EP0527761A1 - Phosphonopeptides avec activite inhibitrice de la collagenase - Google Patents

Phosphonopeptides avec activite inhibitrice de la collagenase

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Publication number
EP0527761A1
EP0527761A1 EP91907169A EP91907169A EP0527761A1 EP 0527761 A1 EP0527761 A1 EP 0527761A1 EP 91907169 A EP91907169 A EP 91907169A EP 91907169 A EP91907169 A EP 91907169A EP 0527761 A1 EP0527761 A1 EP 0527761A1
Authority
EP
European Patent Office
Prior art keywords
amino
leucyl
formula
hydrogen
diazacyclotridecan
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.)
Ceased
Application number
EP91907169A
Other languages
German (de)
English (en)
Inventor
Roger Edward Smithkline Beecham Markwell
Shahzad Sharooq Smithkline Beecham Rahman
Robert William Smithkline Beecham Ward
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Beecham Group PLC
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Beecham Group PLC
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Filing date
Publication date
Application filed by Beecham Group PLC filed Critical Beecham Group PLC
Publication of EP0527761A1 publication Critical patent/EP0527761A1/fr
Ceased 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
    • 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 System
    • 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, i.e. RP(=X)(XH)2 (X = S, 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
    • 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 derivatives, processes for their preparation and their use in medicine.
  • the present invention relates to their use as inhibitors of enzymes of the collagenase family of neutral metalloproteases, for treating arthricic and other diseases.
  • 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 and polymorphonuclear leucocyte gelatinases (also known as collagen-IV-ases), and 'pump-1' (putative metalloprotease 1, uterine metalloprotease) .
  • Interstitial type I! collagenase itself
  • the stromelysins also known as proteoglycanases or transins
  • fibroblast and polymorphonuclear leucocyte gelatinases also known as collagen-IV-ases
  • 'pump-1' putative metalloprotease 1, uterine metalloprotease
  • the range of therapeutic applications of the inve ticr. described hereinafter reflects the fundamental role of collagen and other proteinaceous substrates of the collagenase family of enzyme.s in the connective tissue matrix throughout the body. Applications extend CG clinical interventions in many diseases and phenomena involving the destruction cf collagen and other connective tissue components, and also normal or disordered tissue remodelling.
  • Inhibitors of the collagenase family of enzymes are considered to provide useful treatments for: arthritic diseases, such as rheumatoid and osteo- arthritis, soft tissue rheumatism, polychondritis and tendonitis; bone resorption diseases, such as osteoporosis, Paget's disease, hyperparathyroidism and cholesteatoma; the enhanced collagen destruction that occurs in association with diabetes; the recessive classes of dystrophic epidermolysis bullosa; periodontal disease and related consequences of gingival production of collagenase, or of PMNL collagenase release following cellular infiltration to inflamed gingiva, including by combating the greater susceptibility of diabetes patients to periodontal disease; corneal ulceration, e.g.
  • the compounds described in the present invention being synthetic and low molecular weight inhibitors of this family of enzymes, offer a therapeutically useful way in which a more normal or non-pathological balance between inhibition and enzymic activity can be restored: they thus act to complement and supplement the endogenous enzyme inhibitors. Indeed, because these enzymes usually act only within restricted pericellular environments, before being inactivated by inhibitors circulating in the blood and present in most inflammatory exudates, the low molecular weight inhibitors disclosed here may be more effective than endogenous proteinaceous inhibitors that are excluded by their size from the localized regions of connective tissue destruction.
  • European Patent Application 88310492.9 (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 structurally related compounds 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 is hydrogen, C- j __g alkyl or optionally substituted benzyl
  • R T is hydrogen or C- j __g alkyl; R2 is C3_g alkyl; and
  • R 3 and R 4 are joined together as - (CH 2 ) p -X- (CH 2 ) q - where p is an integer from 1 to 9, q is an integer from 2 to 10, and the moiety -(CH 2 ) p - is adjacent to the carbon atom bearing R3 marked with an asterisk in formula (I) , and X is -NR5- where R5 is selected from hydrogen, C ⁇ _galkyl, C 2 _galkanoyl, C 1 _ 6 alkoxycarbonyl, aroyl, aralkyl or aralkyloxycarbonyl in each of which the aryl moiety is optionally substituted.
