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WO2004074291A1 - Composes de triazole utilises en therapie - Google Patents

Composes de triazole utilises en therapie

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Publication number
WO2004074291A1
WO2004074291A1 PCT/IB2004/000432 IB2004000432W WO2004074291A1 WO 2004074291 A1 WO2004074291 A1 WO 2004074291A1 IB 2004000432 W IB2004000432 W IB 2004000432W WO 2004074291 A1 WO2004074291 A1 WO 2004074291A1
Authority
WO
WIPO (PCT)
Prior art keywords
mmol
chloro
compound
preparation
tetrahydro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2004/000432
Other languages
English (en)
Inventor
Justin Stephen Bryans
Patrick Stephen Johnson
Thomas Ryckmans
Alan Stobie
Rachel Jane Russell
Christopher Peter Wayman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Corp Belgium
Pfizer Ltd Great Britain
Pfizer Corp SRL
Original Assignee
Pfizer Corp Belgium
Pfizer Ltd Great Britain
Pfizer Corp SRL
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to EP04709303A priority Critical patent/EP1597260B1/fr
Priority to SI200430160T priority patent/SI1597260T1/sl
Priority to HR20050681A priority patent/HRP20050681A2/hr
Priority to RSP-2005/0638A priority patent/RS20050638A/sr
Priority to KR1020057015408A priority patent/KR100750028B1/ko
Priority to JP2006500323A priority patent/JP4033886B2/ja
Priority to CA002516557A priority patent/CA2516557C/fr
Priority to AU2004213242A priority patent/AU2004213242B2/en
Priority to MXPA05008923A priority patent/MXPA05008923A/es
Priority to EA200501136A priority patent/EA009460B1/ru
Priority to DE602004003914T priority patent/DE602004003914T2/de
Application filed by Pfizer Corp Belgium, Pfizer Ltd Great Britain, Pfizer Corp SRL filed Critical Pfizer Corp Belgium
Priority to DK04709303T priority patent/DK1597260T3/da
Priority to AP2005003376A priority patent/AP2005003376A0/xx
Priority to BRPI0407676-1A priority patent/BRPI0407676A/pt
Priority to UAA200508142A priority patent/UA79674C2/uk
Publication of WO2004074291A1 publication Critical patent/WO2004074291A1/fr
Priority to IS7957A priority patent/IS2450B/is
Priority to TNP2005000200A priority patent/TNSN05200A1/fr
Anticipated expiration legal-status Critical
Priority to NO20054053A priority patent/NO20054053L/no
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • This invention relates to novel compounds useful in therapy and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives.
  • Japanese patent application No. 09328484 describes triazole quinoxalines useful as anti- allergy and anti-inflammatory agents.
  • Japanese patent application No. 09132576 describes triazole quinoxalines useful as anti-allergy and anti-inflammatory agents.
  • Japanese patent application No. 06135965 describes triazole quinoxalines useful for curing and preventing allergies, inflammation and PAF-associated diseases.
  • Japanese patent application No. 06128262 describes triazole quinoxalines useful for intermediates of drugs and agrochemicals.
  • the compounds of the present invention have been found to have useful pharmaceutical properties. They may be used to treat aggression, Alzheimer's disease, anorexia nervosa, anxiety, anxiety disorder, asthma, atherosclerosis, autism, cardiovascular disease (including angina, atherosclerosis, hypertension, heart failure, edema, hypernatremia), 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, hypernatremia
  • dysmenorrhoea primary and secondary
  • endometriosis emesis (including motion sickness)
  • inflammation including rheumatoid arthritis
  • mittlesmerchz preclampsia
  • premature ejaculation premature (preterm) labor and Raynaud's disease.
  • they exhibit vasopressin antagonistic activity and can be used 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. Where an underlying gynaecological disorder is present, such as endometriosis, pelvic inflammatory disease (PID), fibroids or cancers, secondary dysmenorrhoea will be diagnosed. Secondary 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.
  • PID pelvic inflammatory disease
  • NSAID non-steroidal anti-inflammatory drugs
  • oral contraceptive pill In cases of secondary dysmenorrhoea surgery may be undertaken to correct the underlying gynaecological disorder.
  • 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.
  • V represents -(CH 2 ) d (O) e -, -CO-, or -CH(C 1-6 alkyl)-;
  • W is -O-, -S(0)a-, or -N(R 1 )-
  • R 1 represents H, C 1-6 alkyl, (CH 2 ) b COR 2 , CO(CH 2 ) b NR 2 R 3 , SO 2 R 2 , (CH 2 ) c OR 2 ,
  • het 1 represents a saturated or unsaturated heterocycle of from 3 to 8 atoms containing one or more heteroatoms selected from O, N, or S, optionally substituted with C 1-6 alkyl;
  • X and Y independently represent H, C 1-6 alkyl, halogen, OH, CF 3 , OCF 3 , OR 4 ;
  • Z represents -(CH 2 ) f (O) g -, -CO- or -CH(C 1-6 alkyl)-;
  • Ring A represents a 4-7 membered, saturated N-containing heterocycle, optionally substituted with OH, and in which optionally at least one ring N is substituted with O;
  • Ring B represents phenyl or a 4-7 membered unsaturated N-containing heterocycle, optionally substituted with OH, halogen, CN, CONH 2 , CF 3 , OCF 3 , and in which optionally at least one ring N is substituted with O;
  • R 2 and R 3 independently represent H, C 1-6 alkyl [optionally substituted with OH, halogen, N(C -6 alkyl) 2 , or C -6 alkyloxy], C 1-6 alkyloxy, N(C 1-6 alkyl) 2 , or [C 3-8 cycloalkyl]; or R 2 and R 3 , together with the nitrogen atom to which they are attached independently represent a heterocycle of from 3 to 8 atoms, optionally substituted with C 1-6 alkyl; R 4 represents straight or branched C -6 alkyl, a and c independently represent 0, 1 , or 2; b, e and g independently represent 0 or 1 ; d and f independently represent 1 or 2.
  • halogen means fluoro, chloro, bromo or iodo.
  • Alkyl groups containing the requisite number of carbon atoms, except where indicated, can be unbranched or branched chain. Examples include methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, sec-butyl and t-butyl. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Examples of alkyloxy include methoxy, ethoxy, n- propyloxy, l-propyloxy, n-butyloxy, l-butyloxy, sec-butyloxy and t-butyloxy.
  • Heterocycles included within the definition of "heterocycle” are pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl and quinoxalinyl, together with partially or fully saturated versions thereof as well as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, oxazepanyl, and morpholinyl.
