WO2002006215A1 - 3-arylsulfonyl-2-hydroxy-2-methylpropanoic acid derivates - Google Patents

3-arylsulfonyl-2-hydroxy-2-methylpropanoic acid derivates Download PDF

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WO2002006215A1
WO2002006215A1 PCT/EP2001/007736 EP0107736W WO0206215A1 WO 2002006215 A1 WO2002006215 A1 WO 2002006215A1 EP 0107736 W EP0107736 W EP 0107736W WO 0206215 A1 WO0206215 A1 WO 0206215A1
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hydroxy
phenyl
sulfonyl
methyl
amino
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PCT/EP2001/007736
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French (fr)
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Sergio Mantegani
Pierluigi Bissolino
Francesca Abrate
Paolo Cremonesi
Ettore Perrone
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Pharmacia Italia S.P.A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/64—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
    • C07C323/65—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfone or sulfoxide groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention relates to some 3-sulfonyl carboxylic and hydroxamic acids displaying potent and selective inhibitory activity against gelatinases, in particular MMP-2 (Gelatinase-A), to their use for the treatment of diseases in which the proteolytic activity of these MMPs is involved, to methods for their preparation, and to pharmaceutical compositions containing them.
  • MMP-2 Gellatinase-A
  • MMPs play an important role in normal tissue turnover and development.
  • increased MMP activity and/or impairment of the physiological MMP inhibitors has been associated with a variety of pathological conditions such as cancer, rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, stroke, arteriosclerosis, diabetic rethinopathy, macular degeneration and wound healing.
  • pathological conditions such as cancer, rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, stroke, arteriosclerosis, diabetic rethinopathy, macular degeneration and wound healing.
  • the contribution of MMPs is manifold and not limited to destruction of the extracellular matrix required for local and distal invasion.
  • the proteolytic action of MMPs generates active matrix protein fragments, and influence the release, activation and bioavailability of growth factors.
  • MMPs are involved in cell migration and in the processing or shedding of cell surface proteins. It is now believed that the proteolytic action of MMPs plays a very important role in tumor growth, apoptosis and angiogenesis (see Noel, A. et . al., 'Emerging Roles for Proteinases in Cancer', Invasion Metastasis 17:221-239, 1997).
  • gelatinase-A (MMP-2) is currently reputed as the main target in cancer.
  • MMPIs Potent MMP inhibitors
  • Marimastat and other compounds investigated in patients have been reported to cause a musculoskeletal syndrome (MSS) characterized by joint pain and stiffness, which may be severe and dose-limiting.
  • MSS musculoskeletal syndrome
  • MSS The MSS observed by prolonged administration of MMPIs has been reproduced by others and us in animal models, including rats, cyno monkeys and marmosets.
  • fibroproliferative effects in the joint capsule of the knees and surrounding tissue are the most remarkable histopathological correlate of the MSS.
  • These alterations are thought to arise from an impairment in the normal tissue remodeling that is governed by one or more of the MMPs, or by related Zn-dependent enzymes.
  • MMP-1 interstitial collagenase
  • TACE TNF- convertase
  • MMP-1 sparing or “sheddase sparing” inhibitors has been generated and claimed in the recent patent literature, and a few of them are in clinical development.
  • MMP-3 stromelysin-1
  • MMP-13 collagenase-3
  • MMP-14 membrane-type 1 MMP
  • this syndrome was obseved in cancer patients treated with AG-3340 and BMS-275291, although the former compound has remarkable selectivity for MMP-2 as compared to MMP-1 (about 150-fold), and the latter completely spares TACE and other sheddases.
  • the compounds of the present invention are intended to provide this advantage. These compounds were addressed after our hypothesis that antitumor efficacy in the complete absence of the MSS can be obtained by a remarkable selectivity for MMP-2 over other enzymes, in particular MMP-3 (stromelysin-1), MMP-13 (collagenase-3), and MMP-14 (membrane-type 1 MMP), in addition to sparing MMP-1 and TACE inhibition. The compounds of the present invention showed this peculiar selectivity profile. DESCRIPTION OF THE INVENTION The present invention provides 3-arylsulfonyl-2-hydroxy-2-methyl propanoic acid derivatives of formula (I):
  • X is HO-NH- or HO- ;
  • Rl is selected from -O-Ph, -S-Ph, -S-Het, -Hyd or -CH 2 -Hyd, wherein Ph is a phenyl group, which may be unsubstituted or substituted; Het is a 5- or 6-membered unsaturated heterocychc ring having one to four atoms selected from the group consisting of nitrogen, sulfur and oxygen, which may be substituted or unsubstituted; and Hyd is a hydantoin-3-yl ring, which is substituted by one to three methyl groups;
  • A is a phenyl group, which may be substituted or unsubstituted, or Het as defined above, or a phenyl ring condensed with a 5-membered saturated or unsaturated heterocychc ring having one to three atoms selected from the group consisting of nitrogen, sulfur and oxygen, which may be either unsubstituted or substituted;
  • R2 is either hydrogen or methyl
  • R2 represents a methylene (-CH 2 -) bridge connecting the nitrogen atom to the ortho position of said phenyl, condensed phenyl or heterocyclyl ring A to form a 5-membered lactam. More specifically: when Rl, as indicated above, is -O-Ph or -S-Ph, the phenyl ring which Ph represents can be substituted by one or two substituents, at any position, selected from the group consisting of fluoro, chloro, hydroxy, methyl, methoxy or trifluoromethoxy; when Rl, as indicated above, is -S-Het, the 5- or 6-membered unsaturated heterocychc ring which Het represents, being as defined above, is preferably selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 2-furyl, l,3-thiazol-2-yl, which can be substituted by chloro or methyl; when Rl
  • the compounds of this invention contain a chiral center at the ⁇ -position of the hydroxamic or carboxylic acid, and as such they may be obtained as any of the two separate enantiomers or as a racemic mixture of both.
  • Preferred compounds of this invention are either the racemates or individual isomers having the configuration depicted herebelow:
  • the compounds of the present invention can be converted to pharmaceutically acceptable salts, where appropriate, according to conventional methods.
  • the term 'pharmaceutically acceptable salts' refers to non toxic base or acid addition salts, according to the presence of an acid or basic group in the compounds of formula (I).
  • a base addition salt, especially when X in formula (I) is hydroxy, can be a metal salt, such as sodium, potassium, calcium or magnesium, or an ammonium salt, or a salt with an appropriate organic amine or amino acid such as arginine, procaine and the like.
  • An acid addition salt especially when A in formula (I) is dimethylamino, pyrrolidino and piperidino, can be a hydrochloride, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citrate, 2-hydroxyethyl sulfonate, fumarate and the like.
  • Any compound of formula (I) and salt thereof may be either in the anhydrous or hydrated form, or may be solvated with pharmaceutically acceptable solvents, such as ethanol.
  • the carboxylic acids of the present invention i.e. the compounds of formula (I) wherein X is hydroxy
  • the present invention also provides pharmaceutical compositions which comprise, as active ingredient, a compound of formula (I) or a solvate, hydrate, or pharmaceutically acceptable salt thereof, or an ester prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • Particularly preferred compounds of this invention include the following ones: 3-( ⁇ 4-[(lH-l ,2,3 -benzotriazol-6-ylcarbonyl)amino jphenyl ⁇ sulfonyl)-2-hydroxy-2- (phenoxymethyl)propanoic acid;
  • the compounds of this invention can be prepared in accordance to the process of Scheme 1, wherein Rl, R2, A are as defined above, and R is an alcohol residue such as C 1 -C 4 linear or branched alkyl, optionally substituted benzyl or diphenylmethyl , or a carboxy protecting group known in the art, preferably benzyl, 4-nitrobenzyl, tert-butyl or diphenylmethyl.
  • Rl, R2, A are as defined above, and R is an alcohol residue such as C 1 -C 4 linear or branched alkyl, optionally substituted benzyl or diphenylmethyl , or a carboxy protecting group known in the art, preferably benzyl, 4-nitrobenzyl, tert-butyl or diphenylmethyl.
  • the sulfonyl propanoic acids (la) and their hydroxamic acid derivatives (lb) represent the compounds of formula (I) claimed by the present invention, wherein X is hydroxy and hydroxy
  • a sulfonyl propanoic acid of formula (la) wherein R2 and A ar as defined above, and Rl is not -S-Ph or -S-Het as defined above is obtained from the corresponding sulfanyl propanoic acid (1) by oxidation at sulfur, step a.
  • Suitable oxidizing agents for such conversion are metachloroperbenzoic acid (MCPBA) in an inert organic solvent such as dichloromethane (DCM) at 0 °C or ambient temperature, or hydrogen peroxide in aqueous formic or acetic acid, or potassium peroxymonosulfate (oxone ® ) in an organic solvent such as methanol, DMF, N-methylpyrrolidone, or a mixture of organic solvents, or a mixture of water and a water-miscibile organic solvent, at ambient temperature or under moderate heating.
  • MCPBA metachloroperbenzoic acid
  • DCM dichloromethane
  • oxone ® potassium peroxymonosulfate
  • organic solvent such as methanol, DMF, N-methylpyrrolidone, or a mixture of organic solvents, or a mixture of water and a water-miscibile organic solvent, at ambient temperature or under moderate heating.
  • oxone oxone
  • a sulfonyl propanoic acid (la) is obtained by hydrolysis of an ester of formula (la'), wherein R, Rl, R2 and A are as defined above.
  • Conditins for ester hydrolysis, step b, are those generally known in the art.
  • a preferred condition is alkaline hydrolysis, for example with aqueous NaOH in ethanol; when R is benzyl or 4-nitrobenzyl, a preferred condition is hydrogenolysis, especially in the presence of a palladium catalyst such as Pd on charcoal, in an inert organic solvent such as ethanol or DMF or the like, typically at room temperature and under atmospheric pressure or moderate pressure; when R is 4- nitrobenzyl, another preferred condition is treatment with Zn powder in the presence of acetic acid, which is carried out in an inert organic solvent such as DMF, THF, MeCN, acetone or the like; when R is tert-butyl or diphenylmethyl, a preferred condition is treatment with trifluoroacetic acid in an organic solvent, to which anisole or water may be added.
  • the sulfonyl propanoic esters of formula (la') wherein R, R2 and A ar as defined above, and Rl is either -O-Ph or -Hyd or -CH 2 -Hyd as defined above, can be obtained from the corresponding sulfanyl propanoic esters (la) by oxidation at sulfur, step a', under the same conditions described above for the corresponding acids of formula (la), step a.
  • Said sulfanyl propionic esters (la) can be obtained from the propanoic acids (1) under the general conditions known in the art for acid to ester conversion, or may be prepared as shown in the Scheme 2 below.
  • a sulfonyl propanoic ester of formula (la') wherein R, R2 and A ar as defined above, and Rl is either -O-Ph, -S-Ph or -S-Het as defined above, can be obtained from a diol of formula (2), wherein R, R2 and A are as defined above, by derivatization of its primary hydroxyl into an ether or thioether, step c.
  • Such derivatization entails activation as a mesylate, triflate or tosylate, followed by displacement with a phenol of formula Ph-OH, or a thiol of formula Ph-SH or Het-SH, in the presence of a strong base, preferably sodium hydride, in an aprotic organic solvent, preferably DMF.
  • a strong base preferably sodium hydride
  • a preferred activated derivative of said carbinol of formula (2) is the mesylate, which is preferably obtained by reaction with mesyl chloride and a base in an inert organic solvent.
  • a suitable base is, for example, triethylamine, and a suitable solvent is dichloromethane (DCM).
  • DCM dichloromethane
  • Another preferred base is pyridine, which can be used neat also as the solvent.
  • a compound of formula (la') wherein Rl is -S-Ph can be conveniently obtained from a diol of formula (2) by reaction with a disulfide Ph-S-S-Ph in the presence of a phosphine, preferably tributylphosphine (Hata reaction), in an inert organic solvent such as dioxane, preferably under heating or reflux condition to expedit the reaction.
  • a phosphine preferably tributylphosphine (Hata reaction)
  • an inert organic solvent such as dioxane
  • Rl, R2, A are as defined above, and R is C 1 -C 4 alkyl, especially ethyl or methyl, are useful prodrugs of the carboxylic acids (la) because readily hydrolyzed in vivo, and are comprised within the scope of the present invention.
  • prodrugs of formula (la') can also be obtained from the acids (la) by esterification.
  • prodrugs comprised by the present invention are double ester prodrugs, that is compounds of formula (la') wherein Rl, R2, A are as defined above, and R is acyloxy-methyl such as acetyloxymethyl and benzoyloxymethyl, or l-(acyloxy)ethyl such as 1-acetyloxyethyl, or ethoxycarbonyloxyrnethyl, or l-(ethoxycarbonyloxy)ethyl, or (2-oxo-l,3-dioxolen-4- yl)methyl.
  • double ester prodrugs are preferably obtained by esterification of the corresponding acids of formula (la), according to procedures well known in the art.
  • a preferred method for activation as the acid chloride is reaction with oxalyl chloride, typically in DCM containing DMF as a catalyst, at 0 °C to ambient temperature.
  • a preferred method for activation as a mixed anhydride is reaction with a chlorocarbonate such as chloroethylformate in dry THF or a similar compatible solvent, in the presence of a tertiary amine such as TEA.
  • the acid can be activated by a carbodiimide condensing agent such as dicyclohexylcarbodiimide (DCC) or l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSCDI, water soluble carbodiimide), preferably in the presence of 1-hydroxybenzotriazole (HOBt) in an inert organic solvent such as DMF at 0 °C to room temperature.
  • a carbodiimide condensing agent such as dicyclohexylcarbodiimide (DCC) or l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSCDI, water soluble carbodiimide)
  • DCC dicyclohexylcarbodiimide
  • WSCDI l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • Another method for the activation of a carboxylic acid of formula (la) is reaction with benzotriazolyl-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) in a suitable organic solvent such as MeCN, THF or DCM in the presence of a tertiary amine such as TEA or NMM.
  • BOP reagent benzotriazolyl-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate
  • a further method is reaction with O-benzotriazolyl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or O-benzotriazolyl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), under conditions similar to those described for the BOP reagent.
  • HBTU O-benzotriazolyl-N,N,N',N'-tetramethyluronium tetrafluoroborate
  • TBTU O-benzotriazolyl-N,N,N',N'-tetramethyluronium tetrafluoroborate
  • the acid chloride is usually isolated crude before reaction with the hydroxylamine reagent; when with chloroethylformate, EDC or WSCDI, the hydroxylamine reagent is preferably added after about 1 hour at room temperature; when with the BOP reagent, HBTU or TBTU, the hydroxylamine reagent is preferably protected as O-(benzyl)hydroxylamine, O-(tert-butyl)hydroxylamine, O- (tetrahydropyranyl)hydroxylamine, or N,O-bisO-(trimethylsilyl)hydroxylamine. Removal of protecting groups is performed by methods known in the art.
  • the benzyl group is removed under reductive conditions, preferably with hydrogen and a metal catalyst such as Pd on charcoal, Pd on BaSO , or palladium hydroxide on carbon (Pearlman's catalyst), typically in methanol or ethanol;
  • a metal catalyst such as Pd on charcoal, Pd on BaSO , or palladium hydroxide on carbon (Pearlman's catalyst) typically in methanol or ethanol;
  • the tert-butyl group is removed by treatment with neat or aqueous trifluoroacetic acid, or with HC1 in DCM;
  • the tetrahydropyranyl group is removed by reaction with 4N aqueous HC1 in suitable organic solvents or mixtures thereof, e.g. dioxane and methanol.
  • the hydroxamic acids of formula (lb) are obtained from the carboxylic esters of formula (la'), wherein Rl, R2 and A are as defined above, and R, being ad defined above, is preferably methyl.
  • This reaction is carried out with hydroxylamine in an inert organic solvent, such as methanol, THF and the like, usually in the presence of water, at room temperature or under moderate heating.
  • hydroxylamine reagent is the corresponding hydrochloride
  • hydroxylamine is conveniently generated in situ by addition of aqueous NaOH.
  • the reaction can be carried out with an O-protected hydroxylamine, such as benzyl hydroxylamine, tert-butyl hydroxylamine or tetrahydropyranyl hydroxylamine, in which case the protecting group is removed after the exchange reaction, as described above.
  • O-protected hydroxylamine such as benzyl hydroxylamine, tert-butyl hydroxylamine or tetrahydropyranyl hydroxylamine, in which case the protecting group is removed after the exchange reaction, as described above.
  • the sulfanyl propanoic acids of formula (1), and esters thereof (la) reported in Scheme 1 as intermediates in the preparation of the final sulfonyl propanoic acids (la), prodrugs thereof (la'), and of the final sulfonyl propanoic hydroxamic acids (lb) can be obtained as outlined in Scheme 2.
  • a sulfanyl carboxylic acid of formula (1) wherein R2 and A are as defined above, and Rl is either -O-Ph, -Hyd or -CH -Hyd as defined above, can be obtained by hydrolysis of a corresponding ester of formula (la), wherein R is as stated before, step 1.
  • Preferred groups which R may represent are - linear alkyl, still preferably methyl or ethyl, benzyl, 4-nitrobenzyl, tert-butyl or diphenylmethyl. Ester hydrolysis is carried out under conventional conditions stated in the general art, as exemplified before for the hydrolysis of a compound (la') to a compound (la), step b in Scheme 1.