  • each alkyl group is preferably a C ] __g group, more preferably C- j __g, and may be a straight chain or branched.
  • An aryl moiety is preferably phenyl.
  • Optional substituents for an aryl moiety may be selected from OH, C- j __g alkyl, C- j __g alkoxy and halogen.
  • R is preferably hydrogen, methyl, ethyl or benzyl, especially hydrogen.
  • R ⁇ include hydrogen, methyl, ethyl, isopropyl and n-butyl.
  • R 1 is preferably methyl or ethyl.
  • R 2 is preferably a C4 alkyl group, such as n-butyl, iso-butyl or sec-butyl, especially iso-butyl.
  • R and R 4 together include - (CH 2 ) p -X- (CH 2 ) ⁇ - where p and q have values such that R3 and R 4 form part of an 11- or 13 to l ⁇ -membered azalactam structure, and X is -NR5- where R 5 is hydrogen, methyl, benzyl, t-butoxy- carbonyl or benzyloxycarbonyl.
  • R3 and R 4 are joined together as - (CH 2 ) p -X- (CH 2 ) - where p is 4 and q is 5 or p is 3 and q is 6 or p is 4 and q is 6 or p is 4 and q is 3 and X is -NRr- where R5 is hydrogen or methyl.
  • 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. with hydrochloric acid. 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 ⁇ -configuration at the chiral centre bearing R 2 and the S_-configuration at the chiral centre bearing R3, marked with an asterisk in formula (I) .
  • the compounds of formula (I) or their salts, solvates or hydrates are preferably in pharmaceutically acceptable form.
  • pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • the compounds of formula (I) or their salts, solvates or hydrates are preferably in substantially pure form.
  • a substantially pure form will generally contain at least 50% by weight, preferably 75%, more preferably 90% and still more preferably 95% or 99% or more of the compound of formula I or its salt or solvate.
  • Compounds of formula (I) or their salts, solvates or hydrates may be isolated as crystalline solids or in the form of foams or gums.
  • a preferred pharmaceutically acceptable form is the crystalline form.
  • the present invention provides the compounds of formula (I) or pharmaceutically acceptable salts, solvates or hydrates thereof for use as active therapeutic agents, particularly as agents for treatment of conditions in which degradation of connective tissue and other proteinaceous components of the body occurs, such as musculo-skeletal disorders resulting from collagenolytic activity, particularly rheumatism and/or arthritic conditions, and tissue remodelling.
  • Compounds of formula (I) also have potential utility in the treatment of cancer; for preventing myelin degradation in the central and peripheral nervous system; and in other conditions in which members of the collagenase family of neutral metalloproteases have pathological or other roles.
  • the present invention also provides a process for the preparation of a compound of formula (I) which comprises converting a group R 2Q to hydrogen by cleaving a group R 2Q from a compound of formula (II) :
  • R 2 is alkyl, optionally substituted phenyl, or optionally substituted benzyl and R 21 is hydrogen, alkyl, optionally substituted phenyl, or optionally substituted benzyl and R- j _, R , R3 and R 4 are as defined in formula (I) , and where necessary, converting R 2 -, to hydrogen.
  • Cleavage of R 2 g, and where necessary R 2 ⁇ may be carried out in aqueous acid or alkali or using a trimethylsilyl halide, preferably bromotrimethylsilane, in an inert solvent, for example dichloromethane or acetonitrile.
  • Benzyl esters may alternatively be removed by hydrogenolysis or other standard debenzylation procedures. Phenyl residues may be removed by hydrogenation over platinum oxide.
