WO1999007679A1 - Composes peptidyles presentant une activite inhibitrice du tnf et de la mmp - Google Patents

Composes peptidyles presentant une activite inhibitrice du tnf et de la mmp Download PDF

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Publication number
WO1999007679A1
WO1999007679A1 PCT/GB1998/000272 GB9800272W WO9907679A1 WO 1999007679 A1 WO1999007679 A1 WO 1999007679A1 GB 9800272 W GB9800272 W GB 9800272W WO 9907679 A1 WO9907679 A1 WO 9907679A1
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Prior art keywords
alkyl
aryl
heteroaryl
compound
condition
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PCT/GB1998/000272
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English (en)
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Andrew Douglas Baxter
John Gary Montana
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Chiroscience Limited
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Priority claimed from PCT/GB1997/002149 external-priority patent/WO1998006696A1/fr
Application filed by Chiroscience Limited filed Critical Chiroscience Limited
Priority to AU58719/98A priority Critical patent/AU5871998A/en
Publication of WO1999007679A1 publication Critical patent/WO1999007679A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil

Definitions

  • This invention relates to a novel class of peptidyl derivatives, to processes for their preparation, and to their use in medicine.
  • Metalloproteinases including matrix metalloproteinase (MMP), (human fibroblast) collagenase, gelatinase and TNF convertase (TACE), and their modes of action, and also inhibitors thereof and their clinical effects, are described in WO- A-9611209, WO-A- 9712902 and WO-A-9719075, the contents of which are incorporated herein by reference.
  • MMP matrix metalloproteinase
  • TACE TNF convertase
  • MMP inhibitors may also be useful in the inhibition of other mammalian metalloproteinases such as the adamalysin family (or ADAMs) whose members include TNF convertase (TACE) and AD AM- 10, which can cause the release of TNF ⁇ from cells, and others, which have been demonstrated to be expressed by human articular cartilage cells and also involved in the destruction of myelin basic protein, a phenomenon associated with multiple sclerosis.
  • ADAMs adamalysin family
  • TACE TNF convertase
  • ADAM- 10 TNF convertase
  • MMP inhibitors are also disclosed in WO-A-9509833 and WO-A-9519961.
  • novel compounds of formula (I) which are useful inhibitors of matrix metalloproteinases and/or TNF ⁇ mediated diseases including degenerative diseases (such as defined above) and certain cancers.
  • novel compounds are of general formula (I): R S-CHR 10 -X-NR 11 -CHR 1 -Y-NR 4 R 5 (I)
  • R 1 is C ⁇ -alkyl-R 2 ;
  • R 2 is aryl or heteroaryl optionally substituted with R 3 (heteroaryl does not include unsubstituted 3-indolyl);
  • R 3 may be C ⁇ -alkyl, aryl, heteroaryl, halogen, OR 6 (except when R 2 is aryl), N(R 6 ) 2 where R 6 may be the same or different, CO 2 R 7 , COR 6 , CON(R 6 ) 2 (where R 6 may be the same or different), SOventR 6 (where n is 0-2 and R 6 is not H), SO 2 N(R 6 ) 2 (where R 6 may be the same or different), NR 6 COR 6 (where R 6 may be the same or different), NR 6 CO 2 R 7 (where R 7 is not H), NR 6 CON(R 6 ) 2 (where R 6 may be the same or different) or NR 6 SO 2 R 6 (where R 6 may be the same or different).
