HRP950259A2 - Hydroxamic acid and amino acid derivatives and their use as anti-arthritic agents - Google Patents

Description

The field of technology

The subject of this invention are small molecules that inhibit matrix metalloproteinases, pharmaceutical preparations that contain or contain them, and their use as pharmaceutical agents.

State of the art

There is evidence that stromelysin (MMP-3) and other metalloproteinases (MMPs) play a major role in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to extracellular matrix resorption. This is characteristic of many pathological conditions, such as rheumatoid or osteoarthritis, corneal ulcer, epidermal or gastric ulcer; tumor metastasis or invasion; periodontal or bone diseases. Usually, the regulation of these catabolic enzymes is carried out during their synthesis, as well as during their extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMP (tissue inhibitor of matrix metalloproteinase), which create inactive complexes with MMPs.

Osteo- and rheumatoid arthritis (that is, OA and RA) are diseases that break down articular cartilage, and are characterized by localized erosion of the cartilage surface. Studies have shown that the articular cartilage of the femoral head in people who had OA, for example, showed reduced binding of radiolabeled sulfate during controls, suggesting that there must be an increased level of cartilage breakdown in OA (Mankin et al., J. Bone Joint Surg. 52A, 1970, 424-434). There are four types of protein-degrading enzymes in mammalian cells: serine, cysteine, aspartic acid, and metalloproteinase. Existing knowledge proves that metalloproteinases are responsible for the degradation of the extracellular matrix of articular cartilage in OA and RA. Increased activity of collagenase and stromelysin was detected in OA cartilage and correlated with the severity of damage (Mankin et al., Arthrilis Rheum. 21, 1978, 761-766, Woessner et al., Arthrilis Rheum. 26, 1983, 63-68 and Ibid 27, 1984, 305-312). In addition, immunohistochemical studies (Okada et al. Ann. Rheum. 48, 1989, 645) have shown that stromelysin is synthesized and secreted by synovial cells in RA. Higher levels of stromelysin were also detected in chondrocytes in 90% of OA cartilages, where stromelysin staining was associated with histological findings of pathology and disappearance of proteoglycans (Okada et al. Lab Invest. 66, 1992, 680).

Therefore, stromelysin, a matrix metalloproteinase (MMP-3), has been characterized as one of the key enzymes that cause bone and cartilage damage in mammals. The pathogenesis of such diseases can be expected to be improved by taking MMP inhibitors, and many compounds have already been proposed that could be used for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 25., 175-184, AP , San Diego, 1990).

PCT International Application No. WO 92/213260 describes N-carboxyalkylpeptidyl compounds of the general formula:

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in which SA is an amino acid, and which act as inhibitors of bottesti caused by matrix metalloproteinase.

PCT international application no. WO 90/05716 describes collagenase inhibitors based on hydroxamic acid of the general formula:

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PCT international application bf. WO 92/13831 describes related collagenase-inhibiting hydroxamic acids of the general formula:

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PCT international application no. WO 94/02446 describes metalloproteinase inhibitors which are natural amino acid derivatives of the general formula:

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PCT international application no. WO 93/09097 describes piperazine acid derivatives of the general formula:

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which have an inhibitory effect on collagenase type IV, and are useful as cancer metastasis suppressors.

Ogita et al. (J. Anti. 1992, 45, 1723-1732) describe the isolation of a structurally related species of microbial metabolites, matlistatins, which were discovered by screening as type IV collagenase inhibitors and represented by the general formula:

[image]

European patent application published under no. 574,758 Al, describes hydroxamic acid derivatives as collagenase inhibitors of the general formula:

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The compounds described in the present invention act as stromelysin inhibitors, thereby preventing the loss and degradation of cartilage. The hydroxamic and carboxylic acids and their derivatives described in this invention are bioavailable after oral administration. A certain number of compounds described as inhibitors of metalloproteinases, such as for example collagenase, are not sufficiently bioavailable, and therefore cannot be used as therapeutic agents, especially if oral administration is desired. Weak oral activity has been attributed to relatively high molecular weight, inadequate solubility, and the presence of peptide bonds, which are susceptible to cleavage by mammalian proteases in vivo and which generally act to strongly bind molecules in human serum. Hydroxamic and carbocyclic acids and their derivatives described in this invention have a significant advantage in this sense, since they do not contain cleavable peptide bonds, have low molecular weight and may be hydrophilic, yet inhibit matrix metalloproteinases.

Presentation of the essence of the invention

The subject of this invention are new hydroxamic and carbocyclic acids and their derivatives that inhibit stromelysin, and are therefore useful in the treatment of arthritis. The group of benefits in this treatment procedure is represented by the general formula I:

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or their pharmaceutically suitable salts or prodrug forms, in which:

A selected from -N(R8)CH(R9)CO2H or -CH(R1)CONHOH;

Q is chosen is:

of a C5-C14 carbocyclic ring substituted with 0-4 groups selected from R5, R6, R18 or, -C(=O)R3, or a 5- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms independently selected from oxygen , nitrogen or sulfur, and said heterocyclic ring is substituted with 0-4 groups selected from R5, R6, R8, R18 or -C(=O)R3;

R1 is selected from:

H, OR17, S(O)mR17a;

C1-C4 alkyl substituted with 0-3 R4,

C2-C4 alkenyl substituted with 0-3 R4,

C2-C4 alkynyl substituted with 0-3 R4,

R2 is selected from:

H,

C1-C6 alkyl substituted with 0-3 R17b,

-O-(C1-C8 alkyl)-R20,

-S-(C1-C8 alkyl)-R20,

-CH2O-(C1-C8 alkyl)-R20, or

-CH2S-(C1-C8 alkyl)-R20;

R3 is selected from: OR11, NHCH(R12)COR13,

NHCH(R12)COOR11, NHCH(R12)CONR14R15, NR10R10a;

R4 is selected from:

-OR17, -SOmR17,

-NR8R10, -NHC(=NR8)N(R8)R10,

C1-C4 alkyl,

aryl substituted with 0-5 R18,

C3-C8 cycloalkyl, or

a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl, and said heterocyclic ring is substituted with 0-2 R19;

R4a is selected from:

-OR17, -SOmR17,

C1-C4 alkyl,

aryl substituted with 0-5 R18,

C3-C8 cycloalkyl, or

a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl, pyrrolidinyl, phthalimido, triazolidinyl, oxadiazolidinyl, imidazolidinyl, piperidinyl, and said heterocyclic ring is substituted with 0-5 R18;

R5 and R6 are independently selected from:

hydrogen,

hydroxy,

C1-C6 alkyl substituted with 0-3 R20,

C1-C4 Alkoxy, -NR14R15, -COOR11,

C1-C4 alkoxycarbonyl, hydroxymethyl, -CH2OR13,

C1-C4 alkylaminocarbonyl, -C(=NOH)R14

=O, =S, or their ketal or thioketal form when R5 or R6 is attached to a saturated carbon atom, or = 0 when R5 or R6 is attached to sulfur;

R 5 and R 6 when linked to adjacent ring atoms may be linked to form a 5-7 membered carbocyclic or heterocyclic ring, wherein said carbocyclic ring contains one or two N, O or S atoms, and said carbocyclic or heterocyclic ring is substituted with 0-2 R18;

R8 is a substituent on nitrogen and is selected from hydrogen,

C1-C6 alkyl substituted with 0-3 R20,

C1-C6 alkylcarbonyl,

alkoxycarbonyl,

arylalkyloxycarbonyl,

alkylaminocarbonyl;

R9 is selected from:

H,

C1-C8 alkyl substituted with 0-3 R4a,

C2-C8 alkenyl substituted with 0-3 R4a,

C2-C8 alkynyl substituted with 0-3 R4a;

R10 is selected from:

hydrogen,

C1-C4 Alkoxy,

C1-C6 alkyl substituted with 0-4 R4;

R 10a is selected from hydrogen or C 1 -C 4 alkyl;

R10 and R10a can be joined to form -(CH2)4-, -(CH2)5-, -CH2CH2N(R16)CH2CH2- or -CH2CH2OCH2CH2-;

R 11 is H, benzyl or C 1 -C 4 alkyl;

R12 is selected from:

H,

C1-C4 alkyl substituted with 0-3 R4,

C2-C4 alkenyl substituted with 0-3 R4,

C2-C4 alkynyl substituted with 0-3 R4;

R 13 is C 1 -C 4 alkyl;

R 14 and R 15 are independently selected from H or C 1 -C 4 alkyl;

R 16 is hydrogen or methyl;

R17 is selected from:

hydrogen,

C1-C6 alkyl substituted with 0-3 R17a,

C1-C6 alkylcarbonyl substituted with 0-3 R17a,

C1-C6 alkoxycarbonyl substituted with 0-3 R17a,

phenoxycarbonyl substituted with 0-3 R18;

R17a is selected from:

H,

C1-C4 alkyl;

aryl substituted with 0-5 R18,

C3-C8 cycloalkyl,

heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, pyrrolyl, pyrazolyl, piperidinyl, pyrrolidinyl, pyrimidinyl or pyridazinyl, benzofuranyl, benzothienyl, indolyl, tetrahydrofuranyl, or pyranyl, said heterocyclic ring is substituted with 0-2 R18;

R17b is selected from:

aryl substituted with 0-5 R18,

C3-C8 cycloalkyl,

a heterocycle selected from the group consisting of thienyl, furanyl, thiazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, tetrahydrofuranyl or pyranyl, said heterocyclic ring is substituted with 0-2 R18;

R18, when the substituent is carbon, is selected from one or more of the following compounds:

phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a, -NR10R10a C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11 –NHSO2R11,

a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl;

or R 18 may be a chain of 3 or 4 carbons joined to adjacent ring carbons to form a fused 5- or 6-membered ring, said 5- or 6-membered ring may be substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, NR10OR10a -O or -S when attached to a saturated carbon atom, or =O when attached to sulfur;

R18 when the substituent is nitrogen, is selected from one or more of the following compounds:

Phenyl, Benzyl, Phenethyl, Hydroxy, C1-C4 Hydroxyalkyl, C1-C4 Alkoxy, C1-C4 Alkyl, C3-C6 Cycloalkyl C3-C6 Cycloalkylmethyl-CH2NR10R10a, -NR10R10a, C2-C6 Alkoxyalkyl, C1-C4 Haloalkyl, C1-C4 Alkoxycarbonyl , -CO2H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl;

R19, when the substituent is carbon, is selected from one or more of the following compounds:

phenyl, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a, -NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1- C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11,

a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl;

or R 19 may be a chain of 3 or 4 carbons joined to adjacent ring carbons to form a fused 5- or 6-membered ring, said 5- or 6-membered ring may be substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, -NR10R10a;

R19, when the substituent is nitrogen, is selected from one or more of the following:

Phenyl, Benzyl, Phenethyl, Hydroxy, C1-C4 Hydroxyalkyl, C1-C4 Alkoxy, C1-C4 Alkyl, C3-C6 Cycloalkyl C3-C6 Cycloalkylmethyl, -CH2NR10R10a, -NR10R10a, C2-C6 Alkoxyalkyl, C1-C4 Haloalkyl, C1-C6 C4 alkoxycarbonyl, -CO2H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl;

R20 is selected from:

aryl substituted with 0-5 R18, a heterocycle selected from the group consisting of:

thienyl, furanyl, thiazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, tetrahydrofuranyl, or pyranyl, said heterocyclic ring is substituted with 0-2 R18.

One aspect of this invention relates to a new group of compounds that can be classified within the group of compounds of formula I and to pharmaceutical preparations that contain or contain methods of using said compounds to inhibit stromelysin and to treat OA and RA. These new compounds are represented by formula II:

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or their pharmaceutically acceptable salts or prodrug forms, where:

Q selected from:

C5-C14 carbocyclic ring substituted with 0-4 groups selected from R5, R6, R18 or -C(O)R3, or a 5- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, and said heterocyclic ring is substituted with 0-4 groups selected from R5, R6, R8, R18 or -C(=O)R3;

R1 is selected from:

H, OR17, S(O)mR17a,

C1-C4 alkyl substituted with 0-3 R4,

C2-C4 alkenyl substituted with 0-3 R4,

C2-C4 alkynyl substituted with 0-3 R4,

R2 is selected from:

C1-C6 alkyl substituted with 0-3 R17a,

-O-(C1-C8 alkyl)-R20,

-S-(C1-C8 alkyl)-R20,

-CH2O-(C1-C8 alkyl)-R20, or

-CH2S-(C1-C8 alkyl)-R20;

R3 is selected from -NR10R10a;

R4 is selected from:

-OR17, -SOmR17,

-NR8R10, -NHC(=NR8)N(R8)R10,

C1-C4 alkyl,

aryl substituted with 0-5 R18,

C3-C8 cycloalkyl, or

a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl, and said heterocyclic ring is substituted with 0-2 R18;

R5 and R6 are independently selected from:

hydrogen, hydroxy, C1-C6 alkyl substituted with 0-3 R20,

C1-C4 Alkoxy, -NR14R15, -COOR11,

C1-C4 alkoxycarbonyl, hydroxymethyl, -CH2OR13,

C1-C4 alkylaminocarbonyl, -C(=NOH)R14,

When R 5 and R 6 are attached to adjacent ring atoms they may be linked to form a 5-7 membered carbocyclic or heterocyclic ring, wherein said carbocyclic ring contains one to two N, O or S atoms, and said carbocyclic or heterocyclic ring is substituted with 0-2 R18;

R8 is a substituent on nitrogen and is selected from hydrogen,

C1-C6 alkyl substituted with 0-3 R20,

C1-C6 alkylcarbonyl,

alkoxycarbonyl,

arylalkyloxycarbonyl,

alkylaminocarbonyl;

R10 is selected from:

hydrogen,

C1-C4 Alkoxy,

C1-C6 alkyl substituted with 0-4 R4;

R 10a is selected from hydrogen or C 1 -C 4 alkyl;

R10 and R10a can be joined to form -(CH2)4-, -(CH2)5-, -CH2CH2N(R16)CH2CH2- or –CH2CH2OCH2CH2-;

R 11 is H, benzyl or C 1 -C 4 alkyl;

R12 is selected:

H,

C1-C4 alkyl substituted with 0-3 R4,

C2-C4 alkenyl substituted with 0-3 R4,

C2-C4 alkynyl substituted with 0-3 R4;

R 13 is C 1 -C 4 alkyl;

R 14 and R 15 are independently selected from H or C 1 -C 4 alkyl;

R 16 is hydrogen or methyl;

R17 is selected from:

hydrogen,

C1-C6 alkyl substituted with 0-3 R17a,

C1-C6 alkylcarbonyl substituted with 0-3 R17a,

C1-C6 alkoxycarbonyl substituted with 0-3 R17a, phenoxycarbonyl substituted with 0-3 R18;

R17a is selected from:

H,

C1-C4 alkyl;

aryl substituted with 0-5 R18,

C3-C8 cycloalkyl,

heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, pyrrolyl, pyrazolyl, piperidinyl, pyrrolidinyl, pyrimidinyl or pyridazinyl, benzofuranyl, benzothienyl, indolyl, tetrahydrofuranyl, or pyranyl, said heterocyclic ring is substituted with 0-2 R18;

R17b is selected from:

aryl substituted with 0-5 R18,

C3-C8 cycloalkyl,

a heterocycle selected from the group consisting of thienyl, furanyl, thiazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, tetrahydrofuranyl or pyranyl, said heterocyclic ring is substituted with 0-2 R18;

R18, when the substituent is carbon, is selected from one of the following compounds:

phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a, -NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1- C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11,

a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl;

or R 18 may be a chain of 3 or 4 carbons joined to adjacent ring carbons to form a fused 5- or 6-membered ring, said 5- or 6-membered ring may be substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, NR10R10a, -O or -S when attached to a saturated carbon atom, or =O when attached to sulfur;

R18, when the substituent is nitrogen, is selected from one or more of the following compounds:

Phenyl, Benzyl, Phenethyl, Hydroxy, C1-C4 Hydroxyalkyl, C1-C4 Alkoxy, C1-C4 Alkyl, C3-C6 Cycloalkyl C3-C6 Cycloalkylmethyl, -CH2NR10R10a, -NR10R10a, C2-C6 Alkoxyalkyl, C1-C4 Haloalkyl, C1-C6 C4 alkoxycarbonyl, -CO2H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl;

R19, when the substituent is carbon, is selected from one or more of the following compounds:

phenyl, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a, -NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1- C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11,

a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl;

or R 19 may be a chain of 3 or 4 carbons joined to adjacent ring carbons to form a fused 5- or 6-membered ring, said 5- or 6-membered ring may be substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, NR10R10a;

R19, when the substituent is nitrogen, is selected from one or more of the following:

Phenyl, Benzyl, Phenethyl, Hydroxy, C1-C4 Hydroxyalkyl, C1-C4 Alkoxy, C1-C4 Alkyl, C3-C6 Cycloalkyl C3-C6 Cycloalkylmethyl, -CH2NR10R10a, -NR10R10a, C2-C6 Alkoxyalkyl, C1-C4 Haloalkyl, C1-C6 C4 alkoxycarbonyl, -CO2H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl;

R20 is selected from:

aryl substituted with 0-5 R18,

heterocycle selected from the group consisting of:

thienyl, furanyl, thiazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, tetrahydrofuranyl, or pyranyl, said heterocyclic ring is substituted with 0-2 R18.

under condition:

when R1 is hydrogen and Q is

[image]

then R 2 is not hydrogen, C 3 -C 10 alkyl or (C 1 -C 4 alkyl)aryl.

Preferred compounds of this aspect of the invention are compounds of formula II wherein:

Q is a 5-7-membered saturated heterocyclic ring containing at least one nitrogen, and may also contain an additional heteroatom selected from oxygen, nitrogen or sulfur, and said heterocyclic ring is substituted with 0-4 groups selected from R5, 6, R8, R18 or, -C(=O)R 3 ;

R1 is elected from:

H,

C1-C4 alkyl substituted with 0-3 R4;

R2 is selected from:

C1-C6 alkyl substituted with 0-3 R17b,

-O-(C1-C6 alkyl)-R20,

-S-(C1-C6 alkyl)-R20,

-CH2O-(C1-C5 alkyl)-R20, or

-CH2S-(C1-C5 alkyl)-R20;

R 8 is hydrogen;

R10 is selected from:

Hydrogen

C1-C6 alkyl substituted with 0-4 R4;

More preferred compounds of this aspect of the invention are those compounds of formula II wherein:

Q heterocycle selected from the following compounds hexahydro-1-pyridazinyl, 2-tetrahydro-1,2-oxazinyl, 1-morpholinyl, 1-piperidinyl, 1-pyrrolidinyl, 1-piperazinyl, 4-methylpiperazinyl, tetrahydro-1,4-thiazine- 4-yl, tetrahydro-1,4-thiazin-4-yl-1oxide, tetrahydro-1,4-thiazin-4-yl-1,1-dioxide, 1-oxa-2-piperidinyl, said heterocycle is substituted with 0 -3 groups selected from -C(=O)R 3 , R 5 , R 6 or, R 8 .

Further preferred compounds are those compounds of formula II in which:

Q is:

[image]

Is N or O;

R7 is selected from:

hydrogen, hydroxy, C1-C3 alkyl substituted with 0-3 R20, C1-C4 alkoxy, -NR14R15, -COOR11,

C1-C4 alkoxycarbonyl, hydroxymethyl, -CH2OR13,

C1-C4 alkylaminocarbonyl, -C(=NOH)R14;

provided that R8 is not present when Z equals O.

Particularly preferred compounds of this aspect of the invention are selected from:

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-benzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methoxyphenylsuccinyl]-N-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methoxybenzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino]-2R-isobutyl-3S-methylthiophenylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylthiobenzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-(methylthio-2-thienyl)succinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylacetate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylisopropanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-tert-butanoate]-N-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-thioacetate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-(2-pyridyl)]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-(3-pyridyl)]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-(4-pyridyl)]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylthio-tert-butanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methylsuccinite]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-hexyl-3S-benzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methoxyphenylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methoxybenzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methylthiophenylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methylthiobenzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-hexyl-3S-(methylthio-2-thienyl)succinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-hexyl-3S-benzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methyl-acetate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methyl-isopropanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methyl-tert-butanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methyl-thioacetate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methyl-thioisopropanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methylthio-tert-butanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methyl-(2-pyridyl)]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methyl-(3-pyridyl)]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-hexyl-3S-methyl-(4-pyridyl)]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-benzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methoxyphenylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methoxybenzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methylthiophenylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methylthiobenzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-(methylthio-2-thienyl)succinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-benzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino]-2R-ethylphenyl-3S-methyl-acetate]-N2-(S)-piperazine acid-N-methyl-amide;

(4-(N-hydroxyamino)-2R-ethylphenyl-3S-methyl-isopropanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methyl-tert-butanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methyl-thioacetate]-N2-(S)-piperazine acid-N-methyl amide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methyl-thioisopropanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-ethylphenyl-3S-methylthio-tert-butanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-octyl-3S-methylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-octyl-3S-methylthiophenylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-octyl-3S-methylthiobenzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-octyl-3S-(methylthio-2-thienyl)]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-octyl-3S-methyl-acetate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-octyl-3S-methyl-isopropanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-octyl-3S-methyl-tert-butanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-octyl-3S-methyl-thioacetate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-octyl-3S-methyl-thioisopropanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-octyl-3S-methylthio-tert-butanoate]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxtamino)-2R-octyl-3S-methyl-(2-pyridyl)]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-octyl-3S-methyl-(3-pyridyl)]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-octyl-3S-methyl-(4-pyridyl)]-N2-(S)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-4”(S/R)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinite]-N2-(S)-5”(S/R)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-6”(S/R)-piperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-6”(S/R)-(4-methoxyphenyl)piperazine acid-N-methyl-

amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-4”(S/R)-benzylpiperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-5”(S/R)-benzylpiperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-6”(S/R)-benzylpiperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-[4”,5”]benzopiperazine acid-N-methyl-amide;

[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-[5”,6”]benzopiperazine acid-N-methyl-amide;

Another aspect of this invention includes a group of novel compounds that also fall within the group of compounds of formula I and their pharmaceutical preparations and methods of using these compounds in inhibiting stromelysin and in the treatment of OA and RA. The mentioned compounds are represented by formula III:

[image]

or their pharmaceutically acceptable salts or prodrug forms, in which:

Q is chosen is:

C5-C14 carbocyclic ring substituted with 0-4 groups selected from R5, R6, R18 or -C(=O)R3, or a 5- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, and said heterocyclic ring is substituted with 0-4 groups selected from R5, R6, R8, R18 or -C(=O)R3;

R2 is selected from:

C1-C6 alkyl substituted with 0-3 R17b,

-O-(C1-C8 alkyl)-R20,

-S-(C1-C8 alkyl)-R20,

-CH2O-(C1-C8 alkyl)-R20, or

-CH2S-(C1-C8 alkyl)-R20;

R3 is NR10R10a;

R4 is selected from:

-OR17, -SOmR17,

-NR8R1O, -NHC(=NR8)N(R8)R10,

C1-C4 alkyl,

aryl substituted with 0-5 R18,

C3-C8 cycloalkyl, or

a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl, and said heterocyclic ring is substituted with 0-2 R19;

R4a is selected from:

-OR17, -SOmR17,

C1-C4 alkyl,

aryl substituted with 0-5 R18,

C3-C8 cycloalkyl, or

a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl, pyrrolidinyl, phthalimido, triazolidinyl, oxadiazolidinyl, imidazolidinyl, piperidinyl, and said heterocyclic ring is substituted with 0-5 R18;

R5 and R6 are independently selected from:

hydrogen, hydroxy, C1-C6 alkyl substituted with 0-3 R20, C1-C4 alkoxy, -NR14R15, -COOR11, C1-C4 alkoxycarbonyl, hydroxymethyl, -CH2OR13, C1-C4 alkylaminocarbonyl, -C(=NOH)R14, = O, =S, or its ketal or thioketal form when R 5 or R 6 are attached to a saturated carbon atom, or = O when R 5 or R 6 are attached to sulfur;

When R5 and R6 are attached to adjacent ring atoms they may be linked to form a 5-7 membered carbocyclic or heterocyclic ring, wherein said carbocyclic ring contains one or two N, O or S atoms, and said carbocyclic or heterocyclic ring is substituted with 0-2 R18;

R8 is a substituent on nitrogen and is selected from hydrogen,

C1-C6 alkyl substituted with 0-3 R20,

C1-C6 alkylcarbonyl,

alkoxycarbonyl,

arylalkyloxycarbonyl,

alkylaminocarbonyl;

R9 is selected from:

H,

C1-C8 alkyl substituted with 0-3 R4a,

C2-C8 alkenyl substituted with 0-3 R4a,

C2-C8 alkynyl substituted with 0-3 R4a,

R10 is selected from:

hydrogen,

C1-C4 Alkoxy,

C1-C6 alkyl substituted with 0-4 R4;

R 10a is selected from hydrogen or C 1 -C 4 alkyl;

R10 , R10a can be joined to form -(CH2)4-, -(CH2)5-,

-CH2CH2N(R16)CH2CH2- or –CH2CH2OCH2CH2-;

R 11 is H, benzyl or C 1 -C 4 alkyl;

R12 is selected:

H,

C1-C8 alkyl substituted with 0-3 R4,

C2-C8 alkenyl substituted with 0-3 R4,

C2-C8 alkynyl substituted with 0-3 R4;

R 13 is C 1 -C 4 alkyl;

R 14 and R 15 are independently selected from H or C 1 -C 4 alkyl;

R 16 is hydrogen or methyl;

R17 is selected from:

hydrogen,

C1-C6 alkyl substituted with 0-3 R17a,

C1-C6 alkylcarbonyl substituted with 0-3 R17a,

C1-C6 alkoxycarbonyl substituted with 0-3 R17a,

phenoxycarbonyl substituted with 0-3 R18;

R17a is selected from:

aryl substituted with 0-5 R18,

C3-C8 cycloalkyl,

heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, pyrrolyl, pyrazolyl, piperidinyl, pyrrolidinyl, pyrimidinyl or pyridazinyl, benzofuranyl, benzothienyl, indolyl, tetrahydrofuranyl, or pyranyl, said heterocyclic ring is substituted with 0-2 R18;

R17b is selected from:

aryl substituted with 0-5 R18,

C3-C8 cycloalkyl,

a heterocycle selected from the group consisting of thienyl, furanyl, thiazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, tetrahydrofuranyl or pyranyl, said heterocyclic ring is substituted with 0-2 R18;

R18, when the substituent is carbon, is selected from one of the following compounds:

phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with -NR10R10a, -NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1- C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11, heterocyclic selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl;

or R 18 may be a chain of 3 or 4 carbons joined to adjacent ring carbons to form a fused 5- or 6-membered ring, said 5- or 6-membered ring may be substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, NR10R10a -O or -S when attached to a saturated carbon atom, or =O when attached to sulfur;

R18, when the substituent is nitrogen, is selected from one or more of the following compounds:

Phenyl, Benzyl, Phenethyl, Hydroxy, C1-C4 Hydroxyalkyl, C1-C4 Alkoxy, C1-C4 Alkyl, C3-C6 Cycloalkyl C3-C6 Cycloalkylmethyl, -CH2NR10R10a, -NR10R10a,C2-C6 Alkoxyalkyl, C1-C4 Haloalkyl, C1-C6 C4 alkoxycarbonyl, -CO2H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl;

R19, when the substituent is carbon, is selected from one or more of the following compounds:

phenyl, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CO2H, sulfonamide, C1-C4 alkyl substituted with - NR10R10a, NR10R10a, C1-C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, -S(O)mR11, -NHSO2R11,

a heterocycle selected from the group consisting of thienyl, pyridinyl, morpholinyl, furyl, thiazolyl, piperidinyl, pyrimidinyl or pyridazinyl;

or R19 may be a chain of 3 or 4 carbons joined to adjacent ring carbons to form a fused 5- or 6-membered ring, said 5- or 6-membered ring may be substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, NR10R10a, or

R19, when the substituent is nitrogen, is selected from one or more of the following:

Phenyl, Benzyl, Phenethyl, Hydroxy, C1-C4 Hydroxyalkyl, C1-C4 Alkoxy, C1-C4 Alkyl, C3-C6 Cycloalkyl C3-C6 Cycloalkylmethyl, -CH2NR10R10a, -NR10R10a, C2-C6 Alkoxyalkyl, C1-C4 Haloalkyl, C1-C6 C4 alkoxycarbonyl, -CO2H, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl;

R20 is selected from:

aryl substituted with 0-5 R18,

heterocycle selected from the group consisting of:

thienyl, furanyl, thiazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, tetrahydrofuranyl, or pyranyl, said heterocyclic ring is substituted with 0-2 R18.