  • Preferred groups of compounds are those in which any one or more of the following apply:
  • R 1 is d-e alkyl, and more preferably methyl, i-propyl or n-butyl;
  • R 1 is H;
  • R 1 is (CH 2 ) b het 1 ;
  • het 1 is pyrrolidinyl, piperidinyl, morpholinyl, azetidinyl, oxazepanyl, pyrimidinyl, pyridinyl, thiazolyl, or imidazolyl, (optionally substituted with C,. e alkyl)
  • R 1 is CO(CH 2 ) b NR 2 R 3 ;
  • R 2 is morpholinyl or pyrimidinyl (optionally substituted with C-i-e alkyl
  • R 2 and R 3 together with the nitrogen to which they are attached represent morpholinyl, pyrrolidinyl, piperazinyl, azetidinyl, tetrahydropyranyl, pyrimidinyl or piperidinyl (optionally substituted with C 1-6 alkyl)
  • V is -(CH 2 ) d (0) ⁇ -;
  • Z is -(CH 2 ) f (O) g -;
  • Y is in the 4-position of the phenylene ring (according to the numbering of formula (I)) to which it is attached;
  • Y is halogen, preferably chloro;
  • Y is alkyloxy, preferably methoxy;
  • (xix) Y is alkyl, preferably methyl
  • Y is CF 3 or OCF 3 ;
  • ring A is linked to ring B via a nitrogen atom in ring A;
  • ring A is piperidinyl (optionally substituted with OH, and optionally at least one N is substituted with O);
  • ring B is pyridinyl (optionally substituted with one or more groups selected from OH, halogen, CN, CONH 2 , CF 3 , OCF 3 , and optionally at least one ring N is substituted with O), preferably it is 2-pyridinyl;
  • ring B is pyrimidinyl (optionally substituted with one or more groups selected from OH, halogen, CN, CONH 2 , CF 3 , OCF 3 , and optionally at least one ring N is substituted with O), preferably 2-pyrimidinyl;
  • n is 1 ;
  • Preferred compounds according to the present invention are:
  • W is O, S, or NR 1 R 1 represents H, C 1-6 alkyl, -(CH 2 ) a -[C 3 ⁇ cycloalkyl], phenyl, benzyl, pyridyl, pyrimidyl, - COR 2 , -CO 2 R 2 , -CO-(CH 2 ) a -NR 2 R 3 , -SO 2 R 2 , -(CH 2 ) b -OR 2 , -(CH 2 ) b -NR 2 R 3 , or a saturated heterocycle of from 3 to 8 atoms containing one or more heteroatoms selected from O, N and S;
  • X and Y independently represent H, halogen, OH, CF 3 , OCF 3 , R 4 , -(CH 2 ) d -CONR 4 R 5 , - (CH 2 ) d -CN, -(CH 2 ) d -SO 2 NR R 5 , -(CH 2 ) d -NR 4 SO 2 Me, -(CH 2 ) d -COR 4 , -(CH 2 ) d -OCOR 4 , - (CH 2 ) d -NHCOR 4 , -(CH 2 ) d -NR COR 5 , -(CH 2 ) d -OR 6 or -(CH 2 ) d -CO 2 R 6 ;
  • Ring A represents a piperidinyl, piperazinyl, pyrrolidinyl or azetidinyl group
  • Ring B represents a phenyl, pyridinyl or pyrimidinyl group (optionally substituted with one or more groups independently selected from halogen, CN, CONH 2 , CF 3 , OCF 3 , R 7 , and - (CH 2 )rOR 8 );
  • R 2 , R 3 , R 4 , R 5 and R 7 independently represent H, straight or branched C 1-6 alkyl, -(CH 2 ) C - [C 3-8 cycloalkyl], phenyl, benzyl, pyridyl or pyrimidyl; or R 2 and R 3 , or R 4 and R 5 , together with the nitrogen atom to which they are attached independently represent a heterocycle of from 3 to 8 atoms;
  • R 6 and R 8 independently represent H, straight or branched C 1-6 alkyl, -(CH 2 ) c -[C 3-8 cycloalkyl], -(CH 2 ) e -NR 4 R 5 , -(CH 2 ) e -OR 4 , phenyl, benzyl, pyridyl or pyrimidyl;
  • n 0, 1 or 2;
  • a , c, d and f are all independently selected from 0, 1 , 2 or 3; b and e are independently selected from 2 or 3.
  • 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
  • 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 (1) 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 (1).
  • 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:
  • Compounds of formula (1) 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 racemate of a salt or derivative
  • HPLC chiral HPLC
  • the 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.
  • 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 (and chiral precursors thereof) 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 1 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 25 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.
  • 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.
  • Substitution with positron emitting isotopes such as 11 C, 18 F, 15 O and 13 N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • 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.
  • 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.
  • rings A and B, and groups V, W, X, Y, Z and n are as defined above;
  • rings A and B, and groups V, W, X, Y, Z and n are as defined above, and Z' represents a leaving group such as halogen;
  • rings A and B, and groups V, W, X, Y and Z are as defined above. Unless otherwise provided herein:
  • WSCDI means 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • DCC means N,N'-dicyclohexylcarbodiimide
  • HOAT means 1-hydroxy-7-azabenzotriazole
  • HOBT means 1-hydroxybenzotriazole hydrate
  • PyBOP ® means Benzotriazol-1-yloxytris(pyrrolidino)phosphoniumhexa fluorophosphate
  • PyBrOP ® means bromo-tris-pyrrolidino-phosphoniumhexafluoro phosphate
  • HBTU O-Benzotriazol-1-yl-N,N,N',N'-tetramethyIuronium hexafluoro- phosphate.
  • Mukaiyama's reagent means 2-chloro-1-methyIpyridinium iodide
  • KHMDS potassium bis(trimethylsilyl)amide
  • H ⁇ nig's base means N-ethyldiisopropylamine
  • HMDS means hexamethyldisilazane
  • BINAP means 2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl
  • Dba means dibenzylideneacetone
  • Boc means fe/ ⁇ -butoxycarbonyl
  • CBz means benzyloxycarbonyl
  • p-TSA means p-toluenesulphonic acid
  • TBAF means tetra-butyl ammonium fluoride
  • MeOH means methanol
  • EtOH means ethanol
  • EtOAc means ethyl acetate
  • THF means tetrahydrofuran
  • DMSO means dimethyl sulphoxide
  • DCM means dichloromethane
  • DMF means N,N-dimethylformamide
  • NMP means N-methyl-2- pyrrolidinone
  • Me means methyl, Et means ethyl
  • the reaction of amine (V) with compound (VI) can be carried out by standard methods.
  • R 1 represents an aryl group
  • an aryl halide (VI) + amine (V) optionally in the presence of a catalyst, with an excess of acid acceptor in a suitable solvent.
  • the preferred conditions are: amine (V), 2 eq. HBTU, 2eq acid (R 1 OH) in DCM at room temperature for 18 hours; or amine (V) HOBT, WSCDI, Et 3 N, in DCM at room temperature for 18 hours.
  • Arylation of compound (V) can be carried out by a palladium catalysed cross- coupling reaction using a suitable base (f-BuONa), a catalytic amount of suitable additive such as 2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl and a suitable palladium catalyst in toluene at elevated temp for 1 to 24 hours under an inert atmosphere, to give compound (I').
