AU747280B2 - Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses - Google Patents

Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses Download PDF

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AU747280B2
AU747280B2 AU68744/98A AU6874498A AU747280B2 AU 747280 B2 AU747280 B2 AU 747280B2 AU 68744/98 A AU68744/98 A AU 68744/98A AU 6874498 A AU6874498 A AU 6874498A AU 747280 B2 AU747280 B2 AU 747280B2
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methyl
group
optionally substituted
pharmaceutically acceptable
solvate
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Melwyn A. Abreo
Steven L. Bender
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Agouron Pharmaceuticals LLC
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Description

WO 98/43963 PCT/US98/06365 1 Metalloproteinase Inhibitors, Pharmaceutical Compositions Containing Them and Their Pharmaceutical Uses The present invention relates to compounds that inhibit metalloproteinases, particularly matrix metalloproteinases and tumor necrosis factor-a convertase, and their pharmaceutically acceptable salts and pharmaceutically acceptable prodrugs.
The invention further relates to the uses of these compounds, salts and prodrugs for the therapeutic treatment of humans or animals.
Matrix metalloproteinases ("MMPs") are a family of enzymes, including, but not limited to, collagenases, gelatinases, matrilysin, and stromelysins, which are involved in the degradation and remodelling of connective tissues. These enzymes are found in a number of cell types that are found in or associated with connective tissue, such as fibroblasts, monocytes, macrophages, endothelial cells and metastatic tumor cells. They also share a number of properties, including zinc and calcium dependence, secretion as zymogens, and 40-50% amino acid sequence homology.
Matrix metalloproteinases degrade the protein components of the extracellular matrix, i.e. the protein components found in the linings of joints, interstitial connective tissue, basement membranes, cartilage and the like. These proteins include collagen, proteoglycan, fibronectin and lamanin.
Collagen is the major structural protein of mammalian tissue, comprising onethird of the total protein in mammalian organisms, and is an essential component of many matrix tissues, including cartilage, bone, tendons and skin. Interstitial collagenases catalyze the initial (rate-limiting) cleavage of native collagen types I, II, III and X. These enzymes cleave collagen into two fragments which spontaneously denature at physiological temperature. Denaturation of collagen involves conversion of the rigidly coiled helix to a random coil referred to as gelatin. These gelatin (denatured collagen) fragments are then subject to further cleavage and degradation by less specific enzymes. The net result of collagenase cleavage is thus the loss of structural integrity in the matrix tissue (collagen collapse), an essentially irreversible process.
The gelatinases include two distinct yet highly related enzymes: a 72kiloDalton (kDa) enzyme and a 92-kiloDalton enzyme. The former is released by fibroblasts while the latter is released by mononuclear phagocytes, neutrophils, SUBSTITUTE SHEET (RULE 26) WO 98/43963 PCT/US98/06365 2 corneal epithelial cells, tumor cells, cytotrophoblasts and keratinocytes. Both enzymes degrade gelatins (denatured collagens), collagen types IV (basement membrane) and V, fibronectins (high molecular weight multifunctional glycoproteins found in soft connective tissue and basement membranes) and insoluble elastin (highly cross-linked hydrophobic proteins found in load bearing fibers of mammalian connective tissue).
Stromelysins (1 and 2) cleave a broad range of matrix substrates, including lamanin, fibronectins, proteoglycans and collagen types IV and IX (non-helical).
Matrilysin (putative metalloproteinase or PUMP) also degrades a wide variety of matrix substrates, including proteoglycans, gelatins, fibronectins, elastins and lamanin. Matrilysin has been found in mononuclear phagocytes, rat uterine explants and tumor cells.
In normal tissues, the activity of matrix metalloproteinases is tightly regulated.
As a result, the breakdown of connective tissue mediated by these enzymes is generally in a dynamic equilibrium with synthesis of new matrix tissue.
In a number of pathological disease conditions, however, deregulation of matrix metalloproteinase activity leads to the uncontrolled breakdown of extracellular matrix. These disease conditions include arthritis rheumatoid arthritis and osteoarthritis), periodontal disease, aberrant angiogenesis, tumor metastasis and invasion, tissue ulceration corneal ulceration, gastric ulceration or epidermal ulceration), bone disease, HIV-infection and complications from diabetes.
Administration of matrix metalloproteinase inhibitors has been found to reduce the rate of connective tissue degradation, thereby leading to a favorable therapeutic effect. For example, in Cancer Res., vol. 53, p. 2087 (1993), a synthetic matrix metalloproteinase inhibitor was shown to have in vivo efficacy in a murine model for ovarian cancer with an apparent mode of action consistent with inhibition of matrix remodelling. The design and uses of MMP inhibitors are reviewed, for example, in J.
Enzyme Inhibition, 2, 1-22 (1987); Progress in Medicinal Chemistry 29, 271-334 (1992); Current Medicinal Chemistry, 2, 743-762 (1995); Exp. Opin. Ther. Patents, 1287-1296 (1995); and Drug Discovery Today, 1, 16-26 (1996).
Matrix metalloproteinase inhibitors are also the subject of numerous patents and patent applications, including: U.S. Patent No. 5,189,178; U.S. Patent No.
5,183,900; U.S. Patent No. 5,506,242; U.S. Patent No. 5,552,419; U.S. Patent No.
SUBSTITUTE SHEET (RULE 26) WO 98/43963 PCT/US98/06365 3 5,455,258; European Patent Application No. 0 438 223; European Patent Application No. 0 276 436; WIPO International Publication No. WO 92/21360; WIPO International Publication No. WO 92/06966; WIPO International Publication No. WO 92/09563; WIPO International Publication No. WO 96/00214; WIPO International Publication No. 95/35276; WIPO International Publication No. WO 96/27583, and WIPO International Publication No. WO 96/33172, the disclosures of each of which are incorporated herein by reference.
Tumor necrosis factor-= is a cytokine which is produced as a 28kDa precursor and released in an active 17-kDa form. This active form can mediate a large number of deleterious effects in vivo, including inflammation, fever, cardiovascular effects, haemorrhage, coagulation and acute phase responses, similar to those seen during acute infections and shock states. Chronic administration of TNF-a can cause cachexia and anorexia; accumulation of excess of TNF-a can be fatal.
TNF-a convertase is a metalloproteinase involved in the biosynthesis of TNFa. Inhibition of TNF-a convertase inhibits production of TNF-a.
Since excessive TNF-a production has been noted in several disease conditions characterized by MMP-mediated tissue degradation, including multiple sclerosis, arthritis and cancer, compounds which inhibit both MMPs and TNF-a convertase are especially advantageous for the treatment or prophylaxis of disease conditions in which both mechanisms are involved. Although compounds that both inhibit MMPs activity and TNF-a production have been disclosed in WIPO International Publication Nos. WO 94/24140 and WO 94/02466, the disclosures of which are herein incorporated by reference, there is still a need for effective MMP and/or TNF-a convertase inhibiting agents.
Because of their beneficial therapeutic effects, there is a need for effective inhibitors of metalloproteinase activity. The present invention is therefore directed to certain compounds that inhibit metalloproteinases, such as MMPs and TNF-a convertase, their pharmaceutically acceptable prodrugs, salts and solvates, pharmaceutical compositions containing the same and methods of using the same, as well as to method and intermediates useful in their preparation. Additional features and advantages of the invention will be set forth in the description which SUBSTITUTE SHEET (RULE 26) 4 follows, and in part will be apparent from the description or may be learned from practice of the invention.
To achieve these and other advantages, the present invention provides a compound of formula I: S02S- -Y-Ar wherein: Y is S; Ar is an optionally substituted aryl group or an optionally substituted heteroaryl group; 15 R is H, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or -C(O)RI, 20 wherein RI is hydrogen, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an Soptionally substituted aryl group, an optionally substituted heteroaryl group, or NR 2
R
3 wherein R 2 and R 3 0: 0 25 independently are hydrogen, an optionally substituted *0 alkyl group, an optionally substituted cycloalky group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group; and X is -NH-OH or -OH; or a compound of formula II: O 0 2 S -Y-Ar X H wherein: H:\suzannet\Keep\Speci\68744-98.1 SPECI.doc 28/12/01 4a Y' is O; Ar is an optionally substituted aryl group or an optionally substituted heteroaryl group; R' is H, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group or
C(CH
3 2
-S-CH
2 optionally substituted heteroaryl; X is -NH-OH or -OH; or a pharmaceutically acceptable prodrug, salt or solvate thereof; or a pharmaceutically acceptable prodrug, salt or solvate thereof.
The present invention is also directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or II or a pharmaceutically acceptable prodrug, salt or solvate thereof; and a pharmaceutically acceptable carrier, diluent, vehicle or excipient.
The present invention is further directed to a method of treating a mammalian disease condition mediated S 20 by metalloproteinase activity which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I or II or a pharmaceutically acceptable prodrug, salt or solvate thereof. More particularly, the present invention 25 is directed to a method of treating tumor growth, invasion *or metastasis, osteoarthritis, rheumatoid arthritis, osteoporosis, periodontitis, gingivitis, chronic dermal wounds, corneal ulceration, degenerative skin disorders, multiple sclerosis, stroke, atherosclerosis, glomerular disease. Alzheimer's disease, or a disease condition characterized by unwanted angiogenesis, such as diabetic retinopathy, macular degeneration, angiofibromas, or hemangiomas.
The present invention is still further directed to a method of inhibiting the activity of a metalloproteinase that comprises contacting the metalloproteinase with H:\suzannet\Keep\Speci\68744-98.1 SPECI.doc 28/12/01 4b THIS PAGE IS INTENTIONALLY BLANK *00 p p.
p H:\suzannet\Keep\Speci\58744-98.1 SPECIdoc 28/12/01 an effective amount of a compound of formula or (II) or a pharmaceutically acceptable prodrug, salt or solvate thereof.
As used in the present application, the following definitions apply, unless otherwise indicated: An "alkyl group" is intended to mean a straight or branched chain monovalent radical of saturated and/or unsaturated carbon atoms and hydrogen atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, ethenyl, pentenyl, butenyl, propenyl, ethynyl, butynyl, propynyl, pentynyl, hexynyl, and the like, which may be unsubstituted containing only carbon and hydrogen) or substituted by one or more suitable substituents as defined below.
An "O-alkyl group" or "alkoxy group" is intended to mean an oxygen bonded to an alkyl group, wherein the alkyl group is as defined above.
A "cycloalkyl group" is intended to mean a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon ring atoms, each of which may be saturated or unsaturated, and which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more heterocycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, bicyclo(2.2.1 .]heptyl, bicyclo[2.2.1 yl, bicyclo[2.2.2]octyl, bicyclo[3.2.1 .]nonyl, bicyclo(4.3.0]nonyl, bicyclo[4.4.0]decyl, indan-1-yl, indan-2-yl, tetralin-1-yl, tetralin-2-yl, adamantyl, and the like.
A "heterocycl6alkyl group" is intended to mean a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or unsaturated, containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, and which includes 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the radical is unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, WO 98/43963 PCT/US98/06365 6 dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3oxathianyl, 1,3-dithianyl, azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl, 1,5,9-triazacyclododecyl, and the like.
An "aryl group" is intended to mean an aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing 6, 10, 14, or 18 carbon ring atoms, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluoren-2-yl, indan-5-yl, and the like.
A "heteroaryl group" is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, including 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or aryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of heteroaryl groups include, but are not limited to, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, isoindolyl, benzimidazolyl, benzofuryl, isobenzofuryl, benzothienyl, quinolyl, isoquinolyl, phthalazinyl, carbazolyl, purinyl, pteridinyl, acridinyl, phenanthrolinyl, phenoxazinyl, phenothiazinyl, and the like.
An "acyl group" is intended to mean a -C(O)-R 5 radical, wherein R, is any suitable substituent as defined below.
A "sulfonyl group" is intended to mean a 5 radical, wherein R 5 is any suitable substituent as defined below.
The term "suitable substituent" is intended to mean any of the substituents recognizable to those skilled in the art as not adversely affecting the inhibitory activity of the inventive compounds. Illustrative examples of suitable substituents include, but are not limited to, oxo groups, alkyl groups, hydroxy groups, halo groups, cyano groups, nitro groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, trialkylsilyl groups, SUBSTITUTE SHEET (RULE 26) WO 98/43963 PCT/US98/06365 7 groups of formula (A) o 1I (A) S"-cR, wherein Ra is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, groups of formula (B) 0 IO
(B)
wherein Ra is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, groups of formula (C)
O
o Rb
(C)
I
Rc wherein Rb and R c are independently hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, groups of formula (D)
N'
II (D)
/C
wherein Rd is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a hydroxy group, an alkoxy group, an amino group, an alkylamino group, a dialkylamino group, or an acylamino group; and Re is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an amino group, an alkylamino group, or a dialkylamino group, SUBSTITUTE SHEET (RULE 26) WO 98/43963 PCT/US98/06365 8 groups of formula (E)
O
II
(E)
II
wherein Rf is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, groups of formula (F)
O
-S-N-R (F) II o Rh wherein Rg and Rh are independently hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, groups of formula (G) O
(G)
wherein R, is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a group of formula formula formula formula (defined below), or formula (defined below), groups of formula (H)
N
Rk
(H)
wherein R is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a hydroxy group, an alkoxy group, an amino group, or a group of formula formula formula or formula and wherein Rk is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a group of formula formula formula formula formula or formula groups of formula (J) s\
(J)
SUBSTITUTE SHEET (RULE 26) WO 98/43963 PCT/US98/06365 9 wherein R, is hydrogen, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a group of formula and groups of formula (K)
O
II (K) P-Rm, Rn herein Rm and Rn are independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a hydroxy group, an alkoxy group, an amino group, an alkylamino group, or a dialkylamino group.
The term "suitable organic moiety" is intended to mean any organic moiety recognizable to those skilled in the art as not adversely affecting the inhibitory activity of the inventive compounds. Illustrative examples of suitable organic moieties include, but are not limited to oxo groups, alkyl groups, hydroxy groups, halo groups, cyano groups, nitro groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, trialkylsilyl groups, and groups of formulas and as defined above.
A "hydroxy group" is intended to mean the radical -OH.
An "oxo group" is intended to mean the divalent radical =0.
A "halo group" or is intended to mean any of the radicals -CI, -Br, or -I.
A "cyano group" is intended to mean the radical -C=N.
A "nitro group" is intended to mean the radical -NO 2 A "trialkylsilyl group" is intended to mean the radical -SiRpRqRs, where Rp, Rq, and Rs are each independently an alkyl group.
A "carboxy group" is intended to mean a group of formula wherein Ra is hydrogen.
A "alkoxycarbonyl group" is intended to mean a group of formula wherein Ra is an alkyl group as defined above.
A "carbamoyl group" is intended to mean a group of formula wherein Rb and R C are both hydrogen.
An "amino group" is intended to mean the radical -NH 2 An "alkylamino group" is intended to mean the radical -NHRu, wherein R U is an alkyl group as defined above.
SUBSTITUTE SHEET (RULE 26) 10 A "dialkylamino group" is intended to mean the radical -NRuRv, wherein Ru and Rv, which are the same or different, are each an alkyl group as defined above.
A "pharmaceutically acceptable prodrug" is intended to mean a compound that is converted under physiological conditions or by solvolysis to a compound of the formula I or II.
A "pharmaceutically acceptable solvate" is intended to mean a solvate that retains the biological effectiveness and properties of the biologically active components of compounds of formula I or II.
