Classifications

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  • 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
  • C07D213/72—Nitrogen atoms
  • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
  • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
  • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
• • 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
  • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
  • C07D233/30—Oxygen or sulfur atoms
  • C07D233/32—One oxygen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
  • C07D295/182—Radicals derived from carboxylic acids
  • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
  • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• the present invention relates to new inhibitors of matrix metalloproteinases (hereinafter MMPs), to a process for their preparation, to pharmaceutical compositions containing them, and to the use of such compounds in the prevention, control and treatment of diseases in which the proteolytic action of MMPs is involved.
• MMPs matrix metalloproteinases
• TIMPs tissue inhibitors of metalloproteinases
• MMPs are involved in at least 3 aspects of the growth and spread of tumors (e.g., see A.H. Davidson et al., Chemistry & Industry, 258-261, 1997, and references therein).
• MMPs are used to break down the extracellular matrix, allowing primary tumor cancer cells to invade neighbouring blood vessels where they are transported to different organs and establish secondary tumors. The invasive growth at these secondary sites also needs MMPs to help break down tissue.
• MMP activity contributes to the invasive in-growth of new blood vessels (angiogenesis) which is required for tumors to grow above a certain size.
• Low molecular weight compounds able to inhibit one or more of the matrix metalloproteinases in particular stromelysin-1 (MMP-3; EC 3.4.24.17), gelatinase A (MMP- 2; EC 3.4.24.24), gelatinase B (MMP-9; EC 3.4.24.35), neutrophil collagenase or collagenase-2 (MMP-8; EC 3.4.24.34), interstitial collagenase or collagenase- 1 (MMP-1; EC 3.4.27.7), matrilysin (MMP-7; EC 3.4.24.23), collagenase-3 (MMP-13), and the membrane- type metalloproteinase (MT-MMPs: MMP-14, MMP-15, MMP-16, MMP-17) are currently considered as promising therapeutic agents in degenerative, tumoral and autoimmune pathologies (e.g., P.D.
• MMP-3 matrix metalloproteinases
• MMP inhibitors include those in which the Zn binding group is a hydroxamic acid, and the skeleton, as represented in the general formula (A), mimicks the amino acid sequence of collagen at the site cleaved by collagenase:
• R a , Rb, Re, and R ⁇ j are hydrogen atoms or appropriate substituents (e.g., N.R.A. Beeley et al., "Inhibitors of matrix metalloproteinases (MMP's)", Curr. Opin. Ther. Patents 4:7-16, 1994; J.R. Porter et al., “Recent developments in matrix metalloproteinase inhibitors", Exp. Opin. Ther. Patents 5:1287-1296, 1995; J.R. Morphy et al., "Matrix metalloproteinase inhibitors: Current status", Curr. Med. Chem. 2:743-762, 1995; R.P.
• MMP matrix metalloproteinases
• MMP inhibitors of the prior art can be described as "peptide-based hydroxamates” or “substrate-based” inhibitors (e.g., A.H. Davidson et al., "The inhibition of matrix metalloproteinase enzymes", Chemistry & Industry, 258-261, 1997).
• MMPs have been recognized as drug targets for at least 20 years, and potent MMP inhibitors described by formula (A) have been disclosed since 1986 or before (e.g., see J P. Dickens et al., U.S. Patent 4,599,361), no drug of this type has arrived at the market yet.
• the present invention is concerned with novel MMP inhibitors, specifically characterised by the presence of a nitrogen atom as a sostituent at the carbon atom next to the zinc-binding group, and with less or no peptidic character, as compared to substrate-based inhibitors of o the prior art.
• the present invention provides a compound which is an amine derivative of formula (I)
• W is -CONHOH or -COOH
• Ri and R 2 which are the same or different, are each hydrogen or - a group G, which is methyl, C 2 -C ⁇ o alkyl, C2-C10 alkenyl, C 3 -C 7 cycloalkyl, cycloalkyl-Ci- Cio- alkyl, aryl, aryl-Ci-Cio-alkyl, aryl-C -C ⁇ 0 -alkenyl, heterocyclyl, heterocyclyl-C ⁇ -C ⁇ o- alkyl or heterocyclyl-C 2 -C ⁇ 0 -alkenyl, the said methyl, alkyl, alkenyl, cycloalkyl, aryl and heterocyclyl groups being unsubstituted or substituted by one to three substituents; or -SO 2 -G, wherein G is as defined above; or -SO-G, wherein G is as defined above; or -CO-G, wherein G is as defined above; or -
• G is as defined above and G', which is the same or different, is as defined above for G, or G and G', together with the nitrogen atom to which they are attached, form a saturated or unsaturated 3- to 7-membered azaheterocyclic ring, which may be fused to a carbocyclic, heterocyclic, or aromatic ring, and may be substituted at any carbon or additional nitrogen atom, or
• G and G' are as defined above, or G and G', together with the nitrogen atom to which they are attached, constitute a saturated or unsaturated 3- to 7-membered azaheterocyclic ring, which may be fused to a carbocyclic, heterocyclic, or aromatic ring, and may be substituted at any carbon or additional nitrogen atom, or Ri and R 2 , taken together with the nitrogen atom to which they are attached, form a saturated or unsaturated 3- to 7-membered azaheterocyclic ring, which may be fused to a carbocyclic, heterocyclic, or aromatic ring, and may be substituted at any carbon or additional nitrogen atom;
• Ci -C 6 alkyl is Ci -C 6 alkyl, C 2 -C 6 alkenyl, phenyl, phenyl-(C ⁇ -C 6 )-alkyl, phenyl-(C 2 -C 6 )-alkenyl, heterocyclyl, or heterocyclyl-(C ⁇ -C6)-alkyl, either unsubstituted or substituted by a group selected from F, Cl, Br, Ci -C 4 alkyl, Ci -C 4 alkoxy, alkylthio, arylthio, alkylsulfonyl, and arylsulfonyl; Q, being a secondary or tertiary carboxyamide, is:
• azaheterocyclyl which is either unsubstituted or substituted, is as defined below; with the proviso that when Q is -CONHG, and G is methyl, alkyl-methyl, cycloalkyl-methyl, aryl-methyl or hetherocyclyl-methyl, then such methyl or substituted methyl cannot be further substituted by a group -(CH 2 ) t -CO 2 H, wherein t is 0, or esters and amides thereof, and a pharmaceutically acceptable salt, solvate or hydrate thereof.
• alkyl refers to a straight or branched chain alkyl moiety having from 1 to 10 carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, n-butyl, i- butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl and so on.
• alkenyl refers to a straight or branched chain alkenyl moiety having from 2 to 10 carbon atoms and having in addition one double bond of either E or Z stereochemistry where applicable. Examples of alkenyl groups are: vinyl, allyl, metallyl, butenyl, crotyl and so on.
• cycloalkyl refers to a saturated carbocyclic group of 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.
• aryl refers to a monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 carbon atoms, such as phenyl, naphthyl, indanyl; furthermore, "aryl” as used herein may refer to a diphenyl group (-C ⁇ Ht-C ⁇ Hs), a 4-pyridyl-phenyl group, and a methylenedioxyphenyl group.