  • compound (I') can be prepared by reaction of the amine (V) with compound (VI) by heating at elevated temperature, such as 50°C-140°C, in a suitable solvent such as DMF, NMP or 1 ,4-dioxan for about 1-48 hours with a base such as potassium carbonate, sodium hydrogen carbonate or H ⁇ nig's base.
  • a suitable solvent such as DMF, NMP or 1 ,4-dioxan
  • Preferred conditions are:
  • Alkylation (R 1 substituted alkyl).
  • Z' halo, preferably Br or Cl
  • Alkylation of compound (V) can be performed by reaction with a suitable alkylating agent,
  • R 1 Z' in the presence of a suitable tertiary amine (NMM, Et 3 N or H ⁇ nig's base) or alkali metal base (K 2 CO 3 , Cs 2 CO 3 ) in a suitable solvent (MeCN, DMF), at about room temperature.
  • a suitable tertiary amine NMM, Et 3 N or H ⁇ nig's base
  • alkali metal base K 2 CO 3 , Cs 2 CO 3
  • MeCN MeCN, DMF
  • the preferred conditions are: amine (V) R 1 Z', excess K 2 CO 3 or H ⁇ nig's base in DMF for 18 hours at room temperature.
  • a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride
  • This reaction may be carried out by: stirring the starting materials at temperatures such as 20°C-80°C for 1 to 48 hours in a suitable solvent such as dichloromethane, or heating amine (V) with excess compound (VII) with a suitable Lewis acid catalyst such as titanium tetrachloride or titanium tetraisopropoxide at temperatures such as 50°C- 100°C in a suitable solvent such as dichloroethane or ethanol for 1-18 hours, followed by reduction of the intermediate imine/iminium species with a suitable reducing agent, such as sodium borohydride, or hydrogenolysis over a suitable catalyst, such as platinum oxide or palladium on carbon.
  • a suitable solvent such as dichloromethane
  • Preferred conditions are: amine (V), 1-1.5 eq. aldehyde/ketone (VII), 1-2.0 eq. sodium triacetoxy borohydride in dichloromethane, optionally in the presence of AcOH at room temperature for 2 hours.
  • Scheme 2.1 represents a suitable protecting group for nitrogen, for example Boc, CBz or Allyl carbamate. Standard methodology for nitrogen protecting groups is used, such as that found in textbooks (e.g. "Protecting Groups in Organic Synthesis” by T.W. Greene and P. Wutz).
  • Z represents a leaving group such as halogen.
  • Arylation of compound (III) can be carried out as described in Step (b) above.
  • Preferred conditions are:
  • the preferred methods are: hydrogen chloride in a suitable solvent such as 1 ,4-dioxane at room temperature for 1-16 hours; or a solution of trifluoroacetic acid in dichloromethane for 1-2 hours.
  • the preferred method is hydrogenolysis using a suitable palladium catalyst in a solvent such as ethanol.
  • Prot is an allyl carbamate
  • preferred conditions are thiobenzoic acid and a suitable palladium catalyst such as Pd 2 (Dba) 3 with a suitable phosphine additive such as 1 ,4- bis(dipheny!phosphino)butane in tetrahydrofuran for 20 minutes.
  • a suitable palladium catalyst such as Pd 2 (Dba) 3
  • a suitable phosphine additive such as 1 ,4- bis(dipheny!phosphino)butane in tetrahydrofuran for 20 minutes.
  • Prot represents a suitable protecting group for nitrogen, for example Boc, CBz or Allyl carbamate. Standard methodology for nitrogen protecting groups is used, such as that found in textbooks, (e.g. "Protecting Groups in Organic Synthesis” by T.W. Greene and P. Wutz).
  • Z' represents a leaving group (typically Cl or OH).
  • Z" represents halo (typically Cl).
  • Compound (IX) typically can be prepared from compound (IX") using the methodology described in Step (b) and Step (c) above.
  • Compound (III') typically can be prepared from compound (IX") using the methodology described in Step (d) above.
  • Compounds (I') typically can be prepared by arylation of compounds (III') using the methodology described in Step (b) above.
  • LG represents a leaving group, typically halo, and preferably chloro or bromo.
  • LG is a leaving group, typically halo, and preferably chloro or bromo
  • base such as triethylamine, H ⁇ nig's base or NMM or potassium carbonate as proton acceptor
  • a catalyst e.g. Nal
  • suitable high boiling solvent such as THF, Toluene or DMF
  • Preferred conditions are: 1.1-3 eq. of compound (XI) and 1.1-2.5 eq. of NaH in THF at 20°C for 2 hours.
  • Amine (XX) may be prepared by amination of compound (X) with the amine R 1 NH 2 in a solvent such as ethanol or tetrahydrofuran at 25-75°C for 5-72 hours. Preferred conditions are: Compound (X), excess of R 1 NH 2 in ethanol and THF at room temperature for about 72 hours.
  • Compound (II) may be prepared by coupling of the amine (XX) with the acid (XXI) according to the procedure described previously in step (b).
  • X' represents OH or halo, and preferably represents Cl.
  • LG represents a leaving group, typically halo, and preferably chloro or bromo
  • X' represents OH or halo, and preferably represents Cl.
  • LG is a leaving group, typically halo, and preferably chloro or bromo
  • Compound (XIV) is either commercially available or is known in the literature.
  • Coupling may be undertaken by using either:
  • the preferred conditions are:
  • dehydrating agents such as polyphosphoric acid, phosphorous oxychloride, triflic anhydride are used at temperatures from 20 to 120°C for 5 minutes to 12 hours.
  • the reaction can be carried out in the presence of a base such as pyridine and suitable solvents such as dichloromethane and acetonitrile.
  • a base such as pyridine
  • suitable solvents such as dichloromethane and acetonitrile.
  • the oxadiazole (XII/X) may be prepared according to the method of Rigo et. al. Synth. Commun. 16(13), 1665, 1986.
  • Preferred conditions are: phosphorous oxychloride at 100°C for 8 hours, or 2.5 eq. triflic anhydride in acetonitrile at 20°C for 5 hours.
  • R is typically C,., , alkyl
  • -j Q R is typically C.,_ 2 alkyl
  • R H or CrC alkyl, typically tert-butyl, methyl or ethyl
  • Compounds of formula (XXIH) may be prepared by an intra-molecular coupling of the amino acid (XXII), according to the procedure previously described in step (b).
  • compound (XXII) is treated with 1.4 eq. HBTU, 4.5 eq. NMM in DCM at room temperature for about 18 hours.
  • Compounds of formula (XXIH) may be prepared by base catalysed cyclisation of the amino ester (XXII) typically carried out at room temperature or below for 1-5 hours.
  • bases such as potassium tert-butoxide, sodium ethoxide or isopropyl magnesium chloride are used at or below 20°C in a suitable solvent such as tetrahydrofuran or ethanol for 1 -5 hours.