  • R 3 may also be a C ⁇ -alkyl group substituted by any group previously defined in R 3 ;
  • R 4 and R 5 may be the same or different taken from H or C 1-4 alkyl;
  • R 6 is H, C M -alkyl, aryl, C -alkyl-aryl, heteroaryl or C, ⁇ -alkyl-heteroaryl;
  • R 7 is H, C 1-4 -alkyl, C -alkyl-aryl, or C, ⁇ -alkyl-heteroaryl;
  • R 8 is H or the group COR 9 ;
  • R 9 is C,_ 4 alkyl, aryl, heteroaryl, C M alkyl-aryl or C M alkyl-heteroaryl;
  • R 10 and R 11 may be the same or different taken from the groups, H, C, ⁇ alkyl, (optionally substituted with R 12 ), aryl (optionally substituted with R 12 ), C 1-6 alkyl-aryl (optionally substituted with R 12 ), heteroaryl (optionally substituted with R 12 ), C, ⁇ alkyl- heteroaryl (optionally substituted with R 12 ), cyclo(C 3 ⁇ ) alkyl (optionally substituted with R 12 ) > C ⁇ - 6 alkyl-cyclo(C 3-6 )alkyl (optionally substituted with R 12 ), heterocyclo(C 4 ⁇ )alkyl (optionally substituted with R 12 ) or C M alkyl-heterocyclo(C 4 ⁇ )alkyl (optionally substituted with R 12 );
  • R 12 is COR
  • p and q may be 0 or 1 and may be the same or different;
  • R and S may be CH or N and may be the same or different;
  • Z may be H or C ⁇ alkyl-R 18 and may be attached to any available position on the nng;
  • R 13 is OR 7 , N(R 6 ) 2 where R 6 may be the same or different, C w alkyl, aryl, C w alkyl-aryl, heteroaryl or C I-4 alkyl-heteroaryl;
  • R 14 may be COR 6 , CO 2 R 7 (where R 7 is not H), CON(R 6 ) 2 where R 6 may be the same or different, SO 2 R 16 , or COR 16 ;
  • R 15 is H, C 1-4 alkyl; COR 9 , CO 2 R 19 , CON(R 6 ) 2 where R 6 may be the same or different or SO 2 R 9 ;
  • R 16 is C M alkyl (optionally substituted with R 17 ); R 17 may be CO 2 R 6 ,CON(R 6 ) 2 where R 6 may be the same or different, N(R 6 ) 2 where
  • R 6 may be the same or different, SO 2 R 9 or the groups:
  • R 18 is CO 2 R 6 ,CON(R 6 ) 2 where R 6 may be the same or different, N(R 6 ) 2 where R 6 may be the same or different, NHCO 2 R 19 , NHSO 2 R 9 or NHCOR 9 ;
  • R 19 is C M alkyl, C M alkyl-aryl or C M alkyl-heteroaryl; and the salts, solvates, hydrates and protected amino or protected carboxy derivatives thereof.
  • R 10 and R 11 are the same or different and are selected from H and optionally- substituted alkyl, alkyl-aryl, alkyl-heteroaryl, alkyl-cycloalkyl or alkyl-heterocycloalkyl; and
  • R 12 is NR 6 R 14 , phthalimido or any of the said groups.
  • 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 asymmetric 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 diastereomers, 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 a unique configuration at an asymmetric centre.
  • C, ⁇ alkyl refers to a straight or branched chain alkyl moiety having from one to six carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, butyl, ter/-butyl, pentyl, hexyl and the like.
  • C M alkyl refers to a straight or branched chain alkyl moiety having from one to four carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like.
  • C ⁇ alkyl refers to a straight or branched chain alkyl moiety having from one to four carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like. This term also refers to a case where a substituent, R 2 is directly bonded such as in C ⁇ -alkyl-R 2 and the like;
  • cyclo (C 3 ⁇ ) alkyl refers to a saturated alicyclic moiety having from three to six carbon atoms and includes for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • heterocyclo (C 4 ⁇ ) alkyl refers to a saturated heterocyclic moiety having from three to six carbon atoms and one or more heteroatom from the group N, O, S and includes for example azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and the like.
  • aryl means an optionally substituted phenyl or naphthyl group with the substituent(s) being selected, for example, from halogen, trifluoromethyl, C, ⁇ alkyl, alkoxy, phenyl and the like.
  • heteroaryl refers to aromatic ring systems of five to ten atoms or which at least one atom is selected from the group, O, N, or S and includes for example furan yl, thiophenyl, pyridyl, indolyl, quinolyl and the like.
  • halogen means fluorine, chlorine, bromine or iodine.
  • protected amino and “protected carboxy” mean amino and carboxy groups which are protected in a manner familiar to those skilled in the art.
