EP0612324A1 - Phosphonopeptides with collagenase inhibiting activity - Google Patents

Phosphonopeptides with collagenase inhibiting activity

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Publication number
EP0612324A1
EP0612324A1 EP92922116A EP92922116A EP0612324A1 EP 0612324 A1 EP0612324 A1 EP 0612324A1 EP 92922116 A EP92922116 A EP 92922116A EP 92922116 A EP92922116 A EP 92922116A EP 0612324 A1 EP0612324 A1 EP 0612324A1
Authority
EP
European Patent Office
Prior art keywords
leucyl
phosphono
propyl
methylamide
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP92922116A
Other languages
German (de)
English (en)
French (fr)
Inventor
David James Smithkline Beecham Hunter
Roger Edward Smithkline Beecham Markwell
Robert William Smithkline Beecham Ward
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Publication of EP0612324A1 publication Critical patent/EP0612324A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to novel phosphorus
  • the mammalian collagenase family of enzymes comprises a number of proteases, exemplified by interstitial (type I) collagenase itself, the stromelysins (also known as
  • proteoglycanases or transins fibroblast
  • polymorphonuclear leucocyte gelatinases also known as collagen-IV-ases
  • 'pump-1' putative metalloprotease 1, uterine metalloprotease
  • inhibitors of the collagenase family of enzymes such as are disclosed in the present invention, chronic arthritic diseases leading to extensive loss of the collagen,
  • proteoglycan and elastin components of the cartilage, bone and tendons within the joints should be amenable to
  • proteoglycanases stromelysins
  • gelatinases currently thought to be the major enzymes involved. These enzymes have been detected in extracts of synovial and cartilage tissue, and have also been extensively studied in tissue cultures of a wide range of connective tissues.
  • EPA-320118 (Beecham Group) discloses a class of phosphorus derivatives having activity as inhibitors of collagenase and utility in the treatment of rheumatoid arthritis and related diseases in which collagenolytic activity is a contributing factor.
  • Novel phosphorous derivatives have now been discovered, which are collagenase inhibitors and thus of potential utility in the treatment of diseases in which collagenolytic activity and tissue remodelling is implicated.
  • R 1 is -(CH 2 ) n -W where n is 0-6 and W is amino,
  • R 5 is hydrogen or C 1-6 alkyl and R 6 is hydrogen, C 1-6 alkyl, optionally-substituted phenyl or heteroaryl, or R 5 and R 6 together with the
  • W is -S(O) p -R 7 where p is 0, 1 or 2 and R 7 is C 1-6 alkyl; or W is a group of sub-formula (a), (b), (c) or (d):
  • sub-formula (a), (b) and (c) A represents an optionally-substituted mono or bicyclic aryl or heteroaryl ring, and in sub-formula (c) and (d) q is an integer from 1 to 3;
  • R 2 is C 3-6 alkyl
  • R 3 is hydrogen, C 1-6 alkyl, -CH 2 -Z where Z is optionally substituted phenyl or heteroaryl, -(CH 2 ) r NR 8 R 9 ,
  • each of R 8 and R 9 is independently hydrogen or C 1-6 alkyl or R 8 and R 9 together with the nitrogen atom to which they are bonded form a 5-, 6- or 7-membered ring with an optional oxygen or sulphur atom or an optionally
  • R 10 is
  • R 11 is hydrogen or C 1-6 alkyl or R 11 and R 8 , together with the nitrogen atoms to which they are bonded, form an optionally substituted 5-, 6- or 7-membered ring
  • R 12 is hydrogen or C 1-6 alkyl and R 13 is an optionally substituted piperidyl ring or R 3 is a group:
  • R 14 is hydrogen, C 1-6 alkyl or optionally substituted benzyl and R 15 is hydrogen or C 1-6 alkyl
  • R 4 is hydrogen, C 1-6 alkyl or -(CH 2 ) r NR 8 R 9 in which r, R 8 and R 9 are as defined for R 3 ; or R 3 and R 4 are joined together as -(CH 2 ) m - where m is an integer from 4 to 12, or R 3 and R 4 are joined as - (CH 2 ) x-NR 1 6 - (CH 2 ) y - where x is an integer from 1 to 9, y is an integer from 2 to 10, and the moiety - (CH 2 ) x - is adjacent to the carbon atom bearing R 3 marked with an asterisk in formula (I), and R 16 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkanoyl, C 1-6 alkoxycarbonyl, aroyl, aralkyl or aralkyloxycarbonyl in each of
  • Optional substituents for aryl and heteroaryl groups may be selected from OH, C 1-6 alkyl, C 1-6 alkoxy, halogen,
  • optionally substituted phenyl and R5 and Rg are as defined above.