  • compound (XXII) is treated with 1.1 eq. potassium ter-butoxide in THF at 20°C for about 2 hours.
  • a suitable thionating agent e.g. Lawesson's reagent, P S 10
  • a base e.g. Na 2 CO 3
  • a suitable solvent e.g. THF
  • a strong base such as KO*Bu or LDA
  • a suitable solvent such as THF or ether
  • a suitable solvent typically ethanol at elevated temperature
  • an acid catalysed such as TFA, p-TSA.
  • a suitable solvent typically n-Butan-1-ol at elevated temperature
  • an acid catalysed such as TFA, p-TSA.
  • Certain compounds of formula (I) may be converted to alternative compounds of formula (I) using standard chemical transformations. Examples of these are illustrated below:
  • Arj nation (e.g. examples 40 & 41)
  • R 1 contains a leaving group, such as a chloro substituent
  • this may react with a suitable amine HNR 2 R 3 in the presence of a suitable tertiary amine base (Et 3 N, NMM or H ⁇ nig's base) or alkali metal base (K 2 CO 3 , Cs 2 CO 3 ) in a suitable solvent (e.g. DMF, MeCN), optionally at elevated temperature.
  • a suitable tertiary amine base Et 3 N, NMM or H ⁇ nig's base
  • K 2 CO 3 , Cs 2 CO 3 alkali metal base
  • the chloro compound is treated with an excess of HNR 2 R 3 , in the presence of an excess of K 2 CO 3 in DMF at 70°C.
  • Compounds containing a carbonyl function may be reduced using a suitable reducing agent such as DIBAL or borane in a suitable solvent such as ether or THF at or between room temperature and the reflux temperature of the reaction.
  • a suitable reducing agent such as DIBAL or borane
  • a suitable solvent such as ether or THF
  • the amide compound is treated with 10 eq. borane in THF at reflux, followed by an excess of HCI at reflux.
  • Reductive amination (e.g. examples 69-81 & 84-90)
  • Compounds of formula (I) containing a reactive N atom may react with an aldehyde or ketone, according to the methods described in step (c).
  • the amine of formula (I) is treated with an excess of aldehyde/ketone and 2 eq. Na(OAc) 3 BH in DCM, optionally in the presence of an excess of Et 3 N and acetic acid, at room temperature for up to 18 hours.
  • Compounds of formula (I) containing a Sulphur atom may be oxidised using a suitable oxidising agent such as hydrogen peroxide or meta-chloro perbenzoic acid in a suitable solvent such as trifluoroacetic acid or 1,1,1, 3,3,3-Hexafluoro-propan-2-ol between 0-25°C.
  • a suitable oxidising agent such as hydrogen peroxide or meta-chloro perbenzoic acid
  • a suitable solvent such as trifluoroacetic acid or 1,1,1, 3,3,3-Hexafluoro-propan-2-ol between 0-25°C.
  • the compounds of the present invention are useful because they possess pharmacological activity in animals.
  • 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, hypernatremia), 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, obsess
  • a method of treatment of dysmenorrhoea which comprises administering a therapeutically effective amount of a compound of the invention to a patient suffering from anxiety, cardiovascular disease (including angina, atherosclerosis, hypertension, heart failure, edema, hypernatremia), dysmenorrhoea (primary and secondary), endometriosis, emesis (including motion sickness), intrauterine growth retardation, inflammation (including rheumatoid arthritis), mittlesmerchz, preclampsia, premature ejaculation, premature (preterm) labor or Raynaud's disease.
  • cardiovascular disease including angina, atherosclerosis, hypertension, heart failure, edema, hypernatremia
  • dysmenorrhoea primary and secondary
  • endometriosis including motion sickness
  • inflammation including rheumatoid arthritis
  • mittlesmerchz preclampsia
  • premature ejaculation premature (preterm) labor or Raynaud'
  • cardiovascular disease including angina, atherosclerosis, hypertension, heart failure, edema, hypernatremia
  • dysmenorrhoea primary and secondary
  • endometriosis including motion sickness
  • emesis including motion sickness
  • intrauterine growth retardation inflammation (including rheumatoid arthritis), mittlesmerchz, preclamps
  • 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.
  • the compounds of the present 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.
  • they may be administered in combination with a PDE5 inhibitor.
  • They may also be administered in combination with an NO donor.
  • they may be administered in combination with L-arginine, or as an arginate salt.
  • the compounds of the present invention may also be used in combination with a COX inhibitor.
  • 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.
  • 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", 19 th Edition (Mack Publishing Company, 1995).
  • a pharmaceutical formulation comprising a compound of formula (I) in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • 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 (including muco- adhesive), 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, JJ. (6), 981-986 by Liang and Chen (2001).
  • the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants examples 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 wt% to 25 wt%, preferably from 5 wt% to 20 wt%, 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 ethylcellulose. 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 wt% to 5 wt% of the tablet, and glidants may comprise from 0.2 wt% and 1 wt% 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 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt%, 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 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% 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.
  • 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 Verma et al, Pharmaceutical Technology On-line, 25(2), 1-14 (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, intreperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, 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 suitable processing, for example, the use of high energy spray-dried dispersions (see WO 01/47495) and/or by the use of appropriate formulation techniques, such as the use 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 PGLA microspheres.
  • the compounds of the invention may also be administered topically to the skin or mucosa, either 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 include delivery by iontophoresis, electroporation, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM,
  • 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, the 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 of 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 a 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 HPMC
  • 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, poly-DL-Iactic-coglycolic acid (PGLA).
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • 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.
  • a polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • Formulations for ocular/aural administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.
  • the compounds of the invention may be combined with soluble macromolecular entities such as cyclodextrin or polyethylene glycol-containing polymers 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 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-cyclodextrins, 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 compounds 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 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 will typically be in the range of from about 0.01 to about 15 mg/kg of body weight, depending on the mode of administration.
  • the total daily dose may be administered in a single dose or divided doses throughout the day. These dosages are based on an average human subject having a weight of about 65kg 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.
  • treating and “to treat” mean to alleviate symptoms, eliminate the causation either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms.
  • treatment includes alleviation, elimination of causation (either on a temporary or permanent basis) of, or prevention of symptoms and disorders associated with primary and/or secondary dysmenorrhoea.
  • the treatment may be a pre-treatment as well as a treatment at the on-set of symptoms.
  • 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 ⁇ A ).
  • 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.
  • 25 ⁇ l compound and 25 ⁇ l [ 3 H]-AVP, (final concentration at or below K ⁇ determined for membrane batch, typically 0.5 nM - 0.6 nM) were added to a 96-well round bottom polypropylene plate.
  • 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.
  • 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
  • each response was expressed as a % of the response to the highest concentration of AVP in that row.
  • each response was expressed as a % of the response to AVP.
  • the compounds of the invention may have the advantage that they are more potent, have a longer duration of action, have a broader range of activity, are more stable, have fewer side effects or are more selective, or have other more useful properties than the compounds of the prior art.
