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Definitions

• This invention relates to triazole derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives.
• the triazole derivatives of the present invention are vasopressin antagonists.
• they are antagonists of the Via receptor and have a number of therapeutic applications, particularly in the treatment of dysmenorrhoea (primary and secondary).
• Menstrual pain in the lower abdomen is caused by myometrial hyperactivity and reduced uterine blood flow. These pathophysiological changes result in abdominal pain that radiates out to the back and legs. This may result in women feeling nauseous, having headaches and suffering from insomnia. This condition is called dysmenorrhoea and can be classified as either primary or secondary dysmenorrhoea.
• Primary dysmenorrhoea is diagnosed when no abnormality causing the condition is identified. This affects up to 50% of the female population ⁇ Coco, A.S. (1999). Primary dysmenorrhoea. [Review] [30 refs]. American Family Physician, 60, 489-96.; Schroeder, B. & Sanfilippo, J.S. (1999). Dysmenorrhoea and pelvic pain in adolescents. [Review] [78 refs]. Pediatric Clinics of North America, 46, 555-71 ⁇ . Where an underlying gynaecological disorder is present, such as endometriosis, pelvic inflammatory disease (PID), fibroids or cancers, secondary dysmenorrhoea will be diagnosed.
• PID pelvic inflammatory disease
• Dysmenorrhoea is diagnosed in only approximately 25% of women suffering from dysmenorrhoea. Dysmenorrhoea can occur in conjunction with menorrhagia, which accounts for around 12% of referrals to gynaecology outpatients departments.
• NSAID's non-steroidal anti-inflammatory drugs
• oral contraceptive pill In cases of secondary dysmenorrhoea surgery may be undertaken to correct the underlying gynaecological disorder. Women suffering from dysmenorrhoea have circulating vasopressin levels which are greater than those observed in healthy women at the same time of the menstrual cycle. Inhibition of the pharmacological actions of vasopressin, at the uterine vasopressin receptor, may prevent dysmenorrhoea.
• the compounds of the present invention are therefore potentially useful in the treatment of a wide range of disorders, particularly aggression, Alzheimer's disease, anorexia nervosa, anxiety, anxiety disorder, asthma, atherosclerosis, autism, cardiovascular disease (including angina, atherosclerosis, hypertension, heart failure, edema, hypematremia), cataract, central nervous system disease, cerebrovascular ischemia, cirrhosis, cognitive disorder, Cushing's disease, depression, diabetes mellitus, dysmenorrhoea (primary and secondary), emesis (including motion sickness), endometriosis, gastrointestinal disease, glaucoma, gynaecological disease, heart disease, intrauterine growth retardation, inflammation (including rheumatoid arthritis), ischemia, ischemic heart disease, lung tumor, micturition disorder, mittlesmerchz, neoplasm, nephrotoxicity, non-insulin dependent diabetes, obesity, obsessive/compulsive disorder, ocular hypertension
• cardiovascular disease including angina, atherosclerosis, hypertension, heart failure, edema, hypematremia), dysmenorrhoea (primary and secondary), endometriosis, emesis (including motion sickness), intrauterine growth retardation, inflammation (including rheumatoid arthritis), mittlesmerchz, preclampsia, premature ejaculation, premature (preterm) labour and Raynaud's disease.
• the compounds of the invention and their pharmaceutically acceptable salts and solvates, have the advantage that they are selective inhibitors of the Via receptor (and so are likely to have reduced side effects), they may have a more rapid onset of action, they may be more potent, they may be longer acting, they may have greater bioavailability or they my have other more desirable properties than the compounds of the prior art.
• X represents -[CHJg-R or -[CH 2 ] a -O-[CH 2 ] b -R; a represents a number selected from 0 to 6; b represents a number selected from 0 to 6; R represents H, CF 3 or Het; Het represents a 5- or 6-membered saturated, partially saturated or aromatic heterocyclic ring comprising either (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms, optionally substituted with one or more groups independently selected from W;
• Y represents one or more substituents independently selected from -[O] c -[CH 2 ] d -R 1 , which may be the same or different at each occurrence; c at each occurrence independently represents a number selected from 0 or 1 ; d at each occurrence independently represents a number selected from 0 to 6; R 1 at each occurrence independently represents H, halo, CF 3 , CN or Het 1 ; Het 1 at each occurrence independently represents a 5- or 6-membered unsaturated heterocyclic ring, comprising either (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms;
• V represents a direct link or -O-
• Ring A represents a 5- to 7-membered saturated heterocyclic ring comprising either (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms, or it represents a phenylene group; ring A being optionally substituted with one or more groups selected from C 1-6 alkyl, phenyl or hydroxy;
• Q represents a direct link or -N(R 2 )-;
• R 2 represents hydrogen or C 1-6 alkyl;
• Z represents -[OJ e -tCHJrR 3 , a phenyl ring (optionally fused to a benzene ring or Het 2 , and the group as a whole being optionally substituted with one or more groups independently selected from W), or Het 3 (optionally fused to an benzene ring or Het 4 , and the group as a whole being optionally substituted with one or more groups independently selected from W);
• R 3 represents C 1-6 alkyl (optionally substituted with one or more groups independently selected from W), C 3-6 cycloalkyl, C 3 .
• Het 5 or NR 4 R 5 independently represent a 5- or 6-membered saturated, partially saturated or aromatic heterocyclic ring, comprising either (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms, optionally substituted with one or more groups selected from W;
• Het 3 represents a 4 to 6-membered saturated, partially saturated or aromatic heterocyclic ring, comprising either (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms, optionally substituted with one or more groups selected from W;
• W independently at each occurrence represents halo, [O] g R 6 , SO 2 R 6 , SR 6 , SO 2 NR 6 R 7 , [O]jCHF 2 , phenyl (optionally substituted with halo, C 1-6 alkyl or C 1-6 alkyloxy), CN, phenoxy (optionally substituted with halo), OH, benzyl, NR 6 R 7 , NCOR 6 , benzyloxy, oxo, CONHR 6 , NSO 2 R 6 R 7 , COR 6 , C 1-6 alkylene-NCOR 7 , Het 7 ;
• R 6 represents hydrogen, C -6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl or C ⁇ alkylene- O-C 1-6 alkyl;
• R 7 represents hydrogen or C -6 alkyl;
• i represents a number selected from 0 to 6 h represents a number selected from 0 or 1 ;
• X represents -[CHJg-R or -[CH 2 ] a -O-[CH 2 ] b -R; a represents a number selected from 0 to 6; b represents a number selected from 0 to 6; R represents H, CF 3 or Het; Het represents a 5- or 6-membered heterocyclic ring comprising either (a) 1 to 4 nitrogen atoms, (b) 1 oxygen atom or 1 sulphur atom, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms;
• Z represents -[OJe-fCHJrR 2 , a phenyl ring (optionally fused to a phenyl ring or a 5- or 6- membered saturated, partially unsaturated or aromatic heterocyclic ring, and/or optionally substituted with one or more groups independently selected from W), or a 6- membered aromatic heterocyclic ring (optionally fused to an phenyl ring or a 6- membered aromatic heterocyclic ring, and/or optionally substituted with one or more groups independently selected from W);
• R 2 represents C 1-6 alkyl or C 3-6 cycloalkyl; e represents a number selected from 0 or 1 ; f represents a number selected from 0 to 6;
• W represents halo, [O] 9 R 3 , SO 2 R 3 , SR 3 , SO 2 NR 3 R 4 , [O] h [CH 2 ]iCF 3 , OCHF 2 , phenyl, CN, phenoxy (optionally substituted with halo), OH, benzyl, NCOR 3 , benzyloxy, oxy, CONHR 3 , NSO 2 R 3 R 4 , COR 3 , C L ealkylene-NCOR 3 , Het 2 ; R 3 represents hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or C ⁇ alkylene-O-C ⁇ alkyl; R 4 represents hydrogen or C 1-6 alkyl; i represents a number selected from 0 to 6 h represents a number selected from 0 or 1 ; g represents a number selected from 0 or 1 ; Het 2 represents a 5- or 6-membered saturated, partially unsaturated or aromatic heterocyclic group comprising either (a) 1
• halo means fluoro, chloro, bromo or iodo.
• Alkyl, alkylene and alkyloxy groups, containing the requisite number of carbon atoms, can be unbranched or branched.
• alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl.
• alkyloxy include methoxy, ethoxy, n-propoxy, i- propoxy, n-butoxy, l-butoxy, sec-butoxy and t-butoxy.
