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WO2019116325A1 - Composés tricycliques utilisés en tant qu'antagonistes du récepteur de la vasopressine v1a - Google Patents

Composés tricycliques utilisés en tant qu'antagonistes du récepteur de la vasopressine v1a Download PDF

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Publication number
WO2019116325A1
WO2019116325A1 PCT/IB2018/060078 IB2018060078W WO2019116325A1 WO 2019116325 A1 WO2019116325 A1 WO 2019116325A1 IB 2018060078 W IB2018060078 W IB 2018060078W WO 2019116325 A1 WO2019116325 A1 WO 2019116325A1
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Prior art keywords
dihydro
group
benzazepine
triazolo
chloro
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Inventor
Imre Bata
Zsolt SZELECZKY
Krisztina SZONDINÉ KORDÁS
Gábor SZÁNTÓ
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Richter Gedeon Nyrt
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Richter Gedeon Nyrt
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Priority claimed from HU1700522A external-priority patent/HUP1700522A1/hu
Priority claimed from HU1800332A external-priority patent/HUP1800332A1/hu
Application filed by Richter Gedeon Nyrt filed Critical Richter Gedeon Nyrt
Publication of WO2019116325A1 publication Critical patent/WO2019116325A1/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
    • C07D487/12—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 three hetero rings
    • C07D487/14—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
    • 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
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/08—Oxygen atoms
    • C07D223/10—Oxygen atoms attached in position 2
    • 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

Definitions

  • the present invention relates to 5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine derivatives of the general formula (I) and/or salts thereof and/or geometric isomers thereof and/or stereoisomers thereof and/or enantiomers thereof and/or racemates thereof and/or diastereomers thereof and/or biologically active metabolites thereof and/or prodrugs thereof and/or solvates thereof and/or hydrates thereof and/or polymorphs thereof which are centrally and/or peripherally acting Via receptor modulators, particularly Via receptor antagonists.
  • Additional subject of the present invention is the process for the preparation of the compounds and the intermediates of the preparation process as well.
  • the invention also relates to the pharmaceutical compositions containing the compounds and to the use thereof in the treatment and/or prophylaxis of a disease or condition associated with Via receptor function
  • vasopressin antidiuretic hormone, ADH, CYIQNCPRG
  • ADH a 9-amino acid peptide hormone produced by the magnoceliular neurons of the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus and secreted directly into the posterior lobe of the pituitary gland where the hormone is stored until entering into the bloodstream in the periphery, the major role of vasopressin is in the contraction of blood vessels, as well as in glucose metabolism and in the regulation of excretion.
  • vasopressin may lead to pathological changes in the body, such as the central form of diabetes insipidus or abnormally low blood pressure (hypotension), while in the case of elevated levels of vasopressin or exogenous administration various forms of strengthening of the aggressive behaviour can be observed (Ferris et ai., BMC Neuroscience 2008, 9:111).
  • Oxytocin (OXT, CY!QNGPLG) is a vasopressin-related peptide hormone, differing from that in one amino acid and its receptor is also related to vasopressin receptors.
  • the effects of compounds on the oxytocin receptor show species-specific differences, but the oxytocin hormone itself is identical in the different mammalian species.
  • the vasopressin peptide is the same in ail mammals (except marsupials and pigs) and the effects exerted through its receptors may also show species-specific differences.
  • the anxiolytic effect of oxytocin exerted in the central nervous system is well-known (Neumann ID. J Neuroendocrinal 2008, 20(6): 858-65), therefore the inhibition of the oxytocin receptor in the central nervous system can trigger anxiety as undesirable side effect.
  • V1aR The Via receptor
  • V1bR The V1 b receptors (V1bR) are also can be found in the cortex, hippocampus and pituitary gland, and in the periphery they play an important role in the regulation of the pancreas and the adrenal glands.
  • V2R V2 receptor
  • the V2 receptor is mainly localised on the periphery, in the kidneys where it increases water reabsorption, thereby exerting the antidiuretic effect of vasopressin (Robben et a! , Am J Physiol Renal Physiol 2007, 292(1): F253-60).
  • vasopressin Rosben et a! , Am J Physiol Renal Physiol 2007, 292(1): F253-60.
  • the secondary signalling pathway of Via and V1b receptors include the change of intracellular Ca 2 * concentration through phosphatidylinositol, whereas the V2 receptors activate adenylate cyclase enzyme and influence cAMP levels (Gouzenes et a!., J Physiol 1999, 517(Pt3):771-9; Tahara et al., Pf!ugers Arch 1999, 437(2):219-26).
  • Vasopressin shows sexual dimorphism in inducing behavioural effects, despite the fact that distribution and amount of the V1aR mRNAs do not differ in men and women (Szot et al., Brain Res Mol Brain Res 1994, 24(1-4):1-10) Experiments in mice have shown that the increased water absorption prior to their sleep period was triggered by their internal clock and not their physiological necessities (Gizowski et al., Nature 2016, 537(7622):685- 8). Sleep disorder is a major accompanying symptom of autism (Giickman, Neuroses Blobehav Rev 2010, 34(5): 755-68).
  • Vasopressin acts as a neuromodulator in the brain, its elevated level can be detected in the amygdala under stress (Ebner et al., Eur J Neuroses 2002, 15(2):384-8)
  • Such stressful life situations are well known to increase the likelihood of developing depression and anxiety (Kendier et al., Arch Gen Psychiatry 2003, 60(8):789-96; Simon et al., Recent Pat CNS Drug Discov, 2008, 3(2):77-93; Egashira et al., J Pharmacol Sci 2009, 109(1):44-9; Bielsky et al., Neuropsychopharmacology 2004, 29(3):483-93).
  • V1aR The expression of V1aR is high in the brain, especially in certain parts of the limbic system, such as the amygdala, the lateral septum and the hippocampus which play an important role in the development of anxiety
  • Male V1aR gene knocked out mice exhibited reduced anxiety in the elevated plus maze, the open field and the light-dark box tests, but these differences could not be detected in females (Bielsky et al , Behav Brain Res 2005, 164(1): 132-6).
  • V1aR knockout mice did not show any phenotypic difference in motor performances.
  • V1aR KO mice showed no difference compared to their wild-type littermates, however, in the experiments carried out in continuous darkness the diurnal rhythm of Vi a knockout mice was shifted significantly (Egashira et al., Behav Brain Res 2007, 178(1): 123-7).
  • V1 aR KO mice showed modified activity in the prepu!se inhibition test, in the test which is accepted as animal model of sensory motor deficiency observed in most schizophrenic patients Egashira et al have shown decreased function in the social interaction test, which is suitable to measure socio-cognitive behaviour of the V1 aR KO mice in both sexes, but it was not observed after the treatment with antagonist (Bleickard et al , Psychopharmacology (Berl) , 2009, 202:71 1-18).
  • Two microsateliite polymorphisms associated with autism could be determined in the case of variants of the AVPR1A gene encoding the Via receptor (Kim et al., Mol Psychiatry 2002, 7:503-7; Yirmiya et al., Mol Psychiatry 2006, 11 :488-94; Yang et al., Psychiatry Res, 2010, 178(1): 199 ⁇ 201 ; Yang et al., Neurosci Lett 2010, 479(3): 197-200) It also refers to a genetic connection that altered activation of amygdala could be detected in patients carrying two risk alleles in the V1aR gene. These modified receptors have been shown to be able to alter the activation threshold of amygdala during emotional facial recognition process (Meyer- Lindenberg et al., Mol Psychiatry 2009, 14:968-75).
  • V1aR antagonists Preclinical data also support the efficacy of V1aR antagonists in autism.
  • a widely used and accepted animal model of autism is to study the behaviour of rats exposed to valproate (VPA) treatment in utero.
  • the reduced social behaviour of VPA-treated animals could be reversed by the V1 aR antagonist compound to the normal level in a functional magnetic resonance imaging study it was also found that decreased perfusion values were restored by the V1 aR antagonist in different brain regions of prenata!iy VPA-treated animals.
  • V1aR antagonist The decreased function of the cortex, the inferior colliculus, the hippocampus and the hypothalamus was increased by treatment with the V1 aR antagonist, whereas in the ventral tegmentum, the striatum and the colliculus superior, the augmented perfusion was normalised by the V1aR antagonist (Grundschober et al , Poster presented at Annual Meeting of the American College of Neuropsychopharmacology, 2014, Phoenix, USA). For this reason, V1aR antagonist compounds showing favourable blood-brain barrier penetration are expected to be advantageous.
  • Influencing V1aR with small molecule antagonists is a promising strategy for the treatment of various pathological conditions of the female sex organs (such as, but not limited to, dysmenorrhea, sexual dysfunction), long-lasting pathological conditions in blood pressure control (such as, but not limited to, hypertension and/or chronic heart failure), conditions resulting from inappropriate secretion of vasopressin (such as, but not limited to, diabetes insipidus, renal failure, nephrotic syndrome and cirrhosis). It can be considered another promising strategy in the treatment of anxiety, depression, aggression, and disorders of the central nervous system where one of the symptoms and/or syndromes of the disease may be related to the latter three diseases or show comorbidity with them.
  • pathological conditions of the female sex organs such as, but not limited to, dysmenorrhea, sexual dysfunction
  • blood pressure control such as, but not limited to, hypertension and/or chronic heart failure
  • vasopressin such as, but not limited to, diabetes insipidus
  • autistic spectrum disorder well-functioning autism, Asperger's syndrome, Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS), autism spectrum disorder (ASD) and its various syndromic forms: fragile X syndrome, Prader-Willi syndrome, Reft syndrome, tuberous sclerosis), obsessive compulsive disorder (OCD), various forms of Down syndrome and post-traumatic stress disorder (PTSD).
  • V1aR antagonists are also suitable for the treatment of aggressive behavioural disorders and/or irritability (such as, but not limited to, patients with ASD, or suffering from Huntington's disease (HD) or various forms of schizophrenia), behavioural hyperactivity disorders (such as, but not limited to, attention deficit hyperactivity disorder (ADHD)), cognitive disorders (such as, but not limited to, dementia, mild cognitive disorders (MCI), cognitive impairment associated with schizophrenia (CIAS), and Alzheimer's disease), and other neuropsychiatric disorders (such as, but not limited to, schizophrenia and associated diseases).
  • ADHD attention deficit hyperactivity disorder
  • MCI mild cognitive disorders
  • cognitive impairment associated with schizophrenia CIAS
  • Alzheimer's disease Alzheimer's disease
  • other neuropsychiatric disorders such as, but not limited to, schizophrenia and associated diseases.
