EP0581923A1 - Derives phosphono d'acides amines en tant qu'inhibiteurs de metalloproteases - Google Patents

Derives phosphono d'acides amines en tant qu'inhibiteurs de metalloproteases

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Publication number
EP0581923A1
EP0581923A1 EP93902386A EP93902386A EP0581923A1 EP 0581923 A1 EP0581923 A1 EP 0581923A1 EP 93902386 A EP93902386 A EP 93902386A EP 93902386 A EP93902386 A EP 93902386A EP 0581923 A1 EP0581923 A1 EP 0581923A1
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Prior art keywords
group
alkyl
optionally substituted
hydrogen atom
formula
Prior art date
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EP93902386A
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German (de)
English (en)
Inventor
Nigel Robert Arnold Beeley
Thomas Andrew Millican
John Richard Morphy
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UCB Celltech Ltd
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Celltech R&D Ltd
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Publication of EP0581923A1 publication Critical patent/EP0581923A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07F9/6533—Six-membered rings
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl

Definitions

  • This invention relates to a novel class of phosphonopeptidyl derivatives, to processes for their preparation and to their use in medicine.
  • cellular connective tissue synthesis is offset by extracellular matrix degradation, the two opposing effects existing in dynamic equilibrium.
  • Degradation of the matrix is brought about by the action of proteinases released from resident connective tissue cells and invading inflammatory cells, and is due, in part, to the activity of at least three groups of metalloproteinases. These are the collagenases, the gelatinases (or type-IV collagenases) and the stromelysins.
  • these catabolic enzymes are tightly regulated at the level of their synthesis and secretion and also at the level of their extracellular activity, the latter through the action of specific inhibitors, such as ⁇ 2 -macroglobulins and TIMP (tissue inhibitor of metalloproteinase), which form inactive complexes with metalloproteinases.
  • specific inhibitors such as ⁇ 2 -macroglobulins and TIMP (tissue inhibitor of metalloproteinase), which form inactive complexes with metalloproteinases.
  • Tumour cell gelatinase in particular, has been associated with the potential of tumour cells to invade and metastasise. Tumour invasion and metastasis is the major cause of treatment failure for cancer patients, and the use of a selective gelatinase inhibitor such as a compound of the present invention which is capable of inhibiting tumour cell invasion can be expected to improve the treatment of this disease.
  • R represents a -P(0)(X 1 R 6 )X 2 R 7 group, where X 1 and X 2 , which may be the same or different, is each an oxygen or a sulphur atom, and R 6 and R 7 , which may be the same or different each represents a hydrogen atom or an optionally substituted alkyl, aryl, or aralkyl group;
  • R 1 represents a hydrogen atom or an optionally substituted alkyl, alkenyl, aryl, aralkyl, heteroaralkyl or heteroarylthioalkyl group;
  • R 2 represents an optionally substituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkoxy, or aralkylthio group, or an amino (- NH 2 ), substituted amino, carboxyl (-C0 2 H) or esterified carboxyl group;
  • R 3 represents a hydrogen atom or an alkyl group
  • R 4 represents a hydrogen atom or an alkyl group
  • R 5 represents a group -[Alk ⁇ R 8 where Alk is an alkyl or alkenyl group optionally interrupted by one or more -O- or -S- atoms or -N(R 9 )- groups [where R 9 is a hydrogen atom or a C 1 _ 6 alkyl group], n is zero or an integer 1 , and R 8 is an optionally substituted cycloalkyl or cycloalkenyl group;
  • X represents an amino (-NH 2 ), or substituted amino, hydroxyl or substituted hydroxyl group
  • the compounds according to the invention can contain one or more asymmetrically substituted carbon atoms, for example those marked with an asterisk in formula (I).
  • the presence of one or more of these aysmmetric centres in a compound of formula (I) can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereoisomers, and mixtures, including racemic mixtures, thereof.
  • the -line is used at a potential asymmetric centre to represent the possibility of R- and S- configurations, the — « line and the — — line to represent an unique configuration at an asymmetric centre.
  • 6 alkenyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, n-hexyl, ethenyl, 1 -propenyl, 1 -butenyl or 2-butenyi group optionally substituted by one or more C
  • _ 6 alkoxy e.g.
  • C 6 . 12 aryl e.g. phenyl, C 3 . 8 cycloaIkyl, e.g. cyclohexyl, or C 3 . 8 cycloalkylC . 6 alkyl, e.g. cyclohexylmethyl group]
  • Aryl groups represented by R 1 and/or R 2 in compounds of formula (I) include C 6 . 12 aryl groups such as phenyl or 1-.or 2-naphthyl groups.