• alkylene examples include methylene, 1 ,1-ethylene, 1 ,2-ethylene, 1 ,1 -propylene, 1 ,2-propylene, 1 ,3-propylene and 2,2-propylene.
• Het represents a heterocyclic group, examples of which include tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1 ,4-dioxanyl, 1 ,4-oxathianyl, morpholinyl, 1 ,4-dithianyl, piperazinyl, 1 ,4-azathianyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1 ,2,3,4-tetrahydropyridinyl, 1 ,2,5,6-tetrahydropyridin
• a preferred compound is one in which X represents CH 2 OCH 3 . More preferred is a compound in which X represents -[CHJgR.
• a preferred compound is one in which a represents a number selected from 0 to 5. More preferred is a compound in which a represents a number selected from 0 to 4. Still more preferred is a compound in which a represents a number selected from 0 to 3. Still more preferred is a compound in which a represents a number selected from 0 to 2. Most preferred is a compound in which a represents the number 1.
• a preferred compound is one in which R represents H.
• a more preferred compound is one in which R represents Het. Stoll more preferred is a compound in which R represents triazolyl
• a preferred compound is one in which Y represents one or two substituents.
• a more preferred compound is one in which Y represents a single substituent.
• a preferred compound is one in which Y represents halo.
• a more preferred compound is one in which Y represents chloro and/or fluoro.
• a preferred compound is one in which V represents a direct link.
• a preferred compound is one in which Q is a direct link.
• a more preferred compound is one in which both V and Q represent a direct link.
• a preferred compound is one in which Ring A contains 2 nitrogen atoms.
• a more preferred compound is one in which Ring A contains 1 nitrogen atom.
• a preferred compound is one in which Ring A represents a 5-membered ring.
• a more preferred compound is one in which Ring A represents a 6-membered ring.
• a still more preferred compound is one in which Ring A represents piperidinylene.
• a preferred compound is one in which Ring A is attached to V via a nitrogen atom.
• a more preferred compound is one in which Ring A is attached to Q via a nitrogen atom.
• a preferred compound is one in which Ring A is attached to both Q and V via a nitrogen atom.
• a preferred compound is one in which Z represents Het 3 .
• Het 3 may represent an optionally substituted group selected from indazolyl, indolyl, indenyl, pyrazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiazolyl, benzothienyl, benzothiazolyl, quinolinyl, benzoxazinyl, isoxazolyl, imidazolyl, furyl, benzofuryl, cinnolinyl, morpholinyl, chromenyl, or derivatives thereof.
• a more preferred compound is one in which Z represents phenyl.
• a preferred compound is one in which Z is mono or di substituted.
• a more preferred compound is one in which Z is mono substituted.
• a preferred compound is one in which Z is substituted by tri-fluoromethyl.
• a more preferred compound is one in which Z is substituted by halo.
• a more preferred compound is one in which Z is substituted by chloro and/or fluoro.
• Pharmaceutically acceptable derivatives of the compounds of formula (I) according to the invention include salts, solvates, complexes, polymorphs, prodrugs, stereoisomers, geometric isomers, tautomeric forms, and isotopic variations of compounds of formula (I).
• pharmaceutically acceptable derivatives of compounds of formula (I) comprise salts, solvates, esters and amides of the compounds of formula (I). More preferably, pharmaceutically acceptable derivatives of compounds of formula (I) are salts and solvates.
• the pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof.
• Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, D- and L-lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, palmoate, phosphate, hydrogen phosphate, dihydrogen phosphate, saccharate, stearate, succinate, sulphate, D- and L- tartrate,
• Suitable base salts are formed from bases, which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
• a pharmaceutically acceptable salt of a compound of formula (I) may be readily prepared by mixing together solutions of the compound of formula (I) and the desired acid or base, as appropriate.
• the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
• the degree of ionisation in the salt may vary from completely ionised to almost non-ionised.
• the compounds of the invention may exist in both unsolvated and solvated forms.
• solvate is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
• solvent molecules for example, ethanol.
• hydrate is employed when said solvent is water.
• complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
• complexes of the drug containing two or more organic and/or inorganic components what may be in stoichiometric or non-stoichiometric amounts.
• the resulting complexes may be ionised, partially ionised, or non-ionised.
• references to compounds of formula (I) and pharmaceutically acceptable derivatives include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
• the compounds of the invention include compounds of formula (I) as hereinbefore defined, polymorphs, prodrugs, and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labelled compounds of formula (I).
• the invention includes all polymorphs of the compounds of formula (I) as hereinbefore defined.
• prodrugs of the compounds of formula (I).
• certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, hydrolytic cleavage.
• Such derivatives are referred to as “prodrugs”.
• Further information on the use of prodrugs may be found in "Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and "Bioreversible Carriers in Drug Design", Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).
• Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties know to those skilled in the art as "pro-moieties” as described, for example, in “Design of Prodrugs” by H Bundgaard (Elsevier, 1985).
• prodrugs in accordance with the invention include:
• certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I). Also within the scope of the invention are the metabolites of the compounds of formula (I) when formed in vivo.
• Compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula (I) contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible, and where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ('tautomerism') may occur. It follows that a single compound may exhibit more than one type of isomerism.
• Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, fractional crystallisation and chromatography.
• racemate (or racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compounds of formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
• a suitable optically active compound for example, an alcohol, or, in the case where the compounds of formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
• the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallisation and one or both of the diastereomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
• Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.
• Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds” by E L Eliel (Wiley, New York, 1994).
• the present invention also includes all pharmaceutically acceptable isotopic variations of a compound of the formula (I) one or more atoms is replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen such as 2 H and 3 H, carbon such as 11 C, 13 C and 14 C, nitrogen such as 13 N and 15 N, oxygen such as 15 O, 17 O and 18 O, phosphorus such as 32 P, sulphur such as 35 S, fluorine such as 18 F, iodine such as 123 l and 125 l, and chlorine such as 36 CI.
• isotopically-labelled compounds of formula (I), for example those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
• the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
• substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
• Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using appropriate isotopically-labelled reagents in place of the non-labelled reagent previously employed.
• Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallisation may be isotopically substituted, e.g. D 2 O, d 6 - acetone and d 6 -DMSO.
• a further aspect of the invention is the use of a compound of formula (I), or a pharmaceutically salt or solvate thereof, as a medicament.
• the compounds of the invention show activity as Via antagonists.
• they are useful in the treatment of a number of conditions including aggression, Alzheimer's disease, anorexia nervosa, anxiety, anxiety disorder, asthma, atherosclerosis, autism, cardiovascular disease (including angina, atherosclerosis, hypertension, heart failure, edema, hypematremia), cataract, central nervous system disease, cerebrovascular ischemia, cirrhosis, cognitive disorder, Cushing's disease, depression, diabetes mellitus, dysmenorrhoea (primary and secondary), emesis (including motion sickness), endometriosis, gastrointestinal disease, glaucoma, gynaecological disease, heart disease, intrauterine growth retardation, inflammation (including rheumatoid arthritis), ischemia, ischemic heart disease, lung tumor, micturition disorder, mittlesmerchz, neoplasm, nephrotoxicity, non-insulin dependent diabetes, obesity, obsessive/compulsive disorder
• a further aspect of the invention is the method of treatment of a mammal, including a human being, to treat a disorder for which a Via antagonist is indicated, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, to the mammal.
• the compounds of formula (I) are useful in treating anxiety, cardiovascular disease (including angina, atherosclerosis, hypertension, heart failure, edema, hypematremia), dysmenorrhoea (primary and secondary), endometriosis, emesis (including motion sickness), intrauterine growth retardation, inflammation (including rheumatoid arthritis), mittlesmerchz, preclampsia, premature ejaculation, premature (preterm) labour or Raynaud's disease. Even more particularly, they are useful in treating dysmenorrhoea (primary or secondary).
• a further aspect of the present invention is the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a disorder for which a Via receptor antagonist is indicated.
• WSCDI means 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
• DCC means N,N'-dicyclohexylcarbodiimide
• HOAT means 1 -hydroxy-7-aza benzotriazole
• HOBT means 1-hydroxybenzotriazole hydrate
• PyBOP ® means Benzotriazol-1-yloxytris(pyrrolidino)phosphoniumhexa fluoro phosphate
• PyBrOP ® means bromo-tris-pyrrolidino-phosphoniumhexafluoro phosphate
• HBTU means O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluoro phosphate
• mCPBA means meta-chloroperbenzoic acid
• AcOH means acetic acid
• HCI means hydrochloric acid
• TFA trifluoroacetic
• R, R 1 , R 2 , R 3 , ring A, V, X, Q, Z, Y, Y', Het, Het 1 , and Het 2 are as previously defined for a compound of the formula (I) unless otherwise stated.
