AP930A - Hydroxamic acid derivatives as matrix metalloprotease (MMP) inhibitors. - Google Patents

Hydroxamic acid derivatives as matrix metalloprotease (MMP) inhibitors. Download PDF

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AP930A
AP930A APAP/P/1998/001412A AP9801412A AP930A AP 930 A AP930 A AP 930A AP 9801412 A AP9801412 A AP 9801412A AP 930 A AP930 A AP 930A
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mmp
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Gavin Alistair Whitlock
Kevin Neil Dack
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Pfizer
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Abstract

Compounds of formula (I): or pharmaceutically or veterinarily acceptable salts thereof, or pharmaceutically or veterinarily acceptable solvates of either entity, wherein the broken line represents an optional bond; A is C or CH; B is CH2, O or absent; R1 and R2 are each independently selected from hydrogen, C, to C6 alkyl optionally substituted with C, to C4 alkoxy or phenyl, and C, to C6 alkenyl; or, together with the carbon atom to which they are attached, form a C3 to C6 cycloalkyl group which optionally incorporates a heteroatom linkage selected from O, SO, SO2 and NR6 or which is optionally benzo-fused; R3 is hydrogen, halo, R7 or OR7; R4 is hydrogen, Cn to C4 alkyl, C, to C4 alkoxy, trifiuoromethyl or halo; R8 is hydrogen or C, to C4 alkyl; R7 is an optionally substituted monocyclic or bicyclic ring system; m is 1 or 2; and n is 0, 1 or 2; with the provison that B is not O when A is C; are MMP inhibitors useful in the treatment of, inter alia, tissue ' ulceration, wound repair and skin diseases.

Description

APO 00 9 3 ο -1-
HYDROXAMIC ACID DERIVATIVES AS MATRIX METALLOPROTEASE (MMP) INHIBITORS
This invention relates to a series of substituted a-aminosulphonyl-acetohydroxamic acids which are inhibitors of zinc-dependent metalloprotease enzymes. In particular, the compounds are inhibitors of certain members of the matrix metalloprotease (MMP) family.
Matrix metalloproteases (MMPs) constitute a family of structurally similar zinc-containing metalloproteases, which are involved in the remodelling and degradation of extracellular matrix proteins, both as part of normal physiological processes and in pathological conditions. Since they have high destructive potential, MMPs are usually under close regulation and failure to maintain MMP regulation may be a component of a number of diseases and pathological conditions, including atherosclerotic plaque rupture, heart failure, restenosis, periodontal disease, tissue ulceration, wound repair, cancer metastasis, tumour angiogenesis, age-related macular degeneration, fibrotic disease, rheumatoid arthritis, osteoarthritis and inflammatory diseases dependent on migratory inflammatory cells.
Another important function of certain MMPs is to activate various enzymes, including other MMPs, by cleaving the pro-domains from their protease domains. Thus some MMPs act to regulate the activities of other MMPs, so that over-production of one MMP may lead to excessive proteolysis of extracellular matrix by another. Moreover, MMPs have different substrate preferences (shown in the following Table for selected family members) and different functions within normal and pathological conditions. For recent reviews of MMPs, see Current Pharmaceutical Design, 1996, 2, 624 and Exp. Opin. Ther. Patents, 1996, 6, 1305.
TABLE
Excessive production of MMP-3 is thought to be responsible for pathological tissue breakdown which underlies a number of diseases and conditions. For example, MMP-3 has been found in the synovium and cartilage of osteoarthritis and rheumatoid arthritis patients, thus implicating MMP-3 in the joint damage caused by these diseases: see Biochemistry, 1989, 28, 8691 and Biochem. J., 1989, 258. 115. MMP-13 is also thought to play an important role in the pathology of osteoarthritis and rheumatoid arthritis: see Lab. Invest., 1997, 76, 717 and Arthritis Rheum., 1997, 40, 1391. The compounds of the present invention inhibit both MMP-3 and MMP-13 and thus may be of utility in treating these diseases.
The over-expression of MMP-3 is also thought to be responsible for much of the tissue damage and chronicity of chronic wounds, such as venous ulcers, diabetic ulcers and pressure sores; see Brit. J. Dermatology, 1996, 135. 52. w·
Furthermore, the production of MMP-3 may also cause tissue damage in conditions where there is ulceration of the colon (as in ulcerative colitis and Crohn’s disease; see J. Immunol., 1997 158. 1582 and J. Clin. Pathol., 1994, 47. 113) or of the duodenum (see Am. J. Pathol., 1996, 148, 519).