  • aryl includes phenyl and naphthyl. It will be understood that the term heteroaryl includes aromatic heterocyclic groups containing one or more
  • heteroatoms and includes 5- or 6-membered monocyclic and 9-or 10-membered bicyclic heteroaryl groups which preferably contain one or two heteroatoms selected from nitrogen, oxygen and sulphur.
  • Z is 9- or 10-membered bicyclic heteroaryl the two rings are fused with one 5- or 6-membered ring preferably containing a single heteroatom, for example indolyl.
  • R 5 and R 6 or R 8 and R 9 groups combined with their appended nitrogen atom to form a heterocyclic ring typical examples of a suitable ring structure are piperidine, or pyrrollidine, piperazine and morpholine. When such groups contain a second nitrogen heteroatom this may be optionally substituted, for example, by a C 1-6 alkyl group.
  • R 1 is -(CH 2 ) n -W where n is 0, 1, 2 or 3.
  • W is amino, phenyl, N-phthalimido or 1,8- naphthalenedicarboxamido each of which may be optionally substituted, NHCO 2 CH 2 R 6 where R 6 is optionally substituted phenyl or S(O) p CH 3 where p is 0, 1 or 2.
  • R 1 is 2-hydroxyphenyl, -(CH 2 ) n -w where n is 2 and W is amino, phenyl, 2-hydroxyphenyl, NHCO 2 CH 2 Ph,
  • N-phthalimido 4-bromo-1, 8-naphthalenedicarboxamido, 7,9- dioxo-8-azaspiro [4,5]decyl, methylmercapto, methylsulphinyl or methylsulphonyl, or R 1 is -(CH 2 ) n -w where n is 1, 2 or 3 and W is a 1,8-naphthalenedicarboxamido group.
  • R 2 is a C4 alkyl group, such as n-butyl, iso-butyl or sec-butyl.
  • R2 is iso-butyl.
  • R 3 is benzyl, C 1-6 alkylamino, 4-hydroxybenzyl, C 1-6 alkoxybenzyl such as 4-methoxybenzyl, or 9- or 10-membered fused bicyclic heteroarylmethyl such as
  • R 3 is benzyl, 4-methoxybenzyl, -(CH 2 ) 4 NH 2 or 3-indolylmethyl.
  • R 4 is methyl, ethyl or -(CH 2 ) r NR 8 R 9 .
  • R 4 is methyl or -(CH 2 ) 2 NR 8 R 9 where R 8 and R 9 are both hydrogen or R 8 and R 9 together with the nitrogen atom to which they are bonded form a pyrrolidine or N-methylpiperazine group.
  • x and y have values such that R 3 and R 4 form part of an 11- to 16-membered azalactam
  • R 16 is hydrogen, methyl, benzyl, t-butoxycarbonyl or benzyloxycarbonyl.
  • groups R 3 and R 4 are combined they form a group -(CH 2 ) 10 -.
  • Particular compounds of this invention include:
  • the compounds of formula (I) may form salts with bases e.g. sodium hydroxide.
  • the compounds of formula (I) have a basic nitrogen atom and may form acid addition salts e.g.
  • hydrochloride hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate and similar acid addition salts.
  • Such compounds form part of the present invention.
  • the compounds of formula (I) have at least two, and may have three or more asymmetric centres and therefore exist in more than one stereoisomeric form.
  • the invention extends to all such forms and to mixtures thereof, including racemates, and diastereoisomeric mixtures.