  • a preferred activated derivative of said diol of formula (6) is the mesylate, which is preferably obtained by reaction with mesyl chloride and a base, for example triethylamine or pyridine, in an inert organic solvent, for example DCM.
  • the displacement reaction is carried out in the presence of a strong base, such as sodium methoxide, DBU, or preferably sodium hydride, in an aprotic organic solvent, preferably DMF.
  • a 4-aminothiophenol protected at the amino group is used in the displacement reaction, followed by unmasking of the amino group and acylation with an activated derivative of a carboxylic acid of formula A-COOH, wherein A is as defined above.
  • a preferred a 4-aminothiophenol protected at the amino group is 4- trifluoroacetamido-thiophenol.
  • a preferred condition for unmasking the amino group after the displacement reaction, which has the merit of leaving the ester moiety of (6) unaffected, is refluxing in methanol in the presence of triethylamine.
  • a preferred activated derivative of a carboxylic acid of formula A-COOH is the acyl chloride, which is obtained by conventional procedures, for example by reaction with oxalyl chloride or thionyl chloride, and is reacted with the amine under conventional conditions, that is in an inert oranic solvent such as DCM in the presence of a base, for example triethylamine.
  • This reaction is performed in an inert organic solvent, preferably DMF, in the presence of a base such as sodium methoxide, DBU or potassium carbonate.
  • a 4-aminothiophenol protected at the amino group can be used as the reagent, especially 4-trifluoroacetamidothiophenol, followed by unmasking of the amino group and acylation with an activated derivative of a carboxylic acid of formula A-COOH, as described above.
  • a diol of formula (6) wherein Rl is either -O-Ph, -Hyd or -CH 2 -Hyd as defined above, and R is as defined above, can be obtained by dihydroxylation of the corresponding acrylic ester of formula (5) wherein R' is R, step h, or of the corresponding acrylic acid of formula (5) wherein R' is hydrogen followed by alkylation with a halide of formula R-X, as defined above, for example methyl iodide or ethyl bromide.
  • Suitable oxidizing agents are osmium tetraoxide or permanganate salts.
  • osmium tetraoxide is used in a catalytic amount, in the presence of 1 - 1.5 molar equivalents of N-methylmorpholine N-oxide (NMMNO).
  • NMMNO N-methylmorpholine N-oxide
  • the osmium reagent is used as a solution in tert- butanol, and aqueous acetone or aqueous tert-butanol are used as co-solvents, preferably around room temperature.
  • An epoxide of formula (7) wherein Rl is -O-Ph and R is as defined above can be obtained from the corresponding acrylic ester of formula (5) wherein R' is R, step i.
  • a substituted acrylic acid derivative of formula (5) wherein Rl is -O-Ph or -Hyd as defined above, and R' is either hydrogen or R as defined above, can be obtained from (bromomethyl)acrylic acid or an ester thereof, that is a compound of formula (3) wherein R' is either hydrogen or R, as defined above, by reaction with a phenol of formula Ph-OH, wherein Ph is as defined above, or with l,5,5-trimethyl-l,4-imidazolidinedione in the presence of a strong base or, preferably, by reaction of the preformed salts of said phenol or imidazolidinedione with said bases, step f.
  • displacement is carried out starting from (bromomethyl)acrylic acid, which is commercially available, and the obtained compound of formula (5) wherein R' is hydrogen is then converted to an ester thereof, that is a compound (5) wherein R' is R, as defined above.
  • the substituted acrylate of formula (5) wherein Rl is -O-Ph and R' is methyl can be obtained from (bromomethyl)acrylic acid by reaction with Ph-OH in DMF at about 75 °C, in the presence of NaOH, followed by alkylation with methyl iodide in DMF in the presence of K 2 CO .
  • the substituted acrylate of formula (5) wherein Rl is -Hyd as above defined, and R' is 4-nitrobenzyl can be obtained from (bromomethyl)acrylic acid by reaction with l,5,5-trimethyl-2,4-imidazolidinedione in DMF at about 70 °C, in the presence of NaHCO 3 , followed by reaction with 4-nitrobenzyl bromide in DMF at room temperature in the presence of K 2 CO 3 , CsCO 3 and the like.
  • a substituted acrylic acid derivative of formula (5) wherein Rl is -CH 2 -Hyd as defined above, and R is as defined above, can be obtained from a substituted malonic ester derivative of formula (4) by hydrolysis of one or both the ester groups, followed by alkenylation with formaldehyde, para-formaldehyde and the like, under the standard Mannich conditions, step g.
  • said malonic ester derivative of formula (4) wherein Rl is -CH -Hyd as defined above can be obtained by alkylation of an ester of malonic acid, preferably diethyl or dimethyl malonate, with a halide of formula Hyd-CH 2 -CH -X, wherein X is bromo, chloro, or iodo, under standard conditions.
  • a compound of formula (2) wherein R, R2 and A are as defined above, can be obtained from the corresponding alkene of formula (9), wherein R' is R, by dihydroxylation, step o, under the same conditions described in step h, Scheme 2, for the conversion of an acrylate of formula (5) into a diol of formula (6); preferably, by reaction with N-methylmorpholine N-oxide (TSfMMNO) in a suitable solvent, such as aqueous acetone, in the presence of a catalytic amount of a solution of osmium tetraoxide in tert- butanol.
  • TSfMMNO N-methylmorpholine N-oxide
  • the dihydroxylation can be performed on the acrylic acid of formula (9), wherein R2 and A are as above defined, and R' is hydrogen, and the obtained diol acid is conventionally esterified to give the desired diol ester of formula (2).
  • an acrylic sulfone of formula (9), wherein R2 and A are as defined above, and R' is either hydrogen or R as defined above, can be obtained by oxidation of the corresponding sulfide of formula (8), step n.
  • Suitable conditions for said oxidation are the same reported in step a, Scheme 1, for the conversion of a compound of formula (1) to a compound of formula (la), or of a compound of formula (la) to a compound of formula (la'); preferably, potassium peroxymonosulfate (oxone ® ) in an organic solvent such as methanol, DMF, N- methylpyrrolidone, or a mixture of organic solvents, or a mixture of water and a water- miscibile organic solvent, or hydrogen peroxide in aqueous formic or acetic acid.
  • an organic solvent such as methanol, DMF, N- methylpyrrolidone, or a mixture of organic solvents, or a mixture of water and a water- miscibile organic solvent, or hydrogen peroxide in aqueous formic or acetic acid.
  • Such reaction is carried out in a compatible organic solvent, such as DMF, MeCN, toluene, THF, acetone, dichloromethane and the like, at temperatures ranging from about 0 °C to reflux temperature, preferably from room temperature to 50 °C, in the absence or presence of a suitable base such as sodium carbonate, sodium bicarbonate, cesium carbonate or triethylamine.
  • a suitable base such as sodium carbonate, sodium bicarbonate, cesium carbonate or triethylamine.
  • a particularly preferred condition is DMF, 40 °C, in the i o absence of external bases .
  • a preferred conditions for said reduction is treatment at room temperature with Zn powder in the presence of diluted HC1 in a water-miscible organic solvent, such as acetone, THF or MeCN.
  • a water-miscible organic solvent such as acetone, THF or MeCN.
  • a compound of the present invention can be formulated both as the racemate or as the bioactive resolved enantiomer, as specified above.
  • Chiral resolution from a racemic mixture can be performed on the final compounds of formula (I), such as those represented by formula (la) and (lb) in Scheme 1, or on the final prodrugs or ester derivatives of formula (la'), or on intermediates of formula (7), (2), (la) or (1), by conventional methods known in the art, such as preparative chiral HPLC.
  • racemic carboxylic acids of formula (I) wherein X is hydroxy, as well as said intermediates of formula (1), or 5 the racemic carboxylic acids obtained fron hydrolysis of the esters of formula (6) can be resolved by chiral salt formation, using a chiral base such as (+) or (-)-l-phenylethylamine, (+) or (-)-ephedrine, and the like.
  • a chiral base such as (+) or (-)-l-phenylethylamine, (+) or (-)-ephedrine, and the like.
  • enzymatic hydrolysis of racemic ester intermediates of formula (6), (2) or (la) can be used to obtain the corresponding chiral acids.
  • a chiral ester residue R such as menthyl
  • R can be 0 selected in the preparation of intermediates (7), (6), (2) or (la), giving rise to diastereomeric mixtures, which can be separated by conventional techniques such as fractional crystallization or chromatography.
  • the present invention further provides a compound of formula (I) as defined above for use in a method of treatment or prophylaxis of a disease mediated in a mammal by gelatinases, especially gelatinase-A (MMP-2), such as tumor growth and metastasis, and other diseases where neo-angiogenesis mediated by gelatinases plays a significant contribution, such as o macular degeneration.
  • gelatinases especially gelatinase-A (MMP-2), such as tumor growth and metastasis, and other diseases where neo-angiogenesis mediated by gelatinases plays a significant contribution, such as o macular degeneration.
  • the compounds of the present invention are typically administered in the form of pharmaceutical compositions, which can be prepared by combining the compounds of formula (I) or salts or hydrates or solvates thereof with a solid or liquid pharmaceutically acceptable carrier, and, optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques, hi particular, the 5 compounds of formula (I) can be administered: a) orally, for example, as tablets, coated tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions o may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, maize starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is present as such, or mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone gum tragacanth and gum acacia; dispersing or wetting agents may be naturally-occurring phosphatides, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.
  • dispersing or wetting agents may be naturally-occurring phosphatides, for example lecithin, or condensation products of an
  • the said aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, or one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspension may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oils, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, nalj rally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan mono-oleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents; b) parenterally, either subcutaneously, or intravenously, or intramuscularly, or intrasternally, or by infusion techniques, in the form of sterile injectable aqueous or oleaginous suspensions.
  • This suspension may be formulated according to the known art using those suitable dispersing of wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables; c) topically, in the form of creams, ointments, jellies, plasters, collyriums, solutions or suspensions, and transdermal patches; d) rectally, in the form of suppositories prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non-irritating excipient which is solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • the amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the particular mode of admnistration, the mammalian host treated and his conditions.
  • Daily dosages can vary within wide limits and will be adjusted to the individual requirements in each particular case.
  • a compound of formula (I) is advantageously administered at a dosage and frequency to achieve and maintain, for the whole period of therapy, a blood level in free drug (i.e., not bound to plasma proteins) ranging from about 1 to about 100 times its Ki against the most relevant MMP for the particular disease state, e.g. MMP-2 for cancer.
  • the daily dose may be divided into multiple doses for administration, e.g. two to four times per day.
  • the drug can be administered daily, or at alternate days.
  • an amount of the active compound effective in adult patients will be in the range of 10 to about 500 mg, but it is to be understood that such range may be exceeded depending on the particular compound being used, the severity of the disease being treated, and the requirement of the patient.
  • the compounds of the present invention differ from compounds of the previous art for their enhanced selectivity for MMP-2. This enhanced selectivity is found both with compounds of formula (I) wherein X is hydroxy and the corresponding compounds wherein X is hydroxyamino. general, the compounds of formula (I) wherein X is hydroxy display single-digit nM Ki's against MMP-2, sometimes below nanomolar when tested as the bioactive enantiomers.
  • MMP-1 interstitial collagenase
  • Ki's in the 0.2 -2 mM range.
  • MMP-1 sparing inhibitors of the previous art their potency against other MMPs sharing with MMP-2 an elongated specificity pocket is unexpectedly low, either in absolute terms (e.g., against MMP-3, typical Ki's being in the microM range) or in relative terms (e.g., against MMP-13 and MMP-14, typical Ki's being in the 50 -500 nM range).
  • the compounds of the present invention are much less amenable to side-effects than other MMP inhibitors of the previous art, including the so-called musculoskeletal syndrome which has been observed with the less selective inhibitors tested to date in cancer patients.
  • the compounds of the present invention are in general less bound to plasma proteins than other compounds of the previous art displaying remarkable selectivity for MMP-2, for example Bayer BAY 12-97566.
  • the compounds of the present invention and their preparation will be better understood in connection with the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention.
  • Step 5 l-Hydroxy-l-hydroxymethyl-4-(3,4,4-trimethylhydantoin-l-yl)butanoic acid ethyl ester
  • Step 6) 2- [(4-Trifluoroacetylaminophenylsulfanyl)methyl] -2-hydroxy-4-(3,4,4-trimethyl- hydantoin-l-y ⁇ )butanoic acid ethyl ester
  • Step 7) 2-[(4-anjdnophenylsulfonyl)methyl]-2-hydroxy-4-(3,4,4-trimethylhydantoin-l-yl)- butanoic acid ethyl ester
  • Step 8) 2- [(4-aminophenylsulfonyl)methyl] -2-hydroxy-4-(3 ,4,4-trimethylhydantoin- 1 -yl)- butanoic acid ethyl ester
  • 2- [(4-trifluoroacetylaminophenylsulfonyl)methyl]-2-hydroxy-4-(3 ,4,4- trimethylhydantoin- l-yl)butanoic acid ethyl ester (12 g) in methanol (100 ml) and TEA (50 ml) was refluxed at 100°C overnight.
  • Step 10) A stirred solution of 2-[ ⁇ 4-[(4-chlorobenzoyl)amino]phenyl ⁇ sulfonyl)methyl]-2- hydroxy-4-(3 ,4,4-trimethylhydantoin- l-yl)butanoic acid ethyl ester (0.5 g) in methanol (25 ml) and 1 M NaOH (2 ml) was set aside at room temperature for 5 h.. The cloudy suspension was acidified to pH 2 with 2 N HCl, diluted with ethyl acetate and thoroughly partitioned with brine. The solvent was removed and the residue was crystallized from ethanol to provide the title compound (0.38 g, yield 80%), >100°C decomp.
  • Example 2 A stirred solution of 2-[ ⁇ 4-[(4-chlorobenzoyl)amino]phenyl ⁇ sulfonyl)methyl]-2- hydroxy-4-(3 ,4,4-trimethylhydantoin
  • Step 1) 2-[(4-trifluoroacetylaminophenylsulfanyl)methyl]acrylic acid
  • a stirred solution of 2-bromomethylacrylic acid (12 g) and 4- (trifluoroacetylamino)benzenthiol (14.6 g) in DMF (100 ml) was heated 45°C for 4 h.
  • the reaction mixture was diluted with ethyl acetate and washed with brine. After drying and removal of the solvent, the residue was crystallized from ethyl ether to provide 2-[(4- trifluoroacetylaminophenylsulfanyl)methyl]-acrylic acid (18 g, yield 89%), mp 156-158°C°.
  • Step 3) 2-[(4-trifluoroacetylaminophenylsulfonyl)methyl]acrylic acid methyl ester
  • 2-[(4-trifluoroacetylaminophenylsulfonyl)methyl]acrylic acid (61 g) and 12 M NaOH (16 ml) in DMF (250 ml) was added methyl iodide (40 ml) at room temperature. After stirring overnight, the solvent was removed and the residue taken up in ethyl acetate was thoroughly washed with brine and dried.
  • Step 5) 2-Hydroxy-2-methansolfonyloxymethyl-3-(4-trifluoroacetylarninophenylsulfonyl)- propionic acid methyl ester 5
  • 2-hydroxy-2-hydroxymethyl-3-(4- trifluoroacetylaminophenylsulfonyl)- propionic acid methyl ester 15 g
  • methansolfonylchloride 3.5 ml
  • Step 6) 2-Hy(tooxy-2-(phenylsulfanyl)methyl-3-(4-trifluoroacetylaminophenylsulfonyl)- propionic acid methyl ester 5
  • benzenthiol 15 g
  • DMF 300 ml
  • 60% NaH 5 g
  • 2-hydroxy-2- methansolfonyloxymethyl-3 -(4-trifluoroacetylaminophenylsulfonyl)propionic acid methyl ester 50 g was added and the reaction mixture was set aside for 15 h.
  • 2-hydroxy-2-(phenylsulfanyl)methyl-3-(4- aminophenylsulfonyl)propionic acid methyl ester 1.5 g
  • 4-chlorobenzoylchloride 0.5 ml
  • reaction mixture was diluted with ethyl acetate and thoroughly partitioned with 2 M HCl. After washing with 2 M NaHCO3, brine and dried, the solvent was removed to provide, after crystallization from acetone, 2-hydroxy-2- [(phenylsulfanyl)methyl]-3 - [ ⁇ 4-[(4- chlorobenzoyl)amino]phenyl ⁇ sulfonyl]propanoic acid methyl ester (1.1.6 g, yield 80%>).
  • Step 9) A stirred solution of 2-hydroxy-2-[(phenylsulfanyl)methyl]-3-[ ⁇ 4-[(4- chlorobenzoyl)-amino]phenyl ⁇ sulfonyl]propanoic acid methyl ester (0.75 g) in methanol (25 ml) and 1 M NaOH (4 ml) was st aside at room temperature for 5 h.. The cloudy suspension was acidified to pH 2 with 2 N HCl, diluted with ethyl acetate and thoroughly partitioned with brine.
