Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C327/00—Thiocarboxylic acids
  • C07C327/20—Esters of monothiocarboxylic acids
  • C07C327/32—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
  • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms

Definitions

• Thiol-carboxylic acid derivatives as collagenase inhibitors as collagenase inhibitors.
• the present invention relates to novel thiol-carboxylic acid 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 arthritic 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
• polymorphonuclear leucocyte gelatinases also known as collagen-IV-ases
• 'pump-1' putative metalloprotease 1, uterine metalloprotease
• 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.
• 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
• 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.
• EPA 273689 Beecham Group
• US 4235885 Squibb disclose thiol-carboxylic acid derivatives having activity as
• collagenolytic activity is a contributing factor.
• a novel class of thiol-carboxylic acid derivatives has now been discovered, which are collagenase inhibitors and thus of potential utility in the treatment of diseases in which activity of members of the collagenase family of neutral metalloproteases is implicated.
• R 1 is -OH; alkoxy; aryloxy or aralkyloxy; -NR 6 R 7 , where each of R 6 and R 7 is independently hydrogen or alkyl, or R 6 and R 7 together with the nitrogen atom to which they are bonded form a 5-, 6- or 7-membered ring with an
• R 9 is alkoxy; OH; or -NR 6 R 7 ;
• R 2 is hydrogen; or acyl, such as or , where Z
• R 3 is C 3-6 alkyl;
• R 4 is -(CH 2 ) n NR 10 R 11 , - (CH 2 ) n NHCOR 12 ,
• R 10 and R 11 are independently hydrogen or alkyl, or R 10 and R 11 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 substituted second nitrogen atom in the ring
• R 12 is alkyl, alkoxy, aralkyloxy or -(CH 2 ) m NR 10 R 11 , where m is 1 or 2
• R 13 is hydrogen or alkyl
• R 14 is hydrogen or alkyl or R 14 and R 10 together with the nitrogen atoms to which they are bonded form an optionally substituted 5-, 6- or 7-membered ring
• R 15 is an optionally substituted piperidyl ring
• R 5 is hydrogen, alkyl, -CH 2 - (CH 2 ) n OR 16 , -CH 2 - (CH 2 ) n -OCOR 17 or
• each alkyl or alkoxy group is a C 1-8 group, more preferably C 1-6 , and may be a straight chain or branched.
• An aryl moiety is preferably phenyl.
• Optional substituents for aryl, phenyl and heteroaryl groups may be selected from -OH, C 1-6 alkyl, C 1-6 alkoxy and
• heterocyclic rings formed by the groups R 10 and R 11 include pyrrolidine, piperidine, piperazine and
• R 1 examples include hydroxy; C 1-6 alkoxy, such as methoxy, ethoxy, iso-propoxy or t-butoxy; benzyloxy; and -NR 6 R 7 in which R 6 is hydrogen and R 7 is hydrogen or C 1-8 alkyl such as methyl or ethyl, or -NR 6 R 7 may be N'-methyl-N-piperazinyl or N-morpholinyl.
• R 1 are -NH-CH 2 COOH,
• R 1 is preferably hydroxy, C 1-4 alkoxy especially methoxy or iso-propoxy, or amino. Most preferably R 1 is iso-propoxy.
• R 2 is Z is preferably an optionally substituted phenyl group.
• R 2 are hydrogen, acetyl and benzoyl. Most preferably R 2 is hydrogen or acetyl.
• R 3 is preferably a C 4 alkyl group, such as n-butyl, iso-butyl or sec-butyl. Most preferably R 3 is iso-butyl.
• R 4 is -(CH 2 ) n NR 10 R 11 where R 10 and R 11 are
• R 15 is optionally substituted piperidyl and, in each of the above, n is an integer from 1 to 4.
• R 4 is -(CH 2 ) 4 NH 2 or - (CH 2 ) 4 NHCOR 12 where R 12 is benzyloxy.
• Preferred values for R 5 are hydrogen, methyl or hydroxyethyl. Most preferably R 5 is methyl.
• the compounds of formula (I) may form salts with bases e.g. sodium hydroxide.
• bases e.g. sodium hydroxide.
• the compounds of formula (I) 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 one asymmetric centre and therefore exist in more than one stereoisomeric form.
• the invention extends to all such forms and to
• the compounds of formula (I) or their salts, solvates or hydrates are preferably in pharmaceutically acceptable or substantially pure 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 present invention provides the compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof for use as active therapeutic agents, particularly as agents for treatment of musculo-skeletal disorders resulting from collagenolytic activity, particularly arthritic diseases, and tissue remodelling, and also for the systemic chemotherapy of cancer.
• the present invention also provides a process for the
• L is L 1 which is a conventional sulphur protecting group or L 2 which is a group R-S- where R is any organic residue such that the group R-S- provides a cleavable
• R 1 , R 3 , R 4 and R 5 are as defined for formula (I).
