KR20020038951A - Beta disubstituted metalloprotease inhibitors - Google Patents

Abstract

Compounds which are inhibitors of metalloproteases and which are effective in the treatment of conditions characterized by excessive activity of such enzymes. In particular, the compounds have the structure of formula (I)

(I)

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , G and Z have the meanings described in the specification. The present invention also encompasses optical isomers, diastereoisomers and enantiomers of Formula I, and pharmaceutically acceptable salts, amides, esters and imides thereof. Also disclosed are a pharmaceutical composition containing the compound, and a method of treating a metalloprotease-related disease using the compound or the pharmaceutical composition.

Description

Beta disubstituted metalloprotease inhibitors {BETA DISUBSTITUTED METALLOPROTEASE INHIBITORS}

Many structurally related metalloproteases cause degradation of structural proteins. These metalloproteases often act in intercellular matrices and thus are involved in tissue destruction and remodeling. These proteins are referred to as metalloproteases or MPs.

MP is classified into several different classes by sequence similarity and disclosed in the prior art. These MPs include Matrix-Metallo Protease (MMP); Zinc metalloprotease; Many membrane bound metalloproteases; TNF converting enzyme; Angiotensin-converting enzyme (ACE); Disintegrin, including ADAM (Wolfsberg et al., 131 J. Cell Bio. 275-78, October 1995); And enkephalinase. ≪ / RTI > Examples of MP include human dermal fibroblast collagenase, human dermal fibroblast gelatinase, human dermal collagenase, aggrecanase and gelatinase, and human stromelysin. Collagenase, stromelysin, agrecanase and related enzymes are believed to be important in mediating the symptoms of many diseases.

Potential therapeutic examples of MP inhibitors have been discussed in the literature. See, for example, U.S. Patent 5,506,242 (Ciba Geigy Corp.) and 5,403,952 (Merck &Co.); PCT Publication No. WO 96/06074 (British Bio Tech Ltd.); WO 95/35275 (British Bio Tech Ltd.), WO 95/35275 (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 95/19965 (Glycomed), WO 95 19956 (British Bio Tech Ltd.), WO 95/19957 (British Dio Tech Ltd.), WO 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 (Celltech) 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 (Res. Corp. Tech Inc.), WO 94/10990 ), 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); Japanese Patent Application JP 08053403 (Fujusowa Pharm. Co. Ltd.) and JP 7304770 (Kanebo Ltd.); And [Bird et al . , J. Med. Chem. , vol. 37, pp. 158-69 (1994).

Examples of potential therapeutic uses for MP inhibitors include rheumatoid arthritis - Mullins, DE et al . , Biochim. Biolphys. Acta. (1983) 695: 117-214; Osteoarthritis - Henderson, B. et al., Drugs of the Future (1990) 15: 495-508; Cancer - Yu, AE et al., Matrix Metalloproteinases - Novel Targets for Directed Cancer Therapy , Drugs & Aging , Vol. 11 (3), p. 229-244 (September 1997), Chambers, AF and Matrisian, LM, Review: Changing Views of the Role of Matrix Metalloproteinases in Metastasis , J. of the Nat'l Cancer Inst. , Vol. 89 (17), p. 1260-1270 (September 1997), Bramhall, SR, The Matrix Metalloproteinases and Their Inhibitors in Pancreatic Cancer , Internat'l J. of Pancreatology , Vol. 4, p. (1998), Nemunaitis, J., et al., Combined Analysis 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, HS and McCann, PP, Matrix Metalloproteinase Inhibition as a Novel Anticancer Strategy: A Review with Special Focus on Batimastat and Marimastat , Pharmacol. Ther. , Vol 75 (1), p. 69-75 (1997); Tumor cell metastasis-ibid, Broadhurst, MJ et al., European Patent Application 276,436 (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 ulcers or ulcerative abnormalities of the tissue. For example, ulcerative anomalies may result in the cornea as a result of alkaline burns or as a result of Pseudomonas, caustic amoeba, herpes simplex and vaccinia virus infection. Other examples of conditions characterized by undesirable metalloprotease activity include periodontal disease, watery epidermolysis, hyperthermia, inflammation and scleritis (see, for example, DeCicco et al., International Patent Publication WO 95/29892, November 1995 9).

In view of the relevance of the metalloprotease to a number of disease states, attempts have been made to produce inhibitors for this enzyme. A large number of such inhibitors are disclosed in the literature. Examples include U.S. Pat. No. 5,183,900 (issued February 2, 1993 to Galardy); U. S. Patent No. 4,996, 358 to Handa et al., Issued February 26, 1991; U. S. Patent No. 4,771, 038 to Wolanin et al., Issued September 13, 1988; U.S. Patent No. 4,743,587 (issued May 10, 1988 to Dickens et al.), European Patent Publication No. 575,844 (published by Broadhurst et al. On December 29, 1993); 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 Aug. 12, 1992 by Beckett et al.).

In treating diseases associated with undesirable metalloprotease activity, it would be advantageous to inhibit such metalloprotease. Various MP inhibitors have been produced, but there is a continuing need for powerful matrix metalloprotease inhibitors useful in the treatment of diseases associated with metalloprotease activity.

SUMMARY OF THE INVENTION [

The present invention is a potent inhibitor of metalloprotease and provides compounds effective in the treatment of abnormal conditions characterized by excessive activity of this enzyme. In particular, the present invention relates to compounds of the formula I, or a compound having the structure of the enantiomers, diastereoisomers or enantiomers of the formula I, or a pharmaceutically acceptable salt thereof, or a biodegradable amide, ester or imide will be:

[Wherein:

(A) R ¹ is selected from -OH and -NHOH;

(B) R ² is selected from hydrogen, hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and halogen ;

(C) R ³ is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

(D) R ⁴ is - (CR ⁷ R ⁷ ) _k -X- (CR ⁸ R ⁸ ) ₁ -EA, wherein:

(1) k is from 0 to about 4;

(2) l is from 0 to about 4;

^{(3) R 7, k 7} ', R 8 and R ^8' are present in time, each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, and Haloalkyl;

(4) X is -O-, -S-, -S (O) -, -S (O 2) -, -N (R 9) -, -N (COR 9) -, -N (CO 2 R ^{9) -, -N (CONR 9} R 9 ') - and -N (SO ₂ R ⁹⁾ - is selected from, where, (i) R ⁹ and R ^9' are each, when present, are independently hydrogen, Alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, or (ii) R ⁹ and R ^{9 '} Together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;

(5) E is a covalent bond, -O-, -S-, -S (O ) -, -S (O 2) -, -N (R 10) -, N (COR 10) -, -N (CO ₂ R ¹⁰ ) -, -N (CONR ¹⁰ R ^{10 '} ) - and -N (SO ₂ R ¹⁰ ) -, wherein each of R ¹⁰ and R ^10' , when present, (Ii) R ¹⁰ and R ^{10 '} are independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; Provided that when l = 0, E is a covalent bond;

(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 ⁷ , R ^{7 '} , R ⁸ , R ^8' , R ⁹ , R ^{9 '} , R ¹⁰ or R ^10' , is a 5- to 8-membered ring having 1 to 3 heteroatoms To form an optionally substituted heterocyclic ring;

(E) R ⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

(F) R ⁶ is alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and hydroxyl chamber is selected from; Provided that when k > 0, R ⁶ is -OH, and when k = 0, R ⁶ is not -OH;

(G) G is ^{-S-, -O-, -N (R 11} ) -, -C (R 11) = C (R 11 ') -, -N = C (R 11) - and -N = N -, wherein each R ¹¹ and R ^{11 '} , 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 ¹² R ^{12 '} ) _a -R ¹³

(Wherein:

(a) a is from 0 to about 4;

(b) L is -C≡C-, -CH = CH-, -N = N-, -O-, -S- and -SO ₂ - is selected from;

(c) R ¹² and R ¹² , when present, are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, Alkoxy;

(d) R ¹³ is selected from hydrogen, aryl, heteroaryl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, heterocycloalkyl and cycloalkyl; R ¹³ can also be selected from -CON (R ¹⁴ R ^{14 '} ), provided that when L is -C = C- or -CH = CH-, then (i) R ¹⁴ and R ^14' Alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, or (ii) R ¹⁴ and R ^{14 '} , together with the nitrogen atom to which they are attached, Form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;

(3) -NR ¹⁵ R ^{15 '}

(Wherein:

(a) R ¹⁵ and R ^{15 '} are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heteroalkyl and -C ¹⁶ R ^{16 '} ) _b -R ¹⁷

(Wherein:

(i) b is from 0 to about 4;

(ii) Q is a covalent bond and -N (R ¹⁸⁾ - is selected from;

(iii) each of R ¹⁶ and R ^{16 '} , when present, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, Alkoxy; R ¹⁷ and R ¹⁸ each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, or R ¹⁷ and R ¹⁸ are, they are bound Together with the atoms to which they are attached form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; Or R < ¹⁵ > and R < ¹⁸ > together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms wherein 2 to 3 are heteroatoms; or

(b) R ¹⁵ and R ^{15 '} together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;

(4)

(Wherein:

(a) E 'and M' are independently selected from -CH- and -N-;

(b) L 'is ^{-S-, -O-, -N (R 20} ) -, -C (R 20) = C (R 20') -, -N = C (R 20) - and -N = , Wherein R ²⁰ and R ^{20 '} , when present, are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl ;

(c) c is from 0 to about 4;

(d) R ¹⁹ and R ^{19 '} , when present, are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, Alkoxy;

(e) A 'is a covalent _{bond, -O-, -SO d -, -C} (O) -, C (O) N (R 21) -, -N (R 21) - and -N (R ²¹⁾ C (O) -; Wherein d is 0 to 2 and R ²¹ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkyl;

(f) G 'is - (CR ²² R ^22' ) _e -R ²³ wherein e is from 0 to about 4; R ²² and R ^{22 '} , when present, are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, alkoxy and aryl ≪ / RTI > R ²³ is selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; Or R ²¹ and R ²³ together with the atoms to which they are attached form an optionally substituted heterocyclic ring containing from 5 to 8 atoms of which from 1 to 3 are heteroatoms; Or R < ²⁰ > and R < ²³ > together with the atoms to which they are attached form an optionally substituted heterocyclic ring containing from 5 to 8 atoms in which from 1 to 3 are heteroatoms.

The present invention also encompasses optical isomers, diastereoisomers and enantiomers of the above formula, and pharmaceutically acceptable salts, biodegradable amides, esters and imides thereof.

The compounds of the present invention are useful in the treatment of diseases and conditions characterized by undesirable metalloprotease activity. Accordingly, the present invention also provides a pharmaceutical composition containing such a compound. The present invention also provides a method of treating a metalloprotease-related disease.

The present invention relates to compounds useful in the treatment of diseases associated with metalloprotease activity, particularly zinc metalloprotease activity. The present invention also relates to a pharmaceutical composition containing the compound, and a method for treating a metalloprotease-related disease using the compound or the pharmaceutical composition.

I. Terms and Definitions:

The definitions of the terms used in the text are listed below.

&Quot; Acyl " or " carbonyl " is a radical formed by removal of the hydroxy from a carboxylic acid (i.e., R-C (= O) -). Preferred acyl groups include (for example) acetyl, formyl and propionyl.

&Quot; Alkyl " is a saturated hydrocarbon chain having 1 to 15, preferably 1 to 10, more preferably 1 to 4 carbon atoms. &Quot; Alkene " is a hydrocarbon chain having one or more (preferably one) carbon-carbon double bonds and having 2 to 15, preferably 2 to 10, more preferably 2 to 4 carbon atoms . &Quot; Alkyne " is a hydrocarbon chain having one or more (preferably one) carbon-carbon triple bonds and having 2 to 15, preferably 2 to 10, more preferably 2 to 4 carbon atoms . Alkyl, alkene and alkyne chains (collectively referred to as " hydrocarbon chains ") may be linear or branched and may be substituted or unsubstituted. Preferred branched alkyl, alkene and alkyne chains have 1 or 2, preferably 1 branch. A preferred chain is alkyl. Each of the alkyl, alkene and alkyne hydrocarbon chains may be unsubstituted or substituted with one to four substituents; When substituted, the preferred chain is mono-, di-, or tri-substituted. Each of the alkyl, alkene and alkyne hydrocarbon chains is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, aryloxy (e.g., phenoxy), heteroaryloxy, acyloxy (e.g., acetoxy), carboxy, , 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.

The "lower" alkyl, alkene or alkyne moieties (eg, "lower alkyl") shown in the text mean, in the case of alkyl, 1 to 6, preferably 1 to 4 carbon atoms, in the case of alkenes and alkynes, Is a chain consisting of 2 to 6, preferably 2 to 4, carbon atoms.

&Quot; Alkoxy " is an oxygen radical (i.e., -O-alkyl or -O-alkenyl) having a hydrocarbon chain substituent that is alkyl or alkenyl. Preferred alkoxy groups include (for example) methoxy, ethoxy, propoxy and allyloxy.

&Quot; Aryl " is an aromatic hydrocarbon ring. The aryl ring is a fused ring system or a fused ring system. A monocyclic aryl ring has 6 carbon atoms in the ring. A monocyclic aryl ring is also designated as a phenyl ring. The bicyclic aryl ring has 8 to 17, preferably 9 to 12, carbon atoms in the ring. Bicyclic aryl rings include ring systems wherein one ring is aryl and the other ring is aryl, cycloalkyl or heterocycloalkyl. Preferred bicyclic aryl rings contain 5-, 6- or 7-membered rings fused with a 5-, 6- or 7-membered ring. The aryl ring may be unsubstituted or substituted with one to four substituents on the ring. Aryl is selected from the group consisting of halo, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, aryloxy, alkoxy, heteroalkyloxy, carbamyl, methylenedioxy, heteroaryloxy, May be substituted with any combination of < RTI ID = 0.0 > Preferred aryl rings include naphthyl, tolyl, xylyl and phenyl. The most preferred aryl ring radical is phenyl.

&Quot; Aryloxy " is an oxygen radical having an aryl substituent (i.e., -O-aryl). Preferred aryloxy groups include (for example) phenoxy, naphthyloxy, methoxyphenoxy and methylenedioxyphenoxy.