Examples of pharmaceutically acceptable solvates include, but are not limited to, compounds of formula I or II in combination with water, isopropanol, ethanol, S 15 methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
In the case of solid formulations, it is understood that the inventive compounds may exist in different forms, such as stable and metastable crystalline S 20 forms and isotropic and amorphous forms, all of which are intended to be within the scope of the present invention.
A "pharmaceutically acceptable salt" is intended 0 to mean those salts that retain the biological effectiveness and properties of the free acids and bases 25 and that are not biologically or otherwise undesirable.
*Examples of pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrbsulfates, bisulfates,. sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hyroxybenzoates, methoxyenzoates, phthalates, sulfonates, xylenesulfonates, H:\suzannet\Keep\Speci\68744-98.1 SPECIdoc 28/12/01 10a. phenylacetates, phenyipropionates, phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, napthalene-2-sulfonates, and mandelates.
If the inventive compound is a base, the desired salt may be prepared by any suitable method known to the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, H:\suzarmet\Keep\Speci\68744-98.l SPECIdoc 28/12/01 11 phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acids such as glucuronic acid and galacturonic acid, alpha-hydroxy acids such as citric acid and tartaric acid, amino acids such as aspartic acid and glutamic acid, aromatic acids such as benzoic acid and cinnamic acid, sulfonic acids such a p-toluenesulfonic acid or ethanesulfonic acid, or the like.
If the inventive compound is an acid, the desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal or alkaline earth metal hydroxide or the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, **calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
The inventive compounds may exist as single stereoisomers, racemates :and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention. Preferably the inventive compounds, and prodrugs, salts and solvates thereof, have the formula la or Ila:
H
R
"J H I, V-a) YAr As generally understood by those kJlied in the art, an optically pure compound having one chiral center one asymmetric carbon atom) is one that consists essentially of one of the two possible enantiomers is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure. Preferably, the compounds of the present invention are used in a form that is at least 90% optically pure, that is, a form that contains at least 90% of a single isomer (80% enantiomeric WO 98/43963 WO 9843963PCTIUS98/06365 12 excess or diastereomeric excess more preferably at least 95% e.e. or even more preferably at least 97.5% (95% e.e. or and most preferably at least 99% (98% e.e. or In the compounds, compositions and methods of the present invention, preferably Ar is an aryl group substituted with a suitable substitutent, as defined above, in the position para to the Y moiety. Preferably the suitable substituent is a halogen, an alkyl group, an 0-alkyl group, an aryl group, a heteroaryl group, or an Salkyl group.
Additionally it is preferred that R is an alkyl group, preferably the alkyl group
-(CH
3 2 -S-alkyl, and still more preferably the alkyl group -C(CH 3 2
-S-CH
2 -heteroaryl.
Particularly preferred compounds falling within formula I include: )-N-hydroxy-3 ,3-dimethyl-2-[(4-(4-fluorophenoxy)benzenesulfonyl amino] buta namide, 2(S)-N-hydroxy-3 ,3-dimethyl-2-[(4-(4-chlorophenoxy)benzenesulfonyl)amino] buta na mide, 2 (S )-N-hydroxy-3-methyl-3-(pyrid-2-yl )methyl su lfanyl-2-[(4-(4-fl uorophenoxy)benzenesulfonyl)amino]butanamide, 2(S)-N-hydroxy-3-methyl-3-(pyrid-2-yl )methylsulfanyl-2-I(4-(4-bromophenoxy)benzenesulfonyl)amino]butanamide, N-[4-(4-Bromophenoxy)benzenesulfonyl]-S-[(1 -benzyl-1 H-imidazol-2yl)methyl]-D-penicillamine, N-[4-(4-lodophenoxy)benzenesulfonyl]-S-(pyrid-2-y)methyl]-D-penicillamine, 2(S )-N-hydroxy-3-methyl-3-(pyrid-2-yl )methylsulfanyl-2-[(4-(4-iodophenoxy)benze nesuIfonyl)ami no] buta namid e, romophenoxy)benzenesulfonyl]-S-[(5-methylisoxazol-3-yl )methyl]-Dpenicillamine, 2(S )-N-hyd roxy-3-methyl-3-(5-methyl isoxazol-3-yl)methylsulfanyl-2-[(4-(4fluorophenoxy)benzenesulfonyl )amino]butanamide, )-N-hyd roxy-3-methyl-3-(5-methyl isoxazol-3-yl )methylsu lfanyl-2-[(4-(4bromophenoxy)benzenesulfonyl)amino]butanamide, 2(S )-N-hyd roxy-3-methyl-3-(pyrid-2-yl )methylsu lfanyl-2-[(4-(4-methylphenoxy)benzenesulfonyl )aminolbutanamide, SUBSTITUTE SHEET (RULE 26) 13 2(S )-N-hydroxy-3-methyl-3-(5-methylisoxazol-3-y )methylsulfanyl-2-((4-(pyrid- 4-yloxy)benzenesulfonyl)amino]butanamide, 2(S )-N-hydroxy-3-methyl-3-(5-methylisoxazol-3-yl)methylsulfanl2((-(prd 4-yl)sulfanyllbenzenesulfonyl)amino]butanamide, 2(S )-N-hydroxy-3-methyl-3-( 1 H-imidazol-4-yl)methylsulfanyl-2-((4-(4bromophenoxy)benzenesulfonyl)amino]butanamide, 2(S )-N-hyd roxy-3-methyl-3-(1 -methyl-i H-imidazol-2-yl) methylsulfanyl-2-((4-(4bromophenoxy)benzenesulfonyl)amino]butananlide, 2(S )-N-hyd roxy-3-methyl-3-(1 -methyl-i H-imidazol-4-yl) methylsulfanyl-2-[(4-(4b romo phe noxy)benzenesufonyl)am ino] buta namid e, 2(S )-N-hydroxy-3-n'ethyl-3-(4-methyl-4H-(1 ,2,4]-triazol-3-yl) methylsulfanyl-2- [(4-(4-bromophenoxyjbenzenesuffonyl)aminolbutaflamide, 2(S )-N-hydroxy-3-methyl-3-( 1-methyl-4H(1 ,2,4]-triazol-3-yl) methylsulfanyl-2- [((4-(4-bromophenoxy)benzenesulfoflyl)amiflo]butaflamide, and 2(S )-N-hydroxy-3-methyl-3-methylsulfalyl-2-((4-(4-chlorophenoxy)beflzefe- :sulfonyl)amino]butanamide: and pharmaceutically acceptable prodrugs, salts, and solvates thereof.
The present invention is further directed to methods of inhibiting metalloproteinase activity, for example in mammalian tissue, by administering a compound of the formula 1, or a pharmaceutically acceptable prodrug, salt or solvate thereof. The activity of the inventive compounds as inhibitors of metalloproteinases, such as MMPs (including stromelysins, collagenases, gelatinases and/or matrilysin) and/or TNF-- convertase, may be measured by any of the methods available to *those skilled in the art., including in vivo and/or in vitro assays. Eamples of suitable assays for activity measurements include those described in Anal. Biochem., vol. 147, p. 437 (1985), Anal Biochem., vol. 180, p. 110 (1989), FEBS, vol. 96, p.
263 (1992) and European Patent Application No. 0 606 046.
Administration of the compounds of the formula I or 11, or their pharmaceutically acceptable prodrugs, salts or solvates, may be performed according to any of the accepted modes of administration available to those skilled in the art. Illustrative examples of suitable modes of administration include oral, nasal, parenteral, topical, transdermal and rectal. Preferably, the mode of administration is oral.
The inventive compounds of the formula I or II, or their pharmaceutically acceptable prodrugs, salts or solvates, may be administered as a pharmaceutical composition in any suitable pharmaceutical form recognizable to the skilled artisan.
Suitable pharmaceutical forms include, but are not limited to, solid, semisolid, liquid or lyophilized formulations, such as tablets, powders, capsules, suppositories, suspensions and aerosols. Preferably, the pharmaceutical form is a tablet or capsule for oral administration. The pharmaceutical composition may also include suitable excipients, diluents, vehicles and carriers as well as other pharmaceutically active agents, depending upon the intended use.
Acceptable methods of preparing suitable pharmaceutical forms of the pharmaceutical compositions are known to those skilled in the art. For example, pharmaceutical preparations may be prepared following conventional techniques of the pharmaceutical chemist involving steps such as mixing, granulating and compressing when necessary for tablet forms, or mixing, filling, and dissolving the ingredients as appropriate, to give the desired products for oral, parenteral, topical, Sintravaginal, intranasal, intrabronchial, intraocular, intraaural and/or rectal administration. Illustrative examples of such methods include those described in Remington's Pharmaceutical Sciences, 18th edition (1990).
S. Solid or liquid pharmaceutically acceptable carriers, diluents, vehicles or excipients may be employed in the pharmaceutical compositions. Illustrative solid S* carriers include starch, lactose, calcium sulphate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Illustrative liquid carriers include syrup, peanut oil, olive oil, saline solution and water. The carrier or diluent may include a suitable prolonged-release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. When a liquid carrier is used, the preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid solution), or a nonaqueous or aqueous liquid suspension.
A dose of the pharmaceutical composition contains at least a therapeutically effective amount of the active compound a compound of the formula I or II, or a pharmaceutically acceptable prodrug, salt or solvate thereof) and preferabtly is made up of one or more pharmaceutical dosage units. An exemplary dosage unit for a mammalian host contains an amount of from 0.1 milligram up to 500 milligrams of
STF
T0^ active compound per kilogram body weight of the host, preferably 0.1 to 200 milligrams, more preferably 50 milligrams or less, and even more preferably about milligrams or less, per kilogram of the host weight. The selected dose may be administered to a mammal, for example, a human patient in need of treatment mediated by inhibition of metalloproteinase activity, by any known method of administrating the dose including: topically, for example, as an ointment or cream; orally; rectally, for example, as a suppository; parenterally by injection; or continuously by intravaginal, intranasal, intrabronchial, intraaural or intraocular infusion.
The amount of the inventive compounds, salts, solvates and/or prodrugs to be administered will vary based upon a number of factors, including the specific metalloproteinase to be inhibited, the degree of inhibition desired, the characteristics of the mammalian tissue in which inhibition is desired, the metabolic stability and activity of the particular inventive compound employed, and the mode of administration. One skilled in the art may readily determine a suitable dosage according to methods known to the art. Preferably, the amount of inventive compound of the formula I or II, or their pharmaceutically acceptable prodrugs, salts or solvates, aaministered ranges from 0.1 mg/kg body weight to 100 mg/kg body weight per day.
The inventive compounds, and the salts, solvates, and prodrugs thereof, may 'be prepared by employing the techniques available in the art using starting materials that are readily available. Exemplary methods of preparing the inventive compounds S. are described below. In the following schemes, unless otherwise indicated, R, Ar and Y are as previously defined herein.
16 Scheme 1
HO
o o=s Oxaly HO
H
chloride R Coupling Ill Reagent o 0 PgO-NH 0 0=1 Y.
A
0 O--S PgO
I
cl Ar Coupling
HO-NH
2
H
l Reagent
R
R
IV deprotection V
HO-NH
2
O
I O= Y.Ar 00=S-
Y
A
N
H
R Ib As illustrated in Scheme 1, hydroxamic acids of formula Ib compounds of Formula I, where X is NH-OH) can be prepared by reacting the corresponding carboxylic acids of formula III, compounds of formula I, where X OH) with hydroxylamine in the presence of a suitable peptide coupling reagent, for example, 1,1 '-carbonyldimidazole, N-(dimethylaminopropyl)-N'-ethyl carbodiimide, benzotriazol- 1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, or propane- 'phosphonic anhydride in an inert polar solvent, such as dimethylformamide.
Alternatively, compounds of formula IV can be reacted with hydroxylamine in a suitable solvent mixture, such as THF/t-butanol/dichloromethane or water/dichloromethane, preferably at 0 to give hydroxamic acids of formula II.
Compounds of formula IV can generally be prepared, in a form directly useful for further reaction without isolation, by allowing carboxylic acids of formula III to react with thionyl chloride or oxalyl chloride, preferably in the presence of a catalytic amount of dimethylformamide, in dichoromethane solvent at -78 *C to room temperature.
Alternatively, the coupling reactions described above may be carried out with compounds of formula III (or IV) and O-protected derivatives of hydroxylamine, where Pg is a protecting group, for example, benzyl, tert-butyl, t-butyldimethylsilyl, or tbutyldiphenylsilyl, to give compounds of formula V. Deprotection of compounds of formula V using conventional methods (for example, see "Protective Groups in Organic Synthesis". T.W. Greene and P. G. M. Wuts, Wiley-lnterscience 1991) can provide compounds of formula Ib.
Carboxylic acids III can Be prepared as shown in Scheme 2 by reaction of aamino acids with arylsulfonyl chlorides of formula VIII, under biphasic basic conditions as described, for example, in 'The Chemistry of the Amino Acids", J.P.
Greenstein and M. Winitz, Robert E. Krieger Publishing Company, 1984, p. 886-889.
Scheme 2 Ar o 0 0 0=S O O O= i:o HO' 0 HO" H R =o VIII R 11 CI Vill III protection deprotection v
O
S0 O= YAr Pg.. NH 2 -H-o R O=S=O R VII AI ll VI a-Amino acids are commercially-available, or can be prepared according to methods familiar to those skilled in the art. Carboxylic acids III can also prepared by reaction of a-amino acid derivatives where Pg is any suitable protecting group as described, for example, in "Protective Groups in Organic Synthesis", T.W. Greene and P. G. M. Wuts, Wiley-lnterscience 1991, with aryl sulfonyl chlorides VIII to give sulfonamides VI under any of a variety of reaction conditions known to those skilled in the art for the sulfonylation of amines. Deprotection of VI to give the acids III can OF 0 WO 98/43963 PCT/US98/06365 18 be carried out as appropriate to the protecting group Pg. As is evident to those skilled in the art, manipulations of functionality in the amino acid side chain R or in the aryl group Ar may be readily effected at the stage of VI prior to the deprotection of VI to III. Amino acid derivatives VII, are commercially available, or are prepared according to methods familiar to those skilled in the art.
One variant of sequence shown in Scheme 2 that is particularly preferred in the context of the present invention is outlined in Scheme 3.
Scheme 3 o i
H'
O
NH
2
R
4 3 Si O RN Sio NH 2 R -X HS-- Me HS Me VIIB Me Me V MMe /e VII-A Me 0 Ar R 4 3 Si N Ar 0 0 -S Me II-A Me Me Me Me vil-C Treatment of D-penicillamine with a molar equivalent of a trialkylchlorosilane, such as trimethylsilyl chloride or dimethylthexylsilyl chloride, and a molar equivalent of a suitable base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or diisopropylethylamine, in suitable solvent, such as DMF, at approximately 25 °C for 1 to 6 hours can provide the silyl ester VII-A. The identity of R 4 is dependent upon the reactant used to obtain the silyl ester VII-A, as is recognized by one skilled in the art.
Without isolation, the solution of this ester VII-A can be treated with an additional DBU (at least one molar equivalent) and an alkylating reagent Rs-X, where R 5 is an alkyl group, preferably a CH 2 -heteroaryl group, to give the S-alkylated silyl ester VII- B. Again without isolation, the resulting solution of VII-B can be treated with the aryl sulfonyl chloride VIII to provide the sulfonamide silyl ester VII-C. Upon work-up or, in the case of more stable silyl esters, brief treatment with acidic methanol, the silyl ester VII-C undergoes hydrolysis to provide the desired acid III-A.
