation.
Additionally, they are also contemplated to be useful in preventing or stopping premature labor and delivery. s Since MPs are implicated in the inflammatory response and in the processing of cytokines, the compounds are also useful as anti-inflammatories, for use in disease where inflammation is prevalent including, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pancreatitis, diverticulitis, asthma or related lung disease, rheumatoid arthritis, gout and Reiter's Syndrome.
Where autoimmunity is the cause of the disorder, the immune response often triggers MP and cytokine activity. Regulation of MPs in treating such autoimmune disorders is a useful treatment strategy. Thus MP inhibitors can be used for treating disorders including, lupus erythmatosis, ankylosing spondylitis, and autoimmune keratitis. Sometimes the side effects of autoimmune therapy result in exacerbation of 1s other conditions mediated by MPs, here MP inhibitor therapy is effective as well, for example, in autoimmune-therapy-induced fibrosis.
In addition, other fibrotic diseases lend themselves to this type of therapy, - including pulmonary disease, bronchitis, emphysema, cystic fibrosis, acute respiratory distress syndrome (especially the acute phase response).
Where MPs are implicated in the undesired breakdown of tissue by exogenous agents, these can be treated with MP inhibitors. For example, they are effective as rattle snake bite antidote, as anti-vessicants, in treating allergic inflammation, septicemia and shock. In addition, they are useful as antiparasitics (e.g., in malaria) and antiinfectives.
For example, they are thought to be useful in treating or preventing viral infection, 3s including infection which would result in herpes, "cold" (e.g., rhinoviral infection), meningitis, hepatitis, HIV infection and AIDS.
MP inhibitors are also thought to be useful in treating Alzheimer's disease, amyotrophic lateral sclerosis (ALS), muscular dystrophy, complications resulting from or arising out of diabetes, especially those involving loss of tissue viability, coagulation,
Graft vs. Host disease, leukemia, cachexia, anorexia, proteinuria, and regulation of hair growth.
For some diseases, conditions or disorders MP inhibition is contemplated to be a preferred method of treatment. Such diseases, conditions or disorders include, arthritis (including osteoarthritis and rheumatoid arthritis), cancer (especially the prevention or arrest of tumor growth and metastasis), ocular disorders (especially comeal ulceration,
Jack of comeal healing, macular degeneration, and pterygium), and gum disease (especially periodontal disease, and gingivitis)
Compounds preferred for, but not limited to, the treatment of arthritis (including osteoarthritis and rheumatoid arthritis) are those compounds that are selective for the matrix metalloproteases and the disintegrin metalloproteases. Compounds preferred for, but not limited to, the treatment of cancer (especially the prevention or arrest of tumor growth and metastasis) are those compounds that preferentially inhibit gelatinases or type
IV collagenases. Compounds preferred for, but not limited to, the treatment of ocular disorders (especially corneal ulceration, lack of corneal healing, macular degeneration, and pterygium) are those compounds that broadly inhibit metalloproteases. Preferably is these compounds are administered topically, more preferably as a drop or gel
Compounds preferred for, but not limited to, the treatment of gum disease (especially periodontal disease, and gingivitis) are those compounds that preferentially inhibit collagenases. .
V. Compositions:
The compositions of the invention comprise: (a) a safe and effective amount of a compound of the invention; and (b) a pharmaceutically-acceptable carrier.
As discussed above, numerous diseases are known to be mediated by excess or undesired metalloprotease activity. These include tumor metastasis, osteoarthntis, 3s rheumatoid arthritis, skin inflammation, ulcerations, particularly of the cornea, reaction to infection, periodontitis and the like. Thus, the compounds of the invention are useful in therapy with regard to conditions involving this unwanted activity.
The invention compounds can therefore be formulated into pharmaceutical compositions for use in treatment or prophylaxis of these conditions. Standard 3 pharmaceutical formulation techniques are used, such as those disclosed in Remington's
Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., latest edition.
A "safe and effective amount" of a Formula (I) compound is an amount that is effective, to inhibit metalloproteases at the site(s) of activity in an animal, preferably a mammal, more preferably a human subject, without undue adverse side effects
Lo (such as toxicity, irritation, or allergic response), commensurate with a reasonable s benefit/risk ratio when used in the manner of this invention. The specific "safe and effective amount” will, obviously, vary with such factors as the particular condition being treated, the physical condition of the patient, the duration of treatment, the nature of concurrent therapy (if any), the specific dosage form to be used, the carrier employed, the solubility of the Formula (I) compound therein, and the dosage regimen desired for the composition.