Preferred compounds of the second aspect of this invention are those compounds of formula III in which;

Q is a heterocycle selected from hexahydro-1-pyridazinyl, 2-tetrahydro-1,2-oxazinyl, 1-morpholinyl, t-piperidinyl, 1-pyrrolidinyl, 1-piperazinyl, 4-methylpiperazinyl, tetrahydro-1,4-thiazine -4-yl, tetrahydro-1,4-thiazin-4-yl-1-oxide, tetrahydro-1,4-thiazin-4-yl-1,1-dioxide, and the mentioned heterocycle is substituted with 0-3 groups selected from R5, R6, R8 or -C(=O)R3;

R2 is selected from:

C2-C4 alkyl substituted with 0-3 R17b,

-O-(C1-C6 alkyl)-R20,

-S-(C1-C6 alkyl)-R20,

-CH2O-(C1-C5 alkyl)-R20 or,

-CH2S-(C1-C5 alkyl)-R20;

R 8 is hydrogen;

R9 is selected from:

H,

C1-C4 alkyl substituted with 0-3 R4a,

More preferred compounds of the second aspect of this invention are those compounds of formula III in which:

Q is

[image]

Z is N or O;

provided that R8 is not present when Z equals O.

Particularly preferred compounds of the second aspect of this invention are selected from the following:

N-[1-(R)-carboxy-ethyl]-α-(S)-isobutylglycine-(S)-N2-piperazine acid methyl amide;

N-[1-(R)-carboxy-ethyl]-α-(S)-hexylglycine-(S)-N2-piperazinic acid methyl amide;

N-[1-(R)-carboxy-ethyl]-α-(S)-heptylglycine-(S)-N2-piperazine acid methyl amide;

N-[1-(R)-carboxy-ethyl]-α-(S)-octylglycine-(S)-N2-piperazine acid methyl amide;

N-[1-(R)-carboxy-ethyl]-α-(S)-ethylphenylglycine-(S)-N2-piperazine acid methyl amide;

N-[1-(R)-carboxy-ethyl]-α-(S)-propylphenylglycine-(S)-N2-piperazine acid methyl amide;

N-[1-(R)-carboxy-ethylthiobenzyl]-α-(S)-isobutylglycine-(S)-N2-piperazine acid methyl amide;

N-[1-(R)-carboxy-ethylthiobenzyl]-α-(S)-hexylglycine-(S)-N2-piperazine acid methyl amide;

N-[1-(R)-carboxy-ethylthiobenzyl]-α-(S)-ethylphenylglycine-(S)-N2 piperazine acid methyl amide;

N-[1-(R)-carboxy-ethylthiobenzyl]-α-(S)-propylphenylglycine-(S)-N2-piperazine acid methyl amide;

N-[1-(R)-carboxy-ethyloxybenzyl]-α-(S)-isobutylglycine-(S)-N2-piperazine acid methyl amide;

N-[1-(R)-carboxy-ethyloxybenzyl]-α-(S)-hexylglycine-(S)-N2-piperazine acid methyl amide;

N-[1-(R)-carboxy-ethyloxybenzyl]-α-(S)-ethylphenylglycine-(S)-N2 piperazine acid methyl amide;

N-[1-(R)-carboxy-ethyloxybenzyl]-α-(S)-propylphenylglycine-(S)-N2-piperazine acid methyl amide;

A third aspect of the present invention is the compounds of formula IV or their pharmaceutically acceptable salts or prodrugs used in the treatment of OA and RA in which a stromelysin inhibitor is used as a cartilage protective agent:

[image]

where:

R2 is selected from:

H,

C3-C10 alkyl, or

aryl-(C1-C4 alkyl)-;

R3 is selected from OR11, NHCH(R12)COR13, NR10R10a,

NHCH(R 12 )COOR 11 , or NHCH(R 12 )CONR 14 R 15 ;

R 10 and R 10a are independently selected from hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy;

R 11 , R 12 and R 15 are independently selected from hydrogen or C 1 -C 4 alkyl;

R 13 and R 14 are C 1 -C 4 alkyl.

Detailed description of the invention

The present invention has revealed that the compounds described above are useful as inhibitors of stromelysin and similar matrix metalloproteinases, and are useful in the treatment of rheumatoid arthritis, osteoarthritis and similar pathological conditions.

This invention also describes methods of treating osteo- and rheumatoid arthritis by administering to a patient a pharmaceutically or therapeutically effective amount of a compound of formula (I) as described above. A therapeutically effective amount is that amount of a compound of the present invention that can inhibit stromelysin or treat symptoms of osteo- or rheumatoid arthritis in a patient.

The compounds of the present invention may also be taken in combination with one or more additional therapeutic agents. Taking the compounds of formula I in combination with other therapeutic agents allows taking a smaller dose of both compounds. A reduced dose reduces possible side effects and thus increases the safety level.

"Therapeutically effective amount" means an amount of a compound of formula I which, when administered alone or in combination with another therapeutic agent to a mammal or injected into a cell, effectively inhibits stromelysin and thereby prevents or ameliorates inflammatory disease states or disease development.

"Combination administration" or "combination therapy" means that a compound of formula I and another therapeutic agent are administered at the same time to the mammal being treated. When taken in combination, they can be taken at the same time or one after the other at any time interval. In this way, each component can be taken separately, but still in a short enough time interval to achieve the desired therapeutic effect.

The compounds described in this invention may have asymmetric centers. Unless otherwise indicated, all chiral, diastereometric and racemic forms are included in this invention. Many geometric isomers of olefins, C=N double bonds, and the like may also be present in the compounds of this invention, and all such stable isomers are studied in this invention. It is significant that certain compounds of this invention contain an unsymmetrically substituted carbon atom, and their optically active or racemic forms can be isolated. It is well known how to prepare optically active forms, for example by dissolving racemic forms or by synthesis from optically active starting substances. All chiral, diastereometric, racemic forms and all geometric isomeric forms of a structure are defined, unless specific stereochemical or isomeric forms are specifically indicated.

When a variable (for example, R1 to R20, R10a, m, n, Z, X, etc.) appears more than once in any component or formula (I), its definition at each occurrence is independent of every other occurrence . Thus, for example, if a group is indicated to be substituted with 0-3 R17, then said group may be substituted with zero to three R17, and R17 is independently selected at each occurrence from a defined group of possible R17.

When the bond to a substituent crosses a bond connecting two atoms on a ring, then such a substituent can be bonded to any atom on the ring.

When a substituent is specified, and the atom through which it is connected to the rest of the compound of formula I is not indicated, then such a substituent can be connected through any atom on that substituent. For example, when the substituent is piperazinyl, piperidinyl, or tetrazolyl, unless otherwise indicated, said piperazinyl, piperidinyl, tetrazolyl group may be linked to the rest of the compound of formula I through any atom of the piperazinyl, piperidinyl, or tetrazolyl group.

Combinations and/or variables are permissible if they result in stable compounds. "Stable compound" or "stable structure" means a compound that is stable enough to withstand isolation from a reaction mixture to a certain degree of purity and the preparation of a therapeutically effective agent from that compound.

The term "substituted" in the text means that one or more hydrogens on the indicated atom are replaced with a group from the indicated group, provided that the normal valence of the indicated atom is not exceeded, and that a stable compound is obtained by substitution. When the substituent is keto (ie =O), then 2 hydrogens on the atom are replaced.

"Alkyl", hereinafter, includes both branched and straight chains of saturated aliphatic hydrocarbon groups with a certain number of carbon atoms. "Alkenyl" includes saturated aliphatic hydrocarbon chains of straight or branched configuration having a specified number of carbon atoms (for example, C1-C10 denotes an alkyl containing 1 to 10 carbon atoms); "haloalkyl" includes branched and straight chain saturated aliphatic hydrocarbon groups, having a specified number of carbon atoms, substituted with 1 or more halogens (for example -CvFw where v=1 to 3 and w=1 to (2v+1)); ""Alkoxy" represents an alkyl group with a certain number of carbon atoms connected by an oxygen bond; "cycloalkyl" includes saturated ring groups, including mono-, bi- or polycyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and adamantyl; and ““bicycloalkyl” means saturated bicyclic ring groups such as [3.3.0]bicyclooctane, [4.3.0.]bicyclononane, [4.4.0.]bicyclodecane (decalin), [2.2.2.]bicyclooctane, and so on. "Akenyl" includes hydrocarbon chains of branched or straight configuration and one or more saturated carbon-carbon bonds which may be located at any stable position in the chain, such as ethenyl, propenyl, and the like; "alkynyl" includes hydrocarbon chains of straight or branched configurations and one or more carbon-carbon triple bonds which may be at any stable position in the chain, such as ethynyl, propynyl, and the like.

"Alkylcarbonyl" includes an alkyl group with a certain number of carbon atoms connected via a carbonyl group to the remaining part of the compound at a specified position. "Alkylcarbonylamino" means an alkyl group with a certain number of carbon atoms connected via a carbonyl group to an amino bond, where said bond is connected to the rest of the moiety connection in the marked place. "Alkylcarbonyloxy" means an alkyl group having a certain number of carbon atoms attached to a carbonyl group, where the carbonyl group is attached through an oxygen atom to the remainder of the compound at a certain position.

The terms "alkylene", "alkenylene", "phenylene" and the like denote alkyl, alkenyl or phenyl groups, which are linked by two bonds to the rest of the structure of formula I. Such "alkylenes", "alkenylenes", "phenylenes" and the like can also be designated as "-(alkyl)-", "-(alkenyl)-" and "-(phenyl)-" and the like.

"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo and iodo; and "counterion" means a small, negatively charged ion such as chloride, bromide, hydroxide, acetate, sulfate, and the like.

Hereinafter, "aryl" or "aromatic residue" means phenyl or naphthyl; and the term "arylalkyl" means an aryl group connected with an alkyl bond.

In the following text, "carbon cycle" or "carbon cyclic residue" or "carbon cyclic ring" means any stable 3- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic or up to 26-membered polycyclic carbon ring, from each of which may be saturated, partially saturated, or aromatic.Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

Hereinafter, "heterocycle" or "heteroaryl" or "heterocyclic" means a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atom and from 1 to 4 heteroatoms, independently selected from the group consisting of N, O or S, and in which the nitrogen and sulfur heteroatoms may be oxidized and the nitrogen may also be quadrupled; including any bicyclic group in which any of the above-defined heterocyclic the ring can be fused to a benzene ring. The heterocyclic ring can be attached to an unsaturated group on any heteroatom or carbon atom, resulting in a stable structure. The heterocyclic rings described in the text can be substituted on the carbon or nitrogen atom, if the resulting compound is stable. Examples such heterocycles include, but are not limited to, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imide zolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl or benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tethiahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1, 2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thiophenyl, thianthrenyl, furanyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxatinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl pyridinyl , pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β -carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl or oxazolidinyl. Also included are fused ring compounds and fused compounds containing, for example, the above heterocycles.

The term "amino acid" means an organic compound that contains both a basic amino group and an acidic carboxyl group. This term also includes naturally occurring amino acids, altered and unusual amino acids, as well as amino acids that occur biologically in free or combined form but do not normally occur in proteins. Such altered and unusual amino acids include, for example, those described in "The Peptidea" by Roberts and Vellaccio (1983), 5:342-429, which is incorporated herein. Altered or unusual amino acids that can be used to practice this invention include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, N-Cbz-protected amino acid, ornithine, 2,4-diaminobutyric acid, homoarginine , norleucine, N-methylaminobutyric acid, naphthylalanine, N-methyl-norleucine, 3,4-dehydroproline, N,N-dimethylaminoglycine, N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, trans-4- (aminomethyl)-cyclohexanecarboxylic acid, 2-, 3- and 4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclopropanecarboxylic acid and 2-benzyl-5-aminopentanoic acid.

The term "amino acid residue" means the portion of an amino acid (as defined) present in a peptide.

The term “peptide” as used herein means a compound consisting of two or more amino acids (as defined) joined by a peptide bond. The term "peptide" also includes compounds that contain both peptide and non-peptide components, such as pseudopeptide or peptidomimetic residues or other components that do not contain amino acids. Such a compound that contains both peptide and non-peptide components, in in the text it is marked as "peptide analog".

The term "peptide bond" means a covalent amide bond formed by the loss of a water molecule between the carboxyl group of one amino acid and the amino group of another amino acid.

The term "pharmaceutically suitable salts" refers to derivatives of the described compounds, which are obtained by changing the basic compound of formula (I) by forming acidic or alkaline salts. Examples of pharmaceutically suitable salts include, but are not limited to, salts of mineral and organic acids of alkaline residues, such as which are amines; alkaline or organic salts of acidic residues, such as carboxylic acids and the like.

"Prodrugs" are any covalently bound carriers, which release the active component according to formula (I) in vivo, when a mammal receives such a prodrug. Prodrug forms of compounds of formula (I) are prepared by changing the functional groups present in the compounds, so that the parent compounds are changed in vivo or by conventional means.Prodrugs include compounds of formula (I) in which hydroxy, amino or sulfhydryl groups are attached to any group which, when received by a mammal, is degraded to form a hydroxyl, amino or sulfhydryl group.Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amino functional groups in compounds of formula (I), phosphate esters, dimethylglycine esters, aminoalkylbenzyl esters, aminoalkyl esters and carboxyalkyl esters of alcohol and phenolic functional groups of compounds of formula (I) ; and similar to them.