  • Aralkyl groups represented by R 1 and/or R 2 include C 6 _ 12 arylC.,_ 6 alkyl groups such as phenylC ⁇ galkyl, or 1- or 2-naphthylC ⁇ galkyl, for example benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, 1- or 2- naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl or naphthylpentyl groups.
  • the group R 1 in compounds of formula (I) is a heteroaralkyl group, it may be for example a Cg.gheteroarylC ⁇ galkyl group, such as an optionally substituted pyrrolylmethyl, furanylmethyl, thienyimethyl, imidazolylmethyl, oxazolylmethyl, thiazolylmethyl, pyrazolylmethyl, pyrrolidinylmethyl, pyridinylmethyl, pyrimidinylmethyl, morpholinylmethyl, or piperazinylmethyl group.
  • a heteroaralkyl group such as an optionally substituted pyrrolylmethyl, furanylmethyl, thienyimethyl, imidazolylmethyl, oxazolylmethyl, thiazolylmethyl, pyrazolylmethyl, pyrrolidinylmethyl, pyridinylmethyl, pyrimidinylmethyl, morpholinylmethyl, or piperazinylmethyl group.
  • Heteroarylthioalkyi groups represented by R 1 include C 3 . 6 heteroarylthioC 1 . 6 alkyl groups such as optionally substituted pyrrolylthiomethyl, furanylthio methyl , oxazoiylthiomethyl , thiazolylthiomethyl , py razo ly It hio methyl, py rrolidiny It hio methyl, py ridiny It hi o methyl, pyrimidinylthiomethyl, morpholinylthiomethyl, or piperazinylthiomethyi groups.
  • Optional substituents which may be present on heteroaralkyl or heteroarylthioalkyi groups represented by R 1 include those discussed below in relation to R 1 and/or R 2 when these groups are for example aralkyl or aralkylthioalkyl groups.
  • Cycloalkyl groups represented by the group R 2 in compounds according to the invention include C 3 . 8 cycloalkyl groups such as cyclopentyi or cyclohexyl groups.
  • R 2 is a cycloalkylalkyl group it may be for example a C3.3CycloalkylC.
  • R 2 is an aralkoxy or an aralkylthio group it may be for example a C 6 _ 12 arylC,_ 6 alkoxy or C 6 _ 12 arylC 1 _ 6 alkylthio group such as a phenylC 1 .
  • . 6 alkyti.io group e.g. a benzyloxy, phenylethoxy, phenylpropoxy, phenylbutoxy, benzylthio, phenylethylthio, phenylpropylthio or phenylbutylthio group.
  • the cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkoxy or aralkylthio groups represented by R 1 and/or R 2 in compounds of formula (I) may each optionally be substituted in the cyclic part of the group by one, two or more substituents [R 11 ] selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or Chalky!, e.g. methyl or ethyl, C.,_ 6 alkoxy e.g. methoxy or ethoxy, C 2 . 6 alkylenedioxy, e.g.
  • halogen atoms e.g. fluorine, chlorine, bromine or iodine atoms, or Chalky!, e.g. methyl or ethyl, C.,_ 6 alkoxy e.g. methoxy or ethoxy, C 2 .
  • ethylenedioxy, haloC ⁇ galkyl e.g. tri-fluoromethyl, C ⁇ galkylamino, e.g. methylamino or ethylamino, C- ⁇ gdialkylamino, e.g. dimethylamino or diethylamino, amino (-NH 2 ), nitro, cyano, hydroxyl (-OH), carboxyl (-C0 2 H), -C0 2 R 9 , where R 9 is as defined above, C,_ 6 alkylcarbonyl, e.g. acetyl, sulphonyl (-S0 3 H), C,_ 6 alkyfsulphonyl, e.g.
  • methylsulphonyl aminosulphonyl (-S0 2 NH 2 ), C ⁇ g alkylaminosulphonyl, e.g. methylami ⁇ osulphonyl or ethylaminosulphonyl, C ⁇ gdialkylaminosulphonyl e.g. dimethylaminosulphonyl or diethylaminosulphonyl, carboxamido (-CONH 2 ), C ⁇ galkylaminocarbonyl, e.g. methylaminocarbonyl or ethylaminocarbonyl, C,_ 6 dialkylaminocarbonyl, e.g.
  • R 11 substituents may be present at any ring carbon atom away from that attached to the rest of the molecule of formula (I). Thus, for example, in phenyl groups any substituents may be present at the 2-, 3-, 4-, 5- or 6- positions relative to the ring carbon atom attached to the remainder of the molecule.