In addition to the subject compound, the compositions of the subject invention contain a pharmaceutically-acceptable carrier. The term "pharmaceutically-acceptable carrier”, as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to an animal, preferably a ys mammal, more preferably a human. The term "compatible", as used herein, means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations. Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the subject being treated. The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is determined in-part by the way the compound is to be administered.
Some examples of substances which can serve as pharmaceutically-acceptable 1s carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil 3 and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the Tweens®; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.
Pharmaceutically-acceptable carriers for systemic adminisitration include s sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the pharmaceutically-acceptable carrier, in compositions for to parenteral administration, comprises at least about 90% by weight of the total composition. If the subject compound is to be injected, the preferred pharmaceutically- acceptable carrier is sterile, physiological saline, with a blood-compatible suspending agent, the pH of which has preferably been adjusted to about 7.4.
The compositions of this invention are preferably provided in unit dosage 1s form. As used herein, a "unit dosage form" is a composition of this invention containing an amount of a Formula (I) compound that is suitable for administration to an animal, preferably a mammal, more preferably a human subject, in a single dose, according to good medical practice. These compositions preferably contain from : about 5 mg (milligrams) to about 1000 mg, more preferably from about 10 mg to about 500 mg, more preferably from about 10 mg to about 300 mg, of a Formula (I) compound.
The compositions of this invention may be in any of a variety of forms, suitable (for example) for oral, rectal, topical, nasal, ocular or parenteral administration. Depending upon the particular route of administration desired, a 2s variety of pharmaceutically-acceptable carriers well-known in the art may be used.
These include solid or liquid fillers, diluents, hydrotropes, surface-active agents, and encapsulating substances. Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the
Formula (I) compound. The amount of carrier employed in conjunction with the
Formula (I) compound is sufficient to provide a practical quantity of material for administration per unit dose of the Formula (I) compound. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references, all incorporated by reference herein: Modern
Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, editors, 1979); Lieberman et —— al, Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to s Pharmaceutical Dosage Forms 2d Edition (1976).
Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. These oral forms comprise a safe and effective amount, usually at least about 5%, and preferably from about 25% to about 50%, of the Formula (I) compound. Tablets can be compressed, tablet triturates, enteric- 0 coated, sugar-coated, film-coated, or muitiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and/or melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from is effervescent granules. Such liquid dose forms will optionally contain suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
The pharmaceutically-acceptable carrier suitable for the preparation of unit dosage forms for peroral administration are well-known in the art. Tablets typically 2 comprise conventional pharmaceutically-compatible adjuvants as inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; and lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring 2s agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes % of the subject invention, and can be readily made by a person skilled in the art.

Claims (1)

  1. WHAT IS CLAIMED IS:
    1. A compound having a structure according to Formula (I) 0 R*R® R s Ng z 0, rR? 13 RS t) wherein: (A) R'is selected from -OH and -NHOH; (B) R?is selected from hydrogen, hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and halogen; (C) Ris selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; (D) R*is -(CR'R")-X-(CR®*R¥)-E-A where: (1) kis from O to about 4; (2) [lis from 0 to about 4; (3) each of R’, R”, R®, and R¥, when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, and haloalkyl; (4) X is selected from -O-, -S-, -S(0)-, -S(O2)-, -N(R’)-, -N(COR?®)-, - N(COR®)-, -N(CONR’R’)-, and -N(SO;R’)-, where (i) each R* and R”, when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or (ii) R® and R®, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic rng containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; (5) E is selected from a covalent bond, -O-, -S-, -§(0O)-, -S(0,)-, -NR')-, - N(COR')-, -N(COR'%)-, -N(CONR'®R'®)-, and -N(SO;R'’)-, where (i) each R'® and R'?, when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or (ii) R' and R'?, together
    . + WO 01/27084 PCT/US00/28194 with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; provided that when / = 0, E is a covalent bond; and Co (6) (a) A is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl,
    haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or
    (b) A, together with R’, R”, R®, R¥, R’, R®, R", or R'?, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;
    (E) R® is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
    (F) RS is selected from alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and hydroxyl; provided that when k> 0, R® is -OH and when k = 0, R® is not -OH;
    (G) G is selected from -S-, -O-, -N(R'")-, -C(R"")=C(R'")-, -N=C(R'")-, and -N=N-, where each R'' and R'", when present, is independently selected from hydrogen,
    ) alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
    (H) Z is selected from:
    : (1) cycloalkyl and heterocycloalkyl; (2) -L-(CR'R')a-R" where: (a) ais from 0 to about 4, (b) Lis selected from -C=C-, -CH=CH-, -N=N-, -O-, -S- and -50;-; (c) each R'? and R'Y, when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, ’ cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; and (d) R" is selected from hydrogen, aryl, heteroaryl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, heterocycloalkyl and cycloalkyl; and, if Lis - C=C- or -CH=CH-, then R"® may also be selected from -CON(R'R'*) where (i) R' and R'" are independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalky), or (ii) R* and R'*, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from S to 8 ring atoms of which from 1 to 3 are heteroatoms; .