  • a compound of formula (I) or a pharmaceutically acceptable derivative thereof (i) a compound of formula (I) or a pharmaceutically acceptable derivative thereof; (ii) a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable derivative thereof; (iii) a pharmaceutical formulation including a compound of formula (I) or a pharmaceutically acceptable derivative thereof, together with a pharmaceutically acceptable excipients, diluent or carrier; (iv) a compound of formula (1) or a pharmaceutically acceptable derivative or composition thereof, for use as a medicament; (v) the use of a compound of formula (I) or of a pharmaceutically acceptable derivative or composition thereof, for the manufacture of a medicament for the treatment of aggression, Alzheimer's disease, anorexia nervosa, anxiety, anxiety disorder, asthma, atherosclerosis, autism, cardiovascular disease (including angina, atherosclerosis, hypertension, heart failure, edema, hypernatremia), cataract, central nervous system disease, cerebrovascular ischemia, cirrhos
  • cardiovascular disease including angina, atherosclerosis, hypertension, heart failure, edema, hypernatremia), dysmenorrhoea (primary and secondary), endometriosis, emesis (including motion sickness), intrauterine growth retardation, inflammation (including rheumatoid arthritis), mittlesmerchz, preclampsia, premature ejaculation, premature (preterm) labor or Raynaud's disease;
  • (x) a method as in (vii) where the disease or disorder is dysmenorrhoea (primary and secondary); (xi) intermediates of the formulae (II), (III), (X), (XV), (XXIV), and (XXV);
  • Potassium carbonate (52.5 g, 0.379mol) was charged to a stirred solution of 2- Bromopyridine (60 g, 0.379 mol) and Ethylisonipecotate (59.7 g, 0.379 mol), at an ambient temperature before heating to 120°C for 24 hours. The mixture was cooled to room temperature and propan-2-ol charged to the solution. The reaction mixture was then filtered and telescoped into preparation 1c.
  • the hydrazide of Preparat Oion 3 (2O0.4 g, 69 mOmol) was suspended in phosphorus oxychloride (150 ml) at 100°C for 4 hours. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and was added to water. The aqueous layer was basified by addition of solid sodium hydrogen carbonate and the phases were separated. The aqueous phase was extracted with ethyl acetate (x2) and the combined organic layers were dried over magnesium sulphate and evaporated under reduced pressure. The material isolated was triturated with diethyl ether to give the title compound as a beige solid (15 g).
  • the hydrazide of Preparation 3 (50.0g, 169 mmol) was suspended in acetonitrile (250 ml) and cooled using an ice bath. Trifluoromethanesulfonic anhydride (29.9 ml, 177mmol) was added dropwise at T ⁇ 15°C. The reaction was warmed to room temperature and stirred for 16 hours. The reaction was cooled using an ice bath and a solution of sodium hydrogen carbonate (29.8g, 354mmol) in water (250ml) was added dropwise.
  • the compound from preparation 11 was suspended in 2 molar aqueous hydrochloric acid (20 ml) and heated to 100°C for 4 hours. The solution was allowed to cool, made basic (pH 9) with 0.880 aqueous ammonia and partitioned with ethyl acetate (50 ml). The organic layer was washed with water and saturated brine, and dried over magnesium sulphate. The solution was filtered and then evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol and ammonium hydroxide in dichloromethane as eluant (5:0.5:95) to give the title compound as a brown oil (0.43 g).
  • the title compound was prepared from the alcohol of preparation 8 and the oxadiazole of preparation 5, in 55% yield, using the procedure described in preparation 16.
  • the title compound was prepared from 2-(2-Amino-phenyl)-ethanol and the oxadiazole of preparation 6, in 54% yield, using the procedure described in preparation 23.
  • the hydrazide of preparation 25 (5.0 g, 15.6 mmol) was suspended in dichloromethane (200 ml) and pyridine (6.4 ml, 78 mmol) added before cooling the mixture to 10°C. Trifluoroacetic anhydride (6.6 ml, 39 mmol) was added dropwise over 15 minutes and then stirred at room temperature for 3 hours. The reaction mixture was partitioned with water (50ml) and the organic layer dried over magnesium sulphate. The mixture was filtered and the filtrate evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol in dichloromethane as eluant (2:98) to give the title compound as a white solid (2.95 g).
  • Toluene-4-sulfonic acid (80 mg, 0.46 mmol) was added to a solution of the oxadiazole of preparation 27 (1.28 g, 3.0 mmol) in xylene and heated to 140°C for 18 hours. The xylene was removed under reduced pressure. The residue was partitioned between dichloromethane (100 ml) and sodium hydrogen carbonate solution (25 ml). The aqueous solution was washed with dichloromethane (2x20 ml). The combined organic layers were dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol and ammonium hydroxide in dichloromethane (5:0.5:95) as eluant to give the title compound (730 mg) as a pale yellow foam.
  • the triazole of preparation 28 (700 mg, 1.73 mmol) was dissolved in 1 ,4-dioxan (6 ml) and hydrochloric acid (4M in 1,4-dioxane, 12 ml) added. The reaction mixture was stirred at room temperature for 4 hours. The 1 ,4-dioxane was removed under reduced pressure. The residue was partitioned between dichloromethane (100 ml) and sodium hydrogen carbonate solution (25 ml). The aqueous solution was washed with dichloromethane (2x20 ml). The combined organic layers were dried over magnesium sulphate and evaporated under reduced pressure to give the title compound (410 mg) as a pale yellow foam.
  • the title compound was prepared from 2-Amino-4,5-difluoro-benzoic acid, in 86% yield as a yellow solid, following the procedure described in preparation 7.
  • the title compound was prepared from the alcohol of preparation 32 and the oxadiazole of preparation 5, in 50% yield, using the procedure described in preparation 16.
  • the title compound was prepared from (2-Amino-5-methyl-phenyl)-methanol (see Arch.
  • Lithium hydroxide (28 ml, 1 M in water, 28 mmol) was added to a solution of the ester from preparation 42 (2.85 g, 11 mmol) in tetrahydrofuran (30 ml) and the reaction stirred at room temperature for 19 hours.
  • the mixture was acidified to pH 3 using 2M hydrochloric acid, and then extracted with dichloromethane (2x70 ml).
  • the combined organic extracts were dried over magnesium sulphate and evaporated under reduced pressure to give the title compound as a yellow solid, 2.36 g.
  • the title compound was obtained as an oil, from the amine from preparation 47 and acetic anhydride, following a similar procedure to that described in preparation 48, except that no 4-pyrrolidinopyridine was added.
  • Chlorine (7.3 g) was bubbled into acetic acid (102 g). A portion of this solution (15 g) was added to an ice-cooled solution of the compound from preparation 48 (3.3 g, 14.1 mmol) in acetic acid (50 ml), and the reaction stirred at room temperature for 20 hours. The mixture was concentrated under reduced pressure, and the residue dissolved in ethyl acetate. This solution was washed with saturated sodium carbonate solution and brine. It was then dried over magnesium sulphate and evaporated under reduced pressure, to afford the title compound as a brown solid, 2.7 g.