Pharmaceutically suitable salts of compounds of formula I include conventional non-toxic salts or quaternary ammonium salts of compounds of formula I formed, for example, from non-toxic inorganic and organic acids. For example, such conventional non-toxic salts include derivatives of inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfaniline, 2-acetoxybenzoic, fumaric , toluenesulfonic, methanesulfonic, ethane-disulfonic, oxaline, isethionic, and the like.

Pharmaceutically suitable salts of the present invention can be synthesized by conventional chemical methods from compounds of formula I containing a basic or acidic moiety. In general, salts are prepared by reacting a free base or acid with stoichiometric amounts or with an excess of the desired inorganic or organic acid or base from which the salt was formed, in a suitable solvent or a combination of different solvents.

Pharmaceutically acceptable salts of the acids of formula I with an appropriate amount of a base, such as an alkaline-earth or -alkaline metal hydroxide, such as sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, for example, dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like.

Pharmaceutically suitable salts of the compounds of this invention can be prepared by reacting the free acidic and basic forms of these compounds with a stoichiometric amount of a suitable base or acid in water or in an organic solvent, or in their mixture; generally, anhydrous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. A list of suitable salts is found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, PA (1985) p. 1418

SYNTHESIS

Those skilled in the art of organic synthesis can prepare the compounds of the present invention in many known ways. They can be synthesized according to the procedures described below, as well as according to synthesis procedures known in organic synthesis or similar procedures known to those skilled in organic synthesis. Preferred procedures include those described below. All mentioned references are fully included in the text and form an integral part of it.

New compounds of formula I can be prepared using the reactions and techniques described in this section. The reactions are carried out in solvents appropriate to the substances and reagents used and suitable for the changes being carried out. It should also be emphasized that in the synthesis procedures listed below, all proposed reaction conditions, including the choice of solvent, reaction atmosphere, temperature, duration of the experiment and processing, are presented as standard conditions for the specified reaction, which experts should immediately recognize. It is clear to experts in organic synthesis that the functionality present on different parts of the secreted molecule must be compatible with the reagents and the proposed reaction. Not all compounds of formula I belonging to the given group are compatible with some reaction conditions necessary for carrying out the described procedures. Specialists in organic synthesis must immediately recognize such substituent restrictions and choose other procedures accordingly.

Compounds of formula I in which A is equal to HONHCOCH(R1) and Q is a hydrogenated N-heterocycle connected via N atoms in the ring, are prepared by condensation of acids of formula (V):

[image]

wherein R is an ester protecting group and R1 and R2 are defined as described in the Summary of the Invention, compounds of formula I, with an appropriately substituted N-heterocycle to form an amide bond between the carbonyl of formula (V) and the basic nitrogen in the ring of said heterocycle as shown in Scheme 1.

[image]

Condensation is carried out using any amide bond forming procedure known to those skilled in the art of organic synthesis. These procedures include converting the acid (V) to the corresponding acid chloride (Va) or using standard coupling procedures such as the azide method, the mixed acid carbonic anhydride (isobutyl-chloroformate) method, the carbodiimide method (dicyclohexylcarbodiimide, diisopropylcarbodiimide, or water-soluble carbodiimides), active ester process (p-nitrophenyl-ester, N-hydroxysuccinic imide ester), carbonyldiimidazole process, phosphoric agents such as BOP-Cl. Some of the mentioned procedures (especially carbodiimide) can be enhanced by adding 1-hydroxybenzotriazole. A preferred procedure is to treat the cyclic amine with an acid chloride prepared from (V). Procedures for converting carboxylic acids into acid chlorides are described in (J. March, Adv. Org. Chem. 1985, p. 1146, J. Wiley & Son, USA) and include, for example, treating acid a with oxalyl chloride in the presence of a catalytic amounts of N,N”-dimethylformamide. Removal of the ester protecting group, followed by activation of the resulting acid, for example with isobutylchlorophosphate, and reaction with O-benzylhydroxylamine gives the protected hydroxamic acid. Hydroxamic acid is obtained by deprotection.

Compounds of formula I, wherein A is HONHCOCH(R1) and Q is aryl or heteroaryl, are prepared by treating an acid chloride (Va) prepared from an acid (V) with a metallated aryl or hetephoaryl as shown in Scheme 2, where R, R 1 and R 2 are as defined above, Ar represents an aryl or heteroaryl group and M is lithium, magnesium bromide or trialkyl or triaryltin. Organometallic groups, Ar-M, are obtained by treating an aryl or heteroaryl iodide or bromide with an alkyl or aryllithium reagent, magnesium or trialkyltin reagent to give the corresponding lithium, magnesium bromide or tin group, using procedures known to those skilled in the art. Condensation of trialkyltin groups with acid chlorides in the presence of a catalytic amount of palladium(0) catalyst was described by Stille (Angew. Chem. Int. Ed. Engi., 1986, 25:508). In cases where the heteroaryl groups are sufficiently reactive, either direct metallization or direct condensation of the unactivated heteroaryl compound of said chloride can be performed (see B. Oddo, Gazz. Chim. Itat., 1911, 41:234). The intermediate ester is then converted to the desired hydroxamic acid as described above.

[image]

Acids of formula (V) are prepared as described above (Crimmin et al. Synlett, 1993, 137; Tamaki et al., Tetrahedron Lett. 1993, 34:683) or according to the usual procedure shown in Scheme 3. Appropriately substituted carboxylic acid (VIII) is converted to the chiral oxazolidinone (IX) by Evans deprotonation with a strong base, followed by treatment with t-butylbromoacetate to give intermediate (X). Transesterification of the chiral intermediate with LiOBn, followed by treatment with acid to remove the tert-butyl protecting group and conversion of the acid to the trichloroethyl ester gives a compound of formula (Va)/ where R1 is hydrogen. Hydrolysis of the chiral intermediate can also be achieved with alkaline hydrogen peroxide to give the acid (Vb).

According to scheme B, the α-bromoester of formula (IX) can be treated with the potassium salt of dibenzyl malonate to give the triester (XII). The procedure for the preparation of α-bromoesters of amino-esters is known to experts in organic synthesis (R.S. Compagnone and H. Rapoport, J. Org. Chem. 1986, 51, 1713). Removal of the benzyl ester and decarboxylation gives acid (XIII) which can then be changed to (Va) by changing the functions of the acid using standard procedures. Acids (V) in which R1 is not hydrogen are obtained from the intermediate (XII) by the Mannich reaction, followed by quaternization and elimination to give the methylene compound (XIV). Then, by changing the function of the acid, the desired mono-trichloroethyl ester is obtained. Alkene reduction yields (V) where R1 is methyl. Compounds in which R1 is not hydrogen or methyl are obtained from intermediate (XIV) by 1,4-addition of the corresponding nucleophiles to the α,β-unsaturated part of the acid. Suitable nucleophiles include, alkyllithiums, alkylmagnesium halides, thiols and alkoxides and the like.

[image]

Compounds of formula II, in which Z is equal to N, can be prepared from piperazine acid derivatives of formula (XV), in which R 5 , R 6 , R 7 are defined as described in the summary of the invention related to compounds of formula II.

[image]

Unsubstituted piperazine esters of formula (XV) can be prepared as described by Adams et al. (Synth. Commun. 1988, 38, 2225) or according to the already known procedure described in Scheme 4.

[image]

By asymmetric addition of di-t-butyl diazodicarboxylate to chiral oxazolidinone prepared from a suitably substituted derivative of 5-bromovaleric acid (K.J.Hale, V.M. 7613), followed by removal of BOC groups and hydrolysis of oxazolidinone, piperazine acid derivatives (XVa) are obtained. The preferred procedures used to remove BOC groups are trifluoroacetic acid, neat or in dichloromethane, or HCl in dioxane. Hydrolysis of oxazolidinone is preferably carried out by treatment with aqueous lithium hydroxide. Compounds of formula (XVa) can be readily converted to compounds of formula (XV) by procedures known to those skilled in the art of organic synthesis, for example, treatment of benzylchloroformate in the presence of an appropriate base such as aqueous sodium hydroxide followed by exposure to isobutylene under acid catalysis.

There are also other ways of preparing compounds of formula (XV). According to the Diels-Alder cyclization of 4-phenyl-1,2,4-triazoline-3,4-dione with an appropriately substituted diene (Adams, see above), a compound is obtained which after reduction and alkaline hydrolysis gives piperazine acid derivatives (XVa) which are translated into (XV), as described above.

Compounds of formula II wherein Z is N and R 8 is H can be prepared from piperazine esters of formula (XV) and acids of formula (V) as shown in Scheme 5.

[image]

Piperazine esters (XV) are coupled with acids of formula (V) to give amides of formula (VI) as described above. For the compounds of the formula II in which Z is N, R8 is H and R3 is –NR10R10a, after the synthesis, hydroxylysis of the t-butyl ester of the compound of the formula (VI) is performed, followed by activation of the obtained acid with a coupling reagent selected from the above of a list of standard procedures, for example, isobutylchloroformate, and treatment with an excess of an amine of the formula R10(R10a)NH or the corresponding alcohol to give the corresponding amide. The trichloroethyl ester is removed by reduction followed by conversion to hydroxamic acid as described earlier. Preferred methods for removing TCE esters are reduction with zinc dust or mild basic hydrolysis. To remove benzyl and Cbz groups at once, the following reagents are used: hydrogenation conditions with the help of hydrogen at atmospheric pressure, or Parr's device with elevated hydrogen pressure, or cyclohexene or ammonium formate with palladium, palladium hydroxide on coal or platinum oxide in methanol, ethanol or tetrahydrofuran, or in a combination of said solvents (P.N. Rylander, Hydrogenation Methods, Academic Press, 1985). For compounds in which R1 contains sulfur, removal of the benzyl and Cbz protecting groups is performed with the help of hydrogenation in the presence of a Witkinson catalyst or by treatment with trimethylsilyl iodide.

Another method of preparing compounds of formula II in which R 1 is not hydrogen or methyl is shown in Scheme 6. An acid of formula (XIV) is condensed with a compound of formula (XV) by one of the above methods to give (XVI). This intermediate is further translated into acid (XVII). Compounds of formula II are obtained by Michael addition of the appropriate nucteophile and conversion of the acid functionality to hydroxamic acid. In this way, other compounds of formula II can be prepared by replacing compound (XV) in Scheme 6 with heterocyclic, aryl and heteroaryl reagents, as described above.

[image]

Compounds of formula II can also be prepared according to Scheme 7.

[image]

Compounds of formula II wherein Z is N and R8 is not hydrogen are prepared according to Scheme 8. Compounds of formula (VII) are liberated as described above, followed by alkylation of the resulting free amine with an alkylating agent in the presence of a suitable base. Alkylating agents include alkyl halides, mesylates, tosylates, etc. Suitable bases are triethylamine, N-methylmorpholine or diisopropylethylamine. Compounds in which R 8 is alkylcarbonyl are prepared by treating the liberated (VII) with an acyl halide such as acetyl chloride.

[image]

Compounds of formula II in which Z=O are prepared from hydroxamic acids (XVII) as shown in Scheme 9.

[image]

Hetero-Diels-Alder reaction of hydroxamic acids of formula (XVII) and a suitably substituted diene in the presence of a suitable oxidant gives compounds of formula (XVIII) from which, after reduction, compounds of formula II are obtained.

[image]

Compounds of formula I in which A is -NHCH(R9)CO2H are prepared from amino acids (XIX) according to Scheme 10.

[image]

The N-protected amino acid (XIX) is coupled with the piperazine esters of formula (XV) using the standard coupling techniques previously described to give the hydrazine (XX). Further processing of the t-butyl ester as described earlier and hydrogenation of both Cbz-protecting groups yields the amine of formula (XXI). By reductive amination of the primary amino group with appropriately substituted α-ketobenzyl esters, with the help of procedures already known to experts, compounds of the general formula III are obtained. According to the procedures described above, compound (XV) can be substituted with other N-heterocycles or aryl or heteroaryl derivatives to obtain other compounds of formula III.

The unusual amino acids used in this invention can be synthesized according to standard procedures known to those skilled in the art ("The Peptides: Analysis, Synthesis, Biology, Vol. 5, pp. 342-449, Academic Press, New York (1981)). N -alkyl-amino acids can be prepared according to the procedures described by Cheung et al. (Can. J. Chem. 55, 906, (1977)) and Freidinger et al., (J. Org. Chem. 48, 77 (1982 )), which are incorporated into this text by reference.

The functional groups of the mentioned amino acids must be protected during coupling in order to prevent the formation of undesirable bonds. Protective groups that may be used are listed in Greene's handbook, "Protective Groups in Organic Synthesis" John Wiley & Sons, New York (1981) and "The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the texts of which are incorporated herein by reference.

In another aspect of this invention, we claim that the pharmaceutical compositions of the compounds of formula I (under the specified conditions) are bioavailable drugs for oral administration useful for the treatment of arthritis, since they act as cartilage protectors.

The compounds described in this invention and their preparations are described in more detail in the following examples and procedures, which are only intended to serve as examples, but in no way limit the scope of this invention.

Examples

The following abbreviations are used in the examples below: "1X" for single, "2X" for twice, "3X" for triple, "bs" for broad singlet, "°C" for degrees Celsius, "Cbz" for benzyloxycarbonyl, "d" for doublet, "dd"" for double doublet, ""eq" for equivalent equivalent, "g"" for gram or grams, "ml" for milliliter or milliliters, "H" for hydrogen or hydrogens, "1H" for proton, "hr" for hour or hours, "m" for multiplet, "M" for mole, "min" for minute or minutes, "mp" for melting point, "MHz" for

megahertz, "MS" for mass spectroscopy, "nmr" or "NMR" for nuclear magnetic resonance, "t" for triplet, "tlc" for thin layer chromatography, "v/v" for volume to volume ratio, "α", "β", "R" and "S" are stereochemical designations known to those skilled in the art.