&Quot; Cycloalkyl " is a saturated or unsaturated hydrocarbon ring. The cycloalkyl ring is not aromatic. A cycloalkyl ring is a single ring or fused, spiro or bridged fused ring system. The monocyclic cycloalkyl ring has about 3 to about 9, preferably 3 to 7, carbon atoms in the ring. The bicyclic cycloalkyl ring has 7 to 17, preferably 7 to 12, carbon atoms in the ring. Preferred bicyclic cycloalkyl rings contain a 4-, 5-, 6- or 7-membered ring fused to a 5-, 6- or 7-membered ring. The cycloalkyl ring may be unsubstituted or substituted with one to four substituents on the ring. Cycloalkyl can be substituted with halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaryloxy or any combination thereof. Preferred cycloalkyl rings include cyclopropyl, cyclopentyl, and cyclohexyl.

&Quot; Halo " or " halogen " is fluoro, chloro, bromo or iodo. Preferred halo is fluoro, chloro and bromo; Typically more preferred are chloro and fluoro.

&Quot; Haloalkyl " is a linear, branched, or cyclic hydrocarbon substituted with one or more halo substituents. Preferred are C ₁ -C ₁₂ haloalkyl; More preferably C ₁ -C ₆ haloalkyl; Even more preferred is C ₁ -C ₃ haloalkyl. Preferred halo substituents are fluoro and chloro.

A " heteroatom " is a nitrogen, sulfur or oxygen atom. Groups containing more than one heteroatom may contain different heteroatoms.

&Quot; Heteroalkyl " is a saturated or unsaturated chain containing carbon and one or more heteroatoms, wherein no two heteroatoms are adjacent. The heteroalkyl chain contains 2 to 15, preferably 2 to 10, more preferably 2 to 5, atoms (carbon and heteroatoms) in the chain. For example, alkoxy (e. G., -O-alkyl or -O-heteroalkyl) radicals are included in heteroalkyl. The heteroalkyl chain may be linear or branched. Preferred branched heteroaryls have 1 or 2, preferably 1 branch. Preferred heteroalkyls are saturated. Unsaturated heteroalkyl has at least one carbon-carbon double bond and / or at least one carbon-carbon triple bond. Preferred unsaturated heteroalkyls have one or two double bonds or one triple bond, more preferably one double bond. The heteroalkyl chain may be unsubstituted or substituted with one to four substituents. Preferred substituted heteroalkyl is mono-, di- or tri-substituted. Heteroaryl is selected from the group consisting of lower alkyl, haloalkyl, halo, hydroxy, aryloxy, heteroaryloxy, acyloxy, carboxy, monocyclic aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amino, Keto, thioketo, cyano, or any combination thereof.

&Quot; Heteroaryl " is an aromatic ring having from 1 to about 6 heteroatoms and carbon atoms in the ring. A heteroaryl ring is a fused or fused bicyclic ring system. A monocyclic heteroaryl ring has from about 5 to about 9 atoms in the ring (carbon and heteroatoms), preferably 5 or 6 atoms. The bicyclic heteroaryl ring has 8 to 17 atoms in the ring, preferably 8 to 12 atoms in the ring. Bicyclic heteroaryl rings include ring systems wherein one ring is heteroaryl and the other ring is aryl, heteroaryl, cycloalkyl or heterocycloalkyl. A preferred bicyclic heteroaryl ring system contains a 5-, 6- or 7-membered ring fused to a 5-, 6- or 7-membered ring. The heteroaryl ring may be unsubstituted or substituted with one to four substituents on the ring. Heteroaryl may be substituted with halo, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, alkoxy, aryloxy, heteroaryloxy or any combination thereof. Preferred heteroaryl rings include, but are not limited to,

&Quot; 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, Lt; / RTI > and benzothiazolyloxy.

&Quot; Heterocycloalkyl " is a saturated or unsaturated ring having carbon atoms and 1 to about 4 (preferably 1 to 3) heteroatoms in the ring. The heterocycloalkyl ring is not aromatic. A heterocycloalkyl ring is a ring system, or a fused, bridged or spirocyclic ring system. A monocyclic heterocycloalkyl ring has from about 3 to about 9 atoms, preferably from 5 to 7 atoms (carbon and heteroatoms) in the ring. The bicyclic heterocycloalkyl ring has 7 to 17 atoms, preferably 7 to 12 atoms, in the ring. The bicyclic heterocycloalkyl ring has from about 7 to about 17 ring atoms, preferably from 7 to 12 ring atoms. The bicyclic heterocycloalkyl ring may be a fused, spiro, or bridged link ring system. A preferred bicyclic heterocycloalkyl ring contains a 5-, 6- or 7-membered ring fused to a 5-, 6- or 7-membered ring. The heterocycloalkyl ring may be unsubstituted or substituted with one to four substituents on the ring. Heterocycloalkyl is selected from the group consisting of halo, cyano, hydroxy, carboxy, keto, thioketo, amino, acylamino, acyl, amido, alkyl, heteroalkyl, haloalkyl, phenyl, alkoxy, aryloxy, . ≪ / RTI > Preferred substituents on the heterocycloalkyl include halo and haloalkyl. Preferred heterocycloalkyl rings include, but are not limited to,

As used herein, " mammal metalloprotease " refers to the protease disclosed in the " Background of the Invention " The compounds of the present invention include any metal-containing (preferably zinc-containing) enzymes found in animals, preferably mammals, which are capable of catalyzing the degradation of collagen, gelatin or proteoglycans under suitable assay conditions Lt; RTI ID = 0.0 >" mammalian < / RTI > metalloprotease " Suitable assay conditions are described, for example, in Cawston et al . , Anal. Biochem. (1979) 99: 340-345; U.S. Patent No. 4,743,587; The use of synthetic substrates is described in Weingarten, H. et al. , Biochem. Biophy. Res. Comm. (1984) 139: 1184-1187. [Knight, CG et al., &Quot; A Novel Coumarin-Labeled Peptide for Sensitive Continuous Assays of the Matrix Metalloproteins ", FEBS Letters , Vol. 296, pp. 263-266 (1992). Any standard method of analyzing the degradation of such structural proteins can of course be used. The present compounds are more preferably active against, for example, metalloproteases, which are zinc-containing proteases structurally similar to human stromelysin or dermal fibroblast collagenase. The ability to inhibit the metalloprotease activity of a candidate compound can of course be tested by the assay described above. The isolated metalloprotease enzyme may be used to confirm the inhibitory activity of the compound of the present invention, or crude extracts containing an enzyme range capable of tissue degradation may be used.

&Quot; Spirocyclic " is an alkyl or heteroalkyldi (di) radical substituent of an alkyl or heteroalkyl wherein the di radical substituent is attached in an overlapping manner, the di radical substituent forms a ring, (Carbon or heteroatom), preferably 5 or 6 atoms.

The alkyl, heteroalkyl, cycloalkyl and heterocycloalkyl groups may be substituted with the above mentioned hydroxy, amino and amido groups, but the following are not considered in the present invention:

1. Enol (OH attached to a carbon-carbon double bond).

2. Amino groups attached to carbon-carbon double bonds (other than vinylic amides).

3. More than one hydroxy, amino or amido attached to a single carbon, except when two nitrogen atoms are attached to a single carbon atom and all three atoms are constituent atoms of a heterocycloalkyl ring.

4. Hydroxy, amino or amido attached to the carbon to which the halogen is also attached.

&Quot; Pharmaceutically acceptable salt " is a cationic salt formed in any acidic (e.g., hydroxamic acid or carboxylic acid) group, or an anionic salt formed in any basic (e.g., amino) group. Many such salts are known in the prior art, as described in World Patent Publication No. 87/05297 (Johnston et al., Issued September 11, 1987), which is incorporated herein by reference. Preferred cationic salts include alkali metal salts (e.g., sodium and potassium) and alkaline earth metal salts (such as magnesium and calcium) and organic salts. Preferred anionic salts include halides (e.g., chloride salts), sulfonates, carboxylates, phosphates, and the like.

Such salts are well understood by those skilled in the art, and one of ordinary skill in the art can make any number of salts given the knowledge in the art. It is also recognized that one of ordinary skill in the art may prefer one salt over the other for solubility, stability, ease of formulation, and the like. The determination and optimization of such salts is within the scope of practice of those skilled in the art.

A " biodegradable amide " refers to a compound that does not interfere with the metalloprotease inhibitory activity of the compound or that is readily converted in vivo by an animal, preferably a mammal, more preferably a human subject, to become an active metalloprotease inhibitor Hydroxamic acid-containing (i. E., R < ¹ > in formula I is -NHOH) amide of a metalloprotease inhibitor. Examples of such amide derivatives are the alkoxyamides in which the hydroxyl hydrogen of the hydroxamic acid of formula (I) is replaced by an alkyl moiety and the acyloxyamides in which the hydroxyl hydrogen is replaced by an acyl moiety (i.e., RC (= O) -).

&Quot; Biodegradable hydroxy imide " does not interfere with the metalloprotease inhibitory activity of the compound or is readily converted in vivo by an animal, preferably a mammal, more preferably a human subject, and the active metalloprotease Is an imide of a hydroxamic acid-containing metalloprotease inhibitor which is an inhibitor. Examples of such imide derivatives are those in which the amino hydrogen of the hydroxamic acid of formula I is replaced by an acyl moiety (i. E., R-C (= O) -).

"Birthplace water-esters" are do not interfere with the protease inhibitory activity is a metal of the compound, is easily converted by or animal that protease inhibitor as the active metal carboxylic acid-containing (i. E., That is, the R ¹ of formula (I) -OH) < / RTI > is an ester of a metalloprotease inhibitor. Such esters include lower alkyl esters, lower acyloxy-alkyl esters (e.g., acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxyethyl esters), lactonyl esters Phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (e.g., methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters And alkyl acylaminoalkyl esters (e.g., acetamidomethyl esters).

"Solvate" is a complex formed by the combination of a solute (eg, a metalloprotease inhibitor) and a solvent (eg, water). [J. Honig et al., The Van Nostrand Chemist's Dictionary, p. 650 (1953). Pharmaceutically acceptable solvents used in accordance with the invention include those that do not interfere with the biological activity of the metalloprotease inhibitor (e.g., water, ethanol, acetic acid, N, N-dimethylformamide, Those that are easily determined).

The terms " optical isomer "," stereoisomers ", and " diastereoisomers " have meanings as perceived in the standard art (see, e.g., Hawley's Condensed Chemical Dictionary, Eleventh Edition). Examples of certain protected forms and other derivatives of the compounds of this invention are not intended to be limiting. Other useful protecting groups, salt forms, and the like are within the skill of the skilled artisan.

II. compound:

The present invention relates to compounds of formula (I)

(I)

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , G and Z have the meanings given above. The following provides a description of particularly preferred portions, but is not intended to limit the scope of the claims.

R < ¹ > is selected from -OH and -NHOH; Preferably -OH.

R ² 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.

R ³ is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; Preferably hydrogen or alkyl, more preferably hydrogen.

R ⁴ is - (CR ⁷ R ⁷ ) _k -X- (CR ⁸ R ⁸ ) ₁ -EA. k and l are each independently selected from 0, 1, 2, 3 or 4; Preferably k is 0, 1, 2 or 3; Preferably, l is 0, 1 or 2. ^{R 7, R 7 ', R} 8, and R ^8' are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, selected from halogen and haloalkyl ; Preferably all are hydrogen.

X is -O-, -S-, -S (O) -, -S (O ₂ ) -, -N (R ⁹ ) -, -N (COR ⁹ ) -, -N (CO ₂ R ⁹ ) ^{, -N (CONR 9 R 9 '} ) - and -N (SO ₂ R ⁹⁾ - is selected from, where, R ⁹ and R ^9' are each independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl (Preferably R ⁹ and R ^{9 '} are each hydrogen), or (ii) R ⁹ and R ⁹ are independently selected from alkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl ^'to form a ring with, one to three having from 5 to 8 ring atoms, the hetero atom, an optionally substituted cyclic heteroatom with the nitrogen atom to which they are bonded. Preferably, X is _{-O-, -S-, -N (SO 2} R 9), -N (COR 9), -N (CO 2 R 9), where R ⁹ is preferably lower alkyl or / RTI >

E is a covalent bond, -O-, -S-, -S (O ), -S (O 2) -, -N (R 10) -, -N (COR 10) -, -N (CO 2 R 10 ), -N (CONR ¹⁰ R ^{10 '} ) - and -N (SO ₂ R ¹⁰ ) -, wherein (i) each of R ¹⁰ and R ^10' is independently hydrogen, alkyl, (Preferably each R ¹⁰ and R ^{10 '} is hydrogen), or (ii) is selected from alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl, R ¹⁰ and R ^{10 '} together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring having from 5 to 8 ring atoms in which from 1 to 3 are heteroatoms. Preferably, E is a covalent bond, -O-, -S-, -N (SO 2 R 10) -, -N (COR 10) or - (CO ₂ R ¹⁰⁾ - and, R ¹⁰ is preferably here Is lower alkyl or aryl. When l = 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 alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.

R ⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; Preferably hydrogen or lower alkyl; More preferably, it is hydrogen.

R ⁶ is alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and hydroxyl chamber is selected from; Preferably aryl, heteroaryl or hydroxyl. When k > 0, R ⁶ is -OH, and when k = 0, R ⁶ is not -OH.

G is ^{-S-, -O-, -N (R 11} ) -, -C (R 11) = C (R 11 ') -, -N = C (R 11) - and -N = N- selected from Being; In a preferred embodiment, G is -S- or -C (R ¹¹ ) = C (R ^{11 '} ) -. Each of R ¹¹ and R ^{11 '} is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; Preferably at least one of R < ¹¹ > and R < ¹¹ > is hydrogen, and more preferably both are hydrogen.

Z is selected from cycloalkyl and heterocycloalkyl; -L- (CR ¹² R ^{12 '} ) _a -R ¹³ ; -NR ¹⁵ R ^{15 '} ; And .

When Z is cycloalkyl or heterocycloalkyl, it is preferred that Z is optionally substituted piperidine or piperazine.

When Z is -L- (CR ¹² R ^{12 '} ) _a -R ¹³ , a is 0, 1, 2, 3 or 4, preferably 0 or 1. L is -C≡C-, -CH = CH-, -N = N-, -O-, -S- , and -S (O ₂₎ - is selected from; L is preferably -C? C-, -CH = CH-, -N = N-, -O- or -S-; More preferably, L is -C? C-, -CH = CH- or -N = N-. Each of R ¹² and R ^{12 '} is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy and alkoxy; Preferably each R ¹² is hydrogen and each R ^{12 '} is independently hydrogen or lower alkyl. R ¹³ is selected from aryl, heteroaryl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, heterocycloalkyl, and cycloalkyl; Preferably R < ¹³ > is aryl, heteroaryl, heterocycloalkyl or cycloalkyl. However, if L is -C? C- or -CH = CH-, then R ¹³ can also be selected from -C (O) NR ¹⁴ R ^{14 '} , wherein (i) R ¹⁴ and R ^14' Is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, or (ii) R ¹⁴ and R ^{14 '} Together form an optionally substituted heterocyclic ring having 5 to 8 (preferably 5 or 6) ring atoms of which 1 to 3 (preferably 1 or 2) are heteroatoms.