  • Otsuka discloses benzoheterocyclic derivatives (WO 95/034540 A1 , WO 2009/001968 A1 , WO 2011/052519 A1)
  • Astellas Pharma Yamamoto
  • Yamanouchi discloses condensed benzodiazepine and triazo!e derivatives
  • AbbVie discloses oxindole derivatives (WO 2006/072458 A2, WO 2006/100082 A2)
  • Bayer Pharma discloses aryl- or heteroaryltriazole derivatives (WO 2017/191102 A1 , WO 2017/191107 A1 , WO 2017/191114 A1).
  • Azevan’s V1aR antagonist azetidone derivatives, SRX246 and SRX251 also known as API246 or API251 , WO 03/031407 A2 also reached the clinical trial phase.
  • Clinical trials of SRX246 are also currently ongoing for the treatment of aggression, and intermittent explosive disorder and irritability in Huntington's Disease and post-traumatic stress disorder, as well as in the human behavioural models of anxiety and fear (Adislnsight: SRX 246 - Latest information Update: 16 Feb 2017 http://adisinsiqht.sprinqer.com/drugs/800023656).
  • SRX 251 Clinical trial was conducted with SRX251 to treat dysmenorrhea but both Phase 1 studies were discontinued in 2016 and similarly to SRX246 it was also investigated for aggression in the preciinicai development (Adis!nsight: SRX 251 - Latest information Update: 04 Nov 2017 http://adisinsight.springer.com/drugs/800025117).
  • SRX-246 and SRX-251 are active on the human Via receptor and in rats both compounds were detectable in the brain at approximately 100-fold of the effective concentrations detected in the binding assay (Guilion et a!., Bioorg Med Chem 2007, 15:2054-80; Fabio et a!., J Pharm Sci 2013, 102(6):2033-43).
  • Vantia s V1aR antagonist compound, VA 11 1913 of pyrazoiobenzodiazepine core (WO 2010/097576 A1 ; Adislnsight: VA 111913 - Latest information Update: 25 Aug 2015 http://adisinsiaht.springer.com/drugs/800028777) was tested in Phase 2 clinical trial for the treatment of dysmenorrhea but there is no information about its development since 2015.
  • Otsuka s V1 aR antagonist, the quinolinone derivative OPC 21268 (EPG382185A2; Adislnsight: OPC 21268 - Latest Information Update: 06 Oct
  • V1 aR antagonists that is suitable for the treatment and/or prophylaxis of various pathological conditions of the female sex organs, long-standing conditions in blood pressure control, conditions resulting from inappropriate secretion of vasopressin, anxiety, depression, aggression, disorders of the central nervous system where one of the symptoms and/or syndromes of the disease may be related to anxiety, depression, aggression or show comorbidity with them (autistic spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavioural disorders and/or irritability, behavioural hyperactivity disorders, cognitive disorders or other neuropsychiatric disorders.
  • Our aim was to synthetize novel structured Via receptor antagonists whose physical- chemical (e.g. kinetic or thermodynamic solubility, ionisation, iipophilicity or permeability) or pharmaceutical properties (e.g. metabolic stability, GYP-450 enzyme inhibition) provide the favorable bioavailability, ADME (absorption, distribution, metabolism, excretion), membrane penetration or blood-brain barrier penetration.
  • physical- chemical e.g. kinetic or thermodynamic solubility, ionisation, iipophilicity or permeability
  • pharmaceutical properties e.g. metabolic stability, GYP-450 enzyme inhibition
  • the present invention relates to compounds of general formula (I)
  • ring A is a cycloaikyl or heterocyclyl group
  • Y is -0-, -C(O)-, -GH2-, -NH- or bond if ring B is present; or -N(Ci- 4 aikyi) 2 , C(0)0Ci- 4 alkyl, Ci-4alkyl group optionally substituted with halogen, Ci.4alkoxy group or halogen if ring B is not present;
  • ring B is an optionally substituted heteroaryl, aryl or heterocyclyl group
  • B-Y-A- jointly represents a 3H-spiro[2-benzofuran-1 ,4’ ⁇ piperidin-Y-y!]; or group;
  • R 1 is a hydrogen, halogen, C h alky!, Ci- 4 alkoxy, CF 3 or CN;
  • R 2 is a hydrogen or Gi ⁇ a!ky! group
  • R 3 is a (CHzj n R 4 , C(0)R 5 group or C- ⁇ alkyl optionally substituted with R 6 ;
  • R 2 and R 3 jointly represent - ⁇ CHzjp-CMCHsj c r or ⁇ CH 2 )r group;
  • R 4 is a CN, azide or Cy 1 group
  • R 5 is a Ci -4 alkyl, Ci- 4 alkoxy, OH or NR 7 R 8 group;
  • R 6 is an OR 9 , NR 10 R 11 , oxo, -G(CH 2 ) 2 0- group or one or more halogens;
  • R 7 and R 8 is independently a hydrogen, C ⁇ alkyl, Cy 2 or R 7 and R 8 taken together with the N to which they are attached form a heterocycle;
  • R 9 is a hydrogen; C h alky! optionally substituted with NH 2 or with optionally substituted aryl group; SiCCHsja; or C(Q)R 12 group;
  • R 10 and R 11 is independently a hydrogen; Ci -4 alkyl optionally substituted with C ⁇ alkoxy group; Cy 3 ; C(G)R 13 or R 10 and R 11 taken together with the N to which they are attached form an optionally substituted heterocycle;
  • R 12 is a C h alky! or NR 14 R 15 group
  • R 13 is a Ci- 4 alkyl, Cy 1 or NR 16 R 17 group
  • R 14 and R 15 is independently a hydrogen, optionally substituted aryl or R 14 and R 15 taken together with the N to which they are attached form an optionally substituted heterocycle;
  • R 16 and R 17 is a C h alky! or R 16 and R 17 taken together with the N to which they are attached form an optionally substituted heterocycle;
  • Cy 1 is an optionally substituted heteroaryl group
  • Cy 2 is an optionally substituted aryl or heteroaryl group
  • Cy 3 is an optionally substituted cydoalkyl or heterocyciyl group
  • X is a Ci- 4 alkyl, aryl or heteroaryi group
  • Z is a C h alky! group
  • q is 1 , 2 or 3;
  • r 4, 5 or 6;
  • the present invention also relates to pharmaceutical compositions containing the compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof as active substances.
  • the present invention also relates to the preparation of the compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof, to the intermediates of the preparation process and to the chemical and pharmaceutical preparation of pharmaceutical compositions containing the compounds.
  • the invention also relates to a method for treating a mammal, including humans suffering from a central and/or peripheral disease, where modulation, preferably antagonism of the Via receptor may have therapeutic benefits wherein the compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof or a therapeutically effective amount thereof In a composition is administered.
  • modulation, preferably antagonism of the Via receptor may have therapeutic benefits wherein the compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof or a therapeutically effective amount thereof
  • the invention also relates to the use of the compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof for the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition associated with Via receptor function.
  • the present invention relates to Via receptor modulators, in particular Via receptor antagonists. It is a further objective of the invention to provide selective Via receptor inhibitor compounds since selectivity is less likely to cause undesirable side effects. Another aspect of the invention is to provide compounds with favourable physicochemical properties as favourable physical-chemical properties are expected to result in beneficial bioavailability, ADME (absorption, distribution, metabolism, excretion), membrane penetration or blood- brain barrier penetration of the compounds.
  • ADME absorption, distribution, metabolism, excretion
  • the compounds of general formula (I) of the present invention are thus Vi a receptor antagonists which are centrally and/or peripherally acting therapeutic agents in the treatment and/or prophylaxis of various pathological conditions of the female sex organs, long-standing conditions in blood pressure control, conditions resulting from inappropriate secretion of vasopressin, anxiety, depression, aggression, disorders of the central nervous system where one of the symptoms and/or syndromes of the disease may be related to anxiety, depression, aggression or show comorbidity with them (autistic spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavioural disorders and/or irritability, behavioural hyperactivity disorders, cognitive disorders or other neuropsychiatric disorders.
  • a receptor antagonists which are centrally and/or peripherally acting therapeutic agents in the treatment and/or prophylaxis of various pathological conditions of the female sex organs, long-standing conditions in blood pressure control, conditions resulting from inappropriate secretion of vasopressin, anxiety, depression
  • the present invention relates to compounds of general formula (I)
  • ring A is a cycloalkyl or heterocyclyl group
  • Y is -0-, -C(O)-, -CH2-, -NH- or bond if ring B is present; or -N(Ci- 4 aikyi) 2 , C(0)0Ci-4alkyl, Ci-4alkyl group optionally substituted with halogen, C ⁇ alkoxy group or halogen if ring B is not present;
  • ring B is an optionally substituted heteroaryl, aryl or heterocyclyl group; or B-Y-A- jointly represents a 3H-spiro[2-benzofuran-1 ,4’-piperidin-1’-yl]; or group;
  • R 1 is a hydrogen, halogen, C h alky!, Ci- 4 alkoxy, CF 3 or CN;
  • R 2 is a hydrogen or C ⁇ alkyl group
  • R 3 is a (CHzj n R 4 , C(0)R 5 group or C- ⁇ alkyl optionally substituted with R 6 ;
  • R 2 and R 3 jointly represent -(CHzjp-O-CCHsjq- or ⁇ CH 2 )r group;
  • R 4 is a CN, azide or Cy 1 group
  • R 5 is a Ci -4 alkyl, Ci- 4 alkoxy, OH or NR 7 R 8 group;
  • R 6 is an OR 9 , NR 10 R 11 , oxo, -G(CH 2 ) 2 0- group or one or more halogen;
  • R 7 and R 8 is independently a hydrogen, Ci ⁇ aikyi, Cy 2 or R 7 and R 8 taken together with the N to which they are attached form a heterocycle;
  • R 9 is a hydrogen; C h alky! optionally substituted with NH 2 or with optionally substituted aryl group; S CHsb; or C(Q)R 12 group;
  • R 10 and R 11 is Independently a hydrogen; Ci ⁇ alkyl optionally substituted with Ci- 4 alkoxy group; Cy 3 ; C(G)R 13 or R 10 and 11 taken together with the N to which they are attached form an optionally subsituted heterocycle;
  • R 12 is a C h alky! or NR 14 R 15 group
  • R 13 is a Ci- 4 alkyl, Cy 1 or NR 16 R 17 group
  • R 14 and R 15 is independently a hydrogen, optionally substituted aryl or R 14 and R 15 taken together with the N to which they are attached form an optionally substituted heterocycle;
  • R 16 and R 17 is a C h alky! or R 16 and R 17 taken together with the N to which they are attached form an optionally substituted heterocycle;
  • Cy 1 is an optionally substituted heteroaryl group
  • Cy 2 Is an optionally substituted aryl or heteroaryl group
  • Cy 3 is an optionally substituted cycloalkyl or heterocyclyl group
  • X is a Ci- 4 alkyl, aryl or heteroaryl group
  • Z is a C h alky! group; n is 0 or 1 :
  • p is 1 , 2 or 3;
  • q is 1 , 2 or 3;
  • r 4, 5 or 6;
  • cycloalkyl group refers alone or in combination with other groups to 3 ⁇ to 8-membered, preferably 3- to 6-membered, saturated or unsaturated, preferably saturated carbocyciic groups. Examples include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • cycloalkyl group refers preferably to a 4- to 6-membered saturated carbocyciic group. Examples include cyclobutyl, cyclopentyl or cyclohexyl. Preferably cyclobutyl or eydobexy! group. Particularly preferred is the cyclohexyl group.