  • Esterified carboxyl groups represented by R 2 include groups of formula - C0 2 R 1 2 where R 1 2 is a straight or branched, optionally substituted C 1 . 8 alkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t- butyl group; a C 6 . 12 arylC 1 .
  • alkyl group such as an optionally substituted benzyl, phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethy! group; a C 6.12 aryl group such as an optionally substituted phenyl, 1- naphthyl or 2-naphthyl group; a Cg. ⁇ aryloxyC ⁇ galkyi group such as an optionally substituted phenyloxymethyl, phenyloxyethyl , 1 - naphthyloxymethyl or 2-naphthyloxymethyl group; an optionally substituted C,_ 8 alkanoyloxyC
  • R 12 alkyl group such as an optionally substituted benzoyloxyethyl or benzoyloxypropyl group.
  • Optional substituents present on the groups R 12 include for example one or more halogen atoms such as fluorine, chlorine, bromine or iodine atoms, or C 1 . 4 alkyl, e.g. methyl or ethyl, or C 1 . 4 alkoxy, e.g. methoxy or ethoxy, groups.
  • groups R 3 and R 4 in compounds of formula (I) are alkyl groups, they may be for example C,_ 6 alkyl groups such as methyl or ethyl groups.
  • the groups R 6 and/or R 7 in compounds of formula (I) may each be a hydrogen atom or an optionally substituted straight or blanched C j __ 6 a.kyl t e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl or i-butyl, C 6 . 12 aryl, e.g. phenyl, or Cg. 12 arylC 1 . 6 alkyl l e.g. benzyl, phenylethyl or phenylpropyl group.
  • Optional substituents present on alkyl groups of this type include one or more C
  • C 6 . 12 arylthio e.g. phenylthio, Cg. ⁇ aryiC ⁇ galkoxy e.g. benzyloxy or C 6 _ 12 arylC
  • _ 6 alkylthio e.g. benzylthio.
  • the group Alk when it is present in compounds of formula (I) it may be a straight or branched C,_ 6 alkyl, e.g. methyl, ethyl, n-propyl i-propyl, n-butyl, i- butyl, n-pentyl or n-hexyl or C 2 .
  • 6 alkenyl e.g. ethenyl or 1-propenyl group optionally interrupted by one or more -O- or -S- atoms or -N(R 9 )- groups where R 9 is a hydrogen atom or a C- ⁇ galkyl group such as a methyl group.
  • the group R 8 in compounds of formula (I) may represent a C 3 . 8 cycloalkyl, e.g. cyclopentyi or cyclohexyl, or C 3 . 8 cycioalkenyl e.g. cyclopentenyl or cyclohexenyl, group optionally substituted by one, two or more C ⁇ galkyl, e.g. methyl or ethyl, C ⁇ galkoxy, e.g. methoxy or ethoxy, C,_galkylthio, e.g. methylthio, or hydroxyl groups.
  • X in the compounds of formula (I) represents a substituted amino group it may be for example a group of formula -NR 13 R 14 , where R 13 and
  • R 1 which may be the same or different, is each a hydrogen atom (with the proviso that when one of R 13 or R 14 is a hydrogen atom, the other is not) or an optionally substituted straight ot branched alkyl group, optionally interrupted by one or more -O- or -S- atoms or -N(R 9 )- or aminocarbonyloxy
  • R 13 and/or R 14 is an alkyl group it may be for example a C,_galkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, ort- butyl group, optionally interrupted by one or more -0- or -S- atoms, or - N(R 9 )- or aminocarbonyloxy groups and may be for example a methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl or ethylaminocarbonyloxymethyl group.
  • C,_galkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, ort- butyl group, optionally interrupted by one or more -0- or -S- atoms, or
  • the optional substituents which may be present on such groups include hydroxyl (-OH), carboxyl (-C0 2 H), esterified carboxyl (-C0 2 R 12 ), carboxamido (-CONH 2 ), substituted carboxamido, e.g. a group -CONR 13 R 14 where NR 13 R 14 is as defined herein, amino (-NH 2 ), substituted amino, for example a group of formula -
  • aryl e.g. C 6 _ ⁇ 2 aryl such as phenyl, optionally substituted by one, two or more R 11 substituents selected from those listed above in relation to the group R 2 .
  • cyclic amino groups represented by -NR 13 R 14 include morpholinyl, imidazolyl, piperazinyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, pyrrolidinyl, pyridinyl and pyrimidinyl groups.