When Z is -NR ¹⁵ R ^{15 '} , each of R ¹⁵ and R ^15' is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, (O) -Q- (CR ¹⁶ R ^{16 '} ) _b -R ¹⁷ ; Preferably R ¹⁵ and R ^{15 '} are independently selected from hydrogen, alkyl, aryl and -C (O) -Q- (CR ¹⁶ R ¹⁶ ) _b -R ¹⁷ . When R ¹⁵ and / or R ^{15 '} is -C (O) -Q- (CR ¹⁶ R ^16' ) _b -R ¹⁷ , b is 0, 1, 2, 3 or 4; b is preferably 0 or 1. Q is selected from a covalent bond and -NR < ¹⁸ >-; Q is preferably a covalent bond. Each of R ¹⁶ and R ^{16 '} is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy and alkoxy; Preferably each R ¹⁶ is hydrogen and each R ^{16 '} is independently hydrogen or lower alkyl. Each of R ¹⁷ and R ¹⁸ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl (preferably one is aryl); Or R ¹⁷ and R ¹⁸ together with the nitrogen atom to which they are attached are optionally substituted, with 5 to 8 To form a substituted heterocyclic ring; Preferably R < ¹⁷ > is alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl. Alternatively, R ¹⁵ and R ¹⁸ together with the nitrogen atom to which they are attached have 5 to 8 (preferably 5 or 6) ring atoms with 1 to 3 (preferably 1 or 2) heteroatoms To form an optionally substituted heterocyclic ring. Most preferably, R ¹⁵ is hydrogen or lower alkyl and R ^{15 '} is -C (O) -Q- (CR ¹⁶ R ^16' ) _b -R ¹⁷ wherein Q is a covalent bond, b = 0 , And R < ¹⁷ > is aryl.

Alternatively, R ¹⁵ and R ^{15 '} , together with the nitrogen atom to which they are attached, form 5- to 8 (preferably 5 or 6) ring atoms with 1 to 3 (preferably 1 or 2) To form an optionally substituted heterocyclic ring.

Z is (Represented by the formula (A)), E 'and M' are independently selected from -CH- and -N-; Preferred is that E 'is -CH and M' is -CH. L 'is ^{-S-, -O-, -N (R 20} ) -, -C (R 20) = C (R 20') -, -N = C (R 20) - and from the -N = N- Selected; Preferably L 'is ^{-C (R 20) = C (} R 20') - a. Each of R ²⁰ and R ^{20 '} is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; Preferably hydrogen or lower alkyl. c is 0, 1, 2, 3 or 4, preferably 0 or 1. R ¹⁹ and R ^{19 '} are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy and alkoxy; Preferably each R ¹⁹ is hydrogen and each R ^{19 '} is independently hydrogen or lower alkyl. A 'is a covalent _{bond, -O-, -SO d -, -C} (O) -, -C (O) N (R 21) -, -N (R 21) - and -N (R ²¹⁾ C ( O) -; Preferably A 'is -O- or -S-. d is 0, 1 or 2; R ²¹ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkyl; R < ²¹ > is preferably lower alkyl or aryl. G 'is - (CR ²² R ^22' ) _e -R ²³ . e is 0, 1, 2, 3 or 4, preferably 0 or 1. R ²² and R ^{22 '} are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, alkoxy and aryloxy ; Preferably each R ²² is hydrogen and each R ^{22 '} is independently hydrogen or lower alkyl. R ²³ is selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; Preferably R < ²³ > is lower alkyl or aryl. Alternatively, R < ²¹ > and R < ²³ >, together with the atoms to which they are attached, optionally have 5 to 8 (preferably 5 or 6) atoms with 1 to 3 (preferably 1 or 2) To form a substituted heterocyclic ring. Alternatively, R ²⁰ and R ²³ , together with the atoms to which they are attached, optionally have 5 to 8 (preferably 5 or 6) atoms with 1 to 3 (preferably 1 or 2) To form a substituted heterocyclic ring.

Most preferred compounds Z is -NR ¹⁵ R ^{15 'or} .

A preferred sub-genus compound is a carboxylic acid-containing compound having a structure according to formula (II) or (III): <

^{[Wherein, R 6, X, k,} l, E, A, G and Z are as described for formula I].

III. Compound manufacturing

The compounds of the present invention can be prepared by various processes.

The starting materials used to prepare the compounds of the present invention are known, made by known methods, or marketed. A particularly preferred synthesis method is described in the general reaction formula below. (Groups of R is used to illustrate the reaction schemes are not in necessarily correlated groups wherein each R is used to describe the various aspects of the compound of formula (I). In other words, for example, R ¹ of formula (I) R ₁ a where Is not displayed. Specific examples of the preparation of compounds of the present invention are set forth in Section VIII below.

In Scheme 1, aldehyde S1a is a commercially available material. The utility of the synthesis has been widely recognized, and several conditions have been developed for stereospecific reactions with nucleophiles. In this way, various aryl or alkyl R < ¹ > groups can be introduced to form alcohol S < 1b >, and syn / anti stereochemistry can be controlled according to reaction conditions. The newly formed hydroxyl group of S1b can then be functionalized with a wide variety of alkylating agents using methods well known to the skilled artisan to introduce the substituent R < ² >. The product S1c can then be converted to the target carboxylic acid using methods well documented in the literature of the chemical arts. Thus, the acetonide protecting groups of Boc and S1c can be removed under acidic conditions to give the aminoalcohol S1d . The amino group of this intermediate can be selectively derivatized with a suitable arylsulfonyl chloride using standard < RTI ID = 0.0 > Shott and Bouman < / RTI > conditions to yield the sulfonamide S1e . Further elaboration of the aryl group R < ³ > can be performed at this stage, for example, using the Suzuki coupling method. Finally, the alcohol functionality is converted to the carboxylic acid using standard oxidation methods to produce the target molecule S1f .

If desired, the carboxylic acid functionality in the compound of type S1f can be converted to the hydroxy acid by coupling with a hydroxylamine using a mixed anhydride method, or by forming an intermediate acid chloride.

In Scheme 2, a commercially available epoxy-alcohol is S2a using known methods (.... Zwanenburg, etc., Rec Trav Chim Pay Bas 1992, 111, 1) is converted to the aziridine ester S2e. First, the alcohol is oxidized and the resulting carboxylic acid S2b is esterified to obtain an epoxy ester S2c . The epoxide ring of S2c is then opened by reaction with sodium azide in the presence of ammonium chloride to yield the azido-alcohol S2d as a mixture of regioisomers. Which can be obtained from S2d by treatment with triphenylphosphine aziridine S2e various sulfur-shown in the chemistry literature to be very useful electrophilic chain capable of performing ring-opening reaction with the substrate nucleophile-oxygen-and nitrogen have. For example, thiol reacts with S2e under the catalysis of boron trifluoride etherate to obtain the functionalized amino acid S2f (X = S) in very good yields. Similarly, oxygen or nitrogen-functionalized amino acid S2f (X = O or N), respectively, can be prepared via addition of acetic acid or azide (Legtersen, J. et al . , Rec. Trav. Chim. 111 , 59). The free amino group can then be derivatized with various sulfonyl chlorides to give the sulfonamide ester S2g . If desired, more complex arylsulfonyl groups can be introduced in one of several synthetic steps. Finally, the ester functional group is converted to a carboxylic acid using one of the standard hydrolysis methods to produce the target molecule S2h .

If desired, the ester functionality of the type S2g compound can be converted to the hydroxylic acid by reaction with hydroxylamine under alkaline conditions.

In Scheme 3, well known Evans chemistry was used to determine the absolute and relative stereochemistry of the chiral center of the target amino alcohol S3d . Thus, oxazolidinone bromoacetate S3a reacts with the selected aldehyde to give the bromoalcohol S3b with very high stereoselectivity. In the following step, standard conditions of S _N 2 substitution are applied, and the bromide atom is replaced with azide to give intermediate S 3 c . The hydrolysis of the oxazolidinone group can be carried out using well-described conditions in the literature of chemistry to obtain the core intermediate amino acid S3d. Then the free amino group of S3d are derivatized in a variety of chloride, it is possible to obtain the target inhibitors S3e. If desired, more complex arylsulfonyl groups may be introduced in one of several synthetic steps. If desired, the carboxylic acid functionality of the type S3e compound can be converted to the hydroxy acid by coupling with a hydroxylamine using a mixed anhydride method, or by formation of an intermediate acid chloride.

These steps may be varied to increase the yield of the desired product. Those skilled in the art will recognize that careful selection of reactants, solvents, and temperatures is an important factor in any successful synthesis. Determination of optimum conditions, etc. is conventional. Thus, the skilled artisan can prepare various compounds based on the above reaction equations.

It is recognized that one skilled in the art of organic chemistry can readily perform standard manipulations of organic compounds without further explanation, i. E., Performing such manipulations is within the scope and practice of the skilled artisan. This includes, but is not limited to, reduction of carbonyl compounds to their corresponding alcohols, oxidation of hydroxyls, acylation, aromatic substitution, electrophilic and nucleophilic etherification, esterification, and saponification. Examples of such manipulations are discussed in standard texts such as March, Advanced Organic Chemistry (Wiley), Carey, and Sundberg, Advanced Organic Chemistry (Vol. 2) and other techniques recognized by the skilled artisan.

The skilled artisan will also readily understand that a particular reaction is performed optimally when another potentially reactive functional group on the molecule is masked or protected, avoiding / avoiding all undesirable side reactions or increasing reaction yield. Often, the skilled person will use such protecting groups to achieve such yield increases, or avoid undesirable reactions. These reactions are found in the literature and are also within the scope of the skilled person. Many examples of such operations are described, for example, in [T. Greene, Protecting Groups in Organic Synthesis . Of course, the amino acid used as a starting material with reactive side chains is preferably blocked to prevent undesired side reactions.

The compounds of the present invention may have one or more chiral centers. As a result, one optically isomer can be selectively prepared for the other, including, for example, chiral starting materials, catalysts or solvents, including diastereomers and enantiomers, or both stereoisomers, Both optical isomers, including isomers and enantiomers, can be prepared at once (racemic mixture). Since the compounds of the present invention may exist as racemic mixtures, mixtures of optical isomers, or stereoisomers, including diastereomers and enantiomers may be separated using known methods such as chiral salts, chiral chromatography, and the like.

In addition, one optical isomer or stereoisomer, including diastereoisomers and enantiomers, may have more desirable properties than the other. Thus, when disclosing and claiming the present invention, when one racemic mixture is disclosed, it is evident that both optical isomers, both stereoisomers and enantiomers, or stereoisomers, including diastereomers and substantially enantiomers, It is intended to do.

IV. How to use:

The metalloprotease (MP) found in the body functions, in part, by degrading the extracellular matrix containing extracellular proteins and glycoproteins. Inhibitors of metalloprotease are useful, at least in part, to treat diseases caused by degradation of such proteins and glycoproteins. These proteins and glycoproteins play an important role in maintaining the size, shape, structure and stability of body tissues. Therefore, MP is closely related to tissue remodeling.

As a result of this activity, MP has been said to be active in many diseases associated with one of the following: (1) collapse of tissues, including ocular disease; Degenerative diseases such as arthritis, multiple sclerosis, etc; And the transfer or mobility of body tissues; Or (2) tissue remodeling including heart disease, fibrosing disease, scar formation, and positive hyperplasia.

The compounds of the invention prevent or treat undesirable abnormalities characterized by undesirable or elevated activity due to disease, disease and / or MP. For example, a compound can be used to inhibit MP to:

1. destruction of structural proteins (ie, proteins that maintain tissue stability and structure);

2. Intracellular / intracellular signal transduction inhibition including cytokine up-regulation, and / or involvement of cytokine processes and / or inflammation, tissue degradation and other diseases [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. Promotion of undesirable processes in the subject, such as sperm maturation, fertilization, etc.

As used herein, " MP related disease " or " MP related disease " refers to a biological cascade that causes biological signs or diseases of a disease or disorder; Or undesirable or elevated MP activity as a symptom of the disease. The " association " of such MPs includes:

1. Regardless of whether the activity has been genetically elevated by infection, autoimmunity, trauma, mechanistic cause, lifestyle (eg, obesity), or any other cause, it is desirable as a "cause" of a disease or biological indication No or elevated MP activity;

2. MP as part of an observable indication of disease or disease. That is, the disease or disease can be measured in terms of increased MP activity. From a clinical point of view, an undesirable or elevated MP level refers to disease, but MP can not be said to be a " assurance mark " of disease or disorder; or

3. Undesirable or elevated MP activity is part of a biochemical or cellular cascade that causes or is associated with a disease or disorder. In this regard, inhibition of MP activity blocks cascades and thus regulates disease.

The term " treatment " has been used herein to mean, at least, the administration of a compound of the present invention to ameliorate a disease associated with undesirable or elevated MP activity in a mammalian subject, preferably a human. Thus, the term " treatment " includes: prevention of MP-mediated disease outbreaks in mammals, particularly when mammals are susceptible to disease; MP-mediated disease inhibition; And / or alleviation of MP-mediated disease. It is understood that the term " prevent " is not required to completely interfere with the disease state, as long as the method of the present invention relates to preventing the disease state associated with undesirable MP activity. (See Webster's Ninth Collegiate Dictionary.) Rather, the term prevention, as used herein, refers to the ability of the skilled person to identify groups susceptible to MP-related disease and to allow administration of the compounds of the invention prior to onset . The term does not necessarily mean completely avoiding the disease state. For example, osteoarthritis (OA) is the most common rheumatic disease that can be detected by radiation in some joints in 80% of the population 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 et al, p 11-14 (1992)]. A common risk factor for increasing OA outbreaks is traumatic injuries of the joints. Surgical removal of the meniscus following a knee injury increases the risk of radiation-detectable OA, which 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 and Age." Osteoarthritis Cartilege., Vol. 3, pp 261-267 (1995)). Thus, such patient populations are identifiable and can be administered prior to the onset of the disease. Thus, the progress of the OA in such an entity will be " prevented ".