    3) -NR¥R'* where:
    (a) Rand R' each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heteroalkyl and -C(0)-Q-(CR'*R'*),-R'” where:
    (i) bis from 0 to about 4; (ii) Q is selected from a covalent bond and -N(R'®)-; and (ili) each R'® and R'®, when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; each R'” and R'? is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, or R'7 and RS, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; or R" and R'S, together with the i nitrogen atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 2 to 3 are heteroatoms; or
    (b) RY and R'*, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; and E-M ; \
    uN CRUR)- A'—G'
    4) ¢ , Where:
    (a) FE’ and M’ are independently selected from -CH- and -N-;
    (®) Lis selected from -S-, -O-, -N(R?)-, -C(R**)=C(R¥)-, - N=C(R?)-, and -N=N-, where each R® and R?, when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,
    (c) cis from 0 to about 4;
    (d) each RY and R', when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; oo (e) A’ is selected from a covalent bond, -O-, -SO4, -C(O)-, - C(O)N(R?)-, -N(R?")-, and -N(R*')C(O)~; where d is from 0 to 2 and R* is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkyl; and () Gis -(CR®R®),-R® where ¢ is from 0 to about 4; each R* and R”, when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, alkoxy and aryloxy; and R? is selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; or R? and RZ, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 atoms of which 1 to 3 are heteroatoms; or R¥ and R?, together with the atoms to which they are - bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 atoms of which 1 to 3 are heteroatoms; : or an optical isomer, diastereomer or enantiomer for Formula (I), or a pharmaceutically- acceptable salt, or biohydrolyzable amide, ester, or imide thereof.
    2. The compound according to Claim 1 wherein R' is -OH and R%, R® and R® are independently selected from hydrogen, lower alkyl, arylalkyl and heteroarylalky!l.
    3. The compound according to Claim | or Claim 2 wherein k = 0; R® is ary! or lower alkyl; X is selected from O, S, -N(SO,R'%)-, -N(COR')- and N(CO,R'%)-, where R'® is lower alkyl or aryl (preferably X is -S-); I = 0, 1 or 2; E is selected from a covalent bond, -O- and -S-; and A is selected from lower alkyl, aryl, and heteroaryl.
    4. The compound according to Claim 1 or Claim 2 wherein k= 1, 2 or 3; R® is -OH; X is selected from -O-, -S-, -N(SO2R®)-, -N(COR®)-, and -N(CO;R’)-, where R’ is lower alkyl or aryl (X is preferably -O- or -S-); I= 0, 1 or 2; E is selected from a covalent bond, -O-, -S-, -N(COR'?%)- , -N(CO;R")-, -N(CONR'"R')- and -N(SO,R'’)-; and A is selected from lower alkyl, aryl, and heteroaryl.
    5. The compound according to any of Claims 1-4, wherein E is selected from a covalent bond, -O- and -S-.
    6. The compound according to any of Claims 1-5 wherein G is selected from -S- and - CH=CH- and Z is selected from -L-(CR"R"),R®;, -NR“R'; and E-M 4 \ eM err) ao
    ¢ .
    7. The compound according to any of Claims 1-6 wherein Z is -L-(CR'’R'*),R'* where L is sclected from -C=C-, -C=C- and -N=N-; a is 0; and R" is selected from aryl, heteroaryl, heterocycloalkyl and cycloalkyl.
    8. The compound according to any of Claims 1-7 wherein Z is -NR"”R' where R" is hydrogen and R"" is -C(0)-Q-(CR'*R'®),-R'” where Q is a covalent bond, 5 is 0 and R'" is selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl. -
    9. The compound according to any of Claims 1-8 wherein Z is ) E-M f \ ve L a CRP”) A'—G ’ c where E’ and M’ are both -CH-; c is 0; and L’ is -HC=CH-.