  • group X is a substituted hydroxyl group it may be for example a group -OR 13 where R 13 is as defined above, other than a hydrogen atom.
  • Salts of compounds of formula (1 ) include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, such as hydrochlorides, hydrobromides, hydroiodides, p-toluene sulphonates, phosphates, sulphates, acetates, trifluoroacetates propionates, citrates, malonates, succinates, lactates, oxalates, tartarates and benzoates.
  • inorganic or organic acids such as hydrochlorides, hydrobromides, hydroiodides, p-toluene sulphonates, phosphates, sulphates, acetates, trifluoroacetates propionates, citrates, malonates, succinates, lactates, oxalates, tartarates and benzoates.
  • Salts may also be formed with bases.
  • Such salts include salts derived from inorganic or organic bases, for example alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
  • the group R in compounds of formula (I) may in particular be a - P(0)(OR 6 )OR 7 , e.g. a -P(0)(OH)OR 7 group, or a -P(0)(SH)OR ? or -
  • P(0)(OH)SR 7 group examples include -P(0)(OCH 3 )OCH 3 , - P(0)(OCH 2 CH 3 )OCH 2 CH 3 , -P(0)(OH)OH, -P(0)(OH)SH, -P(0)(SH)OH, - P(0)(OH)OCH 3 , -P(0)(OH)SCH 3 , -P(0)(OH)OCH 2 CH 3 , -P(0)(OH)OPh, - P(0)(OH)SPh, -P(0)(OH)OCH 2 Ph or -P(0)(OH)SCH 2 Ph, where Ph is a phenyl group optionally substituted by one or more substituents R 11 .
  • the group R 1 may in particular be a C j _ 6 alkyl group such as a methyl group, an aralkyl group such as benzyl group, an arylthioalkyl group such as a phenythiomethyl group or a heteroarylthioalkyi group such as thienylthiomethyl, pyridinylthiomethyl or pyrimidinylthiomethyl group or is especially a hydrogen atom.
  • the group R 2 may be in particular an optionally substituted Chalky!, C 3 _ gcycloalkyl, C 3 . 8 cycloalkylC 1 . 6 alkyl, C 6 . 12 aryl, Cg. ⁇ arylC ⁇ galkoxy or C 6 _ 1 2 aralkylthio group and, especially, a Cg_ 12 arylC.,_galkyl group.
  • Particular types of these groups are optionally substituted C 3 .
  • 6 alkyl such as n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl or i-pentyl; cyclopentyi; cyclohexyl; cyclopentylC,_galkyl, such as cyclopentylC 3 . 6 alkyl, e.g. cyclopentylpropyl, cyclopentylbutyl, or cyclopentylpentyl; phenyl; ⁇ - or ⁇ - naphthyl; phenyiC ⁇ galkoxy, e.g.
  • phenylethoxy, phenylpropoxy or phenylbutoxy phenylC ⁇ g alkylthio, e.g. phenylethylthio, phenylpropyfthio or phenylbutylthio; and, especially, phenyiC ⁇ galkyl such as phenylC 3 . 6 alkyl e.g. phenylpropyl, phenylbutyl or phenylpentyl; or 1 - or 2-naphthylC 1 _ 6 alkyl such as 1- or 2-naphthylC 3 . 6 alkyl, e.g...
  • the groups R 3 and R 4 in compounds of formula (I) may each in particular be a methyl group, or, especially, a hydrogen atom.
  • the group R 5 in compounds of formula (I) may be in particular a group - AlkR 8 , where R 8 is an optionally substituted cycloalkyl or cycloalkenyl group.
  • the group R 5 in compounds of formula (I) may be an optionally substituted C 3 _ 8 cycloalkylC,_ 6 alkyl [e.g. cyclopentylC ⁇ galkyl such as cyciopentylmethyl or cyclopentylethyl, or cyclohexyC
  • alkyl such as cyclohexenylmethyl], cycloalkylC,_ 3 alkoxyC ⁇ _ 3 alkyl [e.g. cyclopentylmethoxymethyl, cyclohexylmethoxymethyl] Cg.gcycloalkenylC ⁇ 3 alkoxyC, .3 al ky l [e . g . cyc lo pe n te n y l m et h o xy m et h yl o r cyclohexenylmethoxymethyl] C 3 . 8 cycloalkylC 1 . 3 alkylthioC 1 . 3 alkyii ⁇ e.g. cyclopentyimethylthiomethyl or cyclohexylmethylthiomethyl] or C 3 _
  • the group X in compounds of formula (I) may be in particular an amino (- NH 2 ) or -NR 1 3 R 1 4 group.