Moreover, MMP-3 may also be involved in skin diseases such as dystrophic epidermolysis bullosa (see Arch. Dermatol. Res., 1995, 287. 428) and dermatitis herpetiformis (see J. Invest. Dermatology, 1995,105, 184).
Finally, rupture of atherosclerotic plaques by MMP-3 may lead to cardiac or cerebral infarction; see Circulation, 1997, 96, 396. Thus, MMP-3 inhibitors may find utility in the prevention of heart attack and stroke.
Studies of human cancers have shown that MMP-2 is activated on the invasive tumour cell surface (see J. Biol.Chem., 1993, 268. 14033) and BB-94, a non-selective peptidic hydroxamate MMP inhibitor, has been reported to decrease the tumour burden and prolong the survival of mice carrying human ovarian carcinoma xenografts (see Cancer Res., 1993, 53, 2087). Certain compounds of the present invention inhibit MMP-2 and therefore may be useful in the treatment of cancer metastasis and tumour angiogenesis.
Various series of MMP inhibitors have appeared in the patent literature. For example, α,-arylsulphonamido-substituted acetohydroxamic acids are disclosed in EP-A-0606046, WO-A-9627583 and WO-A-9719068, whilst EP-A-0780386 discloses certain related sulphone-substituted hydroxamic acids.
The compounds of the present invention are inhibitors of some of the members of the MMP family. In particular, they are potent inhibitors of MMP-3 and MMP-13, with certain compounds exhibiting varying degrees of selectivity over other MMPs, such as MMP-1, MMP-2 and MMP-9. Certain of the compounds are potent MMP-2 inhibitors.
Thus, according to the present invention, there is provided a compound of formula (I):
or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate (including hydrate) of either entity, wherein the broken line represents an optional bond; A is C or CH; B is CH2, O or absent; R1 and R2 are each independently selected from hydrogen, to C6 alkyl optionally substituted with C1 to C4 alkoxy or phenyl, and C-, to C6 alkenyl; or, together with the carbon atom to which they are attached, form a C3 to C6 cycloalkyi group which optionally incorporates a heteroatom linkage selected from O, SO, S02 and NR6 or which is optionally benzo-fused; R3 is hydrogen, halo, R7 or OR7; R4 is hydrogen, C3 to C4 alkyl, C3 to C4 alkoxy, trifluoromethyl or halo; R6 is hydrogen or C3 to C4 alkyl; R7 is a monocyclic or bicyclic ring system selected from phenyl, thienyl, furyl, pyridinyl, pyrimidinyl, naphthyl, indanyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, indolyl, quinolinyl, isoquinolinyl, benzodioxolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl and benzodioxanyl, any of which ring systems
is optionally substituted with one or two substituents selected from C3 to C4 alkyl optionally substituted with C1 to C4 alkoxy or hydroxy, CrC4 alkoxy optionally substituted with C3 to C4 alkoxy or hydroxy, C-, to C4 alkylthio, trifluoromethyl, trifluoromethoxy, halo and cyano; m is 1 or 2; and n is 0, 1 or 2; with the proviso that B is not O when A is C.
In the above definition, unless otherwise indicated, alkyl, alkoxy, alkylthio and alkenyl groups having three or more carbon atoms may be straight chain or branched chain. Halo means fluoro, chloro, bromo or iodo.
The compounds of formula (I) may contain one or more chiral centres and therefore can exist as stereoisomers, i.e. as enantiomers or diastereoisomers, as well as mixtures thereof. The invention includes both the individual stereoisomers of the compounds of formula (I) and any mixture thereof. Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation or chromatography (including HPLC) of a diastereoisomeric mixture of a compound of formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of formula (I) may be prepared from a corresponding optically pure intermediate or by resolution, either by HPLC of the racemate using a suitable chiral support or, where appropriate, by fractional crystallisation of the diastereoisomeric salts formed by reaction of the racemate with a suitable optically active base or acid.
Furthermore, compound of formula (I) which contain alkenyl groups can exist as cis-stereoisomers or trans-stereoisomers. Again, the invention includes both the separated individual stereoisomers as well as mixtures thereof.