  • an amino group can be protected by a benzyloxycarbonyl, tert- butoxycarbonyl, acetyl or like groups, or in the form of a phthalimido or like group.
  • a carboxyl group can be protected in the form of a readily cleavable ester such as the methyl, ethyl, benzyl or te/ ⁇ -butyl ester.
  • Salts of compounds of formula (I) include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, such as hydrochlorides, hydrobromides, p-toluenesulphonates, phosphates, sulphates, perchlorates, acetates, trifluoroacetates, propionates, citrates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
  • acid addition salts derived from inorganic or organic acids such as hydrochlorides, hydrobromides, p-toluenesulphonates, phosphates, sulphates, perchlorates, acetates, trifluoroacetates, propionates, citrates, malonates, succinates, lactates, oxalates, tartrates 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 magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
  • the "protected carboxy” group in compounds of the invention is an esterified carboxyl group, it may be a metabolically labile ester of formula CO 2 R 20 where R 20 may be an ethyl, benzyl, phenethyl, phenylpropyl, ⁇ - or ⁇ -naphthyl, 2,4- dimethylphenyl, 4-terf-butylphenyl, 2,2,2-trifluoroethyl, l-(benzyloxy)benzyl, 1- (benzyloxy)ethyl, 2-methyl-l-propionyloxypropyl, 2,4,6-trmethylbenzyloxymethyl or pivaloyloxymethyl group.
  • the present invention also provides a process for preparing a compound of general formula (I) as defined above. It will be appreciated that where a particular stereoisomer of formula (I) is required, the synthetic processes described herein may be used with the appropriate homochiral starting material and/or isomers may be resolved from mixtures using conventional separation techniques (eg. HPLC).
  • the compounds according to the invention may be prepared by the following process.
  • the groups R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R", R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R, S, W, X, Y and Z are as defined above, except where otherwise indicated.
  • functional groups such as amino, hydroxyl or carboxyl groups, present in the various compounds decribed below, and which it is desired to retain, may need to be in protected form before any reaction is initiated.
  • the process required for preparing compounds of general formula (I) comprises deprotecting (for example by hydrolysis) a compound of general formula (II)
  • R 8 represents a suitable protecting group (eg tert-butyl, trityl, benzoyl or acetate).
  • R 1 , R 8 , R 10 and R 11 are as defined above, or an active derivative thereof, with an amine of the formula HNR 4 R 5 (IV) wherein R 4 and R 5 are defined previously.
  • Amines of formula (IV) may be commercially available or can be readily obtained from commercially available starting materials using methods known to those skilled in the art.
  • Active derivatives of acids of formula (III) include for example acid anhydrides or acid halides, such as acid chlorides.
  • the coupling reaction may be performed using standard conditions foramination reactions of this type.
  • the reaction may be achieved in a solvent, for example an inert organic solvent such as an ether, eg. a cyclic ether such as tetrahydrofuran, an amide eg. a substituted amide such as dimethylformamide, or a halogenated hydrocarbon such as dichloromethane at a low temperature eg. -30°C to ambient temperature, such as -20°C to 0°C, optionally in the presence of as base, eg. an organic base such as an amine, eg. triethylamine or a cyclic amine such as N- methylmorpholine.
  • an inert organic solvent such as an ether, eg. a cyclic ether such as tetrahydrofuran, an amide eg. a substituted amide such as dimethylformamide, or a halogenated hydrocarbon such as dichloromethane at
  • 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 triazole such as 1-hydroxybenzotriazole.
  • a condensing agent for example a diimide such as N.N'-dicyclohexylcarbodiimide, advantageously in the presence of a triazole such as 1-hydroxybenzotriazole.
  • the acid may be reacted with a chloroformate for example ethylchloroformate, prior to reaction with the amine of formula (IV).
  • the amine of formula (VI) may be prepared by the coupling of a suitably protected amino-acid of formula (VII)
  • Suitable protecting groups include carbamates such as benzyloxycarbonyl (Cbz) or tert- butyloxycarbonyl (Boc).
  • Active derivatives of acids (V) include for example acid anhydrides or acid halides such as acid chlorides as outlined earlier.
