WO2009130232A1 - Dérivés de pirazolo [1, 5 -a] pyrazine, antagonistes des récepteurs v1b - Google Patents

Dérivés de pirazolo [1, 5 -a] pyrazine, antagonistes des récepteurs v1b Download PDF

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WO2009130232A1
WO2009130232A1 PCT/EP2009/054780 EP2009054780W WO2009130232A1 WO 2009130232 A1 WO2009130232 A1 WO 2009130232A1 EP 2009054780 W EP2009054780 W EP 2009054780W WO 2009130232 A1 WO2009130232 A1 WO 2009130232A1
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oxy
pyrazin
alkyl
acetamide
formula
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PCT/EP2009/054780
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English (en)
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Romano Di Fabio
Gabriella Gentile
Alfonso Pozzan
Luca Tarsi
Silvia Terreni
Federica Tonelli
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Glaxo Group Limited
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Priority claimed from GB0807505A external-priority patent/GB0807505D0/en
Priority claimed from GB0813708A external-priority patent/GB0813708D0/en
Priority claimed from GB0813692A external-priority patent/GB0813692D0/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Publication of WO2009130232A1 publication Critical patent/WO2009130232A1/fr

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    • 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
    • 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

Definitions

  • the present invention relates to novel compounds, processes for their preparation, intermediates used in these processes, pharmaceutical compositions containing them and their use in therapy, as V1 b receptor antagonists.
  • Arginine Vasopressin AVP plays a major role in the regulation of the hypothalamic-pituitary- adrenal (HPA) axis.
  • HPA hypothalamic-pituitary- adrenal
  • ACTH adrenocorticotropin hormone
  • AVP is a weak stimulus in physiological conditions but it participates in the adaptation of the hypothalamic-pituitary- adrenal (HPA) axis during stress through its ability to potentiate the stimulatory effect of corticotrophin releasing factor (CRF) (Rivier and Vale, Nature, 1983, 305, 325-327).
  • HPA hypothalamic-pituitary- adrenal
  • CRF corticotrophin releasing factor
  • An increased HPA axis activity is found in 40-70% of patients with major depression (Heuser et al., 1996, Am J Psychiatry, 153:93-99).
  • AVP synergies with CRF in maintaining this overdrive and plays a major role in prolonged stressful states (Aguilera & Rabadan-Diehl, 2000, Regul Pept, 96, 23-29).
  • CRF is the physiological mediator of ACTH release under acute stressful conditions
  • AVP represents the dynamic mediator of ACTH release and strongly potentiates CRH-induced ACTH release. This situation may be altered in disease states where a dysregulation or hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis is observed. In these cases, the primary control of ACTH release may be shifted from CRH to AVP (Volpi et al., 2004, Ann N Y Acad Sci, 1018:293-3014).
  • HPA hypothalamic-pituitary-adrenal
  • V1 b receptors could be exploited as a possible therapeutic strategy for the treatment of diseases that are characterized by an excessive Cortisol secretion, such as major depression (Scott & Dinan, 1998, Life Sci, 62:1985-1998) and stress-related disorders (Griebel et al. 2003, Curr Drug Targets CNS Neurol Disord, 2:191-200).
  • abnormally elevated HPA activity may results in an over secretion of ACTH causing hypercortislaemia which predisposes to a metabolic syndrome characterised by insulin resistance, hyperinsulinemia, impaired glucose tolerance, dyslipideamia, obesity (in particular abdominal obesity) and non-insulin-dependent diabetes mellitus (NIDDM).
  • AVP effects are mediated via 7-transmembrane G-protein coupled receptor subtypes: Vi a (mainly distributed in vascular wall, liver, kidney, platelet), V1 b or V3 (mainly distributed in anterior pituitary) and V2 (almost exclusively found in the kidney). Activation of Via and V1 b receptors stimulates phosphatidylinositol (IP) hydrolysis and mobilises calcium; V2 receptors are positively coupled to adenylyl cyclase.
  • IP phosphatidylinositol
  • the human V1 b receptor has a pharmacological profile clearly distinct from that of the human Vi a and V2 receptors and activates several signalling pathways via different G proteins of the Gq, Gi and Gs families (Thibonnier et al., 1998, Adv Exp Med Biol, 449:251-276).
  • V1 b mRNA is expressed in 90% of corticotrope cells and immunohistochemical localisation reveals significant expression of V1 b receptors in other brain area such as hippocampus, frontal, piriform and cingulate cortex, caudate putamen, medial habenula, central amygdala, hypothalamus and cerebellum in rats (Hernando et al., 2001 , Endocrinology, 142:1659-1668).
  • V1 b receptor mRNA is not only present in anterior pituitary gland in human and rat, but also in other tissues, such as the adrenal medulla, pancreas, kidney, thymus, heart, lung and uterus (Lolait et al., 1995, Proc Natl Acad Sci U S A, 92:6783-6787).
  • V1 b receptor antagonist SSR149415 (Serradeil Le-GaI et al., 2002, J Pharmacol Exp Ther, 300:1 122-
  • the object of the present invention is to provide novel compounds which are V1 b antagonists.
  • the present invention provides compounds of formula (I) or pharmaceutically acceptable salt or solvate thereof:
  • R is -X-[CH 2 ]nCR 4 R5-Y; or a group G;
  • R 1 is H or C1-C4 alkyl
  • R 2 is aryl, heteroaryl or C3-C7 cycloalkyl, which may be substituted with one or more: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, CN;
  • X is -CR 7 R 8 -, -0-,-NR 9 -, -S-;
  • R 4 is H orC1-C4 alkyl
  • R 5 is H orC1-C4alkyl
  • R 6 is C1-C6 alkyl, C3-C6 cycloalkyl; C3-C6 cycloalkyl-(C1-C2 alkyl); which may be substituted by one or more halogen,
  • R 7 is H orC1-C4alkyl
  • R 8 is H orC1-C4 alkyl
  • R 9 is H orC1-C4alkyl
  • R 10 is H or C1-C4 alkyl, or together with R 11 forms a 4-8 saturated or unsaturated heterocycle ring which may comprise a further heteroatom selected from O, S and - NR 12 ; such heterocycle may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-
  • R 11 is H orC1-C4 alkyl
  • R 12 is H, C1-C6 alkyl, C3-C7 cycloalkyl; C3-C6 cycloalkyl-(C1-
  • C2 alkyl which may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy;
  • G is one of the groups selected from the list consisting of G1,
  • G2 G2, G3, G4, G5, G6, G7,G8, G9, G10, G11 and G12:
  • R 13 is H or C1-C4 alkyl, or together with R 14 forms a 4-8 saturated or unsaturated heterocycle ring which may comprise a further heteroatom selected from O, S and - NR 24 ; such heterocycle may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1- C4 haloalkoxy; and may assume different meanings; R 14 , R 16 is H, C1-C6 alkyl, C3-C7 cycloalkyl; C3-C6 cycloalkyl-(C1- C2 alkyl); which may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; and may assume different meanings;
  • R- 1IS5,> R f ⁇ 17 correspond to H or C1-C4 alkyl and may assume different meanings;
  • R 18 is H or C1-C4 alkyl, or together with R 17 forms a 4-8 saturated or unsaturated heterocycle ring which may comprise a further heteroatom selected from O, S and - NR 25 ; such heterocycle may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1- C4 haloalkoxy;
  • R 25 is H, C1-C6 alkyl, C3-C7 cycloalkyl; C3-C6 cycloalkyl-
  • C1-C2 alkyl which may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1- C4 haloalkoxy; and may assume different meanings;
  • R26> R27> R28> R29 is H, C1-C6 alkyl, C3-C7 cycloalkyl; C3-C6 cycloalkyl-(C1- C2 alkyl); which may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy; correspond to 1 or 2 and may assume different meanings; m, m m , m , m lv , rrf correspond to 0, 1 or 2 and may assume different meanings; n is 1 , 2 or 3; q is 1 , 2 or 3; p, p', p", p'" correspond to 0, 1 , 2 or 3 and may assume different meanings.