  • Preferred isomers are those having the (S)- or (-) -configuration at the chiral centre bearing R 3 when R 3 is other than hydrogen, and those having the (S) -configuration at the chiral centre bearing R 2 , both marked with an
  • the present invention also provides a process for the preparation of a compound of formula (I) which comprises cleaving a group R 20 from a compound of formula (II): wherein R 20 is C 1-6 alkyl, optionally substituted phenyl or optionally substituted benzyl and R 21 is hydrogen,
  • C 1-6 alkyl or optionally substituted benzyl and R 1' R 2 , R 3 and R 4 are as defined in formula (I), and where necessary, converting R 20 to hydrogen by a further cleavage reaction.
  • Cleavage of R 20 and, where necessary, R 21, may be carried out in aqueous acid or alkali or using a trimethylsilyl halide, preferably bromotrimethylsilane, in an inert
  • Benzyl esters may alternatively be removed by hydrogenolysis or other standard debenzylation procedures.
  • R 20 and R 21 are C 1-6 alkyl
  • cleavage of R 20 only - to give to a compound of formula (II) in which R 20 is hydrogen and R 21 is C 1-6 alkyl may be carried out by
  • R 20 is optionally substituted benzyl and R 21 is C 1-6 alkyl
  • the benzyl group only may be cleaved by hydrogenolysis to give a compound of formula (II) in which R 20 is hydrogen and R 21 is C 1-6 alkyl.
  • R 21 is not hydrogen, then cleavage of both R 21 and R 20 is conveniently effected in a single reaction.
  • R 20 and R 21 are both C 1-6 alkyl, such as methyl or ethyl, or R 20 and R 21 are both benzyl.
  • Compounds of formula (II) are believed to be novel and form a further aspect of the invention.
  • the reaction is preferably carried out in the presence of a coupling agent, such as dicyclohexylcarbodiimide or
  • hydrochloride in the presence of 1-hydroxybenzotriazole, or using 1,1'-carbonyldiimidazole, in an inert solvent such as dichloromethane or acetonitrile.
  • compounds of formula (II) in which R 20 and R 21 are C 1-6 alkyl or optionally substituted benzyl may be prepared by the reaction of a compound of formula (V): in which R 2 , R 3 and R 4 are as defined in formula (I), with a compound of formula (VI):
  • R 1 is as defined in formula (I)
  • R 20 and R 21 are C 1-6 alkyl or optionally substituted benzyl and R 17 is a leaving group such as halogen, methanesulphonyloxy or trifluoromethanesulphonyloxy, in the presence of a base such as triethylamine or Proton Sponge (1,8-bis(dimethylamino)naphthalene), or using anhydrous potassium carbonate in an alcoholic solvent.
  • R 17 is an oxygen-based leaving group, for example trifluoromethanesulphonyloxy, which is preferred,
  • displacement of the leaving group is conveniently carried out in the presence of Proton Sponge in an inert solvent such as acetonitrile or dichloromethane, over a period of several days in the absence of light.
  • an inert solvent such as acetonitrile or dichloromethane
  • compounds of formula (II) in which R 20 and R 21 are C 1-6 alkyl, optionally substituted aryl or optionally substituted benzyl may be prepared by reaction of a compound of formula VII:
  • R 18 is C 1-6 alkyl and R 20 and R 21 are as defined for formula (II) provided that R 21 is not hydrogen and
  • the reaction is suitably carried out in an organic solvent such as dichloromethane at reduced temperature, e.g. -10 to 5°C.
  • organic solvent such as dichloromethane at reduced temperature, e.g. -10 to 5°C.
  • the intermediate compounds of formula (III) may be prepared by treating a compound of formula (IX) or a salt thereof:
  • R 1 , R 20 and R 21 are as defined in formula (III), with a compound of formula (XA) or (XB) or a salt thereof:
  • R 2 is as defined in formula (I)
  • R 17 is as defined in formula (VI)
  • R 19 is hydrogen or a carboxyl protecting group, and thereafter removing the R 19 carboxyl protecting group.
  • the reductive amination may be carried out by hydrogenation over a noble metal catalyst such as palladium on carbon or by reaction with sodium cyanoborohydride at pH 6 to 7.
  • a noble metal catalyst such as palladium on carbon
  • sodium cyanoborohydride at pH 6 to 7.
  • Lower alkyl alcohol solvents such as methanol and ethanol are suitable for both reactions. These reactions may be carried out in the presence of molecular sieves.