  • Step 1) 2-Hydroxy-2- henyloxy)methyl-3-(4-trifluoroacetylaminophenylsulfonyl)propionic acid methyl ester
  • Step 2) 2-Hydroxy-2-(phenyloxy)memyl-3-(4-aminophenylsulfonyl)propionic acid methyl ester
  • Step 3 Operating as in Example 3 step 8, 9, but employing 2-hydroxy-2-(phenyloxy)methyl-
  • Example 3 step 8 Operating as in Example 3 step 8, 9, but employing 2-hydroxy-2-(phenyloxy)methyl-3-(4- aminophenylsulfonyl)propionic acid methyl ester instead of 2-hydroxy-2-(phenylsulfanyl)- methyl-3-(4-aminophenylsulfonyl)propionic acid methyl ester and 4-cyanobenzoylchloride instead of 4-chlorobenzoylchloride, the title compound was obtained in overall 43% yield.
  • Example 3 step 8 Operating as in Example 3 step 8, 9, but employing 2-hydroxy-2-(phenyloxy)methyl-3-(4- aminophenylsulfonyl)propionic acid methyl ester instead of 2-hydroxy-2-(phenylsulfanyl)- methyl-3-(4-aminophenylsulfonyl)propionic acid methyl ester and 4-bromobenzoylchloride instead of 4-chlorobenzoylchloride, the title compound was obtained in overall 39 % yield.
  • Example 3 step 8 Operating as in Example 3 step 8, 9, but employing 2-hydroxy-2-(phenyloxy)methyl-3-(4- aminophenylsulfonyl)propionic acid methyl ester instead of 2-hydroxy-2-(phenylsulfanyl)- methyl-3-(4-aminophenylsulfonyl)propionic acid methyl ester and 4-dimethylamino- benzoylchloride hydrochloride instead of 4-chlorobenzoylchloride, the title compound was obtained in overall 35% yield, mp >180°C decomp.
  • Step 2) A stirred solution of 2-hydroxy-2-[(phenyloxy)methyl]-3- ⁇ [4-(l-oxo-l,3-dihydro- 2H-isoindol-2-yl)phenyl]sulfonyl ⁇ propanoic acid methyl ester (5 g) and 2 M NaOH (10 ml) in methanol (75 ml) was heated at 50°C for 7 h. The solvent was removed and the residue dissolved in water was treated with 2 M HCl to pH 2.
  • Step 2) 2-Hydroxy-2-hydroxymethyl-3-[ ⁇ 4-[(4-chlorobenzoyl)methylamino] phenyl ⁇ sulfonylj-propanoic acid methyl ester
  • 2-hydroxy-2-hydroxymethyl-3-(4-aminophenylsulfonyl)propionic acid methyl ester 15 g
  • 2-hydroxy-2-hydroxymethyl-3-(4-aminophenylsulfonyl)propionic acid methyl ester 15 g
  • 4- chlorobenzoylchloride 9 g
  • THF 25 ml
  • Step 3) 2-Hy(hoxy-2-memansolfonyloxymemyl-3-[ ⁇ 4-[(4-cMorobenzoyl)methylan ⁇ no]- phenyl ⁇ sulfonyljpropanoic acid methyl ester
  • 2-hydroxy-2-hydroxymethyl-3-[ ⁇ 4-[(4-chlorobenzoyl)methylamino]- phenyl ⁇ sulfonyljpropanoic acid methyl ester (18 g) in pyridine (100 ml) was added dropwise a solution of methansolfonylchloride (9 g) in pyridine (20 ml) at 5°C.
  • Step 4) To a stirred solution of 2-mercapto-l,3-thiazole (1 g) in DMF (300 ml) was added portionwise 60% NaH (0.25 g) at 5°C. After 1 h of stirring at room temperature, 2-hydroxy- 2-methansolfonyloxymethyl-3-[ ⁇ 4-[(4- chlorobenzoyl)methylamino]phenyl ⁇ sulfonyl]propanoic acid methyl ester (3.13 g) was added and the reaction mixture was set aside for 10 h. The solvent was removed and the residue taken up in ethyl acetate was thoroughly washed with brine.
  • Step 5) A stirred solution of 2-hydroxy-2-[(l,3-thiazol-2-ylsulfanyl)methyl]-3-[ ⁇ 4-[(4- chlorobenzoyl)methylamino]phenyl ⁇ sulfonyl]propanoic acid methyl ester (2 g) and 2 M NaOH (4 ml) in methanol (30 ml) was heated at 50°C for 7 h. The solvent was removed and the residue dissolved in water was treated with 2 M HCl to pH ⁇ 3.
  • Step 1) 4-Nitrobenzyl 2-[(3,4,4-1ximethyl-2,5-dioxo-l-imidazolidinyl)methyl]acrylate Sodium bicarbonate (1.9 g) was added to a stirred solution of 3,4,4-trimethylhydantoin (3.1 g) and 2-(bromomethyl)acrylic acid (3.5 g) in DMF (20 ml) at 90°C.
  • Step 2) 4-Nitrobenzyl 2,3-dmydroxy-2-[(3,4,4-trimethyl-2,5-dioxo-l- imidazolidinyl)methyl] -propanoate
  • 4-nitrobenzyl 2-[(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)methyl]- acrylate (5.1 g) and N-methyl-morpholine (6.6 g) in tert-butanol (25 ml) and water (25 ml) was added a catalytic amount of osmium tetroxide (10 mg).
  • Step 5 4-Nitrobenzyl 3-( ⁇ 4-[(4-chlorobenzoyl)amino]phenyl ⁇ sulfonyl)-2-hydroxy-2-[(3,4,4- trimethyl-2,5-dioxo- 1 -imidazolidinyl)methyl]propanoate
  • Step 6) A solution of 4-nitrobenzyl 3-( ⁇ 4-[(4-chlorobenzoyl)an ⁇ ino]phenyl ⁇ sulfonyl)-2- hy ⁇ roxy-2-[(3,4,4-trm ⁇ emyl-2,5-dioxo-l-in ⁇ idazohdinyl)methyl]propanoate (1 g) in DMF (30 ml) was treated with acetic acid (1.8 ml) and Zn powder (2 g) at room temperature. After 30' of stirring, the suspension was filtered on celite and the resulting solution was diluted with ethyl acetate.
  • Example 8 step 1 Operating as in Example 8 step 1, 2, but employing 2-hydroxy-2-(phenyloxy)methyl-3-(4- aminophenylsulfonyl)propionic acid methyl ester instead of 2-hydroxy-2-(phenylsulphanyl)- methyl-3-(4-aminophenylsulfonyl)propionic acid methyl ester, and as in Example 3 step 8, 9, but employing 4-trifluoromethylbenzoylchloride instead of 4-chlorobenzoylchloride, the title compound was obtained in overall 28% yield, mp 197-200°C.
  • Example 28 Example 28
  • the assay buffer was pH 6.5 for the carboxylates and pH 7.4 for the hydroxamates.
  • Tabulated data refer to racemic mixture or to separate enantiomers, the more active enantiomer showed nearly halved Ki's against the whole enzyme panel.
  • Example 27 5.8
  • Example 28 3.4

Abstract

A compound which is an arylsulfonyl propanoic acid derivative of formula (I) : CH2R1 XC(O)-C(OH)-SO2-C6H4-N(R2)COA (I) wherein X is HO-NH- or HO- , R1 is selected from -O-Ph, -S-Ph, -S-Het, -Hyd or -CH2-Hyd, wherein Ph is a phenyl group; Het is a heterocyclic ring and Hyd is a substituted hydantoin-3-yl ring; A is a phenyl group or Het as defined above, or a condensed phenyl ring; and R2 is either hydrogen or methyl; or R2 represents a methylene (-CH2-) bridge connecting the N atom to the ortho position of said A to form a 5-membered lactam; or a salt or an oral prodrug thereof.The compounds are inhibitors of matrix metallo-proteinases (MMPs) and are therefore useful in the prevention, control and treatment of diseases in which MMPs are involved.

Description

3-ARYLSULFONYL-2-HYDROXY-2-METHYLPROPANOIC ACID DERIVATES
FIELD OF THE INVENTION
The present invention relates to some 3-sulfonyl carboxylic and hydroxamic acids displaying potent and selective inhibitory activity against gelatinases, in particular MMP-2 (Gelatinase-A), to their use for the treatment of diseases in which the proteolytic activity of these MMPs is involved, to methods for their preparation, and to pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION Under physiological conditions MMPs play an important role in normal tissue turnover and development. However, increased MMP activity and/or impairment of the physiological MMP inhibitors has been associated with a variety of pathological conditions such as cancer, rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, stroke, arteriosclerosis, diabetic rethinopathy, macular degeneration and wound healing. In cancer, the contribution of MMPs is manifold and not limited to destruction of the extracellular matrix required for local and distal invasion. The proteolytic action of MMPs generates active matrix protein fragments, and influence the release, activation and bioavailability of growth factors. In addition, MMPs are involved in cell migration and in the processing or shedding of cell surface proteins. It is now believed that the proteolytic action of MMPs plays a very important role in tumor growth, apoptosis and angiogenesis (see Noel, A. et . al., 'Emerging Roles for Proteinases in Cancer', Invasion Metastasis 17:221-239, 1997). Among the several MMPs known to date, gelatinase-A (MMP-2) is currently reputed as the main target in cancer.
Potent MMP inhibitors (MMPIs) were disclosed three decades ago (e.g., see Dickens, J. P. et al., U.S. Patent 4,599,361), but only recently some of them entered clinical trials, and none has arrived at the market yet. Questions remain concerning their specificity, bioavailability, and potential long-term toxicity (see Hodgson, J., 'Remodeling MMPIs', Biotechnology 13:554-557, 1995), especially because they are primarily intended for prolonged therapy. Marimastat and other compounds investigated in patients, such as Novartis CGS-27023A, Agouron AG-3340, and BMS-275291, have been reported to cause a musculoskeletal syndrome (MSS) characterized by joint pain and stiffness, which may be severe and dose-limiting.
The MSS observed by prolonged administration of MMPIs has been reproduced by others and us in animal models, including rats, cyno monkeys and marmosets. In general, fibroproliferative effects in the joint capsule of the knees and surrounding tissue are the most remarkable histopathological correlate of the MSS. These alterations are thought to arise from an impairment in the normal tissue remodeling that is governed by one or more of the MMPs, or by related Zn-dependent enzymes. The current favorite hypotheses focus on undue inhibition of either MMP-1 (interstitial collagenase), or of TNF- convertase (TACE) and related sheddases. According to these hypotheses, a variety of "MMP-1 sparing" or "sheddase sparing" inhibitors has been generated and claimed in the recent patent literature, and a few of them are in clinical development. However, there is no proof that sparing MMP-1 or sheddase inhibition while inhibiting multiple MMPs, in particular MMP-3 (stromelysin-1), MMP-13 (collagenase-3), and MMP-14 (membrane-type 1 MMP), is sufficient to avoid the MSS. For example, this syndrome was obseved in cancer patients treated with AG-3340 and BMS-275291, although the former compound has remarkable selectivity for MMP-2 as compared to MMP-1 (about 150-fold), and the latter completely spares TACE and other sheddases. Thus, there is a strong need for better MMPIs, especially as far as long-term toxicity is concerned. It is believed that a future generation of MMPIs will be defined by the complete absence of the musculoskeletal syndrome at exposures affording the optimal efficacy. The compounds of the present invention are intended to provide this advantage. These compounds were addressed after our hypothesis that antitumor efficacy in the complete absence of the MSS can be obtained by a remarkable selectivity for MMP-2 over other enzymes, in particular MMP-3 (stromelysin-1), MMP-13 (collagenase-3), and MMP-14 (membrane-type 1 MMP), in addition to sparing MMP-1 and TACE inhibition. The compounds of the present invention showed this peculiar selectivity profile. DESCRIPTION OF THE INVENTION The present invention provides 3-arylsulfonyl-2-hydroxy-2-methyl propanoic acid derivatives of formula (I):
Figure imgf000004_0001
and the pharmaceutically acceptable salts thereof, and oral prodrugs thereof, wherein:
X is HO-NH- or HO- ;
Rl is selected from -O-Ph, -S-Ph, -S-Het, -Hyd or -CH2-Hyd, wherein Ph is a phenyl group, which may be unsubstituted or substituted; Het is a 5- or 6-membered unsaturated heterocychc ring having one to four atoms selected from the group consisting of nitrogen, sulfur and oxygen, which may be substituted or unsubstituted; and Hyd is a hydantoin-3-yl ring, which is substituted by one to three methyl groups;
A is a phenyl group, which may be substituted or unsubstituted, or Het as defined above, or a phenyl ring condensed with a 5-membered saturated or unsaturated heterocychc ring having one to three atoms selected from the group consisting of nitrogen, sulfur and oxygen, which may be either unsubstituted or substituted;
R2 is either hydrogen or methyl; or
R2 represents a methylene (-CH2-) bridge connecting the nitrogen atom to the ortho position of said phenyl, condensed phenyl or heterocyclyl ring A to form a 5-membered lactam. More specifically: when Rl, as indicated above, is -O-Ph or -S-Ph, the phenyl ring which Ph represents can be substituted by one or two substituents, at any position, selected from the group consisting of fluoro, chloro, hydroxy, methyl, methoxy or trifluoromethoxy; when Rl, as indicated above, is -S-Het, the 5- or 6-membered unsaturated heterocychc ring which Het represents, being as defined above, is preferably selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 2-furyl, l,3-thiazol-2-yl, which can be substituted by chloro or methyl; when Rl, as indicated above, is -Hyd or -CH2-Hyd, the hydantoin-3-yl ring which Hyd represents is either 3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl, or 4,4-dimethyl-2,5- dioxo-1-imidazolidinyl, or 3-methyl-2,5-dioxo-l-imidazolidinyl; when A, as indicated above, is a substituted phenyl ring, one substituent can be present at the para position, or two substituents at the para and meta position, which are selected from the group consisting of fluoro, chloro, bromo, C1-C4 linear alkyl, ethynyl, hydroxy, hydroxymethyl, trifluoromethyl, -C4 linear alkoxy, trifluoromethoxy, cyano, cyanomethyl, dimethylamino, 1-pyrrolidinyl, 2,5-dihydro-lH-pyrrol-l-yl, 1-piperidinyl; when A, as indicated above, is Het, the 5- or 6-membered unsaturated heterocychc ring which Het represents, being as defined above, is preferably selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 2-furyl, 3-imidazolyl, l,3-thiazol-2- yl, which can be substituted by chloro or methyl; when A, as indicated above, is a phenyl ring condensed with a 5-membered saturated or unsaturated heterocychc ring having one to three atoms selected from the group consisting of nitrogen and oxygen, such group is preferably l,3-benzodioxol-5-yl, or lH-l,2,3-benzotriazol-6-yl; when R2, as indicated above, is a methylene (-CH2-) bridge connecting the nitrogen atom to the ortho position of said aryl or heterocyclyl ring A, the formed group is a 1-isoindolinone, which is either unsubstituted or substituted by fluoro, chloro, bromo, C1-C4 linear alkyl, C C4 linear alkoxy, trifluoromethoxy or dimethylamino. The compounds of this invention contain a chiral center at the α-position of the hydroxamic or carboxylic acid, and as such they may be obtained as any of the two separate enantiomers or as a racemic mixture of both. Preferred compounds of this invention are either the racemates or individual isomers having the configuration depicted herebelow:
Figure imgf000006_0001
wherein X, Rl, R2 and A are as above defined.
The compounds of the present invention can be converted to pharmaceutically acceptable salts, where appropriate, according to conventional methods. The term 'pharmaceutically acceptable salts' refers to non toxic base or acid addition salts, according to the presence of an acid or basic group in the compounds of formula (I). A base addition salt, especially when X in formula (I) is hydroxy, can be a metal salt, such as sodium, potassium, calcium or magnesium, or an ammonium salt, or a salt with an appropriate organic amine or amino acid such as arginine, procaine and the like. An acid addition salt, especially when A in formula (I) is dimethylamino, pyrrolidino and piperidino, can be a hydrochloride, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citrate, 2-hydroxyethyl sulfonate, fumarate and the like. Any compound of formula (I) and salt thereof may be either in the anhydrous or hydrated form, or may be solvated with pharmaceutically acceptable solvents, such as ethanol.
