Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
  • C07D245/02—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms not condensed with other rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to novel thiol carboxylic acid derivatives, processes for their preparation and their use in medicine.
• the present invention relates to novel thiol carboxylic acid derivatives, processes for their preparation and their use in medicine.
• the present invention relates to novel thiol carboxylic acid derivatives, processes for their preparation and their use in medicine.
• the present invention relates to novel thiol carboxylic acid derivatives, processes for their preparation and their use in medicine.
• the present invention relates to novel thiol carboxylic acid derivatives, processes for their preparation and their use in medicine.
• 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
• 'pump-1' putative metalloprotease 1, uterine metalloprotease
• collagenase family of enzymes in the connective tissue matrix throughout the body extend to clinical interventions in many diseases and phenomena involving the destruction of 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 diseaseand 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. that induced by alkali or other burns, by radiation, by vitamin E or retinoid deficiency; ulceration of the skin and gastro-intestinal tract, and abnormal wound healing;
• demyelinating diseases of the central and peripheral nervous systems including syndromes in which myelin loss is the primary pathological event and those in which demyelination follows axonal atrophy.
• myelin loss is the primary pathological event and those in which demyelination follows axonal atrophy.
• sclerosis is mediated by members of the collagenase family of enzymes.
• members of the collagenase family of enzymes As a particular example of the therapeutic value of 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 treatment with inhibitors of the collagenases,
• proteoglycanases stromelysins
• gelatinases currently thought to be the major enzymes involved.
• TIMPS Tissue Inhibitor of Metalloproteases
• 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 0273689 (Beecham Group) discloses a class of thiol-carboxylic acid derivatives having activity as inhibitors of collagenase and useful in the treatment of rheumatoid arthritis and related diseases in which 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 in each of which the aryl group is optionally substituted; -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 optional oxygen or sulphur atom or an optionally
• R 8 is hydrogen; alkyl optionally substituted by -OH, alkoxy, -NR 6 R 7 as defined for R 1 , guanidine, -CO 2 H, -CONH 2 , -SH, or -S-alkyl; or -CH 2 -Ar where Ar is
• R 9 is alkoxy; OH; or -NR 6 R 7 as defined for R 1 ;
• R 2 is hydrogen; C 2-8 alkanoyl; or optionally substituted aroyl;
• R 3 is C 3-6 alkyl;
• R 4 is - (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 marked with an asterisk in formula (I), and X is -NR 5 - where R 5 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkanoyl, C 1-6 alkoxycarbonyl and aroyl, aralkyl or aralkyloxycarbonyl in each of which the aryl moiety is optionally substituted. Unless otherwise specified, each alkyl or alkoxy group is a C 1-8 group, more preferably a C 1-6 group, and may be straight chain or branched.
• aryl groups include naphthyl and phenyl, preferably phenyl.
• Optional substituents for aryl groups may be selected from -OH, C 1-6 alkyl, C 1-6 alkoxy and halogen.
• Values for R 1 include hydroxy; C 1-6 alkoxy, such as methoxy, ethoxy, iso-propoxy or t-butyloxy; 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 is
• R 1 is preferably hydroxy, C 1-4 alkoxy or C 1-6 alkylamino.
• R 1 is hydroxy, methoxy, iso-propoxy or methylamino.
• R 2 is preferably hydrogen, acetyl or Ph-C- in which Ph is an optionally substituted phenyl group. Most preferably R 2 is hydrogen or acetyl.
• R 3 is preferably a C 4 alkyl group, such as n-butyl,
• R 3 is iso-butyl or sec-butyl. Most preferably R 3 is iso-butyl.
• R 4 is preferably - (CH 2 ) p -X- (CH 2 ) q - where p and q have values such that R 4 forms part of an 11- to 16-membered lactam structure, and X is a group -NR 5 - where R 5 is hydrogen, methyl, benzyl, t-butoxycarbonyl or
• R 4 is - (CH 2 ) p -X- (CH 2 ) q - where p is 4 and q is 5 or p is 4 and q is 6 and X is a group -NR 5 - where R 5 is hydrogen.
• 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.
