# US 5,703,092 A · Hydroxamic acid compounds as metalloprotease and TNF inhibitors

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- Number: US 5,703,092 A
- Document ID: US5703092A
- Status: Granted
- Kind: A
- Application number: 08/632,863
- Filed: 1996-04-16
- Granted: 1997-12-30
- Earliest claimed: 1995-04-18
- Assignees: The DuPont Merck Pharmaceutical Company
- Inventors: Chu-Biao Xue; William F. DeGrado; Carl Peter DeCicco; Irina Cipora Jacobson
- Web page: https://patentgrep.com/patent/US5703092A

## CPC

- C07D 233/64: with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- C07C 233/05: having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C 233/11: with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
- C07C 259/06: having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
- C07D 235/14: Radicals substituted by nitrogen atoms (by nitro radicals C07D235/10)
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The present invention provides novel hydroxamic acids and carbocyclic acids and derivatives thereof and to pharmaceutical compositions and methods of use of these novel compounds for the inhibition of matrixmetalloproteinases, such as stromelysin and other matrix metalloproteinases, and also inhibit the production of tumor necrosis factor (TNF), and are therefore useful for the treatment of arthritis and other related inflammatory diseases. These novel compounds are represented by Formula I below: ##STR1##

## Claims

### Claim 1

A compound of the formula I: ##STR25## or pharmaceutically acceptable salts or prodrug forms thereof, wherein: A is --C(R.sup.1)(R.sup.1a)CONHOH;
Q is selected from:
pyridyl substituted with 0-3 R.sup.5, R.sup.6, and/or R.sup.7,
triazole substituted with 0-3 R.sup.5, R.sup.6, and/or R.sup.7,
thiazole substituted with 0-3 R.sup.5, R.sup.6, and/or R.sup.7,
tetrazole substituted with 0-3 R.sup.5, R.sup.6, and/or R.sup.7,
oxazole substituted with 0-3 R.sup.5, R.sup.6, and/or R.sup.7,
isoxazole substituted with 0-3 R.sup.5, R.sup.6, and/or R.sup.7,
pyrazole substituted with 0-3 R.sup.5, R.sup.6, and/or R.sup.7,
thiopyrazole substituted with 0-3 R.sup.5, R.sup.6, and/or R.sup.7,
isoxazoline substituted with 0-3 R.sup.5, R.sup.6, and/or R.sup.7,
benzimidazole substituted with 1-3 R.sup.5, R.sup.6, and/or R.sup.7,
when at least one of R.sup.5, R.sup.6 or R.sup.7 are other than H or C.sub.1 -C.sub.4 alkyl,
benzoxazole substituted with 0-3 R.sup.5, R.sup.6, and/or R.sup.7,
benzothiazole substituted with 0-3 R.sup.5, R.sup.6, and/or R.sup.7,
When R.sup.3 is a cyclohexyl, cyclohexylmethyl, naphthyl, Q can also be a benzimidazole substituted with 0-3 R.sup.5, R.sup.6, and/or R.sup.7, or an imidazole substituted with 0-3 R.sup.5, R.sup.6, and/or R.sup.7,
The phenyl ring of the benzimidazole, benzoxazole and benzothiazole can be optionally replaced with 1-2 nitrogens.
R.sup.1 and R.sup.1a are independently selected from:
H, halogen, OR.sup.17, NR.sup.10 R.sup.10a, NR.sup.8 R.sup.10a, S(O).sub.m R.sup.17a,
C.sub.1 -C.sub.4 alkyl substituted with 0-3 R.sup.4,
C.sub.2 -C.sub.4 alkenyl substituted with 0-3 R.sup.4,
C.sub.2 -C.sub.4 alkynyl substituted with 0-3 R.sup.4,
C.sub.6 -C.sub.10 aryl substituted with 0-3 R.sup.18,
a C.sub.5 -C.sub.11 heterocycle containing from 1-4 heteroatoms selected from N, O or S, said heterocycle optionally substituted with 0-3 R.sup.18, or
C.sub.3 -C.sub.8 cycloalkyl,
Alternately, R.sup.1 and R.sup.1a can be taken together to form a 3-7 membered carbocyclic or heterocyclic, said heterocyclic ring containing from 1-2 heteroatoms selected from N, O or S;
R.sup.2 is selected from:
C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.17b,
--O--(C.sub.1 -C.sub.8 alkyl)--R.sup.20,
--S--(C.sub.1 -C.sub.8 alkyl)--R.sup.20,
--CH.sub.2 O--(C.sub.1 -C.sub.8 alkyl)--R.sup.20, or
--CH.sub.2 S--(C.sub.1 -C.sub.8 alkyl)--R.sup.20 ;
R.sup.3 is selected from:
H,
C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.17b,
--(C.sub.1 -C.sub.6 alkylene)--OR.sup.12,
--(C.sub.1 -C.sub.6 alkylene)--SR.sup.12,
C.sub.6 -C.sub.10 aryl substituted with 0-3 R.sup.18, or
C.sub.3 -C.sub.7 cycloalkyl;