• Q represents NR 2
• Q represents a direct link attached to a nitrogen atom within ring A
• PG represents a suitable N protecting group, typically a benzyl, BOC or CBz group, and preferably BOC.
• Scheme 1 Compounds of formula (II) may be obtained as described in WO 9703986 A1 19970206, or by reaction of the corresponding lower alkyl ester (e.g. methyl or ethyl) with hydrazine under standard conditions, as exemplified in the preparations below.
• Step (a): Compounds of formula (III) may be prepared by reaction of hydrazine (II) with a suitable acetal (e.g. N,N-dimethylacetamide dimethyl acetal) in a suitable solvent such as THF, or DMF, at between room temperature and about 60°C, for up to 18 hours.
• a suitable acetal e.g. N,N-dimethylacetamide dimethyl acetal
• a suitable solvent such as THF, or DMF
• the resulting intermediate may then be treated under acid catalysis (e.g. p-TSA, or TFA) in a high boiling solvent (e.g. toluene, or xylene) for about 18 hours, to provide the compound of formula (III).
• acid catalysis e.g. p-TSA, or TFA
• a high boiling solvent e.g. toluene, or xylene
• N,N-dimethylacetamide dimethyl acetal, triethyl orthopropionate in THF or DMF at room temperature to 60°C for about 18 hours, followed by p-TSA, or TFA (cat), in toluene at reflux for 18 hours.
• Step (b): Formation of triazole (IV) may be achieved by reaction of compound (III) with a suitable aniline, in the presence of a suitable acid catalyst, such as TFA or p-TSA, in a suitable high boiling solvent (e.g. toluene, or xylene), at an elevated temperature.
• a suitable acid catalyst such as TFA or p-TSA
• a suitable high boiling solvent e.g. toluene, or xylene
• PG represents BOC
• the preferred conditions are: 4M HCI in dioxan in MeOH, dioxan or DCM at between room temperature and about 50°C, for up to 18 hours; Or, 2.2M HCI in MeOH for up to 18 hours at room temperature; Or, TFA in DCM at room temperature for about 1 hour.
• compound (V) when PG represents BOC, compound (V) may be prepared directly from compound (III) by treatment with an excess of TFA, typically 1.1-1.5 eq.) and the appropriate aniline in toluene, at the reflux temperature of the reaction, for up to 4 days.
• TFA typically 1.1-1.5 eq.
• the coupling may be undertaken by using either: o (i) an acyl chloride, 2 u + amine (V), with an excess of acid base in a suitable solvent; or (ii) an acid ZCO H with a conventional coupling agent + amine (V) optionally in the presence of a catalyst, with an excess of base in a suitable solvent.
• acyl chloride 2 u + amine
• V 2 u + amine
• an acid ZCO H with a conventional coupling agent + amine (V) optionally in the presence of a catalyst, with an excess of base in a suitable solvent.
• a suitable solvent e.g. EtOH, or DCM
• Step (f): Compounds of formula (IXA) may be prepared by methylation of thiourea (VIIIA), using a suitable methylating agent (e.g. Mel, or MeTosylate), in the presence of a suitable base (e.g. KO'-Bu) in a suitable solvent (e.g. THF, or ether) at between 0°C and the reflux temperature of the reaction, for about 18 hours.
• a suitable methylating agent e.g. Mel, or MeTosylate
• a suitable base e.g. KO'-Bu
• THF e.g. THF, or ether
• Step (g): Compounds of formula (IVA) may be prepared by reaction of compounds (IXA) with a suitable hydrazide (XCONHNH 2 ), optionally under acidic catalysis (e.g. TFA, or p-TSA) in a suitable solvent (e.g. THF, or n-BuOH), at between room temperature and the reflux temperature of the reaction. Preferred conditions: 0.5 eq. TFA, excess hydrazide (XCONHNH 2 ), in THF at reflux for up to 18 hours.
• a suitable hydrazide XCONHNH 2
• a suitable solvent e.g. THF, or n-BuOH
• PG is BOC
• the preferred conditions are: 1 eq. amine (XI), 1 eq. di-t-butyl dicarbonate, in DCM and dioxan, at room temperature, for about 3 hours.
• Step (i): Compounds of formula (XIV) may be prepared by coupling of aniline (XIII) with acid (XII), by analogy with the methods previously described in Step (d). Preferred conditions: 1eq. acid (XII), 1.1eq. amine (XIII), 1.2 eq. WSCDI, 3 eq. Et 3 N in MeCN at room temperature, for about 3 days.
• a suitable thionating agent such as Lawesson's reagent
• a high boiling solvent e.g. toluene
• Preferred conditions 1eq. (XIV), 0.5 eq. Lawesson's reagent in toluene, for between room temperature and reflux, for up to 18 hours.
• Step (k): Di-acylhydrazides (XV) may be prepared by coupling hydrazides (II) with acid or acid chloride ( z , where T represents Cl or OH), by analogy with the methods previously described in Step (d). Preferred conditions: 1 eq. hydrazide (II), 1.1 eq. XCO 2 H, 1.1 eq. WSCDI, 1.1 eq. HOBT, 1.2 eq. Et 3 N, in DMF at room temperature for 18 hours.
• Step (I): Oxadiazole (III) may be prepared by cyclisation of compound (XV), typically under acid catalysis (e.g.
• polyphosphoric acid POCI 3 , triflic anhydride/pyridine, or 1- methylimidazole
• a suitable solvent e.g. DCM
• Compounds of formula (XV) may alternatively be prepared by coupling acid (XII) with a suitable hydrazide (XCONHNH 2 ), by analogy with the methods previously described in Step (d). Preferred conditions: 1 eq. acid (XII), 1 eq. hydrazide, 1.02 eq. WSDCI, in DCM at between 0°C and room temperature.
• the compounds of formula (XVI) may be prepared by reaction of hydrazide (II) with chloroacetyl chloride, in the presence of a suitable 3° amine base (e.g. Et 3 N, or NMM) in a suitable solvent (e.g. EtOAc, or DCM) at between 0°C and room temperature, for about 18 hours.
• a suitable 3° amine base e.g. Et 3 N, or NMM
• a suitable solvent e.g. EtOAc, or DCM
• Preferred conditions 1 eq. (II), 1 eq. acetyl chloride, 1.1 eq. NMM, in DCM, at 10°C to room temperature, for up to 18 hours.
• Step (n): Compounds of formula (III) may be prepared by reaction of compound (XVII) with a suitable Het (containing a reactive N atom), in the presence of a suitable base (e.g. Et 3 N, or K 2 CO 3 ), in a suitable solvent (e.g. DMF, or MeCN), at between room temperature and the reflux temperature of the reaction, for about 18 hours.
• a suitable base e.g. Et 3 N, or K 2 CO 3
• a suitable solvent e.g. DMF, or MeCN
• Ra represents C r4 alkyl or benzyl, and is preferably Me or Et.
• Step (p): The hydrazide of formula (XX) may be prepared by treating ester (XIX) with excess hydrazine in a suitable solvent (e.g. EtOH, or MeOH), at the reflux temperature of the reaction, for up to 18 hours. Preferred conditions: 1 eq. (XIX), 2-4 eq. hydrazine, in MeOH at reflux, for between 10 and 48 hours.
• a suitable solvent e.g. EtOH, or MeOH
• Step (k) using the methods previously described in Step (k).
• compounds of formula (XXII) may be prepared directly from compound (XX) by reaction with an appropriate acetal (e.g. triethyl orthopropionate, N,N- dimethylacetamide dimethyl acetal) by analogy with the methods previously described in Step (a).
• an appropriate acetal e.g. triethyl orthopropionate, N,N- dimethylacetamide dimethyl acetal
• Oxadiazole (XXIV) may be prepared by cyclisation of compound (XXIII), by analogy with the methods previously described in Step (I).
• Compound (XXII) may be prepared by reaction of compound (XXIV) with a suitable Het (containing a reactive N atom), as previously described in Step (n).
• Compounds of formula (I), wherein ring A is attached to the triazole ring through a nitrogen atom, may alternatively be prepared as shown in Scheme 9.
• Compounds of formula (XXVI) may be prepared by reaction of compound (XXV) with the appropriate isothiocyanate (VI), by analogy with the methods previously described in Step (e).
• the compound of formula (XXVII) may be prepared by alkylation of compound (XXVI), by analogy with the methods previously described in Step (f).
• the compound of formula (I) may be prepared by reaction of compound (XXVII) with a suitable hydrazide, as previously described in Step (g).