  • the compounds of the present invention may be in the form of and/or may be administered as a pharmaceutically acceptable salt.
  • suitable salts see Berge et al, J. Pharm. ScL, 1977, 66, 1-19.
  • a pharmaceutically acceptable salt may be readily prepared by using a 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.
  • Suitable pharmaceutically acceptable addition salts are formed from acids which form non-toxic salts and examples are hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, malate, fumarate, lactate, tartrate, citrate, formate, gluconate, succinate, pyruvate, oxalate, oxaloacetate, trifluoroacetate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and isethionate.
  • Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases, including salts of primary, secondary and tertiary amines, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine and N-methyl-D-glucamine.
  • Pharmaceutically acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts, of the compound of formula (I) using conventional methods.
  • prodrugs are also included within the context of this invention.
  • the term "prodrug” means a compound which is converted within the body, e.g. by hydrolysis in the blood, into its active form that has medical effects.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and in D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each of which are incorporated herein by reference.
  • prodrug also encompasses any covalently bonded carriers that release a compound of structure (I) in vivo when such a prodrug is administered to a patient.
  • Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound.
  • Prodrugs include, for example, compounds of this invention wherein amine groups are bonded to any group that, when administered to a patient, cleaves to form the amine groups.
  • representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of amine functional groups of the compounds of structure (I).
  • the compounds of formula (I) may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures or diastereoisomeric mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof.
  • a specific enantiomer may also be prepared from a corresponding optically pure intermediate. Separation of diastereoisomers or cis and trans isomers or syn and anti isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or
  • C1-C6 alkyl refers to a linear or branched alkyl group containing from 1 to 6 carbon atoms; examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert butyl, pentyl or hexyl.
  • C1-C4 alkyl as used herein as a group or a part of the group refers to a linear or branched alkyl group containing from 1 to 4 carbon atoms; examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert butyl.
  • C3-C7 cycloalkyl group means a saturated monocyclic hydrocarbon ring of 3 to 7 carbon atom such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl.
  • C3-C6 cycloalkyl group means a saturated monocyclic hydrocarbon ring of 3 to 6 carbon atom such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • C4-C7 cycloalkyl group means a saturated monocyclic hydrocarbon ring of 4 to 7 carbon atom such as, for example, cyclobutyl, cyclopentyl, cyclohexyl; cycloheptyl.
  • 'C3-6cycloalkylC1-2alkyr as used herein means an alkyl having one or two carbon atoms wherein one hydrogen atom is replaced with a C3-C6 cycloalkyl group as above defined, for example methylcyclopropane.
  • halogen refers to a fluorine, chlorine, bromine or iodine atom.
  • halo C1-C4 alkyl means an alkyl group having one to 4 carbon atoms and wherein at least one hydrogen atom is replaced with halogen such as for example a trifluoromethyl group and the like.
  • C1-C4 alkoxy group may be a linear or a branched chain alkoxy group, for example methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or methylprop-2-oxy and the like.
  • halo C1-C4 alkoxy group may be a C1-C4 alkoxy group as defined before substituted with at least one halogen, preferably fluorine, such as OCHF 2 , or OCF 3 .
  • aryl means an aromatic carbocyclic moiety of 6 to 12 members.
  • Representative aryl include (but are not limited to): phenyl, biphenyl or naphthyl.
  • heteroaryl means an aromatic heterocycle ring of 5 to 10 members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono-and bicyclic ring systems.
  • heteroaryls include (but are not limited to): furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, triazolyl, tetrazolyl, quinazolinyl, benzodioxolyl, benzothiadiazolyl, benzooxadiazolyl, imidazo[1 ,2-a]pyraziny
  • Representative 5-6 membered heteroaryls include (but are not limited to): furyl, thiophenyl, pyrrolyl, indolyl, pyridyl, oxazolyl, isooxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, tetrazolyl, isothiazolyl, thiadiazolyl.
  • the 4-8 saturated or unsaturated heterocycle ring means a 4-8 mono-, bicyclic heterocycle ring which is either saturated, or unsaturated and one to four carbon atoms may be replaced by an heteroatom as defined above.
  • the term include (but are not limited to): azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, hydantoinyl, hexahydro-1 H-azepinyl and octahydroazocinyl.
  • R is -X-[CH 2 ] n CR 4 R 5 -Y or a group G. In another embodiment, R is -X- [CH 2 ] H CR 4 R 5 -Y. In a further embodiment, R is a group G.
  • R 1 s H or C1-C4 alkyl (for example methyl). In another embodiment, R 1 is H. In a further embodiment, R 1 ⁇ s C1-C4 alkyl (for example methyl).
  • R 2 is aryl, heteroaryl or C3-C7 cycloalkyl, which may be substituted with one or more: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN.
  • R 2 is aryl which may be substituted with one or more: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN.
  • R 2 is a phenyl ring which may be substituted with one or more: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy.
  • R 2 is a phenyl ring which m- or m, p- substituted with one or two: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy
  • X is -CR 7 R 8 -, -O-, -NR 9 - or -S-. In another embodiment, X is -CR 7 R 8 - , -O- or -NR 9 -. In a further embodiment, X is -CR 7 R 8 - or -O-. In a still further embodiment, X is -CR 7 R 8 -. In another embodiment, X is -O-.
  • R 4 is H or C1-C4 alkyl. In another embodiment, R 4 is H.
  • R 5 is H or C1-C4 alkyl. In another embodiment, R 5 is H. In one embodiment, R 6 is C1-C6 alkyl, C3-C6 cycloalkyl; C3-C6 cycloalkyl-(C1-C2 alkyl); which may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy. In another embodiment, R 6 is C1-C6 alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkyl-(C1-C2 alkyl). In a further embodiment, R 6 is C1-C6 alkyl. In a still further embodiment, R 6 is /-propyl or f-butyl.