  • R 2Q and R 21 are alkyl
  • cleavage of R 2Q only, to give to a compound of formula (II) in which R 2 g is hydrogen and R 21 alkyl, which is a compound of formula (I) in which R is alkyl may be carried out by treatment with excess alkali under mild conditions, for example with aqueous sodium hydroxide in an alcoholic solvent at room temperature.
  • R 2Q is optionally substituted benzyl and R 21 is alkyl
  • the benzyl group only may be cleaved by hydrogenation to give a compound of formula (II) in which R 2 Q is hydrogen and R 21 is alkyl.
  • R in a compound of formula (I) is hydrogen and R 21 in a compound of formula (II) is not hydrogen, then cleavage of both R 1 and R 2 Q is conveniently effected in a single reaction.
  • R 2 Q and R 2] _ are both alkyl, such as methyl or ethyl, or benzyl.
  • R- j _, R , R 2 Q and R 2l are as defined in formula (II) (except that R 21 is not H) , with a compound of formula (IV) :
  • the reaction is preferably carried out in the presence of a coupling agent, such as dicyclohexylcarbodiimide or l-ethyl-3- [3- (dimethylamino)propyl]carbodiimide hydrochloride in the presence of 1-hydroxybenzotriazole, or using 1, 1'-carbonyldiimidazole, in an inert solvent such as dichloromethane or acetonitrile.
  • a coupling agent such as dicyclohexylcarbodiimide or l-ethyl-3- [3- (dimethylamino)propyl]carbodiimide hydrochloride in the presence of 1-hydroxybenzotriazole, or using 1, 1'-carbonyldiimidazole, in an inert solvent such as dichloromethane or acetonitrile.
  • the intermediate compounds of formula (III) may be prepared by treating a compound of formula (V) or a salt thereof:
  • R ⁇ , R 2Q and R 21 are as defined in formula (III) , with a compound of formula (VIA) or (VIB) or a salt thereof:
  • VA (VIA) (VIB) in which R 2 is as defined in formula (I) , R 11 is a leaving group such as halogen, methanesulphonyloxy or trifluoromethanesulphonyloxy and R 12 is hydrogen or a carboxyl protecting group, and thereafter removing an R 12 carboxyl protecting group.
  • Preferred method is the reaction of (V) with (VIA) .
  • 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 (V) and (VIB) in which any of R 2 Q R 21 or R 12 ' ⁇ - s Denz yl-
  • 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 or aqueous potassium hydroxide in 1,4-dioxane.
  • the compound of formula (V) is a salt, such as the hydrochloride salt
  • the preparation of compounds of formula (III) using a compound of formula (VIA) may be carried out under standard alkylation conditions.
  • a halogen leaving group is preferably bromine and an oxygen-based leaving group is preferably trifluoromethanesulphonyloxy.
  • R 2 is as defined in formula (I) and R 12 is a carboxyl protecting group with an aldehyde
  • 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 (II) in which R 2Q and R 2] _ are alkyl or optionally substituted benzyl may be prepared by the reaction of a compound of formula (VIII) :
  • R- j _ is as defined in formula (I)
  • R 2Q and R 2] _ are alkyl, optionally substituted phenyl, or optionally substituted benzyl and R ⁇ is a leaving group as defined for formula (VIA)
  • a base such as triethylamine or Proton Sponge (1, 8-bis (dimethylamino)-naphthalene)
  • anhydrous potassium carbonate in an alcoholic solvent.
  • R- is an oxygen-based leaving group
  • R- is an oxygen-based leaving group
  • 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 cf several days in the absence of light.
  • a further alternative preparation of compounds of formula (III) may be carried out by reacting a compound of formula (IX) as hereinbefore defined with a compound of formula (VII) in which R ⁇ is a carboxyl protecting group, using conditions as described for the reaction of compounds of formula (VIII) with compounds of formula (IX) , and thereafter removing the protecting group R 12 .
  • Suitable carboxyl protecting groups include alkyl, benzyl, trialkylsilyl and trialkylsilylethyl groups.