Procedure 1

Preparation of tert-butyl ester of N1-benzyloxycarbonyl-S-piperazine acid

A. [4R-(phenylmethyl)-2-oxazolidinyl]-5-bromovaleramide

Bromovaleric acid (68 g, 0.38 g) was dissolved in dry methylene chloride (640 ml) and anhydrous DMF (1 ml) was added. The solution was cooled to 0°C under a nitrogen atmosphere. Oxalyl chloride (36.8 ml, 0.413 mol) was added dropwise over 20 min., after which the mixture was stirred for 1 h at 0°C and then at room temperature until all the gas had evaporated (6 h). The solvent was removed in vivo to give the crude acid chloride.

To a solution of (+)-(S)-4-benzyloxazolidinone (66.56 g, 0.376 mol) in tetrahydrofuran (900 ml), cooled to -78°C, was added n-butyllithium (164 ml, 2.29 M in hexane) over 1 hour. with mechanical stirring. Then the cooling bath was removed, and the solution was stirred for another 18 h. The reaction was then quenched with 10% citric acid (400 ml) and water (600 ml). The phases were separated, the aqueous phase was extracted with ether (3 x 300 ml). The combined organics were washed with saturated aqueous sodium hydrogen carbonate solution (2 x 600 ml), 10% citric acid (2 x 300 ml), water and brine, and then dried over anhydrous magnesium sulfate. Filtration and removal of the solvent gave the crude product (124.0 g, 97%).

Recrystallization from 10:1 heptane in ether gave the pure product in 85% yield. mp 57-59°C. MS m/e 340 (M+H)+. [α]D +81.6.

B. N1,N2-[di-tert-butoxycarbonyl]-S-piperazine acid [4R-(phenylmethyl)-2-oxazolidinonamide]

A similar procedure for the preparation of this compound is described in chemical handbooks (Hale et al., Tetrahedron Letters 1992, 33, 7613). To a previously prepared solution of lithium diisopropylamide (0.2214 mol in 104 ml of tetrahydrofuran), cooled to -78°C, the compound from procedure A (76.8 g, 0.226 mol) was added, but so that the temperature was maintained at or below - 70°C. The resulting mixture was stirred for another 20 min. at -78°C. A solution of di-tert-butyl-diazodicarboxylate (62.44 g, 0.271 mol) in dry methylene chloride (370 ml) was added dropwise, while maintaining the temperature at -70°C. The resulting mixture was stirred for 30 min, and then 0.1 equivalent of tetrabutylammonium iodide was added. The cooling bath was then removed, and the reaction temperature was raised to -10°C with stirring for 30 minutes. HPLC showed a complete change of product. The crude mixture was poured into a solution of ether (800 ml), water (2 ml) and potassium dihydrogen phosphate (50 g). The organic layer was separated, and the aqueous layer was further extracted with ether. The combined organics were washed with saturated aqueous sodium hydrogen bicarbonate solution (500 ml) and brine, followed by drying over anhydrous magnesium sulfate. Filtration and evaporation of the solvent gave a crude oil which was then purified by MPLC-SiO2 (25% ethyl acetate/hexane) to give the desired product (49 gm, 50%). MS m/e 507 (M+H)+. [α]D +35.95 (c 0.370, methanol).

C. S-piperazine acid [4R-(phenylmethyl)-2-oxazolidinonamide]dihydrochloride

A solution of the compound from procedure 1B (10 g, 0.02 ml) in dioxane (10 ml) was added to a cooled solution of 4N hydrogen chloride in dioxane (100 ml). The cooling bath was removed, and the solution was stirred for 4 hours at room temperature. The solvent was removed in vacuo to give the dihydrochloride salt (7.3 g, 98%). MS m/e 290 (M+H)+. [α]D +89.29 (c0.224, methanol), ir 3434, 1782, 1698, 1HNMR (300 MHz) 7.25 (5H, m), 4.81 (1H, dd), 4.40 (1H, m), 4.22 (1H , dd), 3.01 (4H, m), 2.0-1.75 (3H, m), 1.6 (1H, m).

D. N1-(benzyloxycarbonyl)-S-piperazine acid [4R-(phenylmethyl)-2-oxazolidinonamide]

A solution of the compound from procedure 1C (8.03 g, 22.1 mmol) in DMF (45 ml) cooled to 0°C was treated with Hunig's base (15.8 ml, 90.4 mmol) and stirred for 20 min. Benzyl chloroformate (3.76 g, 22.1 mmol) was added dropwise over 20 min., after which the cooling bath was removed and stirring was continued at 20°C for another 18 h. Evaporation of the volatiles gave a brown oil, which was then treated with N ethyl acetate. The white precipitate (diisopropylethylamine hydrochloride) was removed by filtration, and the filtrate was washed with saturated sodium hydrogencarbonate, water and salt solution, after which it was dried over anhydrous magnesium sulfate. Filtration and removal of the solvent in vacuo gave a semi-solid which was recrystallized from pentane/ethyl acetate to give the desired product (6.36 g, 68%) mp 102-103°C. MS m/e 423 (M+H)+. [α]D +33.3 (c 0.664, MeOH).

E. M1-(benzyloxycarbonyl)-S-piperazine acid

The compound from procedure 1D (5 g, 11.8 mmol) was dissolved in a mixture of THF (50 ml) and water (10.2 ml) and cooled to 0°C. Lithium hydroxide monohydrate (1.16 g) was added to the mixture, and then the disappearance of the starting materials was recorded by tlc (1:1 ether/hexane). After completion of the reaction (approximately 4 h), it was quenched with 10% citric acid and extracted with ethyl acetate. Ethyl acetate was then extracted 5 times with saturated sodium bicarbonate solution. Citric acid was added to the aqueous basic phase, and then it was extracted 4 times with ethyl acetate. The organic phase was washed with water, brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave the desired product (2.9 g, 93%) which was used in the next step without purification. MS m/e 282 (M+H)+. [α]D = -31.25 (c 0.0128, MeOH), ir 3200, br 1750, 1692 1HNMR (300 MHz) 7.28 (5H, m), 5.05 (2H, 2), 3.8 (1H, ddd), 3.28 (2H , m), 3.02 (1H, m), 1.85 (1H, m), 1.70 (1H, m), 1.5 (2H, m).

F. N1-(Benzyloxycarbonyl)-S-piperazine acid tert-butyl ester

To a solution of the compound from procedure 1E (11 g) in methylene chloride (100 ml) was added N,N-diisopropyl-O-tert-butylimidate•CuCl2 (35 ml of a 3M solution in methylene chloride), and then the mixture was stirred at 20°C for 18 hours. Acetic acid (20 ml) was added, and the solution was then stirred for another 30 min. Filtration, followed by dilution with water (100 ml) and saturated sodium hydrogencarbonate solution to pH 9-10, resulted in a solution that was vigorously stirred for another 10 min. By separating the organic phase, followed by extraction with methylene chloride, a product layer was obtained, which had to be additionally filtered and the blue gelatinous precipitate removed. The aqueous layer was extracted 3 more times with methylene chloride, and the combined organic layer was washed with water, brine and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give an oil which was triturated with hexane and filtered to remove residual solids. Removal of hexane gave the desired product in the form of an oil (10.3 g, 88%) which solidified at -20°C. MS m/e 280 (M+H)+.[α]D = -33 (c 0.700, MeOH), ir 1732, 1698.

Procedure 2

Preparation of N1-(benzyloxycarbonyl)-6-phenylpiperazine tert-butyl ester

A. 2-carbomethoxy-5,8-diphenylbicyclo [4.3]-1,6,8-triaza-7,9-dioxonon-3-ene

To a solution of N-phenyl-3,4-dioxourazole (9.55 g, 54.5 mmol) in methylene chloride (250 ml) was added a solution of methyl 5-phenyl-2,4-pentenoate (10.25 g, 54.5 mmol) in methylene chloride ( 100 ml) for 20 minutes. The mixture was stirred for 18 hours at room temperature. The solvent was removed using a rotary evaporator to give a semi-solid product which was triturated with 1:1 ether in hexane. White crystals were collected by filtration to give the product (12.34 g, 65%). The trituration was repeated on the filtrate to give more white crystalline product, in a combined yield of 14.16 g (75%). mp 155-156°C. MS m/e 364 (M+H)+.

B. 2-carbomethoxy-5,8-diphenylbicyclo [4.3]-1,6,8-triaza-7,9-dioxonanone

The product from procedure 2A (14.16 g, 39.9 mmol) was diluted in a 3:1 mixture of ethanol in ethyl acetate, and stirred in the presence of 10% palladium on carbon under 1 atm. of hydrogen pressure for 18 hours. The catalyst was removed by filtration and washed with methylene chloride. The solvent was removed by evaporation to give a white solid foam (14.2 g, 100%). Trituration of the foam with 1:1:1 ethyl acetate/ether/hexane, filtration and drying gave the product (12.7 g, 90%). mp 126-128°C. MS 366 (M+H)+.

C. Dihydrochloride of 6-phenylpiperazine acid

The compound from procedure 2B (28.7 g, 78.6 mmol), butanol (210 mL) and potassium hydroxide powder (28.7 g, 511 mmol) were combined and heated at reflux for 24 hours. The mixture was cooled to room temperature and stirred for another 24 hours. Water (225 ml) was added and the mixture was stirred for 30 minutes. The butanol layer was separated and washed with water (225 ml). The combined aqueous phase was washed once with methylene chloride. Then 6N HCl was added to the aqueous phase to pH 2. Evaporation of the volatiles under vacuum gave a solid which was triturated with methanol. The potassium chloride was filtered off and the solvent was removed to give the desired product (21.5 g, 96%). MS m/e 207 (M+H)+ free base.

D. N1-(benzyloxycarbonyl)piperazine acid

The compound from procedure 2C (1 g, 3.6 mmol) was dissolved in water (15 ml) and with the addition of 2N sodium hydroxide the pH was adjusted to 9-9.5. The resulting mixture was cooled to 5°C, and a solution of benzyl chloroformate (0.464 ml, 3.6 mmol) in toluene (2 ml) and a solution of sodium hydroxide (3.58 mmol) in water (2 ml) were added together at the same rate over 5 minutes. The two-phase solution was stirred for 18 hours. 1N HCl was then added to the solution until pH 3, and then the mixture was extracted with ethyl acetate (3X). The organic phase was washed with brine and dried with anhydrous magnesium sulfate. Filtration followed by evaporation in vacuo afforded the title compound (1.16 g, 95%). In the next phase, the obtained raw product was used unchanged. MS m/e 341 (M+H)+, 295 (M+-CO2), 251 (M+-benzyl).

E. N1-(benzyloxycarbonyl)-6-phenylpiperazine acid t-butyl ester

A solution of the compound from procedure 2D (1.22 g, 3.6 mmol) in methylene chloride (10 ml), cooled to 0°C, was treated with N,N-diisopropyl-O-tert-butylimidate•CuCl2 (3.5 ml, 3.5 M solution ). The cooling bath was removed, and the solution was stirred for 4.5 hours at room temperature. The mixture was processed as previously described in procedure 1F. The crude product (1.24 g, 86%) was purified by MPLC (SiO 2 , 4:1 hexane/ethyl acetate) to give the product as a mixture of diastereomers. MS 397 (M+H)+.

Procedure 3

Preparation of (2S,3R)-2'2'2'-trichloroethyl-3-carboxy-2,5-dimethylhexanoate

A. (R)-2-ethenyl-3-(t-butoxycarbonyl)-5-methylhexanoic acid

(R)-Benzyl (2-benzyloxycarbonyl)-3-(tert-butyloxycarbonyl)-5-methylhexanoate (2 g, 4.4 mmol) was prepared as described in European Patent Application WO 90/05719) and dissolved in ethanol (40 ml). Ammonium formate (1.4 g, 21.3 mmol) was added followed by 10% Pd-C (500 mg) as an isopropanol solution. After 90 minutes, the catalyst was removed by filtration on celite to obtain a crude diacid solution. Piperidine (415 g) was added and the mixture was stirred for 10 min. at room temperature. Aqueous formaldehyde (2.1 ml, 40% solution) was added and the mixture was stirred for another 18 hours. The solution was heated under reflux for 90 min., cooled to room temperature and the solvent was evaporated. The crude material was partitioned with ethyl acetate and 10% citric acid solution. The acidic layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give the title compound (0.87 g, 82%) as a colorless oil. MS 242 (M+H)+ , IR 3500-2800, 1730, 1700, 1626 cm-1.

B. 2S-methyl-3R-(tert-butoxycarbonyl)-5-methylhexanoic acid

To a solution of the compound from procedure 3A (0.86 g) in methanol (40 ml) was added 10% Pd-C (120 cng), and then the heterogeneous mixture was stirred under 1 atm of hydrogen gas for 12 hours. The catalyst was filtered and the solvent was evaporated to give the saturated product as a colorless oil (9:1 mixture of diastereomers). MS m/e 244 (M+H)+, [α] +18.2 (c 0.406, methanol)

C. 2'2'2'-trichloroethyl 2S-methyl-3R-(tert-butoxylcarbonyl), 5 methylhexanoate

The compound from procedure 3B (4.4 mmol), trichloroethanol (850 ml, 8.8 mmol) and DMAP (30 mg) were mixed in dry methylene chloride (10 ml) and cooled to 0°C. Dicyclohexylcarbodiimide (908 mg (4.4 mmol)) was added, the cooling bath was removed after 5 min, and the solution was then stirred under nitrogen for 12 h. The dicyclohexylurea precipitate was removed by filtration, after which the organic layer was washed with 10% citric acid. and brine. Evaporation of the solvent gave a semi-solid which was triturated with hexane to give more urea, which was collected by filtration. The hexane layer was stirred vigorously in an equal amount of water for 2 hours to remove excess trichloroethanol. The hexane layer was then separated , washed with brine and dried over MgSO4. Evaporation of the solvent gave a crude oil which was purified by MPLC on silica gel (5% ether/hexane) to give the desired diastereomer as an oil (77%). MS m/e 376 (M +H)+, [α] +7.43 (c 0.350, methanol)

Example 1

[4-(N-hydrocaamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide

A. Tert-butyl ester (2R,3S)-[4-(2'2'2'-trictoroethoxy)-2-isobutyl-3-methylsuccinyl]-N2-(N1-benzyloxycarbonyl)piperazine acid

The compound from procedure 3D (1 g, 3.1 mmol) was dissolved in dry methylene chloride (30 ml) containing 5 drops of dry N,N-dimethylformamide. The solution was cooled to 0°C under N2 followed by the addition of oxalyl chloride (0.297 ml, 3.4 mmol). The solution was stirred for 30 min at 0°C and then for 1 h at RT. The solvent was evaporated in vacuo and washed 3x with dry methylene chloride to remove HCl. The crude acid chloride was dissolved in 15 ml of methylene chloride and added to a mixture of N1-benzyloxycarbonylpiperazine acid (+/-)-t-butyl ester (992 mg, 3.1 mmol) and N-methylmorpholine (341 µl, 3.1 mmol) in methylene chloride. (20 ml) at 0°C. The mixture was then stirred for 18 hours at room temperature and then diluted with 10% citric acid, followed by separation and washing with saturated aqueous sodium bicarbonate, brine and finally drying over anhydrous magnesium sulfate.