  • a hydrogenation reaction is preferred but this process precludes the use of compounds of formulae (IX) and (XB) in which any of R 20 , R 21 or R 19 is benzyl.
  • a carboxyl protecting group is a methyl or ethyl ester. Ester protecting groups may be removed under standard basic hydrolysis conditions using dilute base such as 1 Normal aqueous sodium hydroxide in methanol.
  • the compound of formula (IX) is in the form of the free base
  • the compound of formula (IX) is a salt, such as the hydrochloride salt
  • an oxygen-based leaving group is preferably trifluoromethanesulphonyloxy.
  • R 2 is as defined in formula (I) and R 19 is a carboxyl protecting group with an aldehyde, R 1 -CHO in which R 1 is as defined in formula (I) and treating the
  • condensation product with an appropriate phosphite, for example dimethyl phosphite, diphenyl phosphite or dibenzyl phosphite and thereafter removing the carboxyl protecting group.
  • phosphite for example dimethyl phosphite, diphenyl phosphite or dibenzyl phosphite and thereafter removing the carboxyl protecting group.
  • the carboxyl group is conveniently protected as an alkyl or benzyl ester which may be removed using standard hydrolysis or hydrogenation conditions.
  • compounds of formula (III) may be prepared by treating a compound of formula (XII):
  • R 1 and R 2 are as defined in formula (I) and R 19 is a carboxyl protecting group as defined for formula (XI) with a compound of formula (VIII) as hereinbefore defined using conditions as described for the reaction of compounds of formulae (VII) and (VIII).
  • a further alternative preparation of compounds of formula (III) may be carried out by reacting a compound of formula (VI) as hereinbefore defined with a compound of formula (XI) as hereinbefore defined, using conditions as described for the reaction of compounds of formula (V) with compounds of formula (VI), and thereafter removing the protecting group R 19 .
  • Suitable carboxyl protecting groups include alkyl, benzyl and trialkylsilyl groups.
  • a trialkylsilyl protecting group. for example trimethylsilyl, is especially useful in that it may be readily incorporated, in situ, for example by
  • silylating agents include trimethylsilyl chloride and
  • R 19 alkyl carboxyl protecting group may be removed by base hydrolysis, for example using sodium hydroxide in aqueous methanol.
  • R 19 is alkyl
  • R 20 and R 21 may0 be alkyl or benzyl derivatives, but where R 19 is a benzyl group, R 20 and R 21 are limited to alkyl.
  • R 20 and R 21 are benzyl and R 17 is trifluoromethanesulphonyloxy in the compound of formula (VI) and R 19 is trimethylsilyl or methyl in the compound of formula (XI).
  • Compounds of formula (V) may be prepared by treating a compound of formula (XIII):
  • R 2 is as defined in formula (I) and wherein the amino group is optionally protected, with a compound of formula (IV) as hereinbefore defined, in the presence of a coupling agent as hereinbefore described for the preparation of compounds of formula (II) from compounds of formulae (III) and (IV).
  • Compounds of formula (VII) may be prepared by reaction of an aldehyde R 1 -CHO in which R 1 is as defined in formula (I) with an amine of formula (V) as hereinbefore defined in an organic solvent such as dichloromethane at reduced
  • Compounds of formula (VIII) may be prepared by reaction of the corresponding phosphite, for example dimethylphosphite or dibenzylphosphite with a trialkylsilylhalide, for example trimethylsilyl chloride, in an inert solvent such as
  • hydroxyalkylphosphonate derivatives by conversion of the hydroxyl group to the leaving group R 17 by conventional methods.
  • R 17 is trifluoro- methanesulphonyloxy
  • trifluoromethanesulphonic anhydride may be added to a solution of the hydroxyalkylphosphonate in an inert solvent such as dichloromethane, the reaction being carried out at reduced temperature under an inert
  • Hydroxyalkylphosphonate compounds may in turn be prepared by reaction of the corresponding phosphite, for example
  • R 1 is as defined in formula (I) according to the general method of F. Texier-Boullet and A. Foucaud, Synthesis, 916 (1982).
  • Benzyl and alkyl phosphites are either commercially
  • R 20 or R 21 methyl group may be effected by reaction with diazomethane in a suitable inert solvent.