R.sup.4 is selected from:
--OR.sup.17, --SO.sub.m R.sup.17,
--NR.sup.8 R.sup.10, --NHC(.dbd.NR.sup.8)N(R.sup.8)R.sup.10,
C.sub.1 -C.sub.4 alkyl,
aryl substituted with 0-5 R.sup.18,
C.sub.3 -C.sub.8 cycloalkyl, or
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R.sup.18 ;
R.sup.5 is selected from:
hydrogen, halogen, C.sub.1 -C.sub.4 haloalkyl, hydroxy, C.sub.1 -C.sub.4 alkoxy, --NR.sup.14 R.sup.15, or C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.20 ;
R.sup.6 and R.sup.7 are independently selected from:
H, C.sub.1 -C.sub.4 alkyl, or C.sub.6 -C.sub.10 aryl;
Alternately, R.sup.6 and R.sup.7 may be taken together to be
1. 2-phenylene substituted with 0-2 R.sup.5,
2,3-pyridinylene substituted with 0-2 R.sup.5,
3,4-pyridinylene substituted with 0-2 R.sup.5, or
5,6-pyrimidinylene substituted with 0-2 R.sup.5 ;
R.sup.8 is a substituent on nitrogen and is selected from
hydrogen,
C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.20,
C.sub.1 -C.sub.6 -alkylcarbonyl,
alkoxycarbonyl,
arylalkoxycarbonyl,
alkylaminocarbonyl,
arylsulfonyl,
heteroarylalkoxycarbonyl,
cycloalkoxycarbonyl,
heteroarylsulfonyl,
alkylsulfonyl, or
cycloalkylsulfonyl;
R.sup.10 is selected from:
hydrogen,
C.sub.1 -C.sub.4 alkoxy,
C.sub.1 -C.sub.6 alkyl substituted with 0-4 R.sup.4 ;
R.sup.10a is selected from hydrogen or C.sub.1 -C.sub.4 alkyl;
R.sup.10 and R.sup.10a can alternatively join to form --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --CH.sub.2 CH.sub.2 N(R.sup.18)CH.sub.2 CH.sub.2 --, or --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --;
R.sup.11 is H, or C.sub.1 -C.sub.4 alkyl;
R.sup.12 is C.sub.1 -C.sub.4 alkyl or C.sub.6 -C.sub.10 aryl;
R.sup.14 and R.sup.15 are independently selected from H or C.sub.1 -C.sub.4 alkyl;
R.sup.17 is selected from:
hydrogen,
C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.17a
C.sub.1 -C.sub.6 alkylcarbonyl substituted with 0-3 R.sup.17a,
C.sub.1 -C.sub.6 alkoxycarbonyl substituted with 0-3 R.sup.17a,
phenoxycarbonyl substituted with 0-3 R.sup.18 ;
R.sup.17a is selected from:
H,
C.sub.1 -C.sub.4 alkyl,
aryl substituted with 0-5 R.sup.18,
C.sub.3 -C.sub.8 cycloalkyl
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R.sup.18 ;
R.sup.17b is selected from:
aryl substituted with 0-5 R.sup.18,
C.sub.3 -C.sub.8 cycloalkyl
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R.sup.18 ;
R.sup.18, when a substituent on carbon, is selected from one or more of the following:
phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, --CO.sub.2 H, sulfonamide, C.sub.1 -C.sub.4 alkyl substituted with --NR.sup.10 R.sup.10a, --NR.sup.10 R.sup.10a, C.sub.1 -C.sub.4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylcarbonylamino, --S(O).sub.m R.sup.11, --NHSO.sub.2 R.sup.11,
phenyl, optionally substituted with halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy or NR.sup.10 R.sup.10a,
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R.sup.18 ;
or R.sup.18 may be a 3- or 4- carbon chain attached to adjacent carbons on the ring to form a fused 5- or 6-membered ring, said 5- or 6- membered ring being optionally substituted with halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, --NR.sup.10 R.sup.10a, .dbd.O or .dbd.S when attached to a saturated carbon atom, or .dbd.O when attached to sulfur;
R.sup.18, when a substituent on nitrogen, is selected from one or more of the following:
phenyl, benzyl, phenethyl, hydroxy, C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethyl, --CH.sub.2 NR.sup.10 R.sup.10a, --NR.sup.10 R.sup.10a, C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, --CO.sub.2 H, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl;
R.sup.20 is selected from:
aryl substituted with 0-5 R.sup.18,
a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, isothiazolyl, thiazolinyl, thiazolidinyl, isothiazolinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, pyrrolyl, N-methylpyrrolyl, triazolyl, triazolidinyl, oxazolyl, isoxazolyl, oxazolinyl, isoxazolinyl, oxazolidinyl, oxadiazolyl, oxadiazolidinyl, imidazolyl, imidazolidinyl, said heterocyclic ring system being substituted with 0-5 R.sup.18.