The carboxylic acids of the present invention, i.e. the compounds of formula (I) wherein X is hydroxy, can also be administered, when convienent, as prodrugs, that is as esters with methanol or ethanol, or as other esters which can be cleaved in vivo to release the parent carboxylate, as generally known and described in the art for other carboxylic acid drugs. The present invention also provides pharmaceutical compositions which comprise, as active ingredient, a compound of formula (I) or a solvate, hydrate, or pharmaceutically acceptable salt thereof, or an ester prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient. Particularly preferred compounds of this invention include the following ones: 3-({4-[(lH-l ,2,3 -benzotriazol-6-ylcarbonyl)amino jphenyl} sulfonyl)-2-hydroxy-2- (phenoxymethyl)propanoic acid;
3-({4-[(4-cyanobenzoyl)amino]phenyl}sulfonyl)-2-hydroxy-2-(phenoxymethyl)- propanoic acid; 5 3-( {4-[(4-chlorobenzoyl)amino]phenyl} sulfonyl)-2-hydroxy-2-(phenoxymethyl)- propanoic acid; methyl 3-({4-[(4-chlorobenzoyl)amino]phenyl}sulfonyl)-2-hydroxy-2-(phenoxy- methyl)propanoate; ethyl 3-({4-[(4-chlorobenzoyl)amino]phenyl}sulfonyl)-2-hydroxy-2-(phenoxy- 0 methyl)propanoate;
(2R)-3-({4-[(4-chlorobenzoyl)amino]phenyl}sulfonyl)-2-hydroxy-2-[(phenyl- sulfanyl)methyl]propanoic acid;
3-({4-[(4-chlorobenzoyl)amino]phenyl}sulfonyl)-2-hydroxy-2-[(3,4,4-trimethyl- 2,5-dioxo- 1 -imidazolidinyl)methyl]propanoic acid; 5 2-[( {4-[(4-chlorobenzoyl)amino]phenyl} sulfonyl)methyl]-2-hydroxy-4-(3,4,4- trimethyl-2,5-dioxo- 1 -imidazolidinyl)butanoic acid; sodium 3-( {4-[(4-chlorobenzoyl)amino]phenyl} sulfonyl)-2-hydroxy-2-[(l ,3- thiazol-2-ylsulfanyl)methyl]propanoate; sodium 3-( {4-[(4-chlorobenzoyl)amino]phenyl} sulfonyl)-2-hydroxy-2-[(2- o pyridinyl-sulfanyl)methyl]propanoate;
3-({4-[(4-fluorobenzoyl)amino]phenyl}sulfonyl)-2-hydroxy-2-[(phenylsulfanyl)- methyl]propanoic acid;
2-hydroxy-3-{[4-(isonicotinoylamino)phenyl]sulfonyl}-2-[(phenylsulfanyl)methyl]- propanoic acid; 5 2-hydroxy-3- {[4-(isonicotinoylamino)phenyl]sulfonyl} -2-
(phenoxymethyl)propanoic acid;
2-hydroxy-3-({4-[(4-methoxybenzoyl)amino]phenyl}sulfonyl)-2-(phenoxymethyl)- propanoic acid;
3-( {4-[(l ,3-benzodioxol-5-ylcarbonyl)amino]phenyl} sulfonyl)-2-hydroxy-2- o (phenoxymethyl)propanoic acid; methyl 3-( {4-[(l ,3-benzodioxol-5-ylcarbonyl)amino]phenyl} sulfonyl)-2-hydroxy- 2-(phenoxymethyl)propanoate; ethyl 3-( {4-[(l ,3-benzodioxol-5-ylcarbonyl)amino]phenyl} sulfonyl)-2-hydroxy-2- (phenoxymethyl)propanoate;
3-({4-[(l,3-benzodioxol-5-ylcarbonyl)amino]phenyl}sulfonyl)-2-hydroxy-2- [(phenylsulfanyl)methyl]propanoic acid; 5 2-hydroxy-2-[( {4-[(4-methoxybenzoyl)amino]phenyl} sulfonyl)methyl]-4-(3,4,4- trimethyl-2,5-dioxo- 1 -imidazolidinyl)butanoic acid; sodium 3 - [(4- { [4-(dimethylamino)benzoyl] amino } phenyl)sulfonyl] -2-hydroxy-2- (phenoxymethyl)propanoate;
2-hydroxy-3 -phenoxy-2- { [(4- { [4-( 1 -pyrrolidinyl)benzoyl] amino } phenyl)sulfonyl] - 0 methyl}propanoic acid;
3-({4-[(4-fluorobenzoyl)amino]phenyl}sulfonyl)-2-hydroxy-2-(phenoxymethyl)- propanoic acid;
2-hydroxy-3-({4-[(4-methoxybenzoyl)amino]phenyl}sulfonyl)-2-[(phenylsulfanyl)- methyljpropanoic acid; 5 3-({4-[(4-fluorobenzoyl)amino]phenyl}sulfonyl)-2-hydroxy-2-{[(4- hydroxyphenyl)-sulfanyl]methyl}propanoic acid;
3-[(4-{[(6-chloro-3-pyridinyl)carbonyl]amino}phenyl)sulfonyl]-2-hydroxy-2- (phenoxymethyl)propanoic acid;
3-({4-[(4-bromobenzoyl)amino]phenyl}sulfonyl)-2-hydroxy-2-(phenoxymethyl)- o propanoic acid;
2-[({4-[(4-fluorobenzoyl)amino]phenyl}sulfonyl)methyl]-2-hydroxy-4-(3,4,4- trimethyl-2,5-dioxo- 1 -imidazolidinyl)butanoic acid;
3-({4-[(4-chlorobenzoyl)amino]phenyl}sulfonyl)-2-{[(4-fluorophenyl)sulfanyl]- methyl}-2-hydroxypropanoic acid; 5 3-({4-[(4-chlorobenzoyl)amino]phenyl}sulfonyl)-2-hydroxy-2-{[(4- hydroxyphenyl)-sulfanyl]methyl}propanoic acid;
3-{[4-(benzoylamino)phenyl]sulfonyl}-2-hydroxy-2-(phenoxymethyl)propanoic acid;
2-hydroxy-3-(phenylsulfanyl)-2-[({4-[(4-propoxybenzoyl)amino]phenyl}sulfonyl)- o methyljpropanoic acid;
2-hydroxy-3-(phenylsulfanyl)-2- {[(4- {[4- (trifluoromethoxy)benzoyl]amino}phenyl)-sulfonyl]methyl}propanoic acid; 2-hydroxy-3-(phenylsulfanyl)-2-{[(4-{[4-(trifluoromethyl)benzoyl]amino}phenyl)- sulfonyl]methyl}propanoic acid;
4-chloro-N-(4-{[2-hydroxy-3-(hydroxyamino)-3-oxo-2-(phenoxymethyl)propyl]- sulfonyl}phenyl)benzamide; N-(4-{[2-hydroxy-3-(hydroxyamino)-3-oxo-2-(phenoxymethyl)propyl]sulfonyl}- phenyl)- 1 ,3-benzodioxole-5-carboxamide;
2-hydroxy-3-([4-(l-oxo-l,3-dihydro-2H-isoindol-2-yl)phenyl)sulfonyl]-2- (phenoxymethyl)propanoic acid;
N,2-dihydroxy-3-([4-(l-oxo-l,3-dihydro-2H-isoindol-2-yl)phenyl)sulfonyl]-2- (phenoxymethyl)propanamide.
The compounds of this invention can be prepared in accordance to the process of Scheme 1, wherein Rl, R2, A are as defined above, and R is an alcohol residue such as C1-C4 linear or branched alkyl, optionally substituted benzyl or diphenylmethyl , or a carboxy protecting group known in the art, preferably benzyl, 4-nitrobenzyl, tert-butyl or diphenylmethyl. In Scheme 1, the sulfonyl propanoic acids (la) and their hydroxamic acid derivatives (lb) represent the compounds of formula (I) claimed by the present invention, wherein X is hydroxy and hydroxyamino, respectively.
According to one preferred procedure, a sulfonyl propanoic acid of formula (la) wherein R2 and A ar as defined above, and Rl is not -S-Ph or -S-Het as defined above, is obtained from the corresponding sulfanyl propanoic acid (1) by oxidation at sulfur, step a. Suitable oxidizing agents for such conversion are metachloroperbenzoic acid (MCPBA) in an inert organic solvent such as dichloromethane (DCM) at 0 °C or ambient temperature, or hydrogen peroxide in aqueous formic or acetic acid, or potassium peroxymonosulfate (oxone®) in an organic solvent such as methanol, DMF, N-methylpyrrolidone, or a mixture of organic solvents, or a mixture of water and a water-miscibile organic solvent, at ambient temperature or under moderate heating. On a small or medium scale, a preferred condition is oxone in DMF, or in a mixture of DMF and methanol, at 40 to 70 °C. On a larger scale, a preferred condition is hydrogen peroxide in aqueous formic acid, from 0 °C to room temperature. Scheme 1
Figure imgf000010_0001
Alternatively, a sulfonyl propanoic acid (la) is obtained by hydrolysis of an ester of formula (la'), wherein R, Rl, R2 and A are as defined above. Conditins for ester hydrolysis, step b, are those generally known in the art. Thus, for example, when R is - C4 linear alkyl, a preferred condition is alkaline hydrolysis, for example with aqueous NaOH in ethanol; when R is benzyl or 4-nitrobenzyl, a preferred condition is hydrogenolysis, especially in the presence of a palladium catalyst such as Pd on charcoal, in an inert organic solvent such as ethanol or DMF or the like, typically at room temperature and under atmospheric pressure or moderate pressure; when R is 4- nitrobenzyl, another preferred condition is treatment with Zn powder in the presence of acetic acid, which is carried out in an inert organic solvent such as DMF, THF, MeCN, acetone or the like; when R is tert-butyl or diphenylmethyl, a preferred condition is treatment with trifluoroacetic acid in an organic solvent, to which anisole or water may be added. The sulfonyl propanoic esters of formula (la') wherein R, R2 and A ar as defined above, and Rl is either -O-Ph or -Hyd or -CH2-Hyd as defined above, can be obtained from the corresponding sulfanyl propanoic esters (la) by oxidation at sulfur, step a', under the same conditions described above for the corresponding acids of formula (la), step a. Said sulfanyl propionic esters (la) can be obtained from the propanoic acids (1) under the general conditions known in the art for acid to ester conversion, or may be prepared as shown in the Scheme 2 below.
According to another procedure, a sulfonyl propanoic ester of formula (la') wherein R, R2 and A ar as defined above, and Rl is either -O-Ph, -S-Ph or -S-Het as defined above, can be obtained from a diol of formula (2), wherein R, R2 and A are as defined above, by derivatization of its primary hydroxyl into an ether or thioether, step c. Such derivatization entails activation as a mesylate, triflate or tosylate, followed by displacement with a phenol of formula Ph-OH, or a thiol of formula Ph-SH or Het-SH, in the presence of a strong base, preferably sodium hydride, in an aprotic organic solvent, preferably DMF. A preferred activated derivative of said carbinol of formula (2) is the mesylate, which is preferably obtained by reaction with mesyl chloride and a base in an inert organic solvent. A suitable base is, for example, triethylamine, and a suitable solvent is dichloromethane (DCM). Another preferred base is pyridine, which can be used neat also as the solvent. Alternatively, a compound of formula (la') wherein Rl is -S-Ph can be conveniently obtained from a diol of formula (2) by reaction with a disulfide Ph-S-S-Ph in the presence of a phosphine, preferably tributylphosphine (Hata reaction), in an inert organic solvent such as dioxane, preferably under heating or reflux condition to expedit the reaction. The compounds of formula (la')
Figure imgf000011_0001
wherein Rl, R2, A are as defined above, and R is C1-C4 alkyl, especially ethyl or methyl, are useful prodrugs of the carboxylic acids (la) because readily hydrolyzed in vivo, and are comprised within the scope of the present invention. When convenient, such prodrugs of formula (la') can also be obtained from the acids (la) by esterification. Other prodrugs comprised by the present invention are double ester prodrugs, that is compounds of formula (la') wherein Rl, R2, A are as defined above, and R is acyloxy-methyl such as acetyloxymethyl and benzoyloxymethyl, or l-(acyloxy)ethyl such as 1-acetyloxyethyl, or ethoxycarbonyloxyrnethyl, or l-(ethoxycarbonyloxy)ethyl, or (2-oxo-l,3-dioxolen-4- yl)methyl. These double ester prodrugs are preferably obtained by esterification of the corresponding acids of formula (la), according to procedures well known in the art. Compounds of formula (I) wherein Rl, R2, A are as defined above, and X is -NHOH, represented by structure (lb) in Scheme 1, can be obtained from the corresponding carboxylic acids of formula (la) by activation and coupling with hydroxylamine, or, preferably, with an O-protected hydroxylamine, followed by removal of the protecting group, step e. Activation of the acid can be performed by several routes well known in the art, including the general art of peptide synthesis. For example, the acid can be activated as its chloride or a mixed anhydride. A preferred method for activation as the acid chloride is reaction with oxalyl chloride, typically in DCM containing DMF as a catalyst, at 0 °C to ambient temperature. A preferred method for activation as a mixed anhydride is reaction with a chlorocarbonate such as chloroethylformate in dry THF or a similar compatible solvent, in the presence of a tertiary amine such as TEA. Alternatively, the acid can be activated by a carbodiimide condensing agent such as dicyclohexylcarbodiimide (DCC) or l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSCDI, water soluble carbodiimide), preferably in the presence of 1-hydroxybenzotriazole (HOBt) in an inert organic solvent such as DMF at 0 °C to room temperature. Another method for the activation of a carboxylic acid of formula (la) is reaction with benzotriazolyl-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) in a suitable organic solvent such as MeCN, THF or DCM in the presence of a tertiary amine such as TEA or NMM. A further method is reaction with O-benzotriazolyl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or O-benzotriazolyl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), under conditions similar to those described for the BOP reagent. When the activation is performed with oxalyl chloride, the acid chloride is usually isolated crude before reaction with the hydroxylamine reagent; when with chloroethylformate, EDC or WSCDI, the hydroxylamine reagent is preferably added after about 1 hour at room temperature; when with the BOP reagent, HBTU or TBTU, the hydroxylamine reagent is preferably protected as O-(benzyl)hydroxylamine, O-(tert-butyl)hydroxylamine, O- (tetrahydropyranyl)hydroxylamine, or N,O-bisO-(trimethylsilyl)hydroxylamine. Removal of protecting groups is performed by methods known in the art. For example, the benzyl group is removed under reductive conditions, preferably with hydrogen and a metal catalyst such as Pd on charcoal, Pd on BaSO , or palladium hydroxide on carbon (Pearlman's catalyst), typically in methanol or ethanol; the tert-butyl group is removed by treatment with neat or aqueous trifluoroacetic acid, or with HC1 in DCM; the tetrahydropyranyl group is removed by reaction with 4N aqueous HC1 in suitable organic solvents or mixtures thereof, e.g. dioxane and methanol. According to another procedure, the hydroxamic acids of formula (lb) are obtained from the carboxylic esters of formula (la'), wherein Rl, R2 and A are as defined above, and R, being ad defined above, is preferably methyl. This reaction is carried out with hydroxylamine in an inert organic solvent, such as methanol, THF and the like, usually in the presence of water, at room temperature or under moderate heating. When the hydroxylamine reagent is the corresponding hydrochloride, hydroxylamine is conveniently generated in situ by addition of aqueous NaOH. Alternatively, the reaction can be carried out with an O-protected hydroxylamine, such as benzyl hydroxylamine, tert-butyl hydroxylamine or tetrahydropyranyl hydroxylamine, in which case the protecting group is removed after the exchange reaction, as described above. The sulfanyl propanoic acids of formula (1), and esters thereof (la), reported in Scheme 1 as intermediates in the preparation of the final sulfonyl propanoic acids (la), prodrugs thereof (la'), and of the final sulfonyl propanoic hydroxamic acids (lb), can be obtained as outlined in Scheme 2.
Figure imgf000014_0001
According to Scheme 2, a sulfanyl carboxylic acid of formula (1) wherein R2 and A are as defined above, and Rl is either -O-Ph, -Hyd or -CH -Hyd as defined above, can be obtained by hydrolysis of a corresponding ester of formula (la), wherein R is as stated before, step 1. Preferred groups which R may represent are - linear alkyl, still preferably methyl or ethyl, benzyl, 4-nitrobenzyl, tert-butyl or diphenylmethyl. Ester hydrolysis is carried out under conventional conditions stated in the general art, as exemplified before for the hydrolysis of a compound (la') to a compound (la), step b in Scheme 1.
In turn, a compound of formula (la), wherein R, R2 and A are as defined above, and Rl is either -O-Ph, -Hyd or -CH2-Hyd as defined above, can be obtained from a diol of formula (6), by activation as a mesylate, triflate or tosylate, followed by displacement with a para- substituted thiophenol of formula HS-C6H -N(R2)-C(=O)A, wherein R2 and A are as above defined, step j. A preferred activated derivative of said diol of formula (6) is the mesylate, which is preferably obtained by reaction with mesyl chloride and a base, for example triethylamine or pyridine, in an inert organic solvent, for example DCM. The displacement reaction is carried out in the presence of a strong base, such as sodium methoxide, DBU, or preferably sodium hydride, in an aprotic organic solvent, preferably DMF. Alternatively, a 4-aminothiophenol protected at the amino group is used in the displacement reaction, followed by unmasking of the amino group and acylation with an activated derivative of a carboxylic acid of formula A-COOH, wherein A is as defined above. A preferred a 4-aminothiophenol protected at the amino group is 4- trifluoroacetamido-thiophenol. A preferred condition for unmasking the amino group after the displacement reaction, which has the merit of leaving the ester moiety of (6) unaffected, is refluxing in methanol in the presence of triethylamine. A preferred activated derivative of a carboxylic acid of formula A-COOH is the acyl chloride, which is obtained by conventional procedures, for example by reaction with oxalyl chloride or thionyl chloride, and is reacted with the amine under conventional conditions, that is in an inert oranic solvent such as DCM in the presence of a base, for example triethylamine. Alternatively, a compound of formula (la), wherein R, R2 and A are as defined above, and Rl is -O-Ph as defined above, can be obtained from the corresponding epoxide of formula (7) by reaction with a para-substituted thiophenol of formula HS-C6H4-N(R2)-C(=O)A, wherein R2 and A are as above defined, step k. This reaction is performed in an inert organic solvent, preferably DMF, in the presence of a base such as sodium methoxide, DBU or potassium carbonate. Alternatively, a 4-aminothiophenol protected at the amino group can be used as the reagent, especially 4-trifluoroacetamidothiophenol, followed by unmasking of the amino group and acylation with an activated derivative of a carboxylic acid of formula A-COOH, as described above.