Advantageously, many MPs are not evenly distributed throughout the body. Thus, the distribution of MPs expressed in various tissues is often specific to that tissue. For example, the distribution of metalloprotease related to tissue disruption in the joints is not identical to the distribution of metalloprotease found in other tissues. Although not essential for activity or efficacy, certain diseases, disorders and undesirable conditions are preferably treated with a compound that acts against a particular MP found in a tissue or site with a disease of the body. For example, a compound that exhibits a higher degree of affinity and inhibition of MP found in joints (e.g., chondrocytes) may be useful for the treatment of diseases, disorders or undesirable conditions found in joints than other less specific compounds .

In addition, certain inhibitors have greater bioavailability in certain tissues than others. The choice of an MP inhibitor that has greater bioavailability in a particular tissue and that specifically works on the particular MP found in that tissue is for the specific treatment of a disease, disorder, or undesirable condition. For example, the compounds of the present invention differ in their ability to penetrate the central nervous system. Thus, the compound may be selected to produce an effect mediated through MP that is specifically found outside the central nervous system.

The determination of the specificity of an inhibitor of a particular MP is within the skill of those skilled in the art. Appropriate assay conditions can be found in the literature. In particular, assay methods for stromelysin and collagenase are known. For example, US Pat. No. 4,743,587 refers to the process of [Cawston et al ., Anal Biochem (1979) 99: 340-345]. Also, [Knight, CG et al., &Quot; A Novel Coumarin-labeled Peptides for Sensitive Continuous Assays of the Matrix Metalloproteins ", FEBS Letters , Vol. 296, pp. 263-266 (1992). The use of synthetic substrates in assays is described in Weingarten, H. et al., Biochem Biophy Res Comm (1984) 139: 1184-1187. Any standard method can of course be used to analyze the collapse of structural proteins by MP. The ability of the compounds of the present invention to inhibit the metalloprotease activity can be tested by the assay method found in the literature, or a modification thereof. The isolated metalloprotease may be used to confirm the inhibitory activity of the compound of the present invention, or crude extracts containing enzymes in a range capable of tissue degradation may be used.

The compounds of the present invention are also useful for prophylactic or acute treatment. It is administered in any manner desired by those skilled in the medical or pharmaceutical arts. It is directly apparent to those skilled in the art that the preferred route of administration will depend on the disease state being treated and the selected mode of administration. Preferred routes of systemic administration include oral or parenteral administration.

However, the skilled artisan will readily appreciate the advantages of administering MP inhibitors directly to the lesion for many diseases, disorders or undesirable conditions. For example, a disease, condition or site of an undesirable condition such as a surgical trauma (e.g., angioplasty), scar formation, burn (topical of the skin) or ocular indications and periodontal indication RTI ID = 0.0 > MP < / RTI >

Since bone remodeling is associated with MP, the compounds of the present invention are useful for preventing the implant from loosening. It is known in the art that replacement is required since over time, the implant will loosen, become painful, and cause additional bone injuries. The need for replacement of such implants includes such things as joint replacements (e.g., pelvic, knee and shoulder replacement), dentures, implants that include implants fixed to the maxilla and / or mandible.

MP is also active in cardiovascular remodeling (eg, congestive heart failure). One of the reasons for angioplasty to have a longer term failure rate (re-occlusion over time) than expected is that MP activity is elevated or undesirable in response to what may be perceived as " floating " by the body's basal membrane It has been proposed that Thus, the modulation of MP activity in conditions such as dilated cardiomyopathy, congestive heart failure, atherosclerosis, plaque rupture, reperfusion injury, ischemia, chronic obstructive pulmonary disease, angioplasty restenosis caused by angioplasty restenosis, Can increase the long-term success of other treatments of the disease, or can be treated by itself.

In skin care, MP is associated with remodeling or " turnover " of the skin. As a result, modulation of MP improves the treatment of skin conditions, including, but not limited to, wrinkle restoration, conditioning and prevention and repair of ultraviolet-induced skin damage. It is clear that such treatments include treatment prior to prophylactic or physiological indications. For example, MP may be applied as pretreatment to prevent ultraviolet damage and / or may be applied to prevent or minimize damage during or after exposure. In addition, MP has been implicated in skin diseases and diseases involving metalloprotease activity, such as hydrocephalic epidermolysis, yoghorn, scleroderma and atopic dermatitis, related to abnormal tissues resulting from abnormal transitions. The compounds of the invention are also useful for treating the consequences of " normal " injury of the skin, including, for example, burn-related scar formation or " contraction " of tissue. MP inhibition is also useful for scar formation prevention, including applications such as finger reattachment and refractory surgical procedures (by laser or incision) and surgical procedures involving normal tissue growth promoting skin.

MP is also implicated in diseases related to atypical remodeling of other tissues, such as, for example, biceps and / or osteoporosis in bone, or diseases of certain organs, such as cirrhosis and fibrosing lung disease. Similarly, in diseases such as multiple sclerosis, MP may be involved in atypical remodeling of the blood-brain barrier and / or nervous system aqueducts. Thus, modulation of MP activity can be used as a strategy in the treatment, prevention and control of such diseases.

MP also contains cytomegalovirus (CMV); Retinitis; It is thought to be related to many infections, including AIDS, which is a syndrome of HIV and its consequences.

MP may also be involved in hypervascularity, such as in angiofibroma and angioma, where the surrounding tissue needs to collapse to create new blood vessels.

Because MP disrupts the extracellular matrix, for example, it prevents ovulation, prevents sperm penetration into the extracellular environment of the oocyte, prevents fertilization of the fertilized oocyte, and prevents sperm maturation. Inhibitors of this enzyme, control agent.

In addition, they are also believed to be useful in preventing and preventing precocious labor and labor.

Since MP is involved in inflammatory reactions and cytokine processes, the compounds may also be used as anti-inflammatory agents in the treatment of inflammatory bowel disease, Crohn's disease, ulcerative colitis, pancreatitis, diverticulitis, asthma or related pulmonary disease, rheumatoid arthritis, Lt; / RTI > is useful for use in a major disease.

When autoimmunity is the cause of the disease, immune responses often trigger MP and cytokine activity. Control of MP in the treatment of such autoimmune diseases is a useful therapeutic strategy. Thus, MP inhibitors can be used to treat diseases including red lupus, ankylosing spondylitis, and autoimmune keratitis. Sometimes the side effects of autoimmune therapy lead to the deterioration of other conditions mediated by MP, where MP inhibitor therapy is also effective for, for example, autoimmune-therapy-induced fibrosis.

In addition, other fibrosing diseases, including pulmonary diseases, bronchitis, model, cystic fibrosis, acute respiratory distress syndrome (especially acute phase response) are suitable for this type of treatment.

If MP is involved in undesirable decay of tissue by an exogenous agent, they can be treated with an MP inhibitor. For example, they are effective in the treatment of rattlesnake-bite scars, as allergen-induced inflammation, sepsis and shock. They are also useful as antiparasitic agents (e. G. In malaria) and as antiinfectives. For example, they are believed to be useful in treating or preventing a viral infection, including an infection that may result in herpes, "cold" (eg, a rhinovirus infection), meningitis, hepatitis, HIV infection and AIDS.

MP inhibitors may also be associated with loss of Alzheimer's disease, amyotrophic lateral sclerosis (ALS), muscular dystrophy, diabetes, especially tissue viability, coagulation, Host disease, leukemia, cachexia, anorexia, proteinuria and hair growth control.

MP inhibition is believed to be the preferred treatment for some diseases, conditions or diseases. Such diseases, abnormal conditions or diseases include, but are not limited to, arthritis (including osteoarthritis and rheumatoid arthritis), cancer (particularly prevention or inhibition of tumor growth and metastasis), eye disease (especially corneal ulcer formation, lack of corneal healing, macular degeneration and pterygium) And gum disease (especially periodontal disease and gingivitis).

Preferred compounds for the treatment of arthritis (including osteoarthritis and rheumatoid arthritis) are compounds selective for matrix metalloproteases and disintegrin metalloproteases, but are not limited thereto. Preferred compounds for the treatment of cancer, particularly for preventing or inhibiting tumor growth and metastasis, are compounds which preferentially inhibit gelatinase or type IV collagenase, but are not limited thereto. Preferred compounds for the treatment of eye diseases (particularly corneal ulcer formation, corneal healing deficiency, macular formation and pterygium) are compounds which extensively inhibit metalloprotease, but are not limited thereto. Preferably such compounds are administered topically, more preferably as eye drops or gels. Preferred compounds for the treatment of periodontal disease (particularly periodontal disease and gingivitis) include, but are not limited to, compounds that inhibit collagenase.

V. Composition:

The compositions of the present invention comprise:

(a) a safe effective amount of a compound of the invention; And

(b) a pharmaceutically acceptable carrier.

As discussed above, a number of diseases are known to be mediated by excessive or undesirable metalloprotease activity. These include tumor metastasis, osteoarthritis, rheumatoid arthritis, skin inflammation, ulceration, especially ulceration in the cornea, response to infection, periodontitis and the like. Thus, the compounds of the present invention are useful for treatment of conditions associated with such undesirable activity.

The compounds of the present invention can therefore be formulated into pharmaceutical compositions for use in the treatment or prevention of such conditions. Standard pharmaceutical formulation techniques such as those described in Remington ' s Pharmaceutical Sciences , Mack Publishing Company, Easton, Pa., Current Edition are used.

A " safe effective amount " of a compound of formula (I) is intended to mean that a metalloprotease can be administered to an animal, preferably a mammal, more preferably a human subject, without undesirable adverse side effects (e.g. toxicity, hypersensitivity or allergic response) Which is equivalent to a reasonable benefit / risk ratio when used in the manner of the present invention, The specific " safe effective amount " will obviously vary depending on the particular condition being treated, the physical condition of the patient, the duration of the treatment, the nature of the concurrent treatment (if any), the particular dosage form employed, the carrier employed, Lt; / RTI > will vary depending on factors such as the desired dosage regimen.

In addition to the subject compounds, the compositions of the present invention contain a pharmaceutically acceptable carrier. The term " pharmaceutically acceptable carrier " as used herein means one or more miscible solid or liquid filler diluents or encapsulating materials suitable for administration to an animal, preferably a mammal, more preferably a human. The term " miscible " as used herein means that the components of the composition can be mixed with the main compound, and mutually, in a manner that does not substantially interfere with the pharmaceutical effectiveness of the composition under normal use conditions . The pharmaceutically acceptable carrier should, of course, be sufficiently pure and sufficiently low toxic to be suitable for administration to a subject to be treated. The choice of a pharmaceutically acceptable carrier to be used with the subject compound is determined in part by the manner in which the compound is to be administered.

Some examples of materials or ingredients that can function as a pharmaceutically acceptable carrier include sugars such as lactose, glucose and sucrose; Starches such as corn starch and potato starch; Cellulose and derivatives thereof such as sodium carboxymethylcellulose, ethylcellulose and methylcellulose; 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 and oils of theobroma; Polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; Alginic acid; Emulsifiers such as Tweens ; Wetting agents such as sodium lauryl sulfate; coloring agent; Flavor agent; Tableting agents; Stabilizers; Antioxidants; Preservatives; Pyrogen-free water; Isotonic saline; And phosphate buffer solutions.

Pharmaceutically acceptable carriers for systemic administration include sugars, starches, celluloses and their derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffers, emulsifiers, isotonic saline, The number of non-exothermic factors is included. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol and sesame oil. Preferably, the pharmaceutically acceptable carrier is contained in the composition for parenteral administration in an amount of about 90% by weight or more of the total composition. When the subject compound is injected, a preferred pharmaceutically acceptable carrier is sterile physiological saline with a blood-miscible suspending agent, and the pH is preferably adjusted to about 7.4.

The composition of the present invention is preferably provided in unit dosage form. As used herein, the term "unit dosage form" refers to an amount of a compound of formula (I) that is suitable for administration to a animal, preferably a mammal, more preferably a human subject, The composition of the present invention. Such compositions preferably contain about 5 mg (milligram) to about 1000 mg, more preferably about 10 mg to about 500 mg, and more preferably about 10 mg to about 300 mg of a compound of formula (I).

The compositions of the present invention may be in any of a variety of forms suitable for oral, rectal, topical, nasal, ocular or parenteral administration (for example). Depending on the particular route of administration desired, a wide variety of pharmaceutically acceptable carriers well known in the art may be used. These include solid or liquid fillers, diluents, hydrotropes, surfactants and encapsulating materials. An optional medicinal-active substance which does not substantially interfere with the inhibitory activity of the compound of formula (I) may be included. The amount of carrier used with the compound of formula I is sufficient to provide an actual amount of the dosage material per unit dose of the compound of formula (I). Techniques and compositions for preparing dosage forms useful in the methods of the present invention are all described in the following references incorporated herein by reference: Modern Pharmaceutics , 9 and 10 (Banker & Rhodes, editors, 1979) ; [Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981)]; And [Ansel, Introduction to Pharmaceutical Dosage Forms, Second Edition (1976)].

A variety of oral dosage forms can be used, including solid forms such as tablets, capsules, granules and bulk powders. Such oral dosage forms contain a safe effective amount, generally about 5% or more, and preferably about 25% to about 50% of a compound of formula (I). Tablets may be compressed, tabletted powders, and may be enteric-coated, sugar-coated, film-coated, or multi-compacted and may contain suitable binders, lubricants, diluents, disintegrants, - inducing agents and / or melting agents. Liquid oral dosage forms include suspensions reconstituted from aqueous solutions, emulsions, suspensions, solutions and / or non-effervescent granules, and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms will optionally contain suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.

Pharmaceutically acceptable carriers suitable for the manufacture of unit dosage forms for oral administration are well known in the art. Tablets typically include conventional pharmaceutically acceptable adjuvants, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose, as inert diluents; Binders such as starch, gelatin and sucrose; Disintegrating agents such as starch, alginic acid and croscarmelose; And lubricants such as magnesium stearate, stearic acid and talc. A lubricant, such as silicon dioxide, can be used to improve the flow characteristics of the powder mixture. Colorants, such as FD & C dyes, may be added for appearance. Sweeteners and flavors, such as aspartame, saccharin, menthol, peppermint and fruit flavors. Capsules typically contain one or more of the solid diluents described above. The choice of carrier component depends on secondary considerations that are not essential to the purpose of the subject invention, such as taste, price and storage stability, and can be readily determined by one skilled in the art.