  • the acid of general formula (III) may be prepared by coupling an acid of formula (V), or an active derivative thereof, with an suitably protected amine of formula (VII) followed by removal of any protecting groups as described previously.
  • ⁇ -Thioacetic acids and amino acids and their derivatives such as depicted by general formulae (V) and (VII) respectively can be obtained in optically pure or racemic form. In the homochiral form they provide asymmetric building blocks for the enantiospecific synthesis of compounds of general formula (I). Many of these derivatives can be readily obtained from commercially available starting materials using methods known to those skilled in the art. See “The Practice of Peptide Synthesis” by M. Bodanszk et al, Springer Verlag, New York, (1984) and WO-A-9221360.
  • R 21 represents a suitable leaving group (eg. a halogen such as bromide, or an alkylsulphonate ester such as methanesulphonate) with a thiol of general formula (X)
  • R 8 represents a suitable protecting group (eg. tert butyl, trityl, benzoyl or acetate), using standard conditions known to those skilled in the art, as exemplified in WO-A- 9005719.
  • Thiols of general formula (X) may be obtained from commercially available starting materials using methods known to those skilled in the art. Many thiols of general formula (X) are also commercially available.
  • R 1 , R 21 , R 10 and R 11 are as defined above (or suitably protected versions thereof) or an active derivative thereof, with an amine of formula (IV) using similar coupling conditions to those described for the preparation of compounds of formula (II).
  • Carboxylic acids of the structure depicted in formulae (IX) and (XI) can be obtained in chiral or racemic form. Many of these derivatives can be readily obtained from commercially available starting materials using methods known to those skilled in the art WO-A-9005719.
  • R u is not H and amino acids of general formula (VII) are required, these may be prepared by the nucleophilic displacement of an alkylating agent of formula (XIII) with an amine of formula (XIV)
  • R 11 and R 21 have been defined previously.
  • Amines of formula (XIV) may be commercially available or can be readily obtained from commercially available starting materials using methods known to those skilled in the art.
  • Compounds of formula (I) may also be prepared by interconversion of other compounds of formula (I).
  • a compound of formula (I) wherein R 1 is a C alkyl-R 2 may be prepared by hydrogenation (using palladium on carbon in suitable solvent, such as an alcohol, e.g. ethanol) of a compound of formula (I) wherein R 1 is a C M alkenyl group.
  • a compound of formula (I) wherein R 8 is a group R 9 CO may be prepared by acylation (using a suitable acid chloride R 9 COC1, in the presence of a base such as a triethylamine in a suitable solvent, such as a chlorinated solvent, e.g. dichloromethane) of a compound of formula (I) wherein R 8 is H.
  • a suitable solvent such as a chlorinated solvent, e.g. dichloromethane
  • Any mixtures of final products or intermediates obtained can be separated on the basis of the pysico-chemical differences of the constituents, in known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallization, or by formation of a salt if appropriate or possible under the circumstances.
  • the compounds according to the invention exhibit in vitro inhibiting activities with respect to stromelysin, collagenase and gelatinase. Compounds according to the invention also exhibit in vitro inhibition of TNF release.
  • the activity and selectivity of the compounds may be determined by use of the appropriate enzyme inhibition test, for example as described in Examples A-M hereinafter.
  • This invention also relates to a method of treatment for patients (including man and/or mammalian animals raised in the dairy, meat or fur industries or as pets) suffering from disorders or diseases which can be attributed to stromelysin as previously described, and more specifically, a method of treatment involving the administration of the matrix metalloproteinase inhibitors of formula (I) as the active constituents.
  • the compounds of formula (I) can be used among other things in the treatment of osteoarthritis and rheumatoid arthritis, and in diseases and indications resulting from the over-expression of these matrix metalloproteinases such as found in certain metastatic tumour cell lines.
  • compounds of formula (I) are useful in human or veterinary medicine since they are active as inhibitors of TNF and MMPs.
  • this invention concerns: a method of management (by which is meant treatment of prophylaxis) of disease or conditions mediated by TNF and/or MMPs in mammals, in particular in humans, which method comprises administering to the mammal an effective, amount of a compound of formula (I) above, or a pharmaceutically acceptable salt thereof; and a compound of formula (I) for use in human or veterinary medicine, particularly in the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by TNF and/or MMPs; and the use of a compound of formula (I) in the preparation of an agent for the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by TNF and/or MMPs.