  • substituted cycloaikyi group refers preferably to a cycloalkyl group having gemina! halogen substitution.
  • aryl group refers alone or in combination with other groups to a 6- to 14- membered, preferably 6- to 10-membered aromatic carbocyciic moiety comprising at least one aromatic ring or a condensed ring system containing at least one aromatic ring.
  • examples include, but are not limited to, phenyl, benzyl, naphthyl, biphenyl, antbryi, azulenyi or indany!. Particularly preferred is the phenyl group.
  • heterocyclyl group refers alone or in combination with other groups to 3- to 8-membered, preferably 4 ⁇ to 7-membered, saturated or unsaturated, preferably saturated, monocyclic, bicyclic, condensed and/or bridged ring cycle containing 1 , 2, 3 or 4 heteroatoms selected from O, S or N.
  • Preferred 4- to 7-member monocyclic heterocycle contains 1 N, 2 N, 1 O, 1 N and 1 O or 1 N and 1 S.
  • Examples include, but are not limited to, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, piperazine, morpholine, 1 ,3-oxazolidine, 1 ,3-thiazoiidine, thiomorpho!ine-1 , 1-dioxide and the like.
  • substituted heterocyclyl group refers preferably to a heterocycie substituted with Ci - 4 aikyi.
  • heterocyclyi refers preferably to a 4- to 7-membered saturated heterocyclyi group containing 1 N or 2 N, wherein ring A is attached via a ring nitrogen to Y or to the triazoie ring of the 5 6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine core.
  • Examples include, but are not limited to, azetidinyi, 1 ,3-diazetidinyl, pyrroiidinyi, pyrazolidinyl, imidazolidinyl, piperidinyi, piperazinyi, azepanyl, 1 ,3- or 1 ,4-diazepanyl.
  • azetidinyi piperidinyi or piperazinyi.
  • the heterocyde refers preferably to a 4- to 7-membered saturated heterocyclyi group containing 1 O, more preferably oxetane or tefrabydropyran.
  • heterocyclyi refers preferably a 4- to 7-membered saturated heterocyclyi group containing 1 N or 1 N and 1 O. Examples include, but are not limited to, azetidinyi, pyrroiidinyi, piperidinyi, piperazinyi or morpboiiny!.
  • heterocyde refers preferably to 4- to 7-membered saturated ring containing 1 N, 2 N, 1 N and 1 O or 1 N and 1 S.
  • examples include, but are not limited to, morpholine, 4-meihyi-piperazinyl, pyrroiidinyi, piperidinyi, piperazinyi, 1 ,3-oxazolidine, 1 ,3-thiazoiidine or thiomorpholine-1 , 1-dioxide.
  • heteroaryl group refers alone or in combination with other groups to a cyclic aromatic group containing a single 5- to 6-membered ring containing 1 , 2, 3 or 4 heferoatoms in which group at least one heterocyclic ring is aromatic.
  • the "6-membered mono-heteroaryl group” refers to a monocyclic aromatic group which is a single 6-membered ring containing 1 , 2, or 3 heteroatoms selected from O, S or N. Examples include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl and the like.
  • Preferred single 6-membered mono-heteroaryl groups contain 1 or 2 N.
  • a preferred 6- membered ring is pyridinyl, more preferably pyridin-2-yl and pyridin-3-yl. Particularly preferred is pyridine-2-yl.
  • the term "5-membered mono-heteroaryl” means a monocyclic aromatic group which is a single 5-membered ring containing 1 , 2, 3 or 4 heteroatoms selected from O, S or N.
  • Preferred single 5-membered mono-heteroaryl groups contain 2 N and 1 O, 2 N and 1 S, 4 N, 3 N, 2 N, 1 N or 1 S or 1 N and 1 O.
  • Examples include, but are not limited to, thiophenyl, furanyl, pyrrolyi, tetrazoiyl, triazolyi, imidazoiy!, thiazoiy!, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, 1H-pyrazo!yl and the like. Preferred are isoxazol-3-yl, tetrazoiyl and 1 ,2,4-oxadiazol-5-yl.
  • substituted heteroaryl group refers preferably to a heteroaryl group substituted with Ci ⁇ alkyl or halogen.
  • the optionally substituted heteroaryl refers preferably to a C ⁇ alkyl, more preferably a methyl-substituted single 5-membered mono-heteroaryl group containing 2 N and 1 O or 4 N. Preferred are tefrazo!yl or 3-metbyi-1 ,2,4-oxadiazol-5-yi.
  • heteroaryl refers to a 5- or 6-membered mono-heteroaryl group containing 1 N, 2 N or 1 N and 1 O optionally substituted with halogen, preferably chlorine or C h alky!, preferably methyl.
  • halogen preferably chlorine or C h alky!
  • examples include, but are not limited to, pyridin-2-yl, 3-chioro-pyridin-2-yl, 3-methyl-pyridin-2 ⁇ yl, pyridin-3-yl, pyrimidin- 2-y! or 5-methyl-isoxazol-3-yi.
  • bond refers to a single bond, in which one pair of electrons is shared between two atoms.
  • Ci ⁇ alkyl group or“Ci-salkyl group” refers alone or in combination with other groups to a straight or branched, single or multiple branched, hydrocarbon radical and consists of 1 to 4 or 1 to 5 carbon atoms. Examples include, but are not limited to, methyl, ethyl, propyl, i-propyl (isopropyl), /7-butyl, 2-butyl (sec-butyl), /-butyl (teri- butyl), /7-pentyl-, t- pentyi-, neopentyl ⁇ , isopentyl ⁇ , 2-pentyl ⁇ (sec-pentyl-) or 3-pentyl group.
  • Preferred alkyl groups are those having 1 to 3 carbon atoms. Preferred are methyl, ethyl, isopropyl, /-butyl and /-pentyl groups. Particularly preferred is the methyl group.
  • Ci- 4 alkoxy group refers alone or in combination with other groups to -O- Ci-4alkyl group, wherein the C h alky! group is as defined above. Examples include, but are not limited to, methoxy, ethoxy, propoxy or /-butoxy. Preferred alkoxy groups are methoxy, propoxy or t-butoxy. Particularly preferred are the methoxy and /-butoxy groups.
  • Boc refers alone or in combination with other groups to /-butoxycarbonyl group.
  • halogen refers alone or in combination with other groups to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
  • fluorine chlorine or bromine in R ⁇ more preferred are chlorine or bromine, even more preferred is the chlorine.
  • R 6 more preferred is the fluorine.
  • any atom of the relevant group refers to the substitution by one or more Ci-4alkyl groups or halogens.
  • one or more means from one to the highest possible number of substitution, that is, from replacing one hydrogen to replacing all hydrogens.
  • One, two or three substituents on a given atom are thus preferred.
  • Even more preferred are one or two, or one substitution.
  • Particularly preferred is one substitution for the optionally substituted cycloalkyl, aryl, heterocyciy! or heteroaryl group.
  • optinai!y substituted with halogen refers preferably to a Ci- 4 aikyi group having one, two or three halogen substituents on any atom of the Ci -4 alkyl group, more preferably to a methyl group having three halogen substituents. Particularly preferred is the CFs group.
  • the Ci. 4 alkyl group in the meaning of “C h alky! substituted with R 6' is as defined above.
  • the substituted C h alky! group in the meaning of “C h alky! substituted with R 6“ is preferably a branched, single or multiple branched, hydrocarbon radical consisting of 1 to 4 carbon atoms.
  • the term“substituted” in the meaning of“Ci ⁇ alkyl substituted with R 6 refers to the substitution by one or more R 6 groups on any atom of the relevant group.
  • the "one or more” means from one to the highest possible number of substitution, that is, from replacing one hydrogen to replacing all hydrogens.
  • substituted with R 6 is for example, but is not limited to, -CH2R 6 or -CH(R 6 )CH3, preferably - CH2R 6 .
  • R 6 is oxo or -0(CH 2 ) 2 0- group
  • “Ci -4 alkyl substituted with R 6 is for example, but is not limited to, ⁇ C(R 6 )CH3.
  • R 6 is one or more halogens
  • the terms“C h alky! substituted with R 6 ”,“one or more” and“halogen” are as defined above in this case“C h alky! substituted with R 6 ” is for example, but not limited to, -Chhhalagen, -CH(halogen)CH3 or -Cfba!ogen ⁇ Chh, preferably -CHahalogen.
  • salt refers to pharmaceutically acceptable and/or pharmaceutically non- acceptable salts.
  • the pharmaceutically acceptable salt refers to a conventional acid addition and base addition salts which preserve the biological efficacy and properties of the compounds of general formula (I) and which can be formed with suitable non-toxic organic or inorganic acids or organic or inorganic bases.
  • acid addition salts include salts derived from inorganic acids, such as, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulphamic acid, phosphoric acid, nitric acid and perchloric acid and derived from various organic acids, such as, but not limited to, acetic acid, propionic acid, benzoic acid, glycolic acid, phenylacetic acid, salicylic acid, malonic acid, maleic acid, oleic acid, pamoic acid, palmitic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, oxalic acid, tartaric acid, succinic acid, citric acid, malic acid, lactic acid, glutamic acid, fumaric acid and the like.
  • inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulphamic acid, phospho
  • base addition salts are salts derived from ammonium-, potassium-, sodium- and quaternary ammonium hydroxides such as tetramethylammonium hydroxide. These salts often exhibit more favourable solubility properties than the compounds used for their preparation and are therefore more suitable for use in the preparation for example of liquid or emulsion formulations.
  • the pharmaceutically non-acceptable salts may be preferred for the purification and isolation of the compounds of general formula (I) and therefore also fall within the scope of the invention.
  • prodrug refers to derivatives of compounds of genera!
  • the compounds of genera! formula (I) may exist in various geometric isomeric forms.
  • certain compounds of genera! formula (!) may contain one or more asymmetric centers, thus exist in the form of stereoisomers and diastereomers. All of these compounds, such as cis isomers, trans isomers, diastereomeric mixtures, racemates, non-racemic mixtures of enantiomers, substantially pure and pure enantiomers also fail within the scope of the invention.