A diol of formula (6) wherein Rl is either -O-Ph, -Hyd or -CH2-Hyd as defined above, and R is as defined above, can be obtained by dihydroxylation of the corresponding acrylic ester of formula (5) wherein R' is R, step h, or of the corresponding acrylic acid of formula (5) wherein R' is hydrogen followed by alkylation with a halide of formula R-X, as defined above, for example methyl iodide or ethyl bromide. Suitable oxidizing agents are osmium tetraoxide or permanganate salts. More preferably, osmium tetraoxide is used in a catalytic amount, in the presence of 1 - 1.5 molar equivalents of N-methylmorpholine N-oxide (NMMNO). Under a preferred condition, the osmium reagent is used as a solution in tert- butanol, and aqueous acetone or aqueous tert-butanol are used as co-solvents, preferably around room temperature. An epoxide of formula (7) wherein Rl is -O-Ph and R is as defined above can be obtained from the corresponding acrylic ester of formula (5) wherein R' is R, step i. Suitable conditions for such reaction is treatment with aqueous sodium hypochlorite in DMF under stirring with silica gel. A substituted acrylic acid derivative of formula (5) wherein Rl is -O-Ph or -Hyd as defined above, and R' is either hydrogen or R as defined above, can be obtained from (bromomethyl)acrylic acid or an ester thereof, that is a compound of formula (3) wherein R' is either hydrogen or R, as defined above, by reaction with a phenol of formula Ph-OH, wherein Ph is as defined above, or with l,5,5-trimethyl-l,4-imidazolidinedione in the presence of a strong base or, preferably, by reaction of the preformed salts of said phenol or imidazolidinedione with said bases, step f. Still preferably, displacement is carried out starting from (bromomethyl)acrylic acid, which is commercially available, and the obtained compound of formula (5) wherein R' is hydrogen is then converted to an ester thereof, that is a compound (5) wherein R' is R, as defined above. For example, the substituted acrylate of formula (5) wherein Rl is -O-Ph and R' is methyl can be obtained from (bromomethyl)acrylic acid by reaction with Ph-OH in DMF at about 75 °C, in the presence of NaOH, followed by alkylation with methyl iodide in DMF in the presence of K2CO . Similarly, the substituted acrylate of formula (5) wherein Rl is -Hyd as above defined, and R' is 4-nitrobenzyl, can be obtained from (bromomethyl)acrylic acid by reaction with l,5,5-trimethyl-2,4-imidazolidinedione in DMF at about 70 °C, in the presence of NaHCO3, followed by reaction with 4-nitrobenzyl bromide in DMF at room temperature in the presence of K2CO3, CsCO3 and the like.
A substituted acrylic acid derivative of formula (5) wherein Rl is -CH2-Hyd as defined above, and R is as defined above, can be obtained from a substituted malonic ester derivative of formula (4) by hydrolysis of one or both the ester groups, followed by alkenylation with formaldehyde, para-formaldehyde and the like, under the standard Mannich conditions, step g. hi turn, said malonic ester derivative of formula (4) wherein Rl is -CH -Hyd as defined above can be obtained by alkylation of an ester of malonic acid, preferably diethyl or dimethyl malonate, with a halide of formula Hyd-CH2-CH -X, wherein X is bromo, chloro, or iodo, under standard conditions.
The sulfonyl propanoic ester derivatives of formula (2), reported in Scheme 1 as intermediates in the preparation of the final sulfonyl propanoic acids (la), prodrugs thereof (la'), and of the final sulfonyl propanoic hydroxamic acids (lb), can be obtained as outlined in Scheme 3.
Scheme 3
step n
Figure imgf000017_0001
Figure imgf000017_0002
Thus, a compound of formula (2), wherein R, R2 and A are as defined above, can be obtained from the corresponding alkene of formula (9), wherein R' is R, by dihydroxylation, step o, under the same conditions described in step h, Scheme 2, for the conversion of an acrylate of formula (5) into a diol of formula (6); preferably, by reaction with N-methylmorpholine N-oxide (TSfMMNO) in a suitable solvent, such as aqueous acetone, in the presence of a catalytic amount of a solution of osmium tetraoxide in tert- butanol. Alternatively, the dihydroxylation can be performed on the acrylic acid of formula (9), wherein R2 and A are as above defined, and R' is hydrogen, and the obtained diol acid is conventionally esterified to give the desired diol ester of formula (2). In turn, an acrylic sulfone of formula (9), wherein R2 and A are as defined above, and R' is either hydrogen or R as defined above, can be obtained by oxidation of the corresponding sulfide of formula (8), step n. Suitable conditions for said oxidation are the same reported in step a, Scheme 1, for the conversion of a compound of formula (1) to a compound of formula (la), or of a compound of formula (la) to a compound of formula (la'); preferably, potassium peroxymonosulfate (oxone®) in an organic solvent such as methanol, DMF, N- methylpyrrolidone, or a mixture of organic solvents, or a mixture of water and a water- miscibile organic solvent, or hydrogen peroxide in aqueous formic or acetic acid. In turn, an acrylic sulfide of formula (8), wherein R2 and A are as defined above, and R' is either hydrogen or R as defined above, can be obtained from a compound of formula (3), that is (bromomethyl)acrylic acid or an ester thereof, by reaction with a para-substituted thiophenol of formula HS-C6H4-N(R2)-C(=O)A, wherein R2 and A are as above defined, 5 step m. Such reaction is carried out in a compatible organic solvent, such as DMF, MeCN, toluene, THF, acetone, dichloromethane and the like, at temperatures ranging from about 0 °C to reflux temperature, preferably from room temperature to 50 °C, in the absence or presence of a suitable base such as sodium carbonate, sodium bicarbonate, cesium carbonate or triethylamine. A particularly preferred condition is DMF, 40 °C, in the i o absence of external bases .
The thiols of formula HS-C6H4-NR2-C(=O)-A are known compounds, or can be obtained from known compounds according to general procedures well known in the art. For example, a disulfide of formula A-C(=O)-NH-C6H4-S-S-C6H4-NH-C(=O)-A can be obtained by acylation of commercial 4-[(4-aminophenyl)disulfanyl]phenylamine with an
15 acid chloride of formula A-C(=:O)-Cl, wherein A is as defined above, under conventional conditions, such as at room temperature in DCM and in the presence of triethylamine. Alkylation of said disulfide with methyl iodide in DMF in the presence of sodium hydride affords correspondinding disulfides of formula A-C(=O)-NR2-C6H -S-S-C6H -NR2- C(=O)-A wherein R2 is methyl. Reduction of said disulfides of formula A-C(=O)-NR2-
2 o CeHt-S-S-Cό^-NI^Z-C^O^A wherein R2 is either hydrogen or methyl affords the desired thiol reagents of formula HS-C6H4-NR2-C(=O)-A. A preferred conditions for said reduction is treatment at room temperature with Zn powder in the presence of diluted HC1 in a water-miscible organic solvent, such as acetone, THF or MeCN. When convenient, chemical modifications of the groups R', Rl, R2 or A in intermediates 25 (9), (8), (2), (1) or (la') can be performed in the above process. These include protection and deprotection of carboxylates, protection and deprotection of functional groups which may be present in the residues Rl or A, and conversion of any such intermediate wherein R2 is hydrogen to one wherein R2 is methyl. These chemical modifications are performed according to general procedures well known to those skilled in the art.
30 A compound of the present invention can be formulated both as the racemate or as the bioactive resolved enantiomer, as specified above. Chiral resolution from a racemic mixture can be performed on the final compounds of formula (I), such as those represented by formula (la) and (lb) in Scheme 1, or on the final prodrugs or ester derivatives of formula (la'), or on intermediates of formula (7), (2), (la) or (1), by conventional methods known in the art, such as preparative chiral HPLC. Alternatively, the racemic carboxylic acids of formula (I) wherein X is hydroxy, as well as said intermediates of formula (1), or 5 the racemic carboxylic acids obtained fron hydrolysis of the esters of formula (6), can be resolved by chiral salt formation, using a chiral base such as (+) or (-)-l-phenylethylamine, (+) or (-)-ephedrine, and the like. By another method, enzymatic hydrolysis of racemic ester intermediates of formula (6), (2) or (la) can be used to obtain the corresponding chiral acids. By a still another procedure, a chiral ester residue R, such as menthyl, can be 0 selected in the preparation of intermediates (7), (6), (2) or (la), giving rise to diastereomeric mixtures, which can be separated by conventional techniques such as fractional crystallization or chromatography. Some ester prodrugs of the racemates of formula (I) wherein X is hydroxy, for example the 1-acetyloxyethyl and 1- (ethoxycarbonyloxy)ethyl esters, are diastereomeric compounds, and as such they can be 5 separated to give ester prodrugs of the single bioactive enantiomer.
The present invention further provides a compound of formula (I) as defined above for use in a method of treatment or prophylaxis of a disease mediated in a mammal by gelatinases, especially gelatinase-A (MMP-2), such as tumor growth and metastasis, and other diseases where neo-angiogenesis mediated by gelatinases plays a significant contribution, such as o macular degeneration. The compounds of the present invention are typically administered in the form of pharmaceutical compositions, which can be prepared by combining the compounds of formula (I) or salts or hydrates or solvates thereof with a solid or liquid pharmaceutically acceptable carrier, and, optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques, hi particular, the 5 compounds of formula (I) can be administered: a) orally, for example, as tablets, coated tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions o may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, maize starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is present as such, or mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone gum tragacanth and gum acacia; dispersing or wetting agents may be naturally-occurring phosphatides, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The said aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, or one or more sweetening agents, such as sucrose or saccharin. Oily suspension may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oils, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, nalj rally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan mono-oleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents; b) parenterally, either subcutaneously, or intravenously, or intramuscularly, or intrasternally, or by infusion techniques, in the form of sterile injectable aqueous or oleaginous suspensions. This suspension may be formulated according to the known art using those suitable dispersing of wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition fatty acids such as oleic acid find use in the preparation of injectables; c) topically, in the form of creams, ointments, jellies, plasters, collyriums, solutions or suspensions, and transdermal patches; d) rectally, in the form of suppositories prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the particular mode of admnistration, the mammalian host treated and his conditions.
Daily dosages can vary within wide limits and will be adjusted to the individual requirements in each particular case. As a rule of thumb, a compound of formula (I) is advantageously administered at a dosage and frequency to achieve and maintain, for the whole period of therapy, a blood level in free drug (i.e., not bound to plasma proteins) ranging from about 1 to about 100 times its Ki against the most relevant MMP for the particular disease state, e.g. MMP-2 for cancer. Thus, the daily dose may be divided into multiple doses for administration, e.g. two to four times per day. In case of prolonged plasma levels, the drug can be administered daily, or at alternate days. Generally, an amount of the active compound effective in adult patients will be in the range of 10 to about 500 mg, but it is to be understood that such range may be exceeded depending on the particular compound being used, the severity of the disease being treated, and the requirement of the patient. The compounds of the present invention differ from compounds of the previous art for their enhanced selectivity for MMP-2. This enhanced selectivity is found both with compounds of formula (I) wherein X is hydroxy and the corresponding compounds wherein X is hydroxyamino. general, the compounds of formula (I) wherein X is hydroxy display single-digit nM Ki's against MMP-2, sometimes below nanomolar when tested as the bioactive enantiomers. By contrast, they are almost inactive against MMP-1 (interstitial collagenase), in general having Ki's in the 0.2 -2 mM range. Remarkably, and at variance with other "MMP-1 sparing" inhibitors of the previous art, their potency against other MMPs sharing with MMP-2 an elongated specificity pocket is unexpectedly low, either in absolute terms (e.g., against MMP-3, typical Ki's being in the microM range) or in relative terms (e.g., against MMP-13 and MMP-14, typical Ki's being in the 50 -500 nM range). Compounds of formula (I) wherein X is hydroxyamino are low-picoM inhibitors of MMP-2, comparable to the most potent compounds of the previous art, e.g. Agouron AG-3340. However, their Ki's against MMP-1 are typically in the microM range, while that of this comparator is 6.7 nM in the same assay. Further, the unexpected MMP-2 selectivity in comparison with MMP-3, MMP-13 and MMP-14, proper of compounds (I) wherein X is hydroxy, is retained in compounds (I) wherein X is hydroxyamino. Still further, the compounds of the present invention are inactive against TNF-α convertase. By virtue of this unexpected selectivity for MMP-2, the compounds of the present invention are much less amenable to side-effects than other MMP inhibitors of the previous art, including the so-called musculoskeletal syndrome which has been observed with the less selective inhibitors tested to date in cancer patients. Finally, the compounds of the present invention are in general less bound to plasma proteins than other compounds of the previous art displaying remarkable selectivity for MMP-2, for example Bayer BAY 12-97566. The compounds of the present invention and their preparation will be better understood in connection with the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention. EXPERTMENTAL PART Example 1 2-[{4-[(4-Chlorobenzoyl)amino]phenyl}sulfonyI)methyl]-2-hydroxy-4-(3,4,4-trimethyl- hydantoin-l-yl)butanoic acid
Step 1): l-(2-Bromoethyl)-3,4,4-trimethylhydantoin
Sodium hydride (60% dispersion in mineral oil, 8.5 g) was added to a stirred solution of 3,4,4-trimethylhydantoin (27.5 g) in DMF (150 ml) at room temperature. After 30' of stirring, a solution of 1, 2-dibromoethane (20 ml) in DMF 850 ml) was slowly cannuled and the resulting suspension was stirred for 10 h. The mixture was diluted with ethyl acetate and thoroughly washed with brine. After drying, the solvent was removed and the residue was filtered on a small pad of silica gel eluting with cyclohexane/ethyl acetate 4/1, to furnish l-(2- bromoethyl)-3,4,4-trimethylhydantoin (35 g, yield 73%) as an oil. Step 2): Diethyl [2-(3,4,4-trimethylhydantoin-l-yl)ethyl]malonate To a stirred suspension of sodium hydride (60% dispersion in mineral oil, 6.5 g) in DMF (75 ml) was added dropwise a solution of diethyl malonate (29 ml) in DMF (50 ml) at room temperature. After 30', a solution of l-(2-bromoemyl)-3,4,4-1rimethylhydantoin (15 g) in DMF (ml 50) was slowly cannuled and the resulting solution was heated at 65°C for 3 h. The solvent was removed and the oily residue taken up in ethyl acetate was washed with 20% citric acid solution, then with brine and dried. The solvent was removed and the residue was chromatographed on silica gel eluting with ethyl acetate/cyclohexane 3/1 to provide diethyl [2-(3,4,4-trimethylhydantoin-l-yl)ethyl]malonate (16.6 g, yield 84%) as an oil. Step 3): Ethyl [2-(3,4,4-trimethylhydantoin-l-yl)ethyl]malonate
To a stirred solution of diethyl [2-(3,4,4-trimethylhydantoin-l-yl)ethyl]malonate (16.6 g) in ethanol (100 ml) was added dropwise 2 M NaOH (25.3 ml) at 0°C. After stirring at 0°C for 30', the solution was set aside at room temperature fo 3 h, then the solvent was removed and the residue was taken up in ethyl acetate and acidified with 2 M HC1 to pH= 2. After washing with brine and drying, the solvent was removed to provide ethyl [2-(3,4,4- 1rimethylhydantoin-l-yl)ethyl]malonate practically pure (13.4 g, yield 88%), as a foam. Step 4): 2-Methylen-4-(3,4,4-trimethylhydantoin-l-yl)butanoic acid ethyl ester Piperidine (5.2 ml) was added to a stirred solution of ethyl [2-(3,4,4-trimethylhydantoin-l- yl)ethyl]malonate (13.4 g) in dioxane (200 ml) at room temperature. After 30', formaldehyde (37%) solution in water, 22 ml) was added and the stirring was continued for 2 h at room temperature before heating at 80°C for 2 h. The solution was cooled, the solvent removed and the residue partitioned between ethyl acetate and brine. Drying and removal of the solvent afforded pure 2-methylen-4-(3,4,4-trimethylhydantoin-l-yl)butanoic acid ethyl ester (11.2 g, yield 80%) as an oil.
Step 5): l-Hydroxy-l-hydroxymethyl-4-(3,4,4-trimethylhydantoin-l-yl)butanoic acid ethyl ester
To a stirred solution of 2-methylen-4-(3,4,4-trimethylhydantoin-l-yl)butanoic acid ethyl ester
(11.2 g) in acetone (100 ml), tert-butanol (15 ml) and water (15 ml) was added consecutively N-methylmorpholine-N-oxide (6.5 g) and osmium tetroxide (0.020 g) at room temperature.
After stirring overnight, the reaction mixture was treated with a solution of sodium pirosulfite (5 g) in water (25 ml). The black suspension was filtered on celite and the solvent was removed. The residue was thoroughly partitioned between chloroform and brine. Drying, removal of the solvent afforded, after crystallization from diethylether, 1 -hydroxy- 1- hydroxymethyl-4-(3,4,4-trimethylhydantoin-l-yl)butanoic acid ethyl ester (10.5 g, yield 83%), mp 78-81°C.