• Ra represents C r4 alkyl or benzyl, and is preferably Me or Et.
• Scheme 10 Compounds of formula (XXVIII) are either commercially available or may be prepared from commercially available compounds, using standard chemical transformations.
• Compounds of formula (XXIX) may be prepared by reaction of compound (XXVIII) with the appropriate isothiocyanate (VI), by analogy with the methods previously described in Step (e).
• the compound of formula (XXX) may be prepared by alkylation of compound (XXIX), by analogy with the methods previously described in Step (f).
• the compound of formula (XXXI) may be prepared by reaction of compound (XXX) with a suitable hydrazide, as previously described in Step (g).
• a suitable aqueous solvent e.g. dioxan, or MeOH
• aqueous solvent e.g. dioxan, or MeOH
• Compounds of formula (I) may be prepared by reaction of Z-H (containing a reactive N atom) with acid (XXXII), by analogy with the methods previously described for Step (d).
• Compounds of formula (XXXII) may alternatively be prepared by hydrolysis of the corresponding nitrile compound (XXXIII), under standard conditions (e.g. 5 eq. KOH, 1 eq. nitrile (XXXIII), in ethanol/ethylene glycol dimethyl ether at reflux).
• Step (s): Compounds of formula (XXXVI) may be prepared by cyclisation of compound (XXXV) under acid or base conditions, preferably base catalysis (e.g. alkali metal hydroxide) in aqueous solvent (e.g. water/EtOH), at an elevated temperature, for about 24 hours. Preferred conditions: 1 eq. (XXXV), 10 eq. NaOH (aq) in EtOH at 80°C for 18 hours.
• base catalysis e.g. alkali metal hydroxide
• aqueous solvent e.g. water/EtOH
• Step (t): Alkylation of compound (XXXVI) to provide compound (XXXVII) may be achieved by treatment with a suitable alkylating agent (e.g. Mel, or Me-Tosylate), by analogy with the methods previously described in Step (f).
• a suitable alkylating agent e.g. Mel, or Me-Tosylate
• Preferred conditions 1 eq. (XXXVI), 1 eq. KOt-Bu, 1 eq. Me-Tosylate, in THF at between room temperature and reflux for 3 hours.
• Step (u): Compounds of formula (XXXVIII) may be obtained by oxidation of compound (XXXVII) by treatment with a suitable oxidising agent (e.g. mCPBA, or hydrogen peroxide) in a suitable solvent (e.g. DCM) at room temperature for about 18hours. Preferred conditions: 1 eq. (XXXVII), 4 eq. mCPBA, in DCM at room temperature for 18 hours.
• Step (v): Compounds of formula (I) may be prepared by reaction of sulphoxide (XXXVIII) with an excess of alcohol (XXXIX) in the presence of a suitable base (e.g.
• a suitable solvent e.g. THF, or ether
• Preferred conditions 1 eq. (XXXVIII), 2 eq. NaH, 2 eq. alcohol (XXXIX), in THF for 18 hours at room temperature.
• Certain compounds of formulae (I) (III), (IV), (V), (XXII), and (XXXI) may undergo functional group interconversions (e.g. alkylation, or hydrolysis) to provide alternative compounds of formulae (I) (III), (IV), (V), (XXII), or (XXXI), respectively.
• Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallisation, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
• excipients may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
• excipient' is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
• a further aspect of the invention is a pharmaceutical formulation including a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient, diluent or carrier.
• the pharmaceutical formulation for administration either prophylactically or when pain commences.
• compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences. 19th Edition (Mack Publishing Company, 1995).
• the compounds of the invention may be administered orally.
• Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
• Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations.
• Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
• the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, V ⁇ (6), 981-986, by Liang and Chen (2001 ).
• the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form.
• tablets generally contain a disintegrant.
• disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
• the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.
• Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
• lactose monohydrate, spray-dried monohydrate, anhydrous and the like
• mannitol xylitol
• dextrose sucrose
• sorbitol microcrystalline cellulose
• starch dibasic calcium phosphate dihydrate
• Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
• surface active agents such as sodium lauryl sulfate and polysorbate 80
• glidants such as silicon dioxide and talc.
• surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.
• Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
• Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.
• ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.
• Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.
• Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
• the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
• Consumable oral films for human or veterinary use are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (I), a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function.
• the compound of formula (I) may be water-soluble or insoluble.
• a water-soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes.
• the compound of formula (I) may be in the form of multiparticulate beads.
• the film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.
• ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste- masking agents.
• Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.
• Solid formulations for oral administration may be formulated to be immediate and/or modified release.
• Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
• Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line, 25(2), 1-14, by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.
• the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
• Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intra urethra I, intrastemal, intracranial, intramuscular and subcutaneous.
• Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
• Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non- aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
• excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
• a suitable vehicle such as sterile, pyrogen-free water.
• parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
• solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
• Formulations for parenteral administration may be formulated to be immediate and/or modified release.
• Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
• compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound.
• examples of such formulations include drug-coated stents and poly(o7-lactic-coglycolic)acid (PGLA) microspheres.
• the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
• Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
• Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).
• Topical administration examples include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM, BiojectTM, etc.) injection.
• Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
• the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3- heptafluoropropane.
• the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
• the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
• a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
• the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
• comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
• Capsules made, for example, from gelatin or hydroxypropylmethylcellulose
• blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.
• the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
• Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
• a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 ⁇ l to 100 ⁇ l.
• a typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride.
• Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
• Suitable flavours such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
• Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA.
• Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
• the dosage unit is determined by means of a valve, which delivers a metered amount.
• the overall daily dose will typically be in the range 0.01 ⁇ g to 15 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
• the compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema.
• Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
• Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release.
• Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
• the compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH- adjusted, sterile saline.
• Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non- biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
• the compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
• soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers
• Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
• the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cydodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.
• compositions may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
• the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
• a container, divided bottle, or divided foil packet An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
• the kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
• the kit typically comprises directions for administration and may be provided with a so-called memory aid.
• the total daily dose of the compounds of the invention is typically in the range 0.01 mg to 15 mg depending, of course, on the mode of administration.
• the total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.
• These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
• references herein to "treatment” include references to curative, palliative and prophylactic treatment.
• the compounds of the present invention may be tested in the screens set out below:
• Receptor binding assays were performed on cellular membranes prepared from CHO cells stably expressing the human V 1A receptor, (CHO-hV 1A ).
• the CHO-hV 1A cell line was kindly provided under a licensing agreement by Marc Thibonnier, Dept. of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio.
• CHO-hV 1A cells were routinely maintained at 37°C in humidified atmosphere with 5% CO 2 in DMEM/Hams F12 nutrient mix supplemented with 10 % fetal bovine serum, 2 mM L- glutamine, 15 mM HEPES and 400 ⁇ g/ml G418.
• CHO-hV 1A cells were grown to confluency of 90-100% in 850 cm 2 roller bottles containing a medium of DMEM/Hams F12 Nutrient Mix supplemented with 10 % fetal bovine serum, 2 mM L-glutamine and 15 mM HEPES. Confluent CHO-hV 1A cells were washed, with phosphate-buffered saline (PBS), harvested into ice cold PBS and centrifuged at 1 ,000 rpm. Cell pellets were stored at -80°C until use.
• PBS phosphate-buffered saline
• Cell pellets were thawed on ice and homogenised in membrane preparation buffer consisting of 50 mM Tris-HCI, pH 7.4, 5 mM MgCI 2 and supplemented with a protease inhibitor cocktail, (Roche).
• the cell homogenate was centrifuged at 1000 rpm, 10 min, 4°C and the supernatant was removed and stored on ice. The remaining pellet was homogenised and centrifuged as before. The supematants were pooled and centrifuged at 25,000 x g for 30 min at 4°C.
• the pellet was resuspended in freezing buffer consisting of 50 mM Tris-HCI, pH 7.4, 5 mM MgCI 2 and 20 % glycerol and stored in small aliquots at -80°C until use. Protein concentration was determined using Bradford reagent and BSA as a standard.
• DMSO dimethylsulfoxide
• assay buffer containing 50 mM Tris-HCL pH 7.4, 5 mM MgCI 2 and 0.05% BSA.
• the binding reaction was initiated by the addition of 200 ⁇ l membrane and the plates were gently shaken for 60 min at room temperature.
• the reaction was terminated by rapid filtration using a Filtermate Cell Harvester (Packard Instruments) through a 96-well GF/B UniFilter Plate which had been presoaked in 0.5% polyethyleneimine to prevent peptide sticking.