  • Particular -NR 1 3 R 1 4 groups are -NHR 1 4 groups.
  • Groups of this type include those where R 1 4 is a C,_ 6 alkyl group, for example a methyl, ethyl, or n-propyl group, optionally interrupted by one or more -O- or -S- atoms or -N(R 9 ) [e.g. -NH- or -N(CH 3 )-] or aminocarbonyloxy groups, and optionally substituted by a hydroxyl, carboxyl, carboxyalkyl, e.g.
  • a particularly useful group of compounds according to the invention is that of formula (I) wherein R 5 is an AlkR 8 , group, where Alk is a C ⁇ g alkyl and R 8 is a C 3 . 8 cycloalkyl or C 3 . 8 cycloalkenyl group.
  • R 2 is an optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkoxy or aralkylthio group.
  • a further particularly useful group of compounds of formula (I) are those wherein X is an amino or substituted amino group.
  • R 1 , R 3 and R 4 is each preferably a hydrogen atom.
  • R, R 2 , R 5 and X are as defined for formula (I); and the salts, solvates and hydrates thereof.
  • a particularly useful group of compounds of formula (la) are those wherein R represents a P(0)(OH)OR 7 group; R 2 represents an optionally substituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkoxy or aralkylthio group;
  • R 5 represents a group -AlkR 8 , where Alk is a C ⁇ _ 6 alkyl group and R 8 is a cycloalkyl or cycloalkenyl group;
  • X is an amino (-NH 2 ) or substituted amino group; and the salts, solvates and hydrates thereof.
  • Particuiarly useful compounds of formula (la) are those wherein R 5 is a group -AlkR 8 , and R 8 is an optionally substituted cyclohexyl group.
  • R 5 is a cyclohexylC 1 -6 alkyl group, particularly a cyclohexylmethyl group, are especially useful.
  • R 2 represents a C 3 . 6 alkyl group, particularly an iso-butyl or n-pentyl group, or a cycloalkylC 3 . 6 alkyl group, particularly a cyclohexylpropyl, cyclohexylbutyl or cyclohexylpentyl group, or especially an optionally substituted phenylC 2 . 6 alkyl group particularly an optionally substituted phenylethyl phenylpropyl, phenylbutyl or phenylpentyl group.
  • Optional substituents on the phenyl group may be one, two or more R 11 groups as defined for compounds of formula (I).
  • X may be a -NH 2 group or a group - NR 1 3 R 1 4 as defined for compounds of formula (I).
  • An especially useful group of compounds according to the invention has the formula (la) wherein R 2 is an optionally substituted phenylC 3.6 alkyl group, especially an optionally substituted phenylpropyl or phenylbutyl group, R 5 is a cyclohexylmethyl group; and X is a amino (-NH 2 ) or NR 1 3 R 1 4 group.
  • R 2 is an optionally substituted phenylC 3.6 alkyl group, especially an optionally substituted phenylpropyl or phenylbutyl group
  • R 5 is a cyclohexylmethyl group
  • X is a amino (-NH 2 ) or NR 1 3 R 1 4 group.
  • R 1 , R 2 , R 3 , R 4 , R 5 and X are as defined above, except where otherwise indicated. It will be appreciated that functional groups, such as amino, hydroxyl or carboxyl groups, present in the various compounds described below, and which it is desired to retain, may need to be in protected form before any reaction is initiated. In such instances, removal of the protecting group may be the final step in a particular reaction. Suitable amino or hydroxyl protecting groups include benzyl, benzyloxycarbonyl or t- butyloxycarbonyl groups. These may be removed from a protected derivative by oatalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as an alcohol e.g.
  • Suitable carboxyl protecting groups include benzyl groups, which may be removed from a protected derivative by the methods just discussed, or alkyl groups, such as a t-butyl group which may be removed from a protected derivative by treatment with trifluoroacetic acid in an aqueous solvent.
  • alkyl groups such as a t-butyl group which may be removed from a protected derivative by treatment with trifluoroacetic acid in an aqueous solvent.
  • Other suitable protecting groups and methods for their use will be readily apparent.
  • the formation of the protected amino, hydroxyl or carboxyl group may be achieved using standard alkylation or esterification procedures, for example as described below.
  • a compound of formula (I) may be prepared by coupling an acid of formula (II)
  • Active derivatives of acids for formula (II) include for example acid anhydrides, or acid halides, such as acid chlorides.
  • the coupling reaction may be performed using standard conditions for amination reactions of this type.