The solvent was evaporated to give the crude material which was purified by MPLC on silica gel to give the title compound (0.96 g, 50%) as a 1:1 mixture of diastereomers. MS m/e 623 (M+H)+. IR 1760 cm-1.

B. N-methyl-amide (2R,3S)-[4-(2'2'2'-trichloroethyl)-2-isobutyl-3-methylsuccinyl]-N2-(N1-benzyloxycarbonyl)-piperazine acid

The compound from Example 1A (0.96 g) was added to a solution of 4N HCl/dioxane (35 ml), and the mixture was then stirred for 8 hours at room temperature. By removing the solvent in vacuo, the desired acid was obtained in a quantitative extract. The crude acid was dissolved in CH2Cl2 (10 ml) and treated with N-methylmorpholine (0.19 ml, 1.7 mmol) and cooled to -20°C. After stirring for 10 min at -20, isobutylchloroformate (0.2 ml, 1.5 mmol) was added dropwise over 5 min, and the mixture was stirred for 1 h at room temperature. The resulting mixture was treated with 5 equivalents of 40% aqueous methylamine, and the solution was stirred for 30 min to warm to room temperature. The mixture was then diluted with ethyl acetate, washed with 10% citric acid, water and brine, and then dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a crude oil which was purified by MPLC (5% MeOH/CH2Cl2) to give the desired amide as a 1:1 mixture of diastereomers (770 mg, 89%). MS m/e 578 (M+H)+, IR 3354, 1752, 1716, 1678, 1544 cm-1.

C. N-methyl-amide (2R,3S)-[4-hydroxy-2-isobutyl-3-methylsuccinyl]-N2-(N1-benzyloxycarbonyl)-piperazine acid

The compound from Example 1 B was dissolved in tetrahydrofuran (26 ml) and 5.2 ml of 1 M ammonium acetate solution was added. The solution was cooled to 0°C and then zinc powder (2.3 g, 3 ms. equiv.) was added. The heterogeneous solution was stirred vigorously for 10 minutes at 0°C and then for 6 hours at room temperature. The crude reaction mixture was filtered and washed with ethyl acetate. The solvent was removed by evaporation, and the crude material was diluted with ethyl acetate and washed with water, 10% citric acid (2x), brine and dried over anhydrous magnesium sulfate. Filtration and solvent evaporation, followed by MPLC (10% MeOH/CH2Cl2) afforded the desired product as a 1:1 mixture of diastereomers as a white foam (330 mg, 57%). MS m/e 465 (M+H)+, IR 3324, 2958, 1712, 1680, 1554 cm-1.

D. N-methyl-amide (2R,3S)-[4-benzyloxyamino)-2-isobutyl-3-methylsuccinyl)-N2-(N1-benzyloxycarbonyl)-piperazine acid

The compound from Example 1C (210 mg, 0.47 mmol) was mixed with N-methylmorpholine (0.056 ml) in dry methylene chloride (15 ml) and cooled to -20°C under N 2 . Isobutylchloroformate (0.061 ml, 0.47 mmol) was added, and the solution was then stirred for 1 h. A solution of O-benzylhydroxylamine hydrochloride (77 mg) and N-methylmorpholine (0.056 ml) in methylene chloride (3 ml) was added while washing with methylene chloride, then the mixture was stirred at room temperature for 18 hours. The mixture was diluted with methylene chloride, washed with 10% citric acid (1 x 20 ml), brine, and then dried over anhydrous magnesium sulfate. Evaporation of the solvent gave O-benzyl protected hydroxamic acid (203 mg, 78%) in the form of a mixture of diastereomers, which were separated using HPLC C18 columns, 10% isopropanol/hexane.

Diastereomer A 97 mg (the first product formed) was converted to the corresponding hydroxamic acid as described in Example 1E.

Diastereomer B 95 mg (the second product formed) was converted to the corresponding hydroxamic acid as described in Example 2.

E. (R)-[(2R,3S)-4-(N hydroxyamino)-2-isobutyl-3-methylsuccinyl]-N2-piperazine acid-N-methyl-amide

Diastereomer A from Example 1D (29 mg, 0.052 mmol) was dissolved in ethanol (5 ml) and 10% Pd at C (5 mg) was added. The solution was stirred under a hydrogen balloon for 1 h. The heterogeneous mixture was filtered through a microporous filter and evaporated to complete dryness to afford the title compound (18 mg, quantitative extract). MS m/e 570 (M+H)+, [α]D +54.17 (c 0.216, MeOH), mp 120-130°C, ir 3224, 1624 br, 1HNMR (400 MHz, COSY, CD3OD) 5.1 (1H , dd), 4.08 (1H, dt), 3.09 (1H, ddd), 2.79 (3H, s), 2.4 (1H, ddd), 1.65 (1H, ddd), 2.25 (1H, ddd), 2.19 (1H, dddd), 1.8 (1H, dddd), 1.65 (1H, ddd), 1.55 (2H, m), 1.4 (1H, m), 1.2 (3H, d), 1.19 (1H, m), 0.92 (3H, d ), 0.88 (3H, d), 13CNMR (100 MHz, DEPT, CD3OD) 178.7, 174.8, 173.6, 42.9, 41.7, 41.0, 27.5, 27.3, 26.3, 24.2, 22.3, 22.2, 15.5.

Example 2

(S)-[(2R,3S)-4-(N-butyloxyamino)-2-isobutyl-3-methylsuccinyl]-N2-piperazine acid-N methyl-amide

The diastereomer from Example 1D (15 mg) was dissolved in ethanol (5 ml) and 10% Pd on C (5 mg) was added. The solution was stirred under a hydrogen balloon for 1 hour. The heterogeneous mixture was filtered through a microporous filter, evaporated to dryness to afford the title compound (10 mg). mp 123-127°C, MS m/e 570 (M+H)+, [α]D +6.67 (c 0.009, MeOH), 1HNMR (400 MHz, COSY, CD3OD) 5.15 (1H, dd), 4.00 ( 1H, m), 3.05 (1H, m), 2.8 (1H, m), 2.79 (1H, s), 2.28 (1H, m), 2.10 (1H, m), 1.9 (1H, m), 1.7-1.5 (3H, m), 1.3 (1H, m), 1.05 (1H, m), 1-04 (3H, d), 0.92 (3H, d), 0.83 (3H, d), 13CNMR (100 MHz, DEPT, CD3OD) 180.8, 179.11, 174.6, 52.4, 42.6, 42.5, 28.1, 27.5, 27.1, 27.0, 26.2, 24.5, 22.4, 17.3, 17.1.

Example 3

N-[1(R)-carboxyethyl]-α-(S)-isobutylglycine-(S)-N1-piperazine acid methyl-amide

To a solution of Cbz-L-leucine (1 g, 3.77 mmol) and N,N-dimethylformamide (0.5 ml) in methylene chloride (45 ml) at 0°C, oxalyl chloride (0.329 ml) was added. The solution was stirred for 1 h at 0°C and then for 2 h at room temperature. It was then evaporated in vacuo. The crude acid chloride was taken up in methylene chloride (45 ml) and cooled to 0°C under N 2 . The compound from procedure 1F (1.21 mg, 3.77 mmol) and N-methylmorpholine (0.458 ml) in methylene chloride was added to the acid chloride solution over 10 minutes, and then the mixture was stirred for 18 hours at RT. The mixture was taken up in methylene chloride and washed with 10% citric acid, saturated aqueous sodium hydrogencarbonate, water and brine, and then dried over anhydrous magnesium sulfate. Filtration and evaporation of the solvent gave the amide in the form of an oil, which was purified by MPLC (1.7 g, 79%).

The resulting amide (1.7 mg, 2.98 mmol) was treated with trifluoroacetic acid for 4 hours at room temperature. By evaporating the solvent, a transition acid was obtained, which was used in the next step without purification. Isobutylchloroformate (0.173 ml, 1.32 mmol) was added to a solution of the crude acid cooled to -20°C (660 mg, 1.29 mmol) and N-methylmorpholine (0.145 ml, 1.37 mmol) in methylene chloride. The solution was stirred for 1 hour at -20°C. Aqueous methylamine (40% solution, 5 equiv) was then added and the temperature was raised to ambient. After 1 h, the solution was quenched with 10% citric acid, diluted with CH2Cl2 and washed with water and brine, after which the mixture was dried over MgSO4. Filtration and evaporation of the solvent gave methyl-amide, which was purified by MPLC.

The bis-Cbz protected intermediate was hydrogenated with H2 Pd-C in ethanol for 4 hours at 1 atm. The heterogeneous mixture was filtered and evaporated in vacuo to give the corresponding amine. The final product was obtained by reductive amination with benzylpyruvate as follows: the amine in THF was tritylated with benzylpyruvate at 20°C. Sodium cyanoborohydride was added and an equivalent of p-toluenesulfonic acid in THF was titrated over 1 h. The solvent was evaporated to 1/3 volume, and ethyl acetate and water were then added. The organic phase was separated, and the aqueous phase was washed 3 times with ethyl acetate. The combined organics were washed with water and brine and then dried over MgSO4. Filtration and evaporation of the solvent gave the crude amino acid in the form of a mixture of diastereomers, which was purified by MPLC (60% meOH/CH2Cl2). MS m/e 327 (M+H)+.

Example 45a

(S)-[(2R,3S)-4-(N-hydroxyamino)-2-propylphenyl-3-methylsuccinyl]-N2-piperazinic acid-N-methyl-amide

A. [4R-(phenylmethyl)-2-oxazolidinyl)j-5-phenylvaleramide

The sodium salt of 5-phenylvaleric acid (53.5 mol) was dissolved in THF (100 ml) and anhydrous DMF (1 ml) was added. The solution was cooled to 0°C under a nitrogen atmosphere. Oxalyl chloride (4.67 ml) was added dropwise over 20 min., followed by stirring at 0°C for 1 h, and then at room temperature until gas formation ceased (3 h).

To a solution of (+)-(S)-4-benzyloxazolidinone (8.83 g, 53.5 mmol) in tetrahydrofuran (100 ml) cooled to -78°C, n-butyl lithium (21.4 ml, 2.5 M in hexane) was added with stirring. during 1 hour. After 15 min of mixing, acid chloride (precooled to -78°C) was added over 45 min. The cooling bath was removed, and the solution was stirred for another 18 hours. The reaction was quenched with 10% citric acid (100 ml) and water (100 ml). The phases were separated and the aqueous phase was extracted with ether (3 x 300 ml). The combined organics were washed with saturated aqueous sodium hydrogen carbonate solution (2 x 600 ml), 10% citric acid (2 x 300 ml), water and brine, and then dried over anhydrous magnesium sulfate. Filtration and removal of the solvent afforded the crude product which was then chromatographed using 20% ethyl acetate/hexane to afford 14 g (77%) of the desired product. MS m/e 338 (M+H).

B. [4R-(phenylmethyl)-2-oxazolidinyl)]-2S-(t-butylacetyl)-5-phenylvaleramide

The compound from part A (14 g, 41.5 mmol) was dissolved in 150 ml of anhydrous THF and cooled to -78 under N 2 . LDA (41.5 mmol) was added over 10 min, and the solution was stirred at -78 for 30 min. Tert-butyl bromoacetate (8.1 g, 41.5 mmol) dissolved in 30 ml of THF was added over 20 min., and the resulting mixture was stirred for 30 min at .-78., and then warmed to ambient temperature by removing the cooling bath. After 1 h, the solution was concentrated on a rotary evaporator to 1/4 volume. Ethyl acetate was then added, after which the mixture was washed with 10% citric acid, water and brine and dried over MgSO4. Evaporation of the solvent gave an oil which was purified by MPLC 25% ether/hexane to give 10.75 g (57%) of the addition product. mp 73-75°C, MS m/e 452 (M+H)+, [α]D +74.3 (c 0.214, methanol)

C. Tert-butyl-3S-(hydroxycarbonyl)-6 phenylhexanoate

To a cooled solution (0°C) of the compound from part B (5 g, 11.1 mmol) dissolved in 60 ml of THF/H2O (4:1) was added hydrogen peroxide (30% solution, 4.5 ml, 44.4 mmol), followed by aqueous LiOH (425 mg in 30 ml of water). The solution was stirred for 5 h at 0. During this time, the complete dissolution of the starting substances was recorded with the help of TLC. The THF was removed under reduced pressure, and the resulting aqueous phase was washed with CH2Cl2. 10% HCl was carefully added to the aqueous phase until pH 1. The solution was extracted with ethyl acetate, dried over MgSO4, filtered and evaporated to obtain the crude product. The resulting product was purified by MPLC 7% meOH/CH2Cl2 to give 2.90 g (90%) of the purified acid. MS m/e 293 (M+H)+, [α]D +6.3 (c 0.322, methanol).