  • a trialkylsilyl protecting group for example trimethylsilyl, is especially useful in that it may be readily incorporated, in situ, for example by addition of hexamethyldisilazane to the reactants in acetonitrile in the presence of triethylamine, and selectively removed in aqueous methanol, without imposing any limitations on the value of R 2 Q and R 2 ⁇ «
  • Other -silylating agents include trimethylsilyl chloride and N,N-diethyltrimethylsilylamine.
  • R 12 alkyl carboxyl protecting group may be removed by base hydrolysis, for example using sodium hydroxide in aqueous methanol or potassium hydroxide in aqueous 1,4- dioxane.
  • R 2 Q and R 21 may be alkyl, phenyl or benzyl derivatives, but where R 12 is a benzyl group, R 2Q and R 21 are limited to alkyl and phenyl.
  • R 20 and R 21 are benzyl and R-, -. is trifluoromethanesulphonyloxy in the compound of formula (IX) and R 12 is trimethylsilyl or methyl in the compound of formula (VII) .
  • Compounds of formula (VIII) may be prepared by treating a compound of formula (VII) :
  • R 2 is as defined in formula (I)
  • R 1 is hydrogen 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 (IX) may be prepared from hydroxy- alkylphosphonate derivatives by conversion of the hydroxyl group to the leaving group R ⁇ by conventional methods.
  • R ⁇ is trifluoromethanesulphonyloxy
  • 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 atmosphere, according to the general method of E. Vedejs et a ⁇ . , Journal of Organic Chemistry 50_, 2165, (1985) .
  • Hydroxyalkylphosphonate compounds may in turn be prepared by reaction of the corresponding phosphite, for example dibenzylphosphite, with an aldehyde R- ] _-CHO in which R 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 available compounds or can be prepared from commercially available starting materials by standard methods.
  • Intermediate compounds of formula (V) are either known compounds or may be prepared from known aminoalkyl phosphonic acid derivatives using standard procedures to introduce R 2 Q and R 21 as required.
  • R 2 Q or R 2 - j _ methyl group may be effected by reaction with diazomethane in a suitable inert solvent.
  • Y is a nitrogen protection group
  • Z is R 5 to give the corresponding aldehyde, followed by removal of Z where R is an acyl group; cyclisation and reduction; and thereafter, as necessary, removing the nitrogen protection group Y and interconverting R .
  • Suitable nitrogen protection groups include t.-butoxycarbonyl (BOC) and benzyloxycarbonyl groups.
  • the oxidation may be carried out using pyridinium chlorochromate, or under Swern oxidising conditions, for example by treatment with dimethylsulphoxide and an acyl halide followed by triethylamine, as described by D. Swern et al., J. Org. Chem., 43, 2480 (1978).
  • the cyclisation and reductive amination step may be effected by catalytic hydrogenation over a suitable noble metal catalyst, for example palladium on carbon, or by reaction with sodium cyanoborohydride or sodium borohydride. In some cases the yield of azalactams may be increased by carrying out the reductive amination step under acidic conditions.
  • Nitrogen protection groups may be removed by standard methods.
  • a t.-butoxycarbonyl group may be removed by treatment with trifluoroacetic acid at reduced temperature.
  • Z may be selected to undergo concomitant cleavage during the cyclisation reaction to give a compound in which R5 is hydrogen.
  • Z is a benzyloxycarbonyl group, it will be readily removed by catalytic hydrogenation.
  • An R5 hydrogen may be interconverted to an Re- C- ⁇ .galkyl, aralkyl or aryl group.
  • the secondary amine group in the azalactam ring may be alkylated to form an R5 alkyl group.
  • the amine group may be methylated to form an R5 methyl group.
  • the methylation step may be effected by catalytic hydrogenation over a suitable noble metal catalyst, for example palladium on carbon, in the presence of aqueous formaldehyde.