  • Compounds of formula (IX) of fixed configuration may be prepared by the general method of R. Jacquier et al.,
  • the compounds of formulae (IV) and (XIII) are either known amino acid derivatives or can be made from these derivatives by known methods.
  • Compounds of formula (XA) and (XB) are either known compounds or may be prepared from known
  • pharmaceutically acceptable salts of the compounds of formula (I) may be formed conventionally by reaction with the appropriate acid or base.
  • the compounds of formula (I) exist in more than one diastereoisomeric form.
  • separate diastereoisomeric compounds of formula (I) can be obtained by using stereoisomerically pure starting materials or by separating desired isomers of intermediates at any stage in the overall synthetic process, and converting these intermediates to compounds of formula (I). It will be appreciated that where a single diastereoisomer of a compound of formula (I) is prepared by more than one process variant as hereinbefore described, each of which allows a different chiral centre to be defined, it may be possible to deduce the configuration at a chiral centre which is not pre-determined using a particular process variant.
  • the present invention provides
  • Compounds of formula (I) also have potential utility in the treatment of cancer; for preventing myelin degradation in the central and peripheral nervous system; for the treatment or prevention of colonic damage such as irritable bowel disease; and in other conditions in which members of the collagenase family of neutral metalloproteases have
  • the present invention further provides a pharmaceutical composition, which comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a
  • a composition of this invention is useful in the treatment of musculo-skeletal disorders, particularly arthritic diseases and for modulation of tissue remodelling as well as having potential utility in the treatment of the diseases described above.
  • a composition of the invention which may be prepared by admixture, may contain a diluent, binder, filler,
  • compositions of related peptide enzyme inhibitors such as the ACE inhibitor
  • a composition of the invention may be adapted for oral, topical, rectal or parenteral administration but oral administration is preferred.
  • Parenteral compositions may be administered intravenously, intramuscularly, intraarticularly, intradermally, sub-cutaneously or into the cerebro-spinal fluid.
  • a pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields.
  • a pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields.
  • preparations may be in a pack form accompanied by written or printed instructions for use as an agent in the treatment or prophylaxis of any of the disorders mentioned above.
  • the suitable dosage range for the compounds of the invention may vary from compound to compound and may depend on the condition to be treated. It will also depend, inter alia, upon the relation of potency to absorbability and the mode of administration chosen.
  • the compound or composition of the invention may be
  • Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.
  • compositions for example those suitable for oral administration, may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin,
  • sorbitol tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tableting lubricants for example magnesium stearate
  • disintegrants for example starch, polyvinylpyrrolidone, sodium starch glycollate or
  • microcrystalline cellulose or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
  • Solid compositions may be obtained by conventional methods of blending, filling, tableting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large
  • compositions When the composition is in the form of a tablet, powder, or lozenge, any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • the composition may also be in the form of an ingestible
  • a capsule for example of gelatin containing the compound, if desired with a carrier or other excipients.
  • a carrier or other excipients for example, in a hard gelatin capsule containing the required amount of a compound of the invention in the form of a powder or
  • a lubricant such as magnesium stearate
  • a filler such as macrocrystalline cellulose
  • a disintegrant such as sodium starch
  • compositions for oral administration as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose,
  • edible oils for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline
  • preservatives for example methyl or propyl p-hydroxybenzoate or sorbic acid and, if desired, conventional flavouring or colouring
  • compositions may be formulated, for example for rectal administration as a suppository or for parenteral administration in an injectable form.
  • parenteral administration in an injectable form.
  • the compounds of the invention may be presented in an aqueous or
  • pyrogen-free water or a parenterally acceptable oil or a mixture of liquids which may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically
  • Such forms will be presented in sterile unit dose form such as ampoules or disposable injection devices or in multi-dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an
  • preparations may also be presented as an ointment, cream, lotion, gel, spray, aerosol, wash, skin paint or patch.
  • a unit dose for treating diseases in which enzymes of the collagenase family are involved will generally contain from 10 to 1000 mg and preferably will contain from 10 to 500 mg, in particular 10, 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg.
  • the composition may be administered one or more times a day, for example 2, 3 or 4 times daily, so that the total daily dose for a 70 kg adult will normally be in the range 10 to 3000 mg. Such a dosage corresponds to
  • the unit dose will contain from 2 to 200 mg of a compound of the invention and be administered in multiples, if desired, to give the desired daily dose.