  • the reaction may be achieved in a solvent, for example an inert organic solvent such as an ether, e.g. a cyclic ether such as tetrahydrofuran, an amide e.g. a substituted amide such as dimethylformamide, or a halogenated hydrocarbon such as dichloromethane at a low temperature, e.g. -30°C to amibient temperature, such as -20°C to 0°C, optionally in the presence of a base, e.g. an organic base such as an amine, e.g.
  • the reaction may additionally be performed in the presence of a condensing agent, for example a diimide such as N.N'-dicyclohexylcarbodiimide, advantageously in the presence of a triazoie such as l-hydroxybenzotriazoie.
  • a condensing agent for example a diimide such as N.N'-dicyclohexylcarbodiimide, advantageously in the presence of a triazoie such as l-hydroxybenzotriazoie.
  • the acid may be reacted with a chloroformate for example ethylchloroformate, prior to reaction with the amine of formula (III).
  • Free hydroxyl or carboxyl groups in the starting materials of formulae (II) and (III) may need to be protected during the coupling reaction. Suitable protecting groups and methods for their removal may be those mentioned above.
  • Compounds of formula (II) for use in this reaction are preferably those wherein at least one of R 6 or R 7 in the group R is other than a hydrogen atom.
  • each of R 6 and R 7 is an optionally substituted alkyl, aryl or aralkyl group.
  • Such groups, when present in compounds of the invention may be cleaved as described below to yield other compounds of the invention whe . rein R 6 and/or R 7 is each a hydrogen atom.
  • Compounds of formula (I) wherein R is a group -P(0)(X 1 R 6 )X 2 R 7 and R 6 and/or R 7 is a hydrogen atom may be prepared from a corresponding compound of formula (I) wherein R 6 and/or R 7 is an optionally substituted alkyl, aryl or aralkyl group by a cleavage reaction, usir.g for example a reagent such as trialkylsilyl halide, e.g. a trialkylsilyl bromide such as bromotrimethylsilane, in an inert solvent such as a halogenated hydrocarbon e.g. dichloromethane, or an aqueous acid or alkali; or, when R 6 and/or R 7 is an aralkyl group by hydrogenolysis using reagents and conditions as described below for the preparation of intermediates of formula (II).
  • a reagent such as trialkylsilyl halide, e.g.
  • the groups R 6 and/or R 7 in the group R are preferably other than a hydrogen atom.
  • R 15 is an aralkyl group, such as a benzyl group, by hydrogenolysis, for example by reaction with hydrogen in the presence of a metal catalyst, e.g. palladium, on a support such as carbon.
  • the reaction may be performed in a solvent such as an alcohol, e.g. methanol optionally at an elevated pressure and temperature.
  • the intermediates of formula (IV) may be prepared by reaction of an acrylate of formula (V)
  • R 1 6 is a leaving group, for example a silyl group such as a trialkylsilyl group e.g. a trimethylsiiyi group, at an elevated temperature.
  • Acrylates of formula (V) may be prepared by reaction of an mono-ester of formula (VI)
  • reaction may be performed in a solvent, such as pyridine, optionally at an elevated .temperature.
  • Mono-esters of formula (VI) may be prepared by hydrolysis of the corresponding di-ester of formula (VII)
  • a base for example an alkali hydroxide such as potassium hydroxide, in an inert solvent such as dioxan at a low temperature e.g. around 0°C.
  • Diesters of formula (VII) may be prepared by alkylation of the corresponding malonates of formula R 15 OCOCH 2 C0 2 R 15 with a halide R 2 Hal, where Hal is a halogen atom such as a chlorine or bromine atom in the presence of a base, e.g. a hydride such as sodium hydride in a solvent such as tetrahydrofuran at ambient temperature.
  • a base e.g. a hydride such as sodium hydride in a solvent such as tetrahydrofuran at ambient temperature.
  • Intermediate phosphites of formula :P(OR 1 6 )(X 1 R 6 )X 2 R 7 for use in the preparation of intermediates of formula (IV) may be prepated by reaction of a phosphite HP(0)(X 1 R 6 )X 2 R 7 with an appropriate amine (R 15 ) 2 NH e.g. a silazane, at an elevated temperature, e.g. the reflux temperature.
  • Phosphites of formula HP(0)(X 1 R 6 )X 2 R 7 are either known compounds or may be prepared by methods analogous to those used for the preparation of the known compounds.