  • R 7 is H or C1-C4 alkyl. In another embodiment, R 7 is H.
  • R 8 is H or C1-C4 alkyl. In another embodiment, R 8 is H.
  • Rg is H or C1-C4 alkyl.
  • R 10 is H or C1-C4 alkyl or together with R 11 forms a 4-8 saturated or unsaturated heterocycle ring which may comprise a further heteroatom selected from O, S and -NR 12 ; such heterocycle may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy.
  • R 1O iS C1-C4 alkyl or together with R 11 forms a 4-8 saturated or unsaturated heterocycle ring which may comprise a further heteroatom selected from O, S and -NR 12 ; such heterocycle may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy.
  • R 10 together with R 11 forms a 5-7 saturated heterocycle ring which may comprise a further heteroatom selected from O, S and -NR 12 ; such heterocycle may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy.
  • R 11 is H or C1-C4 alkyl.
  • R 12 is H or C1-C6 alkyl ( for example methyl).
  • G is a group G1 , G2, G3, G4, G5, G6, G7 or G8. In another embodiment, G is a group G1 , G2, G3, G4, G6, G7 or G8. In a further embodiment, G is a group G1 ,G3, G4 or G6. In a still further embodiment, G is a group G4 or G6. In another embodiment, G is a group G3.
  • n is 1 , 2 or 3. In another embodiment, n is 2.
  • R is -X-[CH 2 ] n CR 4 R 5 -Y or a group G;
  • R 1 is H or C1-C4 alkyl (for example methyl);
  • R 2 is a phenyl ring which may be substituted with one or more: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy;
  • X is -CR 7 R 8 - or -O-;
  • R 6 is C1-C6 alkyl, C3-C6 cycloalkyl; C3-C6 cycloalkyl-(C1-C2 alkyl); which may be substituted by one or more halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy;
  • Rg is H or C1-C4 alkyl
  • example compounds of the invention include:
  • example compounds of the present invention include:
  • example compounds of the present invention include:
  • the compounds of formula (I) may be made according to the organic synthesis techniques known to those skilled in this field, as well as by the representative methods set forth in the Examples.
  • n' n-1 and Lg is a suitable leaving group such as mesylate (OMs) or halogen (Cl, Br, I), by methods well known in the art, such as alkylation reactions of secondary amines, e.g. piperidine, using an inorganic base, e.g. K 2 CO 3 , and carrying out the reaction in aprotic solvents, such as MeCN, at temperature comprised between RT and 8O 0 C.
  • OMs mesylate
  • Cl, Br, I halogen
  • TEA in aprotic solvents e.g. DCM
  • aprotic solvents e.g. DCM
  • Lg halides, e.g. Br
  • compounds of formula (IV) may be reacted with carbon tetrabromide in the presence of triphenylphosphine and carrying out the reaction in aprotic solvents, such as DCM, at temperature comprised between 0 0 C and RT.
  • Compounds of formula (Vila), i.e. compounds of formula (VII) wherein R 1 is hydrogen, may be obtained from compounds of formula (VIII), wherein Lg 1 is an halogen (e.g. I), according to Scheme 7, by alkylation reaction with a suitable 2-halo-1-arylketone (IX) using an inorganic base, e.g. Na 2 CO 3 , and carrying out the reaction in aprotic solvents, e.g. DMF, at temperature comprises between RT and 8O 0 C.
  • aprotic solvents e.g. DMF
  • protic solvents such as ethanol
  • n' n-1 and Lg is a suitable leaving group such as mesilate (OMs) or halogen (Cl, Br, I), according to Scheme 12, through standard alkylation reactions of secondary amines, such as piperidine, in the presence of an inorganic base, such as K 2 CO 3 , and carrying out the reaction in aprotic solvents, e.g. MeCN, at temperature comprised between RT and 8O 0 C.
  • OMs mesilate
  • Cl, Br, I halogen
  • R is -O-[CH 2 ] n CH 2 -Y, may be obtained, according to Scheme 18, starting from compounds of formula (XIX), wherein Lg is a suitable leaving group such as mesylate or halogen (e.g. Cl), by alkylation reaction of a secondary alkylamines, such as piperidine, in the presence of an inorganic base, e.g. K 2 CO 3 , and carrying out the reaction in aprotic solvents, e.g. MeCN, at temperature comprised between RT and 80 0 C.
  • Lg is a suitable leaving group such as mesylate or halogen (e.g. Cl)
  • a secondary alkylamines such as piperidine
  • an inorganic base e.g. K 2 CO 3
  • aprotic solvents e.g. MeCN
  • Compounds of formula (XX) may be prepared, according to Scheme 20, by hydrolysis reaction of compounds of formula (XXI).
  • suitable reaction conditions comprise using an inorganic base, such as LiOH, and carrying out the reaction in a mixture of aprotic and protic solvent, e.g. THF and water, at temperature comprises between RT and 60 0 C.
  • aprotic and protic solvent e.g. THF and water
  • Pg is tert-butyldimethylsilyl (TBDMS)
  • TDMMS tert-butyldimethylsilyl
  • a suitable halo-alkylsilyl derivative such as [(3-bromopropyl)oxy](1 ,1-dimethylethyl)dimethylsilane
  • an inorganic base e.g. Na 2 CC>3
  • aprotic solvents e.g. DMF
  • Compound (XXV) may be obtained starting from the commercially available ethyl 4,4,4- trichloroacetoacetate (XXVI), according to Scheme 25, following procedures reported in literature, e.g. Synthesis (2003), (15), 2353-2357.
  • Compounds of formula (XXVII) may be obtained, according to Scheme 27, by hydrolysis reaction of compounds (XXII), for example using an inorganic base, such as LiOH, and carrying out the reaction in a mixture of aprotic and protic solvent, e.g. THF and water, at temperature comprises between RT and 60 0 C.
  • aprotic and protic solvent e.g. THF and water
  • Compounds of formula (XXIX) may be obtained from compounds of formula (XXX), according to Scheme 30, by alkylation reaction with a suitable 2-halo-1-arylketone (IX) using an inorganic base, e.g. Na 2 CO 3 , and carrying out the reaction in aprotic solvents, e.g. DMF, at temperature comprises between O 0 C and RT.
  • a suitable 2-halo-1-arylketone IX
  • aprotic solvents e.g. DMF
  • Compounds of formula (XXX) may be obtained from compounds of formula (XXV), according to Scheme 31 , by reaction with a suitable halo-alkylamine compound of formula HaI[CH 2 ] H CH 2 NR 10 Rn (XXXVIII) wherein Hal is halide, such as 1-(3- chloropropyl)piperidine, in presence of an inorganic base, e.g. K 2 CO 3 , and carrying out the reaction in aprotic solvents, such as MeCN, at temperature comprises between RT and 80 0 C.