• the filters were washed three times with 1 ml ice cold wash buffer containing 50 mM Tris-HCL pH 7.4 and 5 mM MgCI 2 .
• the plates were dried and 50 ⁇ l Microscint-0 (Packard instruments) was added to each well. The plates were sealed and counted on a TopCount Microplate Scintillation Counter (Packard Instruments).
• Non-specific binding was determined using 1 ⁇ M unlabelled d(CH2)5Tyr(Me)AVP ([ ⁇ -mercapto- ⁇ , ⁇ -cyclopentamethylenepropionyl,0-Me- ) ( ⁇ MCPVP), (Sigma).
• the % bound was plotted against the concentration of test compound and a sigmoidal curve was fitted.
• the inhibitory dissociation constant (K) was calculated using the Cheng-Prusoff equation: where [L] is the concentration of ligand present in the well and K d is the dissociation constant of the radioligand obtained from Scatchard plot analysis.
• Intracellular calcium release was measured in CHO-hV 1A cells using FLIPR, which allows the rapid detection of calcium following receptor activation.
• the CHO-hV 1A cell line was kindly provided under a licensing agreement by Marc Thibonnier, Dept. of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio.
• CHO-V 1A cells were routinely maintained at 37°C in humidified atmosphere with 5% CO 2 in DMEM/Hams F12 nutrient mix supplemented with 10 % fetal bovine serum, 2 mM L- glutamine, 15 mM HEPES and 400 ⁇ g/ml G418.
• wash buffer containing Dulbecco's phosphate buffered saline (DPBS) and 2.5 mM probenecid and loading dye consisting of cell culture medium containing 4 ⁇ M Fluo-3-AM (dissolved in DMSO and pluronic acid),(Molecular Probes) and 2.5 mM probenecid was prepared fresh on the day of assay.
• Compounds were solubilised in DMSO and diluted in assay buffer consisting of DPBS containing 1% DMSO, 0.1% BSA and 2.5 mM probenecid.
• the cells were incubated with 100 ⁇ l loading dye per well for 1 hour at 37°C in humidified atmosphere with 5% CO 2 . After dye loading the cells were washed three times in 100 ⁇ l wash buffer using a Denley plate washer. 100 ⁇ l wash buffer was left in each well. Intracellular fluorescence was measured using FLIPR. Fluorescence readings were obtained at 2s intervals with 50 ⁇ l of the test compound added after 30s. An additional 155 measurements at 2s intervals were then taken to detect any compound agonistic activity. 50 ⁇ l of arginine vasopressin (AVP) was then added so that the final assay volume was 200 ⁇ l. Further fluorescence readings were collected at 1s intervals for 120s.
• AVP arginine vasopressin
• FI peak fluorescence intensity
• AVP dose response curves each response was expressed as a % of the response to the highest concentration of AVP in that row.
• IC 50 determinations each response was expressed as a % of the response to AVP.
• the compounds of the invention may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof).
• the compounds of the present invention may be administered in combination with an oral contraceptive.
• a pharmaceutical product containing an Via antagonist and an oral contraceptive as a combined preparation for simultaneous, separate or sequential use in the treatment of dysmenorrhoea.
• the compounds of the present invention may be administered in combination with a PDE5 inhibitor.
• a pharmaceutical product containing a Via antagonist and a PDEV inhibitor as a combined preparation for simultaneous, separate or sequential use in the treatment of dysmenorrhoea.
• PDEV inhibitors useful for combining with Via antagonists include, but are not limited to: ( i ) The PDE5 inhibitors mentioned in International Patent Application publication nos. WO03/000691 ; WO02/64590; WO02/28865; WO02/28859; WO02/38563; WO02/36593; WO02/28858; WO02/00657; WO02/00656; WO02/10166; WO02/00658; WO01/94347; WO01/94345; WO00/15639 and WO00/15228; ( ii ) The PDE5 inhibitors mentioned in US Patents 6,143,746; 6,143,747 and 6,043,252; ( iii) the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in EP-A-0463756; the pyrazolo [4,3-d]pyrimidin-7-ones disclosed in EP-A-0526004; the pyr
• the PDEV inhibitor is selected from sildenafil, tadalafil, vardenafil, DA-8159 and 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]- 2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.
• the PDE5 inhibitor is sildenafil and pharmaceutically acceptable salts thereof.
• Sildenafil citrate is a preferred salt.
• the compounds of the present invention may be administered in combination with an NO donor.
• a pharmaceutical product containing a Via antagonist and a NO donor as a combined preparation for simultaneous, separate or sequential use in the treatment of dysmenorrhoea.
• the compounds of the present invention may be administered in combination with L- arginine, or as an arginate salt.
• a pharmaceutical product containing a Via antagonist and L-arginine as a combined preparation for simultaneous, separate or sequential use in the treatment of dysmenorrhoea is provided.
• the compounds of the present invention may be administered in combination with a COX inhibitor.
• a pharmaceutical product containing a Via antagonist and a COX inhibitor as a combined preparation for simultaneous, separate or sequential use in the treatment of dysmenorrhoea.
• COX inhibitors useful for combining with the compounds of the present invention include, but are not limited to: (i) ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, prapoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, diclofenac, fenclofenec, alclofenac, ibufenac, isoxepac, furofenac, tiopinac, zidometacin, acetyl salicylic acid, indometacin, piroxicam, tenoxicam,
• celecoxib (US Patent No. 5,466,823), valdecoxib (US Patent No. 5,633,272), deracoxib (US Patent No. 5,521 ,207), rofecoxib (US Patent No. 5,474,995), etoricoxib (International Patent Application Publication No. WO 98/03484), JTE-522 (Japanese Patent Application Publication No. 9052882), or a pharmaceutically acceptable salt or prodrug thereof;
• Parecoxib (described in U.S. Patent No. 5,932,598), which is a therapeutically effective prodrug of the tricyclic Cox-2 selective inhibitor valdecoxib (described in U.S. Patent No. 5,633,272), in particular sodium parecoxib;
• ABT-963 (described in International Patent Application Publication No. WO 00/24719)
• Nimesulide (described in U.S. Patent No. 3,840,597), flosulide (discussed in J. Carter. Exp.Qpin.Ther.Patents. 8(1). 21-29 (1997)), NS-398 (disclosed in U.S. Patent No. 4,885,367), SD 8381 (described in U.S. Patent No. 6,034,256), BMS-347070 (described in U.S. Patent No. 6,180,651 ), S-2474 (described in European Patent Publication No. 595546) and MK-966 (described in U.S. Patent No. 5,968,974); (x) The compounds and pharmaceutically acceptable derivatives described in U.S. Patent No.
• Patent No. 6,340,694 U.S. Patent No. 6,376,519, U.S. Patent No. 6,153,787, U.S. Patent No. 6,046,217, U.S. Patent No. 6,329,421 , U.S. Patent No. 6,239,137, U.S. Patent No. 6,136,831 , U.S. Patent No. 6,297,282, U.S. Patent No. 6,239,173, U.S. Patent No. 6,303,628, U.S. Patent No. 6,310,079, U.S. Patent No. 6,300,363, U.S. Patent No. 6,077,869, U.S. Patent No. 6,140,515, U.S. Patent No.
• CDCI 3 deuterochloroform
• D 6 -DMSO deuterodimethylsulphoxide
• CD 3 OD deuteromethanol
• THF tetrahydrofuran
• Ammonia refers to a concentrated solution of ammonia in water possessing a specific gravity of 0.88. Where thin layer chromatography (TLC) has been used it refers to silica gel TLC using silica gel 60 F254 plates, R f is the distance traveled by a compound divided by the distance traveled by the solvent front on a TLC plate.
• TLC thin layer chromatography
• the two microwaves used are the Emrys Creator and the Emrys Liberator, both supplied by Personal Chemistry Ltd.
• the power range is 15-300W at 2.45GHz. The actual power supplied varies during the course of the reaction in order to maintain a constant temperature.
• Preparation 1 4-(5-Methyl-[1 ,3,4]oxadiazol-2-yl)-piperidine-1 -carboxylic acid tert-butyl ester:
• Trifluoroacetic anhydride (9.45 ml, 57 mmol) was added dropwise over 30 minutes to a cooled solution (0 to 5°C) of the compound of preparation 5 (10.2 g, 28.5 mmol) and pyridine (11.5 ml, 142.5 mmol) in dichloromethane (300 ml). Once the addition was complete, the resulting pink suspension was stirred for a further 90 minutes at 10°C. The reaction mixture was poured carefully into saturated sodium bicarbonate solution (600 ml), and the layers were separated. The organic phase was washed with further saturated sodium bicarbonate solution (x2), dried over MgSO , and treated with decolourising charcoal. The mixture was then filtered and the filtrate evaporated under reduced pressure to afford the title compound, 13 g.