  • the disease or conditions referred to above include inflammatory diseases, autoimmune diseases cancer, cardiovascular diseases, diseases involving tissue breakdown such as rheumatoid arthritis, osteoarthritis, osteoporosis, neurodegeneration,
  • Alzheimer's disease atherosclerosis, congestive heart failure, stroke, vasculitis,
  • the compunds of formula (I) may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • the compounds of the invention are effective in the treatment of humans.
  • composition containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to 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, flavouring agents, colouring 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 corn 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 absorption in the gastointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyeryl distearate may be employed. They may also be coated by the techniques described in the US Patents 4,256, 108;4, 166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules where in 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 polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occuring phosphatide, 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 dervied from fatty acids and a hexitol such a polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.
  • dispersing or wetting agents may be a naturally occuring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions 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. These compositions may be preserved by the addition of an anti-oxidant 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, suspending agent and one or more preservatives.
  • a dispersing or wetting agent, suspending agent and one or more preservatives Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavouring and colouring 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 oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally- occuring gums, for example gum acacia or gum tragacanth, naturally-occuring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be in 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.
  • a non-toxic parenterally-acceptable diluent or solvent for example as a solution in 1,3-butane diol.
  • acceptable 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.
  • the compounds of formula (I) may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • topical use creams, ointments, jellies, solutions or suspensions, etc containing the compounds of Formula (I) are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
  • Dosage levels of the order of from about 0.05 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above- indicated conditions (about 2.5 mg to about 7 gms per patient per day), for example, inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day (about 0.5 mg to about 3.5 gms per patient per day).
  • 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 of humans may vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • the following non-limiting Examples are intended to illustrate the preparation of compounds of Formula (I), and as such are not intended to limit the invention as set forth in the claims appended thereto.
  • Diethylacetamidomalonate was added to a stirred solution of sodium methoxide in methanol at room temperature. A yellow solution resulted, which was heated to 42°C and treated in several portions with 2-bromomethyl naphthalene over the course of 2 h. The opaque solution gradually became translucent, and the internal temperature increased to 68°C. Water was then added and the resulting yellow solution allowed to cool overnight. The mixture was then re-heated to 65°C and 46-48 % sodium hydroxide solution was then added over a 2 h . The mixture was then allowed to cool overnight. The mixture was adjusted to pH 9 with 6M HCl and the solution stirred at 26°C.
  • Example 4 /?)-[2-(Sulphanyl)-5-phthalimido]pentanoyl-(5)-2-naphthylalanine /V-methylamide
  • a solution of Example 3 (0.80 g) in methanol (16 ml) at 0°C was treated with aqueous ammonia (3.2 ml) under a nitrogen blanket. The clear, colourless solution was stirred at 0°C for 2 h.
  • the solution was directly preadsorped onto silica and purified using flash column chromatography on a de-gassed column, eluting with 3% methanol in dichloromethane to liberate the title compound as a white solid (0.3 g, 41 %).
  • Example 5 (5)-[2-(Sulphanyl)-5-phthalimido]pentanoyl-(5)-2-naphthylalanine /V-methylamide From Example 1 , as a white solid (52%). TLC R f 0.38 (EtOAc)
  • Example 6 (R, 5)-[2-(Sulphanyl)-5-phthalimido]pentanoyl-(5)-2-naphthylalanine /V-methylamide From Example 3, as a white solid (48%).
  • Example A
  • the potency of compounds of general formula (I) to act as inhibitors of collagenase was determined by the procedure of Cawston and Barrett, (Anal. Biochem., 99:340-345, 1979) whereby a ImM solution of the inhibitor being tested or dilutions thereof was incubated at 37°C for 16 hours with collagen and collagenase (buffered with 50 mM Tris, pH 7.6 containing 5 mM CaCl 2 , 0.05% Brij 35, 60 mM NaCl and 0.02% NaN 3 ).