  • intermediate acids of formula (II) may be prepared by reaction of an acid R 2 CH 2 C0 2 H with a phosphonate P(0)(X 1 R 6 )(X 2 R 7 )CH 2 OR 16 where R 16 is a leaving group, for example a trifluoromethylsulphonyloxy group in the presence of a base such as n- butyllithium in a solvent such as tetrahydrofuran.
  • Phosphonates for use in this reaction may be prepared from the corresponding compound P(0)(X 1 R 6 )(X 2 R 7 )CH 2 OH by reaction with paraformaldehyde in the presence of a base such as triethylamine at an elevated temperature followed by reaction with a halide R 16 Hal in the presence of a base such as sodium hydride in a solvent such as an ether.
  • Phosphonates P(0)(X 1 R 6 )(X 2 R 7 )CH 2 OH are either known compounds or may be prepared by methods analogous to those used for the preparation of the known compounds.
  • the homochiral acids of formula (lla) may be prepared according to another feature of the invention by oxidation of an oxazolidinone of formula (VIII)
  • the compounds of formula (VIII) may be prepared by reaction of an acyl halide RCH 2 CH(R 2 )COHal (where Hal is a halogen atom such as chloride, bromine or iodine atom) with a solution of (S)-4-(phenylmethyl)-2- oxazolidinone in the presence of a base such as n-butyl lithium in a solvent such as tetrahydrofuran at a low temperature, e.g. around -78°C.
  • a base such as n-butyl lithium
  • solvent such as tetrahydrofuran
  • RCH 2 CH(R 2 )COHal may be prepared by treatment of the corresponding known acids RCH 2 CH(R 2 )C0 2 H with conventional halogenating agents for example thionyl halides under standard reaction conditions.
  • the compounds according to the invention are potent and selective inhibitors of gelatinase.
  • the activity and selectivity of the compounds may be determined by the use of appropriate enzyme inhibition test for example as described in Example A hereinafter. In our tests using this approach, compounds according to the invention have been shown to inhibit gelatinase with Ki values in the picomolar-nanomolar range and to have particularly useful selectivity for gelatinase over stromelysin and collagenase.
  • nude mice may be inoculated with a tumour cell line showing gelatinase - dependent invasion and the ability of compounds according to the invention to reduce subsequent lung tumour colonisation may be evaluated in accordance with standard procedures.
  • compounds according to the invention when administered intravenously at 1 mg/kg to mice in the above model have reduced lung tumour colonisation to negligable levels, and do not cause any adverse effects at this dose.
  • the compounds according to the invention can be expected to be of use to prevent tumour cell metastasis and invasion.
  • the compounds may therefore be of use in the treatment of cancer, particularly in conjunction with radiotherapy, chemotherapy or surgery, or in patients presenting with primary tumours, to control the development of tumour metastasises.
  • a compound of formula (I) for use in the treatment of cancer to control the " development of tumour metastasises.
  • Particular cancers may include breast, melanoma, lung, head, neck or bladder cancers.
  • the compounds of formula (I) may be formulated in a conventional manner, optionally with one or more physiologically acceptable carriers, diluents or excipients.
  • composition comprising a compound of formula (I) and a pharmaceutically acceptable diluent, carrier or excipient.
  • the invention provides a process for the production of a pharmaceutical composition comprising bringing a compound of formula (I) into association with a pharmaceutically acceptable diluent, carrier or excipient.
  • Compounds for use according to the present invention may be formulated for oral, buccal, parental or rectal administration or in a form suitable for nasal administration or administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceuticaily acceptable excipients such as binding agents (e.g. pregeiatinised maize starch, polyvinylpyrrolidone or hydroxypropl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregeiatinised maize starch, polyvinylpyrrolidone or hydroxypropl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium glycoll
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles; and preservatives.
  • the preparations may also co'ntain buffer salts, flavouring, colouring and sweetening agents as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds of formula (I) may be formulated for parental administration by injection e.g. by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form.
  • the compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compounds of formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds of formula (I) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.
  • the compounds for use according to the present invention are conventiently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack or dispenser device may be accompanied by instructions for admininstration.
  • doses of compounds of formula (I) used to control the development of tumour metastasises will vary depending on the condition of the patient to be treated but in general may be in the range around 0.5mg to 50mg/kg body weight, particularly from about 1 mg to 40mg/kg body weight. Dosage units may be varied according to the route of administration of the compound in accordance with conventional practice.
  • the tills compound was purified on silica, eluting with 35% ethyl acetate in hexane (10.5g).
  • Peak 2 (elution time 15.98 mins) yielded the SS isomer (58.4mg) as a white solid.
  • the activity and selectivity of the compounds of the invention may be determined as described below.