  • suitable noble metal catalyst for example palladium on carbon
  • Other suitable methylation procedures are described by E. Askitoglu e_t aL. , Helv. Chim. Acta., .68., 7 50, (1985); E. Engler et al.. , Helv. Chim. Acta., 68., 789, (1985); and M. Lennon e a_l., J. Chem. Soc. (Perkin I
  • the reaction may be carried out using standard procedures for forming an amide from a carboxylic acid and an amine, for example using a coupling agent such as 1,1'- carbonyldiimidazole, 1, 3-dicyclohexylcarbodiimide or 1- (3- dimethylaminopropyl)-3-ethylcarbodiimide.
  • a coupling agent such as 1,1'- carbonyldiimidazole, 1, 3-dicyclohexylcarbodiimide or 1- (3- dimethylaminopropyl)-3-ethylcarbodiimide.
  • Compounds of formula (XI) are di-aminoalkanoic acid derivatives. These are known compounds or may be prepared from known starting materials by standard methods.
  • the compound of formula (IV) in which R3 and R ⁇ together are - (CH 2 ) -X-(CH 2 ) Q - where p is 3, q is 6 and X is -NH- is prepared from a compound of formula (XI) derived from ornithine which is commercially available.
  • the compounds of formula (IV) in which R and R 4 together are - (CH 2 ) p -X-(CH 2 ) q - where p is 4, q is 3, 5 or 6 and X is -NH- are prepared from a compound of formula (XI) derived from the amino acid lysine.
  • the compound of formula (XI) derived from S.-lysine, in which Y is t.-butoxycarbonyl and Z is benzyloxycarbonyl, is commercially available.
  • the compound of formula (IV) in which R and R 4 together are - (CH 2 )p-X- (CH 2 )q- where p is 1, q is 8 and X is -NH- may be prepared from 2,3-diaminopropionic acid.
  • the compounds of formula (VII) are either known amino acid derivatives or can be made from these derivatives by known methods.
  • Compounds of formula (VIA) and (VIB) are either known compounds or may be prepared from known compounds by known methods.
  • pharmaceutically acceptable salts of the compounds of formula (I) may be formed conventionally by reaction with the appropriate acid or base. Solvates may be formed by crystallization from the appropriate solvent. As mentioned previously, the compounds of formula (I) exist in more than one diastereoisomeric form. Where the processes of the invention produce mixtures thereof, the individual isomers may be separated one from another by chromatography e.g. HPLC.
  • 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) .
  • the present invention further provides a pharmaceutical composition, which comprises a compound of formula (I),or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • a composition of this invention is useful in the treatment of musculo-skeletal disorders, particularly arthritic diseases and for modulation of tissue remodelling.
  • a composition of the invention also has potential utility in the treatment of cancer; for preventing myelin degradation in the central and peripheral nervous system; and in other conditions in which members of the collagenase family of neutral metalloproteases have pathological or other roles.
  • a composition of the invention which may be prepared by admixture, may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
  • a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
  • these conventional excipients may be employed in conventional manner, for example as in the preparation of compositions of related peptide enzyme inhibitors, such as the ACE inhibitor enalapril.
  • 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, intra- articularly, intradermally, subcutaneously 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.
  • such 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 formulated for administration by any route, the preferred route depending upon the disorder for which treatment is required, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage.
  • 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 may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrroUdone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tableting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrroUdone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrroUdone
  • fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tableting lubricants for example magnesium stearate
  • disintegrants for example starch, polyvinylpyrro
  • 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 quantities of fillers.
  • 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 capsule, for example of gelatin containing the compound, if desired with a carrier or other excipients.
  • a hard gelatin capsule containing the required amount of a compound of the invention in the form of a powder or granulate in intimate mixture with a lubricant, such as magnesium stearate, a filler, such as microcrystalline cellulose, and a disintegrant, such as sodium starch glycollate.
  • a lubricant such as magnesium stearate
  • a filler such as microcrystalline cellulose
  • a disintegrant such as sodium starch glycollate
  • 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, carboxymethylceUulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; aqueous or non ⁇ aqueous vehicles, which include 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
  • compositions may be formulated, for example for rectal administration as a suppository or for parenteral administration in an injectable form.