SUBSTITUTE SHEET (RULE 26) WO 98/43963 PCT/US98/06365 19 Scheme 4 Ar Ar Ar Y/ Y/ yl
CISO
3
H
I I I O=S=0 O=S=0 IX OH X VIII ci Aryl sulfonyl chlorides VIII are most readily available by chlorosulfonylation of the corresponding aryl phenyl ethers (IX, where Y 0) and aryl phenyl sulfides (IX where Y as outlined in Scheme 4. In general, treatment of IX with a little over one molar equivalent of chlorosulfonic acid in a suitable inert solvent, such as 1,2dichloroethane or dichloromethane, at -20 °C to 25 °C for a period of one to twentyfour hours can generate the corresponding sulfonic acid intermediate X. Without isolation, X is further converted to the sulfonyl chloride VIII by reaction with, for example, oxalyl chloride or thionyl chloride and cataltyic DMF. In some cases, excess chlorosulfonic acid is effective at converting IX directly to VIII via the intermediacy of X. Compounds of the formula IX are commercially-available, or may be readily prepared by those skilled in the art from commercially-available materials by the Ullman reaction.
Other compounds of the formula I may be prepared by methods known to those skilled in the art in a manner analagous to the general procedures described above. Specific examples of methods used to prepare the inventive compounds are described below along with illustrative preferred embodiments of the inventive compounds of the formula I, or their pharmaceutically acceptable prodrugs, salts or solvates.
The following specific examples are intended to be illustrative of the invention and should not be construed as limiting the scope of the invention as defined by the appended claims. These examples include preferred embodiments of the inventive compounds.
SUBSTITUTE SHEET (RULE 26) WO 98/43963 PCT/US98/06365 Examples Example 1. Preparation of Intermediate Compounds of formula VIII-A.
O
VIII-a Example 1(a) 4-Phenoxybenzenesulfonyl chloride {VIII-A: Z=H} To a stirred solution of 42.5 g (0.25 mol) of phenyl ether in 200 mL of dichloromethane at -20 °C under argon was slowly added 23.3 g (0.20 mol) of chlorosulfonic acid. After the addition was complete, the reaction was allowed to slowly warm to room temperature. After 16 hours, 150 mL of isooctane was added, and the solution was concentrated to an oily residue. Redissolution in 200 mL of 1:3 dichloromethane/isooctane and reconcentration with cooling to about 100 mL gave a solid. The supernatant was decanted, and the solid was triturated with additional isooctane and then dried in vacuo to give 55.2 g of crude 4-phenoxybenzene sulfonic acid. The crude acid was dissolved in 200 mL of dichloromethane, and 22 mL (32 g, 0.25 mol) of oxalyl chloride was added, followed by 2.5 mL of N,Ndimethylformamide. After 2 days, the reaction solution was poured into 200 mL of ice water, and extracted with 400 mL of hexane. The organic layer was washed with 100 mL of water and 100 mL of brine, dried over magnesium sulfate, and concentrated. Recrystallization of the residue from dichloromethane/isooctane gave 1 38.5 g of 4-phenoxybenzenesulfonyl chloride as a white solid: mp 41.5 H-NMR (CDC13) 5 7.10 (apparent t, 4 H, J 7 Hz), 7.28 1H, J 7 Hz), 7.46 2H, J 8 Hz), 7.98 2H, J 8.8 Hz).
Example 1(b) 4-(4-Methylphenoxy)benzenesulfonyl chloride {VIII-A: Z=CH 3 To a solution of 1.84 g (10.0 mmol) of 4-methyldiphenyl ether Chem. Soc., Perkin Trans. 1; 1992, 407-408) with 2 mL of dichloromethane in an ice-bath was added a solution of chlorosulfonic acid 0.73mL, 11.0 mmol) in 2 mL of dichloromethane dropwise. The resulting mixture was stirred at 0°C to room temperature for 2 hours, and then oxalyl chloride (11.14mL, 13.0 mmol) was added dropwise, followed by 0.15 mL of DMF. The resulting mixture was heated to 40°C for SUBSTITUTE SHEET (RULE 26) WO 98/43963 WO 9843963PCTIUS98/06365 21 1 hour and then allowed to cool to room tempereature over a 2 hour period. The reaction mixture was poured into ice-pH 7 phosphate buffer (5OmL), then extracted with EtOAc:Hexane (3xl 5OmL). The combined organic layers were washed with brine (75mL). The aqueous layer was extracted with EtOAc/Hexane(4:3) The organic layer was dried over Na 2
SO
4 'then evaporated by vacuum to give crude product as white solid. This solid was triturated with hexane and collected by filtration, then dried under high vacuum to give 1.555 g of 4-(4- 1 methylphenoxy)benzenesulfonyl chloride as white solid: mp 295-3000C. H-NMR (DMSO-d6) 6 2.34 3H), 6.91-6.99 (dd, J 7.7,8.4Hz, 4H), 7.24-7.27 J =8.4H-z, 2H), 7.61-7.63 J 8.1 Hz, 2H).
Anal. calc. for C 13
H-
11 0 3 S01: C, 55.22; H, 3.92; S, 11.34; Cl, 12.71. Found: 0, 55.06; H, 3.95; S, 11.28; Cl, 12.71.
Prepared in a similar fashion were the following: Example 1 4-(4-Bromop henoxy) benzenes ulfo nyl chloride {ViII-A: Z=Br}: from 4-bromobiphenyl ether (supplier: Aldrich), mp 81 00.
Example 1(c) 4-(4-Ch lorophen oxy) benzenes ufo nyl chloride {VIII-A: Z=Cl}: from 4-chlorobiphenyl ether (supplier: Transworld), mp 61 00 Example 1 4-(4-Fluorophenoxy)benzenesulfonyI chloride {VIII-A: from 4-fluorobiphenyl ether (supplier: Riedel-de Haen), mp 76 00 Example 1(e) 4-(4-lodophenaxy)benzenesulfonyI chloride Willl-A: Z=1} from 4iodobiphenyl ether (supplier: Transworld): mp 85-88 00.
Example 1 (f 4-(4-Cyanophenoxy)benzenesulfonyl chloride {VIII-A: Z=CN}: from 4-cyanobiphenyl ether (supplier: Transworld): mp 98-1 02 '0 Example 1(g) 4-(4-Trifl uoromethyphenoxy)benzenesulfonyl chloride {VIII-A:
Z=CF
3 from 4-trifluoromethylbiphenyl ether Chem. Sac. Perkin Trans. 1 1988, 3229- 3232): mp 265-270-C; 1 H-NMR (ODC1 3 7.04 J 8.4H-z, 2H), 7.14 J 8.7Hz, 2H), 7.65 J 8.8H-z, 2H), 7.73 J =8.7H-z, 2H)'.
Anal. calc. for 0 13
H
8 0 3
SF
3 C1 (336.71): 0, 46.34; H, 2.39; S, 9.52. Found: C, 46.34; H, 2.49; S, 9.37.
SUBSTITUTE SHEET (RULE 26) WO 98/43963 PCT/US98/06365 22 Example 1(h) 4-(Pyrid-2-yl)oxybenzenesulfonyl chloride 0 O N- From 2-phenoxypyridine (supplier: ICN): 1 H NMR (CDCI3) d 8.25 1H), 8.05 2H, J 9 Hz), 7.81 1H, J 8 Hz), 7.34 2H, J 9 Hz), 7.15 (dd, 1 H, J 5 Hz), 7.06 1H, J 8 Hz).
Example 2. Preparation of Intermediates of Formula VIII.
Example 2(a) 4-(Pyrid-4-yl)oxybenzenesulfonyl chloride hydrochloride 0 Cl-S- O- N HCI To a suspension of 4-(pyrid-4-yl)oxybenzenesulfonic acid (1.3 kg) in acetonitrile (8 was added N,N-dimethylformamide (12.35 mL), and the viscous reaction mixture was heated to 75 Thionyl chloride (756 mL) was added to the reaction mixture over 30 minutes. The reaction mixture slowly became less viscous and became homogeneous after 45 minutes, which indicated the reaction was complete. A portion of the solvent (4 L) was evaporated under vacuum and tert-butyl methyl ether (4 L) was added. The resulting slurry was filtered under inert atmosphere. The filter cake was rinsed with tert-butyl methyl ether (2 L) and the solid dried under vacuum to yield 4-(pyrid-4-yl)oxybenzenesulfonyl chloride hydrochloride (1.35 kg) as a hygroscopic,off-white solid of pearlescent flakes: mp 182 1H NMR
(CDCI
3 5 8.87 J 7 Hz, 2H), 8.24 J 8.5 Hz, 2H), 7.50 J 8.5 Hz, 2H), 7.43 J 7 Hz, 2H).
The starting material was prepared as follows: To a vigorously stirred solution of 1.00 kg (5.85 mol) of 4-phenoxypyridine (Tetrahedron, 1978, 34, 2069-2076) in dry 1,2-dichloroethane (3000 L) at under a stream of argon was added chlorosulfonic acid (974 mL) at a rate so as to maintain the reaction temperature below 0°C. After half of the chlorosulfonic acid was added, the exotherm stopped. The cooling bath was removed and the addition of chlorosulfonic acid continued over 3 hours while the reaction solution warmed to SUBSTITUTE SHEET (RULE 26) WO 98/43963 PCT/US98/06365 23 room temperature. While continually purging with argon, the vigorously stirred reaction mixture was heated to 45°C. After 20 hours, the reaction mixture was cooled to room temperature and slowly poured into vigorously stirred ice cold water Potassium phosphate tribasic (212 g) was added as a solid to the mixture and this was stirred for 10 minutes followed by addition of sodium hydroxide (2M) to pH 2.
After stirring for 1 hour, the pH was changed to 7 by the addition of sodium hydroxide Agitation was continued for 5 minutes; then the organic layer was drained off and discarded. The mixture was extracted a second time with dichloromethane (2 L), and the organic layer drained off and discarded. The remaining aqueous phase was extracted with tetrabutylammonium bromide (940 g) in dichloromethane (6L), adjusting the aqueous phase to pH 7 with 2M aq. sodium hydroxide as necessary.
The extraction was repeated two more times and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved with 20% ethanol in ethyl acetate (8 L, dry), and hydrogen chloride gas added to achieve a pH of 1. The solid was filtered off, and the filter cake was rinsed with the precipitation solvent mixture (20% ethyanol in ethyl acetate, 2 The solid was dried under vacuum at 45°C for 15 hours to yield 4-(pyrid-4-yl)oxybenzenesulfonic acid (1.3 kg) as a white powdery solid.
mp dec. >275 oC; 'H NMR (DMSO-d 6 5 8.86 (dd, J= 1.5, 7.4 Hz, 2H), 7.84 (dd, J 7 Hz, 2H), 7.54 (dd, J 1.5, 7.4 Hz, 2H), 7.35 (dd, J 1.5, 7 Hz, 2H).
Anal. calc. for C, 1
H
9
NO
4 S: C, 52.58; H, 3.61; N, 5.57; S, 12.76. Found: C, 52.50; H, 3.69; N, 5.51; S, 12.67.
Example 4-(Pyrid-4-yl)sulfanylbenzenesulfonyl chloride hydrochloride
O
CI- Q N HCI Prepared as in Example 2(a) from 4-(phenylsulfanyl)pyridine (prepared as in J.
Am. Chem. Soc. 1937, 59, 2697): mp 194°C.
'H NMR (CDCI3) 6 8.61 J 7 Hz, 2H), 8.25-8.20 2H), 7.93-7.8(m, 2H), 7.48 J 7 Hz).
SUBSTITUTE SHEET (RULE 26) WO 98/43963 PCT/US98/06365 24 Example 3. Preparation of Compounds of Formula III-A O O 0 0 \-Z
N
HO
H
w-
III-A
Example S-[(1-Benzyl-1 H-imidazol-2-yl)methyl]-N-[4-(4-fluorophenoxy) benzenesulfonyl]-D-penicillamine {Ill-A, W=(1-Benzyl-1 H-imidazol-2-yl)CH 2
S,
Z=F}
To a suspension of D-penicillamine (0.500 g, 3.35 mmol) in DMF (7 mL) was added diisopropylethylamine (0.70 mL., 4.0 mmol), followed by dimethylthexylsilyl chloride (0.725 mL, 3.68 mmol). After 2.5 hours at room temperature, the solution was cooled to 0 and DBU (1.59 mL, 10.7 mmol) was added, followed by 2chloromethyl-1-benzyl-IH-imidazole hydrochloride (0.977g., 4.02 mmol, Maybridge).
The solution was allowed to warm to room temperature. After 3 hours, the solution was recooled to 0 oC, diisopropylethylamine (0.70 mL., 4.0 mmol) was added, followed by 4-(4-fluorophenoxy)benzenesulfonyl chloride (1.01 4.00 mmol). The solution was allowed to slowly warm to room temperature, stirred for 5 h, and then partitioned between brine and ethyl acetate. The organic layer was washed with brine, filtered through celite, and concentrated. The residue was dissolved in methanol (50 mL), and treated with acetic acid (0.400 mL). After 2 hours at room temperature, the solution was concentrated, and the residue was purified on silica, eluting with 5% methanol/dichloromethane. Trituration of the residue with diethyl ether/hexane gave S-[(1-benzyl-1 H-imidazol-2-yl)methyl]-N-[4-(4fluorophenoxy)benzenesulfonyl]-D-penicillamine as a white solid in 52% yield: mp 172-173 'H-NMR (CDC1 3 6 1.29 3H), 1.44 3H), 3.75-4.02 3H), 5.29 (s, 2H), 6.95-7.65 Anal calcd. for C 28
H
28
FN
3 OsS 2 C, 59.03; H, 4.95; N, 7.38; S, 11.26. Found: C, 58.77; H, 4.97; N, 7.33; S, 11.07.
SUBSTITUTE SHEET (RULE 26) WO 98/43963 WO 9843963PCT[US98/06365 Prepared in a similar manner were Examples 3(b) to 3 Example N-[4-(4-Bromophenoxy)benzenesulfonyl]-S-[( I -benzyl-I Hi midazol -2-yI)methyl] -D-pen icilIlam ine {lII-A, W (I -Benzyl-I H-imidazol-2yl)CH 2 S, Z B~r).
mp 176-177 00; H-NMR (CD 3 OD) 6 1.36 1.41 (2s, 3.67 4.00 (in, 2H-), 5.36 7.01-7.85 (in, 15H); FAB HRMS: expected (M+Cs)=761.9708. Found (M+Cs)=761 .9728 Anal calod. for C 2
,H
2 ,BrN 3
OS
2 0, 53.33; H, 4.48; N, 6.66; S, 10.17. Found: C, 53.25; H, 4.43; N, 6.59; S, 10.06.
Example N-[4-(4-Fluorophenoxy)benzenesulfonyl] -S-[(pyrid-2-yl)methyl]-Dpenicillamine {lll-A, W (pyrid-2-yl)CHA =S F) mp 194 00. H-NMR (DMSO-d6) 6 1.33 3.85-3.97 (mn, 7.12 J 9 Hz, 7.18-7.54 (in, 7.70-7.79 m, 1IH), 7.84 J 9 Hz, 8.3 J =10 Hz, 1IH), 8.4 J 4Hz, 1 12.68 (br s, 1 H).
Anal. calc. for C 23
H
23
FN
2 0 5
S
2 C, 56.31; H, 4.73; N, 5.71. Found: C, 56.06; H, 4.78; N, 5.64.
Example N-[4-(4-Bromophenoxy)benzenesulfonyl-S-[(pyrid-2-yl)methyl]-Dpenicillamine {lll-A, W (pyrid-2-yl)CH 2S, Z Br) mnp 165-168 00; 1 H-NMR (CD 3 OD) 6 1.39 1.45 3.92-3.99 (in, 7.03- 7.12 (dd, J 9 2 Hz, 7.24-7.26 (in, 1IH), 7.53-7.60 (in, 3H), 7.82-7.90 (in, 3H-), 8.52 J 3 Hz, 1IH).