### Claim 2 (depends on 1)

A compound of claim 1 wherein:
R.sup.1 is selected from:
H, or
C.sub.1 -C.sub.4 alkyl substituted with 0-3 R.sup.4 ;
R.sup.2 is selected from:
C.sub.2 -C.sub.4 alkyl substituted with 0-3 R.sup.17b,
--O--(C.sub.1 -C.sub.6 alkyl)--R.sup.20,
--S--(C.sub.1 -C.sub.6 alkyl)--R.sup.20,
--CH.sub.2 O--(C.sub.1 -C.sub.5 alkyl)--R.sup.20, or
--CH.sub.2 S--(C.sub.1 -C.sub.5 alkyl)--R.sup.20 ;
R.sup.3 is selected from:
H,
C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.17b.

### Claim 3 (depends on 1)

A compound of claim 1 selected from the group consisting of:
(a) N-›1(S)-(5-azabenzimidazol-2-yl)-2-(2-naphthyl)ethyl!-›3-hydroxyaminocarbo nyl)-2(R)-isobutyl-3(S)-methyl!propanamide
(b) N-›1(S)-(2-imidazolyl)-2-(2-naphthyl)ethyl!-›3-hydroxyaminocarbonyl)-2(R)- isobutyl-3(S)-methyl!propanamide
(c) N-›1(S)-(5-methoxy -2-benzimidazolyl)-3-methylbutyl!-›3-(N-hydroxyaminocarbonyl)-2(R)-isobuty l-(3S)-methyl!propanamide,
(d) N-›1(S)-(5-methoxy-2-benzimidazolyl)-2-phenylethyl!-›3-(N-hydroxyaminocarb onyl)-3(S)-hydroxy-2(R)-isobutyl!propanamide,
(e) N-›1(S)-(5-methoxy-2-benzimidazolyl)-2,2,2-trimethylethyl!-›3-(N-hydroxyam inocarbonyl)-3(S)-hydroxy-2(R)-isobutyl!propanamide,
(f) N-›1(S)-(5-chloro-2-benzimidazolyl)-2,2,2-trimethylethyl!-›3-(N-hydroxyami nocarbonyl)-3(S)-hydroxy-2(R)-isobutyl!propanamide,
(g) N-›1(S)-(5-azabenzimidazol-2-yl)-2-(2-naphthyl)ethyl!-›3-(N-hydroxyaminoca rbonyl)-3(S)-hydroxy-2(R)-isobutyl!propanamide,
(h) N-›1(S)-(5-azabenzimidazol-2-yl)-2-(2-naphthyl)ethyl!-›3-(N-hydroxyaminoca rbonyl)-3(S)-(2-picolyloxy)-2(R)-isobutyl!propanamide,
(i) N-›1(S)-(5-azabenzimidazol-2-yl)-2-(2-naphthyl)ethyl!-›3-(N-hydroxyaminoca rbonyl)-3(S)-(3-picolyloxy)-2(R)-isobutyl!propanamide,
(j) N-›1(S)-(5-azabenzimidazol-2-yl)-2-(2-naphthyl)ethyl!-›3-(N-hydroxyaminoca rbonyl)-3(S)-(4-picolyloxy)-2(R)-isobutyl!propanamide,
(k) N-›1(S)-(5-azabenzimidazol-2-yl)-2-(2-naphthyl)ethyl!-›3-(N-hydroxyaminoca rbonyl)-3(S)-benzyloxy-2(R)-isobutyl!propanamide,
(l) N-›1(S)-(5-azabenzimidazol-2-yl)-2-(2-naphthyl) ethyl!-›3-(N-hydroxyaminocarbonyl)-3(S)-methyl-2(R)-isobutyl!propanamide,
(m) ›3-(N-hydroxyaminocarbonyl)-3(S)-phenpropyl-2(R)-isobutyl!propanamide,