Step 6) : 2- [(4-Trifluoroacetylaminophenylsulfanyl)methyl] -2-hydroxy-4-(3,4,4-trimethyl- hydantoin-l-yι)butanoic acid ethyl ester A stirred solution of 1 -hydroxy- l-hydroxymethyl-4-(3,4,4-trimethylhydantoin-l-yl)butanoic acid ethyl ester 811.7 g), tri(n-butyl)phosρhine and bis-(4-trifluoroacetylaminophenyl)- disulfide was refluxed at 120°C for 30'. The solvent was removed and the oily residue was chromatographed on silica gel eluting with cyclohexane/ethyl acetate 3/1 to provide 2-[(4- trifluoroacetylaminophenylsulfanyl)methyl] -2-hydroxy-4-(3 ,4,4-trimethylhydantoin- 1 -yl)- butanoic acid ethyl ester (12.3 g, yield 62%>) as a foam.
Step 7): 2-[(4-anjdnophenylsulfonyl)methyl]-2-hydroxy-4-(3,4,4-trimethylhydantoin-l-yl)- butanoic acid ethyl ester
A stirred solution of 2-[(4-trifluoroacetylaminophenylsulfanyl)methyl]-2-hydroxy-4-(3,4,4- trimethylhydantoin-l-yl)butanoic acid ethyl ester (13 g) in DMF (100 ml) was treated portionwise with oxone (35 g) at 45 °C. After stirring for 5 h, the suspension was diluted with ethyl acetate and washed with water, then brine and finally dried. Removal of the solvent and crystallization from a small volume of ethanol afforded 2-[4-(trifluoroace1ylaminophenyl- sulfonyl)methyl]-2-hydroxy-4-(3 ,4,4-trimethylhydantoin- l-yl)butanoic acid ethyl ester (12 g, yield 87%), mp 134-137°C.
Step 8) : 2- [(4-aminophenylsulfonyl)methyl] -2-hydroxy-4-(3 ,4,4-trimethylhydantoin- 1 -yl)- butanoic acid ethyl ester A stirred solution of 2- [(4-trifluoroacetylaminophenylsulfonyl)methyl]-2-hydroxy-4-(3 ,4,4- trimethylhydantoin- l-yl)butanoic acid ethyl ester (12 g) in methanol (100 ml) and TEA (50 ml) was refluxed at 100°C overnight. The solvent was removed and the residue was twice crystallized from isopropanol to give 2-[(4-aminophenylsulfonyl)methyl]-2-hydroxy-4-(3,4,4- trimethylhydantoin-l-yl)butanoic acid ethyl ester (7.9 g, yield 83%o), mp 78-93°C. Step 9): 2-[{4-[(4-Chlorobenzoyl)amino]phenyl}sulfonyl)methyl]-2-hydroxy-4-(3,4,4- 1ximethylhydaιιtoin-l-yl)butanoic acid ethyl ester
A stirred solution of 2-[{4-[(4-amino)phenyl}sulfonylmethyl]-2-hydroxy-4-(3 ,4,4- trimethylhydantoin- l-yl)butanoic acid ethyl ester (0.75 g) in pyridine (10 ml) was treated with 4-chlorobenzoylchloride (0.25 ml) at room temperature. After 3 h, 2 M solution of NaHCO3 (5 ml) were added and the cloudy solution was set aside for 3 h. The reaction mixture was diluted with ethyl acetate and thoroughly partitioned with 2 M HC1. After washing with 2 M NaHCO3, brine and dried, the solvent was removed to give 2-[{4-[(4- cMorobenzoyl)ammo]-phenyl}sulfonyl)me1hyl]-2-hydroxy-4-(3,4,4-trimethyj^ydantom-l- yl)butanoic acid ethyl ester (0.7 g, yield 70%), mp 121-125°C. Step 10): A stirred solution of 2-[{4-[(4-chlorobenzoyl)amino]phenyl}sulfonyl)methyl]-2- hydroxy-4-(3 ,4,4-trimethylhydantoin- l-yl)butanoic acid ethyl ester (0.5 g) in methanol (25 ml) and 1 M NaOH (2 ml) was set aside at room temperature for 5 h.. The cloudy suspension was acidified to pH 2 with 2 N HCl, diluted with ethyl acetate and thoroughly partitioned with brine. The solvent was removed and the residue was crystallized from ethanol to provide the title compound (0.38 g, yield 80%), >100°C decomp. Example 2
2-[{4-[(4-Fluorobenzoyl)amino]phenyl}sulfonyl)methyl]-2-hydroxy-4-(3,4,4-trimethyl- hydantoin-l-yl)butanoic acid
Operating as in Example 1 step 9, 10, but employing 4-fluorobenzoylchloride instead of 4- chlorobenzoyl chloride, the title compound was obtained in overall 63% yield, >100°C decomp.
Example 3
2-[{4-[(4-Methoxybenzoyl)amino]phenyl}suIfonyl)methyl]-2-hydroxy-4-(3,4,4- trimethyl-hydantoin-l-yl)butanoic acid
Operating as in Example 1 step 9, 10, but employing 4-methoxybenzoylchloride instead of 4- chlorobenzoyl chloride, the title compound was obtained in overall 63% yield, >100°C decomp.
Example 4
2-Hydroxy-2-[(phenylsulfanyl)methyl]-3-[{4-[(4- chlorobenzoyl)amino]phenyl} sulfonyl]-propanoic acid
Step 1): 2-[(4-trifluoroacetylaminophenylsulfanyl)methyl]acrylic acid A stirred solution of 2-bromomethylacrylic acid (12 g) and 4- (trifluoroacetylamino)benzenthiol (14.6 g) in DMF (100 ml) was heated 45°C for 4 h. The reaction mixture was diluted with ethyl acetate and washed with brine. After drying and removal of the solvent, the residue was crystallized from ethyl ether to provide 2-[(4- trifluoroacetylaminophenylsulfanyl)methyl]-acrylic acid (18 g, yield 89%), mp 156-158°C°. Step 2): 2-[(4-trifluoroacetylaminophenylsulfonyl)methyl]acrylic acid
A stirred suspension of 2- [(4-trifluoroacetylaminophenylsulfanyl)methyl] acrylic acid (22 g) and oxone (110 g) in DMF (300 ml) was heated 60°C for 2 h. The reaction mixture was diluted with ethyl acetate and washed with 2 M Na2S2O5 solution then with brine. After drying and removal of the solvent, the residue was crystallized from isopropanol to provide 2-[(4-trifluoroacetylaminophenylsulfonyl)methyl]acrylic acid (19 g, yield 86%), mp 240- 242°C.
Step 3): 2-[(4-trifluoroacetylaminophenylsulfonyl)methyl]acrylic acid methyl ester To a stirred solution of 2-[(4-trifluoroacetylaminophenylsulfonyl)methyl]acrylic acid (61 g) and 12 M NaOH (16 ml) in DMF (250 ml) was added methyl iodide (40 ml) at room temperature. After stirring overnight, the solvent was removed and the residue taken up in ethyl acetate was thoroughly washed with brine and dried. Concentration at small volume afforded 2-[(4-trifluoroacetylaminophenylsulfonyl)methyl]acrylic acid methyl ester (54 g, yield 83), mp 168-169°C. Step 4) : 2-Hydroxy-2-hydroxymethyl-3 - [(4-trifluoroacetylaminophenylsulfonyl)methyl] - propio ic acid methyl ester
To a stirred solution of 2- [(4-trifluoroacetylaminophenylsulfonyl)methyl] acrylic acid methyl ester (54 g) and N-methylmorpholine-N-oxide (23 g) in acetone (400 ml), tert-butanol (80 ml) and water (50 ml) was added osmium tetroxide (0.025 g). After stirring overnight at room temperature, 2 M Na2S2O5 (50 ml) were added, then the black suspension was filtered on celite and the solvent was removed. The residue was partitioned between ethylacetate and brine. After drying and removal of the solvent, crystallization from ethyl ether afforded 2- hydroxy-2-hydroxymethyl-3-(4-trifluoroacetylaminophenylsulfonyl)propionic acid methyl ester (53 g, yield 89%), mp 141-143°C.
Step 5) : 2-Hydroxy-2-methansolfonyloxymethyl-3-(4-trifluoroacetylarninophenylsulfonyl)- propionic acid methyl ester 5 To a stirred solution of 2-hydroxy-2-hydroxymethyl-3-(4- trifluoroacetylaminophenylsulfonyl)- propionic acid methyl ester (15 g) in pyridine was added dropwise methansolfonylchloride (3.5 ml) at 5°C. After stirring overnight at room temperature, ethyl acetate was added and the cloudy solution was washed with 5 M HCl, then with 1 M NaHCO3 and brine. Drying and removal of the solvent gave, after crystallization 0 from ethyl ether, 2-hydroxy-2-methansolfonyloxymethyl-3-(4- trifluoroacetylaminophenylsulfonyl)propionic acid methyl ester (15.5 g, yield 86%), mp 141- 43°C.
Step 6) : 2-Hy(tooxy-2-(phenylsulfanyl)methyl-3-(4-trifluoroacetylaminophenylsulfonyl)- propionic acid methyl ester 5 To a stirred solution of benzenthiol (15 g) in DMF (300 ml) was added portionwise 60% NaH (5 g) at 5°C. After 1 h of stirring at room temperature, 2-hydroxy-2- methansolfonyloxymethyl-3 -(4-trifluoroacetylaminophenylsulfonyl)propionic acid methyl ester (50 g) was added and the reaction mixture was set aside for 15 h. The solvent was removed and the residue taken up in ethyl acetate was thoroughly washed with brine. After o drying and removal of the solvent, the residue was filtered on a small pad of sihca gel eluting with cyclohexane/ethyl acetate 5/3 to afford 2-hydroxy-2-(phenylsulfanyl)methyl-3-(4- trifluoroacetylaminophenylsulfonyl)propionic acid methyl ester (39 g, yield 76%), mp 166- 168°C.
Step 7): 2-Hydroxy-2-(phenylsulfanyl)memyl-3-(4-an inophenylsulfonyl)propionic acid 5 methyl ester
A stirred solution of 2-hydroxy-2-(phenylsulfanyl)memyl-3-(4-trifluoroacetylaminophenyl- sulfonyl)propionic acid methyl ester (30 g) in methanol 250 ml) and TEA (100 ml) was refluxed overnight. The solvent was removed and the residue taken up in ethyl ether to provide 2-hydroxy-2-(phenylsulfanyl)methyl-3 -(4-aminophenylsulfonyl)propionic acid o methyl ester (19 g, yield 79%), mp 153-155°C
Step 8): 2-Hydroxy-2-[(phenylsulfanyl)memyl]-3-[{4-[(4-cUoroberκoyl)amino]phenyl}- sulfonyl]ρropanoic acid methyl ester A stirred solution of 2-hydroxy-2-(phenylsulfanyl)methyl-3-(4- aminophenylsulfonyl)propionic acid methyl ester (1.5 g) in pyridine (20 ml) was treated with 4-chlorobenzoylchloride (0.5 ml) at room temperature. After 3 h, 2 M solution of NaHCO3 (15 ml) were added and the cloudy solution was set aside for 3 b... The reaction mixture was diluted with ethyl acetate and thoroughly partitioned with 2 M HCl. After washing with 2 M NaHCO3, brine and dried, the solvent was removed to provide, after crystallization from acetone, 2-hydroxy-2- [(phenylsulfanyl)methyl]-3 - [ { 4-[(4- chlorobenzoyl)amino]phenyl}sulfonyl]propanoic acid methyl ester (1.1.6 g, yield 80%>). Step 9): A stirred solution of 2-hydroxy-2-[(phenylsulfanyl)methyl]-3-[{4-[(4- chlorobenzoyl)-amino]phenyl}sulfonyl]propanoic acid methyl ester (0.75 g) in methanol (25 ml) and 1 M NaOH (4 ml) was st aside at room temperature for 5 h.. The cloudy suspension was acidified to pH 2 with 2 N HCl, diluted with ethyl acetate and thoroughly partitioned with brine. The solvent was removed and the residue was crystallized from ethanol to provide the title compound, 2-hydroxy-2-[(phenylsulfanyl)methyl]-3-[{4-[(4- c orobenzoyl)arnino]phenyl}-sulfonyl]propanoic acid (0.58 g, yield 78%), mp 183-185°C. Example 5
2-Hydroxy-2-[φhenylsulfanyl)methyl]-3-[{4-[(4-methoxybenzoyl)amino]phenyI}- sulfonyl]propanoic acid Operating as in Example 3 step 8, 9, but employing 4-methoxybenzoylchloride instead of 4- chlorobenzoylchloride, the title compound was obtained in overall 65 % yield, mp 197- 200°C. Example 6
2-Hydroxy-2-[(phenylsulfanyl)methyl]-3-[{4-[(isonicotinoyl)amino]phenyl}sulfonyl]- propanoic acid Operating as in Example 3 step 8, 9, but employing isonicotinoylchloride instead of 4- chlorobenzoylchloride, the title compound was obtained in overall 53% yield, mp 247- 250°C. Example 7
2-Hydroxy-2-[(phenyIsuIfanyl)methyl]-3-[{4-[(3,4-methylendioxybenzoyl) amino]phenyl} - sul onyl]propanoic acid
Operating as in Example 3 step 8, 9, but employing 3, 4-methylendioxybenzoylchloride instead of 4-chlorobenzoylchloride, the title compound was obtained in overall 75% yield, mp > 100°C decomp.
Example 8
2-Hydroxy-2-[φhenylsuIfanyl)methyl]-3-[{4-[(4-dimethylaminobenzoyl) amino]phenyl}-sulfonyl]propanoic acid sodium salt Operating as in Example 3 step 8, 9, but employing 4-dimethylaminobenzoylchloride hydrochloride instead of 4-chlorobenzoylchloride, the title compound was obtained in overall
58% yield.
Example 9
2-Hydroxy-2-[(phenyloxy)methyl]-3-[{4-[(4-chlorobenzoyl)amino]pIιenyl}sulfonyl]- propanoic acid
Step 1) : 2-Hydroxy-2- henyloxy)methyl-3-(4-trifluoroacetylaminophenylsulfonyl)propionic acid methyl ester
To a stirred solution of phenol (14 g) in DMF (300 ml) was added portionwise 60% NaH (4.5 g) at 5°C. After 1 h of stirring at room temperature, 2-hydroxy-2-methansolfonyloxymethyl- 3-(4-trifluoroacetylaminophenylsulfonyl)propionic acid methyl ester (50 g) was added and the reaction mixture was set aside for 10 h. The solvent was removed and the residue taken up in ethylacetate was thoroughly washed with brine. After drying and removal of the solvent, the residue was filtered on a small pad of silica gel eluting with cyclohexane/ethyl acetate 1/1 to give 2-hydroxy-2-(phenyloxy)methyl-3-(4- trifluoroacetylaminophenylsulfonyl)propionic acid methyl ester (41 g, yield 87%), mp 190- 200°C
Step 2): 2-Hydroxy-2-(phenyloxy)memyl-3-(4-aminophenylsulfonyl)propionic acid methyl ester A stirred solution of 2-hyQ^oxy-2-(phenyloxy)memyl-3-(4-trifluoroacetylaminophenyl- sulfonyl)propionic acid methyl ester (40 g) in methanol (350 ml) and TEA (150 ml) was refluxed overnight. The solvent was removed and the residue taken up in diethylether provided 2-hydroxy-2-(phenyloxy)methyl-3-(4-aminophenylsulfonyl)propionic acid methyl ester (26 g, yield 83%), mp 135-137°C
Step 3): Operating as in Example 3 step 8, 9, but employing 2-hydroxy-2-(phenyloxy)methyl-
3-(4-aminophenylsulfonyl)propionic acid methyl ester instead of 2-hydroxy-2- (phenylsulfanyl)-methyl-3-(4-aminophenylsulfonyl)propionic acid methyl ester, the title compound was obtained in overall 43% yield.
Example 10
2-Hydroxy-2-[ henyloxy)methyl]-3-[{4-[(4-fluorobenzoyl)amino]phenyl}sulfonyl]- propanoic acid Operating as in Example 3 step 8, 9, but employing 2-hydroxy-2-(phenyloxy)methyl-3-(4- aminophenylsulfonyl)propionic acid methyl ester instead of 2-hydroxy-2-(phenylsulfanyl)- memyl-3-(4-arninophenylsulfonyl)propionic acid methyl ester and 4-fluorobenzoylchloride instead of 4-chlorobenzoylchloride, the title compound was obtained in overall 43% yield, mp 222-226°C Example 11
2-Hydroxy-2-[(phenyloxy)methyl]-3-[{4-[(4-cyano)amino]phenyl}sulfonyl]propanoic acid
Operating as in Example 3 step 8, 9, but employing 2-hydroxy-2-(phenyloxy)methyl-3-(4- aminophenylsulfonyl)propionic acid methyl ester instead of 2-hydroxy-2-(phenylsulfanyl)- methyl-3-(4-aminophenylsulfonyl)propionic acid methyl ester and 4-cyanobenzoylchloride instead of 4-chlorobenzoylchloride, the title compound was obtained in overall 43% yield.