Anal. calc. for C 23
H-
2
AN
3 5 SF90.2 H 2 0: 0, 49.77; H, 4.25; N, 5.05. Found: 0, 49.93; H, 4.19; N, 4.12.
Exam ple N-[4-(4-Fluorophenoxy)benzenesulfonyl] -S-[(pyrid-3-yI)methyl]-Dpenicillamine {III-A, W (pyrid-3-yl)CH 2 S, Z F).
mp 200-201 aC; 1H-NMR (DMSO-d6) 6 1.35 3.87 7.11-8.60 (mn, 12H), 8.25 (br s, 1IH).
Anal. caic. for C 23
H
23
FN
2 0 5
S
2 *0.3 H 2 0: C, 55.49; H, 4.82; N, 5.63. Found: C,55.34; H, 4.67; N, 5.6.
SUBSTITUTE SHEET (RULE 26) WO 98/43963 WO 9843963PCT/US98/06365 26 Example uorophenoxy) benzenes u fony]-S~[pyrid 4-yl)methyl]-D penicillamnine {llI-A, W =(pyrid-4-yI)CH 2 S, Z F).
mp 197*C; 'H-NMR (DMVSO-d6) 6 1.34 6H), 3.80-4.00 (in, 3H), 7.00-8.80 (in, 13H).
8.25 1 H).
Anal. caic. for C 23
H
2 3
FN
2 0 5
S
2 0.1 H 2 0: 0, 56.11; H, 4.75; N, 5.69. Found: 0, 55.78; H, 4.75; N, 5.73.
Example N -[4-(4-Methyl phenoxy) benzenes u Ifonyl]-S-[(pyrid-2-yI) methyl] -Dpenicillamnine {Ill-A, W (pyrid-2-yl)CH S Z Me) mnp 185-187OC; 1H-NMR (CD 3 OD) 6 1.39 3H-) 1.44 3H), 2.39 3.92-4.01 (in, 3H), 6.98-7.04 (in, 7.25-7.28 (in, 3H), 7.54 J 7 Hz, 2H), 7.82-7.85 (in, 3H), 8.42 J 6 Hz, 1 H).
Anal. caic. for 0 2
,H
2
,N
2 0 5
S
2 *0.35 CH 2 C1 2 0, 56.64; H, 5.21; N, 5.43. Found: 0, 56.48; H, 5.32; N, 5.67.
Example N-[4-(4-Cyanophenoxy)benzenesulfonyl-S-[(pyrid-2yl)methyl].Dpenicillamnine {lll-A, W (pyrid-2-yl)CH 2 S, Z CN) mp 170-173OC; 'H-NMR (CD 3 OD) 6_1.42 3H), 1.44 3H), 3.82- 4.01 (mn, 3H), 7.19-7.23 (mn, 5H), 7.60 J 5 Hz, 1 7.79 J 4 Hz, 3H), 7.95-7.98 J 9 Hz, 2H) 8.42-8.43 J 5 Hz,1 H).
Anal. caic. for 0 24
H
2 3
N
3 0 5
S
2 0 .7H 2 Os0.6CH 2 Cl 2 C, 52.23; H, 4.82; N, 7.28 Found: C, 52.22; H, 4.87; N, 7.38.
Example N -[4-(4-Iodophenoxy)benzenesulfonyl]-S-[(pyrid-2-yl)methyl]-Dpenicillamnine {llI-A, W (pyrid-2-yl)CH 2 S, Z 1) mnp 177-180CC; 1 H-NMR (CD 3 OD) 6 1.40 3H), 1.44 3H), 3.87-4.01 (mn, 3H), 6.91 J 8 Hz, 2H), 7.10 J 9 Hz, J 2H), 7.32-7.56 (in, 1 7.77 J 8 Hz, 1 7.81-7.89 (mn, 4H), 8.44 J =5 Hz, 2H-).
Anal. caic. for C 23
H
23
N
2
OS
2 o.1H 2 0: 0,46.15; H, 3.94; N, 4.65. Found: C, 46.15; H, 3.95; N, 4.51.
Example N -[4-(4-(trifl uoromethyl)phenoxy) benzenes u Ifonyl] -S-[(pyri d-2yI)methyl]-D-penicillamine {lII-A, W (pyrid-2-yl)CH 2 S, Z CF 3 mp 182-185OC; 1 H-NMR (CD 3 OD) 6 1.36 3H),1.41 3H), 3.83-3.98 (in, 3H), 7.14-7.30 (mn, 4H), 7.51 J 8 Hz, 2H), 7.69-7.91 (mn, 8.41 J 4 Hz, 2H).
SUBSTITUTE SHEET (RULE 26) WO 98/43963 WO 9843963PCTIUS98/06365 27 Anal. caic. for 0 24
H
23
N
2 0 5
S
2
F
3 *0.35 hexane: C, 54.92: H, 4.93; N, 4.91.
Found: 0, 55.07; H, 5.01; N, 5.06.
Example N-[4-(4-Bromophenoxy)benzenesufonyl].S-(5.methylisoxazol.3 yl)methyl]-D-penicillamine {lll-A, W =(5-methylisoxazol-3-yl)CH 2 SZ B 1r) mp 119 00; 'H-NMR (DMSO-d6) 6 1.35 6H), 2.4 3H), 3.3 (br s,1 3.73 J =14 Hz, 1 3.79 J 14 Hz, 1IH), 6.21 1IH), 7.1-7.2 br s, 1IH), 7.13 J 9 Hz, 2H), 7.15 J 9 Hz, 2H), 7.68 J 9 Hz, 2 7.82 J 9 Hz, 2H).
Anal. caic. for C 22
H
23
BNAOS
2 .1i H 2 0*0.3 CHC 3 C, 45.16; H, 3.99; N, 4.72.
Found: C, 45.24; H, 4.03; N, 4.7.
Example N-[4-(4-Fluorophenoxy)benzenesulfonyl]-S-[(5..methylisoxazol.3yI)methyl]-D-penicillamine {IlI-A, W (5-methylisoxazol-3-y)CH 2 SZ F) mp 12-113 0 C; 'H-NMR (DMSO-d6) 61.35 6H), 2.40 3H), 3.3-3.97 (br s,IH), 3.73 J 13 Hz, 1IH), 3.79 J 13 Hz, 1 6.24 1IH), 6.9-7.2 (br s, 1 7.07 J =9 Hz, 2H), 7.2-7.38 (in, 4H), 7.8 J =9 Hz, 2H).
Anal. calc. for C 22
H
23
FN
2 0S 2 00.1H 2 000.3 CHC 3 C, 50.33; H, 4.45; N, 5.26.
Found: C, 50.27; H, 4.35; N, 5.3.
Example S-Benzyl-N -[4-phen oxylbenzenes ulfonyl]-D-pe nicilIlam ine {lll-A, W =PhCH 2 SZ =H) mnp 92-95 00; 'H-NMR (ODCd 3 6 1.36 3H), 1.59 3H), 2.25 (br s, 1 5.46 J 10 Hz, 2H), 6.99-7.39 (in, 7H), 7.61-7.85 (in, 7H).
Anal. caic. for C 24
H-
26 N0 5
S
2 o0.8 NH 3 C, 59.32; H, 5.89; N, 5.13. Found: C, 59.58; H, 5.92; N, 5.13.
Example S-(t-Butoxycarbonyl)methyl-N-[4-(4-fluorophenoxy)benzene.
sulfonyl]-D-penicillamine (Ill-A, W t-BUO 2
CCH
2 S, Z F) mnp 7500C; 'H-NMR (ODCd 3 6 1.26 3H), 1.34 3H), 1.43 9H), 3.16 J Hz, 1 3.26 J 15 Hz, 1 3.76 J 8 Hz, 1 6.5 (br s, 1 6.94 (d, J 9 Hz, 2H), 6.97-7.1 (mn, 4H), 7.82 J 9 Hz, 2H).
Anal. caic. for C 23
H
28
FNO
7
S
2 *0.2CHC 3 0, 51.84; H, 5.29; N, 2.61. Found; C, 51.79; H, 5.26; N, 2.70.
Example N-[4-(4-Bromophenoxy)benzenesulfonyl].S{1 -methyl-I H imidazol-2-yl)methylj-D-penicillamine (Ill-A, W (1 -methyl-I H-imidazol-2yI)CH 2 S, Z B3r): 'H NMVR (DMSO): 6 1.20 3H), 1.27 3H), 3.61 3H), SUBSTITUTE SHEET (RULE 26) WO 98/43963 WO 9843963PCTIUS98/06365 28 3.79 1IH), 3.93 6.81 1 7.06-7.14(m, 5H), 7.62 2H, J 9.0 Hz), 7.70 2H, J 9.0 Hz); ESIMS Calcd for C 22
H
24
O
5
N
3
S
2 Br: 554/556. Found: 554/556.
Anal. Calcd for 0 22
H
24 0 5
N
3
S
2 0.08 HOAc: C, 45.59; H, 4.38; N, 7.51; S, 11.47; Br, 14.29.
Found: C, 45.55; H, 4.37; N, 7.37; S, 11.46, Br, 14.34 Example N-[4-(4-Chlorophenoxy)benzenesulfonyl]-D-tert-leucine {llI-A, W =CH 3 Z CI}.
To a suspension of D-tert-leucine (0.250 1.91 mnmol, Aldrich) in dichloromethane (3 mL) and DMF (1.5 mL) was added N-methylmorpholine (0.50 mL., 4.55 mmol), followed by chlorotrimethyl si lane (0.30 mL., 2.36 mmol) and the mixture stirred at room temperature for 6 hours. Dilsopropylethylamine (0.300 mL., 1.72 mmol) was added, followed by 4-(4-chlorophenoxy)benzenesulfony chloride (0.636g., 2.10 mmol, from example 1 portionwise via a solid addition funnel. The resulting solution was then stirred at room temperature for 3.5 hours, and then partitioned between ethyl acetate and 1IN aq. sodium bisulfate. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified on silica gel, eluting with 40% ethyl acetate in hexane followed by 10% methanol in dichloromethane, to give chlorophenoxy)benzenesulfonyl]-D-tert-leucine as a white solid in 62% yield: mp 138-140 1 H-NMR (CDCI 3 6 0.949 9H), 3.51-3.54 1 H, J 10.3 Hz), 5.55-5.59 (in, 1 6.94-7.83 (mn, 8H).
FAB HRMS: expected (M +H)=398.0829, found(M+H)=398.0840 Examples and 3(s) were prepared following the procedure provided in Example 3(p): Example N-[4-(4-Fluorophenoxy)benzenesulfonyl]-D-tert-leucine {lll-A, W =CH 3 Z mp 170-17400C Example N-[4-Phenoxybenzenesulfonyl]-D-tert-leucine {lll-A, W CH 3
Z=
H}
mp 147-150'C; 'H-NMR (CDCd 3 6 0.98 3.59 J =10.7Hz, 1 5.17 J 10.5H-z, 1IH), 6.99-7.43 (in, 7.77 d, J 7.0Hz, 3H).
SUBSTITUTE SHEET (RULE 26) WO 98/43963 WO 9843963PCT/US98/06365 29 Anal. caic. for C 18
H-
21 N0S90.3 H 2 0 (368.82): C, 58.61; H, 5.90; N, 3.80.
Found: 0, 58.72; H, 5.90; N, 3.74.
Example N -[4-(4-Bromophenoxy)benzenesu lfonyl]-D-(f-hydroxy)valine {lllA W OH, Z B~r} Starting from D-3-hydroxyvaline, which was prepared by the method described in J. Org. Chem. 1996, 61, 2582-2583; mp 153-4o0. 'H NMR (DMSO-d6): a60.88 (s, 1.07 2.80 1IH, J =6.0 Hz), 6.79 1IH, J 6.0 Hz), 7.06 -7.11 (in, 4H), 7.62 2H-, J 9.0 Hz), 7.76 2H, J 8.1 Hz); ESIMS Calcd for
C
17
H
18
O
6 ,NSBr: 444/446. Found: 444/446.
Anal. Calcd for C 1 7
H
1 8 BrNOrS: 0, 45.96; H, 4.08; N, 3.15; S, 7.22; Br, 17.98.
Found: 0, 45.73; H, 4.05; N, 3.08; S, 7.08, Br, 17.91.
In a similar fashion may be prepared: Example N-[4-(4-Bromophenoxy)benzenesufonyl]-D-tert.Ieucine {111-A, W
=CH
3 Z B~r} Example N-[4-(4-Chlorophenoxy)benzenesulfonyl]..D.(Ohydroxy)valine (Ill-A, W OH, Z CI} Example N-[4-(4-Chlorophenoxy)benzenesulfonyl]-D-valine (11111-A, W H, z c) Example 4. Preparation of Compounds of Formula 1ll.
Prepared in a similar manner as in Example 3(a) were Examples 4(b) and 4(c).
Example S-Benzyl-N-[4-(pyrid-4-yl)oxybenzenesulfonyl]-D..penicil lam mne 0 11 N, 5.89 SUBSTITUTE SHEET (RULE 26) WO 98/43963 WO 9843963PCTIUS98/06365 Example S-[(5-Methylisoxazol-3-yl)methyIJ-N-[4(pyrid-4-y)oxybenzenesulfonyl]-D-penicillamine.
0 HO H Me mp 90-92 00. 'H NMR (0D01 3 6 1.42 1.46 2.40 3.80 (dd, 3H-, J 14.3, 19.3 Hz), 5.75 1 H, J 10.2 Hz), 6.02 1IH), 6.82 2H-, J Hz), 7.08 2H-, J 8.7 Hz), 7.98 2H-, J 8.7 Hz), 8.40 2H-, J 6.5 Hz); FAB HRMS Calcd for C 2
,H
24 0 6
N
3
S
2 478.1107. Found: 478.1117.
Anal. Calcd for 0 21
H-
23 0ANS 2 01.5 H 2 0: 0, 49.99; H, 5.19; N, 8.33; S, 12.71.
Found: 0, 49.57; H, 4.94; N, 8.15; S, 12.43.
Exam pie S-[(5-Methylisoxazol-3-yl)methyl]-N-[4(pyrid-4-y) sulfanylbenzenesulfonyl]-D-penicillamine.
0 HO NH 0- Me mp 79-8500C 1 1- NMR (DMSO-d 6 6 1.27 1.29 2.33 3.73 (dd, 2H, J 12.6 Hz), 3.77-3.83 (in, 1 6.14 1IH, J 1.6 Hz), 7.13 (dd, 1IH, J 1.6, 4.7 Hz), 7.68 2H-, J 8.7 Hz), 7.85 21-, J 8.7 Hz), 8.32-8.47 (in, IR (KBr): 3425, 3248, 17.13, 1608, 1557, 1478,1337,1161, 1096, 1077, 756, 620 HR FABMS Calcd for 0 2 1
H
24 NA0S 3 494.0878. Found: 494.0890.
Anal. Calcd for C 2
,H
23
N
3 0 5
S
3 .0.1 C 7
H-
16 0 0.3 CHC 3 C, 48.98; H, 4.65; N, 7.79; S, 17.83. Found: C, 48.77; H, 4.69; N, 7.63; S, 17.76.
Prepared in a manner similar to Example 3(p) was Example 4(d).
SUBSTITUTE SHEET (RULE 26) WO 98/43963 PCT/US98/06365 31 Example N-[4-(Pyrid-2-yl)oxy)benzenesulfonyl]-D-tert-leucine.