    10. A compound selected from the group consisting of: (2R,3S)-2-(4'-Methoxy-biphenyl-4-sulfonylamino)-3-(4-methyl-benzyloxy)-3-thiazol-2- yl-propionic acid, (2R,3S5)-2-(4'-Methylsulfanyl-biphenyl-4-sulfonylamino)-3-(4-methyl-benzyloxy)-3- thiazol-2-yl-propionic acid, (2R,3S)-3-Benzothiazol-2-yl-3-methoxy-2-(4'-methoxy-biphenyl-4-sulfonylamino)- propionic acid, (2S,3R)-3-Ethylsulfanyl-2-(4'-fluoro-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid, (2S, 3R)-3-Ethylsulfanyl-2-(4’-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid, (2S,3R)-2-(4'-Methoxy-biphenyl-4-sulfonylamino)-3-methylsulfanyl-3-phenyl-propionic acid
    . ~ WO 01/27084 PCT/US00/28194 (2S, 3R)-2-(4'-Methoxy-biphenyl-4-sulfonylamino)-3-phenyl-3-phenylsulfanyl-propionic acid,
    (2S.3R)-2-(4'-Bromo-biphenyl-4-sulfonylamino)-3-phenyl-3-(pyridin-3-ylsulfanyl)- oo propionic acid, (2S, 3R)-2-(4'-Bromo-biphenyl-4-sulfonylamino)-3-phenyl-3-(pyrimidin-2-ylsulfanyl)- propionic acid, (2S, 3R)-3-(4-Fluoro-phenylsulfanyl)-2-(4'-methoxy-biphenyl-4-suifonylamino)-3- phenyl-propionic acid, (25,3R)-2-(4'-Methoxy-biphenyl-4-sulfonylamino)-3-phenyl-3-(thiazol-2-ylsulfanyl)- propionic acid, (2S, 3R)-2-(4'-Methoxy-biphenyl-4-sulfonylamino)-3-(1-methyl-1H-imidazol-2- ylsulfanyl)-3-phenyl-propionic acid,
    (25.3R)-2-(4'-Chloro-biphenyl-4-sulfonylamino)-3-(oxazol-2-ylsulfanyl)-3-phenyl- propionic acid, (25,3R)-2-(4'-Methylsulfanyl-biphenyl-4-sulfonylamino)-3-(1-methyl-1H-[1,2,4]triazol- 3-ylsulfanyl)-3-phenyl-propionic acid, (2S,3R)-2-(4'-Methoxy-biphenyl-4-sulfonylamino)-3-(1-methyl-1H-[1,2,4]triazol-3- ylsulfanyl)-3-phenyl-propionic acid, } (2S,3R)-2-[Benzyl-(4'-methoxy-biphenyl-4-sulfonyl)-amino]-3-phenyl-3-phenylsulfanyl- propionic acid, (2S, 3R)-3-Benzylsulfanyl-2-(biphenyl-4-sulfonylamino)-3-phenyl-propionic acid, (2S,3R)-3-Benzylsulfanyl-2-(4'-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid, (2S,3R)-2-(Bipheny!-4-sulfonylamino)-3-phenethylsulfanyl-3-phenyl-propionic acid, (2S, 3R)-3-(4-Methyl-benzylsulfanyl)-3-phenyl-2-(4'-trifluoromethyl-biphenyl-4- sulfonylamino)-propionic acid, (2S, 3R)-3-(4-Methoxy-benzylsulfanyl)-2-(4'-methyl-biphenyl-4-sulfonylamino)-3- phenyl-propionic acid, (2S,3R)-3-(4-Fluoro-benzylsulfanyl)-2-(4'-methoxy-biphenyl-4-sulfonylamino)-3-phenyl- propionic acid, (2S,3R)-3-(2,4-Difluoro-benzylsulfanyl)-2-(4'-methoxy-biphenyl-4-sulfonylamino)-3- phenyl-propionic acid,
    (2S.3R)-2-(4"-Methylsulfany)-biphenyl-4-sulfonylamino)-3-phenyl-3-(pyridin-4- ylmethylsulfanyl)-propionic acid,
    (2S, 3R)-2-[(4'-Methoxy-biphenyl-4-sulfonyl)-mcthyl-amino]-3-phenyl-3-(pyridin-3- ylmethylsulfanyl)-propionic acid, (2S, 3R)-2-(4'-Methoxy-biphenyl-4-sulfonylamino)-3-phenyl-3-(pynidin-2- yimethylsulfany!)-propionic acid, (25, 3R)-2-(4'-Methoxy-biphenyl-4-sulfonylamino)-3-(5-methyl-oxazol-2- ylmethylsulfanyl)-3-phenyl-propionic acid, (25, 3R)-3-(Benzothiazol-2-ylsulfanyl)-2-(4'-methoxy-biphenyl-4-sulfonylamino)-3- phenyl-propionic acid,