• heterocyclyl refers to a 3- to 7-membered, saturated or unsaturated heterocyclyl ring, containing at least one heteroatom selected from O, S and N, wherein any ring nitrogen may be oxidized as an N-oxide, any ring carbon may be oxidized as a carbonyl, and any ring sulfur may be oxidized as a sulfoxide or sulfone; and wherein said heterocyclyl ring may be optionally fused to a second 5- or 6-membered , saturated or unsaturated heterocyclyl ring, or to a C 3 -C 7 cycloalkyl ring, or to a benzene or naphthalene ring.
• heterocyclyl groups are pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, thienyl, tetrahydrothienyl, fiiryl, tetrahydrofuryl, aziridinyl, oxiranyl, azetidinyl, succinimido, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyridazinyl, hexahydropyridazinyl, pyrimidinyl, pyranyl, tetrahydropyranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isobenzofuranyl, benzofuranyl, berizimidazolyl, indazolyl
• azaheterocyclyl as used herein includes any of the heterocyclyl groups, as defined above, containing at least one nitrogen atom, said heterocyclyl group being linked to the rest of o the molecule by a nitrogen atom.
• Substituents which may be present in the methyl, alkyl, alkenyl, aryl, cycloalkyl, heterocyclyl and azaheterocyclyl groups in any of the above specifications include the following ones:
• Hal is halo (i.e., fluoro, bromo, chloro or iodo)
• t is an integer 5 - a group -(CH 2 ) t -CF 3 , or a group -(CH 2 ) r CHF 2 , wherein t is as defined above;
• - phenyl biphenyl (i.e., -CoF -CoHs), methylenedioxyphenyl, methylenedioxyphenylmethyl (hereinafter piperonyl), benzyl, phenethyl, phenpropyl, naphthyl, naphthylmethyl, naphthylethyl, naphthylpropyl, either unsubstituted or substituted by one to three substituents selected from by C ⁇ -C 4 alkyl, hydroxy, C ⁇ -C alkoxy, amino, methylamino, dimethylamino, chloro and fluoro.
• carboxy, hydroxy, mercapto and amino groups may be either free or in a protected form.
• Protected forms of said groups are any of those generally known in the art, as described, for example, by T.W. Greene in "Protective Groups in Organic Chemistry", Wiley Interscience.
• carboxy groups are protected as esters thereof, in particular methyl, ethyl, tert-butyl, benzyl, and 4-nitrobenzyl esters.
• hydroxy groups are protected as ethers or esters thereof, in particular methoxymethyl ethers, tetrahydropyranyl ethers, benzyl ethers, acetates, benzoates, pivalates.
• mercapto groups are protected as thioethers or thioesters, in particular tert-butyl thioethers, thioacetates, thiobenzoates.
• amino groups are protected as carbamates, e.g. tert-butoxycarbonyl and benzyloxycarbonyl derivatives, or as amides, e.g. acetamides and benzamides.
• the present invention provides the salts of those compounds of formula (I) that have salt-forming groups, especially the salts of the compounds having an acid group, especially a carboxylic group, a N-hydroxycarbamoyl group, and a sulfo group, or the salts of the compounds having a basic group, especially an amino or guanidino group.
• the salts are especially physiologically tolerable salts, for example alkali metal and alkaline earth metal salts (e.g. sodium, potassium, lithium, calcium and magnesium salts), ammonium salts and salts with an appropriate organic amine or amino acid (e.g. arginine, procaine salts), and the addition salts formed with suitable inorganic acids (e.g.
• hydrochlorides, hydrobromides, sulfates, phosphates) or carboxylic and sulfonic organic acids e.g. acetates, trifluoroacetates, citrates, succinates, malonates, lactates, tartrates, fumarates, maleates, methanesulfonates, ?-toluenesulfonates.
• carboxylic and sulfonic organic acids e.g. acetates, trifluoroacetates, citrates, succinates, malonates, lactates, tartrates, fumarates, maleates, methanesulfonates, ?-toluenesulfonates.
• hydrates, solvates of compounds of formula (I), and physiologically hydrolyzable derivatives (i.e., prodrugs) of compounds of formula (I) are included within the scope of the present invention.
• Particularly preferred prodrugs of the compounds of formula (I) are ester derivatives. They include esters of compounds of formula (I) wherein W is -COOH, or wherein a carboxy group is present in any of the substituents Ri, R 2 , R 3 and Q, which may be obtained by condensation of such carboxy group with a pharmaceutically acceptable alcohol, e.g.
• a pharmaceutically acceptable carboxylic acid e.g. acetic acid, pivalic acid, benzoic acid and the like.
• Other particularly preferred prodrugs within the present invention are the cyclic condensation products between compounds of formula (I), wherein W is -CONHOH and Ri is hydrogen, and formaldehyde, or an aldehyde of formula T-CHO, or a ketone of formula TT'CO, wherein T and T' are carbon radicals, such as lower alkyl, phenyl, benzyl, optionally substituted by one to three substituents selected from by C ⁇ -C alkyl, hydroxy, C ⁇ -C alkoxy, amino, methylamino, dimethylamino, chloro and fluoro.
• T and T' are carbon radicals, such as lower alkyl, phenyl, benzyl, optionally substituted by one to three substituents selected from by C ⁇ -C alkyl, hydroxy, C ⁇ -C alkoxy, amino, methylamino, dimethylamino, chloro and fluoro.
• condensation products which are represented herebelow, are obtained by mixing the two components, optionally in the presence of acid catalysts, as those employed for the formation of ketals from alcohols and ketones, and removing water by evaporation, azeotropically or by molecular sieves.
• the present invention encompasses all the possible stereoisomers (e.g. diastereoisomers, epimers, geometrical isomers) of the compounds of formula (I), as well as their racemic or optically active mixtures.
• the present invention also includes, within its scope, pharmaceutical compositions comprising one or more of the compounds (I) as active ingredients, in association with pharmaceutically acceptable carriers, excipients or other additives, if desirable.