• the hydrazide of preparation 7 (5.0 g, 15.6 mmol) was suspended in dichloromethane (200 ml) and then pyridine (6.4 ml, 78 mmol) was added before cooling the mixture to 10°C. Trifluoroacetic anhydride (6.6 ml, 39 mmol) was added dropwise over 15 minutes and then the mixture was stirred at room temperature for 3 hours. The reaction was then partitioned with water (50ml), the organic layer was dried over magnesium sulphate, filtered and the filtrate was evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol in dichloromethane as eluant (2:98) to afford the title compound as a white solid (2.95 g).
• Trifluoroacetic acid (1 ml, 13.2 mmol) was added to a solution of the compounds of preparation 9a (8.8 g, 26.5 mmol) and 4-chloroaniline (5 g, 39.75 mmol) in toluene (200 ml) and the reaction mixture was stirred at reflux for 5 hours. The cooled mixture was diluted with dichloromethane, then washed with 1 N sodium hydroxide solution and brine, and evaporated under reduced pressure.
• the residual brown oil was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 90:10:1) and then re-columned using ethyl acetate:methanol:0.88 ammonia (100:0:0 to 90:10:1) to afford the title compound, (2.3 g).
• N-Methylimidazole (4.66 g, 56.75 mmol) and dichloromethane (20 ml) were added to the bis-acyl hydrazide from preparation 170 (5.00 g, 14.19 mmol), and the resulting solution was cooled to -20°C.
• Trifluoromethanesulfonic acid anhydride (6.00 g, 21.28 mmol) was added, keeping the temperature below 0°C.
• the reaction was warmed to ambient temperature and stirred for 15 hours.
• the reaction was quenched with H 2 O (10 ml), the phases were separated and the aqueous layer was re- extracted with dichloromethane (10 ml).
• the concentrate was dissolved in ethyl acetate (120 L) and the solution was washed with 1 N hydrochloric acid (1 x 40 L, 7 x 20 L, 4 x 15 L). The aqueous washings were combined and extracted with ethyl acetate (3 x 21 L). The organic phases were combined, dried over magnesium sulphate, filtered and concentrated to dryness giving a mixture of the title compounds (25 kg). 1 H NMR spectroscopic analysis indicated that this was a 6:5 mixture of N-2/N-1 isomers.
• the title compound was obtained as a white solid from the compound of preparation 15 and hydrazine following a similar procedure to that described for preparation 16, except that 5 equivalents of hydrazine were used, and isopropanol was used as the reaction solvent.
• the title compound was obtained from 3-methyl 1 ,2,4-oxadiazol-5-yl-acetic acid methyl ester (NL 7807076) and hydrazine following a similar procedure to that described for preparation 16, except that 8 equivalents of hydrazine were used, and isopropanol was used as the reaction solvent.
• Triethylamine (24 mL, 17 mmol) was added slowly to a cooled (10°C) solution of the acid chloride of preparation 14 (5.64 g, 35.4 mmol) in dichloromethane (200 mL), followed by tert-butyl carbazate (5.6 g, 42.5 mmol) and the reaction was stirred at room temperature for 18 hours.
• the reaction was diluted with ethyl acetate and the precipitate was filtered off. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using an elution gradient of ethyl acetate: pentane (50:50 to 100:0) to provide the title compound.
• Oxalyl chloride (5.16 mL, 59.2 mmol) was added to a solution of ⁇ -(3,5-dimethyl-4- isoxazolyl)propionic acid (J. Org. Chem. 59(10); 1994; 2882) (2.5 g, 14.8 mmol) in dichloromethane (50 mL) and N,N-dimethylformamide (1 drop), and the solution was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure and the residue was azeotroped with dichloromethane (5x) to provide a brown liquid.
• Trifluoroacetic anhydride (1.56 mL, 11.18 mmol) was added dropwise to an ice-cooled solution of the compound of preparation 29 (3.0 g, 10.65 mmol) and N- methylmorpholine (1.29 mL, 11.7 mmol) in dichloromethane (50 mL), and the reaction was stirred at room temperature for 18 hours. The resulting precipitate was filtered off, washed with dichloromethane and dried to afford the title compound, 1.78 g.
• N-Methylmorpholine (2.60 g, 26.6 mmol), and then ethoxyacetyl chloride (WO 01/46150 ex 33A) (1.09 g, 8.87 mmol) were added to a solution of the compound of preparation 29 (2.5 g, 8.87 mmol) in dichloromethane (70 mL), and the reaction was stirred at room temperature for 18 hours. The mixture was washed with water, then ammonium chloride solution and finally sodium carbonate solution. It was dried over MgSO 4 and evaporated under reduced pressure to afford the title compound.
• Triethylamine (1.4 mL, 10 mmol) was added to a suspension of 4-chlorophenyl isothiocyanate (1.69 g, 10 mmol) and 4-cyano-4-phenylpiperidine hydrochloride (2.22 g, 10 mmol) in dichloromethane (100 mL), and the reaction was then stirred at room temperature for 20 minutes. The mixture was washed with 2N hydrochloric acid, then brine, it was dried over MgSO and evaporated under reduced pressure to afford the title compound as a white solid, 3.62 g.
• Potassium tert-butoxide (20.1 g, 0.18 mol) was added portionwise to a cooled (10°C) solution of the compound of preparation 34 (53 g, 0.15 mol) in tetrahydrofuran (1 L), in order to maintain the temperature at 10°C.
• Methyl iodide (11.2 mL, 0.18 mol) was added dropwise, in order to maintain the temperature at 10°C, and the reaction was then allowed to warm slowly to room temperature. The reaction was stirred for a further 90 minutes, then it was quenched by the addition of water. The reaction was diluted with ethyl acetate and washed with water.
• reaction was stirred at room temperature or 18 hours, and the product was additionally purified by column chromatography on silica gel using dichloromethane:methanol as eluant.
• the title compound was obtained from 4-hydrazinocarbonyl-piperidine-1 -carboxylic acid tert-butyl ester (WO 2000039125, prep 27) and 3,3,3-trifluoropropionic acid, following a similar procedure to that described for preparation 61.
• ⁇ /, ⁇ /-Dimethylformamide dimethyl acetal (5.71 g, 47.9 mmol) was added to a solution of the compound of preparation 4 (9.0 g, 31.94 mmol) in tetrahydrofuran (6 mL), and the reaction was stirred for 18 hours at 50°C. Tic analysis showed that starting material remained, so additional ⁇ /, ⁇ /-dimethylformamide dimethyl acetal (15 mmol) was added and stirring was continued for a further 2 hours. The mixture was concentrated under reduced pressure and the residue was suspended in toluene (32 mL). p-Toluene sulphonic acid (1 g, 5.26 mmol) was added and the reaction was heated at 110°C for 18 hours.
• ⁇ /, ⁇ /-Dimethylacetamide dimethyl acetal (6.38 g, 47.9 mmol) was added to a solution of the compound of preparation 29 (9.0 g, 31.94 mmol) in N,N-dimethylformamide (20 mL), and the reaction was stirred at room temperature for 1 hour. It was then stirred for a further 2 hours at 40°C. The mixture was diluted with toluene (150 mL), heated to 110°C and then p-toluene sulphonic acid (400 mg, 2.22 mmol) was added. The reaction was heated at 110°C for 18 hours, then cooled and concentrated under reduced pressure.
• Triethyl orthopropionate (1.63 g, 9.23 mmol) was added to a solution of the compound of preparation 29 (2.0 g, 7.1 mmol) in N,N-dimethylformamide (10 mL), and stirred at 60°C for 3 hours. Tic analysis showed that starting material remained, so additional triethyl orthopropionate (0.5 g, 2.83 mmol) was added and the reaction was stirred at 60°C for a further 18 hours. The mixture was concentrated under reduced pressure, the residue was suspended in toluene (15 mL) and trifluoroacetic acid (5 drops) was added. The reaction was heated under reflux for 18 hours, then cooled and concentrated under reduced pressure. The crude product was purified by column chromatography using a silica gel cartridge and dichloromethane:methanol (100:0 to 95:5) as eluant to afford the title compound as an oil, 1.6 g.