Also included in the invention are radiolabelled derivatives of compounds of formula (I) which are suitable for biological studies.
Compounds of formulae (I) may provide pharmaceutically or veterinarily acceptable base-salts, in particular non-toxic alkali metal salts, with bases. .Examples include the sodium and potassium salts. The pharmaceutically or veterinarily acceptable salts of the compounds of formula (I) which contain a basic centre are, for example, non toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulphuric and phosphoric acid, with organo-carboxylic acids, or with organo-sulphonic acids. A preferred group of compounds of formula (I) is that wherein B is absent; R1 is hydrogen, C·, to C4 alkyl optionally substituted with methoxy or phenyl, or C3 to C5 alkenyl; R2 is hydrogen or C1 to C4 alkyl; or R1 and R2, together with the carbon atom to which they are attached, form a C4 to C5 cycloalkyi group which optionally incorporates a heteroatom linkage selected from O and NR6 or which is optionally benzo-fused; R3 is selected from 4-phenyl, 4-pyridinyl, 4-(indan-5-yl), 4-(2,3-dihydrobenzofuran-5-yl), 4-(quinolin-3-yl), 4-(benzodioxol-5-yl) and 4-(benzimidazol-5-yl), any of which is optionally substituted with one or two substituents selected from C·, to C3 alkyl optionally substituted with methoxy or hydroxy, C3 to C3 alkoxy optionally substituted with methoxy or hydroxy, methylthio, trifluoromethyl, trifluoromethoxy, fluoro, chloro and cyano; R4 is hydrogen, methyl, ethyl, methoxy, trifluoromethyl, fluoro or chloro; R6 is methyl; m is 2; and n is 1. A more preferred group of compounds of formula (I) is that wherein R1 is hydrogen, methyl, ethyl, 2-methyIprop-1-yl, but-1-yl, 2-methoxyethyl, benzyl, 3-phenylprop-1-yl, allyl, 2-methylallyl, 3,3-dimethylallyl; R2 is hydrogen, methyl or ethyl; or R1 and R2, together with the carbon atom to which they are attached, form a cyclobutyl, cyclopentyl, tetrahydropyran-4,4-diyl, 1-methylpiperidin-4,4-diyl or indan-2,2-diyl group; R3 is 4-phenyl, 4-(2-methylphenyl), 4-(3- methylphenyl), 4-(3-ethylphenyl), 4-[3-(prop-2-yl)phenyl], 4-(3,5-dimethylphenyl), 4-(3-methoxymethylphenyl), 4-(3-hydroxymethylphenyl), 4-(2-methoxyphenyl), 4-(3-methoxyphenyl), 4-(3-ethoxyphenyl), 4-(4-ethoxyphenyl), 4-[3-(prop-1-oxy)phenyl], 4-[3-(prop-2-oxy)phenyl], 4-[4-(prop-2-oxy)phenyl], 4- , (3,4-dimethoxyphenyl), 4-[3-(2-methoxyethoxy)phenyl], 4-[3-(2-hydroxyethoxy)phenyl], 4-(3-methylthiophenyl), 4-(3-trifluoromethylphenyl), 4-(3-trifluoromethoxyphenyl), 4-(2-fluorophenyl), 4-(3-chloro-4-fIuorophenyl), 4-(3-cyanophenyl), 4-(pyridin-2-yl), 4-(pyridin-3-yl), 4-(pyridin-4-yl), 4-(6-ethoxypyridin-2-yl), 4-(5-ethoxypyridin-3-yl), 4-(indan-5-yl), 4-(2,3- * dihydrobenzofuran-5-yl), 4-(quinolin-3-yI), 4-(benzodioxol-5-yl), 4-(2,2- , dimethylbenzodioxol-5-yl) and 4-(1,2-dimethylbenzimidazol-5-yl); and R4 is ” hydrogen, 2-methyl, 3-methyl, 3-ethyI, 3-methoxy, 3-trifluoromethyl, 3-fluoro or 3-chloro. 1 A particularly preferred group of compounds of formula (I) is that wherein R1 and R2 are both hydrogen or methyl or, together with the carbon atom to j which they are attached, form a cyclobutyl, cyclopentyl, tetrahydropyran-4,4-diyl « or 1-methylpiperidin-4,4-diyl group; R3 is 4-phenyl, 4-(3-methoxyphenyl), 4-(3-ethoxyphenyl), 4-[3-(2-methoxyethoxy)phenyl], 4-[3-(2-hydroxyethoxy)phenyl] or 4-(6-ethoxypyridin-2-yl); and R4 is 3-methyl or 3-methoxy.