• Preferred compounds within the present invention have the structure (F):
• W is -CONHOH or -COOH
• R 2 is a group G which is:
• Ci-Cio alkyl or C 2 -C ⁇ o alkenyl either unsubstituted or substituted by C -C 7 cycloalkyl, or by one to three substituents selected from chloro, fluoro, hydroxy, C C alkoxy, C ⁇ -C 4 alkyl, amino, methylamino, dimethylamino, -CONH 2 , -CONHCH 3 or -CONHC(CH 3 ) 3 , C C 4 alkylthio, C ⁇ -C alkylsulfonyl, phenoxy, phenylthio and phenylsulfonyl, wherein the phenyl group may in turn be substituted by chloro, fluoro, methoxy or methyl; or
• aryl group more preferably phenyl, methylenedioxyphenyl, naphthyl or indanyl, each of which is optionally substituted by one to three substituents selected from chloro, fluoro, hydroxy, C ⁇ -C 4 alkoxy, amino, methylamino, dimethylamino, Cj-C 4 alkyl, C 3 -C 7 cycloalkyl, C ⁇ -C 4 alkylthio, C ⁇ -C 4 alkylsulfonyl, phenoxy, phenylthio and phenylsulfonyl, phenyl, benzyl, phenethyl, phenpropyl, naphthyl and pyridyl, and wherein any phenyl, naphthyl and pyridyl ring may in turn be substituted by one to three substituents selected from chloro, fluoro, methyl, hydroxy, methoxy, amino, methylamino and
• an unsaturated heterocyclyl group selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, thienyl, furyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzothienyl, benzothiazolyl, benzoxazolyl, isobenzofuranyl, benzofuranyl, benzimidazolyl, indazolyl, chromenyl, indolyl, oxindolyl, quinolyl, isoquinolyl, isoindolyl, cinnolinyl and purinyl, each of which is optionally substituted by one to three substituents selected from chloro, fluoro, hydroxy, C ⁇ -C alkoxy, amino, methyl
• Ri is hydrogen or methyl
• R 2 is -CONHG or -CONGG', wherein G is as defined above and G', which is the same or different, is as defined above for G; or
• Ri and R 2 taken together with the nitrogen atom to which they are attached, form a 3- to 7- membered azaheterocyclyl ring, optionally containing N, O, S or SO 2 as an additional ring member, which may be substituted by oxo on one or two carbon ring atoms adjacent to the linking nitrogen atom, and which is optionally fused with a benzene ring, the azaheterocyclyl group being either unsubstituted or substituted at one or more carbon and/or nitrogen atoms by chloro, fluoro, hydroxy, C ⁇ -C 4 alkoxy, amino, methylamino, dimethylamino, C C 4 alkyl, phenyl, 4-fluorophenyl, benzyl, 4-fluorobenzyl, alpha-methylbenzyl, methylenedioxyphenyl, 2- phenethyl, 2-(4-fluorophenyl)ethyl, piperonyl, carbamoyl
• Ri is hydrogen or methyl and R 2 is -SO 2 -azaheterocyclyl, wherein azaheterocyclyl is as defined above; or Ri is hydrogen or methyl, and R is -CO-azaheterocyclyl, wherein azaheterocyclyl is as defined above;
• R 3 is -CH 2 -alkyl, -(CH 2 ) deliberately-cycloalkyl, -(CH 2 ) n -O-alkyl, -(CH 2 ) n -O-(CH 2 ) ra -cycloalkyl, -(CH 2 ) n - O-(CH 2 ) m -aryl, -(CH 2 ) n -O-(CH 2 ) m -heterocyclyl, -(CH 2 ) n -S-alkyl, -(CH 2 ) n -S-(CH 2 ) m - cycloalkyl, -(CH 2 ) n -S-(CH 2 ) m -aryl, -(CH 2 ) n -S-(CH 2 ) m -heterocyclyl, -(CH 2 ) n -SO-alkyl, - (CH 2 ) n
• phenyl group is either unsubstituted or substituted by chloro, fluoro, cyano, cyanomethyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, phenoxy, 4-chlorophenoxy, 4- fluorophenoxy, benzyloxy, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 4- cyanophenyl, 4-cyanomethylphenyl, 4-pyridyl, 4-pyridyloxy; Q is:
• G and G ⁇ being as defined above, are preferably selected from C ⁇ -C 6 straight or branched alkyl, Cs-C ⁇ cycloalkyl, phenyl, tolyl, methylenedioxyphenyl, piperonyl and pyridyl, either unsubstituted or substituted by one to three substituents selected from chloro, fluoro, hydroxy, hydroxymethyl, C C alkoxy, amino, methylamino, dimethylamino, C C alkyl, C 3 -C 7 cycloalkyl, -CONH 2 , -CONHCH 3 , - CONHC(CH 3 ) 3 , -CONH(4-fluorophenyl), -
• azaheterocyclyl being as defined above, is, either unsubstituted or substituted by one to three substituents selected from hydroxy, hydroxymethyl, C ⁇ -C 4 alkoxy, carbamoyl, carbomethoxy, carbethoxy, mesyl, C ⁇ -C 6 linear or branched alkyl, trifluoromethyl, C 3 -C cycloalkyl, aryl, heterocyclyl and aryl-(Cj-C 3 )alkyl or heterocyclyl-(C ⁇ -C 3 )alkyl; or said azaheterocyclyl group is substituted by a group -CONH- R ⁇ , wherein R ⁇ , being as defined above, is selected from methyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, 4-fluor
• the azaheterocyclyl ring is preferably selected from aziridine, azetidine, morpholine, thiomorpholine, piperidine, pyrrolidine, piperazine, thiazolidine, tetrahydroisoquinoline, hexahydropyridazine, succinimido, phthalimido, saccharinyl, hydantoinyl, and oxoisoindolinyl.
• the azaheterocyclyl moiety is preferably morpholino or piperidino.
• Q is a group -CO-azaheterocyclyl
• the azaheterocyclyl moiety is preferably selected from azetidine, morpholine, thiomorpholine, pyrrolidine, piperidine, piperazine, pyridazine, thiazolidine, tetrahydroisoquinoline, hexahydropyridazine and hexamethylenimine.
• the aryl group or moiety in the definitions of Q is preferably selected from phenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl, methylenedioxyphenyl, naphthyl, and heterocyclyl is preferably pyridyl.
• a further preferred group of compounds are cyclic acetonide prodrugs of formula (IF): wherein R 2 , R 3 and Q are as defined above and T is methyl or a hydrogen atom, and T' is methyl, C 2 -C lower alkyl, phenyl, benzyl, optionally substituted by one to three substituents selected from by C ⁇ -C alkyl, hydroxy, C ⁇ -C alkoxy, amino, methylamino, dimethylamino, chloro and fluoro. More preferably, T and T' are methyl.
• the present invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and, as an active ingredient, a compound of the invention as defined above.
• Compounds of the general formula (I) may be prepared by any suitable method known in the art, and/or by the following processes, which form another aspect of the invention.
• the groups W, Ri , R 2 , R and Q are as defined above. It is understood that in the processes below any functional group (e.g. carboxyl, hydroxyl or amino), if needed or desired, can be masked by conventional methods and unmasked at the end or when convenient.
• a preferred process for preparing a compound of formula (I) comprises: (a) reacting a beta-lactam compound of formula (III): W
• R 2 and R are as defined above, and W' is COOH, CONHOH or a protected derivative thereof, with:
• a process for preparing preferred compounds of formula (F) comprises: (a') reacting a beta-lactam compound of general formula (IIF):
• the reaction between the beta-lactam of formula (III) or (III') and an amine among those hereabove detailed in step (a) or (a') above can be carried out in organic solvents, especially dimethylformamide (hereinafter DMF), tetrahydrofuran (hereinafter THF), acetonitrile, dimethylsulfoxide (hereinafter DMSO) and toluene, or in aqueous organic solvents, especially aqueous THF, aqueous DMF, and aqueous acetonitrile, at temperatures ranging from 0 to 120 °C, either in the absence or in the presence of external bases.