O
O 0=6 2 HO H mp 202 °C (decomp); 'H-NMR (CDC 3 5 1.02 9H), 3.55 1H, J 10 Hz), 5.30 1H, J 10 Hz), 7.05-8.21 8H); FAB HRMS: Expected M+Cs)+= 497.0147. Found (M+Cs) 497.0160.
Example 4 N-[4-(4-(Furan-3-yl)phenoxy)benzenesulfonyl]-S-[(pyrid-2yl)methyl]-D-penicillamine.
O O=s HO H
S
To a suspension of 221 mg (0.40 mmol) of N-[4-(4-bromophenoxy) benzenesulfonyl]-S-[(pyrid-2-yl)methyl]-D-penicillamine (from example in 2 mL of benzene and 2 mL of 2M aqueous Na 2
CO
3 solution was added a solution of 71 mg (0.48 mmol) of 3-furan boronic acid Org. Chem. 1984, 49, 5237-5243) in 2 mL of EtOH. To the resulting mixture was added solid Pd(PPh 3 4 (46mg, 0.04 mmol) under a flow of Ar. The mixture was heated at 80 0 C with vigorous stirring for 72 hours, cooled to room temperature, and partitioned between ehtyl acetate and AcOH/HO0 buffer (pH The aqueous layer was adjusted to pH of 3 by adding AcOH, then extracted with EtOAc (2x70mL). The combined organic layers were washed with brine, dried over Na 2
SO
4 ,and concentrated. The residual yellow solid was chromatographed on silica gel, eluting first with CHCl2, then with methanol in dichloromethane to elute the product fractions. After concentration of the product-containing fractions, the residue was triturated with hexane/t-butyl methyl ether, and the solid was collected by filtration. The solid was dried in high vacuum to give 166.1 mg of N-[4-(4-(furan-3-yl)phenoxy)benzenesulfonyl]- SUBSTITUTE SHEET (RULE 26) WO 98/43963 WO 9843963PCTIUS98/06365 32 S-[(pyrid-2-yI )methyl]-D-penicillamine as a yellow solid: mp 185-1 8900; H-NM R (CDCd 3 5 1.40 3H-) 1.44 3.32-4.01 (in, 6.83 11H), 7.10-7.13 (in, 7.22-7.23 (in, 2H), 7.57-7.92 (in, 8.42 J 4 Hz, 2H-).
Anal. caic. for C 27
H
26
N
2 0 6
S
2 0, 60.20; H, 4.87; N, 5.20. Found: 0, 60.00; H, 4.88; N, 4.94.
Example 5. S-Carboxymethyl-N-[4-(4-fluorophenoxy)benzenesu Ifonyl]-Dpenicillamine 0 0oo=S o /\F HO NH
HO
2
C---S
To a solution of S-(t-Butoxycarbonyl)methyl-N-[4-(4fluorophenoxy)benzenesulfonyl]-D-penicillamine (188.8 mg, 0.367 mmol) in 3.4 mL of dichloromethane at 20 0 C was added trifluoroacetic; acid (0.85 mL). The solution was stirred for 16 h and concentrated in vacuo. The residue was partitioned between ethyl acetate (25 ml-) and 1 M aq. phosphate buffer (pH 7).
The aqueous layer was extracted with two additional portions of ethyl acetate mL), and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was triturated with diethyl ether (5 ml-) to give 67 mg of S -Ca rboxymethyl-N uoro phen oxy)benzen esulIfonyl]-Dpenicillamine as an off-white solid: mp 69 1H-NMR (DMSO-d6) 6 1.32 (br s, 3.25-3.5 (br m, 7.12 J 8 Hz, 7.2-7.5 (in, 7.82 J 8 Hz, 2H), 8.00-8.40 (br s, 1 12.5-13.2 (v br s, 1 H).
Anal. calc. for C 19
H
2 FN0.
7
S
2 e0.7 H 2 0o 0.2 Et 2 O: C, 49.04; H, 4.86; N, 2.89.
Found: 0, 49.04; H, 4.91; N, 2.78.
Example 6: Preparation of Compounds of Formula Ill.
Example 6(a) S-Methyl-N-[4-(phenoxy)benzenesulfonyl]-D-penicillamine {11111-
A,W=CH
3 SZ =H) To a solution of S-methyl-N-[4-(phenoxy)benzenesulfony]-D-penicillamine methyl ester (0.250g., 0.610 inmol) in DMSO (3 ml) at room temperature was SUBSTITUTE SHEET (RULE 26) WO 98/43963 PCT/US98/06365 33 added sodium thiomethoxide (171 mg., 2.44 mmol) in one portion. The solution was heated at 45 oC forl8 hours, and then cooled to 0 °C and acidified to using 1N aqueous sodium bisulfate. The mixture was partitioned between ethyl acetate and water, and the organic phase was washed with brine, dried over MgSO 4 and concentrated. The residue was purified on silica eluting with 8 to 12% methanol in dichloromethane to give S-methyl-N-[4-(phenoxy)benzenesulfonyl]-Dpenicillamine as a white solid in 95 yield: mp 156-158 1 H-NMR (DMSO-d6) 6 1.28 3H), 1.31 3H), 1.97 7.08-7.82 Anal. calc. for C, 18 -HNOsS 2 O0.5 CH 2
CI
2 C, 50.73; H, 5.06; N, 3.20. Found: C, 50.46; H, 5.00; N, 3.24.
The starting material was prepared as follows: S-Methyl-D-penicillamine methyl ester To a 0 °C solution of D-penicillamine methyl ester hydrochloride (0.250g., 1.25 mmoles) in DMF (4 mL) was added DBU (0.382 ml., 2.56 mmoles), followed by methyl iodide (0.081 ml., 1.31 mmoles). After 1 hour, the solution was partitioned between brine and ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated. The residue was purified on silica, eluting with 6% methanol in dichloromethane to give S-methyl-D-penicillamine methyl ester as a colorless oil in 81 yield: 1 H-NMR (CDCI3) 6 1.25 3H) 1.35 3H), 2.02 (s, 3H), 3.44 3.72 3H); FAB HRMS:expected(M+H)=178.0902, found(M+H)=178.0905.
(ii) S-Methyl-N-[4-(phenoxy)benzenesulfonyl]-D-penicillamine methyl ester To a solution of S-methyl-D-penicillamine methyl ester (0.160g., 0.904 mmol) and diisopropylethylamine (0.172 mL, 0.99 mmol) in dichloromethane (3 mL) was added 4-phenoxybenzenesulfonyl chloride (0.304 g, 1.13 mmol) via solid addition funnel. After 2.5 hours at room temperature, the solution was concentrated and the residue was purified on silica, eluting with 20% ethyl acetate in hexane, to give S-methyl-N-[4-(phenoxy)benzenesulfonyl]-D-penicillamine methyl ester as a white solid in 87 yield: 'H NMR (CDCI3) 6 1.31 3H), 1.37 3H), 1.96 3.48 3H), 3.79 1H, J=9 Hz), 5.34 1H, J=10 Hz), 6.99-7.79 9H); FAB HRMS: expected (M+Na)=432.0915, found(M+Na)=432.0907.
SUBSTITUTE SHEET (RULE 26) WO 98/43963 PCT/US98/06365 34 Prepared in a similar manner was the following: Example S-Methyl-N-[4-(4-chlorophenoxy)benzenesulfonyl]-Dpenicillamine {Ill-A, W CHS, Z Cl} mp 203 °C (decomp); 1 H NMR (CDC 3 d 1.21 3H), 1.25 3H), 1.88 3H), 3.75-3.84 1H), 6.91-7.95 9H); FAB HRMS: expected 561.9526.
Found 561.9538.
Example 7 S-[2-(Methoxycarbonyl)ethyl]-N-[4-(4-fluorophenoxy)benzenesulfonyl]-D-penicillamine {III-A, W EtO 2
C(CH)
2 S, Z F} To a 0 °C solution of N-[4-(4-fluorophenoxy)benzenesulfonyl]-S-[2- (methoxycarbonyl)ethyl]-D-penicillamine allyl ester (0.36 g, 0.687 mmol) in 5 mL of ethyl acetate was added N-methylaniline followed by Pd(PPh 3 4 (16 mg, 0.014 mmol). After 3 hours, the solution was concentrated, and the residue was purified by chromatography on silica gel, eluting first with 1:1 ethyl acetate:hexane and then with 10% methanol in dichloromethane to give fluorophenoxy)b enesulfonyl]-S-[2-(methoxycarbonyl)ethyl]-D-penicillamine as a white solid in 89% yield: mp 123-124 'H-NMR(CDC 3 5 1.27 3H), 1.35 (s, 3H), 2.40-2.82 4H), 3.71 3H), 3.94 1H, J 11 Hz), 5.60 1 H, J 11 Hz), 6.93-7.82 8H); FAB HRMS: expected (M+Cs) 618.0033.
Found(M+Cs)=618.0038 The starting material was prepared as follows: N-(tert-Butoxycarbonyl)-S-[2-(methoxycarbonyl)ethyl]-D-penicillamine allyl ester To a suspension of D-penicillamine (10.0 67.02 mmol) in methanol (100 mL) at 0 °C was added 14.5 mL (67 mmol) of a 25 wt% solution of sodium in methanol dropwise. After 15 minutes, methyl acrylate (6.35 mL, 70 mmol) was added dropwise, and the solution was allowed to warm to room temperature overnight. Removal of the solvent by rotary evaporation provided a white solid, which was dissolved in 50% aqueous (100 mL). To the resulting solution was added triethylamine (14 mL, 100 mmol), followed by di-t-butyldicarbonate (16.05 73.6 mmol). After stirring for 12 hours at room temperature, the mixture was concentrated to remove most of the THF, and the resulting aqueous solution was acidified with acetic acid and then extracted with ethyl acetate. The organic layer SUBSTITUTE SHEET (RULE 26) WO 98/43963 PCT/US98/06365 was washed with brine, dried over magnesium sulfate, and concentrated. The residue was dissolved in THF (75 mL) and DBU (10.2 mL, 68.2 mmol) added, followed by addition of allyl bromide (6.14 mL, 71.0 mmol). The solution was stirred at room temperature for 5 hours, and then the solvent was removed by concentration under reduced pressure. The residue was purified on silica gel, eluting with 5% to 10% to 20% ethyl acetate in hexane, to provide N-(tertbutoxycarbonyl)-S-[2-(methoxycarbonyl)ethyl]-D-penicillamine allyl ester as a colorless oil in 44% overall yield: 1 H-NMR (CDCI 3 1.36 3H), 1.38 3H), 1.44 9H), 2.52-2.57 2H, J 8 Hz), 2.75-2.82 2H), 3.69 3H), 4.32- 4.35 1H), 4.62-4.64 2H), 5.27-5.39 3H), 5.85-6.00 FAB HRMS: expected (M+Cs)=508.0770, found(M+Cs)=508.0750.
(ii) S-[2-(Methoxycarbonyl)ethyl]-D-penicillamine allyl ester, trifluoroacetate salt.
To a solution of N-(tert-butoxycarbonyl)-S-[2-(methoxycarbonyl)ethyl]-Dpenicillamine allyl ester (2.00g., 5.51 mmol) in dichloromethane (25 mL) at 0 °C was added trifluoroacetic acid (6.7 mL) added. After 10 minutes, the solution was allowed to warm to room temperature. After 2.5 hours, the solution was concentrated and then azeotroped with benzene to give S-[2- (methoxycarbonyl)ethyl]-D-penicillamine allyl ester as a trifluoroacetate salt in yield: 'H-NMR (CDCI 3 6 1.37 3H), 1.59 3H), 2.54-2.87 (2m, 4H), 3.71 (s, 3H), 4.13 4.69-4.74 2H), 5.31 1H, J 9.5 Hz), 5.39 1H, J 17.3 Hz), 5.88-5.97 1H); FAB HRMS: expected(M+H)=276.1270, found(M+H)=276.1263.
(iii) N-[4-(4-Fluorophenoxy)benzenesulfonyl]-S-[2-(methoxycarbonyl)ethyl]-Dpenicillamine allyl ester To a solution of S-[2-(methoxycarbonyl)ethyl]-D-penicillamine allyl ester, trifluoroacetate salt (0.500g., 1.29 mmol) in dichloromethane (3 mL) at 0 °C was added DBU (0.425 mL, 2.84 mmol) followed by 4-(4-[fluorophenoxy])phenyl sulfonyl chloride(0.438 1.74 mmol). The solution was stirred at 0 "C for minutes and then was allowed to warm to room temperature. After 15 hours, the solution was concentrated, and the residue was purified on silica eluting with 10 ethyl acetate in hexane to give N-[4-(4-fluorophenoxy)benzenesulfonyl]-S-[2- (methoxycarbonyl)ethyl]-D-penicillamine allyl ester as a white solid in 66 yield: SUBSTITUTE SHEET (RULE 26) WO 98/43963 WO 9843963PCT/1US98/06365 36 'H NMR (CDCI 3 5 1.36 3H), 1.40 3H), 2.47-2.53 2.72-2.76 (in, 2H), 3.70 3H), 3.83 1IH, J 10 Hz), 4.29-4.42 (in, 2H), 5.22 1 H, J =5 Hz), 5.27 1IH, J 12 Hz), 5.54 I1H, J 10 Hz), 5.68-5.78 (m,I1H), 6.95-7.79 (in, 8H); FAB HRMS: expected(M+Cs) 658.0346, found (M+Cs) 658.0370.
Example 8. Preparation of Compounds of Formula Ill-A Example S-[2-Hydroxyethyl]-N-[4-(4-fl uorophenoxy)benzenesu lfonyl]-Dpen icillamine (Ill-A, W HO(CH 2 2 S, Z F} Deprotection of S-12-hydroxyethyl]-N-[4-(4-fluorphenoxy)benzenesulfonyl].
D-penicillamine allyl ester was carried in the same manner as in example 7.
Purification on silica, eluting with 10% methanol in dichloromethane provided S-[2hyd roxyethyl]-N-[4-(4-fluorophenoxy)benzenesufonyl]-D-pen icilla mine as a white solid in 61 yield: mp 198-200 (decomp); 'H-NMR (MeOD) 6 1.36 3H), 1.40 (s, 3H), 2.58-2.74 (in, 3.60 2H, J=7 Hz), 3.66 1 7.04-7.88 (in, 8H).
Anal. calc. for O 19
H
22
FNO
6
S
2 *0.5CH 2 0 2 C, 48.19; H, 4.77; N, 2.88. Found: C, 48.44; H, 4.71; N, 2.93.
The starting material was prepared as follows: N-[4-(4-fl uorophenoxy)benzenesulfonyl] -0 -pen icil lam ine allyl ester.
To a stirred solution of N-[4-(4-fluorophenoxy)benzenesulfonyl]-S-[2- (inethoxycarbonyl)ethyl]-D-penicillamine allyl ester (0.100g., 0.19 inmol) in DMSO(1 ml.) at room temperature was added sodium thiomnethoxide (0.053g., 0.762 inmol). After 3.5 hours, the reaction was then acidified with 1 N aqueous sodium bisulfate to pH=4 and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, and concentrated. The residue was purified on silica eluting with 20% ethyl ethyl acetate in hexane to give fluorophenoxy)benzenesulfonyl]-D-penicillainine allyl ester as a colorless oil in yield. IH-NMR COCl 3 6'1.43 6H), 1.93 (s,1 3.82-3.86 1IH, J=11 Hz),4.25-4.38 (in, 2H), 5.23-5.29 (in, 2H), 5.49-5.53 1 H, J=1 1 Hz), 5.63-5.78 (mn,1 6.96-7.79 (mn, 8H) SUBSTITUTE SHEET (RULE 26) WO 98/43963 WO 9843963PCTIUS98/06365 37 S-[2-Hydroxyethyl]-N-[4-(4-fluorophenoxy)benzenesulfonyl].D penicillamine allyl ester.