    (2S.3R)-3-(2-tert-Butoxycarbonylamino-ethylsulfanyl)-2-(4'-methoxy-biphenyl-4- sulfonylamino)-3-phenyl-propionic acid,
    (25. 3R)-3-(2-Acetylamino-ethylsulfanyl)-2-(4'-methoxy-biphenyl-4-sulfonylamino)-3- phenyl-propionic acid, (25, 3R)-3-[2-(Methanesulfonyl-pyridin-3-yl-amino)-ethylsulfanyl]-2-(4'-methoxy- biphenyi-4-sulfonylamino)-3-phenyl-propionic acid, (2S, 3R)-2-(4'-Bromo-biphenyl-4-sulfonylamino)-3-{2-(methanesulfonyl-pyridin-3-yl- amino)-ethylsulfanyl}-3-phenyl-propionic acid, (25, 3R)-3-(2-Benzyloxy-¢thylsulfanyl)-2-(4'-methoxy-biphenyl-4-sulfonylamino)-3- phenyl-propionic acid, (2S, 3R)-2-(4'-Bromo-biphenyl-4-sulfonylamino)-3-(2-phenoxy-ethylsulfanyl)-3-phenyi- propionic acid, :
    (25.3R)-2-(4'-Methoxy-biphenyl-4-sulfonylamino)-3-(2-phenoxy-ethylsulfanyl)-3- phenyl-propionic acid,
    (2S. 3R)-3-[2-(4-Fluoro-phenoxy)-ethylsulfanyl]-3-phenyl-2-(4'-trifluoromethyl-biphenyl- 4-sulfonylamino)-propionic acid,
    (2S. 3R)-3-Ethylsulfanyl-2-[5-(4-methoxy-phenyl)-thiophene-2-sul fonylamino]-3-phenyl- propionic acid, (2S,3R)-3-Ethylsulfanyl-2-[4-(4-methoxy-phenylethynyl)-benzenesulfonylamino]-3- phenyl-propionic acid, 2S, 3R)-3-Ethylsulfanyl-2-[4-(4-methoxy-benzoylamino)-benzenesulfonylamino]-3- phenyl-propionic acid,
    (2R.35)-2-(4'-“Methoxy-biphenyl-4-sulfonylamino)-3-methylsulfanyl-3-phenyl-propionic acid, (2R, 35)-3-Ethylsulfanyl-2-(4'-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propionic acid,
    , - WOe127084 PIR Tl evrostbiasios k) (2R, 35)-2-(4'-Methoxy-biphenyl-4-sulfonylamino)-3-phenyl-3-phenylsulfanyl-propionic ) acid, (2R, 35)-3-Benzylsulfanyl-2-(4'-methoxy-biphenyl-4-sulfonylamino)-3-phenyl-propionic } acid, (2R, 35)-4-Benzyloxy-3-hydroxy-2-(4'-methoxy-biphenyl-4-sulfonylamino)-butyric acid, (2R,35)-3-Hydroxy-2-(4'-methoxy-biphenyl-4-sulfonylamino)-4-phenoxy-butyric acid (2R,35)-4-Benzyloxy-2-(biphenyl-4-sulfonylamino)-3-hydroxy-butyric acid, (2R,3R)-3-Hydroxy-2-(4'-methoxy-biphenyl-4-sulfonylamino)-5-phenoxy-pentanoic acid, (2R,3R)-3-Hydroxy-2-(4'-methoxy-biphenyl-4-sulfonylamino)-5-(pyridin-3-yloxy)- pentanoic acid, (2R,35)-3-Hydroxy-2-(4'-methoxy-biphenyl-4-sulfonylamino)-4-(thiazol-2-ylsulfanyl)- butyric acid, (2R,3S5)-4-(4-Fluoro-benzylsulfanyl)-3-hydroxy-2-(4'-methoxy-biphenyl-4- sulfonylamino)-butyric acid, (2R,35)-3-Hydroxy-2-(4'-methoxy-biphenyl-4-sulfonylamino)-4-(1-methyl-1H-imidazol- 2-ylsulfanyl)-butyric acid,