  • the substantially pure enantiomers contain up to 5 wt%, preferably 2 wt%, most preferably 1 wt%, of the corresponding opposite enantiomer.
  • Optical isomers can be prepared by resolving the racemic mixtures by known methods, for example, by using an optically active acid or base to form diastereoisomeric salts or by forming covalent diastereomers.
  • Suitable acids include, for example, tartaric acid, diacetyltartaric acid, dibenzoy!tartaric acid, dito!uoyltartaric acid and camphorsulfonic acid.
  • Diastereoisomeric mixtures can be separated into individual diastereomers based on their physical and/or chemical differences, by methods known to those skilled in the art, such as chromatography or fractional crystallization. Subsequently, the optically active bases or acids are liberated from the separated diastereoisomeric salts.
  • optical isomers include chiral chromatography (e.g., chiral HPLC columns) optionally used by derivatization with the aim to maximize the separation of enantiomers.
  • Appropriate chiral HPLC columns are Diacel columns, such as CHIRALPAK or CHIRALCEL columns, which can be routinely chosen as desired.
  • enzymatic separations carried out by derivatization may also be used.
  • the optically active compounds of general formula (!) can also be prepared using optically active starting materials using chiral synthesis without racemization reaction conditions.
  • the absolute configuration of the chiral compounds was determined by VCD (vibrational circular dichroism spectroscopy) method described in the literature (Freedman et al. , Chirality 2003, f5(9):743-58; Stephens et a! , Chirality 2008, 20:643-663) and/or by 1 H NMR spectroscopic assays of the diastereomeric pair of compounds produced from chiral compounds (Seco et al., J Org Chem 1999, 64: 4869-4675; Seco et ai , Tetrahedron Asymmetry 2001 , 12: 2915-2925; Latypov et al , JAm.Chem.Soc. 1998, 120, 4741-4751).
  • the compounds of genera! formula (!) may exist in various polymorphic forms.
  • polymorphism is the ability of a compound to crystallize in more than one crystalline form, i.e. in polymorphic form.
  • Polymorphic forms of a particular compound can be defined by identical chemical formula or composition and differ in their chemical structure like the crystalline structures of two different chemical compounds.
  • solvates refers to non-covalent combinations of solvent and solute.
  • hydrate refers to non-covending combinations of water and solute.
  • the present invention further relates to pharmaceutical compositions containing the compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof.
  • the present invention also relates to the chemical and pharmaceutical preparation of pharmaceutical compositions containing the compound of general formula (!) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof.
  • compositions of the present invention may be formulated in various pharmaceutical formulations, such as, but not limited to, solid ora! dosage forms such as tablets (e.g. buccal, sublingual, effervescent, chewable, orally dispersible), capsules, pills, piiuias, orally dispersible films, granules, powders; liquid formulations such as solutions, emulsions, suspensions, syrups, elixirs, drops; parenteral dosage forms such as intravenous injections, intramuscular injections, subcutaneous injections; other forms of medicine such as eye drops, semi-solid ophthalmic preparations, semi-solid derma! preparations (such as ointments, creams, pastes), transdermai therapeutic systems, suppositories, rectal capsules, rectal solutions, emulsions and suspensions, etc.
  • solid ora! dosage forms such as tablets (e.g. buccal, sublingual, effervescent, chewable, orally dispersible), capsules,
  • compositions for paediatric use such as, but not limited to, solutions, syrups, elixirs, suspensions, powders for the preparation of suspensions, dispersible or effervescent tablets, chewable tablets, orodispersible tablets, tablets or coated tablets, orally sparkling powders or granules, capsules.
  • compositions of the present invention may be prepared by methods known perse, such as conventional mixing, dissolution, emulsification, suspending, microencapsulation, lyophilisation, extrusion and spheronisation, lamination, film coating, granulation, encapsulation, drageeing or pressing.
  • compositions of the present invention may be formulated in the usual way using one or more physiologically acceptable excipients, including binders, which promote the incorporation of the active substance into pharmaceutically acceptable pharmaceutical forms.
  • physiologically acceptable excipients including binders, which promote the incorporation of the active substance into pharmaceutically acceptable pharmaceutical forms.
  • the proper formulation depends on the mode of administration chosen. Any of the techniques and excipients well known in the art can be used.
  • excipients applicable in the preparation may be selected from the following categories, such as, but not limited to, fillers of tablets and capsules, binders of tablets and capsules, modified drug release agents, disintegrants, glidants, lubricants, sweeteners, taste-masking agents, flavourants, coating materials, surfactants, stabilisers, preservatives or antioxidants, buffering agents, complexing agents, wetting or emulsifying agents, salts for adjusting the osmotic pressure, lyophilisation excipients, microencapsulating agents, ointment materials, penetration enhancers, solubilisers, solvents, suppository materials, suspending agents .
  • Suitable pharmaceutical excipients can be for example: starch, microcrystalline cellulose, talc, glucose, lactose, gelatin, silica, talc, magnesium stearate, sodium stearate, glycerol monostearate, cellulose derivatives, sodium chloride, glycerol, propylene glycol, water, ethanol and the like.
  • Another embodiment of the present invention relates to the use of special binders that can improve the solubility, dissolution, penetration, absorption or bioavai!abi!ity of the active substance(s), such as, but not limited to, hydrophilic polymers, hot melting extruding excipients, surfactants, buffering agents, complexing agents, emulsifying agents, lyophilization excipients, disintegrants, microencapsulating agents, penetration promoters, solubilisers, cosolvents, suspending agents.
  • hydrophilic polymers such as, but not limited to, hydrophilic polymers, hot melting extruding excipients, surfactants, buffering agents, complexing agents, emulsifying agents, lyophilization excipients, disintegrants, microencapsulating agents, penetration promoters, solubilisers, cosolvents, suspending agents.
  • disease or condition associated with Vi a receptor function or “disease or condition associated with the central and/or peripheral modulation, preferably antagonisation of the Via receptor” refer to a disease or condition selected from the group consisting of various pathological conditions of the female sex organs, long-standing conditions in blood pressure control, conditions resulting from inappropriate secretion of vasopressin, anxiety, depression, aggression, disorders of the central nervous system where one of the symptoms and/or syndromes of the disease may be related to anxiety, depression, aggression or show comorbidity with them (autistic spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavioural disorders and/or irritability, behavioural hyperactivity disorders, cognitive disorders or other neuropsychiatric disorders.
  • the various pathological conditions of the female sex organs include, but not limited to, dysmenorrhea (primary and/or secondary) or sexual dysfunction.
  • the long-standing conditions in blood pressure control include, but not limited to, hypertension and/or chronic heart failure.
  • vasopressin The conditions resulting from inappropriate secretion of vasopressin include, but not limited to, diabetes insipidus, renal failure, nephrotic syndrome or cirrhosis.
  • the disorders of the central nervous system where one of the symptoms and/or syndromes of the disease may be related to anxiety, depression, aggression or show comorbidity with them include, but not limited to, autistic spectrum disorder (well-functioning autism, Asperger's syndrome, Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS), autism spectrum disorder (ASD) and its various syndrome forms: fragile X syndrome, Prader-Willi syndrome, Rett syndrome, tuberous sclerosis), obsessive compulsive disorder (OCD), various forms of Down syndrome and post-traumatic stress disorder (PTSD).
  • autistic spectrum disorder well-functioning autism, Asperger's syndrome, Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS), autism spectrum disorder (ASD) and its various syndrome forms: fragile X syndrome, Prader-Willi syndrome, Rett syndrome, tuberous sclerosis), obsessive compulsive disorder (OCD), various forms of Down syndrome and post-traumatic stress disorder (PTSD).
  • the aggressive behavioral disorders and/or irritability include, but not limited to, ASD, Huntington's disease or different forms of schizophrenia.
  • the behavioral hyperactivity disorders include, but not limited to, attention deficit hyperactivity disorder.
  • the cognitive disorders include, but not limited to, dementia, mild cognitive disorders, cognitive impairment associated with schizophrenia or Alzheimer's disease.
  • the other neuropsychiatric disorders include, but not limited to, schizophrenia and associated diseases.
  • the disease or condition associated with Via receptor function or disease or condition associated with the central and/or peripheral modulation, preferably antagonisation of Via receptor refers to autistic spectrum disorder.
  • the present invention relates to a method for treating and/or preventing a disease or condition associated with Vi a receptor function, comprising the administration to a subject in need of treatment and/or prophylaxis, preferably a mammal, more preferably a human being, of a therapeutically effective amount of a compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof alone or with at least one pharmaceutically acceptable excipient in the form of a pharmaceutical formulation.
  • a subject in need of treatment and/or prophylaxis preferably a mammal, more preferably a human being, of a therapeutically effective amount of a compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer
  • the present invention relates to a method for the treatment of a subject, preferably a mammal, more preferably a human being, suffering from a disease or condition selected from the group consisting of various pathological conditions of the female sex organs, long- standing conditions in blood pressure control, conditions resulting from inappropriate secretion of vasopressin, anxiety, depression, aggression, disorders of the central nervous system where one of the symptoms and/or syndromes of the disease may be related to anxiety, depression, aggression or show comorbidity with them (autistic spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavioural disorders and/or irritability, behavioural hyperactivity disorders, cognitive disorders or other neuropsychiatric disorders, or combination of the these diseases.
  • a disease or condition selected from the group consisting of various pathological conditions of the female sex organs, long- standing conditions in blood pressure control, conditions resulting from inappropriate secretion of vasopressin, anxiety, depression, aggression, disorders of the central
  • This method of treatment comprises the administration to a subject in need of such treatment, preferably a mammal, more preferably a human being, the therapeutically effective amount of the compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof.
  • the method of treatment may include the administration to a subject in need of such treatment, preferably a mammal, more preferably a human being, of a therapeutically effective amount of a pharmaceutical composition comprising the compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof.
  • a pharmaceutical composition comprising the compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof.
  • the present invention relates to the use of the compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof for the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition associated with Via receptor function.
  • treatment refers to the alleviation of a specific pathological condition, the elimination or reduction of one or more of the symptoms of the condition, the slowing or elimination of the progression of the disease state, and the prevention or delay of recurrence of the pathological condition of a patient or subject already suffering from or diagnosed with the disease "Prevention" (or prophylaxis or delay of occurence of the disease) is typically performed by administering the drug in the same or similar way as if it were given to a patient with a disease or condition already developed.
  • terapéuticaally effective amount refers to the amount of active substance resulting in the treatment, cure, prevention or improvement of the disease or pathological condition or side effect, and reduces the progression of the disease or pathological condition in comparison with the corresponding subject who did not receive such amount.
  • the term also includes effective amounts to enhance normal physiological functioning.