  • the present invention additionally provides a method of treating conditions in which degradation of connective tissue and other proteinaceous components of the body occurs which comprises administering to the mammal in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment of conditions in which degradation of connective tissue and other proteinaceous components of the body occurs.
  • Salicylaldehyde (1.83g), leucine benzylester p-toluene sulfonate salt (5.9g) and triethylamine (2.1 ml) in toluene (100 ml) were heated at reflux for 2 h in a Dean-Stark apparatus. The solution was cooled and solvent removed in vacuo. Diethyl phosphite (3.2g) was added and the solution heated at 120°C for 24 h. The reaction mixture was cooled and column chromatography on silica gel, eluting with ethyl acetate, gave the title compound as a yellow oil (2.8g). Description 2
  • 3-Amino-1-propanol (3.75g) was dissolved in dichloromethane (500 ml) and dimethylformamide (50 ml) and naphthalic anhydride (9.9g) added, followed by triethylamine (6.9 ml). The solution was stirred at room temperature for 2h and 1-hydroxybenzotriazole (8.75g) and 1-ethyl-3(3-dimethylaminopropyl)carbodiimide hydrochloride (13.4g) added and the solution stirred at room temperature for 24h. The solution was filtered, washed with water, 1N hydrochloric acid, saturated sodium bicarbonate solution and dried with
  • reaction mixture stirred at 0°C for 15 min, then at room temperature for 15 min.
  • the title compound (3.33g) was prepared as a mixture of 2 diastereoisomers from 4-(1,8-naphthalenedicarboximido)butanal D11) (3.96g), (S)-leucyl-(S)-phenylalanine-N- methylamide (4.32g) and dibenzyl trimethylsilylphosphite (4.99g) by the procedure described in Description 6.
  • the title compound (3.0g) was prepared as a mixture of 2 diastereoisomers from 2-(1,8-naphthalenedicarboximido)-ethanal (D14) (3.13g), (S)-leucyl-(S)-phenylalanine-N-methylamide (3.81g) and dibenzyl trimethylsilylphosphite (4.4g) by the procedure described in Description 6.
  • the title compound (2.5g) was prepared from 3-(1,8-naphthalenedicarboximido) propanal (D5) (3.5g), (S)-leucyl- (S)-phenylalanine-N-methylamide (4.03g) and dibenzyl
  • the methyl ester (D17A) (1.35g) was dissolved in dioxan (30 ml) and water (15 ml). Sodium hydroxide (0.12g) was added and the solution was stirred at room temperature for 24h. The dioxan was evaporated in vacuo and the aqueous solution washed with ether, acidified with 2N hydrochloric acid and extracted with ethyl acetate (2x). The organic extracts were dried with sodium sulphate and the solvent evaporated in vacuo to give the title compound, as a white solid (0.65g), as a single diastereoisomer (D18A).
  • the acid (D18A) (0.6g) was dissolved in dichloromethane (20 ml), cooled to 0°C and 1-hydroxybenzotriazole (0.23g) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.33g) were added. The solution was stirred at 0°C for 15 min, then at room temperature for 15 min, cooled to 0°C and (S)-phenylalanine-N-methylamide (0.24g) in dichloromethane (20 ml) added. The solution was stirred at room temperature for 24h, washed with water, 10% citric acid solution and saturated sodium chloride solution. The organic solution was dried with anhydrous sodium sulphate and the solvent evaporated in vacuo to give a beige solid (0.69g).
  • the title compound was prepared from 3-(phthalimido-propyl)propanal (3.36g) and (S)-leucine benzyl ester, p-toluene sulphonate salt (6.51g) by the procedure described in Description 20.
  • the title compound (D27) was prepared from 3-(4-bromo-1,8-naphthalenedicarboxamido)propanal (D26) (3.0g) and (S)-leucine, trimethylsilylethyl ester (2.17g) by the procedure described in Description 20.