• Triflic anhydride (1.98 mL, 11.7 mmol) was added to an ice-cooled solution of the compound of preparation 30 (1.77 g, 4.69 mmol) and pyridine (1.53 mL, ' 18.74 mmol) in dichloromethane (40 mL). The mixture was then allowed to warm to room temperature and stirred for 18 hours. The reaction was diluted with dichloromethane, washed with 2N hydrochloric acid, then saturated aqueous sodium bicarbonate solution. It was dried over MgSO 4 and evaporated under reduced pressure.
• A 3-hydrazinocarbonyl-pyrrolidine-1 -carboxylic acid tert-butyl ester was used (obtained from CB Research and Development Inc.).
• Trifluoroacetic acid (0.35 mL, 4.3 mmol) was added to 4-morpholinpropanoic acid hydrazide (Comptes Rendus des Seances de I'acadamie des Sciences, Serie C;Sciences Chimiques 1976; 282 (17); 857-60) (1.5 g, 8.7 mmol) and the compound of preparation 46 (2.7 g, 7.25 mmol) in tetrahydrofuran (18 mL), and the reaction was heated under reflux for 8 hours. The cooled mixture was diluted with dichloromethane, washed with 1 N sodium hydroxide solution, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 10:10:1) to give the title compound, 2.2 g.
• A 1-imidazol-1-yl acetic acid hydrazide was used; prepared as described in Boll. Chim. Farm. 114(2); 70-72; 1975.
• Acetic hydrazide (16.9 g, 228 mmol) followed by trifluoroacetic acid (4.4 mL, 57.1 mmol) were added to a solution of the compound of preparation 56 (43.6 g, 114 mmol) in tetrahydrofuran (250 mL) and the mixture was heated under reflux for 7 hours. The cooled mixture was then washed with dilute ammonia solution, the layers were separated and the aqueous phase was extracted further with ethyl acetate. The combined organic solutions were dried over MgSO 4 and evaporated under reduced pressure. The residue was triturated with ether (100 mL) and the resulting crystals were filtered off and dried in vacuo to afford the title compound, 32.4 g.
• Trifluoroacetic acid (0.84 mL, 10.85 mmol) followed by acetic hydrazide (2.41 g, 32.6 mmol) were added to a solution of the compound of preparation 47 (7.38 g, 21.7 mmol) in tetrahydrofuran (100 mL), and the reaction was heated under reflux for 3 hours. The cooled mixture was partitioned between ethyl acetate and aqueous ammonia and the layers were separated. The organic phase was washed with brine, dried over MgSO 4 and evaporated under reduced pressure. The crude product was triturated with ether to provide the title compound as a white solid, 5.04 g.
• Trifluoroacetic acid (0.41 mL, 5.3 mmol) was added to a solution of the hydrazide of preparation 18 (3.6 g, 10.6 mmol) and the compound of preparation 47 (2.24 g, 15.9 mmol) in tetrahydrofuran (50 mL), and the reaction was heated under reflux for 15 hours. The cooled mixture was partitioned between ethyl acetate and brine and the layers were separated. The organic phase was filtered, dried over MgSO 4 and evaporated under reduced pressure to provide the title compound as a gum.
• Methoxyacetic acid hydrazide (1.95 g, 18.75 mmol) was added to a solution of the compound of preparation 49 (4.80 g, 12.50 mmol) in tetrahydrofuran (200 mL) and the solution was stirred for 10 minutes. Trifluoroacetic acid (710 mg, 6.25 mmol) was added and the reaction was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the crude product was purified by column chromatography using a silica gel cartridge and dichloromethane:methanol (100:0 to 90:10) as eluant, and repeated using ethyl acetate as eluant to afford the title compound as a foam, 1.84 g.
• Acetic hydrazide (6.51 g, 88 mmol) was added to a solution of the compound of preparation 52 (32.46 g, 88 mmol) in n-butanol (250 mL) and the reaction was heated under reflux for 18 hours. The reaction was heated for a further 5 days under reflux with additional acetic hydrazide (36.5 g in total) added periodically. The cooled mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5) to provide the title compound as a white foam.
• Acetic hydrazide (1.65 g, 22.3 mmol) was added to a solution of the compound of preparation 51 (3.3 g, 8.93 mmol) in n-butanol (5 mL) and the reaction was heated under reflux for 2 days. The cooled mixture was concentrated under reduced pressure and the residue was pre-adsorbed onto slica gel. It was then purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5), and the product was triturated with ethyl acetate to provide the title compound as a solid.
• Trifluoroacetic acid (2.14 g, 18.83 mmol) was added to a solution of the compound of preparation 57 (7.0 g, 23.54 mmol) and 4-chloroaniline (3.60 g, 28.24 mmol) in toluene (50 mL), and the reaction mixture was heated under reflux for 18 hours. The cooled solution was concentrated under reduced pressure and the residue was purified by column chromatography using a silica gel cartridge and an elution gradient of dichloromethane:methanol (100:0 to 90:10) to afford the title compound as an oil, 4.25 g.
• the title compound was obtained as an oil in 75% yield from the compound of preparation 72 and 4-chloroaniline, following a similar procedure to that described for preparation 98, except that 1 eq. of trifluoroacetic acid and 2 eq. of 4-chloroaniline were used.
• the title compound was prepared from the oxadiazole of preparation 1 and 2,4- dichloroaniline, following a similar procedure to that described for preparation 105, except that 2 equivalents of aniline were used.
• LCMS m/z APCI * 359 [MH] *
• Trifluoroacetic acid 25 mL was added to an ice-cooled solution of the compound of preparation 93 (2.80 g, 6.63 mmol) in dichloromethane (25 mL) and the solution was stirred at room temperature for an hour. The mixture was concentrated under reduced pressure and the residue was re-dissolved in ethyl acetate, then washed with 1 N sodium hydroxide solution. The organic solution was dried over MgSO 4 and evaporated under reduced pressure. The crude product was purified by column chromatography using a silica gel cartridge and an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 90:10:1 ) to afford the title compound as an oil, 780 mg.
• Trifluoroacetic acid (2.49 g, 21.8 mmol) was added to a solution of 4-chloroaniline (3.63 g, 28.4 mmol) and the compound of preparation 58 (8.0 g, 21.9 mmol) in toluene (50 mL), and the reaction heated was under reflux for 48 hours. Tic analysis showed that starting material remained, so additional trifluoroacetic acid (8 mL) was added and the reaction was heated for a further 4 hours under reflux. The cooled mixture was extracted with water, the aqueous solution was basified using potassium hydroxide and then extracted with dichloromethane (4x100 mL). The combined organic extracts were dried over MgSO and evaporated under reduced pressure.
• the crude product was purified by column chromatography using a silica gel cartridge and an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 85:15:1.5) to give the title compound, 4.34 g.
• Trifluoroacetic acid 600 ⁇ L, 8.1 mmol was added to a suspension of 4-chloroaniline (2.1 g, 16.2 mmol) and 4-(5-methyl-1 ,3,4-oxadiazol-2-yl)benzonitrile (Journal f ⁇ r Praktician Chemie, 1994; 336(8); 678-85) (3.0 g, 16.2 mmol) in tetrahydrofuran (50 mL) and the reaction was heated at reflux for 22 hours. The cooled mixture was partitioned between ethyl acetate (300 mL) and 20% aqueous 0.88 ammonia (120 mL), and then the layers were separated.
• the title compound was obtained as a white solid, from the ester of preparation 91, following a similar procedure to that described for preparation 158, except that 10 eq. of sodium hydroxide were used in the reaction.
• Preparation 161 ⁇ /-(4-Chlorophenyl)-2-(2H-1 ,2,3-triazol-2- ylacetyl)hydrazinecarbothioamide 4-Chlorophenylisothiocyanate (8.58 g, 50.6 mmol) was added portionwise to a suspension of the hydrazide of preparation 18 (7.0 g, 50.6 mmol) in ethanol (200 mL) and the mixture was stirred at room temperature for 72 hours. The resulting precipitate was filtered off, washed with ether and dried to afford the title compound as a white solid, 14.5 g.
• iso-propanol 150 mL was added and the homogeneous solution was concentrated in vacuo to approx 165 mL, heated to approx. 70°C, and allowed to cool to ambient temperature with stirring.
• the resulting thick white slurry was filtered in vacuo, washing with iso-propanol (15 mL and 30 mL) and dried in vacuo at 50°C to give the title compound as a white solid, 25.3 g (55%).
• the liquors from the filtration were concentrated under reduced pressure to low volume, the resulting syrup was treated with water (50 mL) and vigorously stirred to give a thick slurry within two minutes. After overnight granulation, the slurry was filtered (rapid filtration), the residues washed with water (2 * 10 mL) and dried in vacuo at 50°C to give additional product, 8.5 g (18%).