To a 0 00 solution of N-[4-(4-fluorophenoxy)benzenesulfonyl]-Dpenicillamine allyl ester (0.200g., 0.456 mmol) in DMF (2 ml) was added DBU 102 ml., 0.68 mmol), followed by 2-bromoethanol (0.049 ml., 0.68 mmol). After 1 hour at 0 'C and 5 hours at room temperature, the reaction was partitioned between brine and ethyl acetate. The organic layer was washed with brine, dried over Na 2
SO
4 and concentrated. Purification of the residue on silica, eluting with ethyl acetate in hexane followed by 10% methanol/ methylene chloride, provided S-[2-hydroxyethyl]-N-[4-(4-fluorophenoxy)benzenesulfonylpDpenicillamine allyl ester as a white solid in 72% yield. 1 H-NMR (ODCd 3 6 1.39 (s, 1.40 2.75-2.80 (in, 3.67-3.78 3.87 (d,11H, J=10 Hz), 4.25- 4.38 5.22-5.29 5.66-5.76 1H), 5.93 (djIH, J=10 Hz), 6.95-7.77 (in, FAB HRMS: expected (M +Cs)=616.0240, found(M+Cs)=616.0265 The following was prepared in a similar manner: Exam pie 8(b) S-[2-(Aminocarbonyl)ethyl]-N-[4-(4-fluorophenoxy)benzenesulfonyl]-D-penicillamine {lll-A, W H 2
N(O=)C(CH
2 2 S, Z F) mp 186-l87 00(decomp); 1 H-NMR (CD 3 OD) 6 1.37 1.43 2.40- 2.44 (m,2 2.72-2.91 (in, 2 3.60 1 7.02-7.87 (in, 8 H).
Example 9. Preparation of Compounds of Formula Il-A 0
H
W 1l-A Example 9(a) 2(S)-N-Hydroxy-3-methyl-3-methylsulfanyl-2-[(4-phenoxybenzenesulfonyl)amino~butanamide {ll-A, W CH 3 S, Z =H) To a solution of S-inethyl-N-[4-(phenoxy)benzenesulfonyl]-o-pen icillainine mg., 0.190 inmol) and DMF (0.003 inL., 0.04 minol) in 1 ml- of dichioroinethane at 75 00 was added dropwise oxalyl chloride (0.022 inL., 0.247 iniol). The solution was stirred at -75 0C for 15 minutes and then allowed to warm to -25 00 over 45 minutes. The ice bath was then removed, and THF(1 mL.) SUBSTITUTE SHEET (RULE 26) WO 98/43963 WO 9843963PCTIUS98/06365 38 was added, followed by aqueous hydroxylamine (0.126 mL., 1 .90 mmol, sol'n.). The mixture was stirred at room temperature for 2 hours and then partitioned between ethyl acetate and 0.5 N aqueous sodium bisulfate. The organic later was washed with brine, filtered over celite, concentrated, and the residue was azeotroped with benzene. Trituration of the residue with 25% diethyl ether in hexane provided 2(S)-N-hydroxy-3-methyl-3-methylsulfanyl-2-[(4phenoxybenzenesulfonyl)amino]butanamide as a white solid in 74% yield: mp.
161-163 00; 'H NMR (DMSO-d6) 6 1.25 1.28 3H), 1.97 3.62- 3.66 7.09-8.91 (in, 10H); FAB HRMS: expected (M +H)=411.1048, found(M+H)=41 1.1062.
Anal. caic. for C 1 ,1H 22 NA0S 2 0, 52.66; H, 5.40; N, 6.82. Found: C, 52.58; H, 5.35; N, 6.75.
Prepared in a similar fashion were the following: Example 9(b) 2(S).N-hydroxy-3-methyl-3-methylsulfanyl-2-[(4-(4chlorophenoxy)benzenesulfonyl)amino]butanamide Il-A, W CH 3 S, Z C111 mp 194-1 95 00; 'H-NMR (MeOD) 6 1.34 1.36 3H), 2.01 3.59 1H), 7.09-7.88 (in, 9H).
Anal. calc. for C 18
H
21 01N 2 0 5
S
2 C, 48.59; H, 4.76; N, 6.30. Found: 0, 48.49; H, 4.7 5; N, 6.2 1.
Example 9(c) 2(S)-N-hydroxy-3-methyl-3-(5-methylisoxazol-3-yl)methylsulfanyl- 2-[(4-(4-fluorophenoxy)benzenesulfonyl)amino]butanamide (ll-A, W methyllisoxazol-3-yl)CHAS Z- F) mp 159 00; 1 H- NMR (DMSO-d6) 6 1.3 3H), 1.33 2.42 3.70-3.83 (in, 6.20 1 7.09 J 8 Hz, 7.2-7.4 (2 in, 4H), 7.83 J 7 Hz, 2H), 8.08 J 9 Hz, 1 8.94 1 10.67 1 H).
Anal. calc. for 0 22
H
24
FN
3 0 6
S
2 0, 51.86; H, 4.75; N, 8.25; Found: C, 51.86; H, 4.75; N, 8.25.
SUBSTITUTE SHEET (RULE 26) WO 98/43963 WO 9843963PCT/US98/06365 39 Example 9(d) 2(S)-N-hydroxy-3-methyl-3-(5-methylisoxazol-3-yl)methylsulfany.
2-[(4-(4-bromophenoxy)benzenesulfonyl)ami no]butanamide {II-A, W methylisoxazol-3-yl)CH 2 S, Z Br} mnp 15400; 1H-NMR (DMSO-d6) 6 1.31 1.33 2.42 3.70-3.82 (in, 6.22 1 7.10-7.18 (overlapping d, J 9.1, 8.8 Hz, 7.65 J Hz, 7.85 J 8.5 Hz, 8.12 J 9.1 Hz, 1 10.68 1IH).
Anal. caic. for O 22
H-
24 BrNAOS 2 0, 46.32; H, 4.24; N, 7.37; Found: 0, 46.19; H, 4.29; N, 7.18.
Example 9(e) 2(S)-N-hydroxy-3-methyl-3-(pyrid-2-yl)methylsulfanyl-2-[(4-(4bromophenoxy) benzenes ulfonyl)ami no] butanam ide (ll-A, W-(pyrid-2yI)CH 2 S, Z=Br} mnp 70-73 00; 1H-NMR (00013) 5 1.21 1.62 3.82-3.89 (in, 3H-), 4.92 J=5 Hz, I1H), 5.98 J=5 Hz, 1 6.85-7.14 (in, 7.41-7.95 (in, 7H-), 8.42 (br s, 1 H) Anal. calc. for 0 23
H
24
N
3
OS
2 Br*0.4 H 2 0*0.5 hexane: 0, 49.43, H 4.79, N 7.06.
Found 0, 49.50; H, 4.38; N, 6.90 Example 9(f) 2(S)-N-hydroxy-3-methyl-3-(pyrid-2-yl)methylsulfanyl-2-[(4-(4iodophenoxy)benzenesulfonyl)amino]butanamide {11-A, W=(pyrid-2-yl)CH 2
S,
z=I} mnp 85-87 00; 1'H-NMR (00013) 5 1.55 1.63 3.84-3.97 (in, 2H-), 4.96 J=5.5 Hz, 1 5.45 J=5.6 Hz, 1 5.97 J=4.6Hz, 1 6.83-7.26 (in, 7.68-7.89 (in, 11.22 1 H) Anal.calc. for C 23
H
24
N
3 0 5
S
2 1: 0, 45.30; H, 4.30; N, 6.40. Found: 0, 45.33; H, 4.12; N, 6.31.
Example 9(g) 2(S)-N-hydroxy-3-methyl-3-(pyrid-2-yl)methylsulfanyl-2-(4-(4methyl phenoxy)benzenesulfonyl)amino]butanamide {ll-A, W=(pyrid-2yl)CH 2 S, Z=CH 3 mp 105-108 00; 1 H-NMR (00013) 6 1.54 3H), 1.68 2.40 3.85- 4.01 (mn, 4.95 J=6.0 Hz, 1 5.45 J=5.5 Hz, 1IH), 5.89 J=6.2Hz, 1 6.98-7.03 (mn, 4H), 7.18-7.22 (mn, 7.26-7.86 (irn, 8.47 4.6H-z, 2H-) Anal. calc. for 0 24
H
27
N
3
OS
2 0.hexane*l.1AcOH: 0,5564; H, 5.66; N, 7.35 Found: 0, 55.62; H, 5.78; N, 7.38 SUBSTITUTE SHEET (RULE 26) WO 98/43963 PCT/US98/06365 Example 9(h) 2(S)-N-hydroxy-3-methyl-3-(pyrid-2-yI)methylsulfanyl-2-[(4-(4fluorophenoxy)benzenesulfonyl)amino~butanamide (IlI-A, W=(pyrid-2-yl)CHS,
Z=F)
rnp 66-69 0 C; 'H-NMR (CDC 3 6 1.23 6H), 3.38 2H), 4.89-4.91 1H), 5.58-5.59 J=10.2 Hz,1H), 5.98-6.01 J=7.5 Hz, 1H), 6.97-7.11 4H), 7.58-8.13 6H), 8.41 2H).
Anal. caic. for C 23
H
24
N
3
O,S
2 FoO.2 H 2 090.2 hexane: C, 55.96; H, 5.52; N, 7.77. Found: C, 55.90; H, 5.47; N, 7.67.
Example 9(i) 2(S)-N-hydroxy-3-methyl-3-benzylsulfanyl-2-[(4phenoxybenzenesulfonyl)amino]butanamide (Il-A, W PhCH 2 S, Z H) mp 35-37 00; 'H-NMR (CDC1) )6 1.21 3H); 1.61 3H), 3.62-3.82 2H), 6.98-7.04 6H), 7.21-7.54 6H), 7.89-7.91 2H).
Anal. calc. for C 24
H
26
N
2
O
5
S
2 0.65H 2 0*0.2NH 3 C, 57.45; H, 5.61; N, 6.14.
Found: C, 57.42; H, 5.59; N, 6.11 Example 9(j) 2(S)-N-hydroxy-3-methyl-3-(t-butoxycarbonyl)methylsulfanyl-2- [(4-(4-fluorophenoxy)benzenesulfony)aminolbutanamide {I1-A, Wt- BuO 2
CCH
2 S, Z=F} mp 1380; 1H-NMR (DMSO-d6) 61.28 6H), 1.45 9H), 3.38 1H), 3.67 (d, J 9.6 Hz, 1 7.09 J 8.8 Hz, 2H), 7.20-7.36 (2m, 4H), 7.81 J 8.8 Hz, 2H), 8.02 J 9.9 Hz, 1H), 8.90 1H), 10.60 1H).
Anal. caic. for C 23
H
2
,FN
2 0 7
S
2 C, 52.26; H, 5.53; N, 5.30. Found: C, 52.21; H, 5.54; N, 5.21.
Example 9(k) 2(S)-N-hydroxy-3,3-dimethyl-2-[(4-phenoxybenzenesulfonyl)amino]butanamide {1I-A, W CH 3 Z H} mp 129-132oC; 1 H-NMR (CDC 3 6 0.92 9H), 3.32 1H), 5.60 (br, 1H), 6.99- 7.18 4H), 7.21-7.42 (in, 4H), 7.77 J 9.0 Hz, 2H).
Anal. caic. for C 18
H
22
N
2 Se0.3 H 2 0: C, 56.32; H, 5.93; N, 7.30; Found: C, 56.31; H, 6.03; N, 7.68 Example 9(I) 2(S)-N-hydroxy-3,3-dimethyl.2-[(4-(4-fluorophenoxy)benzenesulfonyl)aminolbutanamide W CH 3 Z F} mp 122-125 0C; 1 H-NMR (CDC13)60.98 9H), 3.29 J 9.6 Hz,1 5.60 J 10.5 Hz, 1H), 6.97-7.09 (in, 6H), 7.77 J 8.5 Hz, 2H).
SUBSTITUTE SHEET (RULE 26) WO 98/43963 WO 9843963PCTIUS98/06365 41 Anal. caic. for C 18
H
2
,FN
2 0,S: C, 54.53; H, 5.34; N, 7.07 Found: C, 54.43; H, 5.33; N, 7.13 Exam pie 9(m) 2(S)-N-hydroxy-3,3-dimethyl-2-[(4-(4chlorophenoxy)benzenesulfonyl)amino]butanamide {1I-A, W CH 3
Z
cI} mp 164-165 00; H-NMR(CD 3 OD): 1.00 9 3.30 11H), 7.08-7.86 (in, FAB HRMS: expected (M +H)=41 3.0938, Found(M+H)=41 3.0951.
Anal. caic. for ClBH 21 CtN 2 0 5 S: C, 52.36; H, 5.13; N, 6.79 Found: C, 52.21; H, 5.23; N, 6.66.
Example 9(n) 2(S)-N-hydroxy-3-methyl-3-(I -methyl-I H-imidazol-2-yl)methylsu lfanyl-2-[(4-(4bromophenoxy)benzenesulfonyl)amino]butanamide {ll-A, W {1 methyl-I H1-imidazol-2-yI)CHAS Z Br}: 'H NMR (DMSO): 6 1,23 3H-), 1.28 3.32 3.67 1 H, J =9.9 Hz), 3.80 1 H, J 13.6 Hz, AB), 3.90 1IH, J 13.6 Hz, AB), 6.77 1IH), 7.04-7.12 (in, 5H), 7.59 (d, 2H-, J 9.0 Hz), 7.76 2H-, J 8.7 Hz), 8.05 1 H, J 9.9 Hz), 9. 10 (s, 1H), 10.96 1IH).
ESIMS Calcd for C 22
H
25 BrN 4
O
5
S
2 569/571. Found: 569/571.
Examples 9(o) through 9(s) may be prepared in a similar fashion: Example 9(o) 2 -hydroxy-3-methyl -m ethyl -I H -i m idazol-2-yI) methylsulfanyi-2-[(4-(4-bromophenoxy)benzenesulfonyl)ami no]butanamide {lI-A, W (11 -methyl-I H-imidazol-2-yl)CH 2 S, Z =Blr} Example 9(p) 2(S)-N-hydroxy-3-methyl-3-(1 H-imidazol-4-yl)methylsulfanyl-2- [(4-(4-bromophenoxy)benzenesulfonyl)amino]butanamide f{11-A, W (1 Himidazol-4-yl)CH 2 S, Z Br} Example 9(q) 2(S)-N-hydroxy-3-methyl-3-(I -methyl-I H-imidazol-4-yI) methylsulfanyl-2-[(4-(4-bromophenoxy)benzenesulfonyl)amino]butanamide (1l-A, W (I -methyl-I H-imidazol-4-yl)CH 2 S, Z Br} Example 9(r) 2(S)-N-hydroxy-3-methyl-3-(4-methyl-4H-[I ,2,4J-triazol-3-yl) methylsulfanyl-2-[(4-(4-bromophenoxy)benzenesulfonyl)amino]butanam ide {Il-A, W (4-methyl-4H-[I,2,4]-triazol-3-y)CH 2 S, Z Br} SUBSTITUTE SHEET (RULE 26) WO 98/43963 WO 9843963PCT/US98/06365 42 Example 9(s) 2(S)-N-hydroxy-3-methyl-3-(1 -methyl-4H-[1 ,2,4]-triazol-3-yl) methylsulfanyl-2-[(4-(4-bromophenoxy)benzenesulfonyl)aminojbutanamide f{1l-A, W (I -methyl-4H-[1,2,4]-triazol-3-y)CH 2 S, Z Br} Examples 10O(a), 10O(b), and 10O(c) were prepared in a manner similar to that described in Example 9(a).