  • the compound of general formula (1) and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof as well as any pharmaceutically acceptable salt thereof may be administered in a therapeutically effective amount as a raw chemical.
  • the active substance can be made available as a pharmaceutical formulation.
  • the exact therapeutically effective amount of the compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof depends on a number of factors including, but not limited to, the age and body weight of the subject (patient) treated, the precise type of disease requiring treatment and its seriousness, the nature of the medicinal product and the route of administration.
  • the term “mammal” refers to any member of the "Mammalia” class, including, but not limited to, humans.
  • the present invention also relates to pharmaceutical compositions comprising the compound of general formula (I) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof suitable for the treatment of a disease or condition associated with the central and/or peripheral modulation, preferably antagonisation of the Vi a receptor.
  • the compound of the invention may also be used in combination with one or more of the compounds of the invention or with one or more other active substance (e.g., psycholeptics, psychoanaleptics, antihypertensives, spasmolytics, antiepileptics or other agents) in a mammal, including, but not limited to, humans, suffering from a central and/or peripheral disease, where the central and/or peripheral modulation, preferably antagonisation of Via receptor has therapeutic benefits.
  • active substance e.g., psycholeptics, psychoanaleptics, antihypertensives, spasmolytics, antiepileptics or other agents
  • Psycholeptics include, but not limited to, antipsychotics, anxiolytics, and sedatohipnotics or narcotics.
  • Antipsychotics include, but not limited to, typical and atypical antipsychotics, such as phenofhiazines with aliphatic side chains (chlorpromazine, promazine, levomepromazine, acepromazine, trifluproazine, ciamemazine, chlorproethazine, protipendyl), piperazine- derived phenothiazines (dixyrazine, fiufenazine, perazine, perfenazine, prochlorperazine, thiopropazate, trifluoperazine, acetophenazine, thioproperazine, butaperazine, perazine), piperidine-derived phenothiazines (periciazine, thioridazine, mesoridazine, pipofhiazine), thioxanthenes (chiorprothixene, ciopenthixoie, flupentixol, thio
  • Anxiolytics include, but not limited to, benzodiazepines (diazepam, chlorodiazepoxide, medazepam, oxazepam, potassium chlorazepate, iorazepam, adinazo!am, bromazepam, ciobazam, kefazoiam, prazepam, alprazolam, ha!azepam, pinazepam, camazepam, nordazepam, fludiazepam, ethyl ioflazepate, etizolam, ciotiazepam, coxazolam, tophizopam), diphenylmethane derivatives (hydroxyzine, eaptodiame), carbamates (meprobamate, emiicamate, mebutamate), dibenzobicydooctadiene derivatives (benzoquinone), azaspirode-diones (
  • Sedative hypnotics or narcotics include, but not limited to, barbiturates (pentobarbital, amobarbital, butobarbitai, barbital, aprobarbitai, secobarbital, talbutal, vinylbital, vinbarbital, cyclobarbital, heptabarbita!, reposal, methohexitol, hexobarbital, thiopental, etha!iobarbitai, aliobarbitoi, proxibarbital), aldehydes (chloral hydrate, chioralodol, acetylglycinamide chloral hydrate, dichloralphenazone, paraldehyde), benzodiazepines (fiurazepam, nitrazepam, flunitrazepam, estazolam, triazolam, lormetazepam, temazepam, midazolam, broti
  • Psychoanaleptics include, but not limited to, psychostimulants or antidepressants.
  • Psychostimulants include, but not limited to, centrally acting sympathomimetics (amphetamine, dexamphetamine, methamphetamine, methylphenidate, pemoline, fencamfamine, modafinil, phenozolone, atomoxetine, phenetiiline, dexmethylphenidate, lysdexamfetamine), nootropics or other psychostimulants (caffeine, propentofylline, meclofenoxate, pyhtinol, piracetam, deanol, fipexide, citoco!ine, oxiracetam, pirisudanol, linopirdine, nizofenone, aniracetam, acetylcarnitine, idebenone, proiintane, pipradrol, pramiracetam, adrafinil, vinpocetine, tacrine, donepezil, rivastigmine, ga!antamine,
  • Antidepressants include, but not limited to, non-selective monoamine reuptake inhibitors (desipramine, imipramine, imipramine oxide, clomipramine, opipramoi, trimipramine, lofepramine, dibenzepine, amitriptyline, nortriptyline, protriptyline, doxepin, iprindole, melitracene, butripty!ine, dosu!epin, amoxapine, dimetacrine, amineptin, maprotiline, quinupramine), serotonin modulator and stimulators (vilazodone, vortioxetine), selective serotonin reuptake inhibitors (zimeldine, fluoxetine, paroxetine, sertraline, aiaprodate, fluvoxamine, etoperidone, cita!opram, escitalopram), non-selective hydrazide- derived monoamine oxid
  • Antihypertensives indude, but not limited to, b receptor blockers, thiazide diuretics, angiotensin-converting-enzyme inhibitors, calcium antagonists, angiotensin receptor antagonists (losartan), auwo!fia alkaloids (rescinnamine, reserpine, deserpidine, methoserpidine, bietaserpine), methyidopa, imidazoline receptor agonists (donidine, guanfacine, tolonidine, moxonidine, riimenidine), ganglion blocking antiadrenergic agents (su!fonium derivative trimetapban, secondary and tertiary amine mecamylamine), peripherally acting antiadrenergic agents, alpha-adrenoreceptor blockers (prazosin, indoramin, trimazosin, doxazosin, urapidii), guanidine derivatives (betanidine, gu
  • Spasmolytics or antispasmodics include, but not limited to, peripheral muscle relaxants, curare alkaloids, choline derivatives, other quaternary ammonium muscle relaxants (pancuronium, gailamine, vecuronium, atracurium, hexafluronium, pipecuronium bromide, doxacurium chloride, camdinium bromide, rocuronium bromide, mivacurium bromide, cisatracurium, botulinum toxin), centra!
  • nervous system muscle relaxants carbamic acid esters (phenprobamate, carisoprodol, metocarbamoi, styramate, febarbamate), oxazole-, thiazine- and triazine derivatives (ch!ormezanone, chlorzoxazone), ethers related to antihistamines (orphenadrine, guaifenesin) and other histaminergic agents (such as histamine Hs receptor antagonists/inverse agonists e.g.
  • esters with a tertiary amino group (oxyphencydimine, camylofin, mebeverine, trimebutine, rociverine, dicydoverine, dihexyverine, difemerine, piperidoiate), quaternary ammonium compounds (benziione, glycopyrronium, oxyphenonium, penthienate, propantheline, otilonium bromide, methantheline, tridihexethyl, isopropamide, hexocyclium, poldine, mepenzolate, bevonium, pipenzolate, diphemanii, e etonium iodide, tiemoniu iodide, prifinium bromide, timepidium bromide and fenpiverinium), amides with tertiary amines (astra 1397, nicofetamide, tiropramide), papaverine and its derivatives (drot
  • Antiepileptics include, but not limited to, barbiturates and their derivatives (methylphenobarbital, phenobarbital, primidone, barbexaclone, metharbitai), hydantoin derivatives (ethotion, phenytoin, amino(diphenylhydantoin) valeric acid, mepbenytoin, fosphenytoin), oxazoiidine derivatives (paramethadione, trimethadione, ethadion), succinimide derivatives (ethosuximide, phensuximide, mesuximide), benzodiazepine derivative clonazepam, carboxamide derivatives (carbamazepine, oxcarbazepine, rufinamide), fatty acid derivatives (valproic acid, valpromide, aminobutyric acid, vigabatrin, progabide, tiagabine) and other antiepileptics (sultiam
  • agents include, but not limited to, medicinal products (probiotics, digestive aids/digestives, herbal extracts), vitamins (both water soluble and fat soluble, such as, but not limited to, vitamin A, D3, E, K, B1 , B5, B6, B12, C or their derivatives) and nutritional supplements (coenzymes e.g. Q10, flavonoids e.g. resveratrol, lecithin, unsaturafed fatty acids, including fatty acids w-3 and w-6).
  • medicinal products probiotics, digestive aids/digestives, herbal extracts
  • vitamins both water soluble and fat soluble, such as, but not limited to, vitamin A, D3, E, K, B1 , B5, B6, B12, C or their derivatives
  • nutritional supplements coenzymes e.g. Q10, flavonoids e.g. resveratrol, lecithin, unsaturafed fatty acids, including fatty acids w-3 and w-6).
  • the compounds of the invention may also be used in combination with phosphodiesterase 5 isoenzyme inhibitors (PDE5), nitric oxide donors, cyclooxygenase inhibitors, other Via receptor antagonists (such as balovaptan) or L-arginine for the treatment and/or prophylaxis of a disease or condition associated with Via receptor function.
  • PDE5 phosphodiesterase 5 isoenzyme inhibitors
  • nitric oxide donors cyclooxygenase inhibitors
  • cyclooxygenase inhibitors such as balovaptan
  • L-arginine such as balovaptan
  • the combinational composition may comprise the compound of the invention together with another active substance in a single dosage form or separately.
  • the combinational composition may be administered simultaneously, separately or sequentially.
  • Suitable dosage forms include oral, rectal, mucous, transdermai or intestinal administration; parenteral administration including intramuscular, subcutaneous, intravenous, intramedullary injections as well as intraarticuiar, intrathecal, direct intraventricular, intraperitoneal, intranasai or intraocular injections and eye drops.
  • the compounds may be administered locally and not systemicaily, for example by direct injection of the compound to the kidney or the heart, often in a modified release formulation in addition, the drug may be administered in a targeted carrier system, for example in a tissue-specific antibody encapsulated liposome.
  • a targeted carrier system for example in a tissue-specific antibody encapsulated liposome. The liposomes transfer the active substance selectively to the target organ, which absorbs it.
  • the pharmaceutical composition may be administered in various ways and in pharmaceutical forms.
  • the compound of the invention may be administered alone or in combination with pharmaceutically acceptable excipients, in single or multiple doses.
  • the dose required to achieve the appropriate therapeutic effect may vary widely and must always be adapted to individual needs with regard to the stage of disease, the condition and weight of the patient to be treated, and the sensitivity to the active substance, the way of dosage regimen, and the numbers of daily treatments.
  • the pharmaceutical compositions consist of dosage units that contain the amount of drug to be administered once, or a small number of its multiple, or half, one third, one quarter.
  • dosage units are, for example, tablets that can be provided with a half or quarter groove to facilitate halving or quarter-splitting of the tablet in order to measure the required amount of drug.
  • compositions containing the active substance according to the invention generally contain from 0.01 to 500 mg of active substance per dosage unit it is of course also possible that the amount of active substance in each formulation exceeds the above limit either up or down.