Oral compositions also include liquid solutions, emulsions, suspensions, and the like. Pharmaceutically acceptable carriers suitable for the manufacture of such compositions are well known in the art. Typical ingredients for carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, Avicel RC-591, tragacanth and sodium alginate; Typical wetting agents include lecithin and polysorbate 80; Typical preservatives include methyl paraben and sodium benzoate. Oral liquid compositions may also contain one or more ingredients such as the sweeteners, flavorings and coloring agents described above.

Such compositions may also be coated by conventional methods, typically with a pH or time-dependent coating, to allow the subject compound to be released from the gastrointestinal tract at various times, close to the desired topical application, or extending the desired action . Such dosage forms typically include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, ethylcellulose, Eudragit Coatings, waxes, and shellac, but is not limited thereto.

The compositions of the subject invention optionally comprise other drug active agents.

Other compositions useful for obtaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more soluble filler materials such as sucrose, sorbitol and mannitol; And binders such as acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose. Lubricants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.

The compositions of the present invention may also be administered topically to the subject, for example, by direct application or spreading of the composition to the epidermis or epithelial tissue of the subject, or percutaneously through a " patch ". Such compositions include, for example, lotions, creams, solutions, gels and solids. These topical compositions preferably contain a safe effective amount, generally about 0.1% or more, and preferably about 1% to about 5%, of a compound of formula (I). Suitable carriers for topical administration are preferably left on the skin as a continuous film and are resistant to being removed by sweating or submersion. In general, the carrier is organic in nature and can be dispersed or dissolved in the compound of formula (I). The carrier may include pharmaceutically acceptable softening agents, emulsifying agents, thickening agents, solvents, and the like.

VI. Method of administration :

The present invention also provides a method of treating a disease associated with excessive or undesirable metalloprotease activity in a human or other animal subject by administering a safe effective amount of a compound of formula I to said subject. As used herein, " a disorder associated with excessive or undesirable metalloprotease activity " is any disease characterized by the degradation of a matrix protein. The methods of the invention are useful for treating the diseases described above.

As shown, the compositions of the present invention may be administered topically or systemically. Systemic applications include any method of introducing a compound of Formula I into body tissues, including, but not limited to, intraarticular (especially rheumatoid arthritis treatment), intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, Sublingual, rectal and oral administration. The compounds of formula I of the invention are preferably administered orally.

The particular dose of the compound to be administered as well as the duration of treatment and the local or systemic involvement of the treatment are interdependent. The dosage and the therapeutic regimen may also vary depending on the particular compound of formula I used, the treatment instructions, the ability of the compound of formula I to reach the minimum inhibitory concentration in the place of the inhibitor metalloprotease, the individual attributes of the subject (e.g. body weight) And the presence and severity of any adverse side effects of treatment.

Typically, from about 5 mg to about 3000 mg, more preferably from about 5 mg to about 1000 mg, and more preferably from about 10 mg to about 100 mg, of a compound of Formula I, for a human adult (about 70 kg body weight) Is administered per day by systemic administration. It will be appreciated that such dosage ranges are merely exemplary and that daily administration can be adjusted according to the factors listed above.

A preferred method of administration for treatment of rheumatoid arthritis is parenteral administration via oral or intraarticular injection. As is known and practiced in the art, all formulations for parenteral administration should be sterile. For mammals, especially humans (estimated at about 70 kilograms of body weight), individual doses of about 10 mg to about 1000 mg are preferred.

A preferred method of systemic administration is oral administration. Separate doses of about 10 mg to about 1000 mg, preferably about 10 mg to about 300 mg, are preferred.

Topical administration can be used to systemically deliver a compound of formula I, or to treat a subject locally. The amount of the compound of formula I administered topically will depend on the skin sensitivity, the type and location of the tissue to be treated, the composition being administered and the carrier (if any), the particular compound of formula I being administered, And the degree to which the effect is required).

The compounds of the present invention can be targeted at specific locations where the metalloprotease has accumulated by using the targeting ligand. For example, in order to direct the compound to the metalloprotease contained in the tumor, the compound is conjugated to an antibody or fragment thereof immunoreactive to the tumor marker, as is generally understood in the production of general immunotoxins. The targeting ligand may also be a ligand suitable for a receptor present in the tumor. Any targeting ligand that specifically reacts with a marker for the intended target tissue may be used. Methods for coupling compounds of the present invention to a targeting ligand are well known and are analogous to coupling to the carrier described below. The conjugate is formulated and administered as described below.

For localized conditions, topical administration is preferred. For example, to treat ulcerated corneas, direct application to the diseased eye may use formulations such as eye drops or aerosols. For corneal treatment, the compounds of the present invention may also be formulated into gels, eyedrops, or ointments, or incorporated into collagen or hydrophilic polymeric shields. The material may also be inserted as a contact lens or reservoir, or as a subconjunctival formulation. For treatment of skin inflammation, the compound is topically and topically applied with a gel, paste or ointinent. For treatment of oral diseases, the compound can be applied locally with a gel, a paste, a mouthwash or an implant. The mode of treatment therefore reflects the nature of the condition, and suitable formulations for any selected route are available in the art.

In all of the above, of course, the compounds of the present invention may be administered alone or as a mixture, and the composition may additionally contain additional drugs or excipients appropriate for the directions.

Some of the compounds of the present invention also inhibit bacterial metalloproteases. While substantial differences are found between the diastereomers of inhibitors in their ability to inactivate mammalian proteases, some bacterial metalloproteases may be less dependent on the stereochemistry of the inhibitors. Thus, this mode of activity can be used to distinguish between mammalian enzymes and bacterial enzymes.

VII. Preparation and use of antibodies :

A metalloprotease that is active at a particular desired site (e.g., an organ or a specific type of cell) can be conjugated to a targeting ligand that is specific for a marker of its location, such as an antibody or its segment or receptor ligand Can be gated and targeted. Methods of conjugation are known in the art.

The present invention also relates to various other methods of utilizing the unique properties of these compounds. Accordingly, in another aspect, the invention relates to a compound of formula I that is conjugated to a solid support. Such a conjugate can be used as an affinity reagent for the purification of the desired metalloprotease.

In another aspect, the invention relates to a compound of formula (I) conjugated to a label. As the compounds of the present invention are bound to one or more metalloproteases, the labels can be used to detect the presence of a relatively high level of metalloprotease in vivo or in vitro cell culture.

In addition, the compounds of formula I can be conjugated to a carrier which allows these compounds to be used in immunization protocols to make antibodies specifically immunoreactive to the compounds of the invention. Typical conjugation methods are known in the art. Such antibodies are then useful for both therapeutic and inhibitory drug administration observations.

The compounds of the present invention may also be coupled to a label such as a sintigraphic marker, e. G., Technetium 99 or I-131, using standard coupling methods. The labeled compound is administered to a subject to measure the excessive location of one or more metalloproteases in vivo. The ability of inhibitors to selectively bind metalloprotease is thus used to generate an intrinsic distribution map of these enzymes. Techniques can also be used in methods of histology, and labeled compounds of the invention can be used in competitive immunoassays.

Non-limiting examples of the following sections VIII and IX illustrate the compounds, compositions and methods of the present invention.

VIII. Example-compound preparation

Typically, tetrahydrofuran (THF) was distilled from sodium and benzophenone, diisopropylamine was distilled from calcium hydride, and all other solvents were purchased in a suitable grade. Chromatography was suitably carried out on silica gel (70-230 mesh; Aldrich) or (230-400 mesh; Merk). Thin layer chromatography analysis (TLC) was performed on glass silica gel plates (200-300 mesh; Baker) and visualized with 5% phosphomolybdic acid in UV or ethanol (EtOH).

The following abbreviations are used in the text:

MeOH: methanol

EtOAc: ethyl acetate

Ph: phenyl

DMF: N, N-dimethylformamide

DME: Dimethoxyethane

conc .: concentration

DCC: 1,3-dicyclohexylcarbodiimide

Et ₃ N: Triethylamine

Et ₂ O: diethyl ether

boc: t-Butyloxycarbonyl

acac: acetyl acetate

dil .: dilution

wrt .: about with respect to

HOBT: 1-hydroxybenzotriazole

The R group used to illustrate the compound example is not correlated with the respective R group used to describe the various moieties of formula (I). That is, for example, in Section II of the overview section and the detailed description of the invention used to describe the general formula I R ^1, R ² and R ³ denote the same parts as in the section VIII of R _1, R ₂ and R ₃ It is not.

Example 1-3

The following chart shows the structure of the compounds prepared according to the description of Examples 1-3 described below:

Example 1

( 2R, 3S ) -2- (4'-methoxy-biphenyl-4-sulfonylamino) -3- (4-methyl-benzyloxy) -3-thiazol-2-yl-propionic acid.

a) 4- (Hydroxy-thiazol-2-yl-methyl) -2,2-dimethyl-oxazolidin-3-carboxylic acid tert-butyl ester. A solution of (S) -4-formyl-2,2-dimethyl-oxazolidin-3-carboxylic acid tert-butyl ester (4.86 g, 21.2 mmol) in dichloromethane (100 mL) , 2- (trimethylsilyl) thiazole (5.0 g, 31.8 mmol) in dichloromethane (30 mL) was added dropwise over 30 minutes. The resulting mixture was stirred at room temperature overnight. After removal of the solvent under reduced pressure, the mixture was treated with 1N tetrabutylammonium fluoride in THF (31.8 mL, 31.8 mmol). The resulting mixture was stirred at room temperature for 1 hour and then the solvent was removed under reduced pressure. The addition of saturated NaHCO ₃ solution, and the resulting mixture was extracted with EtOAc. The organic extracts were dried (Na ₂ SO ₄ ) and concentrated to an oil under reduced pressure. The product was purified by chromatography on silica gel using 8/2 hexane / EtOAc to give the desired product as a white solid.

b) 2,2-Dimethyl-4 - [(4-methyl-benzyloxy) -thiazol-2-yl-methyl] -oxazolidin-3-carboxylic acid tert-butyl ester. To a solution of 4- (hydroxy-thiazol-2-yl-methyl) -2,2-dimethyl-oxazolidin-3-carboxylic acid tert- butyl ester 1a (3.95 g, 12.6 mmol) in DME (100 mL) After stirring at room temperature, sodium hydride (0.55 g, 13.9 mmol, 1.1 eq.) Was added. The mixture was stirred at room temperature for 15 minutes and then 4-methylbenzylbromide (2.57 g, 13.9 mmol, 1.1 eq.) Was added. After the resulting mixture was stirred at room temperature overnight, the reaction was quenched by the addition of saturated NaHCO ₃ solution (20 mL). The mixture was poured into water and extracted with methylene chloride. The organic extracts were dried (Na ₂ SO ₄ ) and concentrated to an oil under reduced pressure. The oil was purified by chromatography on silica gel using 9/1 hexane / EtOAc as the eluent to give the desired product as a colorless oil.

c) ( 2S, 3S ) -2-Amino-3- (4-methyl-benzyloxy) -3-thiazol-2-yl-propan- To a solution of 2,2-dimethyl-4 - [(4-methyl-benzyloxy) -thiazol-2-yl-methyl] -oxazolidin-3-carboxylic acid tert- butyl ester 1b (5.05 g, 12.06 mmol) were stirred at room temperature and then Amberlyst 15 (10 g) was added. The resulting heterogeneous mixture was stirred at room temperature for 24 hours. The mixture was treated with triethylamine (30 mL) and stirred at room temperature for 1 hour. The resulting mixture was filtered through celite using methanol. The solvent was then removed to leave the desired product as a pale brown oil.

d) ( 2S, 3S ) -4-Bromo-N- [1 -hydroxymethyl-2- (4-methyl-benzyloxy) -2-thiazol-2-yl-ethyl] -benzenesulfonamide. Dioxane (40 mL) and water (40 mL) of (2S, 3S) -2- amino-3- (4-methyl-benzyloxy) -3-thiazol-2-yl-propan-1-ol 1c ( 3.05 g, 10.9 mmol) was stirred at room temperature followed by the addition of triethylamine (2.20 g, 21.8 mmol) followed by 4-bromobenzenesulfonyl chloride (3.06 g, 11.9 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was diluted with IN HCl and extracted with methylene chloride. The organic extracts were dried and concentrated to an oil under reduced pressure.

e) ( 2R, 3S ) -2- (4-Bromo-benzenesulfonylamino) -3- (4-methyl-benzyloxy) -3-thiazol-2-yl-propionic acid methyl ester. To a solution of ( 2S, 3S ) -4-bromo-N- [1-hydroxymethyl-2- (4- methyl- benzyloxy) -2-thiazol- Sulfonamide 1d (3.05 g, 6.13 mmol) was stirred at room temperature and Jones reagent (8N, 30 mL, excess) was slowly added. After the resulting mixture was stirred at room temperature for 3 hours, the reaction was quenched by the addition of isopropanol. After stirring the mixture for 30 minutes, a green precipitate formed. The solution was then filtered through celite using acetone. The filtrate was concentrated to an oil under reduced pressure. The oil was dissolved in methanol and an etheric solution of diazomethane was added. When excess diazomethane was added, the mixture became slightly yellow. The mixture was concentrated to a pale yellow solid. The solid was purified by chromatography on silica gel using 8/2 hexane / EtOAc as the eluent to give the product as a yellow solid.

f) ( 2R, 3S ) -2- (4'-Methoxy-biphenyl-4-sulfonylamino) -3- (4- methyl- benzyloxy) -3-thiazol-2- yl-propionic acid methyl ester . Yl ) -propionic acid methyl ester 1e (590 mg, 1.12 mmol) was added to a solution of ( 2R, 3S ) -2- (4- bromo-benzenesulfonylamino) -3- ) and 4-methoxyphenyl boronic acid (260 mg, 1.68 mmol) in 10 mL of benzene, 1.5 mL of EtOH and 1.5 mL of water, _{Pd (PPh 3) 4 (40} mg, 0.03 mmol) and 237 mg of Na taken under ₂ CO ₃ is present, the mixture was refluxed for 18 hours. The mixture was cooled to room temperature, poured into water and extracted with methylene chloride. The organic layer is dried over Na ₂ SO ₄ and, filtered and evaporated. The crude product was purified by silica gel chromatography using 6/4 hexane / EtOAc to give the desired product as a colorless oil.

g) ( 2R, 3S ) -2- (4'-Methoxy-biphenyl-4-sulfonylamino) -3- (4-methyl-benzyloxy) -3-thiazol-2-yl-propionic acid. (2R, 3S) -2- (4'- methoxy-biphenyl-4-sulfonyl) -3- (4-methyl-benzyloxy) -3-thiazol-2-yl-propionic acid methyl ester 1f ( 550 mg, 1.00 mmol) was dissolved in water / methanol / THF (5 mL / 5 mL / 5 mL) followed by lithium hydroxide (1 g, excess). The resulting mixture was stirred at room temperature overnight. After acidification of the reaction with 1N HCl, the product precipitated from solution to form a white powder. The product was filtered and the desired product was obtained as a white powder.