Especially preferred individual compounds of the invention include N-hydroxy-2-{4-[4-(3-ethoxyphenyl)-3-methylphenyl]-1,2,3,6-tetrahydropyridin-1-ylsulphonyl}acetamide; N-hydroxy-2-{4-[4-(3-ethoxyphenyl)-3-methylphenyl]-1,2,3,6-tetrahydropyridin-1-ylsulphonyl}-2-methylpropanamide; N-hydroxy-2-{4-[4-(3-ethoxyphenyl)-3-methylphenyl]piperidin-1- ylsulphonyl}-2-methylpropanamide; N-hydroxy-1-{4-[4-(3-methoxyphenyl)-3-methylphenyl]piperidin-1- ylsulphonyljcyclopentanecarboxamide; N-hydroxy-1-{4-[4-(3-methoxyphenyl)-3-methylphenyl]piperidin-1- ylsulphonyljcyclobutanecarboxamide; N-hydroxy-2-{4-[4-(3-ethoxyphenyl)-3-methoxyphenyl]piperidin-1- ylsulphonyl}-2-methylpropanamide; N-hydroxy-2-{4-[4-(6-ethoxypyridin-2-yl)-3-methylphenyl]piperidin-1- ylsulphonyl}-2-methylpropanamide; N-hydroxy-2-{4-[4-(3-[2-methoxyethoxy]phenyl)-3-methylphenyl]-piperidin-1 -ylsulphonyl}-2-methylpropanamide; and N-hydroxy-2-{4-[4-(3-[2-hydroxyethoxy]phenyl)-3-methylphenyl]piperidine -1-ylsulphonyl}-2-methylpropanamide.
In a further aspect, the present invention provides processes for the preparation of a compound of formula (i), or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate (including hydrate) of either entity, as illustrated below.
It will be appreciated by persons skilled in the art that, within certain of the processes described, the order of the synthetic steps employed may be varied and will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent for use in the said synthetic steps.
Illustrative of protecting group strategies are the synthetic routes to Example 64, in which an O-benzyl protected hydroxamate is formed prior to the required Suzuki reaction step, and to Example 66, in which alcohol protection using a t-butyldiphenyisilyl group is employed.
It will also be appreciated that various standard substituent or functional group interconversions and transformations within certain compounds of formula (I) will provide other compounds of formula (I). An example is the conversion of the tetrahydropyridine derivative (Example 28) to the piperidine , derivative (Example 29) by hydrogenation.
The following processes are illustrative of the general synthetic procedures which may be adopted in order to obtain the compounds of the invention. A compound of formula (I) may be prepared directly from an ester of formula (II):
wherein R5 is C3 to C3 alkyl, and the broken line, A,B, R1, R2, R3, R4, m and n are as previously defined for formula (I), or via the intermediacy of the corresponding carboxylic acid of formula (II) wherein R5 is hydrogen.
When prepared directly from an ester of formula (II), the reaction may be carried out by treatment of the ester with up to a 3-fold excess of hydroxylamine in a suitable solvent at from about room temperature to about 85°C. The hydroxylamine is conveniently generated in situ from its hydrochloride salt by conducting the reaction in the presence of a molar equivalent amount of a suitable base such as an alkali metal carbonate or bicarbonate, e.g. potassium carbonate. Preferably the solvent is methanol, optionally combined with tetrahydrofuran or dichloromethane as co-solvent, and the reaction temperature is from about 65 to 70°C.
Alternatively, the ester may be converted by conventional hydrolysis to the corresponding carboxylic acid which is then transformed to the required hydroxamic acid of formula (I).
PreferablyThe hydrolysis is effected under basic conditions using up to .about a 6-fold excess of an alkali metal hydroxide in aqueous solution, optionally in the presence of a co-solvent, at from about room temperature to about 85°C. Typically the co-solvent is selected from methanol, 1,4-dioxan, a mixture of methanol and tetrahydrofuran and a mixture of methanol and 1,4-dioxan and the reaction temperature is from about 40 to about 70°C.