Example 12
2-Hydroxy-2-[(jphenyloxy)methyl]-3-[{4-[(isonicotinoyl)amino]phenyl}sulfonyl]- propanoic acid Operating as in Example 3 step 8, 9, but employing 2-hydroxy-2-(phenyloxy)methyl-3-[(4- aminophenylsulfonyl)methyl]propionic acid methyl ester instead of 2-hydroxy-2- henylsulfanyl)methyl-3-[(4-aninophenylsulfonyl)methyl]propionic acid methyl ester and isonicotinoylchloride hydrocloride instead of 4-chlorobenzoylchloride, the title compound was obtained in overall 62% yield. Example 13
2-Hydroxy-2-[(phenyloxy)methyl]-3-[{4-[(4-bromobenzoyl)amino]phenyl}sulfonyl)]- propanoic acid
Operating as in Example 3 step 8, 9, but employing 2-hydroxy-2-(phenyloxy)methyl-3-(4- aminophenylsulfonyl)propionic acid methyl ester instead of 2-hydroxy-2-(phenylsulfanyl)- methyl-3-(4-aminophenylsulfonyl)propionic acid methyl ester and 4-bromobenzoylchloride instead of 4-chlorobenzoylchloride, the title compound was obtained in overall 39 % yield.
Example 14
2-Hydroxy-2-[(phenyloxy)methyl]-3-[{4-[(dimethylanu^obenzoyl)amino]phenyl}- sulfonyljpropanoic acid sodium salt
Operating as in Example 3 step 8, 9, but employing 2-hydroxy-2-(phenyloxy)methyl-3-(4- aminophenylsulfonyl)propionic acid methyl ester instead of 2-hydroxy-2-(phenylsulfanyl)- methyl-3-(4-aminophenylsulfonyl)propionic acid methyl ester and 4-dimethylamino- benzoylchloride hydrochloride instead of 4-chlorobenzoylchloride, the title compound was obtained in overall 35% yield, mp >180°C decomp.
Example 15
2-Hydroxy-2-[(pb.enyloxy)methyl]-3-[{4-[(methoxybenzoyl)amino]phenyl}sulfonyl]- propanoic acid
Operating as in Example 3 step 8, 9, but employing 2-hydroxy-2-(phenyloxy)methyl-3-(4- aminophenylsulfonyl)propionic acid methyl ester instead of 2-hydroxy-2-(phenylsulfanyl)- methyl-3-(4-aminophenylsulfonyl)propionic acid methyl ester and 4-methoxybenzoylchloride instead of 4-chlorobenzoylchloride, the title compound was obtained in overall 59% yield, mp 170-175°C Example 16 2-Hydroxy-2-[ phenyloxy)methyl]-3-[{4-[(3,4-methylendioxybenzoyl)aιmno]phenyl}- sulfonyl]propanoic acid
Operating as in Example 3 step 8, 9, but employing 2-hydroxy-2-(phenyloxy)methyl-3-(4- aminophenylsulfonyl)propionic acid methyl ester instead of 2-hydroxy-2-(phenylsulfanyl)- methyl-3-(4-aminophenylsulfonyl)propionic acid methyl ester and 3,4-methylendioxy- benzoylchloride instead of 4-chlorobenzoylchloride, the title compound was obtained in overall 75% yield, mp 180-182°C Example 17 2-Hydroxy-2-[φhenyloxy)methyl]-3-[{4-[ enzoyl)anMno]phenyl}sulfonyl]propanoic acid
Operating as in Example 3 step 8, 9, but employing 2-hydroxy-2-(phenyloxy)methyl-3-(4- aminophenylsulfonyl)propionic acid methyl ester instead of 2-hydroxy-2-(phenylsulfanyl)- methyl-3-(4-aminophenylsulfonyl)propionic acid methyl ester and benzoylchloride instead of 4-chlorobenzoylchloride, the title compound was obtained in overall 72% yield Example 18
2-Hydroxy-2-[(phenyloxy)metb.yl]-3-{[4-(l-oxo-l,3-dihydro-2H-isoindol-2-yl)phenyl]- sulfonyl}propanoic acid Step 1): To a stirred solution of methyl 2-(phenoxymethyl)-2-oxiranecarboxylate (4.16 g) and 2-(4-sulfanylphenyl)-l-isoindolinone (5.3 g) in DMF (50 ml) was added K2CO3 (0.1 g) at room temperature and the reaction was set aside overnight. Oxone (27 g) was then added and the suspension was heated at 60°C for 4 h. The reaction mixture was diluted with ethyl acetate and washed with brine and dried. Crystallization from methanol gave 2-hydroxy-2- [(phenyloxy)methyl]-3-{[4-(l-oxo-l,3-dihydro-2H-isoindol-2-yl)phenyl]sulfonyl}propanoic acid methyl ester (7.4 g, yield 75%), mp 179-181°C
Step 2): A stirred solution of 2-hydroxy-2-[(phenyloxy)methyl]-3-{[4-(l-oxo-l,3-dihydro- 2H-isoindol-2-yl)phenyl]sulfonyl}propanoic acid methyl ester (5 g) and 2 M NaOH (10 ml) in methanol (75 ml) was heated at 50°C for 7 h. The solvent was removed and the residue dissolved in water was treated with 2 M HCl to pH 2. The precipitate was filtered off washed with water and subsequently crystallized from boiling methanol to afford 2-hydroxy-2- [(phenyloxy)methyl]-3- {[4-(l -oxo-1 ,3-dihydro-2H-isoindol-2-yl)phenyl]sulfonyl}propanoic acid (3.8 g, yield 78%), mp 263-265°C Example 19 2-Hydroxy-2-[(phenyloxy)methyl]-3-[{4-[(4- chlorobenzoyl)methylaminomethyl]phenyl}-sulfonyl]propanoic acid Operating as in Example 16, but employing 4-chloro-N-methyl-N-(4- sulfanylphenyl)benzamide instead of 2-(4-sulfanylphenyl)-l-isoindolinone, the title compound was obtained in 32% yield. Example 20 2-Hydroxy-2-[(l,3-thiazol-2-ylsulfanyl)methyl]-3-[{4-[(4-chlorobenzoyl)amino]phenyl}- sulfonyl]propanoic acid Step 1): 2-Hydroxy-2-hydroxymemyl-3-(4-aminophenylsulfonyl)propionic acid methyl ester A stirred solution of 2-hydroxy-2-hydroxymethyl-3-(4-trifluoroacetylaminophenylsulfonyl)- propionic acid methyl ester (35 g) in methanol (300 ml) and TEA (150 ml) was refluxed overnight. The solvent was removed and the residue taken up in ethyl ether afforded 2- hydroxy-2-hydroxymethyl-3-(4-aminophenylsulfonyl)propionic acid methyl ester (21 g, yield 77%).
Step 2): 2-Hydroxy-2-hydroxymethyl-3-[{4-[(4-chlorobenzoyl)methylamino] phenyl} sulfonylj-propanoic acid methyl ester To a stirred solution of 2-hydroxy-2-hydroxymethyl-3-(4-aminophenylsulfonyl)propionic acid methyl ester (15 g) in pyridine (150 ml) was added dropwise a solution of 4- chlorobenzoylchloride (9 g) in THF (25 ml) at 5°C. After stirring overnight at room temperature, the solvent was removed and the residue taken up in ethyl acetate was washed with 1 M HCl, 2 M NaHCO3, then with brine. After drying and removal of the solvent, the residue was twice crystallized from a small volume of acetone to give 2-hydroxy-2- hydroxymethyl-3-[{4-[(4-chlorobenzoyl)methylamino]phenyl} sulfonyl]propanoic acid methyl ester (19 g, yield 90%)
Step 3): 2-Hy(hoxy-2-memansolfonyloxymemyl-3-[{4-[(4-cMorobenzoyl)methylanύno]- phenyl} sulfonyljpropanoic acid methyl ester To a stirred solution of 2-hydroxy-2-hydroxymethyl-3-[{4-[(4-chlorobenzoyl)methylamino]- phenyl} sulfonyljpropanoic acid methyl ester (18 g) in pyridine (100 ml) was added dropwise a solution of methansolfonylchloride (9 g) in pyridine (20 ml) at 5°C. After stirring overnight at room temperature, the reaction mixture was taken up in ethyl acetate and thoroughly washed with 5 M HCl, 2 M NaHCO3, then with brine. After drying and removal of the solvent, the residue was crystallized from ethanol to give, 2-hydroxy-2- methansolfonyloxymethyl-3-[{4-[(4-chlorobenzoyl)methylamino]phenyl}sulfonyl]propanoic acid methyl ester (15.5 g, yield 77%)
Step 4): To a stirred solution of 2-mercapto-l,3-thiazole (1 g) in DMF (300 ml) was added portionwise 60% NaH (0.25 g) at 5°C. After 1 h of stirring at room temperature, 2-hydroxy- 2-methansolfonyloxymethyl-3-[{4-[(4- chlorobenzoyl)methylamino]phenyl}sulfonyl]propanoic acid methyl ester (3.13 g) was added and the reaction mixture was set aside for 10 h. The solvent was removed and the residue taken up in ethyl acetate was thoroughly washed with brine. After drying and removal of the solvent, the residue was chromatographed on silica gel eluting with cyclohexane/ethyl acetate 2/1 to give, after crystallization from ethanol, 2-hydroxy-2-[(l,3-thiazol-2-ylsulfanyl)methyl]- 3-[{4-[(4-cMoroberj^oyl)memylamino]phenyl}sulfonyl]-propanoic acid methyl ester (2.1 g, yield 67%)
Step 5): A stirred solution of 2-hydroxy-2-[(l,3-thiazol-2-ylsulfanyl)methyl]-3-[{4-[(4- chlorobenzoyl)methylamino]phenyl}sulfonyl]propanoic acid methyl ester (2 g) and 2 M NaOH (4 ml) in methanol (30 ml) was heated at 50°C for 7 h. The solvent was removed and the residue dissolved in water was treated with 2 M HCl to pH < 3. After extraction with ethyl acetate, washing with brine and drying, the solvent was removed to provide after crystallization from methanol the title compound, 2-hydroxy-2-[(l,3-thiazol-2- ylsulfanyl)methyl]-3-[{4-[(4-chlorobenzoyl)methylamino]phenyl}sulfonyl jpropanoic acid (1.3 g, yield 69%) Example 21 2-Hydroxy-2-[(pyridyl-2-ylsulfanyl)methyl]-3-[{4-[(4-chlorobenzoyl)amino]pIιenyl}- sulfonyljpropanoic acid
Operating as in Example 17 step 3, 4, but employing 2-mercaptopyridine instead of 2- mercapto-1, 3-thiazole, the title compound was obtained in overall 37% yield Example 22 2-Hydroxy-2-[(-[(4-hydroxyphenylsulfanyl)methyl]-3-[{4-[(4-chlorobenzoyl)amino]- phenyl} sulfonyljpropanoic acid
Operating as in Example 17 step 3, 4, but employing 4-hydroxybenzenthiol instead of 2- mercapto-1, 3-thiazole, the title compound was obtained in overall 24% yield, mp >220°C decomp Example 23
2-Hydroxy-2-[(-[(4-fluorophenylsulfanyl)methyl]-3-[{4-[(4- chlorobenzoyl)amino]phenyl}-sulfonyl]propanoic acid
Operating as in Example 17 step 3, 4, but employing 4-fluorobnzenthio instead of 2- mercapto-1, 3-thiazole, the title compound was obtained in overall 32% yield, mp 124-126°C Example 24 N-Hydroxy-2-hydroxy-2-[(phenoxy)methyl]-3-[{4-[(4-chlorobenzoyl)aιnino]plιeιιyl}- sulfonyljpropanamide
A cold solution of 12 M NaOH (2.8 ml) and hydroxylamine hydrochloride (2.6 g) in water (10 ml) was added to solution of 2-hydroxy-2-[(phenoxy)methyl]-3-[{4-[(4-chlorobenzoyl)- amino]phenyl} sulfonyljpropanoic acid methyl ester (7 g) in methanol (50 ml), water (50 ml) and THF (150 ml). The resulting cloudy solution was set aside at room temperature for 5 days. The solvent was removed and the residue taken up in ethyl acetate was washed with 1 M NaHCO3, brine then dried. After removal of the solvent, the residue was filtered on a small pad of silica gel eluting with cyclohexane/acetone 4/1. Crystallization from a small volume of ethanol provided the title compound (2.9 g, yield 41%), mp 218-220°C Example 25
3-({4-[(4-Chlorobenzoyl)amino]phenyl}sulfonyl)-2-hydroxy-2-[(3,4,4-trimethyl-2,5- dioxo-l-imidazolidinyl)methyl]propanoic acid Step 1): 4-Nitrobenzyl 2-[(3,4,4-1ximethyl-2,5-dioxo-l-imidazolidinyl)methyl]acrylate Sodium bicarbonate (1.9 g) was added to a stirred solution of 3,4,4-trimethylhydantoin (3.1 g) and 2-(bromomethyl)acrylic acid (3.5 g) in DMF (20 ml) at 90°C. After 7 h of stirring, the suspension was filtered and the resulting solution was treated with CsCO3 (3.3 g) and 4- nitrobenzyl bromide (4.5 g). The reaction mixture was stirred at room temperature for about 3 h, diluted with ethyl acetate and eventually washed with brine. After drying, the solvent was removed in vacuo and the crude residue was purified on silica gel by flash chromatography (n-hexane/ethyl acetate 1/1) affording the title compound as an oil (5.1 g, yield 78%).
Step 2): 4-Nitrobenzyl 2,3-dmydroxy-2-[(3,4,4-trimethyl-2,5-dioxo-l- imidazolidinyl)methyl] -propanoate To a stirred solution of 4-nitrobenzyl 2-[(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)methyl]- acrylate (5.1 g) and N-methyl-morpholine (6.6 g) in tert-butanol (25 ml) and water (25 ml) was added a catalytic amount of osmium tetroxide (10 mg). After 3 h of stirring at room temperature, 2M Na2S2O5 (10 ml) was added, the black suspension was filtered on celite and the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and brine. After drying and removal of the solvent, crystallization from ethyl ether afforded the title compound as a white solid (4 g, yield 75%) Step 3): 4Nnitrobenzyl 2-hydroxy-3-[(me1hylsulfonyl)oxy]-2-[(3,4,4-trimethyl-2,5-dioxo-l- imidazolidinyl)methyl]propanoate
To a stirred solution of 4-nitrobenzyl 2,3-dihydroxy-2-[(3,4,4-trimethyl-2,5-dioxo-l- imidazolidinyl)methyl]propanoate (4 g) in DMF (20 ml) were sequentially added triethylamine (2.3 ml) and methansulfonylchloride (1.3 ml) dropwise at 0°C. After 1 h of stirring at room temperature, ethyl acetate was added and the resulting solution was washed with 1M citric acid and brine. Drying and removal of the solvent gave a crude residue which was purified on silica gel by flash chromatography (n-hexane/ethyl acetate 1/1) affording the title compound as a white solid (4 g, yield 84%) Step 4): 4-Nitrobenzyl 3-({4-[(4-chlorobenzoyl)amino]phenyl}sulfanyl)-2-hydroxy-2-[(3,4,4- trimethyl-2,5-dioxo- 1 -imidazolidinyl)methyl]propanoate
Sodium hydride (60% dispersion in mineral oil (200 mg) was added to a stirred solution of 4-chloro-N-(4-sulfanylphenyl)benzamide (1.2 g) in DMF (15 ml) at room temperature. After 30' of stirring, a solution of 4-nitrobenzyl 2-hydroxy-3-[(methylsulfonyl)oxy]-2-[(3,4,4- trimethyl-2,5-dioxo-l-imidazolidinyl)methyl]propanoate (2 g) in DMF (30 ml) was slowly cannulated and the resulting suspension was stirred for 2h. The reaction mixture was diluted with ethyl acetate and thoroughly washed with brine. After drying, the solvent was removed in vacuo and the residue was purified by silica gel flash chromatography to give the title compound as a white solid (2 g, yield 74%>) Step 5): 4-Nitrobenzyl 3-({4-[(4-chlorobenzoyl)amino]phenyl}sulfonyl)-2-hydroxy-2-[(3,4,4- trimethyl-2,5-dioxo- 1 -imidazolidinyl)methyl]propanoate
To a solution of 4-nitrobenzyl 3-({4-[(4-chlorobenzoyl)amino]phenyl}sulfanyl)-2-hydroxy-2- [(3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl)methyl]propanoate (2 g) in dichloromethane (50 ml) was added 3-chloroperoxybenzoic acid (1.6 g). The reaction mixture was stirred at room temperature for 3 h and then diluted with DCM (50 ml), washed with saturated aqueous Na2S2O5, sodium bicarbonate and eventually with brine. After drying over sodium sulfate, the solvent was removed and the resulting residue was chromatographed on silica gel (n- hexane/ethyl acetate 1/1) to give the purified title compound as a white solid (1.9 g, yield
91%) Step 6): A solution of 4-nitrobenzyl 3-({4-[(4-chlorobenzoyl)anιino]phenyl}sulfonyl)-2- hyαroxy-2-[(3,4,4-trmιemyl-2,5-dioxo-l-inιidazohdinyl)methyl]propanoate (1 g) in DMF (30 ml) was treated with acetic acid (1.8 ml) and Zn powder (2 g) at room temperature. After 30' of stirring, the suspension was filtered on celite and the resulting solution was diluted with ethyl acetate. The crude product was extracted by a solution of saturated sodium bicarbonate and then re-extracted by ethylacetate after acidification of the aqueous phase with concentrated acid chloride. The organic phase was washed with brine, dried and rotoevaporated to give a residue which was then purified by crystallization from ethyl ether to provide the title compound as a white solid (0.6 g, yield 75%) mp 213-215 °C Example 26
2-Hydroxy-3-phenoxy-2-{ [(4-{ [4-(trifluoromethoxy)benzoyl] amino}phenyl)sulfonyl]- methyl}propanoic acid Operating as in Example 8 step 1, 2, but employing 2-hydroxy-2-(phenyloxy)methyl-3-(4- aminophenylsulfonyl)propionic acid methyl ester instead of 2-hydroxy-2-(phenylsulphanyl)- methyl-3-(4-aminophenylsulfonyl)propionic acid methyl ester, and as in Example 3 step 8, 9, but employing 4-trifluoromethoxybenzoylchloride instead of 4-chlorobenzoylchloride, the title compound was obtained in overall 30% yield, mp 204-7°C. Example 27
2-Hydroxy-3-phenoxy-2-{[(4-{[4-(trifluoromethyl)benzoyl]amino}phenyl)sulfonyl]- methyl}propanoic acid
Operating as in Example 8 step 1, 2, but employing 2-hydroxy-2-(phenyloxy)methyl-3-(4- aminophenylsulfonyl)propionic acid methyl ester instead of 2-hydroxy-2-(phenylsulphanyl)- methyl-3-(4-aminophenylsulfonyl)propionic acid methyl ester, and as in Example 3 step 8, 9, but employing 4-trifluoromethylbenzoylchloride instead of 4-chlorobenzoylchloride, the title compound was obtained in overall 28% yield, mp 197-200°C. Example 28
3-({4-[(4-Fluorobenzoyl)amino]phenyl}sulfonyl)-2-hydroxy-2-{[(4-hydroxyplιenyl)- sulfanyl]methyl}propanoic acid
Operating as in Example 19 step 2, 3, 4, 5, but employing 4-fluorobenzoylchloride instead of 4-chlorobenzoylchloride and 4-hydroxythiophenol instead of 2-mercapto-l, 3-thiazole, the title compound was obtained in overall 41% yield. BIOLOGICAL DATA The inhibitory constants (Ki's, nanoM) of the compounds of the present invention were determined against MMP-1 (human interstitial collagenase), MMP-2 (human gelatinase-A), MMP-9 (human gelatinase-B), MMP-13 (human collagenase-3) and MMP-14 (MT1-MMP, human membrane-type 1 matrix metalloproteinase). Selected results are reported in Table 1. The assay buffer was pH 6.5 for the carboxylates and pH 7.4 for the hydroxamates. Tabulated data refer to racemic mixture or to separate enantiomers, the more active enantiomer showed nearly halved Ki's against the whole enzyme panel.