• organic solvents especially dimethylformamide (hereinafter DMF), tetrahydrofuran (hereinafter THF), acetonitrile, dimethylsulfoxide (hereinafter DMSO) and toluene
• aqueous organic solvents especially aqueous THF, aqueous DMF, and aqueous
• W' is a protected carboxy derivative, it is preferably benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxy- benzyloxycarbonyl, tert-butoxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, trimethylsilyloxycarbonyl, tert-butyldimethyl-silyloxycarbonyl, phenyl-dimethyl-silyloxy- carbonyl, allyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl and n-butoxycarbonyl.
• W' is a protected derivative of CONHOH
• it is preferably a group of formula CONHORio or CON(Rn)OR ⁇ 0
• Rio and Rn are, respectively, hydroxy- and amino-protecting groups, known per se and removable by hydrogenolysis or by hydrolysis.
• Preferred Rio and Rn groups include benzyl, p-methoxybenzyl, p-nitrobenzyl, trimethylsilyl, tert- butyl, tert-butoxycarbonyl, tetrahydropyranyl, and trityl.
• step (F) in step (b) above may include any or all of the following steps in any order:
• a preferred conversion of this type is hydrogenolysis, especially in the presence of a palladium catalyst, in an inert organic solvent 5 such as ethanol or DMF or the like, especially at room temperature and under atmospheric pressure or moderate pressure, which is suitable for the conversion, e.g., of benzyl and p- nitrobenzyl esters into the parent carboxylic acids, or of O-benzyl and O,N-bis-benzyl hydroxamates into the parent hydroxamic acids.
• Another preferred conversion of this type is acid hydrolysis, especially by trifluoroacetic acid, hydrochloric acid, or by aluminium 0 trichloride, in the presence or absence of anisole, in inert organic solvents such as THF, acetonitrile and the like, especially between -20 and +30 °C, which is suitable for the conversion, e.g., of tert-butyl esters and p-methoxybenzyl esters into the parent carboxylic acids, or of O-tert-butylhydroxamates, O-(p-methoxybenzyl)-hydroxamates, and O,N-bis(p- methoxybenzyl) hydroxamates into the parent hydroxamic acids.
• a further preferred 5 conversion of this type is alkalyne hydrolysis, especially by NaOH, KOH, LiOH, KOSi(CH 3 ) 3 , in an inert organic solvent or in water or in admixtures thereof, which is particularly suitable for the conversion of lower alkyl esters, e.g. the methyl, ethyl and n- butyl esters, into the parent carboxylic acids.
• -(b 11 ) the conversion of the group W', which is carboxy or an activated derivative thereof, o into a group W, which is -CONHOH.
• This conversion entails the condensation of such compounds of formula (IN) with hydroxylamine or a salt thereof, or with an O-protected hydroxylamine of formula R ⁇ 0 O- ⁇ H , or an N,O-diprotected hydroxylamine of formula RioO-NHRii , wherein Rio and R are as defined above, or a salt thereof, and then removal of said protecting groups Rio and Rn , if present, according to (b 1 ) above.
• Such condensation 5 is carried out according to general methodologies for the conversion of carboxylic acids or activated derivatives thereof into hydroxamic acids, which are well known in the art.
• activated derivatives of the carboxy group are the acid chloride, mixed anhydrides, and esters.
• the acid chloride is obtained by reacting the acid or a salt thereof with reagents such as oxalyl chloride or thionyl chloride; mixed anhydrides are obtained by o reacting the acid or a salt thereof with chlorocarbonates, such as ethyl chlorocarbonate, or with acid halides, such as pivaloyl chloride; esters, which are, preferably, the methyl, ethyl, n- butyl, pentafluorophenyl, hydroxysuccinyl, or hydroxybenzotriazolyl esters, are obtained by reaction of the acid with the corresponding alcohols in the presence of a dehydrating agent, for example dicyclohexyl carbodiimide (hereinafter DCC), N,N-dimethylaminopropyl-N'- ethyl carbodiimide (EDC), and 2-ethoxy-l -ethoxycarbonyl- 1,2-dihydroquinoline (EED)
• Esters in particular the methyl, ethyl, and n-butyl esters, may be present from the beginning in the azetidinone intermediates of formula (III) and (III') above.
• An O-protected 5 hydroxylamine is, preferably, O-benzylhydroxylamine, O-tert- butylhydroxylamine, O-tert- butyldiphenylsilyl hydroxyamine, O-(4-methoxybenzyl)-hydroxylamine, O-(4- nitrobenzyl)hydroxylamine, O-trimethylsilylhydroxylamine, and O-(tert- butoxycarbonyl)hydroxylamine.
• N,O-diprotected hydroxylamine is, preferably, N,O- bis(benzyl)hydroxylamine, N,O-bis(4-methoxybenzyl)hydroxylamine, N,O-bis(tert-butoxy- l o carbonyl)hydroxylamine, N-(tert-butoxycarbonyl)-O-(tert-butyldimethylsilyl)hydroxylamine, and N-(tert-butoxycarbonyl)-O-(tetrahydropyranyl)hydroxylamine.
• the condensation reaction with hydroxylamine, O-protected hydroxylamines, N,O-diprotected hydroxylamines, and the salts thereof is carried out in an inert organic solvent, such as DMF, THF, acetonitrile, dichloromethane, toluene and the like, at temperatures ranging from -20 to
• R 2 is an amino protecting group, according to methods well known per se, for example by the methods of removal of amino protecting groups which are part of the techniques of peptide chemistry.
• Particularly preferred R 2 groups for such conversion are electron-withdrawing groups, in particular alkoxy- or benzyloxy-carbonyl groups such as tert-butoxycarbonyl, benzyloxycarbonyl and 4-nitro or 4-methoxy derivatives
• R 2 is tert-butoxycarbonyl, which can be removed by treatment with trifluoroacetic acid (TFA), optionally in the presence of anisole, in an inert organic solvent; in another preferred embodiment, R 2 is benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, which can be removed
• Ri and R 2 groups are the same groups detailed for the preferred compounds of formula (I). Such conversion encompasses functionalizations of amino groups well known in the art, such as alkylation, acylation, sulfonylation, and the like, and is performed according to methods well known per se.
• such conversion is performed on compounds of formula (IV) or (IV) wherein W' is protected carboxy, thereafter removing the protecting group to obtain a compound of formula (I) or (F) wherein W is carboxy, by the general methodology described under (b 1 ) above and, optionally, by converting the so-obtained compound of formula (I) or (F) wherein W is carboxy into the corresponding compound wherein W is -CONHOH, by the general methodology described under (b") above; -(b v ): the conversion of any group W, Ri , R 2 , R 3 and Q into any different group Ri , R 2 , R 3 and Q, to be selected within the specifications stated above, by methodologies known per se.
• the resultant compounds of formula (I) or (F) may be converted into the desired salts, prodrugs, hydrates or solvates thereof by means of well known reactions, which include salt preparation by reaction with a pharmaceutically acceptable acid, or conversion of any hydroxy or carboxy group into an ester thereof, if desired, by condensation with a pharmaceutically acceptable alcohol or with a pharmaceutically acceptable carboxylic acid.
• the amines used in step (a) above are known compounds or are prepared from known compounds by known methods.
• beta-lactams of formula (III) or (IIF) above are known compounds or can be prepared from known compounds by methodologies known per se or by analogy with the specific preparative examples herein.