  • a suitable halo-alkylamine compound of formula HaI[CH 2 ] H CH 2 NR 10 Rn XXXVIII
  • Hal is halide
  • an inorganic base e.g. K 2 CO 3
  • aprotic solvents such as MeCN
  • R is -O-[CH 2 ] n CH 2 -Y
  • R 1 is C1-C4 alkyl, may be obtained from compounds of formula (XXXI), according to Scheme 32, by reaction with a suitable halo-alkylamine compound of formula Hal[CH 2 ] n CH 2 NR 10 Rn (XXXVIII), such as 1-(3-chloropropyl)piperidine, in presence of an inorganic base, e.g. K 2 CO 3 , and carrying out the reaction in aprotic solvents, such as MeCN, at temperature comprises between RT and 80 0 C.
  • a suitable halo-alkylamine compound of formula Hal[CH 2 ] n CH 2 NR 10 Rn (XXXVIII), such as 1-(3-chloropropyl)piperidine in presence of an inorganic base, e.g. K 2 CO 3 , and carrying out the reaction in aprotic solvents, such as MeCN, at temperature comprises between RT and 80 0 C.
  • Compounds of formula (XXXI) may be obtained from compounds of formula (Va), as define above, according to Scheme 33, by in situ formation of the boronate derivatives using a boronate agent, e.g. 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane, an inorganic base, e.g. potassium acetate, and a catalyst, e.g. palladium (II) acetate, in an aprotic solvent , e.g. DMF, at temperature comprises between 50 and 100 0 C, followed by formation of the hydroxy derivatives using an oxidant agent, e.g. hydroperoxy(oxo)borane in a mixture of protic and aprotic solvents, e.g. water/THF, at RT.
  • a boronate agent e.g. 4,4,4',4',5,5,5',5'-
  • R is -O-[CH 2 ] n CH(CH 3 )-Y, may be obtained from compounds of formula (XXXII), according to Scheme 34, by reductive amination procedure well described in the art, for example using a secondary alkylamine, e.g. piperidine, using a reductive agent, e.g. NaBH 3 CN, and carrying out the reaction in aprotic solvents, e.g. acetonitrile, at atmospheric pressure and at RT.
  • a secondary alkylamine e.g. piperidine
  • a reductive agent e.g. NaBH 3 CN
  • Compounds of formula (XXXII) may be obtained by usual alkylation methods well described in the art from compounds of formula (XXXI), according to Scheme 35, using halo-alkylketone of formula Hal[CH 2 ] n COCH 3 (XXXIX), such as 4-chloro-2-butanone, and carrying out the reaction in presence of an inorganic base, such as K 2 CO 3 , in aprotic solvents, e.g. DMF, at temperature comprises between RT and 8O 0 C.
  • aprotic solvents e.g. DMF
  • R is -NR 9 -[CH 2 ] n CH 2 -Y, may be obtained, according to Scheme 36, starting from compounds of formula (V), wherein Lg 1 is as above define, by Cu-catalyzed cross coupling methodology well known in the art, for example using CuI as catalyst, a secondary alkylamine,e.g. N-methyl piperidine, and carrying out the reaction in presence of a ligand, e.g. LD-proline, and of an inorganic base, e.g. K 2 CO 3 , in aprotic solvents, e.g. DMSO, at temperature comprises between 80-100 0 C (18-48 h).
  • a ligand e.g. LD-proline
  • an inorganic base e.g. K 2 CO 3
  • aprotic solvents e.g. DMSO
  • G6 G7 G8 may be obtained from compounds of formula (XXXI), according to Scheme 37, through alkylation reaction with an appropriate halo-alkylcycloamine derivative, such as 3- (chloromethyl)-i -methylpiperidine hydrochloride,
  • an inorganic base i.e. K 2 CO 3 or Cs 2 CO 3
  • aprotic solvents e.g. DMF or DMSO
  • triphenylphosphine and diethyl azodicarboxylate and carrying out the reaction in aprotic solvents, e.g. THF, at temperature comprises between O 0 C and RT.
  • G6 G7 G8 and Ri is H may be obtained, according to Scheme 38, by compounds of formula (L), wherein G' corresponds to G6, G7, G8, G9, G10, G11 or G12 in which R 21, R 221 R 23, R 26 , R 2 7, R 2 8 or R 29 are H, by reductive alkylation procedure well described in the art, for example using and aldehyde, e.g. formaldehyde, and a reductive agent, e.g. NaBH 3 CN, carrying out the reaction in aprotic solvents, e.g. acetonitrile, at atmospheric pressure and at RT.
  • aprotic solvents e.g. acetonitrile
  • Compounds of formula (LIV) may be obtained from compounds of formula (LV), according to Scheme 43, by by alkylation reaction with a suitable 2-halo-1-arylketone (IX) using an inorganic base, e.g. Na 2 COs, snd carrying out the reaction in aprotic solvents, e.g. DMF, at temperature comprises between RT and 8O 0 C.
  • a suitable 2-halo-1-arylketone (IX) using an inorganic base, e.g. Na 2 COs, snd carrying out the reaction in aprotic solvents, e.g. DMF, at temperature comprises between RT and 8O 0 C.
  • Compounds of formula (LV), may be obtained from compounds of formula (XXV), according to Scheme 44, by Mitsunobu reaction with a suitable N-protecting group- hydroxy-alkylamine derivative of formula (LVI) (HO-C-Pg 1 ), such as N-Boc-4- hydroxypiperidine, using triphenylphosphine and di-tert-butyl azodicarboxylate and carrying out the reaction in aprotic solvents, e.g. THF, at temperature comprises between
  • compounds of formula (Id), as above defined may be obtained according to Scheme 58, starting from compounds of formula (XCIV), by intramolecular condensation in an appropriate acidic media, e.g. polyphosphoric acid, in mixture of solvents, e.g. ethanol and toluene, at high temperature such as 90 0 C.
  • an appropriate acidic media e.g. polyphosphoric acid
  • solvents e.g. ethanol and toluene
  • Compounds of formula (XCIV) may be prepared, according to Scheme 59, starting from compounds of formula (XCV) by reaction with compounds of formula (XCVI), wherein R3 is as defined for compounds of formula (I), using a condensing reagent, e.g. o- (benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), and a base, e.g. diisopropil ethyl amine, in an aprotic solvent, e.g. DMF, at RT
  • a condensing reagent e.g. o- (benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU)
  • TBTU o- (benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
  • Compounds of formula (XCVII) may be prepared, according to Scheme 61 , starting from compounds of formula (XCVIII), by reaction with a compound of formula (XCIX) or its HCI salt, wherein Lg is a suitable leaving group such as chloride, in the presence of a base, eg potassium carbonate, potassium iodide in an aprotic solvent such as acetone at reflux temperature.