  • N ⁇ -t.-Butyloxycarbonyl-N ⁇ -benzyloxycarbonyllysine-N- (benzyloxycarbonyl aminoethyl) amide (1.22g) (D37) was dissolved in dichloromethane (20ml) and trifluoroacetic acid (15ml) added. The solution was stirred at room temperature for 2h and the solvent evaporated in vacuo. The residue was dissolved in dichloromethane (25ml) and triethylamine added to pH10 to give N ⁇ -benzyloxycarbonyllysine-N- (benzyloxycarbonylaminoethyl) amide. The title compound was prepared from the above amine (1.0g) and the acid (0.95g) (D21) by the procedure described in Description 19.
  • the title compound was prepared from the aldehyde (3.2g) (D43), (S)-leucine, benzyl ester p-toluene sulphonate salt (5.7g) and dimethyl trimethylsilyl phosphite (2.6g) by the procedure described in Description 20.
  • The---title compound was prepared as a single diastereoisomer (D45A) (1.7g) from the benzyl ester (D44A) (2.1g) by the procedure described in Description 21.
  • ⁇ (CDCl 3 ) 0.96 (6H, dd), 1.50 (6H, m), 1.70 (6H, m), 1.74 (1H, m), 2.06 (1H, broad s), 2.60 (4H, s), 2.98 (1H, m), 3.76 (3H, d), 3.81 (3H, d), 3.90 (2H, m), 4.03 (1H, m).
  • N-[N-(1-Dimethoxyphosphinyl)-3-phthalimidopropyl)-(S)- leucyl]-(S)-phenylalanine-N-methylamide (lg) (D9) was dissolved in a 0.2M methanol solution of hydrazine (50ml) and the solution stirred at room temperature for 24h. The solvent was evaporated in vacuo and the mixture treated with methanol, filtered and the solvent evaporated in vacuo to give the title compound as a mixture of 2 diastereoisomers (0.7g) (D48) which was used in the next stage without further purification.
  • N-[N-(1-(Dimethoxyphosphinyl)-3-amino ⁇ ropyl)-(S)-leucyl]- (S)-phenylalanine-N-methylamide (4.5g) (D48) was dissolved in water (20ml) and dioxan (20ml). Benzyl chloroformate (1.8ml) was added and the pH maintained at 9 - 9.5 by the addition of 10% sodium hydroxide solution. After stirring at room temperature overnight, the solution was extracted with chloroform. The organic extracts were washed with water, dried with anhydrous sodium sulphate, filtered and the solvent evaporated in vacuo to give a colourless oil.
  • the dibenzyl ester (D6A) (0.5g) was dissolved in ethanol (100 ml) and hydrogenated over 10% palladium on charcoal at atmospheric pressure for 24h. The solution was filtered and the solvent evaporated in vacuo to give the title compound as a single diastereoisomer (E2A) (0.38g).
  • diastereoisomer (E6A) from the dibenzyl ester (D16A) by the procedure described in Example 2.
  • the title compound (0.4g) was also prepared as a single diastereoisomer (E6A) from the dimethyl ester (D22) by treatment with bromotrimethylsilane (1ml) in dichloromethane (50ml) at room temperature under nitrogen for 48h.
  • the solvent was evaporated in vacuo and the residue dissolved in methanol (25ml) and water (5ml) and stirred for 2 h.
  • the solvent was evaporated in vacuo to give the title compound (E6A) (0.4g) as a white solid.
  • the title compound was prepared as a single diastereoisomer (0.62g) (E15) from the dimethyl ester (1.0g) (D35) by
  • the title compound was prepared as a single diastereoisomer (0.6g) (E16) from the dimethyl ester (0.7g) (D36) by treatment with bromotrimethylsilane for 48h as described in Example 6.
  • the product was dissolved in methanol/water and converted to the di-sodium salt by the addition of two equivalents of sodium hydroxide.
  • ⁇ (CD 3 OD) 0.98 (6H, m), 1.10-1.98 (22H, m), 2.18 (1H, broad S), 2.68 (2H, m), 3.63 (1H, q), 4.30 (3H, m), 7.75 (2H, q), 8.24 (2H, t), 8.46 (2H, t)
  • the title compound was prepared as a single diastereoisomer (0.37g) (E20A) from the dimethyl ester (0.4g) (D46A) by treatment witn bromotrimethylsilane for 48h as described in Example 6.