  • injectable form for injection, for example by intra- articular injection or by injection into the cerebro- spinal fluid or via other routes which will gain access to sites of demyelination, such as by intramuscular, intradermal or subcutaneous injection, as freely soluble solutions or as poorly dispersed depot stores, the compounds of the invention may be presented in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g.
  • sterile 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 acceptable additives.
  • 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 injectable formulation.
  • the 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 approximately 0.15 to 50 mg/kg per day.
  • 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, such as rheumatism and/or arthritic conditions in mammals, such as humans, which comprises administering to themammal 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 such as rheumatism and/or arthritic conditions.
  • the title compound was prepared by the general method of E. Vedejs et al. [J. Org. Chem. 1985, 50(12), 2165].
  • a solution of dibenzyl (l-hydroxypropyl)phos-phonate (DI) (24.97g, 0.078 mole) in methylene chloride (180 ml) was cooled to -50°C under N .
  • 2,6-Lutidine (11.12 ml, 0.095 mole) was added followed by trifluoro- methanesulphonic anhydride (15.1 ml, 0.0898 mole) keeping the temperature -50°C.
  • the mixture was allowed to warm slowly to 0°C and then taken into cold ether.
  • the solution was subjected to a rapid aqueous work-up by washing the organic layer with ice-cold water, dilute hydrochloric acid (x2) and finally brine.
  • the organic layer was dried (anhydrous MgS0 4 ) and evaporated to dryness to give the title compound as a pinkish orange oil (33.77g, 96%) which was used without further purification.
  • Dibenzyl ( (1-trifluoromethanesulphonyloxy)propyl)- phosphonate (D2) (4.5g, 0.01 mole) was then added and the mixture maintained at 40-42°C for 48h.
  • the reaction can also be carried out at ambient temperature. After cooling the mixture was filtered, washed with methanol and the filtrate evaporated to dryness. The residue was taken up in chloroform and washed with dilute HCl (x2) and finally water. The chloroform layer was dried (anhydrous Na 2 S0 4 ) , filtered and evaporated to dryness to give an orange gummy solid (3.67g) .
  • the other isomer, N- (1- (S) -dibenzyloxyphosphinylpropyl) - (S) -leucine (D3B) can be obtained by preparative HPLC using a Hamilton PRP-1 column, 300 x 7.0mm, 264R with a 40:60 acetonitrile:water eluent mixture and a flow rate of 4.0 ml/min. Under these conditions the R,S isomer (D3A) elutes first with a retention time of 34.6 min and the S,S isomer (D3B) is well separated at 42.7 min.
  • the single isomer can be hydrolysed separately.
  • N-(1-(S)-dibenzyloxy ⁇ phosphinylpropyl)-(S)-leucine methyl ester on hydrolysis by the above method gave N-(1-(S)-dibenzyloxy ⁇ phosphinylpropyl)-(S)-leucine (D3B) , m.p. 71-73°C.
  • D3B N-(1-(S)-dibenzyloxy ⁇ phosphinylpropyl)-(S)-leucine
  • the aldehyde (D5) (1.8g, 3.88 mmol) was dissolved in ethanol (180 ml) and hydrogenated over 5% palladium on charcoal (200 mg) at atmospheric pressure and 35°C for 72h. The suspension was filtered through Kieselguhr and evaporated in vacuo to give crude 3-[N-tert-butoxy- carbonyl]amino- (S)-1,8-diazacyclotridecan-2-one.
  • the aldehyde (D5) was hydrogenated at about 100 psi over 5% palladium on charcoal in methanol, and then in acidic methanol to afford crude (S)-3-[N-tert- butoxycarbonyl]amino-1,8-diazacyclotridecan-2-one.
  • the amine was treated with benzylchloroformate and purified as described in Method A to yield the identical title compound (D6) .
  • the aldehyde (D10) (2.5g) in methanol (300 ml) was treated with 5% palladium on charcoal (2.5g).