Exam pie 10(a) 2(S)-N-hydroxy-3-methyl-3-(5.methylisoxazol-3yl)methylsu lfanyl-2-[(4-(pyrid-4-yloxy)benzenesulfonyl)ami nolbutanamide 0 HO,. N-'l4 H s N-0 Prepared according to the procedure described in Example mp 71-72 CC. 'H- NMR (CD 3 OD) 6 1.4 1.6 2.4 3.68 1 3.78 21-, J 10.6 Hz), 6.08 1 7.08 2H-, J 5.0 Hz), 7.26 2H-, J 9.0 Hz), 7.94 (d, 2H-, J =9.0 Hz), 8.44 2H-, J 6.2 Hz).
Anal. Calcd for 0 2
,H
24 0 6
N
4
S
2 *05 H 2 0*1.1 HOAc: C, 49.09; H, 5.22; N, 9.87; S, 11.30. Found: C, 49.33; H, 5.23; N, 9.69; S, 10.94.
Exam pie 10O(b) 2(S)-N-hydroxy-3-methyl-3-(5-methylisoxazol-3yl)methylsufanyl-2-[(4-{(pyrid-4yl)sulfanyl~benzenesulfonyl)amino]butanamide 0 0 O=SC S-C'N HO..
NH-
H
N-0 'H NMR (acetone-d 6 6 1.36 3H), 1.40 2.38 3.75 I1H, J 13.4 Hz), 3.83 1IH, J 13.4 Hz), 3.88 I 6.18 1IH), 7.10-7.22 (in, 2H-), 7.68 21-, J 7.4 Hz), 7.94 21-, J 7.4 Hz), 8.35-8.50 (in, IR: 3222, 1670, 1578, 1332, 1165 HR FABMS: Calcd for C 2
,H
24
N
4
O
5
S
3 CS 640.9963. Found: 640.9988. Anal. Calcd for C 21
H-
24 NA0S 3 0.1 C 7 H-1 6 0.3
CHCI
3 C, 47.66; H, 4.71; N, 10.10; 3, 1.7.35. Found: 0, 47.67; H, 4.69; N, 10.05; S, 17.42.
SUBSTITUTE SHEET (RULE 26) WO 98/43963 WO 9843963PCTIUS98/06365 43 Example 10(c) 2(S)-N-hydroxy-3,3-dimethyl-2-[4-(pyrid-2-yl)oxybenzenesulfonyl)amino]butanamide 0 HO0N
H
mp 186-1 87 00; 1 H NMR (CD 3 OD) 6 1.0 1 9H), 3.30 1IH), 7.15-8.22 (in, 8 H); FAB HRMS: expected(M+Cs)=51 2.0256, Found (M+Cs)=51 2.0267 Example 11. S(RIS)-N-hydroxy-3-methyl-3-(pyrid-2-yl)methylsulfinyl-2- [(4-(4-bromophenoxy)benzenesulfonyl)amino]butanamide 0 0O=-C \O Br HO,
N
H
To a 0 00 solution of 2 (S)-N-hyd roxy-3-methyl-3-(pyrid-2-yl) methyl sulfa nyl 2-I(4-(4-bromophenoxy)benzenesulfonyl)amino]butanamide (57 mg) in dichloromethane (11 ml-) was added 17 mg of m-chloroperbenzoic acid. The mixture was allowed to warm slowly to room temperature overnight, and then partitioned between ethyl acetate and sat. aq. sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel, eluting first with ethyl acetate and then with 10% methanol in dichloromethane. The product fractions were concentrated and then triturated with t-butyl methyl ether/hexane to give 23.8 mg (41 of S(RIS)-N-hydroxy-3-methyl-3-(pyrid-2-yl)methylsulfinyl-2-[(4-(4bromophenoxy) benzenesulfonyl)amino]butanamide as a white solid: mp 103- 10500; 'H-NMR (ODCd 3 6 1.21 1.25 3H), 4.09-4.14 4.65 (d, Hz, 1 5.62 1IH), 6.02 (br 1 6.91-7.00 (in, 5H), 7.40-7.47 (in, 6H), 8.52 2H), 10.02 1 H).
SUBSTITUTE SHEET (RULE 26) WO 98/43963 PCT/US98/06365 44 Example 12. 2(S)-N-hydroxy-3-methyl-3-(carboxymethyl)sulfanyl-2-[(4-(4fluorophenoxy)benzenesulfonyl)amino]butanamide To a solution of 59.5 mg (0.113 mmol) of 2(S)-N-hydroxy-3-methyl-3-(t-
O
HO
N
lH S- C02H butoxycarbonyl)methylsulfanyl-2-[(4-(4-fluorophenoxy)benzenesulfonyl)amino] butanamide (Example in dichloromethane (1.1 mL) at 20 oC was added trifluoroacetic acid (0.26 mL). After 16 hours, an additional 0.1 mL of trifluoroacetic acid was added. After an additional 6 hours, the reaction was diluted with 5 mL of benzene and then concentrated. The residue was purified by chromatography on silica gel, eluting with 5% methanol in chloroform containing 0.1% acetic acid, to give 28.9 mg of 2(S)-N-hydroxy-3-methyl-3- (carboxymethyl)sulfanyl-2-[(4-(4-fluorophenoxy)benzenesulfonyl)amino]butanamide as an off-white solid: mp 180°C; H-NMR (DMSO-d6) 5 1.19 3H), 1.25 3H), 3.03 J 16.9 Hz, 1H), 3.13 J 16.9 Hz, 1H), 3.85-4.00 (br s, 1H), 7.08 J 8.8 Hz, 2H), 7.2-7.36 (2m, 4H), 7.77 J 8.8 Hz, 2H), 8.30-8.50 (br s, 1H), 8.70-8.90 (br s, 1H), 11.90-12.20 (br s, 1H).
Anal. calc. for C 1
,H
21
FN
2 0OS 2 e0.5 H 2 00.5 CHCI,: C, 43.28; H, 4.19; N, 5.17.
Found: C, 43.36; H, 4.40; N, 4.91.
The results obtained during biological testing of some preferred embodiments of the inventive compounds are described below.
BIOLOGICAL DATA Isolation of MMP's for Assays The catalytic domain of human collagenase-1 was expressed as a fusion protein with ubiquitin in E. coli (see Gehring, J Biol. Chem., 1995, 270, 22507). After purification of the fusion protein, the fibroblast collagenase-1 catalytic domain (HFC) was released either by treatment with purified, active stromelysin-1 (1:50 w/w ratio), which generated nearly 100% N-terminal Phel, or by autoprocessing the concentrated collagenase-1 fusion and then incubating at SUBSTITUTE SHEET (RULE 26) WO 98/43963 PCT/US98/06365 37 °C for 1 hour. Final purification was completed using zinc chelate chromatography.
The propeptide and catalytic domain of human collagenase-3 (Coll3) was expressed in E. coil as an N-terminal fusion protein with ubiquitin. After purification of the fusion from inclusion bodies, the catalytic domain was liberated by treatment with 2mM APMA at room temperature overnight. Final purification was completed using copper chelate chromatography.
The catalytic domain of human stromelysin (Sin) was obtained by expression and purification of a C-terminally truncated prostromelysin-1 from E.
coli host BL21 (see Marcy et al. Biochem., 1991, 30, 6476). The subsequent activation of the mature form (Sin) was completed with 2mM APMA for 1 hour at 37 followed by separation using a sizing column.
Human matrilysin (Matr) was expressed in E. coil as a fusion protein with ubiquitin. After purification of the matrilysin/ubiquitin fusion from inclusion bodies, the catalytic domain was liberated by treatment with 2mM APMA at 37 °C for 2 hours. Final purification was complete using copper chelate chromatography.
The catalytic and fibronectin-like portion of human progelatinase A (GelA) was expressed as a fusion protein with ubiquitin in E. Coli. Assays were carried out on autocatalytically activated material.
Compounds of Formula I exhibited the ability to inhibit MMPs when tested in the following assay.
In Vitro Assay Procedure Assays were performed in assay buffer (50 mM Tricine pH 7.5, 200 mM sodium chloride, 10 mM calcium chloride, 0.5 mM zinc acetate containing 2% dimethyl sulfoxide (DMSO)) once the substrate and inhibitor were diluted into it.
Stock solutions of inhibitors were prepared in 100% DMSO. Stock solutions of the substrate were prepared in 100% DMSO at a concentration of 6 mM.
The assay method was based on the hydrolysis of MCA-Pro-Leu-Gly-Leu- DPA-Ala-Arg-NH 2 (American Peptide Co.) at 37 °C (see Knight, C.G. et al., FEBS, 1992, 296, 263-266). The fluorescence changes were monitored with a Perkin- Elmer LS-50B fluorimeter using an excitation wavelength of 328 nm and an emission wavelength of 393 nm. The substrate concentration used in the assays was 10 pM. The inhibitor was diluted into the assays from a solution in 100% SUBSTITUTE SHEET (RULE 26) WO 98/43963 PCT/US98/06365 46 DMSO, and controls substituted an equal volume of DMSO so that the final DMSO concentration from inhibitor and substrate dilution in all assays was The concentration of enzyme in the assay ranged from 60 pM for gelatinase A to nM for stromelysin and is a function of the enzymes respective kcat/Km for the MCA peptide substrate. Proper determination of steady-state rates of substrate cleavage required assay lengths of 60 minutes to allow for complete equilibration of the enzyme-inhibitor complex.
The Km for the MCA peptide substrate with the matrix metalloproteinases is quite high and exceeds its solubility under assay conditions. Consequently, the apparent K, (Ki,app) was determined to describe the strength of inhibition. However, in this case, K.app would be essentially equal to Ki since For the determination of K,app, the concentration of the inhibitor was varied at a constant and low concentration of substrate and the steady-state rates of fluorescence change determined. In most cases absorptive quench due to the presence of ligand was not observed. For slow-binding inhibitors, onset of inhibition curves were collected for at least 45 minutes so that equilibrium was established. Steadystate rates of fluorescence change were obtained by fitting a curve to an equation for a single exponential decay containing a linear phase. The fitted value of the linear phase was taken as the steady-state rate. The steady-state rates were fitted to the Michaelis equation describing competitive inhibition by non-linear methods. Data resulting from tight-binding inhibition was analyzed, and Ki,,app determined by fitting the data to the tight-binding equation of Morrison (Biochem.
Biophys. Acta, vol. 185, pp. 269-286 (1969)) by non-linear methods.
The results of the above-described tests are presented below in Table 1.
All Ki values are in nM units.
SUBSTITUTE SHEET (RULE 26) WO 98/43963 WO 9843963PCTIUS98/06365 47 TABLE 1 Example Structure Sin Ki Matri HFC Gel A CoMl Ki Ki Ki Ki 0 3a 0i<4F 1300 11 200 0 HO-J HBr 0 3b -N'N 558 1.8 108 0
N-.
N. F 3c 2550 44 110 0 0N o
HI
HD Br 3d 1500 75000 34000 7 178 SUBSTITUTE SHEET (RULE 26) WO 98/43963 PCTIUS98/06365 xample Structure Sin Ki Matri HFC Gel A Cot3 Ki Ki Ki Ki 0 0N o
HI
3e 6900 517 1100
N
0 0N 0 H 00 3f 6300 311 829 o 0 H 0 II I il
HO
0 3g 1313 10 117 0 0
A
o I 3h N 8200 73 258 0 o N H II I Is 01P 3i 1180 3.3 196 SUBSTITUTE SHEET (RULE 26) WO 98/43963 WO 9843963PCTIUS98/06365 Example Structure Sin Ki Matri HFC Gel A CoII3 Ki Ki Ki Ki 0 o H!
I
0
F
3j F 2950 48 0 0 3k 2600 4.2 209
K
0 0 0 0 0
HO)KNB-)
3m 01000 46 907 0 0 HB 11 1 S0
F
00 5700 183 574 SUBSTITUTE SHEET (RULE 26) WO 98/43963 WO 9843963PCT[US98/06365 Example Structure Sin Ki Matri HFC Gel A cowI Ki Ki Ki Ki 0 0 3o S N2150 34 0 0 H 11
I
3p HO K NCI 9500 62 203 ~~0 0
F
3q 014000 150 1180 0 0 HI
II
3r 012745 104 616 0 0 H 11Z'
I
HCO N- B r 3s 0348000 900
IN'NOH
SUBSTITUTE SHEET (RULE WO 98/43963 WO 9843963PCTIUS98/06365 SUBSTITUTE SHEET (RULE 26) WO 98/43963 WO 9843963PCTIUS98/06365 SUBSTITUTE SHEET (RULE 26) WO 98/43963 PCT/US98/06365 xample Structure Sin Ki Matri HFC Gel A CoII3 Ki Ki Ki Ki 0 o 0 H ii
I
00 8b 0 5700 334 0 0 H 0 HO HI 9a H 2.2 0.069 0.067 s0 0 HH Oa 9b H 0 1.5 115 30 0.065 0.042 0 o
F
9c H 0 0.63 0.024 N-0 0 0 0 H, LN\ Br 9d H 0 0.24 0.007 0.013 I's l SUBSTITUTE SHEET (RULE 26) WO 98/43963 WO 9843963PCTIUS98/06365 Example Structure Sin Ki Matri HFC Gel A ColI3 Ki Ki Ki Ki 0 9eS 0.26 7.9 4.1 0.009 0.009
N/
0 H 0 9f -0.29 0.007 0.015 0 H 0'I
N--
H 0 9g -0.73 0.036 0 0 H 0 H0t 9i H 0 1.4 26 33 0.038 0.16 SUBSTITUTE SHEET (RULE WO 98/43963 WO 9843963PCT/US98/06365 Example Structure Sin Ki Matri HFC Gel A CoII Ki Ki Ki Ki 0 aF H 0 9i 1.6 33 0.048 0.091 0 00 HOJJK N- S 9kH 04.2 376 53 0.091 0.057 0~~ o1 H 0 91H 01.8 120 30 0.109 0.059 0 9m N CI 1 93 21 0.09 0.034 H 0 0 0 \a Br 0 9n NH 0.2 0.11
CH
3 C SUBSTITUTE SHEET (RULE 26) WO 98/43963 PCTIUS98/06365 xample Structure Sin Ki Matri HFC Gel A CoII3 Ki Ki Ki Ki 0 o
N
N Y H 0
H
11.4 0.32 0 s o
II
N
H
1 .S 38 0.75 1.6
NI
00 H 71 2268 960 5.1 4.6 0
H
11 0 1 24 0.049 0.028 0 0 H iF 12 0s 5.7 0.53 0.27 -Ts- SUBSTITUTE SHEET (RULE 26) r r r
I
~r Example 13. Comparative Example The compound of Example 9 from WO 95/35276, N-hydroxy-2-(toluene-4sulfonylamino)acetamide (compound 13 shown below in Table was prepared and its Ki's against gelatinase A and Stromelysin were determined. Table 2 shows these results in comparison to the results obtained for representative preferred compounds from the present invention.
TABLE 2 COMPOUND NO. STROMELYSIN Ki (nM) GELATINASE Kj (nM) 13 3400 3500 9d 0.24 0.007 9e 0.26 0.009 9m 1.0 0.09 Thus, the compounds of Examples 9d, 9e, and 9m are 3400 to 500,000 times more potent as inhibitors of stromelysin and gelatinase A than the composition of Example 13, not according to the invention.