Example 2

( 2R, 3S ) -3- (4-methyl-benzyloxy) -2- (4'-methylsulfanyl-biphenyl-4-sulfonylamino) -3-thiazol-2-yl-propionic acid.

a) Synthesis of methyl ( 2R, 3S ) -3- (4-methyl-benzyloxy) -2- (4'- methylsulfanyl- biphenyl- 4- sulfonylamino) -3-thiazol- ester. Yl -propionic acid methyl ester 1e (660 mg, 1.26 mmol) was added to a solution of ( 2R, 3S ) -2- (4- bromo-benzenesulfonylamino) -3- ) and 4-methoxyphenyl boronic acid omega T (320 mg, 1.88 mmol) of Pd (PPh ₃₎ in 10 mL of benzene, 1.5 mL of EtOH and 1.5 mL of water, ₄ (44 mg, 0.03 mmol) and 267 mg of Taken in the presence of Na ₂ CO ₃ and refluxed for 4 hours. The mixture was cooled to room temperature, poured into water and extracted with methylene chloride. The organic layer is dried over Na ₂ SO ₄ and, filtered and evaporated. The crude product was purified by silica gel chromatography using 8/2 hexane / EtOAc to give the desired product as a colorless oil.

b) ( 2R, 3S ) -3- (4-Methyl-benzyloxy) -2- (4'-methylsulfanyl-biphenyl-4-sulfonylamino) -3-thiazol-2-yl-propionic acid. (2R, 3S) -3- (4- methyl-benzyloxy) -2- (4'-methylsulfanyl-biphenyl-4-sulfonyl) -3-thiazol-2-yl-propionic acid methyl ester 2a (500 mg, 0.88 mmol) was dissolved in water / methanol / THF (5 mL / 5 mL / 5 mL) and then lithium hydroxide (1 g, excess) was added. The resulting mixture was stirred at room temperature overnight. The reaction was acidified with 1N HCl and the product precipitated from solution. The product (345 mg) was obtained as a white powder.

Example 3

(2R, 3S) -3-benzothiazol-2-yl-3-methoxy-2- (4'-methoxy-biphenyl-4-sulfonylamino) -propionic acid.

a) 4- (Benzothiazol-2-yl-hydroxy-methyl) -2,2-dimethyl-oxazolidin-3-carboxylic acid tert-butyl ester. A solution of (S) -4-formyl-2,2-dimethyl-oxazolidin-3-carboxylic acid tert-butyl ester (7.37 g, 32.1 mmol) in dichloromethane (150 mL) , 2- (trimethylsilyl) benzothiazole (10.0 g, 48.2 mmol) in dichloromethane (30 mL) was added dropwise over 30 minutes. The resulting mixture was stirred at room temperature overnight. After removal of the solvent under reduced pressure, the mixture was treated with 1N tetrabutylammonium fluoride in THF (48 mL, 48 mmol). The resulting mixture was stirred at room temperature for 1 hour and then the solvent was removed under reduced pressure. The addition of saturated NaHCO ₃ solution, and the resulting mixture was extracted with EtOAc. After drying the organic extracts (Na ₂ SO _4), and concentrated to an oil under reduced pressure. The product was purified by chromatography on silica gel using 85/15 hexane / EtOAc to give the desired product as a white solid.

b) 4- (Benzothiazol-2-yl-methoxy-methyl) -2,2-dimethyl-oxazolidin-3-carboxylic acid tert-butyl ester. To a solution of 4- (benzothiazol-2-yl-hydroxy-methyl) -2,2-dimethyl-oxazolidine-3- carboxylic acid tert- butyl ester 3a (3.40 g, 9.30 mmol) in DME (75 mL) Was stirred at room temperature and sodium hydride (60%, 0.45 g, 11.2 mmol, 1.1 eq.) Was added. The mixture was stirred at room temperature for 15 minutes and then methyl iodide (1.45 g, 10.2 mmol, 1.1 eq.) Was added. The resulting mixture was stirred overnight at room temperature and then the reaction was quenched by the addition of saturated NaHCO ₃ solution (20 mL). The mixture was poured into water and extracted with methylene chloride. After drying the organic extracts (Na ₂ SO _4), and concentrated to an oil under reduced pressure. The oil was purified by chromatography on silica gel using 8/2 hexane / EtOAc as the eluent to give the desired product as a colorless oil.

c) ( 2S, 3S ) -2-Amino-3-benzothiazol-2-yl-3-methoxy-propan- To a solution of 4- (benzothiazol-2-yl-methoxy-methyl) -2,2-dimethyl-oxazolidin-3-carboxylic acid tert- butyl ester 3b (2.00 g, 5.28 mmol) in methanol (100 mL) Was stirred at room temperature and then Amberlyst 15 (5 g) was added. The resulting heterogeneous mixture was stirred at room temperature for 24 hours. The mixture was treated with triethylamine (25 mL) and stirred at room temperature for 1 hour. The resulting mixture was filtered through celite using methanol. The solvent was then removed to give the desired product as a pale brown oil.

d) ( 2S, 3S ) -N- (2-Benzothiazol-2-yl-1-hydroxymethyl-2-methoxy-ethyl) -4-bromo-benzenesulfonamide. Dioxane (20 mL) and water (20 mL) of (2S, 3S) -2- amino-3-benzothiazol-2-yl-3-methoxy-propan-1-ol 3c (1.0 g, 4.20 mmol ) Was stirred at room temperature and then triethylamine (0.85 g, 8.40 mmol) was added followed by 4-bromobenzenesulfonyl chloride (1.18 g, 4.6 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was diluted with 1N HCl and extracted with methylene chloride. The organic extracts were dried and concentrated to an oil under reduced pressure.

e) ( 2S, 3S ) -4'-Methoxy-biphenyl-4-sulfonic acid (2-benzothiazol-2-yl-1-hydroxymethyl-2-methoxy-ethyl) -amide. 4-bromo-benzenesulfonamide 3d (505 mg, 1.10 mmol) and ( 2S, 3S ) -N- (2-benzothiazol- 4-methoxyphenyl boronic acid (252 mg, 1.65 mmol) in 10 mL of benzene, 1.5 mL of EtOH and 1.5 mL of water, _{Pd (PPh 3) 4 (38} mg, 0.03 mmol) and 225 mg of Na ₂ CO ₃ and refluxed for 18 hours. The mixture was cooled to room temperature, poured into water and extracted with methylene chloride. The organic layer is dried over Na ₂ SO ₄ and, filtered and evaporated. The crude product was purified by silica gel chromatography using 6/4 hexane / EtOAc to give the desired product as a colorless oil.

f) ( 2R, 3S ) -3-Benzothiazol-2-yl-3-methoxy-2- (4'-methoxy-biphenyl-4-sulfonylamino) -propionic acid. Methoxy-biphenyl-4-sulfonic acid (2-benzothiazol-2-yl-1-hydroxymethyl-2-methoxy-ethyl) -amide 3e (400 mg) was stirred at room temperature and then Jones reagent (8N, 15 mL, excess) was slowly added. After the resulting mixture was stirred at room temperature for 3 hours, the reaction was quenched by the addition of isopropanol. Green precipitate formed after stirring the mixture for 30 minutes. The solution was then filtered through celite with acetone. The filtrate was concentrated to an oil under reduced pressure. The oil was dissolved in methanol and an etheric solution of diazomethane was added. When excess diazomethane was added, the mixture became slightly yellow. The mixture was concentrated to a pale yellow solid. The solid was purified by chromatography on silica gel using 8/2 hexane / EtOAc as the eluent to give the product as a white solid.

Examples 4-36

The following chart shows the structure of the compound prepared according to the description in Example 4-36 described below:

Example 4

( 2S, 3R ) -3-ethylsulfanyl-2- (4'-fluoro-biphenyl-4-sulfonylamino) -3-phenyl-

a) ( 2S, 3R ) -2-Amino-3-ethylsulfanyl-3-phenyl-propionic acid methyl ester. To a solution of methyl (2R, 3S) - (+) - 3-phenyl aziridine-2-carboxylate (30 mg, 1.70 mmol, prepared according to Letgers et Travaux Chimiques des Pays-Bas ) And ethanethiol (0.260 mL, 3.51 mmol) in dichloromethane (5 mL) was added boron trifluoride diethyl etherate (0.220 mL, 1.74 mmol). The mixture was stirred overnight at room temperature. Saturated aq. NaHCO ₃ was added to the reaction. The layers were separated and the aqueous layer was extracted with additional methylene chloride. Dry the combined organic extracts were Na ₂ SO _4, and filtered under reduced pressure, and concentrated. The crude product was purified by column chromatography (silica gel, 10-20% EtOAc / CH ₂ Cl ₂ ) to give the desired product as a pale yellow oil.

b) ( 2S, 3R ) -3-Ethylsulfanyl-2- (4'-fluoro-biphenyl-4-sulfonylamino) -3-phenyl-propionic acid methyl ester. To a solution of ( 2S, 3R ) -2-amino-3-ethylsulfanyl-3-phenyl-propionic acid methyl ester 4a (49 mg, 0.20 mmol) in methylene chloride (2.0 mL) was added triethylamine (0.060 mL, 0.43 mmol ) And 4'-fluoro-4-biphenylsulfonyl chloride (66 mg, 0.24 mmol). The mixture was stirred at room temperature overnight under argon. The reaction was diluted with methylene chloride and washed with 1.0 N aq. Lt; / RTI > The aqueous layer was extracted with methylene chloride. And drying the combined organic layers with Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 20% EtOAc / hexanes) to give the desired product.

c) ( 2S, 3R ) -3-Ethylsulfanyl-2- (4'-fluoro-biphenyl-4-sulfonylamino) -3-phenyl-propionic acid. Pyridine (3 mL) of (2S, 3R) -3-ethylsulfanyl-2- (4'-fluoro-biphenyl-4-sulfonyl) -3-phenyl-propionic acid methyl ester 4b (28 mg, 0.059 mmol) and lithium iodide (105 mg, 0.785 mmol) was stirred under argon overnight. The mixture was cooled to room temperature and extracted with ethyl acetate and 1.0 N aq. HCl. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by reversed phase preparative HPLC (gradient eluent 0.1% aq. Trifluoroacetic acid / acetonitrile) to give the desired product as a pale orange solid.

Example 5

( 2S, 3R ) -3-ethylthio-2 - [(4'-methoxy [1,1'-biphenyl] -4-yl) sulfonyl] amino) -3-phenyl-propionic acid.

a) Methyl ( 2S, 3R ) -3-ethylthio-2 - [(4-iodophenyl) sulfonyl] amino) -3-phenyl-propanoate. To a solution of methyl ( 2S, 3R ) -2-amino-3-ethylthio-3-phenyl-propionate 4a (248 mg, 1.04 mmol) in methylene chloride was added triethylamine (0.290 mL, 2.08 mmol) . The mixture was cooled to 0 C and treated dropwise with a solution of pipsyl chloride (378 mg, 1.25 mmol) in methylene chloride (1 mL). The mixture was warmed to 0 <Lt; / RTI > The mixture was diluted with methylene chloride and washed with 1.0 N aq. Lt; / RTI > The aqueous layer was extracted with methylene chloride. Dry the combined organic extracts were Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 15% EtOAc / hexanes) to give the desired product.

b) Synthesis of methyl ( 2S, 3R ) -3-ethylthio-2 - [(4'-methoxy [1,1'-biphenyl] -4- yl) sulfonyl] amino) -3-phenyl-propionate . To a solution of methyl ( 2S, 3R ) -3-ethylthio-2 - [(4-iodophenyl] sulfonyl] amino) -3-phenyl- propanoate 5a (376 mg, 0.744 mmol) in benzene Was added to a solution of sodium carbonate (158 mg, 1.49 mmol), water (0.75 mL), tetrakis (triphenylphosphine) palladium (0) (25 mg, 0.202 mmol) -Methoxyphenylboronic < / RTI > acid (166 mg, 1.09 mmol). The mixture was refluxed under argon for 24 hours. The mixture was cooled to room temperature, treated with 35 wt% hydrogen peroxide (0.300 mL) and stirred for 0.25 h. The reaction was diluted with water and extracted three times with diethyl ether. The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 15-30% EtOAc / hexanes) to give the desired product as a pale yellow solid.

c) ( 2S, 3R ) -3-ethylthio-2 - [(4'-methoxy [1,1'-biphenyl] -4-yl) sulfonyl] amino) -3-phenyl-propionic acid. The title compound was prepared from 5b using ester hydrolysis conditions analogous to the preparation of example 4.

Examples 6-36

Example 6-36 was prepared from the corresponding thiol and S2e using the procedure described for Example 4 or 5. [

Example 37

( 2S, 3R ) -3-Ethylsulfanyl-2- [5- (4-methoxy-phenyl) -thiophene-2-sulfonylamino] -3-phenyl-propionic acid. This compound was prepared according to the procedure described in Example 5 using 5-bromothiophenylsulfonyl chloride instead of pipsyl chloride.

Example 38

( 2S, 3R ) -3-Ethylsulfanyl-2- [4- (4-methoxy-phenylethynyl) -benzenesulfonylamino] -3-phenyl-propionic acid. This compound was prepared according to the procedure described in Example 5 using 4-methoxyphenylacetyleneboronic acid instead of 4-methoxyphenylboronic acid.

Example 39

( 2S, 3R ) -3-Ethylsulfanyl-2- [4- (4-methoxy-benzoylamino) -benzenesulfonylamino] -3-phenyl-propionic acid. This compound was prepared according to the method described in Example 5, substituting 4-nitrobenzenesulfonyl chloride for piptyl chloride, followed by 1) reduction of the nitro group with tin (II) chloride and 2) amidation with 4-methoxybenzoyl chloride ≪ / RTI >

Examples 40-43

The following chart shows the structure of the compounds prepared according to the description of Examples 40-43 described below:

Examples 40-43

Examples 40-43 were prepared from the methyl (2S, 3R) - (-) - 3-phenyl aziridine-2-carboxylate using the procedure described in Example 4 or 5.

Examples 44-68

The following chart shows the structure of the compounds prepared according to the description of Examples 44-48 described below:

Example 44

( 2R, 3S ) -4-Benzyloxy-3-hydroxy-2- (4'-methoxy-biphenyl-4-sulfonylamino) -butyric acid.