  • a base eg potassium carbonate, potassium iodide in an aprotic solvent such as acetone at reflux temperature.
  • Compounds of formula (XCX) may be prepared, according to Scheme 63, starting from compounds of formula (XCXI), wherein Lg is a suitable leaving group such as bromine, by reaction with 1 ,1-dimethylethyl hydrazinecarboxylate, a base, e.g. diisopropil ethyl amine, in an aprotic solvent, e.g. DMF, at 5°C, followed by reaction of the obtained intermeditate with dialkyl 2-butynedioate of formula (XCXII), wherein alkyl group (AIk) is as above defined, in a protic solvent, e.g. ethanol at rt.
  • a protic solvent e.g. ethanol at rt.
  • R is X-[CH 2 JnCR 4 R 5 -Y; X is oxygen; n is 2; R 4 and R 5 are hydrogen; R 10 and R 11 form a piperidine ring; R 1 is hydrogen; R 2 is 3-CF 3 , 4-F phenyl and R 6 is /-propyl.
  • compound of formula (XCVIII), where AIk is as above defined may be prepared, according to Scheme 64, starting from compounds of formula (XCXI), by oxidation under appropriate conditions.
  • Possible oxidation conditions involved the use of pure oxygen gas or air in basic conditions, in the presence of a catalytic amount of a metal salt such as iron (Il or III) chloride , potassium hexacyanoferrate , cobalt (Il or III ) chloride or Copper (I or II) chloride.
  • a metal salt such as iron (Il or III) chloride , potassium hexacyanoferrate , cobalt (Il or III ) chloride or Copper (I or II) chloride.
  • conditions involve the use of an acid medium (for example H 2 SO 4 ) and K 2 S 2 Os in acetonitrile at reflux temperature.
  • Suitable protecting groups for use according to the present invention are well known to those skilled in the art and may be used in a conventional manner. See, for example, "Protective groups in organic synthesis” by T. W. Greene and P. G. M. Wuts (John Wiley & sons 1991 ) or "Protecting Groups” by PJ. Kocienski (Georg Thieme Verlag 1994).
  • suitable amino protecting groups include acyl type protecting groups (e.g.
  • aromatic urethane type protecting groups e.g. benzyloxycarbonyl (Cbz) and substituted Cbz
  • aliphatic urethane protecting groups e.g. 9-fluorenylmethoxycarbonyl (Fmoc), t- butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl
  • alkyl type protecting groups e.g. benzyl, trityl, chlorotrityl.
  • the subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 0, 31 P, 32 P, 35 S, 18 F, 36 CI, 123 I and 125 I.
  • Isotopically- labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H, 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography), and 125 I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging, lsotopically labelled compounds of formula I and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • the compounds of the present invention and their pharmaceutically acceptable salts and solvates may be useful in therapy.
  • the compounds of the present invention may be useful for the manufacture of a medicament for the treatment or prevention of diseases influenced by modulation of the activity of the HPA axis.
  • the compounds may be useful for the manufacture of a medicament for the treatment of schizophrenia, anxiety, hot flushes, addiction, anorexia nervosa, stress- related disorders, sleep disorders, autistic spectrum disorders and Alzheimer's dementia.
  • the compounds may be useful for the manufacture of a medicament for the treatment of a metabolic syndrome characterised by insulin resistance, hyperinsulinemia, impaired glucose tolerance, dyslipideamia, obesity (in particular abdominal obesity) and non-insulin-dependent diabetes mellitus (NIDDM).
  • the compounds of the present invention may be useful for the manufacture of a medicament for the treatment or prevention of depression.
  • the present invention further includes a method for the treatment of a mammal, including a human, suffering from or liable to suffer from depression or any of the aforementioned disorders, which comprises administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof.
  • Depression states in the treatment of which the compounds of the present invention and their pharmaceutically acceptable salts and solvates may be particularly useful are those classified as mood disorders in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition- Text Revised, American Psychiatric Association, Washington D. C. (2000), including mood episodes, depressive disorders, bipolar disorders and other mood disorders.
  • compression includes:
  • Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major
  • Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance- Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90): Bipolar Disorders including Bipolar I Disorder, Bipolar Il Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80);
  • anxiety disorders includes:
  • the present invention provides a method of treating a condition for which inhibition of V1 b receptors is beneficial, which comprises administering to a mammal (e.g. human) in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof.
  • a mammal e.g. human
  • the invention also provides a a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof for use in therapy.
  • the invention also provides a a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a condition in a mammal (e.g. Human) for which inhibition of V1 b receptors is beneficial.
  • a mammal e.g. Human
  • the invention also provides the use of a a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a condition in a mammal (e.g. human) for which inhibition of V1 b receptors is beneficial
  • the above mentoned condition is depression.
  • Treatment includes prophylaxis, where this is appropriate for the relevant condition(s).
  • the compounds of the present invention, or a pharmaceutically acceptable salt or solvate thereof are usually administered as a standard pharmaceutical composition.
  • the present invention therefore provides in a further aspect a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be for use in the treatment of any of the conditions described herein.
  • Compound of the invention may be administered by any convenient method, for example by oral, parenteral (e.g. intravenous), buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
  • Compound of the invention or a pharmaceutically acceptable salt or solvate thereof, which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • the formulation may also contain a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device.
  • the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted.
  • the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochloro- hydrocarbon.
  • the aerosol dosage forms can also take the form of a pump-atomiser.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
  • compositions suitable for transdermal administration include ointments, gels and patches.
  • the composition is in unit dose form such as a tablet, capsule or ampoule.
  • a suitable daily dose for any of the above mentioned disorders will be in the range of 0.001 to 50 mg per kilogram body weight of the recipient (e.g. a human) per day, preferably in the range of 0.01 to 20 mg per kilogram body weight per day.
  • the desired dose may be presented as multiple sub-doses administered at appropriate intervals throughout the day.
  • Each dosage unit for oral administration contains for example from 1 to 250 mg (and for parenteral administration contains for example from 0.1 to 25 mg) of a compound of the invention calculated as the free base.
  • the compounds of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 500 mg, for example between 10 mg and 400 mg, e.g. between 10 and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, for example between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more.
  • NMR Nuclear Magnetic Resonance
  • Mass spectra are typically taken on a Agilent MSD 1 100 Mass Spectrometer, operating in ES (+) and ES (-) ionization mode, or on an ion-trap Finnigan MS LCQ, operating in ES (+) and ES (-) ionization mode, or on an Agilent LC/MSD 1100 Mass
  • Flash silica gel chromatography was carried out on silica gel 230-400 mesh (supplied by Merck AG Darmstadt, Germany) or on silica gel 300-400 mesh supplied by SCRC (Sinopharm Chemical Reagent Co., Ltd.). or over Varian Mega Be-Si pre-packed cartridges or over pre-packed Biotage silica cartridges.
  • SPE-SCX cartridges are ion exchange solid phase extraction columns supplied by Varian.