  • the collagen was acetylated 3 H or 14 C-collagen prepared by the method of Cawston and Murphy (Methods in Enzymolgy, 80:711, 1981).
  • the potency of compounds of general formula (I) to act as inhibitors of stromelysin was determined using the procedure of Nagase et al (Methods in Enzymology Vol 254, 1994), whereby a 0.1 mM solution of the inhibitor being tested or dilutions thereof was incubated at 37°C for 16 hours with stromelysin and 3 H transferrin (buffered with 50 mM Tris, pH 7.6 containing 10 mM CaCl 2 , 150M NaCl, 0.05% Brij, 35, and 0.02% NaN 3 ). The transferrin was carboxymethylated with 3 H iodoacetic acid.
  • the potency of the compounds of general formula (I) to act as inhibitors of gelatinase was determined using the procedure of Harris & Krane (Biochem Biophys. Acta, 25J5:566 - 576, 1972), whereby a 1 mM solution of the inhibitor being tested or dilutions thereof was incubated at 37°C for 16 hours with gelatinase and heat denatured 3 H or 14 C-acetylated collagen (buffered with 50 mM Tris, pH 7.6 containing 5 mM CaCl 2 , 0.05% Brij 35 and 0.02% NaN 3 ).
  • the 3 H or 1 C gelatin was prepared by denaturing 3 H or 14 C-collagen produced according to the method of Cawston and Murphy (Methods in Enzymology, 80: 711 , 1981 ) by incubation at 60°C for 30 minutes. Undigested gelatin was precipitated by addition of trichloroacetic acid and centrifugation. The gelatinase activity in the presence of 1 mM, or dilution thereof, was compared to the activity in a control devoid of inhibitor and results reported as that inhibitor concentration effecting 50% inhibition of the gelatinase (IC 50 ).
  • Example D MMP Inhibition Activity-Fluorimetric Assay
  • the potency of compounds of general formula (I) to act as inhibitors of collagenase- 1 (MMP- 1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), gelatinase-A (MMP-2), gelatinase-B (MMP-9) and stromelysin- l(MMP-3) was determined using the following procedure: Inhibitors are dissolved in dimethylsulphoxide containing 0.02% ⁇ -mercaptoethanol and serial dilutions are prepared. Activated enzyme is incubated in assay buffer containing 50mM Tris, pH 7.4, 5mM CaCl 2 , 0.002% NaN 3 and Brij 35 in the presence and absence of inhibitor.
  • Samples are preincubated at 37°C for 15 minutes before the addition of the fluorimetric substrate (Mca-Pro-Leu-Gly-Leu-Dpa- Ala- Arg-NH 2 ) to a final concentration of lO ⁇ M.
  • the assay is incubated for 20-30 min at 37°C and then read in a Fluoroscan II at ⁇ * (340nm) and ⁇ (405nm).
  • the potency of the compounds of general formula (I) to act as inhibitors of the production of TNF ⁇ is determined using the following procedure.
  • a lOO ⁇ M solution of the inhibitor being tested or dilutions thereof is incubated at 37° C in an atmosphere of 5% CO 2 with THP-1 cells (human monocytes) suspended in RPMl 1640 medium and 20 ⁇ M ⁇ -mercaptoethanol at a cell density of 1 x 10 6 /ml and stimulated with LPS. After 18 hours the supernatant is assayed for the levels of TNF ⁇ using a commercially available ELISA kit (R & D Systems).
  • PBMC peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • PBMC HL-60 cells.
  • PBMC are isolated from buffy coats by standard procedures using Ficoll.
  • a lOO ⁇ M solution of the inhibitor being tested or dilutions thereof is incubated for 24h at 37° C in an atmosphere of 5% CO 2 with 2 x 10 6 /ml HL-60 cells stimulated with PMA.
  • the cells are centrifuged down and the supernatants tested for sIl-6R using a commercially available ELISA kit (R & D Systems).
  • the potency of the compounds of general formula (I) to act as inhibitors of the shedding of TNF RII is determined using the following procedure.