  • ⁇ (CD 3 OD) 0.97 (6H, d), 1.50 (4H, m), 1.72 (8H, m), 2.17 (1H, m), 2.65 (4H, s) , 2.69 (3H, s), 2.75 (1H, m) 2.98 (1H, m), 3.12 (1H, m), 3.77 (2H, m), 4.39 (1H, q), 4.68 (1H, q), 7.28 (5H, m).
  • compositions for oral administration may be prepared by combining the following:
  • the mixture may be compressed to tablets, or filled into hard gelatin capsules.
  • the tablet may be coated by applying a suspension of film former (e.g. HPM cellulose), pigment (e.g. titanium dioxide) and plasticiser (e.g. diethyl phthalate) and drying the film by evaporation of the solvent.
  • film former e.g. HPM cellulose
  • pigment e.g. titanium dioxide
  • plasticiser e.g. diethyl phthalate
  • the film coat can comprise 2.0% to 6.0% of the tablet weight, preferably about 3.0%.
  • Example 23 The medicinal compound is dispersed or dissolved in the liquid carrier, with a thickening agent added, if required.
  • the formulation is then enclosed in a soft gelatin capsule by suitable technology.
  • a pharmaceutical composition for parenteral administration may be prepared by combining the following:
  • test is performed essentially as in Cawston and Barrett, Anal. Biochem. 99, 340-345 (1979).
  • Compounds for testing are dissolved in methanol by sonication and added to
  • collagenase purified from culture supernatants from the human lung fibroblast cell line, WI-38
  • the assay tubes are cooled to 4°C and 3 H-acetylated rat skin type I collagen is added.
  • the assay tubes are incubated at 37°C overnight.
  • the 3 H-collagen forms insoluble fibrils, which are the substrate for the enzyme.
  • the assay tubes are spun at 12000 rpm for 15 minutes. Undigested 3 H-collagen is pelleted, while digested 3 H-collagen is found as soluble peptides in the supernatant. A sample of the supernatant is taken for liquid scintillation counting. The activity of collagenase inhibitors (IC 50 : 50% inhibitory concentration) is expressed as that concentration of
  • the compounds of Examples 2-12 had IC 50 values in the range 2.3 ⁇ 10 -6 - 1.3 ⁇ 10 -8 M.

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EP92922116A 1991-10-28 1992-10-16 Phosphonopeptides with collagenase inhibiting activity Withdrawn EP0612324A1 (en)

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GB9122859 1991-10-28
GB919122859A GB9122859D0 (en) 1991-10-28 1991-10-28 Novel compounds
PCT/GB1992/001903 WO1993009136A1 (en) 1991-10-28 1992-10-16 Phosphonopeptides with collagenase inhibiting activity

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US6013792A (en) * 1993-08-05 2000-01-11 Syntex (U.S.A.), Inc. Matrix metalloprotease inhibitors
JPH09501430A (ja) * 1993-08-05 1997-02-10 シンテックス（ユー・エス・エイ）・インコーポレイテッド マトリックスメタロプロテアーゼ阻害因子
US5773428A (en) * 1993-08-05 1998-06-30 Syntex (U.S.A.) Inc. Matrix metalloprotease inhibitors
US5831004A (en) 1994-10-27 1998-11-03 Affymax Technologies N.V. Inhibitors of metalloproteases, pharmaceutical compositions comprising same and methods of their use
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
ES2576643T3 (es) 2007-03-09 2016-07-08 Second Genome, Inc. Compuestos de bicicloheteroarilo como moduladores de P2X7 y usos de los mismos
EP2326619B1 (en) 2008-08-01 2019-02-27 Bioxiness Pharmaceuticals, Inc. Methionine analogs and methods of using same

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GB8726714D0 (en) * 1987-11-14 1987-12-16 Beecham Group Plc Compounds
EP0401963A1 (en) * 1989-04-13 1990-12-12 Beecham Group p.l.c. Phosphonopeptides with collagenase inhibiting activity
GB9008078D0 (en) * 1990-04-10 1990-06-06 Beecham Group Plc Novel compounds
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CA2122147A1 (en) 1993-05-13
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GB9122859D0 (en) 1991-12-11
MX9206191A (es) 1993-06-01

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