  • enzyme e.g. gelatinase, stromelysin, collagenase
  • substrate e.g. a range of inhibitor concentrations (0.1 -50 x Ki) and substrate (approx.
  • the reaction is stopped by adjusting the pH to 4 using 0.1 M sodium acetate buffer and the fluorescence read at an excitation wavelength of 280nm and emission wavelength of 346nm.
  • V 0 is the initial rate of reaction in the absence of inhibitor
  • V j is the initial rate in the presence of inhibitor
  • [E] is the total enzyme concentration
  • [j] the total inhibitor concentration in the reaction mixture.
  • Kj (app) was assumed to approximate to the true K j as [S] « K m for the substrate hydrolysis.
  • K j was determined by performing the analyses at several substrate concentrations. A plot of K j (app) vs. [S] then gave the true K j as the value of the y-axis intercept.

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Abstract

On décrit des composés de la formule (I) leurs sels, leurs solvates et leurs hydrates. Dans cette formule, R représente un groupe -P(O)(X1R6)X2R7, où X1 et X2 peuvent être les mêmes ou différents en étant chacun un atome d'oxygène ou de soufre et R6 et R7 peuvent être les mêmes ou différents en étant chacun un atome d'hydrogène ou un groupe alkyle, aryle ou aralkyle, le cas échéant substitué; R1 représente un atome d'hydrogène ou un groupe alkyle, alcényle, aryle, aralkyle, hétéroalkyle ou hétéroarylthioalkyle, le cas échéant substitué; R2 représente un groupe alkyle, alcényle, cycloalkyle, cycloalkylalkyle, aryle, aralkyle, aralcoxy, ou aralkylthio, le cas échéant substitué, ou un groupe amino (-NH2), un groupe amino substitué, un groupe carboxyle (-CO2H) ou carboxyle estérifié; R3 représente un atome d'hydrogène ou un groupe alkyle; R4 représente un atome d'hydrogène ou un groupe alkyle; R5 représente un groupe -[Alk]nR8 où Alk est un groupe alkyle ou alcényle, le cas échéant coupé par un ou plusieurs atomes -O- ou -S- ou par des groupes -N(R9)- [R9 est un atome d'hydrogène ou un groupe (C1-C6)alkyle], n est égal à zéro ou au nombre entier 1 et R8 est un groupe cycloalkyle ou cycloalcényle, le cas échéant substitué; X représente un groupe amino (-NH2) ou un groupe amino substitué, un groupe hydroxyle ou un groupe hydroxyle substitué. Ces composés sont des inhibiteurs des métalloprotéases et en particulier ils ont une activité sélective contre l'enzyme gélatinolytique et ils peuvent être utilisés dans le traitement du cancer pour combattre le développement de métastases tumorales.
EP93902386A 1992-01-15 1993-01-15 Derives phosphono d'acides amines en tant qu'inhibiteurs de metalloproteases Withdrawn EP0581923A1 (fr)

Applications Claiming Priority (2)

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GB9200826 1992-01-15
GB929200826A GB9200826D0 (en) 1992-01-15 1992-01-15 Peptidyl derivatives

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EP0581923A1 true EP0581923A1 (fr) 1994-02-09

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US5840698A (en) * 1994-10-27 1998-11-24 Affymax Technologies N.V. Inhibitors of collagenase-1 and stormelysin-I metalloproteases, pharmaceutical compositions comprising same and methods of their use
US5831004A (en) * 1994-10-27 1998-11-03 Affymax Technologies N.V. Inhibitors of metalloproteases, pharmaceutical compositions comprising same and methods of their use

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DK425582A (da) * 1981-09-25 1983-03-26 Wellcome Found Fremgangsmaade til fremstilling af amider
EP0328834A1 (fr) * 1988-02-16 1989-08-23 Merrell Dow Pharmaceuticals Inc. Inhibiteurs d'aspartate transcarbamylase
FR2652087B1 (fr) * 1989-09-15 1993-10-15 Bioprojet Ste Civile Derives d'amino-acides, leur procede de preparation et leurs applications therapeutiques.
DE4003574A1 (de) * 1990-02-07 1991-08-08 Bayer Ag Neue dipeptide, verfahren zu ihrer herstellung und ihre verwendung als renininhibitoren in arzneimitteln
GB9008078D0 (en) * 1990-04-10 1990-06-06 Beecham Group Plc Novel compounds

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WO1993014096A1 (fr) 1993-07-22
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JPH06506483A (ja) 1994-07-21
CA2105309A1 (fr) 1993-07-16

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