Throughout this specification and the claims, the words "comprise", "comprises" and "comprising" are used in a non-exclusive sense".

Claims (8)

1. A compound of formula I: 0 0 2 S -Y-Ar XH R wherein: Y is S; Ar is an optionally substituted aryl group or an optionally substituted heteroaryl group; R is H, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted 15 heteroaryl group, or -C(O)R 1 wherein Ri is hydrogen, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally 20 substituted heteroaryl group, or NR 2 R 3 wherein R 2 and R 3 independently are hydrogen, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group; X is -NH-OH or -OH; or a pharmaceutically acceptable prodrug, salt or solvate thereof.
2. A compound according to claim 1, wherein Ar is an aryl group substituted with a suitable substituent in the position para to the Y moiety; or a pharmaceutically acceptable prodrug, salt or solvate thereof.
3. A compound according to claim 2, wherein said suitable substituent is a halogen, an alkyl group, an O- alkyl group, an aryl group, a heteroaryl group, or an S- alkyl; or a pharmaceutically acceptable prodrug, salt or solvate thereof. H:\Leanne\Keep\68744-98.doc 21/08/01
4. A compound according to any one of claims 1 to 3, wherein R is an alkyl group; or a pharmaceutically acceptable prodrug, salt or solvate thereof. A compound according to claim 4, wherein R is the alkyl group -C-(CH 3 2 -S-alkyl; or a pharmaceutically acceptable prodrug, salt or solvate thereof.
6. A compound according to claim 5, wherein R is the alkyl group -C(CH 3 2 -S-CH 2 -heteraryl; or a pharmaceutically acceptable prodrug, salt or solvate thereof.
7. A compound according to claim 1, wherein said compound has the formula [a: 0 u 2 Y -Ar (la) N\ H or a pharmaceutically acceptable prodrug, salt or solvate thereof.
8. A compound according to claim 1, wherein said compound is selected from: (S N -hyd roxy-3,3 -d imet hyl -2 u orop h en oxy) be nze nes u fo nyl)- amino]butanamide, 2 N-h yd roxy-3,3 -d im eth yl-2 Io roph e noxy)be nze nes u fo nyl)- amino]butanamide, 2(S )-N-hyd roxy-3-methyl-3-(pyrid-2-yl )methylsu lfanyl-2-[(4-(4-fluoro- ph enoxy)benzenesu Ifonyl )amino] buta namid e, 2(S)-N-hydroxy-3-methyl-3-(pyrid-2-yl)methylsulfanyl-2-[(4-(4-bromophen- oxy)benzenesulfonyl)amino]butanamide, N-[4-(4-Bromophenoxy)benzenesulfonyl]-S-[(1 -benzyl-1 H-imidazol-2- yl) methyl]-D-pe nicil la mine, 3 0 N-[4-(4-lodophenoxy)benzenesulfonyl]-S-[(pyrid-2-yl)methyl-D- penicillamine, 2(S )-N-hyd roxy-3-methyl-3-(pyrid-2-yl)methylsulfanyl2[(4.(4.iodophen. oxy)be nze nesu lfonyl)a mino] buta namid e, romophenoxy)benzenesulfonyl]-S-(5-methylisoxazol-3yl )methyl]- 0-penicillamine, \\me IbfNI es \home$\Lean~ne\ Keep\ 68 7
44-98 -doc. 2 1/08/01 2(S )-N-hydroxY-3-methyl-3-(5-methylisoxazol- 3 -yl )methylsulfaflyl-2-[(4-(4- fluorophenoxy)benzenesulfonyI)aio]butaflamlide, bromophenoxy)benzenesulfoflyl)amiflo]butaflamide, phenoxy)benzenesulfonyl)amino]butanamide, (pyrid-4-yloxy)beflzeesulfoflyl)amilo]butalaid e, 2(S )-N-hydroxy-3-methyl-3-(5-methylisoxazol-3-yl )methylsulfanyl-2-[(4- {(pyrid-4-yl)sulfanyl)benzenesulfonyl)amino]butalalide, 2(S )-N-hydroxy-3-methyl-3-( 1 H-imidazol-4-yI )methylsulfanyl-2-[(4-(4- bromophenoxy)belzelesulfoflyl)amilo]butaflamlide, Ott.2(S )-N-hydroxy-3-methyl-3-(I -methyl-I H-imidazol-2-yI) methylsulfanyl-2-[(4- 15 (4-bromophenoxy)benzenesulfoflyl)aila]butalamlide, 0.0 2(S )-N-hydroxy-3-methyl-3-(1 -methyl-I H-imidazol-4-yI) methylsulfanyl-2-[(4- (4-bromophenoxy)benzenesulfoflyl)amilo]butaflamide, 2(S)-N-hydroxy-3-methyl-3-(4-methyl-4H-[1 ,2,4]-triazol-3-yl) methylsulfanyl- ~2-[(4-(4-bromophenoxy)bflefesulfoflyl)amliflo]butaflamide, 2(S )-N-hydroxy-3-methyl-3-(1 -methyl-4H-[1.2 ,4]-triazol-3-yl) methylsulfanyl- 2[(4-(4-bromophenoxy)benzelesulfnflyl)amiflbutaflamide, *an phulonlamaceutallyacJeptbl prodrugs, salts, and solvates thereof. 9. A pharmaceutical composition comprising: a therapeutically effective amount of a compound as defined in any one of claims 1 to 8 or a pharmaceutically acceptable prodrug,.salt or solvate thereof; and a pharmaceutically acceptable carrier, diluent, vehicle or excipient. A method of treating a mammalian disease condition mediated by metalloproteinase activity which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound as defined in any one of claims 1 to 8 or a pharmaceutically ~-~7N.acceptable prodrug, salt or solvate thereof. \\melb-fi es\honme$\LeNnne\Keep\b8744-98.(Ioc 21/08/01 61 11. A method according to claim 10, wherein the mammalian disease condition is tumor growth, invasion or metastasis. 12. A method according to claim 10, wherein the mammalian disease condition is osteoarthritis, rheumatoid arthritis, osteoporosis, periodontitis, or gingivitis. 13. A method according to claim 10, wherein the mammalian disease condition is chronic dermal wounds, corneal ulceration, or degenerative skin disorders. 14. A method according to claim 10, wherein the mammalian disease condition is multiple sclerosis or stroke. 15. A method according to claim 10, wherein the mammalian disease condition is atherosclerosis, glomerular disease, or Alzheimer's disease. 16. A method according to claim 10, wherein the mammalian 15 disease condition is characterized by unwanted angiogenesis. 17. A method according to claim 10, wherein the mammalian disease condition is diabetic retinopathy, macular degeneration, angiofibromas, or hemangiomas. 20 18. A method according to claim 10, wherein the mammalian Sdisease condition is mediated by matrix metalloproteinase S* activity. 19. A method according to claim 10, wherein the mammalian disease condition is mediated by TNF-a convertase activity. A method of inhibiting the activity of at least one metalloproteinase which comprises contacting said at least one metalloproteinase with an effective amount of a compound as defined in anyone of claims 1 to 8 or a pharmaceutically acceptable prodrug, salt or solvate thereof. 21. A method according to claim 20, wherein at least one metalloproteinase is a matrix metalloproteinase. 22. A method according to claim 20 wherein at least one metalloproteinase is TNF-a convertase. \melbbfiles\home$\Leanne\Keep\68744-98.oc 21/08/01 62 23.A compound of formula II: 0 02S Ar S (II) X H wherein: Y' is O; Ar is an optionally substituted aryl group or an optionally substituted heteroaryl group; R' is H, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group or C(CH 3 2 -S-CH 2 optionally substituted heteroaryl; S 15 X is -NH-OH or -OH; or a pharmaceutically acceptable prodrug, salt or solvate thereof. 24. A compound according to claim 23, wherein Ar is an aryl group substituted with a suitable substituent in the position para to the position where Y is bonded to Ar; or a pharmaceutically acceptable prodrug, salt or solvate e* thereof. 25 25. A compound according to claim 24, wherein said suitable substituent is a halogen, an alkyl group, an 0- alkyl group, an aryl group, a heteroaryl group, or an S- alkyl; or a pharmaceutically acceptable prodrug, salt or solvate thereof. 26. A compound according to claim 23, wherein said compound has the formula IIa: 0 2 /Y--Ar 3 5 II I a) H:\suzaet\Keep\Speci\68744-98.1 SPECIdoc 28/12/01 63 or a pharmaceutically acceptable prodrug, salt or solvate thereof. 27. A pharmaceutical composition comprising: a therapeutically effective amount of a compound as defined in anyone of claims 23 to 26 or a pharmaceutically acceptable prodrug, salt or solvate thereof; and a pharmaceutically acceptable carrier, diluent, vehicle or excipient. 28. A method of treating a mammalian disease condition mediated by metalloproteinase activity which comprises S 15 administering to a mammal in need thereof a therapeutically effective amount of a compound as defined in any one of claims 23 to 26 or a pharmaceutically acceptable prodrug, salt or solvate thereof. 29. A method according to claim 28, wherein the mammalian disease condition is tumor growth, invasion or metastasis. :30. A method according to claim 28, wherein the mammalian disease condition is osteoarthritis, rheumatoid arthritis, 25 osteoporosis, periodontitis, or gingivitis. 31. A method according to claim 28, wherein the mammalian disease condition is chronic dermal wounds, corneal ulceration, or degenerative skin disorder. 32. A method according to claim 28, wherein the mammalian disease condition is multiple sclerosis or stroke. 33. A method according to claim 28, wherein the mammalian disease condition is atherosclerosis, glomerular disease or Alzheimer's disease. H:\Suzarmet\Keep\Speci\68744- 9 8.1 SPECI.doc 28/12/01 64 34. A method according to claim 28, wherein the mammalian disease condition is characterized by unwanted angiogenesis. 35. A method according to claim 28, wherein the mammalian disease condition is diabetic retinopathy, macular degeneration, angiofibromas, or hemangiomas. 36. Compounds of formula or processes for their preparation, pharmaceutical compositions containing them or methods of treatment or inhibition involving them, substantially as hereinbefore described with reference to the non-comparative examples. Dated this 28th day of December 2001 By their Patent Attorneys 9*o GRIFFITH HACK Fellows Institute of Patent and Mr A Trade Mark Attorneys of Australia TaeMr toreso utai H:\suzamet\Keep\Speci\68744-98.1 SPECIdoc 28/12/01
AU68744/98A 1997-04-01 1998-03-31 Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses Ceased AU747280B2 (en)

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Families Citing this family (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999004780A1 (en) 1997-07-22 1999-02-04 Shionogi & Co., Ltd. Therapeutic or prophylactic agent for glomerulopathy
WO1999006340A2 (en) * 1997-07-31 1999-02-11 The Procter & Gamble Company Sulfonylamino substituted hydroxamic acid derivatives as metalloprotease inhibitors
IL127496A0 (en) * 1997-12-19 1999-10-28 Pfizer Prod Inc The use of MMP inhibitors for the treatment of ocular angiogenesis
US6410580B1 (en) 1998-02-04 2002-06-25 Novartis Ag Sulfonylamino derivatives which inhibit matrix-degrading metalloproteinases
SK11692000A3 (en) 1998-02-04 2001-02-12 Novartis Ag Sulfonylamino derivatives which inhibit matrix-degrading metalloproteinases
US6075136A (en) * 1998-02-17 2000-06-13 Incyte Pharmaceuticals, Inc. Prostate-associated serine protease
US6492394B1 (en) 1998-12-22 2002-12-10 Syntex (U.S.A.) Llc Sulfonamide hydroxamates
US6200996B1 (en) 1999-01-27 2001-03-13 American Cyanamid Company Heteroaryl acetylenic sulfonamide and phosphinic acid amide hydroxamic acid tace inhibitors
US6753337B2 (en) 1999-01-27 2004-06-22 Wyeth Holdings Corporation Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase/tace inhibitors
US6313123B1 (en) 1999-01-27 2001-11-06 American Cyanamid Company Acetylenic sulfonamide thiol tace inhibitors
US6340691B1 (en) 1999-01-27 2002-01-22 American Cyanamid Company Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase and tace inhibitors
US6946473B2 (en) 1999-01-27 2005-09-20 Wyeth Holdings Corporation Preparation and use of acetylenic ortho-sulfonamido and phosphinic acid amido bicyclic heteroaryl hydroxamic acids as TACE inhibitors
US6277885B1 (en) 1999-01-27 2001-08-21 American Cyanamid Company Acetylenic aryl sulfonamide and phosphinic acid amide hydroxamic acid TACE inhibitors
US6762178B2 (en) 1999-01-27 2004-07-13 Wyeth Holdings Corporation Acetylenic aryl sulfonamide and phosphinic acid amide hydroxamic acid TACE inhibitors
US6326516B1 (en) 1999-01-27 2001-12-04 American Cyanamid Company Acetylenic β-sulfonamido and phosphinic acid amide hydroxamic acid TACE inhibitors
US6225311B1 (en) 1999-01-27 2001-05-01 American Cyanamid Company Acetylenic α-amino acid-based sulfonamide hydroxamic acid tace inhibitors
US6358980B1 (en) 1999-01-27 2002-03-19 American Cyanamid Company Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase/tace inhibitors
HUP0202199A2 (en) 1999-03-03 2002-10-28 Procter & Gamble Alkenyl- and alkynyl-containing metalloprotease inhibitors
PL350452A1 (en) 1999-03-03 2002-12-16 Procter & Gamble Dihetero-substituted metalloprotease inhibitors
US6696456B1 (en) * 1999-10-14 2004-02-24 The Procter & Gamble Company Beta disubstituted metalloprotease inhibitors
EP1440057A1 (en) 2001-11-01 2004-07-28 Wyeth Holdings Corporation Allenic aryl sulfonamide hydroxamic acids as matrix metalloproteinase and tace inhibitors
WO2003055851A1 (en) 2001-12-27 2003-07-10 Sumitomo Pharmaceuticals Company, Limited Hydroxamic acid derivative and mmp inhibitor containing the same as active ingredient
EP1511488B1 (en) 2002-06-12 2013-05-22 Symphony Evolution, Inc. Human adam-10 inhibitors
WO2005021489A2 (en) 2002-12-23 2005-03-10 Wyeth Holdings Corporation Acetylenic aryl sulfonate hydroxamic acid tace and matrix metalloproteinase inhibitors
US20090018094A1 (en) * 2006-12-01 2009-01-15 Loma Linda University Medical Center Inhibition of brain enzymes involved in cerebral amyloid angiopathy and macular degeneration
JP2022512584A (en) 2018-10-04 2022-02-07 アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル EGFR inhibitor for treating keratoderma

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6022898A (en) * 1994-06-22 2000-02-08 British Biotech Pharmaceuticals Limited Metalloproteinase inhibitors
US5863949A (en) * 1995-03-08 1999-01-26 Pfizer Inc Arylsulfonylamino hydroxamic acid derivatives
EP0757984B1 (en) * 1995-08-08 2002-10-30 Ono Pharmaceutical Co., Ltd. Hydroxamic acid derivatives useful for inhibiting gelatinase
SI0874830T1 (en) * 1995-12-08 2003-08-31 Agouron Pharmaceuticals, Inc. A metalloproteinase inhibitor, a pharmaceutical composition containing it and the pharmaceutical use and method useful for the preparation thereof
CZ298814B6 (en) * 1996-01-23 2008-02-13 Shionogi & Co., Ltd. Sulfonated derivatives of amino acids and metalloprotease inhibitors in which said derivatives are comprised

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