  • Further preferred groups of compounds of general formula (I) are those wherein each embodiments of ring A, ring B, X, Y, Z, R'-R 17 , Cy 1 -Cy 3 , n, p, q and r described below are optionally combined.
  • ring A in the compounds of general formula (I) is a 4 to 0-membered saturated carbocycle.
  • ring A in the compounds of general formula (I) is cyclobutyl or cyc!ohexyi.
  • ring A in the compounds of general formula (I) is cyclohexyl.
  • ring A in the compounds of general formula (I) is a 4- to 7-membered saturated heterocyciyi group containing 1 or 2 N, wherein ring A is attached via a ring nitrogen to Y.
  • ring A in the compounds of general formula (I) is a 4- to 7-membered saturated heterocyciyi group containing 1 or 2 N, wherein ring A is attached via a ring nitrogen to the triazole ring of the 5,6-dihydro-4H-[1 ,2,4]triazolo[4,3- a][1]benzazepine core.
  • ring A in the compounds of general formula (I) is azetidinyl, 1 ,3-diazetidinyi, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, azepanyi, 1 ,3- or 1 ,4-diazepanyl, wherein ring A is attached via a ring nitrogen to Y.
  • ring A in the compounds of general formula (I) is azetidinyl, 1 ,3-diazetidinyi, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, azepanyi, 1 ,3- or 1 ,4-diazepanyl, wherein ring A is attached via a ring nitrogen to the triazole ring of the 5,8-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine core.
  • ring A in compounds of general formula (I) Is azetidin-1 ,3-diyl, piperidin ⁇ 1 ,4 ⁇ dly! or piperazine-1 , 4-diyl, wherein ring A is attached via a ring nitrogen to Y or to the triazole ring of the 5,6-dihydro-4H- [1 ,2,4]triazo!o[4,3-a][1]benzazepine core.
  • ring B in the compounds of general formula (I) is optionally substituted heteroaryl group. In certain preferred embodiments of the invention, ring B in the compounds of general formula (I) is optionally substituted 5- or 6-membered mono-heteroaryl group containing 1 N, 2 N or 1 N and 1 O.
  • ring B in the compounds of general formula (I) is pyrdin-2-yi, 3-chioro-pyridin-2-yi, 3-methyl-pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl or 5-methyl ⁇ isoxazol-3-yl.
  • ring B in the compounds of genera! formula (I) is pyridin-2-yi.
  • ring B in the compounds of general formula (I) is optionally substituted aryl group.
  • ring B in the compounds of general formula (I) is optionally substituted phenyl.
  • ring B in the compounds of general formula (I) is optionally substituted heterocyclyl group.
  • ring B in the compounds of general formula (I) is optionally substituted 4- to 7-membered heterocyclyl group containing 1 N or 1 N and 1 O.
  • ring B in the compounds of general formula (!) is azetidin-1-yl, pyrrolidin-1-yl, piperidinyl, piperazinyl or morpholin-4-yl.
  • Y in the compounds of general formula (I) is -0-, if ring B is present.
  • Y in the compounds of general formula (I) is -C(O)-, if ring B is present.
  • Y in the compounds of general formula (I) is -CH2-, if ring B is present.
  • Y in the compounds of general formula (I) is -NH-, if ring B is present.
  • Y in the compounds of formula (I) is a single bond, if ring B is present.
  • Y in the compounds of general formula (I) is -N(Ci-4alkyl)2, C h alky! group optionally substituted with halogen, Ci- 4 alkoxy group, C(0)0Ci- 4 alkyl or halogen, if ring B is not present.
  • Y in the compounds of general formula (I) is Ci -4 alkyl optionally substituted with halogen or Ci. 4 aikoxy group, if ring B is not present.
  • Y in the compounds of general formula (I) is Ci-salkyl group, if ring B is not present.
  • Y in the compounds of general formula (!) is methyl or ethyl group, if ring B is not present.
  • Y in the compounds of general formula (I) is Ch-aalkoxy group, if ring B is not present.
  • Y in the compounds of general formula (I) is methoxy or ethoxy group, if ring B is not present.
  • Y in the compounds of general formula (I) is CFs group, if ring B is not present.
  • Y in the compounds of general formula (I), if ring B is not present, refers to one group selected from the group consisting of -N(Ci -4 alkyl)2, C(0)OCi -4 alkyl, C h alky! optionally substituted with halogen, Ci -4 alkoxy group and halogen.
  • Y in the compounds of general formula (I), if ring B is not present, refers to one group selected from the group consisting of dimethylamine and CF 3 group.
  • Y in the compounds of general formula (I), if ring B is not present, refers to two groups selected from the group consisting of Ci -4 alkyl group optionally substituted with halogen, Ci- 4 aikoxy group and halogen.
  • Y in the compounds of general formula (I), if ring B is not present, refers to two groups selected from the group consisting of Ci-salkyl, Ci ⁇ aikoxy and fluorine.
  • Y in the compounds of general formula (I), if ring B is not present, refers to two groups selected from the group consisting of methyl, ethyl, methoxy, ethoxy group and fluorine.
  • Y in the compounds of genera! formula (I), if ring B is not present, refers to two groups selected from the group consisting of methyl and methoxy group.
  • ring A is cyclobutyl or cyclohexyl
  • Y refers to one group selected from the group consisting of -N(Ci- 4 alkyl) 2 , CFs and halogen and ring B is not present.
  • ring A is eyc!obutyl or cyclohexyi
  • Y refers to two groups selected from the group consisting of C ⁇ alkyl group optionally substituted with halogen, Ci- 4 alkoxy group and halogen and ring B is not present.
  • ring A is cyclobutyl or cyclohexyi
  • Y is -O- or a single bond
  • B is phenyl, 2- methyl-phenyl, azetidin-1-yi, pyrrol idin- 1 -y I , morpholin-4-yl, pyrdin-2-yl, 3-ch!oro-pyridin-2-yl, 3-methy!-pyridin-2-yi, pyridin-3-yl, pyrimidin-2-ly or 5-methyl-isoxazol-3-yi.
  • ring A is cyclohexyi
  • Y is -O-
  • B is pyridin-2-yl, pyridin-3-yi, 3-chioro-pyridin-2- yl, 3-methy!pyridin-2 ⁇ yi, pyrimidin-2-yl or 5-mefhy!isoxazo! ⁇ 3 ⁇ yl.
  • ring A is cyclohexyi
  • Y is -O-
  • B is pyridin-2-yi
  • ring A is cyclohexyi
  • Y is a single bond
  • ring B is morpholin-4-yl
  • ring A is cyc!obutyl or cyclohexyi
  • Y is -C(O)-
  • ring B is azetidin-1-yl, pyrrolidin-1-yl or morpholin-4-yi.
  • ring A is cyclobutyi or cyclohexyi
  • Y is -Chh-
  • ring B is an optionally substituted aryl, heterocyciyi or heteroaryl group.
  • ring A is cyclobutyi or cyclohexyi
  • Y is -CH 2 -
  • ring B is optionally substituted 4- to 7-membered heterocyciyi group containing 1 N or 1 N and 1 O.
  • ring A is azetidin-1 ,3-diyi, piperidin-1 ,4-diyl or piperazin-1 ,4-diyi, wherein ring A is attached via a ring nitrogen to Y or to the triazole ring of the 5,6-dihydro-4H ⁇ [1 ,2,4]triazolo[4,3-a][1]benzazepine core, Y is -O- or a single bond and ring B is phenyl, 2- methy!-pbenyi, azetidin-1-yl, pyrrolidin-1-yl, morpholin-4-yl, pyrdin-2-yi, 3-chloro-pyridin-2-yl, 3-methyl-pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl or 5-methyl-isoxazol-3-yl.
  • ring A is azetidin-1 ,3-diyl, wherein ring A is attached via a ring nitrogen to Y or to the triazole ring of the 5,6-dibydro-4H-[1 ,2,4]triazoio[4,3-a][1]benzazepine core, Y is a single bond and ring B is pyrdin-2-yl, pyrimidin-2-yi, piperidinyl or optionally substituted phenyl.
  • B-Y-A- in the compounds of general formula (I) jointly represents 3H-spiro[2-benzofuran-1 ,4'-piperidin-1’-yl], 1-oxa-3-azaspiro[4.5]decan- 2-on-8-yi substituted at 3-position by Ci -4 a!ky! or 2-azaspiro[4.5]decan-1-on-8-yl substituted at 2-position by C h alky!, aryl or heteroaryl.
  • B-Y-A- in the compounds of formula (I) jointly represents 3W-spiro[2-benzofuran-1 ,4'-piperidin-1’-yl], (5S,8S)-3-methyl-1-oxa-3- azaspiro[4.5]decan-2-on-8-yl, (5R,8R)-3-methyl-1-oxa-3-azaspiro[4.5]decan-2-on-8-yl, (5 ,8 )-2-(propan-2-yl)-2-azaspiro[4.5]decan-1-one or (5S,8S)-2-(propan-2-yl)-2- azaspiro[4 5]decan-1-one.
  • R 1 in the compounds of general formula (I) is a hydrogen.
  • R 1 in the compounds of general formula (I) is a halogen.
  • R 1 in the compounds of general formula (I) is a chlorine, bromine or fluorine.
  • R 1 in the compounds of general formula (I) is a chlorine.
  • R 1 in the compounds of general formula (I) is a Ci- 4 alkyl group.
  • R 1 in the compounds of general formula (I) is a methyl group.
  • R 1 in the compounds of general formula (I) is a Ci- 4 aikoxy group. In certain preferred embodiments of the invention, R 1 in the compounds of general formula (I) is a methoxy group.
  • 1 in the compounds of general formula (I) is a CF3 group.
  • R 1 in the compounds of general formula (I) is a CN group.
  • R 2 is a hydrogen or Ci-4alkyl group
  • R 3 is a (CH 2 ) n R 4 , C(0)R 5 or Ci-4alkyl group optionally substituted with R 6 .
  • R 2 is a hydrogen
  • R 3 is a (CH2) n R 4 , C(0)R 5 or Ci ⁇ alkyl group optionally substituted with R 6 .
  • R 2 is a hydrogen
  • R 3 is a (CH 2 ) n R 4 group, wherein R 4 is CN, azide or optionally substituted 5- membered mono-heteroaryl group containing 2 N and 1 O or 4 N and n is 0 or 1.
  • R 2 is a hydrogen
  • R 3 is a (ChhJ n R 4 group, wherein R 4 is CN and n is 0 or 1
  • R 2 is a hydrogen
  • R 3 is a (CHz) n R 4 group, wherein R 4 is tetrazolyl or 3-methyl- 1 ,2, 4-oxadiazol- 5-yi and n is 0 or 1.
  • R 2 is a hydrogen
  • R 3 is a C(0)R 5 group, wherein R 5 is Ci-4alkyl group.