  • Chlorine (1.88 g) was bubbled into a solution of the compound from preparation 49 (6.4 g, 26.6 mmol) in acetic acid (30 ml) and the reaction stirred at room temperature for 24 hours. The mixture was concentrated under reduced pressure and the residue suspended in ethyl acetate. The solution was then washed with sodium bicarbonate solution and brine, before being dried over magnesium sulphate and evaporated under reduced pressure. The product was recrystallised from isopropyl ether and methanol to give the title compound, 3.5g.
  • Methylamine (2.23 ml, 33% solution in ethanol, 17.9mmol) was added to a solution of the chloride from preparation 5 (1 g, 3.59 mmol) in tetrahydrofuran (20 ml), and the solution stirred at room temperature for 18 hours. Additional methylamine (10 ml, 33% solution in ethanol) was added and the reaction stirred for a further 72 hours. The reaction was evaporated under reduced pressure, the solid triturated with ethyl acetate and the precipitate removed by filtration. The filtrate was concentrated under reduced pressure and the residue azeotroped with dichloromethane to afford the title compound as a crystalline solid.
  • tert-Butyl-4-oxo-piperidinecarboxylate (628 mg, 3.16 mmol) and sodium triacetoxyborohydride (1.12 g, 5.26 mmol) were added to a suspension of the amine from example 4 (1 g, 2.63 mmol) in dichloromethane (50 ml), and the reaction was stirred at room temperature for 72 hours. TLC analysis showed starting material remaining, so additional tert-butyl-4-oxo-piperidinecarboxylate (628 mg, 3.16 mmol) and sodium triacetoxyborohydride (1.12 g, 5.26 mmol) were added, and the reaction stirred for a further 5 hours.
  • Chloro-acetic acid tert-butyl ester (500 mg, 3.34 mmol) was added to a solution of the amine of preparation 10 (1.04 g, 6.65 mmol) in THF (20 ml) and the reaction mixture was heated to 65°C for 20 hours. The mixture was allowed to cool and was filtered. The filtrate was evaporated under reduced pressure and the resulting gummy residue was purified by column chromatography on silica gel using ethyl acetate to elute to give the title compound (726 mg) as a white crystalline solid.
  • Formaldehyde (37% w/v aqueous, 5 ml, 60 mmol) was added to a suspension of the amine of preparation 82 (8.4 g, 42.7 mmol) in dichloromethane (140ml) and acetic acid (1 ml). The mixture was stirred at room temperature for 0.25 hours before adding sodium triacetoxyborohydride (14 g, 64.1 mmol) portionwise, and it was stirred for a further 30 minutes. The reaction mixture was partitioned between 2N aqueous hydrochloric acid (50 ml) and dichloromethane (200 ml). The organic layer was extracted a second time with 2N aqueous hydrochloric acid (50 ml) before being discarded.
  • Example 1 1-(3,4,5,6-Tetrahydro-2H- [1 ,2']bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b- tetraaza-benzo[e]azulene
  • Toluene-4-sulfonic acid (100 mg, 0.58 mmol) was added to a solution of the oxadiazole of preparation 13 (2.45 g, 6.8 mmol) and heated to 150°C for 18 hours.
  • the mixture was cooled and purified by chromatography on silica gel using methanol and ammonium hydroxide in dichloromethane (5:0.5:95) as eluant, followed by chromatography on silica gel using methanol and ammonium hydroxide in ethyl acetate (10:1:90), followed by methanol and ammonium hydroxide in dichloromethane (7:1 :93) as eluant to give, after trituration with ethyl acetate, the title compound (770 mg) as a brown solid.
  • Formaldehyde (37% w/v aqueous, 1 ml, 81 mmol) was added to a solution of the amine of example 1 (100 mg, 0.28 mmol) in dichloromethane (20ml). The mixture was stirred at room temperature for 0.25 hours before sodium triacetoxyborohydride (500mg, 2.4 mmol) was added. The reaction mixture was stirred for a further 0.25 hours. The dichloromethane was removed under reduced pressure. The residue was partitioned between 2N aqueous sodium hydroxide solution (50ml) and ethyl acetate (50ml).
  • Toluene-4-sulfonic acid (100 mg, 0.58 mmol) was added to a solution of the oxadiazole of preparation 14 (4.65 g, 12 mmol) and heated to 140°C for 18 hours. The mixture was cooled and purified by chromatography on silica gel using methanol and ammonium hydroxide in dichloromethane (5:0.5:95) as eluant to give the title compound (2.0 g) as an off-white solid.
  • Example 4b 8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-yl)-5,6-dihydro-4H-
  • Trifluoroacetic acid (2.9 ml, 38 mmol) was added to a tetrahydrofuran solution of the oxadiazole of preparation 14b (10 g, 25 mmol) and heated to 65-67°C for 6 hours. The reaction mixture was cooled and adjusted to pH 7 with sodium hydroxide (5M) before vacuum distillation to ethyl acetate.
  • Example 5b 8-Chloro-5-methyl-1-(3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-yl)-5,6- dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azuIene
  • Example 5c 8-Chloro-5-methyl-1-(3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-yl)-5,6- dihydro-4H-2,3,5,1 Ob-tetraaza-benzo[e]azulene trihydrochloride
  • Acetic acid (3 ml, 52 mmol) was added to a solution of the amine of example 4b (10 g, 26 mmol) in dichloromethane (100 ml) followed by formaldehyde (37% w/v aqueous, 3.2 ml, 39 mmol).
  • sodium triacetoxyborohydride (6.7 g, 31 mmol) was slurried in dichloromethane and cooled to ⁇ 10°C. The imine solution was then added dropwise to the cold slurry over 15 minutes. The reaction mixture was stirred at room temperature for 0.5 hours, after which time the reaction mixture was partitioned between 2N aqueous sodium hydroxide solution and dichloromethane.
  • Acetone (0.1 ml, 1.36 mmol) was added to a solution of the amine of example 4 (200 mg, 0.53 mmol) in dichloromethane (5ml). The mixture was stirred at room temperature for 0.25 hours before sodium triacetoxyborohydride (500mg, 2.4 mmol) was added, and the reaction mixture stirred for a further 18 hours. The reaction mixture was partitioned between 2N aqueous sodium hydroxide solution (10ml) and dichloromethane (10ml). The organic layer was evaporated under reduced pressure and purified by chromatography on silica gel using methanol in dichloromethane (5:95) as eluant.
  • Example 7 8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-yl)-5-(tetrahydro-pyran-4- yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene
  • Tetrahydro-pyran-4-one (68 mg, 0.68 mmol) was added to a solution of the amine of example 4 (130 mg, 0.34 mmol) in dichloromethane (5ml). The mixture was stirred at room temperature for 0.25 hours before sodium triacetoxyborohydride (217mg, 1.0 mmol) was added, and the reaction mixture was stirred for a further 18 hours. Further tetrahydro-pyran-4-one (68 mg, 0.68 mmol) and sodium triacetoxyborohydride (217mg, 1.0 mmol) were added and the reaction mixture was heated to 40°C for 24 hours.