D. (2R)-[4-(tert-butoxy)-2-propylphenylsuccinyl]-N2-(N1-benzyloxycarbonyl)-S-piperazine acid

The compound from part C (2.50 g, 8.56 mmol) was dissolved in 100 ml of anhydrous toluene and cooled to -10°C. DMP (0.5 ml) was added, followed by oxalate chloride (1.39 g). The resulting solution was stirred for 1 h at -10, after which the solvent was evaporated under high vacuum at -10. The crude acid chloride was diluted with 50 ml of CH2Cl2 and then cooled to 0°C under N2. In a separate vessel, N-benzyloxycarbonyl-S-piperazine acid (2.26 g) was dissolved in 35 ml of CH2Cl2 and treated with 3.68 ml of triethylamine. After 5 min., the resulting solution was transferred for 10 min to another container. Stirring was continued for another 1 h at 0 and 1 h at ambient temperature. The reaction was quenched with 10% citric acid and extracted 3 times with CH2Cl2. The organic phase was washed with water, brine and dried with MgSO4. Filtration and evaporation of the solvent followed by MPLC (7% meOH/CH2Cl2) afforded 1.95 g (42%) of the desired product MS m/e 539 (M+H)+, [α]D -10.6 (c 1.002, methanol) .

E. (2R)-[4-(tert-butoxy)-2-propylphenylsuccinyl]-N2-(N1-benzyloxycarbonyl)-piperazine acid -N-methyl-amide

To the compound from part D (1.90 g, 3.53 mmol) dissolved in 40 mL of CH 2 Cl 2 , was added NMM (413 µl). The solution was cooled to -20 and then IBCF (459 µl, 3.53 mmol) was added. The mixture was stirred for 1.5 h, and then 0.6 ml of 40% aqueous methylamine was added. The cooling bath was removed, and the solution was stirred for 1 h at ambient temperature. The reaction was quenched by adding 10% citric acid. The organic phase was separated, washed with water, brine and dried over MgSO4. Filtration and evaporation of the solvent gave the crude product which was purified by MPLC (75% MeOH/CH2Cl2) to give 1.6 g (82%) of product. MS m/e 552 (M+H)+, [α]D -29.9 (c 0.166, methanol).

F. (2R)-[4-hydroxy-2-propylphenylsuccinyl]-N2-(N1-benzyloxycarbonyl)-piperazine acid-N-methyl-amide

1.6 g of the compound from part E was treated with 50 ml of 1N HCl in dioxane for 2 hours. The solvent was then evaporated under reduced pressure to give the crude acid, which was purified by MPLC (7% MeOH/CH2Cl2 to 13% MeOH/CH2Cl2). 930 mg (65%) of pure desired product was obtained. MS m/e 496 (M+H)+, [α]D =-34.8 (c 0.118, methanol).

G. (2R)-[4-(Benzoxyamino)-2-propylphenylsuccinyl]-N2-(N1-benzyloxycarbonyl)-piperazine acid N-methyl-amide

In a manner similar to that described in Example 1D, the title compound was prepared from 930 mg of the compound of Example 45a, part F to give 620 mg (54%) of the desired product. MS m/e 601 (M-CH3)+, [α]D =-30.7 (c 0.114, methanol)

H. (2R)-[4-(hydroxyamino)-2-propylphenylsuccinyl]-N2-(N1-benzyloxycarbonyl)-piperazine acid-N-methyl-amide

In a similar manner to that described in Part 1E, the title compound was prepared in 80% yield (40 mg). MS m/e 376 (M+H)+, [α]D =-12.5 (c 0.080, methanol) 1HNMR (MeOH-d4) 7.25-7.15 (5H, m), 5.05 (1H, m), 3.9 (1H , m), 2.95 (1H, m), 2.8 (1H, m), 2.76 (3H, s), 2.6 (2H, m), 2.5 (1H, dd), 2.19 (1H, dd), 2.01 (1H, m), 1.95 (1H, m), 1.7-1.4 (6H, m).

The compounds shown in Tables 1-3 (shown below) can be prepared using the procedures described above and variations thereof.

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USABILITY

The compounds of formula I have an MMP-3 inhibiting effect and are therefore useful as protective agents for the hyacinth in the treatment of inflammatory diseases. The MMP-3 inhibitory activity of the compounds of the present invention was demonstrated by assays performed, for example, using the MMP-3 activity inhibitor assay procedure described below. The compounds of this invention are bioavailable in vivo as shown in the ex vivo assay described below. Compounds of formula I prevent/inhibit cartilage degradation in vivo, for example as seen in the animal model of acute cartilage degradation described below.

The compounds described in the present invention are useful as standards and reagents for determining the potency of a potential pharmaceutical agent to inhibit MMP-3. These would be included in a commercial kit incorporating a compound of the present invention.

Matrix metalloproteinases are also responsible for breaking down basement membranes to allow cancer cells to enter the circulation and later into other tissues, leading to tumor metastases (Stetler-Stevenson, Cancer and Metastasis Reviews, 9, 289-303, 1990). The compounds of the present invention should be useful for the prevention and treatment of invasive tumors by inhibiting metastasis.

The compounds of the present invention would also be useful in the treatment and prevention of osteopenia associated with the breakdown of cartilage and bone caused by matrix metalloproteinases, which occurs in patients suffering from osteoporosis.

"µg" in the text means microgram, "mg" means milligram, "g" means gram, "µL" means microliter, "ml" means milliliter, "1" means liter, "nM" means nanomolar, "µM" means micromolar, "mM" millimolar, "M" molar, and "nm" nanometer. "Sigma" means Sigma-Aldrich Corp. of St. Louis, MO.

A compound is considered active if the IC50 or Ki value is less than 1 mM for MMP-3 inhibition.

Fluorescence test of bisacetylated substance P/MMP-3

A high-throughput enzyme assay was performed to detect potential MMP-3 inhibitors. The test used a derivative of the peptide substrate, substance P (Arg-PrO-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met), which is cleaved by MMP-3 exclusively at the place of the glutamine-phenylalanine bond. In order to adapt the test to widely applicable testing, we developed a fluorimetric product detection method. Production of the hydrolysis product, substance P 7-11, is measured by reaction with fluorescamine, a fluorogenic compound that reacts with the primary amine from this moiety. Substance P of the substrate is biacetylated to block the primary amines of the intact substrate. In this way, the obtained fluorescence represents the formation of the product (7-11 peptide) formed after cleavage by MMP-3, and is measured using a standard curve made with the help of known concentrations of the 7-11 peptide. Kinetic studies in which the bisacetylated counterpartate was used gave the following parameters for MMP-3: Km = 769 +/- 52 µM; Vmax = 0.090 +/- 0.003 nmole 7-11 peptides/min

To assess MMP-3 inhibition, compounds were prepared at concentrations of 10 mM in 100% methanol, and further diluted to 20X molar mass. Five microliters of each amount of drug was added to the test mixture in the presence of 20 nM fragmented MMP-3 in 67.5 mM tricine (pH 7.5), 10 mM CaCl2. 40 mM NaCl, and 0.0005% Brij 35 in a final volume of 100 microliters. Biacetylated substance P (1000 mM) was added, and the test was run for 1 hour at 25ºC. The reaction was then quenched with EDTA (20 mM), and the product was detected fluorometrically after the addition of fluorescamin (0.075 mg/ml). The fluorescence of each sample was converted to the amount of product formed using a standard curve for substance P 7-11. Under these conditions, the assay is linear in relation to the amount of MMP-3 up to 10 pmol. Inhibition of MMP-3 was determined by comparing the amount of product formed in the presence and absence of compound.

The activities of representative compounds of the present invention from the assay described above are shown in Table A. Ki values are indicated as follows: +++=<50 nM; + +=50 nM to 100 nM; + =>100 nM.

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Ex vivo bioavailability test of MMP-3 inhibitors

Blood samples were taken from rats by cardiac puncture at different time periods after dosing J.V., J.P. or P.O. with compound to determine inhibitor levels. Plasma was extracted with 10% TCA in 95% methanol and placed on ice for 10 minutes. Then the plasma was centrifuged for 15 minutes at 14,000 rpm in an Eppendorf microcentrifuge. The supernatants were removed, centrifuged again, and the obtained supernatant was diluted in a ratio of 1:10 M with 50 mM tricine, pH 8.5. The pH of the sample was adjusted to 7.5 and then tested in the MMP-3 substance P fluorescent enzyme assay. Rat plasma was extracted in the same way and used as a negative control group. This plasma was also used to obtain a plasma curve of the desired compound. Known concentrations of the compound were added to control plasma, which was extracted in the same way and then tested in the MMP-3 enzyme assay. A standard curve was obtained showing the ratio of the percentage of inhibition in the MMP-3 test and the concentration of the drug added to the samples. Based on inhibition in the presence of plasma from dosed rats, compound concentrations were determined using a standard curve.

Table B shows the results of oral dosing of representative compounds of this invention in rats at 100 mg/kg.

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A model of acute cartilage degradation in rats

An in vivo model of acute cartilage degradation in rats was characterized as a procedure for determining the proteoglycan content in the synovial fluid after the onset of cartilage degradation. Experimental groups showed increased levels of proteoglycan content in synovial fluid compared to control groups of rats. The criterion for showing the activity of the compound in this model is the possibility of inhibiting the breakdown of cartilage, which is measured by the increased proteoglycan content in the synovial fluid of rats after taking the compound. Indomethacin, a nonsteroidal anti-inflammatory drug, is inactive in this model. Prescribed indomethacin does not interfere with the display of cartilage degradation in experimental animals. In contrast, administration of the compounds of this invention significantly inhibited the display of cartilage degradation in this model.

Dosage and formulation

The compounds described in the present invention can be taken orally using any pharmaceutically acceptable dosage method known in the art. The active component can be prepared in hard doses, such as dry powders, granules, tablets or capsules, or in liquid forms such as syrups, or aqueous suspensions. The active component can be taken alone, but is usually taken with a pharmaceutical carrier. A useful handbook of pharmaceutical dosage forms is Remington's Pharmaceutical Sciences, Mack Publishing.

The compounds of this invention may be taken in the form of tablets, capsules (including both sustained release and timed release), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They can also be given intravenously (bolus injection or infusion), intraperitoneally, subcutaneously or intramuscularly.

An effective but non-toxic amount of the desired compound can be used as an anti-inflammatory or anti-arthritic agent.

The compounds of this invention can be taken by any means that allows the active component to contact the site of action of the agent, MMP-3 in the body of a mammal. They may be taken in any conventional manner together with other pharmaceutical ingredients, either as single therapeutically active ingredients or in combination of therapeutically active ingredients, with a pharmaceutical carrier selected based on standard pharmaceutical practice.

The prescribed dose will vary depending on known factors such as: pharmacodynamic characteristics of individual active components, and the method and form of intake; recipient's age, state of health and body mass; nature and duration of symptoms; type of simultaneous therapy, frequency of the procedure; the patient's renal or hepatic function and the desired effect. An average expert veterinarian or doctor will thus determine and prescribe the effective amount of medicine necessary to prevent or suppress the development of the disease state.

The usual daily dose of the active component, when used for the stated effects, will be from 0.001 to 1000 mg/kg body weight, preferably from 0.01 to 100 mg/kg body weight per day, and best from 1.0 to 20 mg/kg /Daily. For a normal male adult of approximately 70 kg body weight, this would be approximately 70 to 1400 mg per day. Intravenously, the most preferred doses would be 1 to 10 mg/kg per minute at a constant infusion rate. It is an advantage that the compounds of this invention can be taken in the form of one daily dose, or the daily dose can be divided into two, three or four daily doses.

The compounds of this invention can be taken intranasally, by local application of a suitable intranasal agent, or transdermally, using known transdermal skin patches. If given as a transdermal delivery system, then the dosage will be constant rather than intermittent.

In the methods described in this invention, the compounds can form an active component and are taken together with suitable pharmaceutical diluents, excipients or carriers (in the text collectively called carriers), appropriately chosen in relation to the form of taking the drug, i.e. oral tablets, capsules, elixirs, syrups and the like, and in accordance with pharmaceutical practice.

For example, for oral administration in the form of tablets and capsules, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate , calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water, and the like. Moreover, if desired or necessary, appropriate binders, lubricants, disintegrants as well as coloring agents may also be incorporated into the mixture. Suitable binding agents such as starch, gelatin, natural sugars such as glucose or lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants included in the doses include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrating agents include starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in the form of a liposomal delivery system, such as small unilamellar bodies, large unilamellar bodies, and multilamellar bodies. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

The compounds of the present invention can also be conjugated to soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethylenedioxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of this invention can be combined into a group of bioavailable polymers useful for achieving controlled drug release, for example, polylactic acid, polyglycolic acid, polylactic and polyglycolic acid copolymers, polyepsilon-caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and cross-linked or amphipathic hydrogel block copolymers.

Appropriate doses of the drug (pharmaceutical preparations) may contain from 1 mg to 100 mg of the active component per unit. In these pharmaceutical preparations, the active component will be present in the amount of 0.5-95% of the total mass of the preparation. The active component can be taken orally in solid forms, such as capsules, tablets and powders, or in liquid forms, such as elixirs, syrups and suspensions. It can also be administered parenterally in the form of sterile liquid doses.

Gelatinous capsules can contain the active component and pulverized carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used for compressed tablets. Tablets and capsules can be manufactured as sustained-release products to allow continuous release of the drug over several hours. Compressed tablets can be coated with sugar or some other coating to avoid unpleasant taste and to protect them from atmospheric influences, or they can be enteric-coated for selective release in the digestive tract. Liquid forms for oral administration can be colored or sweetened to make them easier for the patient to accept. Generally water, suitable oil, saline, aqueous dextrose (glucose) and related sugar solutions and glycols, such as propylene glycol or polyethylene glycols, are suitable carriers for parenteral solutions. Solutions for parenteral administration contain the active component, a suitable stabilizer and, if necessary, buffer substances. Antioxidants, such as sodium bisulfite, sodium sulfite, or ascorbic acid, alone or in combination, are suitable stabilizers. Citric acid and its salts as well as EDTA are also used. In addition, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl or propyl paraben and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference in the art.

Useful pharmaceutical preparations for administering the compounds of this invention are as follows:

Capsules

Capsules can be prepared by usual procedures, so that the dose contains 500 mg of active component, 100 mg of cellulose and 10 mg of magnesium stearate.

A large number of individual capsules can be prepared by filling standard hard two-part gelatin capsules with 100 mg of active ingredient powder, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Syrup

Mass %.

Active component 10

Liquid sugar 50

Sorbitol 20

Glycerin 5

Aromas, colors, and

preservatives as needed

Water as needed

A final volume of 100% is achieved by adding distilled water.

Aqueous suspension

Mass %.