    (2R.3R)-3-Hydroxy-2-(4'-methoxy-biphenyl-4-sulfonylamino)-6-(1-methyl-1H-imidazol- 2-ylsulfanyl)-hexanoic acid, (2R,3S)-3-Hydroxy-2-(4'-methoxy-biphenyl-4-sulfonylamino)-4-(1-methyl-1H-imidazol- 2-yloxy)-butyric acid, (2R,3R)-3-Hydroxy-2-(4'-methoxy-biphenyl-4-sulfonylamino)-5-(1-methyl-1H- [1,2,4]triazol-3-ylsulfanyl)-pentanoic acid, (2R,3S)-4-(Benzooxazol-2-ylsulfanyl)-3-hydroxy-2-(4'-methoxy-biphenyl-4- sulfonylamino)-butyric acid, (2R,3R)-5-(Benzooxazol-2-ylsulfanyl)-3-hydroxy-2-(4'-methoxy-biphenyl-4- sulfonylamino)-pentanoic acid, (2R,3R)-3-Hydroxy-2-(4'-methoxy-biphenyl-4-sulfonylamino)-6-phenoxy-hexanoic acid, (2R,35)-4-(3,3-Dimethyl-butoxy)-3-hydroxy-2-(4'-methoxy-biphenyl-4-sulfonylamino)- butyric acid, (2R,3S)-3-Hydroxy-2-(4'-methoxy-biphenyl-4-sulfonylamino)-4-(3-methyl-butoxy)- butyric acid, (2R,3S5)-3-Hydroxy-4-(2-isopropoxy-ethoxy)-2-(4'-methoxy-biphenyl-4-suifonylamino)- butyric acid,
    (2R,35)-3-Hydroxy-4-(2-isopropoxy-ethoxy)-2-(4'-methylsulfanyl-biphenyl-4- sulfonylamino)-butyric acid,
    (2R.3R)-5-tert-Butoxycarbonylamino-3-hydroxy-2-(4'-methoxy-biphenyl-4- sulfonylamino)-pentanoic acid, (2R,3R)-6-tert-Butoxycarbonylamino-3-hydroxy-2-(4'-methoxy-biphenyl-4- sulfonylamino)-hexanoic acid, (2R,3R)-5-tert-Butoxycarbonylamino-3-hydroxy-2-(4-methoxy-benzenesulfonylamino)- pentanoic acid, (2R,3R)-2-(4-Butoxy-benzenesulfonylamino)-5-tert-butoxycarbonylamino-3-hydroxy- pentanoic acid (2R,3R)-3-Hydroxy-4-(methanesulfonyl-phenyl-amino}-2-(4'-methoxy-biphenyl-4- sulfonylamino)-butyric acid, (2R,3R)-3-Hydroxy-5-(methanesulfonyl-pyridin-3-yi-amino}-2-(4'-methoxy-biphenyl-4- sulfonyfamino)-pentanoic acid, and (2R,3R)-4-(2-tert-Butoxycarbonylamino-ethoxy)-3-hydroxy-2-(4'-methoxy-biphenyl-4- sulfonylamino)-butyric acid.
    11. A pharmaceutical composition comprising: (a) a safe and effective amount of a compound according to any of Claims 1-10; and {b) a pharmaceutically-acceptable carrier.
    12. The use of a safe and effective amount of a compound according to anyone of the claims | to 10 in a method of treating a disorder modulated by malleoproteases, wherein the disorder is selected from the group consisting of arthritis, cancer, cardiovascular disorders, skin disorders, ocular disorders, inflammation and gum disease.
    13. The use according to claim 12 wherein the disorder is (i) arthritis, and is chosen from the group consisting of osteoarthritis and rheumatoid arthritis, (ii) cancer, and the use prevents or arrests tumor growth and metasis, or (iii) a cardiovascular disorder chosen from the group consisting of dilated cardiomyopathy, congestive heart failure, atherosclerosis, plaque rupture, reperfusion injury, ischemia, chronic obstructive pulmonary disease, angioplasty restenosis and aortic aneurysm. 7 AMENDED SHEET
ZA200202207A 1999-10-14 2002-01-01 Beta disubstituted metalloprotease inhibitors. ZA200202207B (en)

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AU8014500A (en) 2001-04-23
NO20021748L (en) 2002-06-14
NZ517983A (en) 2004-01-30
CZ20021161A3 (en) 2002-08-14
PE20011003A1 (en) 2001-09-26
HUP0203118A3 (en) 2003-05-28
WO2001027084A1 (en) 2001-04-19

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