  • the suspension was hydrogenated at 100 psi and ambient temperature for 48h, treated with 2.5M aqueous hydrochloric acid (2 ml) and hydrogenation continued at the said pressure for a further 24h.
  • the suspension was- filtered through kieselguhr and evaporated in vacuo to give crude 3-(N-tert-butoxy- carbonyl)amino-(S)-1,7-diazacyclotridecan-2-one.
  • the aldehyde (D15) (5.0g) in methanol (450 ml) was treated with 5% palladium on charcoal (5.5g) .
  • the suspension was hydrogenated at 140 psi and ambient temperature for 48h, treated with 2.5M aqueous hydrochloric acid (3 ml) and hydrogenation continued at the said pressure for a further 24h.
  • the suspension was filtered through Kieselguhr and evaporated in vacuo to give crude (S)-3- (N-tert-butoxy- carbonyl)amino-1,8-diazacyclotetradecan-2-one.
  • a solution of diazalactam (D6) (0.35g) in methanol (20 ml) was treated with 5% palladium on charcoal (0.2g) and hydrogenated for 24h at atmospheric pressure and room temperature.
  • the suspension was filtered through kieselguhr, and the filtrate diluted with methanol to a •total volume of 50 ml.
  • the solution was treated with 5% palladium on charcoal (0.3g) followed by 40% aqueous formaldehyde (1 ml) , and the resulting suspension hydrogenated for 48h at a pressure of 100 psi.
  • the suspension was filtered through Kieselguhr, solvent evaporated in vacuo, to yield an oil which on exposure to diethyl ether solidified.
  • the test is performed essentially as in Cawston and Barrett, Anal. Biochem. £9, 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) in buffer. After a 5 min pre-incubation at 37°C, the assay tubes are cooled to 4°C and ⁇ H-acetylated rat skin type I collagen is added. The assay tubes are incubated at 37°C overnight. The ⁇ -collagen forms insoluble fibrils, which are the substrate for the enzyme.
  • the assay tubes are spun at 12000 rpm for 15 minutes. Undigested J H-collagen is pelleted, while digested ⁇ -collagen is found as soluble peptides in the supernatant. A sample of the supernatant is taken for liquid scintillation counting.
  • IC 50 50% inhibitory concentration
  • the compounds of Examples E1-E7 had IC 50 values in . the range 6 x 10 "8 - 3 x 10 _6 M.

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Abstract

Dérivés d'azalactame, procédés servant à leur préparation et utilisation comme inhibiteurs de collagénase, ayant le formule (I).
EP91907169A 1990-04-10 1991-04-05 Phosphonopeptides avec activite inhibitrice de la collagenase Ceased EP0527761A1 (fr)

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AU (1) AU637903B2 (fr)
CA (1) CA2080228A1 (fr)
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EP0520573A1 (fr) * 1991-06-27 1992-12-30 Glaxo Inc. Dérivés d'imides cycliques
GB9122859D0 (en) * 1991-10-28 1991-12-11 Smithkline Beecham Plc Novel compounds
US5326760A (en) * 1992-06-29 1994-07-05 Glaxo, Inc. Aminobutanoic acid compounds having metalloprotease inhibiting properties
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
US5827840A (en) * 1996-08-01 1998-10-27 The Research Foundation Of State University Of New York Promotion of wound healing by chemically-modified tetracyclines

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GB8726714D0 (en) * 1987-11-14 1987-12-16 Beecham Group Plc Compounds
EP0401963A1 (fr) * 1989-04-13 1990-12-12 Beecham Group p.l.c. Phosphonopeptides avec activité inhibitrice de collagénase

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ZA912574B (en) 1992-10-28
AU7650291A (en) 1991-10-30
IE911165A1 (en) 1991-10-23
CA2080228A1 (fr) 1991-10-11
GB9008065D0 (en) 1990-06-06
WO1991015506A1 (fr) 1991-10-17
PT97281A (pt) 1992-01-31

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