(a) 4 ( S ) -Benzyl-3 - [( 2S, 3R ) -4-benzyloxy-2-bromo-3-hydroxy-butyryl] -oxazolidin-2-one. To a solution of 4 ( S ) -benzyl-3- (2-bromo-acetyl) -oxazolidin-2-one (1.621 g, 5.43 mmol, prepared as described previously (J. Am. Chem. Soc. 1986, 108, 4595)) the solution was cooled to -78 ℃, triethylamine (770 mg, 7.61 mmol) followed by dibutyl boron triflate (1.84 g, 5.98 mmol) was added. The cooling bath was removed and the reaction mixture was stirred for 2.5 hours. The reaction mixture was cooled to -78 ° C, benzyloxyacetaldehyde (898 mg, 5.98 mmol) was added and after stirring for 10 minutes, the mixture was warmed to 0 ° C. and stirred for 3 hours. The reaction mixture was diluted with ether, washed with 1N aq KHSO ₄ and the solvent was removed under vacuum. The residue was dissolved in methanol (10 mL), cooled to 0 C and 30% hydrogen peroxide (5 mL) was added. The cooling bath was removed and the mixture was stirred at room temperature for 2 hours. Saturated aq. It was added to NaHCO ₃ and methylene chloride to the reaction mixture. The layers were separated and the aqueous layer was extracted with additional methylene chloride. The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 1% MeOH / CH ₂ Cl ₂ ) to give the desired product as a pale yellow oil.

(b) 4 ( S ) -3 - [( 2R, 3S ) -2-Azido-4-benzyloxy-3-hydroxy-butyryl] -4-benzyl-oxazolidin- To a solution of 4 ( S ) -benzyl-3 - [( 2S, 3R ) -4-benzyloxy-2-bromo-3-hydroxy-butyryl] -oxazolidin- (969 mg, 2.16 mmol) in dichloromethane (5 mL) was added sodium azide (211 mg, 3.25 mmol) and the reaction mixture was stirred at 35 < 0 > C for 4 h. The mixture was diluted with ethyl acetate, washed several times with water, brine, dried over Na ₂ SO _4. Filtration and solvent removal under vacuum afforded 4 ( S ) -3 - [( 2R, 3S ) -2-azido-4-benzyloxy-3-hydroxy-butyryl)] - 4-benzyl-oxazolidin- -One as an oil.

(c) ( 2R, 3S ) -2-Azido-4-benzyloxy-3-hydroxy-butyric acid. To a solution of 4 ( S ) -3 - [( 2R, 3S ) -2-azido-4-benzyloxy-3-hydroxypyridine in dioxane-water (3.5 mL, 6: 1, v / To a solution of lithium hydroxide hydrate (113 mg, 2.7 mmol) in water (1.5 mL) was added a solution of the reaction mixture < RTI ID = 0.0 & Was stirred at room temperature for 2 hours. Then, a 1N hydrogen chloride (4 mL) solution was added, and the solvent was removed under reduced pressure. The residue was dissolved in methylene chloride and washing the organic phase with water, brine and dried over Na ₂ SO _4. Filtration under vacuum and solvent removal yielded ( 2R, 3S ) -2-azido-4-benzyloxy-3-hydroxy-butyric acid as a thick oil.

(d) ( 2R, 3S ) -4-Benzyloxy-3-hydroxy-2- (4'-methoxy-biphenyl-4-sulfonylamino) -butyric acid. To a solution of ( 2R, 3S ) -2-azido-4-benzyloxy-3-hydroxy-butyric acid (50 mg) in methanol (1 mL) was added tin (II) chloride (60 mg) And the mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo and the residue was dissolved in dioxane-water (1.6 mL, 1: 1, v / v). To the mixture was added triethylamine (0.1 mL) and (4'-methoxy [1,1'-biphenyl] -4-yl) sulfonyl chloride (110 mg) and the mixture was stirred at room temperature for 10 hours . The volatiles were removed in vacuo and the residue was treated with methanol (3 mL) and acetic acid (1 mL). The precipitate was filtered off and the filtrate was concentrated and the crude product was purified using RF HPLC to give ( 2R, 3S ) -4-benzyloxy-3-hydroxy-2- (4'-methoxy- -4-sulfonylamino) -butyric acid as a white, crystalline solid.

Examples 45-68

Examples 45-68 were prepared using the corresponding aldehyde and S3a according to the procedure described in Example 44. MS

IX. Examples - Compositions and Methods of Use

The compounds of the present invention are useful for preparing compositions for the treatment of diseases associated with undesirable MP activity. EXAMPLES The following compositions and methods are not intended to limit the invention, but are intended to provide those skilled in the art with guidance in making and using the compounds, compositions and methods of the present invention. In each case, other compounds within the scope of the present invention may be substituted with the exemplary compounds shown below to provide substantially similar results. Skilled artisans will appreciate that the embodiment provides guidance and can be varied based on the condition being treated and the patient.

The following abbreviations are used:

EDTA: Ethylenediamine tetraacetic acid

SDA: synthetically modified alcohol

USP: United States Pharmacopoeia

Example A

A tablet composition for oral administration according to the present invention comprising:

ingredient amount

15 mg of the compound of Example 1

Lactose 120 mg

Maize starch 70 mg

Talc 4 mg

Magnesium Stewart 1 mg

A human female subject of 60 kg (132 lbs) with rheumatoid arthritis was treated by the method of the present invention. Specifically, for two years, three daily regimens were administered orally to the subject.

At the end of the treatment period, the patient was found to have reduced inflammation and improved mobility with no pain.

Example B

A capsule for oral administration according to the present invention containing the following was prepared:

Ingredient Amount (% w / w)

Compound of Example 4 15%

Polyethylene glycol 85%

A 90 kg (198 lbs.) Human male subject with osteoarthritis was treated by the method of the present invention. Specifically, for 5 years, the capsules containing 70 mg of the compound of Example 4 were administered daily to the subject.

At the end of the treatment period, the patient was examined by x-ray, arthroscopy and / or MRI and found that the erosion / fibrillation of articular cartilage had not progressed any further.

Example C

A salt-based composition for topical administration according to the present invention comprising:

Ingredient Amount (% w / w)

The compound of Example 7, 5%

Polyvinyl alcohol 15%

Salt water 80%

The composition was dispensed twice daily in each eye of patients with severe corneal abrasions. Without visible sequelae, healing was accelerated.

Example D

A topical composition for topical administration according to the present invention comprising:

ingredient Composition (% w / v)

The compound of Example 9, 0.20

Benzalkonium chloride 0.02

Thimerosal 0.002

d-sorbitol 5.00

Glycine 0.35

Fragrance 0.075

Purified water Suitable amount

Total amount 100.00

The patient was subjected to chemical burn at each dressing change (b.i.d.). Scar formation was substantially reduced.

Example E

An inhalation aerosol composition, according to the present invention, comprising:

ingredient Composition (% w / v)

Compound of Example 13 5.0

Alcohol 33.0

Ascorbic acid 0.1

Menthol 0.1

Sodium saccharin 0.2

Injectors (F12, Fl14) Suitable amount

Total amount 100.0

The asthmatic patient injected 0.01 mL of the composition into the mouth during the inhalation via the pump device. Asthma symptoms decreased.

Example F

A topical eye composition, according to the present invention, comprising:

ingredient Composition (% w / v)

Compound of Example 16 0.10

Benzalkonium chloride 0.01

EDTA 0.05

Hydroxyethylcellulose (NATROSOL M) 0.50

Sodium metabisulfite 0.10

Sodium chloride (0.9%) Suitable amount

Total amount 100.0

A human male subject of 90 kg (198 lbs), suffering from corneal ulcerations, was treated by the method of the present invention. Specifically, for 2 months, a saline solution containing 10 mg of the compound of Example 16 was administered twice a day to the eye with the subject's disease.

Example G

A composition for parenteral administration was prepared containing:

ingredient amount

Compound of Example 12 100 mg / mL carrier

carrier:

Sodium citrate buffer (weight% in the carrier) containing:

Lecithin 0.48%

Carboxymethylcellulose 0.53

Povidone 0.50

Methyl paraben 0.11

Propyl paraben 0.011

The ingredients are mixed to form a suspension. Approximately 2.0 mL of the suspension was administered by injection to human subjects with untransfected tumors. The site of injection was parallel to the tumor. This dose was repeated twice daily for about 30 days. After 30 days, symptoms of the illness subsided and the dosage to maintain the patient gradually decreased.

Example H

Oral cleaning compositions were prepared:

ingredient % w / v

Compound 14 of Example 14

SDA 40 Alcohol 8.0

Flavor 0.08

Emulsifier 0.08

Sodium fluoride 0.05

Glycerin 10.0

Sweetener 0. O2

Benzoic acid 0.05

Sodium hydroxide 0.20

Dye 0.04

Fit to 100% water

Patients with gum disease used 1 mL of mouthwash three times a day to prevent further mouth degeneration.

Example I

A lozenge composition was prepared:

ingredient % w / v

Compound of Example 35 0.01

Sorbitol 17.50

Mannitol 17.50

Starch 13.60

Sweetener 1.20

Flavor 11.70

Colorant 0.10

Fit corn syrup to 100%

The patient used the lozenge to prevent loosening of the maxillary implant.

Example J

A chewing gum composition was prepared containing:

ingredient w / v%

Compound of Example 55 0.03

Sorbitol crystal 38.44

Paloja-T Sword Base 20.0

Sorbitol (70% aqueous solution) 22.0

Mannitol 10.0

Glycerin 7.56

Flavor 1.0

The patient chewed the sword and prevented the dentures from loosening.

Example K

ingredient w / v%

Compound of Example 28 4.0

USP number 50.656

Methyl paraben 0.05

Propyl paraben 0.01

Xanthan gum 0.12

Guar Gum 0.09

Calcium carbonate 12.38

Foam inhibitor 1.27

Sucross 15.0

Sorbitol 11.0

Glycerin 5.0

Benzyl alcohol 0.2

Citric acid 0.15

Coolant 0.00888

Flavor 0.0645

Colorant 0.0014

The composition was prepared by first mixing 80 kg of glycerin and benzyl alcohol and heating to 65 DEG C and then slowly adding and mixing methylparaben, propylparaben, water, xanthan gum and guar gum. These ingredients were mixed in a Silverson in-line mixer for about 12 minutes. The following ingredients were then added in the following order: residual glycerin, sorbitol, foam inhibitor C, calcium carbonate, citric acid and sucrose. The flavor and coolant were mixed separately and then slowly added to the other ingredients. The mixture was mixed for about 40 minutes. The patient ingested the formulation and prevented recurrence of colitis.

Example L

The capsules described in Example B were administered to a human female subject of obesity who was thought to be susceptible to osteoarthritis to prevent the symptoms of osteoarthritis. Specifically, the capsules were daily administered to the subjects.

Patients were examined using x-ray, arthroscopy and / or MRI to find that there was no significant progression of erosion / fibrillation of articular cartilage.

Example M

90 kg (198 lbs.) Human male subjects with sports injuries were administered the capsules described in Example B to prevent symptoms of osteoarthritis. Specifically, the capsules were daily administered to the subjects.

Patients were examined using x-ray, arthroscopy and / or MRI to find that there was no significant progression of erosion / fibrillation of articular cartilage.

All references cited in the text are incorporated by reference.

Although specific embodiments of the subject invention have been described, it will be apparent to those skilled in the art that various changes and modifications of the subject invention may be made without departing from the spirit and scope of the invention. It is intended by the appended claims to cover all such modifications that fall within the scope of the invention.

Claims (13)