• a protecting group L is a substituted benzyl group, such as alkoxybenzyl, e.g. 4-methoxybenzyl, or an aliphatic or aryl acyl group such as acetyl or benzoyl.
• L 1 is acyl it is of course identical to R 2 , so these compounds of formula (II) are themselves compounds of the invention.
• L is L 1
• L 1 is a substituted benzyl sulphur
• L 1 may be removed by treatment with mercury acetate in trifluoroacetic acid containing anisole, followed by reaction with hydrogen sulphide in dimethylformamide, in a procedure analogous to that described in Chem. Pharm. Bull., 1978, 26, 1576.
• L 1 is an acyl group it may be removed by treatment with a base, for example aqueous ammonia or dilute aqueous sodium hydroxide, or by treatment with an acid, for example
• a base for example aqueous ammonia or dilute aqueous sodium hydroxide
• an acid for example
• the dimerized compound may be split at the disulphide link by treatment with zinc and hydrochloric acid or by passing hydrogen sulphide through the solution.
• R 1 , R 3 , R 4 and R 5 are as defined in formula (I) with a thiol of formula (IV): in which L 1 is as defined in formula (II).
• L 1 is R 2
• the compounds of formula (II) thereby produced are compounds of the invention.
• reaction is preferably carried out in the presence of a coupling agent, such as 1,1'-carbonyldiimidazole, or 1-ethyl- 3-[3-(dimethylamino)propyl] carbodiimide hydrochloride in the presence of 1-hydroxybenzotriazole.
• a coupling agent such as 1,1'-carbonyldiimidazole, or 1-ethyl- 3-[3-(dimethylamino)propyl] carbodiimide hydrochloride in the presence of 1-hydroxybenzotriazole.
• those compounds of formula (II) in which R 1 is hydroxy may be prepared under acid conditions by hydrolysis of compounds in which R 1 is alkoxy, aryloxy or aralkyloxy or by hydrogenolysis of compounds in which R 1 is benzyloxy or substituted benzyloxy in the presence of a catalyst such as palladium black.
• Those compounds of formula (II) in which R 1 is -NR 6 R 7 may be prepared from compounds in which R 1 is hydroxy by treating the latter compounds with an amine of formula NHR 6 R 7 in the presence of a coupling agent such as N,N-dicyclohexylcarbodiimide or 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide in the presence of 1-hydroxybenzotriazole, or ethyl chloroformate.
• a coupling agent such as N,N-dicyclohexylcarbodiimide or 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide in the presence of 1-hydroxybenzotriazole, or ethyl chloroformate.
• R 1 is -NH-CH(R 8 )-COR 9
• R 1 is OH by treatment with amine derivatives of formula NH 2 CH(R 8 )COR 9 where R 9 is an alkoxy or amine group, followed by hydrolysis to give an R 9 hydroxy group, if desired.
• compounds of the invention in which R 2 is acyl can be converted to further compounds of the invention with concomitant cleavage of the acyl group to give compounds of formula (I) in which R 2 is hydrogen.
• those compounds of formula (I) in which R 1 is -OH and R 2 is hydrogen may be prepared by hydrolysis of compounds in which R 1 is alkoxy, aryloxy or aralkyloxy and R 2 is acyl under basic conditions such as treatment with dilute sodium hydroxide.
• the intermediate compounds of formula (III) may be prepared by treating a compound of formula (VII):
• the thiols of formula (IV) are known compounds.
• the intermediate compounds of formula (V) may be prepared by treating a compound of formula (VII), as defined above, with a thiol of formula (IV). It may be necessary or convenient to protect the carboxyl function in compounds of formula (VII), for example by esterification, prior to treatment with the thiol of formula (IV) and subsequently remove the protecting group under acid conditions.
• R 5 and R 13 are as defined in formula (I), Z is optionally substituted pyridyl and Y is a nitrogen protection group, by conversion of Q to R 4 and removal of the nitrogen protection group, Y.
• a compound of formula (VI) in which R 4 is -(CH 2 ) n NR 10 R 11 may be prepared by alkylation of a compound of formula (VIII) in which Q is -(CH 2 ) n NH 2 using standard alkylation procedures.
• a compound of formula (VI) in which R 4 is -(CH 2 ) n NHCOR 12 may be prepared by reaction of a compound of formula (VIII) in which Q is -(CH 2 ) n NH 2 with a carboxylic acid R 12 CO 2 H, in the presence of a coupling agent.
• -(CH 2 ) n CONH(CH 2 ) q NR 10 R 11 may be prepared by reaction of a compound of formula (VIII) in which Q is -(CH 2 ) n CO 2 H with an amine derivative, NH 2 (CH 2 ) q NR 10 R 11 in the presence of a coupling agent, and thereafter if R 10 or R 11 is hydrogen optionally protecting the basic nitrogen atom.