• the compounds of formula (I) have at least three
• the invention extends to all such forms and to mixtures thereof, including racemates, and diastereoisomeric mixtures.
• Preferred isomers are those having the (S)-configuration at the chiral centre marked with an asterisk in formula (I).
• the compounds of formula (I) and their pharmaceutically acceptable salts 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 pharmaceutically acceptable salt.
• the present invention provides the compounds of formula (I) or pharmaceutically acceptable salts 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.
• 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 process comprises the reaction of a compound of formula (II):
• R 1 , R 3 and R 4 are as defined in formula (I), with a thiol of formula (III): L - SH (III) wherein L is a conventional sulphur protection group, to give a compound of formula (IV):
• a sulphur protection group L is a substituted benzyl group, such as alkoxybenzyl, for example
• L is a substituted benzyl sulphur protection group, such as 4-methoxybenzyl, then L may be removed by
• L 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 methanolic hydrochloric acid.
• a base for example aqueous ammonia or dilute aqueous sodium hydroxide
• an acid for example methanolic hydrochloric acid.
• those compounds of formula (IV) in which R 1 is -OH 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 (IV) in which R 1 is -NR 6 R 7 may be prepared from compounds in which R 1 is -OH by treating the latter compounds with an amine of formula NHR 6 R 7 in the presence of a coupling agent such as
• compounds of formula (IV) in which R 1 is -NR 6 R 7 may be prepared from compounds of formula (IV) in which R 1 is alkoxy by aminolysis of the latter compound with an amine of formula NHR 6 R 7 in the presence of a catalytic amount of cyanide. Aminolysis procedures are described by Hogber, T. et al., J. Org. Chem. 1987, 52, 2033-2036; De Ferand, R.J. et al., J. Org. Chem. 1963, 28, 2915-2917.
• compounds of formula (IV) in which L is an acyl group can be converted to compounds of the invention with interconversion of R 1 and 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 of formula (IV) in which R 1 is alkoxy, aryloxy or aralkyloxy and L is acyl, under basic conditions such as treatment with dilute sodium hydroxide.
• the intermediate compounds of formula (II) may be prepared by treating a compound of formula (V):
• reaction is suitably carried out in the presence of a coupling agent, such as 1,1'-carbonyldiimidazole.
• a coupling agent such as 1,1'-carbonyldiimidazole.
• Suitable values for Y include t-butoxycarbonyl (BOC) and benzyloxycarbonyl groups, preferably t-butoxycarbonyl.
• the oxidation may be carried out using pyridinium
• 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.
• Nitrogen protection groups may be removed by standard methods. When Y or Z are t-butoxycarbonyl groups these may be removed by treatment with trifluoroacetic acid at reduced temperature.
• Y or Z are benzyloxycarbonyl groups these may be removed by conventional hydrogenation over palladium on carbon, or by treatment with either formic acid-methanol and palladium black, or with HBr and glacial acetic acid.
• the group Z may be selected to undergo concomitant cleavage during the cyclisation reaction to give a compound in which R 5 is hydrogen.
• Z is a benzyloxycarbonyl group, it will be readily removed by catalytic hydrogenation.
• R 5 hydrogen in compounds of formulae (I), (II), (IV), (VI) and (VII) may be interconverted to an R 5 C 1-6 alkyl, aralkyl or acyl group.
• the nitrogen atom in R 4 may be alkylated, for example methylated to form an R 5 methyl group, or acylated to form an R 5 C 1-6 alkoxycarbonyl or aralkyoxycarbonyl group.
• 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 N-ethyl-N'-dimethylaminopropylcarbodiimide.
• Compounds of formula (VIII) are di-aminoalkanoic acid derivatives. These are known compounds or may be prepared from known starting materials by standard methods.
• the compound of formula (VI) in which R 4 is - (CH 2 ) p -X- (CH 2 ) q - where p is 3, q is 6 and X is -NH- is prepared from a compound of formula (VIII) derived from ornithine which is commercially available.
• the thiols of formula (III) and the amino alcohols of formula (IX) are known compounds or may be prepared from known compounds by known methods.
• Intermediate compounds of formulae (II) and (IV) disclosed herein are novel compounds and form an aspect of the present invention.