(n) N-›1(S)-(5-azabenzimidazol-2-yl)-2-(2-naphthyl)ethyl!-›3-(N-hydroxyaminoca rbonyl)-3(S)-(2-pyridylpropyl)-2(R)-isobutyl!propanamide,
(o) N-›1(S)-(5-azabenzimidazol-2-yl)-2-(2-naphthyl)ethyl!-›3-(N-hydroxyaminoca rbonyl)-3(S)-propargyl-2(R)-isobutyl!propanamide,
(p) N-›1(S)-(5-azabenzimidazolyl)-2-(2-naphthyl)ethyl!-›3-(N-hydroxyaminocarbo nyl)-3(S)-allyl-2(R)-isobutyl!propanamide,
(q) N-›1(S)-(5-azabenzimidazolyl)-2-(2-naphthyl)ethyl!-›3-(N-hydroxyaminocarbo nyl)-3(S)-(1-pyrazolylpropyl)-2(R)-isobutyl!propanamide, and
(r) N-›1(S)-(5-azabenzimidazolyl)-2-(2-naphthyl)ethyl!-›3-(N-hydroxyaminocarbo nyl)-3(S)-(1-imidazolylpropyl)-2(R)-isobutyl!propanamide.

### Claim 4 (depends on 1)

A pharmaceutical composition comprising a suitable pharmaceutical carrier and a therapeutically effective amount of a compound of claim 1.

### Claim 5 (depends on 2)

A pharmaceutical composition comprising a suitable pharmaceutical carrier and a therapeutically effective amount of a compound of claim 2.

### Claim 6 (depends on 3)

A pharmaceutical composition comprising a suitable pharmaceutical carrier and a therapeutically effective amount of a compound of claim 3.

### Claim 7 (depends on 1, 2, 3)

A method of treating diseases mediated by matrix metalloproteinase and/or tumor necrosis factor in a mammal comprising administering to the mammal an effective amount of a compound of any one of claims 1 through 3.

### Claim 8 (depends on 7)

A method of claim 7 wherein the disease is one mediated by matrix metalloproteinase.

### Claim 9 (depends on 7)

A method of claim 7 wherein the disease is selected from rheumatoid arthritis, osteoarthritis, periodonitis, gingivitis, corneal ulceration or tumor invasion by secondary metastases.

### Claim 10 (depends on 7)

A method of claim 7 wherein the disease is one mediated by tumor necrosis factor.

### Claim 11 (depends on 7)

A method of claim 7 wherein the disease is selected from inflammation, fever, cardiovascular effects, hemorrhage, coagulation and acute phase response, cachexia and anorexia, an acute infection, a shock state, a graft versus host reaction or autoimmune disease.