  • the eluent used with SPE-SCX cartridges is methanol followed by 2N ammonia solution in methanol.
  • SPE-Si cartridges are silica solid phase extraction columns supplied by Varian. The following abbreviations are used in the text: dried refers to a solution dried over anhydrous sodium sulphate or by phase separator cartridge; BOC : te/f-butyloxycarbonyl; r.t.
  • the filtrate was diluted with DMF and Na 2 CO 3 (1.22g) and [(3-bromoethyl)oxy](1 ,1-dimethylethyl)dimethylsilane (2.1 ml.) were added and the mixture was stirred at 60 0 C for additional 36h. After cooling, the mixture was diluted with Et 2 O, washed with chilly water, dried, filtered and evaporated under reduced pressure.
  • the crude was dissolved in DCM (15 ml.) and 2,6-lutidine (1.08 ml.) and [(3-bromoethyl)oxy](1 ,1-dimethylethyl)dimethylsilane (0.86 ml.) were added at 0 0 C and the mixture was stirred at rt for 1 h.
  • the mixture was diluted in DCM, washed with NaHCO 3 sat and then with HCI 0.25N.
  • the organic layer was dried and the solvent evaporated under reduced pressure.
  • the crude was purified by flash chromatography on silica column eluting with Cy/AcOEt with a gradient of Cy from 100% to 80% to give the title compound as colourless oil (0.63 g).
  • Preparation 27 2-[6-(3-chloro-4-fluorophenyl)-2-[(3-hydroxypropyl)oxy]-4- oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1 -methylethyl)acetamide and 2-( ⁇ 6-(3-chloro- 4-fluorophenyl)-2-[(3-hydroxypropyl)oxy]pyrazolo[1,5-a]pyrazin-4-yl ⁇ oxy)- ⁇ /-(1 - methylethyl)acetamide (P27 mixture)
  • Preparation 36 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-2-[(3-hydroxypropyl)oxy]-4- oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1 -methylethyl)acetamide and 2-( ⁇ 6-[4-fluoro- 3-(trifluoromethyl)phenyl]-2-[(3-hydroxypropyl)oxy]pyrazolo[1,5-a]pyrazin-4-yl ⁇ oxy)- ⁇ /-(1-methylethyl)acetamide (P36 mixture)
  • Preparation 48 2-[2-[(3-hydroxypropyl)oxy]-6-(6-methyl-2-pyridinyl)-4- oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]- ⁇ /-(1 -methylethyl)acetamide and 2- ⁇ [2-[(3- hydroxypropyl)oxy]-6-(6-methyl-2-pyridinyl)pyrazolo[1 ,5-a]pyrazin-4-yl]oxy ⁇ - ⁇ /-(1- methylethyl)acetamide (P48, mixture)
  • aqueous phase was extracted with ethyl acetate (2 x 700 mL) and the combined organics were washed with brine (800 mL), dried on sodium sulphate, filtered and evaporated to dryness.
  • 60 g of crude material were purified using a Biotage Amino Silica KP-NH column eluted with cycloexane/ethyl acetate from 9:1 to 1 :1 to obtain title compound (41.3 g, 85 mmol, 56.5 % yield) as yellow oil.
  • N- ⁇ [(1 ,1-dimethylethyl)oxy]carbonyl ⁇ glycine 159 g, 908 mmol
  • Dichloromethane 1.6 L
  • 1 -Ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride 226 g, 1 180 mmol
  • the resulting solution was cooled down in an ice bath and, at 2 0 C (internal temperature), isopropylamine (100 ml, 1 162 mmol) was added dropwise (the addition was slowly exothermic at the beginning) and the resulting mixture was stirred overnight at room temperature.
  • the organic phase was washed with water, brine, dried over Na2SO4 and the solvent removed under reduced pressure to give 154 mg of a crude material mostly containing the title product.
  • the aqueous phase was passed through a MCX cartridge (1g), eluting subsequently with water, methanol and 2N NH3/MeOH to give 230 mg of a crude material mostly containing the free base of the title product.
  • This material was dissolved in DCM (10 ml), BOC-anhydride (0.160 ml, 0.687 mmol) was added and the reaction mixture was stirred for 2h. The reaction mixture was concentrated under reduced pressure, the residue was jointed with the previous crude material (154 mg) and was purified by FC on silica
  • N-(1 ,1-dimethylethyl)-2-[6-(3-methylphenyl)-4-oxo-2- ⁇ [3-(1- piperidinyl)propyl]oxy ⁇ pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]acetamide (55 mg, E3) was dissolved in dry DCM (2 ml.) and hydrogen chloride (1.25 M solution in MeOH) (92 ⁇ l_) was added. The solvent was evaporated and the residue thus obtained triturated with dry diethyl ether. Then diethyl ether was removed and the resultant solid dried under vacuum to provide the title compound (53 mg) as a white solid.
  • Example 6 2-[6-(3-chlorophenyl)-4-oxo-2- ⁇ [3-(1 -piperidinyl)propyl]oxy ⁇ pyrazolo[1 ,5- a]pyrazin-5(4H)-yl]- ⁇ /-(1,1-dimethylethyl)acetamide hydrochloride (E6)
  • Example 8 N-(1 -methylethyl)-2-[4-oxo-2- ⁇ [3-(1-piperidinyl)propyl]oxy ⁇ -6-[3- (trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrazin-5(4H)-yl]acetamide hydrochloride (E8)
  • Example 10 N-(1 -methylethyl)-2-[4-oxo-2- ⁇ [3-(1 -piperidinyl)propyl]oxy ⁇ -6- ⁇ 3- [(trifluoromethyl)oxy]phenyl ⁇ pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]acetamide hydrochloride (E10)
  • the title compound was prepared with an analogous procedure to that described in Example 1 in 18 mg yield as a white solid from a mixture of 2-[6-(3-chlorophenyl)-2-[(2- hydroxyethyl)oxy]-4-oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide and 2-( ⁇ 6-(3-chlorophenyl)-2-[(2-hydroxyethyl)oxy]pyrazolo[1 ,5-a]pyrazin-4-yl ⁇ oxy)-N-(1- methylethyl)acetamide (250 mg, P20 mixture).