• 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.
• the compounds of formula (I) exist in more than one diastereoisomeric form.
• the processes of the invention produce mixtures thereof, the individual isomers may be separated one from another by chromatography, e.g. column chromatography or HPLC.
• 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.
• a composition of the invention which may be prepared by admixture, may contain a diluent, binder, filler,
• 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 captopril.
• composition of the invention may be adapted for oral, topical, rectal or parenteral administration but oral administration is preferred.
• Parenteral compositions may be administered e.g. intravenously, intramuscularly or intra-articularly.
• Preferably compositions are in unit dosage form or in a form that a patient can administer to himself in a single dose.
• 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
• 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
• tabletting lubricants for example magnesium stearate
• disintegrants for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose
• 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 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
• 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.
• 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.
• 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,
• emulsifying agents for example lecithin, sorbitan monooleate, or acacia
• aqueous or non-aqueous vehicles which include edible oils, such as almond oil and fractionated coconut oil, oily esters, for example esters of glycerine, propylene glycol, 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 agents.
• the compounds of this invention may also be administered by a non-oral route.
• a non-oral route In accordance with routine
• compositions may be any pharmaceutical procedure, the compositions may be any pharmaceutical procedure.
• injectable form for injection, for example by
• 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
• 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
• preparations may also be presented as an ointment, cream, lotion, gel, spray, aerosol, wash, skin paint or patch.
• inventions 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.
• a unit dose for treating diseases and physiological phenomena in which enzymes from 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 once 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 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 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 such as rheumatism and/or arthritic conditions.
• 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 aldehyde (D3) (1.8g, 3.88 mmol) was dissolved in ethanol (180 ml) and hydrogenated over 10% palladium on charcoal (200 mg) at atmospheric pressure and 35°C for 72h. The suspension was filtered through Keiselguhr and evaporated in vacuo to give crude (S)-3-(N-tert-butoxy- carbonyl)amino-1,8-diazacyclotridecan-2-one. The crude amine was dissolved in a mixed solvent system of
• the aldehyde (D8) (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.
• the crude amine was dissolved in a mixed solvent system of
• the aldehyde (D8) (5.8g) in methanol (600 ml) was treated with 5% palladium on charcoal (6g)and hydrogenated at 50 psi for 18h. The suspension was filtered through
• thiolacetic acid 35 ml was set aside at room temperature for 18 days and then evaporated to dryness in vacuo.
• the product was subjected to flash-column chromatography on silica gel using diethyl ether, followed by diethyl ether-ethyl acetate (4:1) v/v as the eluent.
• the first fractions to contain solids on evaporation of solvent were combined and recrystallised from diethyl ether-pentane to afford the title compound (El) (0.32g), m.p. 135-138°C. (Found: C, 62.29; H, 8.03; N, 6.59. C 33 H 51 O 7 N 3 S requires C, 62.53; H, 8.11; N, 6.63%).
• isopropanol (5 ml), previously purged with nitrogen, was added a solution of sodium hydroxide (0.02g) in water (1 ml) and the resulting solution was stirred at room temperature, under nitrogen for 18h. The solution was acidified with an excess of ethereal-HCl and then
• compositions for oral administration are 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.
• the film coat can comprise 2.0% to 6.0% of the tablet weight, preferably about 3.0%.
• the medicinal compound is dispersed or dissolved in the liquid carrier, with the thickening agent added, if present.
• the formulation is then enclosed in a soft gelatin capsule by suitable technology.
• Example 8 A pharmaceutical composition for parenteral administration is prepared by combining the following:
• the solution is sterilised and sealed in sterile
• the test is performed essentially as in Cawston and
• the assay tubes After a 5 min pre-incubation at 37°C, the assay tubes are cooled to 4°C and 3 ⁇ -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. To terminate the assay, the assay tubes are spun at 12000 rpm for 15 minutes. Undigested 3 ⁇ -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 compounds of Examples E1-E6 had IC 50 values in the range 4.7 x 10 -6 - 9.7 x 10 -8 M.

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• 1991
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  • 1991-10-09 WO PCT/GB1991/001749 patent/WO1992006966A1/en not_active Application Discontinuation
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