• a compound of the formula (VI) in which R 4 is -(CH 2 ) n -R 15 where R 15 is an optionally substituted piperidyl group may be prepared by hydrogenation of a compound of formula (VIII) in which Q is -(CH 2 ) n -z and optionally thereafter protecting the piperidyl nitrogen atom.
• Suitable nitrogen protection groups for Y and for any primary amino function in R 4 include t-butoxycarbonyl (BOC) and benzyloxycarbonyl groups.
• suitable nitrogen protecting groups include benzyloxycarbonyl groups.
• Nitrogen protection groups may be removed by standard
• a t-butoxycarbonyl group may be removed by
• a compound of formula (VIII) may be prepared from a compound of formula (IX):
• Q' is Q in protected form or Q' is a precursor to Q and Y and Q are as defined for formula (VIII).
• the reaction may be carried out by reaction with an amine, NH 2 R 5 , 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, or 1-ethyl-3-[3- (dimethylamino)propyl] carbodiimide in the presence of
• a coupling agent such as 1,1'-carbonyldiimidazole, or 1-ethyl-3-[3- (dimethylamino)propyl] carbodiimide
• Compounds of formula (IX) are known compounds or may be prepared from known starting materials by standard methods.
• the compound of formula (IX) in which Q' is (CH 2 ) 4 NHCO 2 CH 2 Ph and Y is t-butoxycarbonyl is derived from lysine and is commercially available.
• the compound of formula (IX) in which Q' is CH 2 CO 2 CH 2 Ph and Y is t-butoxycarbonyl is derived from aspartic acid and is commercially available.
• 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.
• the individual isomers may be separated one from another by chromatography, e.g. column chromatography or 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, solvate or hydrate thereof, and a pharmaceutically acceptable carrier.
• a composition of this invention is useful in the treatment of rheumatism and arthritis and in the treatment of other collagenolytic conditions.
• 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, percutaneous, rectal or parenteral - intravenous, intramuscular, sub-cutaneous, intradermal or intra-articular administration, but oral administration is preferred.
• the preferred route for administration will depend 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 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.
• 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.
• the compositions for example those suitable for oral
• binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
• fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
• tabletting lubricants for example magnesium
• 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, tabletting or the like. Repeated blending operations may be used to distribute the active agent
• 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 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.
• 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
• flavouring or colouring agents for example almond oil,
• compositions may be formulated, for example for rectal administration as a suppository or for parenteral administration in an injectable form.
• the compounds of the invention may be presented in an aqueous or non-aqueous solution, suspension or emulsion in a
• 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
• 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
• the preparations may also be presented as an ointment, cream, lotion, gel, spray, aerosol, wash, or skin paint or patch.
• a unit dose for inflammatory diseases 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 dose corresponds to approximately 0.15 to 50 mg/kg per day.
• the unit dose will suitably contain from 2 to 20 mg of a compound of the invention and be
• the present invention additionally provides a method of treating a collagenolytic condition such as rheumatism and/or arthritic conditions or cancer, or other diseases in which enzyme-mediated breakdown of connective tissue components plays a role in mammals, such as humans, which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof, to the mammal .
• the present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof, for the manufacture of a medicament for use as an active therapeutic substance, particularly in the treatment of collagenolytic conditions such as rheumatism, cancer, bone disorders, skin diseases, periodontal disease or corneal ulceration, in mammals.
• N ⁇ -tert-Butoxycarbonyl-N ⁇ -benzyloxycarbonyl-(S)-lysine methylamide D2
• a solution of N ⁇ -tert-butoxycarbonyl-N ⁇ -benzyloxycarbonyl- (S)-lysine (50g, 0.13 mol) in dichloromethane (500 ml) was cooled in ice and treated with 1,1'-carbonyldiimidazole (22g, 0.136 mol). After 30 min the mixture was warmed to room temperature for 15 min then cooled again in ice.
• compositions for oral administration may be prepared by combining the following: 1) Solid Dosage Formulation
• Microcrystalline cellulose 86.5% 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.
• the film coat can comprise 2.0% to 6.0% of the tablet weight, preferably about 3.0%.
• 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
• ⁇ -mercaptoethanol may be incorporated in the methanol solvent and/or the diluent buffers to give a final concentration of 9.6 ⁇ 10 -5 M.
• the minimal direct effect of ⁇ -mercaptoethanol on the degradation of collagen by human collagenase is controlled for. After a 5 min pre-incubation at 37°C, 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 compound that inhibits a known (standard) concentration of enzyme by 50%.
• the compound of Example 4 had an IC 50 value of 1.1 ⁇ M.

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