  • R 2 is a hydrogen
  • R 3 is a C(0)R 5 group, wherein R 5 is methyl-, ethyl-, isopropyi- or /-butyl group.
  • R 2 is a hydrogen
  • R 3 is a C(0)R 5 group, wherein R s is methyl-group.
  • R 2 is a hydrogen
  • R 3 is a C(0)R 5 group, wherein R 5 is C ⁇ alkoxy group.
  • R 2 is a hydrogen
  • R 3 is a C(0)R 5 group, wherein R 5 is methoxy-, ethoxy-, propoxy- or f-butoxy group.
  • R 2 is a hydrogen
  • R 3 is a C(G)R 5 group, wherein R 5 is methoxy group.
  • R 2 is a hydrogen
  • R 3 is a C ⁇ 0)R 5 group, wherein R 5 is OH group.
  • R 2 is a hydrogen
  • R 3 is a C(0)R 5 group, wherein R 5 is NR 7 R 8 group, wherein R 7 and R 8 are independently hydrogen, C h alky! or Cy 2 .
  • R 2 is a hydrogen
  • R 3 is a C(0)R 5 group, wherein R 5 is NR 7 R 8 group, R 7 and R 8 are hydrogen.
  • R 2 is a hydrogen
  • R 3 is a C(0)R 5 group, wherein R 5 is NR 7 R 8 group, R 7 is hydrogen, R 8 is methyl-, ethyl-, isopropyl- or f-butyi-group.
  • R 2 is a hydrogen
  • R 3 is a C(0)R 5 group
  • R 5 is NR 7 R 8 group
  • R 7 and R 8 are independently methyl-, ethyl-, isopropyl- or f-butyl-group.
  • R 2 is a hydrogen
  • R 3 is a C(0)R 5 group, wherein R 5 is NR 7 R 8 group, R 7 and R 8 are methyl-groups.
  • R 2 is a hydrogen
  • R 3 is a C(0)R 5 group, wherein R 5 is NR 7 R 8 group, R 7 is hydrogen, R 8 is optionally substituted aryl or heteroaryl group.
  • R 2 is a hydrogen
  • R 3 is a C(Q)R 5 group
  • R 5 is NR 7 R 8 group
  • R 7 and R 8 are taken together with the N to which they are attached form an optionally substituted heterocycle.
  • R 2 is a hydrogen
  • R 3 is a C(Q)R 5 group, wherein R 5 is NR 7 R 8 group, R 7 and R 8 are taken together with the N to which they are attached form an optionally substituted 4- to 7 ⁇ membered saturated heterocycle containing 1 N, 2 N, 1 N and 1 O or 1 N and 1 S.
  • R 2 is a hydrogen
  • R 3 is a C h alky! group optionally substituted with R 6 , wherein R 6 is OR 9 , NR 10 R 11 , oxo, -0(CH 2 ) m 0- group or one or more halogens.
  • R 2 is a hydrogen
  • R 3 is a methyl, ethyl or isopropyl group.
  • R 2 is a hydrogen
  • R 3 is an isopropyl group
  • R 2 is a hydrogen
  • R 3 is a single or multiple branched Ci ⁇ alkyl substituted with R 6 , wherein R 6 is OR 9 , NR 10 R 11 group or one or more halogens.
  • R 2 is a hydrogen
  • R 3 is a single or multiple branched C ⁇ alkyl substituted with R 6 , wherein R 6 is one or more halogens.
  • R 2 is a hydrogen
  • R 3 is a -Chhhalogen, -CH(halogen)CH 3 or -C(halogen) 2 CH 3 group.
  • R 2 is a hydrogen
  • R 3 is a -CHzhalogen group.
  • R 2 is a hydrogen
  • R 3 is a -ChhF group.
  • R 2 is a hydrogen
  • R 3 is a C h alky! group substituted with R 6 , wherein R 6 is oxo or -GiChh ⁇ O- 9 roup.
  • R 2 is a hydrogen
  • R 3 is a single or multiple branched Ci ⁇ alkyl group substituted with R 6 , wherein R 6 is OR 9 or NR !0 R 11 group.
  • R 2 is a hydrogen
  • R 3 is a -CH 2 R 6 or -CH(R 6 )CH 3 group, wherein R 6 is OR 9 or NR ⁇ R 11 group.
  • R 2 is a hydrogen
  • R 3 is a -CHzR 6 group, wherein R 6 is OR 9 or NR '°R 11 group.
  • R 2 is a hydrogen
  • R 3 is a C h alky! group substituted with R 6 , wherein R 6 is OR 9 .
  • R 2 is a hydrogen
  • R 3 is a -CH 2 R 6 or ⁇ CH( 6 )CH 3 group
  • 6 is OR 9 , wherein R 9 is hydrogen.
  • R 2 is a hydrogen
  • R 3 is a -CH 2 R 6 or -CH(R 6 )CH 3 group
  • R 6 is OR 9 , wherein R 9 is Ci- 4 alkyl optionally substituted with NH 2 or with optionally substituted aryl group .
  • R 2 is a hydrogen
  • R 3 is a -CH 2 R 6 or -CH(R 6 )CH 3 group
  • R 6 is OR 9 , wherein R 9 is NH 2 substituted ethyl or isopropyl .
  • R 2 is a hydrogen
  • R 3 is a -CH 2 R 6 or -CH(R 6 )CH 3 group
  • R 6 is OR 9 , wherein R 9 is ethyl or isopropyl.
  • R 2 is a hydrogen
  • R 3 is a -CH 2 R 6 or -GH(R 6 )CH3 group
  • R 6 is OR 9 , wherein R 9 is Si(CH 3 ) 3 .
  • R 2 is a hydrogen
  • R 3 is a -CH 2 R 6 or -CH(R 6 )CH 3 group
  • R 6 is OR 9 , wherein R 9 is C(0)R 12 group, R 12 is Ci-salkyl.
  • R 2 is a hydrogen
  • R 3 is a -CH 2 R 6 or -CH(R 6 )CH 3 group
  • R 6 is OR 9 , wherein R 9 is C(G)R 12 group, R 12 is methyl group.
  • R 2 is a hydrogen
  • R 3 is a -CH 2 R 6 or -CH(R 6 )CH 3 group
  • R 6 is OR 9 , wherein R 9 is C ⁇ 0)R 12 group, R 12 is NR 1 4 R 15 group.
  • R 2 is a hydrogen
  • R 3 is a -CH 2 R 6 or ⁇ CH(R 6 )CH 3 group
  • R 6 is OR 9 , wherein R 9 is G(0)R 12 group, R 12 is NR 14 R 1 5 group, wherein R 14 and R 15 is hydrogen.
  • R 2 is a hydrogen
  • R 3 is a -CH 2 R 6 or -CH(R 6 )CH 3 group
  • R 6 is OR 9 , wherein R 9 is C(0)R 12 group, R 12 is NR 14 R 15 group, wherein R 14 and R 15 are independently hydrogen or optionally substituted aryl.
  • R 2 is a hydrogen
  • R 3 is a -CH2R 6 group
  • R 6 is OR 9 , wherein R 9 is C(0)R 12 group, R 12 is NR 14 R 15 group, wherein one of R 14 is hydrogen, R 15 is 4-f!uoro-phenyl.
  • R 2 is a hydrogen
  • R 3 is a -CH2R 6 or -CH(R 6 )CH3 group
  • R 6 is OR 9 , wherein R 9 is C(0)R 12 group
  • R 12 is NR 14 R 15 group, wherein R 14 and R 15 taken together with the N to which they are attached form an optionally substituted 4- to 7-membered saturated heterocycle containing 1 N, 2 N, 1 N and 1 O or 1 N and 1 S.
  • R 2 is a hydrogen
  • R 3 is -CH2R 6 group
  • R 6 is OR 9
  • R 9 is C(0)R 12 group
  • R 12 is NR 14 R 15 group
  • R 14 and R 15 taken together with the N to which they are attached form a morpholine.
  • R 2 is a hydrogen
  • R 3 is a C h alky! group substituted with R 6 , wherein R 6 is NR '°R 11 group.
  • R 2 is a hydrogen
  • R 3 is a -CH2R 6 or -CH(R 6 )CH3 group
  • R 6 is NR 10 R 1 1 group, wherein R 10 and R 11 is hydrogen.
  • R 2 is a hydrogen
  • R 3 is a -CH2R 6 or -CH(R 6 )CH3 group
  • R 6 is NR '°R 11 group
  • R 10 and R 11 are independently hydrogen or Ci -4 a!ky! optionally substituted with Ci- 4 alkoxy group.
  • R 2 is a hydrogen
  • R 3 is a -CH2R 6 or -CH(R 6 )CH3 group
  • R 6 is NR ⁇ R 11 group
  • R 10 and R 11 are independently hydrogen, methyl, ethyl, isopropyl, s-butyl or f-butyl group.
  • R 2 is a hydrogen
  • R 3 is a -CH2R 6 or -CH(R 6 )CH3 group
  • R 6 is NR 10 R 1 1 group, wherein R 1 0 and R 11 are independently hydrogen and methyl, ethyl or isopropyl substituted with methoxy or ethoxy group.
  • R 2 is a hydrogen
  • R 3 is a -CH2R 6 or -CH(R 6 )CH3 group
  • R 6 is NR 10 R 1 1 group
  • R 10 and R 11 are independently hydrogen or Cy 3 .
  • R 2 is a hydrogen
  • R 3 is a -CH2R 6 or -CH(R 6 )CH3 group
  • R 6 is NR ⁇ R 11 group
  • R 10 is hydrogen
  • R 11 is a 4- to 7-membered saturated heterocydyi group containing 1 O or C 4-6 cycloalkyl group having geminal halogen substitution.
  • R 2 is a hydrogen
  • R 3 is a C h alky! group substituted with R 6
  • R 6 is NR ⁇ R 11 group, wherein R 10 and R 11 are independently hydrogen or C(0)R 13 .
  • R 2 is a hydrogen
  • R 3 is a -CH 2 R 6 or -CH(R 6 )CH 3 group
  • R 6 is NR ⁇ 'R 11 group
  • R 10 is hydrogen
  • R 11 is C(0)R 13
  • R 13 is C h alky!
  • R 2 is a hydrogen
  • R 3 is a -CH 2 R 6 group
  • R 6 is NR 10 R" group
  • R 10 is hydrogen
  • R 11 is C(0)R 13
  • R 13 is methyl group.
  • R 2 is a hydrogen
  • R 3 is a C h alky! group substituted with R 6
  • R 6 is NR ⁇ R 11 group
  • R 10 and R 11 are independently hydrogen or C(0)R 13
  • R 13 is Cy 1
  • R 2 is a hydrogen
  • R 3 is a C h alky! group substituted with R 6
  • R 6 is NR ⁇ R 11 group
  • R 10 and R 11 are independently hydrogen or C(0)R 13
  • R 13 is NR 16 R 17 group.