• a preferred preparation of compounds of formula (III) or (IIF) includes:
• -(d 1 ) cyclization of an aspartic acid derivative to obtain a compound of formula (III) or (IIF) wherein R 3 is hydrogen, by reaction with a suitable condensing agent; -(d 11 ): conversion of a compound of formula (III) or (IIF) wherein R 3 is hydrogen into a compound of formula (III) or (IIF) wherein R 3 is as described above, by deprotonation with a strong base and alkylation of the resulting beta-lactam enolate with an agent of formula R 3 - X, wherein X is halo, e.g. chloro, bromo or iodo, or sulfonyloxy, e.g.
• step (d 1 ) above are described in the literature, the preferred aspartic acid derivative being usually dibenzyl aspartate or di(4-nitro)benzyl aspartate.
• step (d 1 ) is described in the literature, the preferred aspartic acid derivative being usually dibenzyl aspartate or di(4-nitro)benzyl aspartate.
• Some of the resultant azetidinones (III) or (IIF) wherein R 3 is hydrogen, W' is carboxy or an ester thereof, and R 2 is hydrogen or tert-butyldimethylsyl are also commercially available.
• a preferred compound in step (d") is a compound of formula (III) or (IIF) wherein R 3 is hydrogen, R 2 is tert-butyldimethylsilyl, and W' is free carboxy, since the carboxylate anion helps at avoiding racemization at the azetidinone 4-C, and increases regioselectivity of alkylation by the R 3 -X reagent at the azetidinone 3-C.
• the conditions described in steps (a), (b), (c) and (d) do not usually promote epimerization or racemization at pre-existing chiral centers.
• step (d 1 ) above is an L-aspartic acid derivative
• the reaction affords a chiral azetidinone of formula (IIF), wherein R 3 is hydrogen and R 2 , W' are as described above.
• R 3 is hydrogen
• the configuration at the C-4 atom addresses stereoselective alkylation, by the R 3 -X reagent, in a transoid relationship with the W' substituent.
• step (d") above stereoselectively affords the corresponding azetidinones of formula (IIF) wherein R 3 , being as described above, is different from hydrogen, with the depicted configurations at the two chiral centers. Said configurations of the two chiral centers are the same as found in compounds of formula (F) herein specifically preferred. Accordingly, it can be appreciated that steps (d 1 ) and (d") above are essential part of an original, fully stereocontroUed route to the compounds of formula (F).
• Another process for the preparation of compounds of formula (I) comprises: (e) alkylation of an aspartic acid derivative of formula (V):
• step (e) predominantly or exclusively affords a compound of formula (VI'):
• step (e) wherein W', Ri, R 2 , R 3 and Q' are as described above, from which the preferred compounds of formula (F) are obtained by step (f) above.
• the reaction of step (e) above is carried out according to conventional carbanion chemistry, i.e. with 2-4 equivalents of a strong base, such as LDA and the like, in aprotic organic solvents, such as THF, DMF, N-methylpyrrolidone, HMPA and the like, at temperatures ranging from -70°C to room temperature.
• a preferred W' group is free carboxy.
• a preferred Ri group is hydrogen.
• a preferred R 2 group is tert-butoxycarbonyl.
• Preferred Q' groups are either the acyclic or cyclic tertiary carboxamides described within Q above, or a carboxy ester, which in step (f) can be converted into the group Q above as generally known for the preparation of carboxamides.
• the compounds of formula (I) and (F) provided by the present invention are characterized by high inhibitory activity on matrix metalloproteinases (MMPs), especially collagenases, gelatinases and stromelysins.
• MMPs matrix metalloproteinases
• the following protocol was used to assess the biochemical activity of compounds of formula (F) against MMP-1, MMP-2, and MMP-3 (respectively, human interstitial collagenase, gelatinase A, and stromelysin-1).
• BIOCHEMICAL ASSAY Protocol A
• Human collagenase (MMP-1) was obtained as truncated recombinant enzyme encompassing residues 101-269 and did not require activation.
• Human gelatinase-A (MMP-2) was obtained as pro-enzyme (72 kDa) and was activated with 1 mM 4-aminophenylmercuric acetate for 30 min at 37 °C immediately prior to use.
• Human stromelysin-1-255 (MMP-3) was obtained as a recombinant pro-enzyme isolated from£. coli and activated by heat (1 h, 55 °C).
• the substrate was the commercial quenched-fluorescence peptide Mca-Pro-Leu-Glv-Leu- Dpa-Ala-Arg-NH ⁇ that is (7-methoxycoumarin-4-yl)Acetyl-Pro-Leu Gl -Leu-(3-[2,4- dinitrophenyl]-L-2,3-diamino-propionyl)-Ala-Arg-NH 2 (CG. Knight et al., FEBS Lett.296:263, 1992).
• the enzymes cleave at the Gly-Leu bond, removing the internally quenching Dpa group.
• concentration of the activated enzyme was determined by titration against representative inhibitors described in the literature and synthesized in house: Roche Ro31-9790 (N.G.
• Enzyme concentrations in the tests were set at 1.0 nM for MMP-1, 0.04 nM for MMP-2, and 3.0 nM for MMP-3. Under our assay conditions, we measured kcat / K M values of 26900,
• Example compound MMP-1 MMP-2 MMP-3 o Example 2 1.1 2.8 13
• Example 7 0.070 0.25 0.72
• Example 10 0.18 0.34 2.2
• Example 12 0.041 0.19 0.38
• Example 15 17 0.63 6.5
• Example 16 6.4 0.094 2.4
• Example 17 9.4 0.61 4.3
• Example 18 0.85 0.079 0.86
• Example 19 4.5 0.23 1.1
• Example 20 2.0 0.04 0.39
• Example 22 0.015 0.067 0.73
• Example 23 0.003 0.016 0.145
• Example 24 0.17 0.40
• Example 25 0.076 0.19 2.3
• Example 26 0.071 0.10 0.60
• Example 27 0.0065 0.02 0.24
• Example 28 7.5 0.60
• Example 30 0.0036 0.025 0.27
• Example 32 2.6 0.037 0.50
• Example 33 >10 0.46 6.6
• Example 34 2.4 0.021 1.4
• Example 35 0.0029 0.008 0.031
• Example 37 0.0018 0.0026 0.035
• Example 39 0.76 0.09 0.806
• Example 42 1.4 0.016 0.76
• Example 44 0.0089 0.0023
• THP-1 cells cultured in RPMI 1640 supplemented with 10% FCS, were distributed into 24- well plates, 1 mL of a suspension of lxl 0 6 cells/mL in each well. Compounds to be tested, dissolved in DMSO and diluted with the culture medium (1% final DMSO concentration) were added. Plates were incubated for 30 min at 37 °C in 5% CO 2 , and lipopolisaccharide (LPS 0111 :B4, 5 ⁇ g/mL) was added as a stimulant. After a further 4 h incubation, cells were harvested, centrifuged (2,000 ⁇ m, 7 min), and the surnatant was collected and freezed (-20 °C) until analysis.