• Examples 1 to 162 illustrated below were synthesised as a library. The following solutions were used: carboxylic acid, ZC0 2 H, was dissolved in dimethylacetamide (anhydrous) plus 3
• reaction Scale was between 20 and 30 micromoles per well (experimental details shown for 20 //mole reaction, scale can be adjusted accordingly within this range).
• Reactions were performed in a polypropylene 96 well plate. a) Amine solutions (0.1 ml, 20 ⁇ moles, 1 eq.) were added to the wells b) Carboxylic acid solutions (0.15ml, 30 ⁇ moles, 1.5 eq.) were added to the wells c) HBTU Solution (0.15 ml, 30 ⁇ moles, 1.5 eq.) was added to each well d) The polypropylene 96 well plate was sealed with a PTFE and Rubber gasket and clamped between a pair of metal plates.
• Gilson LC Pump Initial Conditions Solvents A% 80.0 B% 20.0 Flow (ml/min) 8.000 Gilson LC Pump Gradient Timetable: Time A% B% Flow (ml/min) 0.00 80.0 20.0 8.000 0.20 80.0 20.0 8.000 7.00 5.0 95.0 8.000 9.00 5.0 95.0 8.000 9.10 80.0 20.0 8.000 10.5080.0 20.0 8.000
• Gilson 119 uv detector monitoring at 254nm Collector set at 225nm Dual sensitivity 200 Peak sensitivity 80 Peak width 0.3 min.
• HPLC analysis conditions and Mass Spectrometer details Column: Phenomenex Luna C18, 5um, 30 x 4.6 mm id.
• Eluent A 0.05% Diethylamine in water
• Eluent B Acetonitrile Samples dissolved in: 90% Dimethylsulphoxide in water Sample loaded using Gilson Quad Z with Injection Volume of 5 ⁇ l
• the gradient Timetable contains 4 entries, which are: Time A% B% Flow 0.00 95.0 5.0 2.500 3.00 5.0 95.0 2.500 3.50 95.0 5.0 2.500 Total run time 4.50 mins
• Example 165a ⁇ 4-[4-(4-Chloro-phenyl)-5-[1 ,2,3]triazol-2-ylmethyl-4H-[1 ,2,4]triazol-3-yl]- piperidin-1-yl ⁇ -(3,5-difluoro-phenyl)-methanone
• Example 165b ⁇ 4-[4-(4-Chloro-phenyl)-5-[1 ,2,3]triazol-2-ylmethyl-4H-[1 ,2,4]triazol-3-yl]- piperidin-1-yl ⁇ -(3,5-difluoro-phenyl)-methanone
• Triethylamine (3.2ml, 23.0mmol) was added to a slurry of the bis salt from preparation 12b (4.89g, 7.12mmol) in dichloromethane (25ml) giving a pale yellow solution.
• the solution was cooled in an ice-bath and then 3,5-difluorobenzoyl chloride (0.95ml, 8.09mmol) was added.
• the reaction was stirred for 30 minutes, and then water (20ml) was added. After a further 20 minutes of stirring, the phases were separated and the organic phase was washed successively with aqueous citric acid, water, aqueous sodium hydrogen carbonate and half-saturated brine.
• A 4 eq. of triethylamine were used, and the crude product was not treated with polymer supported amine.
• S 10 eq. of polymer supported N-ethyldiisopropylamine was used in place of N- ethyldiisopropylamine.
• the appropriate acid chloride (W-PhCOCI) (1.0 to 1.5 eq.) was added to a solution of the appropriate amine hydrochloride, or amine, selected from preparations 120 to 121, 132, 134 to 135, 137, 139 to 142, 151, 153 to 154, and 169 (1 eq ), and triethylamine (1.2 to 5 eq.) in dichloromethane (10 to 25 mLmmol "1 ). The reaction was stirred at room temperature for 18 hours. The mixture was then diluted with dichloromethane, it was washed with saturated sodium carbonate solution, followed by ammonium chloride solution, and then it was concentrated under reduced pressure. The crude products were purified by column chromatography on silica gel using dichloromethane:methanol (100:0 to 90:10) as eluant to afford the title compounds.
• Example 188 4-[4-(4-Chlorophenyl)-5-(1H-imidazol-1-ylmethyl)-4H-1 ,2,4-triazol-3-yl]-1- (3,3-dimethylbutanoyl)piperidine
• A 5-(trifluoromethyl)-2-pyridinecarboxylic acid was used and may be prepared as described in J. Org. Chem. (European) 2003; (8); 1559-1568.
• B reaction was performed in the absence of 1-hydroxybenzotriazole hydrate and triethylamine.
• A 3-difluoromethyl benzoic acid was used. It can be prepared according to
• Oxalyl chloride (0.04 mL, 0.55 mmol) was added to a solution of the acid of preparation 160 (50 mg, 0.15 mmol) in dichloromethane (50 mL), and the solution was stirred at room temperature for 20 minutes. Additional oxalyl chloride (0.02 L, 0.27 mmol) was added and the solution was stirred for a further 10 minutes. The solution was then evaporated under reduced pressure and the residue was azeotroped with dichloromethane (3x). The oily residue was dissolved in dichloromethane (10 mL). Isopropylamine (0.19 mL, 2.25 mmol) was added to the solution and the mixture was then stirred at room temperature for 18 hours.
• Triethylamine 105 ⁇ L, 0.75 mmol
• benzoyl chloride 79.6 ⁇ L, 0.69 mmol
• a solution of the amine of preparation 145 200 mg, 0.69 mmol
• dichloromethane 5 mL
• the reaction was stirred at room temperature for 5 minutes.
• Water 5 mL was added and the mixture was stirred vigorously for 5 minutes.
• the mixture was then filtered using a phase separation cartridge and the organic layer was concentrated under reduced pressure. The residue was then azeotroped with ether to provide the title compound as an off-white solid, 278 mg.
• Trifluoroacetic acid (5 mL) was added to a cooled (5°C) solution of the compound of preparation 102 (1.3 g, 3.43 mmol) in dichloromethane (5 mL), and the solution was then stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and then triethylamine (450 mg, 4.47 mmol) and dichloromethane (30 mL) were added.
• Example 230 1-(2-Chlorobenzoyl)-3-[4-(4-chloro-2-methylphenyl)-5-methyl-4H-1 ,2,4- triazol-3-yl]piperidine
• Example 231 3-[1-(2-Chlorobenzoyl)pyrrolidin-3-yl]-4-(4-chloro-2-methylphenyl)-5- methyl-4H-1 ,2,4-triazole
• Tetrahydrofuran (2 mL) was added to sodium hydride (24 mg, 60% in mineral oil), which had been pre-washed with pentane (2 mL), and the suspension was stirred at room temperature.
• tert-Butyl 4-hydroxy-1-piperidinecarboxylate (119 mg, 0.6 mmol) was then added and the mixture was stirred at room temperature for a further 30 minutes.
• the compound of preparation 164 (100 mg, 0.3 mmol) was added and the reaction was stirred at room temperature for a further 18 hours. The reaction was then partitioned between dichloromethane (20 mL) and brine (20 mL), the layers separated and the organic phase evaporated under reduced pressure.
• tert-Butylamine hydrochloride (223 mg, 2.0 mmol), followed by a solution of the acid chloride of preparation 157 (150 mg, 0.4 mmol) in dichloromethane (3 mL), was added to a solution of triethylamine (300 ⁇ L, 2.0 mmol) in dichloromethane (2 mL) and the reaction was stirred at room temperature for an hour. The mixture was then partitioned between dichloromethane and aqueous citric acid solution, and the phases were separated. The aqueous layer was further extracted with dichloromethane (2x25 mL) and the combined organic solutions were dried over MgSO 4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (93:7:1 ) as eluant to afford the title compound, 122 mg.
• A 3-isopropyl-1 -methyl-1 H-pyrazole-5-carboxylic acid was used; see DE 3029281.
• B 5-bromo-2-methoxynicotinic acid was used, see EP 306251, preparation I.
• C 5-methyl-2-phenyl-1H-imidazole-4-carboxylic acid was used, see J. Chem Soc. 1948; 1969.
• D 3-(1 -oxo-1, 3-dihydro-2H-isoindol-2-yl)propanoic acid was used, see J. Med. Chem. 83; 26(2); 243.
• E 1-ethylpiperidine-2-carboxylic acid was used, see Journal of Inorganic and Nuclear medicine; 1978; 40(6); 1103-6.
• F 3-[(pyrimidin-2-ylthio)methyl]benzoic acid was used, see J. Indian Chem. Soc. (97);

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