The subsequent coupling step may be achieved using conventional amide-bond forming techniques, e.g. via the acyl chloride derivative and hydroxylamine hydrochloride in the presence of an excess of a tertiary amine such as triethylamine or pyridine to act as acid-scavenger, optionally in the presence of a catalyst such as 4-dimethylaminopyridine, in a suitable solvent such as dichloromethane, at from about 0°C to about room temperature. For convenience, pyridine may also be used as the solvent.
In particular, any one of a host of amino acid coupling variations may be used. For example, the acid of formula (II) wherein R5 is hydrogen may be activated using a carbodiimide such as 1,3-dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminoprop-1-yl)carbodiimide optionally in the presence of 1-hydroxybenzotriazole and/or a catalyst such as 4-dimethylaminopyridine, or by using a halotrisaminophosphonium salt such as bromotris(pyrrolidino)-phosphonium hexafluorophosphate. Either type of coupling is conducted in a suitable solvent such as dichloromethane or dimethylformamide, optionally in the presence of a tertiary amine such as N-methylmorpholine or N-ethyldiisopropylamine (for example when either the hydroxylamine or the activating reagent is presented in the form of an acid addition salt), at from about 0°C to about room temperature. Typically, from 1.1 to 2.0 molecular equivalents of the activating reagent and from 1.0 to 4.0 molecular equivalents of any tertiary airline present are employed. A preferred reagent for mediating the coupling reaction is 0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU).
Preferably a solution of the acid and from 1.0 to 1.2 molecular equivalents of N-ethyldiisopropylamine in a suitable solvent such as anhydrous dimethylformamide or anhydrous 1-methylpyrrolidin-2-one, under nitrogen, is treated with up to a 50% excess of HATU at about room temperature followed, after about 15 to 30 minutes, with up to about a 3-fold excess of hydroxylamine I hydrochloride and up to about a 4-fold excess of N-ethyldiisopropylamine, optionally in the same solvent, at the same temperature.
An ester of formula (II) may be prepared from an amine of formula (III):
wherein the broken line, A,B, R3, R4, m and n are as previously defined for formula (II), by sulphonylation with a compound of formula (IV):
(IV) wherein Z is halo, R5 is C1 to C3 alkyl and R1 and R2 are as previously defined for formula (II). Preferably, Z is chloro.
When R is hydrogen, it will normally be advantageous to protect this secondary amino linkage with a conventional amine protecting group.
The reaction may be effected in the presence of up to a 50% excess of an appropriate base in a suitable solvent at from about 0°C to about room temperature. For example, when both R1 and R2 are hydrogen, an appropriate base is 1,8-diazabicyclo[5.4.0]undec-7-ene and a suitable solvent is dichloromethane.
Alternatively, the anion of (III) may be generated initially using up to a 20% excess of a strong base in a suitable solvent, under nitrogen, and then the sulphonylation with from 1.0 to 1.2 molecular equivalents of (IV) effected.
Conveniently, such a coupling may be carried out at room temperature with N,O-bis(trimethylsilyl)acetamide as base and anhydrous tetrahydrofuran as solvent.
Further routes to the preparation of an ester of formula (II), wherein R3 is R7, rely on exploitation of either a Suzuki reaction or a Stille reaction with an ester of formula (II) wherein R3 (but not R4) is either bromo or iodo. !
Thus, in the Suzuki reaction, the latter ester is treated with from 1.0 to j 1.5 molecular equivalents of a boronic acid of formula R7B(OH)2, in the presence of from 2.0 to 3.0 molecular equivalents of an alkali metal fluoride, about 0.1 molecular equivalents of a triarylphosphine and about 0.05 molecular equivalents of a palladium catalyst in a suitable solvent, under nitrogen, at from about 65 to about 100°C. Typically, the fluoride is cesium fluoride, the phosphine is tri-o-tolylphosphine, the catalyst is tris(dibenzylideneacetone)-dipalladium(O) and the solvent is degassed 1,2-dimethoxyethane optionally with 1-methylpyrrolidin-2-one as co-solvent.

Claims (1)

  1. Original document published without claims.
APAP/P/1998/001412A 1997-12-05 1998-12-03 Hydroxamic acid derivatives as matrix metalloprotease (MMP) inhibitors. AP930A (en)

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