• LPS 0111 :B4 lipopolisaccharide
• Example 7 A 4.0
• Example 13 A 6.71
• Example 19 A 7.5
• Table 4 reports the maximum plasma concentration (Cmax) and oral bioavailability (%F; calculated from dose-normalised ratio of oral to i.v. mean AUC values) after oral administration to rats or cynomolgus monkeys of a 10-15 mg single dose of some representative compounds of the present invention .
• Compounds of formula (I) can be used in human or veterinary medicine in the form of pharmaceutical preparations which contain them in association with a compatible pharmaceutical carrier material.
• a distinct aspect of the present invention is the preparation of pharmaceutical compositions carrying a compound of formula (I) as active ingredient, and a method of management (i.e. treatment or prophylaxis) of diseases or conditions mediated in humans and warm blood animals by MMPs and/or TACE, which method comprises administering an effective amount of a compound of formula (I) above, or a pharmaceutically acceptable salt thereof.
• the compounds of formula (I) can be administered:
• 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 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 adso ⁇ tion 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 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, hydroxy propylmethylcellulose, 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 al
• 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 flavouring 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, naturally-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;
• 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;
• Daily doses are in the range of about 0.1 to about 50 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the disease, and the frequency and route of administration; preferably, daily dosage levels for humans are in the range of 10 mg to 2 g.
• the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
• a formulation intended for the oral administration to humans may contain from 5 mg to 2 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
• Dosage unit forms will generally contain between from about 5 mg to about 1 g of active ingredient.
• compositions containing a compound of formula (I) can be used in medicine for the treatment of disease states characterised by a systemic or local imbalance of active MMPs and their natural inhibitors.
• MMP inhibitors in medicine has been illustrated above, and is well described in the recent literature: see, for example, D.E. Levy & A.M. Ezrin, "Matrix Metalloproteinase Inhibitor Drugs", in: Emerging Drugs: The Prospect for Improved Medicines, Chapter Ten (pp 205-230), Ashley Publications Ltd., 1997.
• the compounds of the present invention can be used, in particular, for the treatment of:
• inflammatory and autoimmune diseases especially rheumatoid arthritis, osteoarthritis, bone reso ⁇ tion, periodontal disease, multiple sclerosis, inflammatory bowel diseases;
• cancer including both tumor growth and tumor invasion by secondary metastases, with particular reference to breast cancer, small cell lung cancer, non- small cell lung cancer, glioblastoma, prostate cancer, ovarian cancer, gastric and esophageal cancers, pancreatic cancer, colorectal tumors, and bony metastases;
• angiogenic disorders especially diabetic retinopathies and macular diseases
• - cardiovascular diseases especially congestive hearth failure and vascular restenosis
• tissue diseases including ocular inflammation, corneal or tissue ulceration, wound healing;
• the present invention also includes the use of compounds of formula (I), for the treatment of any of the diseases above, as adjuncts to other conventional treatments; for example, together with anti-inflammatory or immunosuppressive drugs for the treatment of rheumatoid arthritis and multiple sclerosis, and together with cytotoxic or cytostatic drugs for the treatment of tumoral diseases.
• Step A (4-Benzyloxy-3 S-tert-butoxycarbonylamino-2R-isobutyl)succinyl-piperidinamide (prepared as described Example 1, step A; 1 g) was dissolved in 95% aqueous trifluoroacetic acid (5 mL), and the solution was stirred 2 hr at room temperature.
• step A above 340 mg
• 10% Pd/C 70 mg
• EtOH and THF 1 : 1; 30 mL
• the catalyst was removed by filtration (Celite filter aid ) and the solvent was evaporated, to leave the title compound as a white solid (245 mg).
• step A above 300 mg and 10% Pd/C (100 mg) were suspended in EtOH (20 mL) and stirred under a hydrogen atmosphere for 3 hr at room temperature.
• the catalyst was removed by filtration (Celite filter aid), washing with additional EtOH.
• the solvent was removed in vacuo to give the title compound (210 mg) as white solid.
• Step B In a manner analogous to that described in Example 1 (step B) , from the material of step A above (500 mg), with 10% Pd/C (50 mg) and under a hydrogen atmosphere, the title compound was obtained (290 mg) as a white solid.
• FT- R (KBr) 3411 br (NH,OH), 1750- 1714 br (acid and carbamate CO), 1630 (amide CO) cm “1 .
• Step B In a manner analogous to that described in Example 2 (step B), from the material of step A above (300 mg) and 10% Pd/C (60 mg), under a hydrogen atmosphere, the title compound was obtained as white solid (240 mg).
• step B In a manner analogous to that described in Example 1 (step B), from the material of step A above (290 mg), with 10% Pd/C (50 mg) under a hydrogen atmosphere, the title compound 0 was obtained as an amorphous solid (200 mg).
• step A reaction of (4-hydroxy-2R- isobutyl-3S-(4-toluenesulfonyl)amino)succinyl-mo ⁇ holinamide (200 mg) with O-benzyl- hydroxylamine hydrochloride (93 mg), N-methylmo ⁇ holine (0.13 mL) and TBTU (186 mg) o afforded (4-benzyloxyamino-2R-isobutyl-3 S-(4-toluenesulfonyl)amino)succinyl-morpholin- amide (176 mg) as a white solid.
• step B From the material of step A above (170 mg) with 10% Pd/C (50 mg) under hydrogen atmosphere, the title compound was obtained as a white solid.
• step A reaction of 4S- benzyloxycarbonyl- 1 -tert-butoxycarbonyl-3R-(4-methoxy)phenpropyl)azetidin-2-one (600 mg; see Preparation C) with morpholine (0.23 mL) afforded (4-benzyloxy-3 S-tert- butoxycarbonylamino-2R-(4-methoxy)phenpropyl)succinyl-mo ⁇ holinamide as a yellow oil (700 mg).
• step B From the material of step A above (700 mg) with 10% Pd/C (100 mg), under a hydrogen atmosphere, the title compound was obtained as a white solid (600 mg).
• step B From the material of step A above (300 mg), with 10% Pd/C (50 mg) under a hydrogen atmosphere, the title compound was obtained as pinkish solid (250 mg).
• step A reaction of 4S- benzyloxycarbonyl-l-tert-butoxycarbonyl-3-(4-methoxy)phenpropyl)azetidin-2-one (350 mg; see Preparation D) with piperidine (0.15 mL) afforded (4-benzyloxycarbonyl-3S-tert-butoxy- carbonylamino-2R-(4-methoxy)phenpropyl)succinyl-piperidinamide as a yellow oil (400 mg).
• step B From the material of step A above (250 mg), with 10% Pd/C (50 mg) under a hydrogen atmosphere, (3S-tert- butoxycarbonylamino-4-hydroxy-2R-(4-methoxy)phenpropyl)succinyl-piperidinamide was obtained as a colourless oil (200 mg).
• step A reaction of (3 S-tert-butoxy- carbonylamino-4-hydroxy-2R-(4-methoxy)phenpropyl)succinyl-piperidinamide (200 mg) with O-benzylhydroxylamine hydrochloride (85 mg), N-methylmorpholine (0.12 mL) and TBTU (172 mg) afforded (4-benzyloxyamino-3S-tert-butoxycarbonylamino-2R-(4- methoxy)phenpropyl)succinyl-piperidinamide (240 mg) as a white solid.