  • Example 16 2-[6-(3-chlorophenyl)-2- ⁇ [3-(4-morpholinyl)propyl]oxy ⁇ -4- oxopyrazolo[1,5-a]pyrazin-5(4H)-yl]- ⁇ /-(1,1-dimethylethyl)acetamide hydrochloride (E16)
  • Example 18 2-[6-(3-chlorophenyl)-2- ⁇ [3-(4-morpholinyl)propyl]oxy ⁇ -4- oxopyrazolo[1 ,5-a]pyrazin-5(4H)-yl]- ⁇ /-(1 -methylethyl)acetamide hydrochloride (E18)
  • Example 20 2-[6-(3-chlorophenyl)-4-oxo-2- ⁇ [4-(1 -piperidinyl)butyl]oxy ⁇ pyrazolo[1 ,5- a]pyrazin-5(4H)-yl]- ⁇ /-(1-methylethyl)acetamide hydrochloride (E20)
  • Example 21 2-[6-(3-chloro-4-fluorophenyl)-4-oxo-2- ⁇ [3-(1 - piperidinyl)propyl]oxy ⁇ pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]- ⁇ /-(1-methylethyl)acetamide
  • Example 22 2-[6-(3-chloro-4-fluorophenyl)-4-oxo-2- ⁇ [3-(1 - piperidinyl)propyl]oxy ⁇ pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]- ⁇ /-(1-methylethyl)acetamide hydrochloride (E22)
  • Example 25 ⁇ /-(1,1-dimethylethyl)-2-[4-oxo-2- ⁇ [3-(1 -piperidinyl)propyl]oxy ⁇ -6-[3- (trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrazin-5(4H)-yl]acetamide (E25)
  • Example 27 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2- ⁇ [3-(1 - piperidinyl)propyl]oxy ⁇ pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide
  • X Ray Powder Diffraction (XRPD) analysis was performed on the batch obtained with the methodology described in method c), on Panalytical X'Pert Pro, using x'celerator / type RTMS detector.
  • the acquisition conditions were: radiation: Cu K(, generator tension: 40 kV, generator current: 4OmA, start angle: 2.0 °2(, end angle: 45.0 °2( step size: 0.0170 °2(depends on actual X'celerator used) time per step: 32.3024 sec (about 10 min) slow scan or 9.5 sec for fast scan.
  • the sample was prepared on a low background sample holder.
  • X-Ray Powder Diffraction (XRPD) analysis was performed on the batch obtained with the methodology described in method d), on a Panalytical Cubix Pro, using an X'celerator RTMS (real time multi-strip) detector.
  • the acquisition conditions were: radiation: Cu Ka, generator tension: 40 kV, generator current: 4OmA, start angle: 2.0 °2 ⁇ , end angle: 40.0 °2 ⁇ step size: 0.0201 °2 ⁇ depends on actual X'celerator used) time per step: 19.050 sec.
  • the sample was prepared on a low background sample holder.
  • X-Ray Powder Diffraction (XRPD) analysis was performed on the batch obtained with the methodology described in method g), on a Panalytical Cubix Pro, using an X'celerator RTMS (real time multi-strip) detector.
  • the acquisition conditions were: radiation: Cu Ka, generator tension: 40 kV, generator current: 4OmA, start angle: 2.0 °2 ⁇ , end angle: 40.0 °2 ⁇ step size: 0.0201 °2 ⁇ depends on actual X'celerator used) time per step: 19.050 sec.
  • the sample was prepared on a low background sample holder. It will be recognised that spectra and diffraction data will vary slightly according to various factors such as the temperature, concentration and instrumentation used.
  • X-Ray Powder Diffraction (XRPD) analysis was performed on the batch obtained with the methodology described in method h), on a Panalytical Cubix Pro, using an X'celerator RTMS (real time multi-strip) detector.
  • the acquisition conditions were: radiation: Cu Ka, generator tension: 40 kV, generator current: 4OmA, start angle: 2.0 °2 ⁇ , end angle: 40.0 °2 ⁇ step size: 0.0201 °2 ⁇ depends on actual X'celerator used) time per step: 19.050 sec.
  • the sample was prepared on a low background sample holder. It will be recognised that spectra and diffraction data will vary slightly according to various factors such as the temperature, concentration and instrumentation used.
  • the skilled person will recognise that XRPD peak positions are affected by differences in sample height. The peak positions quoted herein are thus subject to a variation of +/- 0.15 degrees 2-theta.
  • X-Ray Powder Diffraction (XRPD) analysis was performed on the batch obtained with the methodology described in method i), on a Panalytical Cubix Pro, using an X'celerator RTMS (real time multi-strip) detector.
  • the acquisition conditions were: radiation: Cu Ka, generator tension: 40 kV, generator current: 4OmA, start angle: 2.0 °2 ⁇ , end angle: 40.0 °2 ⁇ step size: 0.0201 °2 ⁇ depends on actual X'celerator used) time per step: 19.050 sec.
  • the sample was prepared on a low background sample holder.
  • Example 28 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2- ⁇ [3-(1- piperidinyl)propyl]oxy ⁇ pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]- ⁇ /-(1-methylethyl)acetamide hydrochloride (E28)
  • Example 29 ⁇ /-(1,1-dimethylethyl)-2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2- ⁇ [3-(1-piperidinyl)propyl]oxy ⁇ pyrazolo[1,5-a]pyrazin-5(4H)-yl]acetamide hydrochloride (E29)
  • Example 30 2-[6-(3-chloro-2-fluorophenyl)-4-oxo-2- ⁇ [3-(1 - piperidinyl)propyl]oxy ⁇ pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]-N-(1-methylethyl)acetamide hydrochloride (E30)
  • Example 31 2-[6-[3,5-bis(trifluoromethyl)phenyl]-4-oxo-2- ⁇ [3-(1 - piperidinyl)propyl]oxy ⁇ pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]- ⁇ /-(1-methylethyl)acetamide hydrochloride (E31)
  • Example 33 2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]-4-oxo-2-[4-(1 -pyrrolidinyl)-1 - piperidinyl]pyrazolo[1 ,5-a]pyrazin-5(4H)-yl]- ⁇ /-(1 -methylethyl)acetamide dihydrochloride (E33)
  • Example 35 2-[2-[(1 -cyclopentyl ⁇ -piperidinylJoxyl- ⁇ - ⁇ -fluoro-S-
  • Example 36 2-[2-[(1 -cyclopentyl ⁇ -piperidinylJoxyl- ⁇ - ⁇ -fluoro-S-
  • the in vitro assessment of the V1 b antagonist compounds used a functional assay system to determine the potency against the V1 b receptor.
  • the functional activity of the compounds of the invention for the V1 b receptor may be determined by the FLIPR/Ca 2+ assay as described below. Such potency is typically calculated as an IC 50 value obtained in FLIPR experiments as the concentration of a compound necessary to decrease 50% of the calcium release following cells exposure to a concentration of AVP eliciting 80% response (i.e. EC80).
  • plC 50 values (corresponding to the antilogarithm of IC 50 ) are used instead of IC 50 ; plC 50 results are only estimated to be accurate to about 0.3- 0.5.
  • AVP is an endogenous agonist and can activate the receptor, thereupon causing an increase in the level of calcium in the cells sensed by Fluo4-AM and measured by FLIPR. Antagonist effects are monitored by the blockade or decrease in calcium release once cells co-expressing h-V1 b receptor are exposed to a concentration of AVP eliciting 80% response (i.e. EC80). A non-linear, 4 parameter logistic curve-fit of the data generated plC 50 value.