  • a lOO ⁇ M solution of the inhibitor being tested or dilutions thereof are incubated at 37° C in an atmosphere of 5% CO 2 with THP-1 cells (human monocytes) suspended in RPMl 1640 medium and 20 ⁇ M ⁇ -mercaptoethanol at a cell density of 1 x 10 6 /ml and stimulated with LPS. After 18 hours the supernatant is assayed for the levels of sTNF RII using a commercially available ELISA kit (R & D Systems).
  • the anti-metastatic potential of compounds of general formula (I) is evaluated in a B16 melanoma model in C57BL/6.
  • Mice are injected intravenously with 2 x 10 5 B 16/F 10 murine tumour cells harvested from in vitro cultures.
  • Inhibitors are administered by the oral route as a suspension in 1% methyl cellulose or intraperitoneally as a suspension in phospate buffered saline pH7.2 + 0.01% Tween-20. Mice are killed 14 days after cell inoculation and the lungs removed and weighed prior to fixing in Bouin's solution. The number of colonies present on the surface of each set of lungs is then counted by eye.

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Abstract

Composés peptidyles répondant à la formule générale (I) dans laquelle X représente C=O ou C=S; Y représente C=O, C=S ou S(O)m où m=1-2; R1 représente C¿0-4?-alkyl-R?2; R2¿ représente un aryle ou un hétéroaryle éventuellement substitué. Ces composés ont une utilité thérapeutique de par leur activité inhibitrice du facteur de nécrose tumorale (TNF) et de la MMP (métalloprotéinase matricielle).
PCT/GB1998/000272 1997-08-08 1998-01-29 Composes peptidyles presentant une activite inhibitrice du tnf et de la mmp WO1999007679A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU58719/98A AU5871998A (en) 1998-01-29 1998-01-29 Peptidyl compounds having mmp and tnf inhibitory activity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/GB1997/002149 WO1998006696A1 (fr) 1996-08-08 1997-08-08 Composes peptidyle avec activite inhibitrice de mmp et de tnf
US08/908,990 US5955435A (en) 1996-08-08 1997-08-08 Peptidyl compounds having MMP and TNF inhibitory activity

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1992636A2 (fr) 1999-11-12 2008-11-19 Amgen Inc. Procédé pour la correction d'un mauvais repliement de bisulfure dans les molécules Fc
EP2087908A1 (fr) 2001-06-26 2009-08-12 Amgen, Inc. Anticorps opgl

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995009833A1 (fr) * 1993-10-06 1995-04-13 Florida State University Mercaptosulfures inhibiteurs de la metalloproteinase matrice
WO1995013289A1 (fr) * 1993-11-10 1995-05-18 Chiroscience Limited Composes peptidyles et leur utilisation therapeutique en tant qu'inhibiteurs des metalloproteases
WO1995019961A1 (fr) * 1994-01-22 1995-07-27 British Biotech Pharmaceuticals Limited Inhibiteurs de metalloproteinase
WO1996011209A1 (fr) * 1994-10-05 1996-04-18 Chiroscience Limited Composes de peptidyle et leur usage therapeutique en tant qu'inhibiteurs des metalloproteases

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995009833A1 (fr) * 1993-10-06 1995-04-13 Florida State University Mercaptosulfures inhibiteurs de la metalloproteinase matrice
WO1995013289A1 (fr) * 1993-11-10 1995-05-18 Chiroscience Limited Composes peptidyles et leur utilisation therapeutique en tant qu'inhibiteurs des metalloproteases
WO1995019961A1 (fr) * 1994-01-22 1995-07-27 British Biotech Pharmaceuticals Limited Inhibiteurs de metalloproteinase
WO1996011209A1 (fr) * 1994-10-05 1996-04-18 Chiroscience Limited Composes de peptidyle et leur usage therapeutique en tant qu'inhibiteurs des metalloproteases

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1992636A2 (fr) 1999-11-12 2008-11-19 Amgen Inc. Procédé pour la correction d'un mauvais repliement de bisulfure dans les molécules Fc
EP2087908A1 (fr) 2001-06-26 2009-08-12 Amgen, Inc. Anticorps opgl
EP3492100A1 (fr) 2001-06-26 2019-06-05 Amgen Inc. Anticorps pour opgl

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