• step B From the material from step C above (240 mg), with 10% Pd/C (50 mg), under a hydrogen atmosphere, the title compound was obtained as a pinkish solid (175 mg).
• step A reaction of the compound described in Example 13, step A (600 mg), with 95% aqueous trifluoroacetic acid (5 mL) and work-up afforded (3 S-amino-4-benzyloxy-2R-(4-methoxy)phenpropyl)succinyl-morpholin- amide (500 mg), trifluoroacetate salt, as a yellow oil.
• step B reaction of the material from step A above (350 mg) with 37% aqueous HCHO (10 mL) and NaCNBH 3 (100 mg) afforded
• step C reaction of the material from step B above (250 mg) with 10% Pd/C (50 mg) under a hydrogen atmosphere afforded (3S-
• Step D In a manner analogous to that described in Example 5 (step A), reaction of the material from step C above (190 mg) with O-benzylhydroxylamine hydrochloride (95 mg), N-methyl- mo ⁇ holine (0.15 mL) and TBTU (193 mg) afforded (4-benzyloxyamino-3S-N,N- dimethylamino-2R-(4-methoxy)phenpropyl)succinyl-mo ⁇ holinamide (160 mg) as a colourless oil.
• Step E In a manner analogous to that described in Example 5 (step A), reaction of the material from step C above (190 mg) with O-benzylhydroxylamine hydrochloride (95 mg), N-methyl- mo ⁇ holine (0.15 mL) and TBTU (193 mg) afforded (4-benzyloxyamino-3S-N,N- dimethylamino-2R-(4-methoxy)phenpropyl)succinyl-mo ⁇ holin
• step B reaction of the material from step D above (160 mg) with 10% Pd/C (30 mg) under a hydrogen atmosphere afforded the title compound (130 mg) as a white solid.
• step A reaction of the material from Example 19, step A (270 mg), with (4-methoxybenzenesulfonyl)chloride (185 mg) and triethylamine (0.17 mL) afforded (4-benzyloxy-3S-(4-methoxyphenylsulfonyl)amino-2R-(4- methoxy)phenpropyl)succinyl-morpholinamide as a white solid (100 mg).
• step B reaction of the material from step A above (100 mg) with 10% Pd/C (20 mg) under a hydrogen atmosphere afforded 90 mg of (4-hydroxy-3 S-(4-methoxyphenylsulfonyl)amino-2R-(4-methoxy)phenpropyl)succinyl- mo ⁇ holinamide was obtained as a colourless oil.
• step A reaction of the material from step B above (90 mg) with O-benzylhydroxylamine (33 mg), N-methylmorpholine (0.05 mL) and TBTU (65 mg) afforded (4-benzyloxyamino-3S-(4-methoxyphenylsulfonyl)amino-2R-(4- methoxy)phenpropyl)succinyl-mo ⁇ holinamide (88 mg ) as a white solid.
• step B reaction of the material from step C above (88 mg) with 10% Pd/C (20 mg) under a hydrogen atmosphere afforded the title compound as a white solid (70 mg).
• step B reaction of the material from step A above (500 mg) with 10% Pd/C (100 mg) under a hydrogen atmosphere afforded (3S- tert-butoxycarbonylamino-2R-cyclopentylmethyl-4-hydroxy)succinyl-piperidinamide as a colourless oil (410 mg).
• Step C In a manner analogous to that described in Example 2 (step A), reaction of (3S-tert- butoxycarbonylamino-2R-cyclopentylmethyl-4-hydroxy)succinyl-piperidinamide (410 mg) with O-benzylhydroxylamine hydrochloride (205 mg), N-methylmorpholine (0.29 mL) and TBTU (410 mg) afforded (4-benzyloxyamino-3S-tert-butoxycarbonylamino-2R-cyclopentyl- methyl)succinyl-piperidinamide as a white solid (500 mg).
• Step D In a manner analogous to that described in Example 2 (step B), reaction of the material from step C above (500 mg) with 10% Pd/C (100 mg) under a hydrogen atmosphere afforded the title compound was obtained as a pink solid (400 mg).
• ESI-MS 420 MNa) + , 398 (MH) + , 342, 309, 298, 237 m/z.
• Step B A mixture of the compound from Step A above (5.6 g) and 5% Pd/C (1.2 g ) in EtOH (200 mL) was exposed to a hydrogen atmosphere for 2 hours under stirring. After purging the mixture with nitrogen, the catalyst was removed by filtration over Celite, and the filtrate was concentrated to dryness under reduced pressure, giving (3S-tert-butoxycarbonylamino-2R- cyclopentylmethyl-4-hydroxy)succinyl-piperidinamide (4.5 g) as a colourless oil .
• step A reaction of (3S-amino-4- benzyloxy-2R-cyclopentylmethyl)succinyl-piperidinamide trifluoroacetate salt (630 mg) with (4-methoxyphenylsulfonyl)chloride (400 mg) and triethylamine (0.78 mL) afforded (4- benzyloxy-2R-cyclopentylmethyl-3S-(4-methoxyphenylsulfonyl)amino)succinyl-piperidin- amide as a white solid (200 mg).
• step B reaction of the material from step A above (200 mg) with 10% Pd/C (60 mg) under a hydrogen atmosphere afforded
• step A reaction of the material from step B above (250 mg) with O-benzylhydroxylamine hydrochloride (110 mg), N-methyl- mo ⁇ holine (0.15 mL) and TBTU (215 mg) afforded (4-benzyloxyamino-2R-cyclopentyl- methyl-3S-(4-methoxyphenylsulfonyl)amino)succinyl-piperidinamide (265 mg) as a white solid.
• step B reaction of the material from step C above (260 mg) with 10% Pd/C (50 mg) under a hydrogen atmosphere afforded the title compound (125 mg) as a white solid.
• step B reaction of the material from step A above (220 mg) with 10% Pd/C (50 mg) under a hydrogen atmosphere afforded (3S-
• step A reaction of the material from step B above (180 mg) with O-benzylhydroxylamine hydrochloride (77 mg), N-methyl-
• step B reaction of the material from step C above (180 mg) with 10% Pd/C (50 mg) under a hydrogen atmosphere afforded (3S- tert-butoxycarbonylamino-4-hydroxyamino-2R-isobutyl)succinyl-dicyclohexylmethylamide
• Step A In a manner analogous to that described in Example 28 (step A), reaction of 4S-benzyl- oxycarbonyl-l-tert-butoxycarbonyl-3R-isobutylazetidin-2-one (360 mg; see Preparation A) with diphenylmethylamine (0.34 ml) and NaN 3 (33 mg) afforded (4-benzyloxy-3S-tert- butoxycarbonylamino-2R-isobutyl)succinyl-diphenylmethylamide (150 mg) as a white solid.
• step B reaction of the material from step A above (150 mg) with 10% Pd/C (30 mg) under a hydrogen atmosphere afforded (3S- tert-butoxycarbonylamino-4-hydroxy-2R-isobutyl)succinyl-diphenylmethylamide as a white solid (100 mg).