  • Cells are cultured in DMEM/F12 supplemented with 10% FBS, 2mM Glutamine and
  • Cells are then put in the FLIPR for the stimulus addition corresponding to a concentration of AVP eliciting 80% of the response.
  • the response of cells to the agonist is fast and measured for 2min after AVP addition.
  • Preferred examples show plC 50 comprised between 6 and 10 towards V1 b receptor.

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Abstract

L'invention porte sur de nouveaux composés de formule (I) ou leurs sels. Dans cette formule (I): R représente -X-[CH2]nCR4R5-Y; ou un groupe G sélectionné parmi G1, G2, G3, G4, G5, G6, G7, G8, G9, G10, G11 et G12, le reste des variables étant spécifiées dans les revendications. L'invention porte également: sur leurs procédés de préparation, sur des intermédiaires utilisés dans ces procédés; sur des préparations pharmaceutiques les contenant, et sur leur utilisation thérapeutique en tant qu'antagonistes des récepteurs V1b, par exemple pour traiter la dépression et l'anxiété.
PCT/EP2009/054780 2008-04-24 2009-04-22 Dérivés de pirazolo [1, 5 -a] pyrazine, antagonistes des récepteurs v1b WO2009130232A1 (fr)

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WO2012043791A1 (fr) 2010-10-01 2012-04-05 大正製薬株式会社 Dérivé de 1,2,4-triazolone
WO2013062027A1 (fr) 2011-10-27 2013-05-02 大正製薬株式会社 Dérivé azole
JP2013518823A (ja) * 2010-02-08 2013-05-23 バイオウタ サイエンティフィック マネジメント プロプライエタリー リミテッド 呼吸器合胞体ウイルス感染症を治療するための化合物
WO2013135769A1 (fr) * 2012-03-13 2013-09-19 Abbvie Inc. Procédé de sélection ou d'identification d'un sujet pour une thérapie par antagoniste du v1b
WO2013147117A1 (fr) 2012-03-30 2013-10-03 大正製薬株式会社 Dérivé d'azole fondu
WO2013143663A1 (fr) 2012-03-28 2013-10-03 Merck Patent Gmbh Dérivés bicycliques de pyrazinone
JP2014224108A (ja) * 2013-04-26 2014-12-04 大正製薬株式会社 アゾール誘導体を含有する医薬
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US10190168B2 (en) 2013-06-17 2019-01-29 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Method for predicting a treatment response to a CRHR1 antagonist and/or a V1B antagonist in a patient with depressive and/or anxiety symptoms
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US10857129B2 (en) 2012-06-15 2020-12-08 B.R.A.H.M.S Gmbh V1B receptor antagonist for use in the treatment of patients having an elevated AVP level and/or an elevated copeptin level
US10967078B2 (en) 2014-12-03 2021-04-06 Janssen Pharmaceutica Nv Radiolabelled mGluR2 PET ligands
US11033641B2 (en) 2015-12-18 2021-06-15 Janssen Pharmaceutica Nv Radiolabelled mGluR2/3 pet ligands
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JP2013518823A (ja) * 2010-02-08 2013-05-23 バイオウタ サイエンティフィック マネジメント プロプライエタリー リミテッド 呼吸器合胞体ウイルス感染症を治療するための化合物
US9163029B2 (en) 2010-02-08 2015-10-20 Biota Scientific Management Pty Ltd. Substituted imidazo[1,2-a]pyrrolo[1,2-d]pyrazines for treating respiratory syncytial virus infections
WO2012043791A1 (fr) 2010-10-01 2012-04-05 大正製薬株式会社 Dérivé de 1,2,4-triazolone
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US9193695B2 (en) 2010-10-01 2015-11-24 Taisho Pharmaceutical Co., Ltd. 1, 2, 4-triazolone derivative and use thereof as an antagonist on the arginine-vasopressin 1B receptor
JP5787237B2 (ja) * 2010-10-01 2015-09-30 大正製薬株式会社 １，２，４−トリアゾロン誘導体
CN103889951A (zh) * 2011-10-27 2014-06-25 大正制药株式会社 唑类衍生物
WO2013062027A1 (fr) 2011-10-27 2013-05-02 大正製薬株式会社 Dérivé azole
RU2622639C2 (ru) * 2011-10-27 2017-06-19 Тайсо Фармасьютикал Ко., Лтд. Производные азолов
JPWO2013062027A1 (ja) * 2011-10-27 2015-04-02 大正製薬株式会社 アゾール誘導体
KR20140081824A (ko) 2011-10-27 2014-07-01 다이쇼 세이야꾸 가부시끼가이샤 아졸 유도체
US9522914B2 (en) 2011-10-27 2016-12-20 Taisho Pharmaceutical Co., Ltd Azole derivative
CN103889951B (zh) * 2011-10-27 2016-12-14 大正制药株式会社 唑类衍生物
WO2013135769A1 (fr) * 2012-03-13 2013-09-19 Abbvie Inc. Procédé de sélection ou d'identification d'un sujet pour une thérapie par antagoniste du v1b
CN104303060A (zh) * 2012-03-13 2015-01-21 艾伯维公司 选择或鉴别用于v1B拮抗剂治疗的受试者的方法
JP2015511609A (ja) * 2012-03-28 2015-04-20 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ 二環式ピラジノン誘導体
WO2013143663A1 (fr) 2012-03-28 2013-10-03 Merck Patent Gmbh Dérivés bicycliques de pyrazinone
CN104185625A (zh) * 2012-03-30 2014-12-03 大正制药株式会社 稠环唑类衍生物
WO2013147117A1 (fr) 2012-03-30 2013-10-03 大正製薬株式会社 Dérivé d'azole fondu
US10857129B2 (en) 2012-06-15 2020-12-08 B.R.A.H.M.S Gmbh V1B receptor antagonist for use in the treatment of patients having an elevated AVP level and/or an elevated copeptin level
JP2014224108A (ja) * 2013-04-26 2014-12-04 大正製薬株式会社 アゾール誘導体を含有する医薬
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US10190168B2 (en) 2013-06-17 2019-01-29 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Method for predicting a treatment response to a CRHR1 antagonist and/or a V1B antagonist in a patient with depressive and/or anxiety symptoms
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US10072014B2 (en) 2014-12-03 2018-09-11 Janssen Pharmaceutica Nv 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one compounds and their use as negative allosteric modulators of MGLUR2 receptors
US10967078B2 (en) 2014-12-03 2021-04-06 Janssen Pharmaceutica Nv Radiolabelled mGluR2 PET ligands
US11033641B2 (en) 2015-12-18 2021-06-15 Janssen Pharmaceutica Nv Radiolabelled mGluR2/3 pet ligands
US11045562B2 (en) 2015-12-18 2021-06-29 Janssen Pharmaceutica Nv Radiolabelled mGluR2/3 PET ligands

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