  • the reaction mixture was partitioned between 2N aqueous sodium carbonate solution (10ml) and ethyl acetate (50ml).
  • the organic layer was washed three times with 2N aqueous sodium carbonate solution (10ml), once with saturated aqueous brine, and then dried over magnesium sulphate before filtering and evaporating the filtrate under reduced pressure.
  • the residue was purified by chromatography on silica gel using a gradient of ethyl acetate in pentane (0% to 30%) as eluant, followed by chromatography on silica gel using a gradient of methanol in dichloromethane (0% to 5%) as eluant, to afford the title compound as a brown foam (80 mg).
  • Acetyl chloride (0.1 ml, 1.4 mmol) was added to an ice cooled solution of the amine of example 4 (200 mg, 0.53 mmol) in dichloromethane (5ml) and stirred at room temperature for 20 hours.
  • Dichloromethane was evaporated off under reduced pressure and the residue purified by chromatography on silica gel using methanol in dichloromethane (5:95) as eluant. The residue was dissolved in dichloromethane (2ml) and hydrochloric acid (1M in diethyl ether, 2ml) was added, and the solvents evaporated under reduced pressure to give the title compound as a brown foam (110 mg).
  • Example 11 8-Chloro-5-methanesulfonyl-1 -(3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-yl)- 5,6-dihydro-4H-2,3,5, 10b-tetraaza-benzo[e]azulene
  • Methanesulfonyl chloride (0.1 ml, 1.29 mmol) was added to an ice cooled solution of the amine of example 4 (200 mg, 0.53 mmol) in dichloromethane (5ml) and stirred at room temperature for 20 hours. The dichloromethane was evaporated off under reduced pressure and the residue purified by chromatography on silica gel using methanol in dichloromethane (5:95) as eluant, to afford the title compound as a brown foam (71 mg).
  • Toluene-4-sulfonic acid (5 mg, 0.03 mmol) was added to a solution of the oxadiazole of preparation 15 (2.34 g, 5.9 mmol) and heated to 140°C for 18 hours. The mixture was cooled and purified by chromatography on silica gel using methanol and ammonium hydroxide in dichloromethane (5:0.5:95) as eluant to afford the title compound (1.12 g) as an off-white solid.
  • Formaldehyde (37% w/v aqueous, 0.1 ml, 1.2 mmol) was added to a solution of the amine of example 12 (100 mg, 0.26 mmol) in dichloromethane (5ml). The mixture was stirred at room temperature for 0.25 hours before sodium triacetoxyborohydride (111mg, 0.53 mmol) was added, and the reaction mixture was stirred for a further 18 hours. The mixture was partitioned between 2N aqueous sodium hydroxide solution (10ml) and dichloromethane (10ml).
  • Example 17 1 -[8-Chloro-1 -(1 -pyrimidin-2-yl-piperidin-4-yl)-4H,6H-2,3,5, 10b-tetraaza- benzo[e]azulen-5-yl]-2,2-dimethyl-propan-1-one
  • Example 20 4-(8-Chloro-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulen-1-yl)-3,4,5,6- tetrahydro-2H-[1 ,2']bipyridinyl-6'-carbonitrile
  • Example 21 4-(8-Chloro-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azuIen-1-yl)-3,4,5,6- tetrahydro-2H-[1 ,2']bipyridinyl-6'-carboxylic acid amide
  • Toluene-4-sulfonic acid (50 mg, 0.3 mmol) was added to a solution of the oxadiazole of preparation 41 (1.35 g, 3.3 mmol) and heated to 140°C for 2 hours. The mixture was cooled and purified by chromatography on silica gel using ethyl acetate followed by methanol and ammonium hydroxide in dichloromethane (5:0.5:95) as eluant, to afford the title compound (273 mg) as an off-white solid.
  • Example 23 1 -[13-Chloro-3-(3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-yl)-2,4,5,8-tetraaza- tricyclo[9.4.0.0*2,6*]pentadeca-1 (11),3,5,12,14-pentaen-8-yl]-ethanone
  • Acetic anhydride 35 Dl, 0.37 mmol was added to a solution of the amine of example 22 (120 mg, 0.30 mmol) and triethylamine in dichloromethane (5ml) and stirred at room temperature for 2 hours.
  • the dichloromethane was evaporated off under reduced pressure and the residue was purified by chromatography on silica gel using methanol and ammonium hydroxide in dichloromethane (5:0.5:95) as eluant, to afford the title compound as a white solid (120 mg).
  • Example 24 13-Chloro-8-methyl-3-(3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-yl)-2,4,5,8- tetraaza-tricyclo[9.4.0.0 * 2,6 * ]pentadeca-1 (11),3,5,12,14-pentaene
  • Example 25 3-(1 -Pyrimidin-2-yl-piperidin-4-yl)-8-oxa-2,4,5-triaza- tricyclo[9.4.0.0*2,6 * ]pentadeca-1 (11),3,5,12,14-pentaene
  • Example 27 13-Chloro-3-(3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-yl)-8-oxa-2,4,5-triaza- tricyclo[9.4.0.0 * 2,6*]pentadeca-1(11),3,5,12,14-pentaene
  • the title compound was prepared from the oxadiazole of preparation 20, in 60% yield, using the procedure described in example 22.
  • the title compound was prepared from the oxadiazole of preparation 16, in 41 % yield, using the procedure described in example 22.
  • Triethylamine (1.37 ml, 9.81 mmol) and chloroacetyl chloride (0.35 ml, 4.35 mmol) were added to a solution of the amine from example 4 (1.5 g, 3.95 mmol) in dichloromethane (50 ml), and the reaction stirred at room temperature for 2 hours. TLC analysis showed starting material remained, so additional chloroacetyl chloride (0.35 ml, 4.35 mmol) was added and the reaction was stirred for an additional 1.5 hours. The mixture was partitioned between dichloromethane and 2N sodium hydroxide solution and the layers separated.
  • Example 40 2-Azetidin-1-yl-1-[8-chloro-1-(3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-yl)- 4H,6H-2,3,5,10b-tetraaza-benzo[e]azulen-5-yl]-ethanone
  • Example 41 1-[8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-yl)-4H,6H-2,3,5,10b- tetraaza-benzo[e]azulen-5-yl]-2-pyrrolidin-1-yl-ethanone
  • Example 50 8-Chloro-5-pyrrolidin-(2S)-2-ylmethyl-1 -(3,4,5,6-tetrahydro-2H- [1 ,2']bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5, 10b-tetraaza-benzo[e]azulene
  • Example 55 5-Azetidin-3-yl-8-chloro-1-(3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-yl)-5,6- dihydro-4H-2,3,5, 10b-tetraaza-benzo[e]azulene
  • Example 56 8-Chloro-5-pyrrolidin-3-yl-1-(3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-yl)-5,6- dihydro-4H-2,3,5,1 Ob-tetraaza-benzo[e]azulene
  • Example 58 8-Chloro-5-[1 ,4]oxazepan-6-yl-1-(3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-yl)- 5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene trihydrochloride
  • Example 64 ⁇ 2-[8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-4-yl)-4H,6H-2,3,5,10b- tetraaza-benzo[e]azulen-5-yl]-ethyl ⁇ -dimethyl-amine trihydrochloride
  • the colourless gum was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (93:7:1) as eluant, to afford a colourless gum.