TABLE 1
Example Compound MMP-2 MMP-1 MMP-9 MMP-13 MMP-
14
Example 1 14.7
Example 2 51.0
Example 3 15.0
Example 4 2.2 30655 22.8 63.9
Example 5 0.99
Example 6 25.2
Example 7 1.4
Example 8 0.81
Example 9 5.8 135000
Example 10 8.3
Example 11 12.3 105600
Example 12 68.2
Example 13 2.8
Example 14 1.26
Example 15 2.5
Example 16 3.3
Example 17 10.2 1436 485.5
Example 18 11.9 1500 104.2
Example 20 2.33
Example 21 2.91
Example 22 1.33
Example 24 < 0.2 2250 3.2 3.82 52.3
Example 25 3.0 106000 90.9 161.6 121.0
Example 26 6.1
Example 27 5.8 Example 28 3.4

Claims

1. A compound which is an arylsulfonyl propanoic acid derivative of formula (I)
Figure imgf000041_0001
wherein:
X is HO-NH- or HO- ;
Rl is -O-Ph, -S-Ph, -S-Het, -Hyd or -CH2-Hyd, wherein Ph is a phenyl group which is unsubstituted or substituted; Het is a 5- or 6-membered unsaturated heterocychc ring having one to four atoms selected from nitrogen, sulfur and oxygen, which is unsubstituted or substituted; and Hyd is a hydantoin-3-yl ring, which is substituted by one to three methyl groups;
A is a phenyl group which is unsubstituted or substituted, or is Het as defined above, or a phenyl ring condensed with a 5-membered saturated or unsaturated heterocychc ring having one to three atoms selected from nitrogen, sulfur and oxygen, which is either unsubstituted or substituted; and
R2 is either hydrogen or methyl; or R2 represents a methylene (-CH2-) bridge connecting the nitrogen atom to the ortho position of said phenyl, condensed phenyl or heterocyclyl ring which A represents to form a 5-membered lactam; or a pharmaceutically acceptable salt thereof , or an oral prodrug of a said derivative or salt thereof.
2. A compound as claimed in claim 1 wherein Rl is -O-Ph or -S-Ph, and the phenyl ring which Ph represents is unsubstituted or substituted by one or two substituents, at any position, selected from fluoro, chloro, hydroxy, methyl, methoxy and trifluoromethoxy ;
-S-Het, wherein Het is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 2-furyl 5 and l,3-thiazol-2-yl, which is unsubstituted or substituted by chloro or methyl or
-Hyd or -CH2-Hyd, wherein Hyd represents 3,4,4-trimethyl-2,5-dioxo-l-imidazolidinyl, 4,4-dimethyl-2,5-dioxo- 1 -imidazolidinyl, or 3-methyl-2,5-dioxo- 1 -imidazolidinyl.
3. A compound according to claim 1 or 2, wherein A is 0 a substituted phenyl ring, one substituent being present at the para position, or two substituents at the para and meta positions, said substituents being selected from fluoro, chloro, bromo, CrC4 linear alkyl, ethynyl, hydroxy, hydroxymethyl, trifluoromethyl, C1-C4 linear alkoxy, trifluoromethoxy, cyano, cyanomethyl, dimethylamino, 1-pyrrolidinyl, 2,5- dihydro-lH-pyrrol-1-yl and 1-piperidinyl; s Het selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 2-furyl, 3-imidazolyl and 1,3- thiazol-2-yl, which is unsubstituted or substituted by chloro or methyl; or a l,3-benzodioxol-5-yl, or lH-l,2,3-benzotriazol-6-yl group.
4. A compound according to claim 1,2 or 3, wherein R2 is a methylene (-CH -) bridge and the resulting group is a 1-isoindolinone, which is either unsubstituted or substituted by 0 fluoro, chloro, bromo, -C4 linear alkyl, C C4 linear alkoxy, trifluoromethoxy or dimethylamino.
5. A compound as claimed in claim 1 which is selected from the group consisting of
3-({4-[(lH-l,2,3-benzotriazol-6-ylcarbonyl)amino]phenyl}sulfonyl)-2-hydroxy-2- (phenoxymethyl)propanoic acid; 5 3-( {4-[(4-cyanobenzoyl)amino]phenyl} sulfonyl)-2-hydroxy-2-(phenoxymethyl)- propanoic acid;
3-({4-[(4-chlorobenzoyl)amino]phenyl}sulfonyl)-2-hydroxy-2-(phenoxymethyl)- propanoic acid; methyl 3-({4-[(4-chlorobenzoyl)amino]phenyl}sulfonyl)-2-hydroxy-2-(phenoxy- o methyl)propanoate; ethyl 3-( {4-[(4-chlorobenzoyl)amino]phenyl} sulfonyl)-2-hydroxy-2-(phenoxy- methyl)propanoate; (2R)-3-({4-[(4-chlorobenzoyl)amino]phenyl}sulfonyl)-2-hydroxy-2-[(phenyl- sulfanyl)methyl]propanoic acid;
3-({4-[(4-cMorobenzoyl)amino]phenyl}sulfonyl)-2-hydroxy-2-[(3,4,4-trimethyl- 2,5-dioxo- 1 -imidazolidinyl)methyl]propanoic acid; 5 2-[({4-[(4-chlorobenzoyl)amino]phenyl}sulfonyl)methyl]-2-hydroxy-4-(3,4,4- trimethyl-2,5-dioxo-l-imidazolidinyl)butanoic acid; sodium 3-({4-[(4-chlorobenzoyl)amino]phenyl}sulfonyl)-2-hydroxy-2-[(l,3- thiazol-2-ylsulfanyl)methyl]propanoate; sodium 3-( {4-[(4-chlorobenzoyl)amino jphenyl} sulfonyl)-2-hydroxy-2-[(2- i o pyridinyl-sulfanyl)methyl]propanoate;
3-({4-[(4-fluorobenzoyl)amino]phenyl}sulfonyl)-2-hydroxy-2-[(phenylsulfanyl)- methyljpropanoic acid;
2-hydroxy-3-{[4-(isonicotinoylamino)phenyl]sulfonyl}-2-[(phenylsulfanyl)methyl]- propanoic acid; 15 2-hydroxy-3-{[4-(isonicotinoylamino)phenyl]sulfonyl}-2-
(phenoxymethyl)propanoic acid;
2-hydroxy-3-({4-[(4-methoxybenzoyl)amino]phenyl}sulfonyl)-2-(phenoxymethyl)- propanoic acid;
3-({4-[(l,3-benzodioxol-5-ylcarbonyl)amino]phenyl}sulfonyl)-2-hydroxy-2- 20 (phenoxymethyl)propanoic acid; methyl 3-({4-[(l,3-benzodioxol-5-ylcarbonyl)amino]phenyl}sulfonyl)-2-hydroxy- 2-(phenoxymethyl)propanoate; ethyl 3-({4-[(l,3-benzodioxol-5-ylcarbonyl)amino]phenyl}sulfonyl)-2-hydroxy-2- (phenoxymethyl)propanoate; 25 3-({4-[(l,3-benzodioxol-5-ylcarbonyl)amino]phenyl}sulfonyl)-2-hydroxy-2-
[(phenylsulfanyl)methyl]propanoic acid;
2-hydroxy-2-[({4-[(4-methoxybenzoyl)amino]phenyl}sulfonyl)methyl]-4-(3,4,4- trimethyl-2,5-dioxo-l-imidazolidinyl)butanoic acid; sodium 3-[(4-{[4-(dimethylamino)benzoyl]amino}phenyl)sulfonyl]-2-hydroxy-2- 3 o (phenoxymethyl)propanoate;
2-hydroxy-3 -phenoxy-2- { [(4- { [4-( 1 -pyrrolidinyl)benzoyl] amino } phenyl)sulfonyl] - methyl}propanoic acid; 3-({4-[(4-fluorobenzoyl)amino]phenyl}sulfonyl)-2-hydroxy-2-(phenoxymethyl)- propanoic acid;
2-hydroxy-3-({4-[(4-methoxybenzoyl)amino]phenyl}sulfonyl)-2-[(phenylsulfanyl)- methyljpropanoic acid; 5 3-({4-[(4-fluorobenzoyl)amino]phenyl}sulfonyl)-2-hydroxy-2-{[(4- hydroxyphenyl)-sulfanyl]methyl}propanoic acid;
3-[(4-{[(6-chloro-3-pyridinyl)carbonyl]amino}phenyl)sulfonyl]-2-hydroxy-2- (phenoxymethyl)propanoic acid;
3-({4-[(4-bromobenzoyl)amino]phenyl}sulfonyl)-2-hydroxy-2-(phenoxymethyl)- o propanoic acid;
2-[({4-[(4-fluorobenzoyl)amino]phenyl}sulfonyl)methyl]-2-hydroxy-4-(3,4,4- trimethyl-2,5-dioxo-l-imidazolidinyl)butanoic acid;
3-({4-[(4-chlorobenzoyl)amino]phenyl}sulfonyl)-2-{[(4-fluorophenyl)sulfanyl]- methyl}-2-hydroxypropanoic acid; 5 3-( {4-[(4-chlorobenzoyl)amino]phenyl} sulfonyl)-2-hydroxy-2- { [(4- hydroxyphenyl)-sulfanyl]methyl}propanoic acid;
3-{[4-(benzoylamino)phenyl]sulfonyl}-2-hydroxy-2-(phenoxymethyl)propanoic acid;
2-hydroxy-3-(phenylsulfanyl)-2-[({4-[(4-propoxybenzoyl)amino]phenyl} sulfonyl)- o methyl]propanoic acid;
2-hydroxy-3-(phenylsulfanyl)-2- {[(4- {[4- (trifluoromethoxy)benzoyl]amino}phenyl)-sulfonyl]methyl}propanoic acid;
2-hydroxy-3-(phenylsulfanyl)-2-{[(4-{[4-(trifluoromethyl)benzoyl]amino}phenyl)- sulfonyl]methyl}propanoic acid; 5 4-chloro-N-(4-{[2-hydroxy-3-(hydroxyamino)-3-oxo-2-(phenoxymethyl)propyl]- sulfonyl}phenyl)benzamide;
N-(4- { [2-hydroxy-3 -(hydroxyamino)-3 -oxo-2-(phenoxymethyl)propyl] sulfonyl} - phenyl)-l,3-benzodioxole-5-carboxamide;
2-hydroxy-3-([4-(l-oxo-l,3-dihydro-2H-isoindol-2-yl)phenyl)sulfonyl]-2- o (phenoxymethyl)propanoic acid and
N,2-dihydroxy-3-([4-(l-oxo-l,3-dihydro-2H-isoindol-2-yl)phenyl)sulfonyl]-2- (phenoxymethyl)propanamide; and the pharmaceutically acceptable salts thereof; and the oral prodrugs of the said compounds and salts.
6. A process for producing a compound as defined in claim 1, wherein R2 and A are as defined in claim 1, and Rl is not -S-Ph or -S-Het as defined in claim 1, which process comprises: - oxidising at sulfur the sulfanyl propanoic acid of the formula (1)
Figure imgf000045_0001
wherein Rl, R2 and A are as above defined; and optionally converting the resultant compound of the formula la
Figure imgf000045_0002
wherein Rl, R2 and A are as above defined into another compound of the formula I wherein X is -NHOH by activation and coupling with hydroxylamine or with an O-protected hydroxylamine, followed by removal of the protecting group.
7. A process for producing a compound of the formula (la')
Figure imgf000045_0003
wherein R is an alcohol residue and Rl, R2 and A are as defined in claim 6, which process comprises either oxidising at sulfur an ester of the formula (la)
Figure imgf000046_0001
wherein R, Rl, R2 and A are as defined above, or derivatizating the primary hydroxyl of the compound of the formula 2
Figure imgf000046_0002
wherein R, R2 and A are as defined above, by means of activation followed by displacement with a phenol of formula Ph-OH, a thiol of formula Ph-SH or Het-SH, in the presence of a strong base, in an aprotic organic solvent.
8. A process for producing a compound of formula (I) as defined in claim 1, which process comprises: either hydrolysing a carboxylic ester of formula (la') as defined in claim 7, and optionally converting the resultant compound of the formula la
Figure imgf000046_0003
wherein Rl, R2 and A as defined in claim 1, into another compound of the formula I wherein X is -NHOH as described in claim 6; or reacting the carboxylic esters of formula (la') as defined in claim 7 with hydroxylamine or an O-protected hydroxylamine, in an inert organic solvent and, if necessary, removing the protecting group to give a compound of the formula I wherein X is -NHOH .
9. A compound of the formula la' as defined in claim 7.
10. A compound of the formula la' as claimed in claim 9, wherein R represents -C4 alkyl, acyloxy-methyl, l-(acyloxy)ethyl, ethoxycarbonyloxymethyl, l-(ethoxycarbonyloxy)ethyl or (2-oxo-l,3-dioxolen-4-yl)methyl.
11. A process for producing a prodrug of formula (la'), which process comprises the esterification of an acid of formula (la) as defined in claim 6 or 8.
12. A pharmaceutical composition which comprises a pharmaceutically acceptable diluent or carrier and, as an active ingredient, a compound as defined in any of claims 1 to 5, 9 and 10.
13. A compound as claimed in claim 1 for use in a method of treatment of the human or animal body by therapy.
14. A compound as claimed in claim 13 for use as an inhibitor of MMP-2.
PCT/EP2001/007736 2000-07-14 2001-07-05 3-arylsulfonyl-2-hydroxy-2-methylpropanoic acid derivates WO2002006215A1 (en)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2020070239A1 (en) 2018-10-04 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Egfr inhibitors for treating keratodermas

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5847153A (en) * 1996-09-27 1998-12-08 Pharmacia & Upjohn Company β-sulfonyl hydroxamic acids
EP0994104A1 (en) * 1996-06-27 2000-04-19 Ono Pharmaceutical Co., Ltd. Aryl (sulfide, sulfoxide and sulfone) derivatives and drugs containing the same as the active ingredient

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0994104A1 (en) * 1996-06-27 2000-04-19 Ono Pharmaceutical Co., Ltd. Aryl (sulfide, sulfoxide and sulfone) derivatives and drugs containing the same as the active ingredient
US5847153A (en) * 1996-09-27 1998-12-08 Pharmacia & Upjohn Company β-sulfonyl hydroxamic acids

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020070239A1 (en) 2018-10-04 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Egfr inhibitors for treating keratodermas

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