• step A reaction of the material from step B above (100 mg) with O-benzylhydroxylamine hydrochloride (42 mg), N-methyl- mo ⁇ holine (0.06 mL) and TBTU (85 mg) afforded (4-benzyloxyamino-3S-tert-butoxy- carbonylamino-2R-isobutyl)succinyl-diphenylmethylamide (100 mg) as a white solid.
• step B reaction of the material from step C above (100 mg) with 10% Pd/C (20 mg) under a hydrogen atmosphere afforded (3S- tert-butoxycarbonylamino-4-hydroxyamino-2R-isobutyl)succinyl-diphenylmethylamide as a white solid (90 mg).
• Step E In a manner analogous to that described in Example 3, reaction of the material from step D above (90 mg) with 95% aqueous trifluoroacetic acid (5 mL) afforded the title compound as a white solid (85 mg; trifluoroacetate salt). In DMSO solution, the compound is present as mixture of two rotamers (M, major; m, minor).
• step A reaction of 4S- benzyloxycarbonyl- l-tert-butoxycarbonyl-3R-cyclopentylmethylazetidin-2-one (500 mg; see Preparation D) with 1-piperonylpiperazine (545 mg) in acetonitrile afforded (4-benzyl- oxycarbonyl-3S-tert-butoxycarbonylamino-2R-cyclopentylmethyl)succinyl-(4-piperonyl)- piperazinamide (800 mg) as an oil.
• Step B In a manner analogous to that described in Example 1 (step B), reaction of the material from step A above (800 mg) with 10% Pd/C (100 mg) under a hydrogen atmosphere afforded (3S- tert-butoxycarbonylamino-2R-cyclopentylmethyl-4-hydroxy)succinyl-(4-piperonyl)piperazin- amide (600 mg) as a white solid.
• Step C In a manner analogous to that described in Example 2 (step A), reaction of the material from step B above (600 mg) with O-benzylhydroxylamine hydrochloride (160 mg), N-methyl- mo ⁇ holine (0.27 mL) and TBTU (385 mg) afforded (4-benzyloxyaminocarbonyl-3S-tert- butoxycarbonylamino-2R-cyclopentylmethyl)succinyl-(4-piperonyl)piperazinamide (280 mg) as a white solid.
• Step D In a manner analogous to that described in Example 2 (step B), reaction of the material from step C above (280 mg) with 10% Pd/C (50 mg) under a hydrogen atmosphere afforded the title compound (160 mg) as a white solid.
• Trifluoroacetate salt In DMSO, the compound is present as two conformers, ca. 1 : 1, whose H'-NMR signals coalesce upon heating.
• H J -NMR 400 MHz, DMSO-d 6 ): 1.21 and 1.22 (each s; 9 H, t-Bu of 2 conformers), 1.2-1.8 (m, 8 H, CH-CFiCH 2 -CH 2 Ph + piperidine 3-,5- methylene), 2.30 (m, 1 H, piperidine 4-proton), 2.45 (m, 2 H, OHb-Ph).
• H 1 - NMR 400 MHz, DMSO-d 6
• the compound is present as two conformers, ca. 1: 1, whose H ⁇ NMR signals coalesce upon heating.
• H'-NMR 400 MHz, DMSO-dg: 1.2-1.9 (m, 8 H, CH-C ⁇ CH CHJh + piperidine 3-, 5 -methylene), 2.45
• Step B A solution of the material from step A above (1 g) in CH 3 CN (15 mL) was treated with DMAP (4-dimethylaminopyridine; 46 mg) and Boc O (di-tert-butyldicarbonate; 1.67 g) at 40 °C for 30 min and then at room temperature overnight. After removal of the solvent in vacuo, the residue was dissolved in EtOAc and sequentially washed with aqueous 1M KHSO , aqueous saturated NaHCO 3 and brine. Drying over Na 2 SO 4 and evaporation left the title compound as a yellow oil.
• step B reaction of the material from step A above (8.6 g) with DMAP (300 mg) and Boc 2 O (7.93 g) afforded the title compound as a yellow oil (9.1 g).
• Step C In a manner analogous to that described in Preparation A (step B), reaction of the material from step B above (1.3 g) with DMAP (21 mg) and Boc 2 O (566 mg) afforded the title compound as a colourless oil (530 mg).
• Methanesulfonyl chloride (25.5 mL) was added dropwise to a solution of cyclopentane- methanol (32.4 mL) and triethylamine (46 mL) in dichloromethane (500 ml) at 0 °C After stirring overnight at room temperature, the mixture was sequentially washed with water, 2% hydrochloric acid, 4% aqueous sodium bicarbonate and water again. Following drying over sodium sulfate, the solvent was removed under vacuum, affording crude cyclopentylmethyl methanesulfonate (ca. 50 g) as a colourless oil.
• Methanesulfonyl chloride (31 mL) was added dropwise to a solution of 3-(4- methoxyphenyl)-l-propanol (50 g) and triethylamine (56 mL) in dichloromethane (800 mL) at 0 °C The resulting mixture was stirred overnight at room temperature. After washing with water, 2 % hydrochloric acid and 4 % aqueous sodium bicarbonate, the organic solution was dried over sodium sulfate and rotoevaporated to yield crude 3 -(4-methoxyphenyl)-l -propyl methanesulfonate as a colourless solid (ca. 83 g).
• This product and sodium iodide (75 g) in acetone (800 mL) were heated at reflux in the dark for 20 hours. After cooling to room temperature, the reaction mixture was poured into n-hexane/EtO Ac/water 1:1:1 (1.5 L) under stirring. The organic layer was washed with water, diluted aqueous sodium metabisulfite and 4 % aqueous sodium bicarbonate, then dried (Na 2 SO 4 ) and concentrated under reduced pressure. The residue was purified by passing it through a short pad of silica gel (eluting with n-hexane/EtOAc 95:5). The title compound was obtained as a pale yellow solid (75 g).
• the organic layer (mainly containing dicyclohexylacetyl azide as shown by IR abso ⁇ tion band at 2128 cm “1 ) was separated, washed twice with brine, dried (Na SO 4 ), then heated at reflux for 2 hr. Following evaporation of the solvent, a waxy solid was obtained which mainly consisted of dicyclohexylmethyl isocyanate (IR absorption band at 2275 cm “1 ). This crude isocyanate was suspended in 20% hydrochloric acid (100 mL) and heated at reflux for 8 h. The insoluble material was filtered off and the filtrate was concentrated in vacuo.
• Step A A solution of the compound from step A above (700 mg) in ethanol (30 mL) was exposed to a hydrogen atmosphere in the presence of 10% Pd-C (70 mg) for 4 hr at room temperature. After filtration (Celite filter aid) and rotoevaporation, N-(tert-butoxycarbonyl)-L-aspartic acid 4-piperidinamide (500 mg) was obtained as a yellowish foam.
• Step C The material from step B above (200 mg) in dry THF (5 mL) was treated at -40 °C under a nitrogen atmosphere with a 2 M solution of LDA in heptane/THF/benzene (Aldrich; 1.07 mL).
• Tablets containing the following ingredients may be produced in a conventional manner:

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