Active component 10

Sodium saccharin 0.01

Keltrol® (Edible xanthan gum) 0.2

Liquid sugar 5

Aromas, colors, and

preservatives as needed

Water as needed

Xanthan gum is slowly added to distilled water before adding the active ingredient and other ingredients. The final suspension is passed through a homogenizer to achieve the quality of the final product.

Resuspending powder

mass %

Active component 50.0

Lactose 35.0

sugar 10.0

Acacia 4.7

Sodium carboxymethylcellulose 0.3

Each ingredient is finally turned into a powder and mixed. The powder can also be prepared in the form of a suspension and then dried by spraying.

Semi-hard gel

mass %

Active component 10

Sodium saccharin 0.02

Gelatin 2

Aromas, colors and

preservatives as needed

Water as needed

Gelatin is prepared in hot water. The active component in powder is suspended in a gelatinous solution, and then the other ingredients are mixed in. The suspension is filled into appropriate containers and cooled to form a gel.

Semi-hard paste

mass %

Active component 10

Gelcarin® (Carrageenan gum) 1

Sodium saccharin 0.01

Gelatin 2

Aromas, colors and

preservatives as needed

Water as needed

Gelcarin® is dissolved in hot water (approximately 80°C), and then the fine powder of the active component is suspended in that solution. Sodium saccharin and other ingredients are added to this suspension while it is still warm. The suspension is homogenized and filled into appropriate containers.

Emulsion paste

mass %

Active component 30

Tween® 80 and Span® 80 6

Keltrol® 0.5

Mineral oil 63.5

All ingredients are carefully mixed to obtain a homogeneous paste.

Soft gelatin capsules

A mixture of the active component in edible oil, such as soybean, olive or cottonseed oil, is prepared and injected with the help of a special pump ("positive displacement pump") into the gelatin, in order to obtain soft gelatinous capsules with 100 mg of the active component each . The capsules are washed and dried.

Pills

Tablets can be prepared by the usual procedures by preparing a dose of 500 mg of the active component, 150 mg of lactose, 50 mg of cellulose and 10 mg of magnesium stearate.

A large amount of tabtet is prepared in the usual way, by mixing 100 mg of the active component, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 milligrams of starch and 98.8 mg of lactose. Correspondingly, it can be applied to facilitate swallowing or delay dissolution.

Injections

Parenteral preparations suitable for injection are prepared by mixing 1.5% of the mass of the active component with 10% of the volume of propylene glycol and water. The solution is isotonized with the addition of sodium chloride, and then sterilized.

Suspension

The aqueous suspension is prepared for petoral administration so that each 5 ml contains 100 mg of the finally divided active component, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P. and 0.025 ml of vanilla.

The compounds of the present invention may be administered in combination with another therapeutic agent, particularly a non-steroidal anti-inflammatory drug (NSAID). The compound of formula I and such other therapeutic agent may be administered separately or in combination as a single formulation, in any of the formulations and routes of administration described above.

A compound of formula I may be prepared together with another therapeutic agent in a single formulation (ie, combined in a capsule, tablet or powder, liquid, etc.). When the compound of formula I and the second therapeutic agent are not in the same preparation, they may be taken at the same time, or in any order, for example the compound of formula I first and then the second agent. When they are not taken at the same time, it is preferable that the interval between taking the compound of formula I and the other therapeutic agent is not more than one hour, and preferably less than 5 to 30 minutes.

The best way to take a compound of formula I is orally. it is easily preferred that the compound of formula I and the other therapeutic agent are taken in the same way (eg, perorally) if desired, they can be taken in different ways (eg, one orally and the other intravenously).

The prescribed dose of a compound of formula I when taken alone or in combination with another therapeutic agent will vary depending on known factors such as: the pharmacodynamic characteristics of the individual active component, and the route and form of administration; recipient's age, state of health and body mass; nature and duration of symptoms; door of simultaneous therapy, the frequency of the procedure, and the desired effect. Therefore, when a compound of formula I and another agent are taken in the same preparation, they are prepared in such a way that physical contact between the active components is minimal. For example, one active component can be enteric coated. Enteric coating of one active component reduces the physical contact between the two components, and also controls the release of one component in the digestive tract, so that one component is not released in the stomach, but in the intestines. One active component can be coated with a delayed release agent to delay release through the digestive tract and reduce physical contact between the two components. Furthermore, the sustained release component can be enteric coated to allow the release of the component to be in the intestine. There are other ways, such as the preparation of a combination product in which one component would be coated with a delayed release polymer or an enteric polymer and the other would be coated with a polymer such as low viscosity hydroxypropyl methylcellulose (HPMC) or similar suitable substances known in chemistry, in order to separate the components even better. The polymer coating serves as an additional barrier to the interaction of the two components.

It will be very apparent to those skilled in the art after studying the present invention that there are ways to reduce the contact between the components in the combination products, whether they are taken in individual preparations or as separate forms, but at the same time and in the same manner.

The present invention also includes a pharmaceutical kit used, for example, for the treatment and prevention of osteoarthritis and rheumatoid arthritis, which includes one or more containers containing a composition with a therapeutically effective amount of a compound of formula I. Such kit may further include, if necessary , one or more different conventional components of a pharmaceutical kit, such as, for example, containers with one or more pharmaceutically suitable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, whether inserted or in the form of labels, indicating the quantities of components to be taken, methods of taking and/or mixing the components, may also be included in the kit.

Finally, it should be noted that the listed substances and conditions are important for the implementation of this invention, but unlisted substances and conditions are not excluded if they do not prevent the realization of the essence of the invention.

The term "consisting primarily of" in this invention means that all specified substances and conditions are important for carrying out this invention, but that unspecified substances and conditions are not excluded unless they represent an obstacle to the realization of this invention.

This description contains all the necessary information that will enable those skilled in the art to carry out this invention. Since the cited references can contribute to a better understanding, they are included in this text.

Although certain aspects are described in this invention, the details of those aspects are not intended to limit the invention in any way. Various equivalents, modifications and changes may be applied without departing from the spirit of the invention, and it is therefore intended that such similar aspects form part of the present invention.

Claims (27)

1. A method of treating rheumatoid and osteoarthritis in a mammal, comprising administering to a mammal in need thereof a therapeutically effective amount of a cartilage protecting agent of formula I: [image] or a pharmaceutically acceptable salt or prodrug form thereof, indicated by that A is -N(R8)CH(R9)CO2H or -CH(R1)CONHOH; Q is: C5-C14 carbocyclic ring substituted with 0-4 groups selected from R5, R6, R18 or -C(=O)R3, or A 5- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms, which are independently selected from oxygen, nitrogen or sulfur, and said heterocyclic ring is substituted with 0-4 groups selected from R5, R6, R8, R18 or -C( =O)R3; R1 is: H, OR17, S(O)mR17a; C1-C4 alkyl substituted with 0-3 R4, C2-C4 alkenyl substituted with 0-3 R4, C2-C4 alkynyl substituted with 0-3 R4, aryl substituted with 0-5 R18, heterocycle selected from the group consisting of: thienyl, furanyl, thiazolyl, oxazolyl, isoxazolinyl, isothiazolyl, triazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, tetrahydrofuranyl, or pyranyl, said heterocyclic ring is substituted with 0-2 R18. 2. Compound of formula II: [image] or its pharmaceutically acceptable salts or prodrug forms, indicated by that. Q: C5-C14 carbocyclic ring substituted with 0-4 groups selected from R5, R6, R18 or -C(O)R3, or A 5- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, and said heterocyclic ring is substituted with 0-4 groups selected from R5, R6, R8, R18 or -C(=O) R3; R1 is: H, C1-C4 alkyl substituted with 0-3 R4, C2-C4 alkenyl substituted with 0-3 R4, C2-C4 alkynyl substituted with 0-3 R4, R2 is: C1-C6 alkyl substituted with 0-3 R17b, -O-(C1-C8 alkyl)-R20, provided that R8 is not present when W is equal to O. 3. The compound from claim 2, indicated by the fact that it is selected from [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-benzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methoxyphenylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methoxybenzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylthiophenylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylthiobenzylsuccinyl]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-(methylthio-2-thienyl)succinyl]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylacetate]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylisopropanoate]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-tert-butanoate]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-thioacetate]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-(2-pyridyl)-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-(3-pyridyl)]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-(4-pyridyl)]-N2-(S)-piperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-6'(S/R)-(4-methoxyphenyl)piperazine acid-N-methyl- amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-4'(S/R)-benzylpiperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-5'(S/R)-benzylpiperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-6'(S/R)-benzylpiperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)- [4',5'] benzopiperazine acid-N-methyl-amide; [4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-N2-(S)-[5',6') benzopiperazine acid-N-methyl-amide; 4. Compound of formula III: [image] or its pharmaceutically acceptable salts or prodrug forms, indicated by that Q is: C5-C14 carbocyclic ring substituted with 0-4 groups selected from R5, R6, R18 -C(=O)R3, or A 5- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, and said heterocyclic ring is substituted with 0-4 groups selected from R5, R6, R8, R18 or ,C(= O)R3; R2 is: C1-C6 alkyl substituted with 0-3 R17b, -O-(C1-C8 alkyl)-R20, -S-(C1-C8 alkyl)-R20, 5. The compound from claim 7 characterized in that it is selected from the group containing the following compounds N-[1-(R)-carboxy-ethyl]-α-(S)-isobutylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethyl]-α-(S)-hexylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethyl]-α-(S]-heptylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethyl]-α-(S)-octylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethyl]-α-(S)-ethylphenylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethyl]-α-(S)-propylphenylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethylthiobenzyl]-α-(S)-isobutylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethylthiobenzyl]-α-(S)-hexylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethylthiobenzyl]-α-(S)-ethylphenylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethylthiobenzyl]-α-(S)-propylphenylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethyloxybenzyl]-α-(S)-isobutylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethyloxybenzyl]-α-(S)-hexylglycine-(S)-N2-piperazine acid methyl amide; N-(1-(R)-carboxy-ethyloxybenzyl]-α-(S)-ethylphenylglycine-(S)-N2-piperazine acid methyl amide; N-[1-(R)-carboxy-ethyloxybenzyl]-α-(S)-propylphenylglycine-(S)-N2-piperazine acid methyl amide; 6. A method of treating rheumatoid and osteoarthritis in a mammal, including administering to a mammal in need thereof a therapeutically effective amount of a cartilage protecting compound of formula IV: [image] or pharmaceutically acceptable salts or prodrug forms, indicated by that R2 is: H, C3-C10 alkyl, or aryl-(C1-C4 alkyl)-; R3 and OR11, NHCH(R12)COR13, NR10R10a, NHCH(R12)COOR11, or NHCH(R12)CONR14R15, R 10 and R 10a are independently hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy; R 11 , R 12 and R 15 are independently hydrogen or C 1 -C 4 alkyl; R 13 and R 14 are C 1 -C 4 alkyl. 7. Pharmaceutical preparation, characterized in that it contains the compound of claim 2 and a pharmaceutically suitable carrier. 8. Pharmaceutical preparation, characterized in that it contains the compound of claim 3 and a pharmaceutically suitable carrier. 9. Pharmaceutical preparation, characterized in that it contains the compound of claim 4 and a pharmaceutically suitable carrier. 10. Pharmaceutical preparation, characterized in that it contains the compound of claim 5 and a pharmaceutically suitable carrier. 11. Pharmaceutical preparation, characterized in that it contains the compound of claim 6 and a pharmaceutically suitable carrier. 12. Pharmaceutical preparation, characterized in that it contains the compound of claim 7 and a pharmaceutically suitable carrier. 13. Pharmaceutical preparation, characterized in that it contains the compound of claim 8 and a pharmaceutically suitable carrier. 14. Pharmaceutical preparation, characterized in that it contains the compound of claim 9 and a pharmaceutically suitable carrier. 15. Pharmaceutical preparation, characterized in that it contains the compound of claim 10 and a pharmaceutically suitable carrier. 16. The method of treating rheumatoid and osteoarthritis in mammals, characterized by the fact that it also includes the administration of a therapeutically effective amount of the cartilage protection agent from claim 2. 17. The method of treating rheumatoid and osteoarthritis in mammals, characterized by the fact that it also includes the administration of a therapeutically effective amount of the cartilage protection agent from claim 3. 18. The method of treating rheumatoid and osteoarthritis in mammals, characterized by the fact that it also includes the administration of a therapeutically effective amount of the cartilage protection agent from claim 4. 19. A method of treating rheumatoid and osteoarthritis in mammals, characterized by the fact that it also includes the administration of a therapeutically effective amount of the cartilage protection agent from claim 5. 20. The method of treating rheumatoid and osteoarthritis in mammals, characterized by the fact that it also includes the administration of a therapeutically effective amount of the cartilage protection agent from claim 6. 21. The method of treating rheumatoid and osteoarthritis in mammals, characterized by the fact that it also includes the administration of a therapeutically effective amount of the cartilage protection agent from claim 7. 22. The method of treating rheumatoid and osteoarthritis in mammals, characterized by the fact that it also includes the administration of a therapeutically effective amount of the cartilage protection agent from claim 8. 23. A method of treating rheumatoid and osteoarthritis in mammals, characterized by the fact that it also includes the administration of a therapeutically effective amount of the cartilage protection agent from claim 9. 24. The method of treating rheumatoid and osteoarthritis in mammals, characterized by the fact that it also includes the administration of a therapeutically effective amount of the cartilage protection agent from claim 10. 25. A method of treating rheumatoid and osteoarthritis in mammals, characterized by the fact that it also includes the administration of a therapeutically effective amount of a non-steroidal anti-inflammatory agent in combination with the cartilage protection compound of claim 2. 26. The method of treating rheumatoid and osteoarthritis in mammals, characterized by the fact that it also includes the administration of a therapeutically effective amount of a non-steroidal anti-inflammatory agent in combination with the cartilage protection compound of claim 7. 27. A method of treating rheumatoid and osteoarthritis in mammals, indicated by the fact that it also includes the administration of a therapeutically effective amount of a non-steroidal anti-inflammatory agent in combination with the cartilage protection compound of claim 11.