A compound having the structure of an optical isomer, diastereoisomer or enantiomer of the formula (I) or (I), or a pharmaceutically acceptable salt thereof, or a biodegradable amide, ester or imide: (I) [Wherein: (A) R ¹ is selected from -OH and -NHOH; (B) R ² is selected from hydrogen, hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and halogen ; (C) R ³ is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; (D) R ⁴ is - (CR ⁷ R ⁷ ) _k -X- (CR ⁸ R ⁸ ) ₁ -EA, wherein: (1) k is from 0 to about 4; (2) l is from 0 to about 4; ^{(3) R 7, k 7} ', R 8 and R ^8' are present in time, each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, and Haloalkyl; (4) X is -O-, -S-, -S (O) -, -S (O 2) -, -N (R 9) -, -N (COR 9) -, -N (CO 2 R ^{9) -, -N (CONR 9} R 9 ') - and -N (SO ₂ R ⁹⁾ - is selected from, where, (i) R ⁹ and R ^9' are each, when present, are independently hydrogen, Alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or (ii) R ⁹ and R ^{9 '} Together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; (5) E is a covalent bond, -O-, -S-, -S (O ) -, -S (O 2) -, -N (R 10) -, N (COR 10) -, -N (CO ₂ R ¹⁰ ) -, -N (CONR ¹⁰ R ^{10 '} ) - and -N (SO ₂ R ¹⁰ ) -, wherein each of R ¹⁰ and R ^10' , when present, (Ii) R ¹⁰ and R ^{10 '} are independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl; Together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; Provided that when l = 0, E is a covalent bond; (6) A is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or (b) A, together with R ⁷ , R ^{7 '} , R ⁸ , R ^8' , R ⁹ , R ^{9 '} , R ¹⁰ or R ^10' , is a 5- to 8-membered ring having 1 to 3 heteroatoms To form an optionally substituted heterocyclic ring; (E) R ⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; (F) R ⁶ is alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and hydroxyl chamber is selected from; Provided that when k > 0, R ⁶ is -OH, and when k = 0, R ⁶ is not -OH; (G) G is ^{-S-, -O-, -N (R 11} ) -, -C (R 11) = C (R 11 ') -, -N = C (R 11) - and -N = N -, wherein each R ¹¹ and R ^{11 '} , 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 ¹² R ^{12 '} ) _a -R ¹³ (Wherein: (a) a is from 0 to about 4; (b) L is -C≡C-, -CH = CH-, -N = N-, -O-, -S- and -SO ₂ - is selected from; (c) R ¹² and R ¹² , when present, are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, And alkoxy; (d) R ¹³ is selected from hydrogen, aryl, heteroaryl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, heterocycloalkyl and cycloalkyl; R ¹³ can also be selected from -CON (R ¹⁴ R ^{14 '} ), provided that when L is -C = C- or -CH = CH-, then (i) R ¹⁴ and R ^14' Alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, or (ii) R ¹⁴ and R ^{14 '} , together with the nitrogen atom to which they are attached, Form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; (3) -NR ¹⁵ R ^{15 '} (Wherein: (a) R ¹⁵ and R ^{15 '} are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heteroalkyl and -C ¹⁶ R ^{16 '} ) _b -R ¹⁷ (Wherein: (i) b is from 0 to about 4; (ii) Q is a covalent bond and -N (R ¹⁸⁾ - is selected from; (iii) each of R ¹⁶ and R ^{16 '} , when present, is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, Alkoxy; R ¹⁷ and R ¹⁸ each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, or R ¹⁷ and R ¹⁸ are, they are bound Together with the atoms to which they are attached form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; Or R < ¹⁵ > and R < ¹⁸ > together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms wherein 2 to 3 are heteroatoms; or (b) R ¹⁵ and R ^{15 '} together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; (4) (Wherein: (a) E 'and M' are independently selected from -CH- and -N-; (b) L 'is ^{-S-, -O-, -N (R 20} ) -, -C (R 20) = C (R 20') -, N = C (R 20) - and -N = N -, wherein R ²⁰ and R ^{20 '} , when present, are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; (c) c is from 0 to about 4; (d) R ¹⁹ and R ^{19 '} , when present, are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, Alkoxy; (e) A 'is a covalent _{bond, -O-, -SO d -, -C} (O) -, C (O) N (R 21) -, -N (R 21) - and -N (R ²¹⁾ C (O) -; Wherein d is 0 to 2 and R ²¹ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkyl; (f) G 'is - (CR ²² R ^22' ) _e -R ²³ wherein e is from 0 to about 4; R ²² and R ^{22 '} , when present, are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, alkoxy and aryl ≪ / RTI > R ²³ is selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl; Or R ²¹ and R ²³ together with the atoms to which they are attached form an optionally substituted heterocyclic ring containing from 5 to 8 atoms of which from 1 to 3 are heteroatoms; Or R < ²⁰ > and R < ²³ > together with the atoms to which they are attached form an optionally substituted heterocyclic ring containing from 5 to 8 atoms in which from 1 to 3 are heteroatoms. The compound of claim 1, wherein R ¹ is -OH and R ² , R ^3, and R ⁵ are independently selected from hydrogen, lower alkyl, arylalkyl, and heteroarylalkyl. 3. The compound according to claim 1 or 2, wherein k = 0; R < ⁶ > is aryl or lower alkyl; X is selected from O, S, -N (SO ₂ R ¹⁰ ) -, -N (COR ¹⁰ ) - and N (CO ₂ R ¹⁰ ) - (preferably X is -S-) R < ¹⁰ > is lower alkyl or aryl; l = 0, 1 or 2; E is selected from a covalent bond, -O- and -S-; A is selected from lower alkyl, aryl and heteroaryl. 3. The compound according to claim 1 or 2, wherein k = 1, 2 or 3; R < ⁶ > is -OH; X is _{-O-, -S-, -N (SO 2} R 9) -, -N (COR 9) - and -N (CO ₂ R ⁹⁾ - is selected from (X is preferably -O- or -S-, wherein R < ⁹ > is lower alkyl or aryl; l = 0, 1 or 2; E is a covalent bond, -O-, -S-, -N (COR 10) -, -N (CO 2 R 10) -, -N (CONR 10 R 10 ') - and -N (SO ₂ R ¹⁰⁾ - selected from; A is selected from lower alkyl, aryl and heteroaryl. 5. The compound according to any one of claims 1 to 4, wherein E is selected from a covalent bond, -O- and -S-. The method according to any one of claims 1 to 5, wherein, G is selected from -S-, and -CH = CH-, Z is ^{-L- (CR 12 R 12 ')} a R 13; -NR ¹⁵ R ^{15 '} ; And ≪ / RTI > The method according to any one of claims 1 to 6, Z is ^{-L- (CR 12 R 12 ')} a R 13 , and where, L is -C≡C-, -C = C- and -N = N-; a is 0; R < ¹³ > is selected from aryl, heteroaryl, heterocycloalkyl and cycloalkyl. 8. Compounds according to any one of claims 1 to 7, wherein Z is -NR ¹⁵ R ^{15 '} , wherein R ¹⁵ is hydrogen and R ^15' is -C (O) -Q- (CR ¹⁶ R ^{16 '} ) _b R ^17, and Q is a covalent bond, and herein, and b is 0, R ¹⁷ is a compound selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl. 9. Compounds of formula I according to any one of claims 1 to 8, wherein Z is , Wherein E 'and M' are both -CH-; c is 0; L 'is -HC = CH-. A compound selected from the group consisting of: ( 2R, 3S ) -2- (4'-methoxy-biphenyl-4-sulfonylamino) -3- ( 2R, 3S ) -2- (4'-Methylsulfanyl-biphenyl-4-sulfonylamino) -3- (2R, 3S) -3-benzothiazol-2-yl-3-methoxy-2- (4'-methoxy-biphenyl-4-sulfonyl-amino) -propionic acid, ( 2S, 3R ) -3-ethylsulfanyl-2- (4'-fluoro-biphenyl-4-sulfonylamino) ( 2S, 3R ) -3-ethylsulfanyl-2- (4'-methoxy-biphenyl-4- sulfonylamino) ( 2S, 3R ) -2- (4'-methoxy-biphenyl-4-sulfonylamino) -3-methylsulfanyl- ( 2S, 3R ) -2- (4'-methoxy-biphenyl-4-sulfonylamino) -3-phenyl-3-phenylsulfanyl- ( 2S, 3R ) -2- (4'-Bromo-biphenyl-4-sulfonylamino) -3-phenyl-3- (pyridin- ( 2S, 3R ) -2- (4'-Bromo-biphenyl-4-sulfonylamino) -3-phenyl-3- (pyrimidin- ( 2S, 3R ) -3- (4-fluoro-phenylsulfanyl) -2- (4'- methoxy- biphenyl- 4- sulfonylamino) -3-phenyl- ( 2S, 3R ) -2- (4'-methoxy-biphenyl-4-sulfonylamino) -3-phenyl-3- (thiazol- ( 2S, 3R ) -2- (4'-methoxy-biphenyl-4-sulfonylamino) -3- ( 2S, 3R ) -2- (4'-chloro-biphenyl-4-sulfonylamino) -3- (oxazol- ( 2S, 3R ) -2- (4'-methylsulfanyl-biphenyl-4-sulfonylamino) -3- -3-phenyl-propionic acid, ( 2S, 3R ) -2- (4'-methoxy-biphenyl-4-sulfonylamino) -3- 3-phenyl-propionic acid, ( 2S, 3R ) -2- [benzyl- (4'-methoxy-biphenyl-4-sulfonyl) -amino] ( 2S, 3R ) -3-benzylsulfanyl-2- (biphenyl-4-sulfonylamino) -3-phenyl- ( 2S, 3R ) -3-benzylsulfanyl-2- (4'-methoxy-biphenyl-4-sulfonylamino) ( 2S, 3R ) -2- (biphenyl-4-sulfonylamino) -3-phenethylsulfanyl-3-phenyl- ( 2S, 3R ) -3- (4-methyl-benzylsulfanyl) -3-phenyl-2- (4'-trifluoromethyl- (2S, 3R) -3- (4- methoxy-benzyl-sulfanyl) -2- (4'-methyl-biphenyl-4-sulfonyl) -3-phenyl-propionic acid, ( 2S, 3R ) -3- (4-Fluoro-benzylsulfanyl) -2- (4'- methoxy- biphenyl- 4- sulfonylamino) -3-phenyl- ( 2S , 3R ) -3- (2,4-Difluoro-benzylsulfanyl) -2- (4'- methoxy- biphenyl- 4- sulfonylamino) -3-phenyl- ( 2S, 3R ) -2- (4'-Methylsulfanyl-biphenyl-4-sulfonylamino) -3-phenyl-3- (pyridin- 4- ylmethylsulfanyl) ( 2S, 3R ) -2 - [(4'-methoxy-biphenyl-4- ( 2S, 3R ) -2- (4'-methoxy-biphenyl-4-sulfonylamino) -3-phenyl-3- (pyridin- 2- ylmethylsulfanyl) ( 2S, 3R ) -2- (4'-methoxy-biphenyl-4-sulfonylamino) -3- (5-methyl- oxazol- 2- ylmethylsulfanyl) ( 2S, 3R ) -3- (benzothiazol-2-ylsulfanyl) -2- (4'- methoxy- biphenyl- 4- sulfonylamino) -3-phenyl- ( 2S, 3R ) -3- (2-tert-butoxycarbonylamino-ethylsulfanyl) -2- (4'- methoxy- biphenyl- 4- sulfonylamino) ( 2S, 3R ) -3- (2-Acetylamino-ethylsulfanyl) -2- (4'- methoxy- biphenyl- 4- sulfonylamino) -3-phenyl- ( 2S, 3R ) -3- [2- (Methanesulfonyl-pyridin-3-yl-amino) -ethylsulfanyl] -2- (4'-methoxy- -Phenyl-propionic acid, ( 2S, 3R ) -2- (4'-Bromo-biphenyl-4-sulfonylamino) -3- [2- (methanesulfonyl- -Phenyl-propionic acid, ( 2S, 3R ) -3- (2-benzyloxy-ethylsulfanyl) -2- (4'- methoxy- biphenyl- 4- sulfonylamino) -3-phenyl- ( 2S, 3R ) -2- (4'-Bromo-biphenyl-4-sulfonylamino) -3- (2- phenoxy- ethylsulfanyl) ( 2S, 3R ) -2- (4'-methoxy-biphenyl-4-sulfonylamino) -3- (2- phenoxy- ethylsulfanyl) ( 2S, 3R ) -3- [2- (4-Fluoro-phenoxy) -ethylsulfanyl] - propionic acid, ( 2S, 3R ) -3-Ethylsulfanyl-2- [5- (4-methoxy- phenyl) ( 2S, 3R ) -3-ethylsulfanyl-2- [4- (4-methoxy- phenylethynyl) -benzenesulfonylamino] ( 2S, 3R ) -3-ethylsulfanyl-2- [4- (4-methoxy-benzoylamino) -benzenesulfonylamino] ( 2R, 3S ) -2- (4'-methoxy-biphenyl-4-sulfonylamino) -3-methylsulfanyl- ( 2R, 3S ) -3-ethylsulfanyl-2- (4'-methoxy-biphenyl-4-sulfonylamino) ( 2R, 3S ) -2- (4'-methoxy-biphenyl-4-sulfonylamino) -3-phenyl-3-phenylsulfanyl- ( 2R, 3S ) -3-benzylsulfanyl-2- (4'-methoxy-biphenyl-4-sulfonylamino) ( 2R, 3S ) -4-benzyloxy-3-hydroxy-2- (4'- methoxy- biphenyl- 4- sulfonylamino) ( 2R, 3S ) -3-hydroxy-2- (4'-methoxy-biphenyl4- sulfonylamino) -4-phenoxy- butyric acid, ( 2R, 3S ) -4-Benzyloxy-2- (biphenyl-4-sulfonylamino) -3-hydroxy- butyric acid, ( 2R, 3R ) -3-hydroxy-2- (4'-methoxy-biphenyl-4-sulfonylamino) -5- ( 2R, 3R ) -3-hydroxy-2- (4'-methoxy-biphenyl-4-sulfonylamino) -5- (pyridin- 3- yloxy) -pentanoic acid, ( 2R, 3S ) -3-hydroxy-2- (4'-methoxy-biphenyl-4-sulfonylamino) -4- (thiazol- ( 2R, 3S ) -4- (4-fluoro-benzylsulfanyl) -3-hydroxy-2- (4'- methoxy- biphenyl- 4- sulfonylamino) (2 R, 3 S) -3- hydroxy-2- (4'-methoxy-biphenyl-4-sulfonyl) -4- (1-methyl -1H- imidazol-2-ylsulfanyl) - Butyric acid, (1-methyl-1H-imidazol-2-ylsulfanyl) -hexanoic acid was prepared in analogy to the procedure described for the synthesis of ( 2R, 3R ) -3- , ( 2R, 3S ) -3-hydroxy-2- (4'-methoxy-biphenyl-4- sulfonylamino) -4- ( 2R, 3R ) -3-hydroxy-2- (4'-methoxy-biphenyl-4-sulfonylamino) -5- Trifluoromethyl-phenyl) -pentanoic acid, ( 2R, 3S ) -4- (benzooxazol-2-ylsulfanyl) -3-hydroxy-2- (4'- methoxy- biphenyl- 4- sulfonylamino) ( 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- ( 2R, 3S ) -4- (3,3-dimethyl-butoxy) -3-hydroxy-2- (4'- methoxy- biphenyl- 4- sulfonylamino) (2R, 3S) -3- hydroxy-2- (4'-methoxy-biphenyl-4-sulfonyl) -4- (3-methyl-butoxy) butyric acid, ( 2R, 3S ) -3-hydroxy-4- (2-isopropoxy-ethoxy) -2- (4'- methoxy- biphenyl- 4- sulfonylamino) ( 2R, 3S ) -3-hydroxy-4- (2-isopropoxy-ethoxy) -2- (4'- methylsulfanyl- biphenyl- 4- sulfonylamino) ( 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) ( 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) (4-methoxy-biphenyl-4-sulfonylamino) -pentanoic acid and ( 2R, 3R ) -3-hydroxy-5- (methanesulfonyl-pyridin- ( 2R, 3R ) -4- (2-tert-butoxycarbonylamino-ethoxy) -3-hydroxy-2- (4'-methoxy-biphenyl-4-sulfonylamino) -butyric acid. A pharmaceutical composition comprising: (a) a safe effective amount of a compound according to any one of claims 1 to 10; And (b) a pharmaceutically acceptable carrier. Wherein the disease is selected from the group consisting of arthritis, cancer, cardiovascular disease, skin disease, eye disease, inflammation and gum disease, wherein the mammal in need of such treatment is administered a safe effective amount Comprising administering a compound according to any one of claims 1 to 10. 13. The method of claim 12, wherein the disease is selected from the group consisting of (i) arthritis selected from the group consisting of osteoarthritis and rheumatoid arthritis; (ii) cancer that prevents or inhibits tumor growth and metastasis by treatment; Or (iii) a cardiovascular disease selected from the group consisting of dilated cardiomyopathy, congestive heart failure, atherosclerosis, plaque rupture, reperfusion injury, ischemia, chronic obstructive pulmonary disease, angioplasty restenosis due to angioplasty, Lt; / RTI >