  • This gum was treated with ethereal hydrochloric acid to afford the title compound (194 mg).
  • Example 68 1-[8-Chloro-1-(3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-yl)-4H,6H-2,3,5,10b- tetraaza-benzo[e]azulen-5-yl]-3-dimethylamino-propan-1-one
  • Example 69 8-Chloro-5-(1 -methyl-pyrrolidin-(2S)-2-ylmethyl)-1 -(3,4,5,6-tetrahydro-2H- [1 ,2']bipyridinyI-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene trihydrochloride
  • Formaldehyde (0.1 ml, 33 wt.% solution in water) and sodium triacetoxyborohydride (64 mg, 0.30 mmol) were added to a suspension of the amine from example 50 (70 mg, 0.15 mmol) in dichloromethane (5 ml) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned between dichloromethane and 2 N sodium hydroxide solution and the phases separated. The organic solution was evaporated under reduced pressure and the residue purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (93:7:1 ) as eluant. The product was treated with ethereal hydrochloric acid, and the solution evaporated under reduced pressure to give the title compound (35 mg).
  • Example 73 and 74 (+) and (-) 8-Chloro-5-(4-methyl-morpholin-2-ylmethyl)-1 -(3,4,5,6- tetrahydro-2H-[1 ,2']bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5, 10b-tetraaza-benzo[e]azulene

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Abstract

L'invention concerne un composé représenté par la formule (I) ou un dérivé pharmaceutiquement acceptable de celui-ci. Dans cette formule, V représente -(CH2)d(O)e-, -CO-, ou -CH(C1-6 alkyl)-; W représente -0-, -S(O)a, ou -N(R1 ), -R1 représentant H, C1-6 alkyle, (CH2)bCOR2, CO(CH2)bNR2R3, S02R2, (CH2 )cOR2, (CH2)c,NR2R3 ou (CH2)bhet1 et het1 représentant un hétérocycle saturé ou insaturé de 3 à 8 atomes contenant un ou plusieurs hétéroatome(s) sélectionné(s) dans le groupe constitué par O, N ou S, éventuellement substitué par C1-6 alkyle; X et Y représentent indépendamment H, C1-6 alkyle, halogène, OH, CF3, OCF3, OR4; Z représente -(CH2)f(O)g, -CO- ou -CH(C 1-6 alkyl)-; le noyau A représente un hétérocycle de 4-7 éléments, contenant N saturé éventuellement substitué par OH, et dans lequel au moins un noyau N est éventuellement substitué par O; le noyau B représente phényle ou un hétérocycle de 4-7 éléments contenant N insaturé éventuellement substitué par OH, halogène, CN, CONH2, CF3, OCF3, et dans lequel au moins un noyau N est éventuellement substitué par O; R2 et R3 représentent indépendamment H, C1-6 alkyle [éventuellement substitué par OH, halogène, N(C1-6 alkyl)2, ou C1-6 alkyloxy], C1-6 alkyloxy, N(C1-6 alkyl)2, ou [C3-8 cycloalkyl]; ou R2 et R3 représentent indépendamment avec l'atome d'azote auquel ils sont fixés un hétérocycle de 3 à 8 atomes, éventuellement substitué par C1-6 alkyle; R4 représente C1-6 alkyle droit ou ramifié; a et c représentent indépendamment 0, 1, ou 2; b, e et g représentent indépendamment 0 ou 1; d et f représentent indépendamment 1 ou 2. Ledit composé est utilisé pour traiter la dysménorrhée.
PCT/IB2004/000432 2003-02-19 2004-02-09 Composes de triazole utilises en therapie Ceased WO2004074291A1 (fr)

Priority Applications (18)

Application Number Priority Date Filing Date Title
DE602004003914T DE602004003914T2 (de) 2003-02-19 2004-02-09 Für die therapie geeignete triazolverbindungen
HR20050681A HRP20050681A2 (en) 2003-02-19 2004-02-09 Triazole compounds useful in therapy
RSP-2005/0638A RS20050638A (sr) 2003-02-19 2004-02-09 Triazolska jedinjenja korisna u terapiji
KR1020057015408A KR100750028B1 (ko) 2003-02-19 2004-02-09 치료에 유용한 트리아졸 화합물
JP2006500323A JP4033886B2 (ja) 2003-02-19 2004-02-09 治療に有用なトリアゾール化合物
CA002516557A CA2516557C (fr) 2003-02-19 2004-02-09 Composes de triazole utilises en therapie
AU2004213242A AU2004213242B2 (en) 2003-02-19 2004-02-09 Triazole compounds useful in therapy
MXPA05008923A MXPA05008923A (es) 2003-02-19 2004-02-09 Compuestos de triazol utiles en terapia.
DK04709303T DK1597260T3 (da) 2003-02-19 2004-02-09 Triazol forbindelser, der er anvendelige i behandling
EP04709303A EP1597260B1 (fr) 2003-02-19 2004-02-09 Composes de triazole utilises en therapie
SI200430160T SI1597260T1 (sl) 2003-02-19 2004-02-09 Spojine triazola, uporabne pri terapiji
EA200501136A EA009460B1 (ru) 2003-02-19 2004-02-09 Триазольные соединения, полезные в терапии
AP2005003376A AP2005003376A0 (en) 2003-02-19 2004-02-09 Triazole compounds useful in therapy.
BRPI0407676-1A BRPI0407676A (pt) 2003-02-19 2004-02-09 compostos de triazol,uso e processos para fabricação do mesmo
UAA200508142A UA79674C2 (en) 2003-07-23 2004-09-02 Triazol compounds suitable for use in therapeutics
IS7957A IS2450B (is) 2003-02-19 2005-07-25 Tríasól efnasambönd sem eru gagnleg við meðferð
TNP2005000200A TNSN05200A1 (fr) 2003-02-19 2005-08-19 Triazoles utiles en therapeutique
NO20054053A NO20054053L (no) 2003-02-19 2005-08-31 Triazolforbindelser anvendbare i terapi.

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TW200500367A (en) 2005-01-01
CN1751047A (zh) 2006-03-22
PA8596101A1 (es) 2005-08-04
UY28201A1 (es) 2004-09-30
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GT200400020A (es) 2004-09-21

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