  • R 2 is a Ci- 4 alkyl group
  • R 3 is a (Ch l n R 4 , C(0)R 5 or Ci- 4 alkyl group optionally substituted with R 6 .
  • R 2 is a Ci- 4 alkyl group
  • R 3 is a (CH 2 ) n 4 group.
  • R 2 is a Ci- 4 alkyl group
  • R 3 is a C(0)R s group.
  • R 2 and R 3 are C h alky! groups.
  • R 2 and R 3 are C h alky! groups.
  • R 2 and R 3 is independently a methyl, ethyl or isopropyl group.
  • R 2 and R 3 are methyl groups.
  • R 2 is a Ci- 4 alkyl group
  • R 3 is a Ci- 4 aikyi group substituted with R 6 , wherein R 6 is OR 9 .
  • R 2 is a C h alky! group
  • R 3 is a Ci -4 a!ky! group substituted with R 6
  • R 6 is OR 9 , wherein R 9 is Ci- 4 alkyl group.
  • R 2 is a methyl or ethyl group
  • R 3 is a -CH 2 R 6 or -CH(R 6 )CH 3 group
  • R 6 is OR 9 , wherein R 9 is hydrogen.
  • R 2 is a C h alky! group
  • R 3 is a Ci- 4 aikyi group optionally substituted with R 6 , wherein R 6 is N I °R " , OXO -0(GH 2 ) m O- group or one or more halogen.
  • R 2 and R 3 jointly represent -(CH 2 ) P -0-(CH 2 )q- group, wherein p is 1 , 2 or 3 and q is 1 , 2 or 3.
  • R 2 and R 3 jointly represent -(CH 2 ) P -0-(CH 2 )q- group, wherein the sum of p and q is 3.
  • R 2 and R 3 jointly represent -(CH 2 ) p -0-(GH 2 ) q - group, wherein the sum of p and q is 4.
  • R 2 and R 3 jointly represent -(Chhjp-G-iGh jq- group, wherein p is 1 and q is 2.
  • R 2 and R 3 jointly represent -(CH 2 ) p -0- ⁇ CH 2 ) q - group, wherein p is 1 and q is 3.
  • R 2 and R 3 jointly represent -(CH 2 ) p -0-(CH 2 ) q - group, wherein p is 2 and q is 2.
  • R 2 and R 3 jointly represent ⁇ (CH 2 ) r group, wherein r is 4, 5 or 6.
  • R 2 and R 3 jointly represent ⁇ (CH 2 ) r group, wherein r is 4
  • R 1 is a hydrogen, fluorine, chlorine, bromine, methyl, methoxy, CFs or CN.
  • ring A is a 3- to 6-membered saturated carbocydic or a 4- to 7-membered saturated beterocyde containing 1 or 2 N;
  • ring B is an optionally substituted 6- or 5-membered mono-beteroaryi group, 6- to 10- membered aromatic carbocyde, or 4- to 7-membered saturated, monocyclic, bicyclic, fused and/or bridged heterocycle containing 1 , 2 or 3 heteroatoms selected from O, S or N;
  • B-Y-A- jointly represents a 3H-spiro[2-benzofuran-1 ,4’-piperidin-T-yl]; or group;
  • X is isopropyl group
  • Z is methyl group
  • ring B is optionally substituted 6-membered mono-heteroaryi group, phenyl, or 4- to 6-membered saturated, monocyclic heterocycie containing 1 or 2 heteroatoms selected from O, S or N.
  • R 3 is a -CH 2 R 6 or -CH(R 6 )CH3 group.
  • a preferred group of compounds of general formula (I) of the present invention are, for example, the following compounds and/or salts and/or solvates and/or hydrates and/or polymorphs and/or biologically active metabolites and/or prodrugs thereof:
  • the present invention also relates to the synthesis of compounds of formula (I). Accordingly, the compounds of formula (! of the present Invention can be prepared by one of the following methods:
  • R 2 is a hydrogen
  • R 3 is a C(0)R 5 group
  • R 5 is a C,.. 4 alkoxy group
  • ring A is a cydoaikyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y
  • the compounds of general formula (I) of the present invention are prepared by reacting the compounds of general formula (II)
  • ring B and Y are as defined above for genera! formula (1) and ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y - and the compounds of genera! formu!a (!!!)
  • R 1 is as defined above for general formula (I)
  • 3 is a C(0)R 5 group and R 5 is Ci- 4 aikoxy group.
  • step a) of Scheme 1 the acid hydrazide of general formula (II) is reacted with the benzazepine-fhione of general formula (111).
  • the reaction is preferably carried out in a suitable solvent, at the boiling point of the solvent, with a reaction time required from 4 to 120 hours.
  • suitable solvents include e.g. xylene, n-butanol, 1 ,4-dioxane.
  • Preferred embodiments are, for example, the following:
  • step a) of Scheme 2 the carboxylic acid esters of general formula (IV) are reacted with hydrazine hydrate in a suitable alcohol at the boiling point of the solvent to obtain the acid hydrazides of general formula (II) or, in step c), the carboxylic acids of general formula (V) is reacted with fe/f-butyl-carbazate and the protecting group of the protected carboxylic acid hydrazide derivative of general formula (VI) is removed with a suitable acid (step d)).
  • Preferred embodiments are, for example, the following:
  • step a) methanol or ethanol, hydrazine hydrate, reflux temperature, 4 to 50 hours;
  • step b) methanol, thionyl chloride, 0 to 25°C, 4 to 24 hours;
  • step c) ferf-butyl-carbazate, /V, V ⁇ dimefbylformam!de, A/,/V-di!sopropy!etby!am!ne, A/ ⁇ (3 ⁇ dimethy!aminopropyl)-/V-ethylcarbodiimide hydrochloride, 1- hydroxybenzotriazole hydrate, room temperature, 4 to 20 hours;
  • step d) hydrogen chloride in ethyl acetate, room temperature, 4 to 20 hours.
  • the carboxylic acid esters of general formula (IV) and the carboxylic acids of general formula (V) are either commercially available or can be prepared according to the methods described in the Examples.
  • the acid derivative of general formula (VII) - wherein R 1 is as defined above for genera! formula (I) - is esterified (step a)) to give the ester derivative of genera! formula (VI! I) from which oxime derivative of genera! formula (IX) is prepared (step b)).
  • the oxime of genera! formula (IX) is converted by Beckmann rearrangement to the benzazepine compound of genera! formula (X) (step c)) from which the benzazepine-thione derivative of general formula (lll-a) Is prepared (step d)).
  • Preferred embodiments are, for example, the following:
  • step a) methanol, concentrated sulfuric acid, reflux temperature, 4 to 20 hours;
  • step b) methanol, sodium acetate, hydroxy!amine hydrochloride, reflux temperature, 2 to 6 hours;
  • step c) polyphosphoric acid, 100 to 120°C, 15 to 60 minutes;
  • step d) i) Lawesson reagent, pyridine, reflux temperature, 2 to 10 hours, or
  • step a) of Scheme 4 the acetyl derivative of genera! formula (XI) can be obtained either in one step or in three consecutive steps.
  • the compound of genera! formula (X!) is a key intermediate, from which the dioxo!ane compound of genera! formula (XII) (step b)), the dif!uoro derivative of general formula (XI! ! (step c)), the protected compound of general formula (XIV) (step d)) - wherein PG 1 is a protecting group (Peter G. M. Wuts: Greene's Protective Groups in Organic Synthesis: Fifth Edition, Chapter 7.
  • the unprotected hydroxy derivative of general formula (XV-a) can be converted to the compound of general formula (X!X) (step h)) by protecting the free hydroxy group - wherein PG 2 is a protecting group different from PG 1 (Peter G. M. Wuts: Greene's Protective Groups in Organic Synthesis: Fifth Edition, Chapter 2 Protection for the Hydroxyl Group, Including 1 ,2- and 1 ,3-Dio!s, pages 17-471), preferably a siiyi protecting group.
  • Preferred embodiments are, for example, the following:
  • step a) methyl lithium solution, tetrahydrofuran, diethyl ether, ( ⁇ 1Q°C) to 5°C, 2 to 3 hours or
  • step i) aqueous sodium hydroxide solution, methanol, room temperature 0.5-3 hours, then
  • step ii) N-methoxymethanamine hydrochloride, /V-(3-dimethylaminopropyl)-A/'- ethylcarbodiimide hydrochloride, L/,/V-dimeihyiformamide, N,N- diisopropylethylamine or thethylamine, 1-hydroxybenzotriazole hydrate, room temperature, 2 to 20 hours, then
  • step iii) methylmagnesium bromide solution in diethyl ether, tetrahydrofuran, ( ⁇ 10°C) to 0°C, 2 to 12 hours;
  • step b) ethylene glycol, p-toiuenesuifonic acid, toluene, reflux temperature, 6 to 12 hours;
  • step c) and f) diethylaminosulfur trifiuoride, dichloro ethane; (-78) to 10°C, 4 to 12 hours;
  • step d) 4-methoxybenzylchloride, sodium hydride, A ,A/-dimethylformamide, 0 to 25°C, 3 to 6 hours;
  • step e-1) and e-2) sodium borohydride, ethanol or methanol, room temperature, 0.5 to 2 hours;
  • step g) i) ammonium cerium nitrate, water, acetonitrile, 0 to 25°C, 6 to 18 hours, or ii) trif!uoroacetic acid, dichloromethane, room temperature, 12 to 24 hours, or iii) trifluoromethanesulfonic acid, dichloromethane, room temperature, 2 to 12 hours;
  • step h) fe/f-butyldimethylsilyl trifluoromethanesulfonate, 2,6-lutidine, dichloromethane, A/,A/-dimethylformamide, 0 to 25°C, 6 to 18 hours.
  • the alcohol derivative of general formula (XV) is provided with a protecting group (step a) of Scheme 5) - wherein PG 1 is a protecting group, preferably 4-methoxybenzyl, PG 2 is a protecting group other than PG 1 (Peter G. M Wuts: Greene's Protective Groups in Organic Synthesis: Fifth Edition, Chapter 2 Protection for the Hydroxyl Group, Including 1 ,2- and 1 ,3-Diols, pages 17-471), preferably a silyl protecting group - to obtain the compound of general formula (XVIII).
  • the protecting group PG 1 is removed from the latter (step b)) to obtain the compound of general formula (XIX).
  • the compound of general formula (XX) - wherein alkyl represents a C h alky! group - can be prepared by the alkylation of the hydroxy compound of general formula (XV) (step c)) and then the compound of general formula (XXI) can be prepared by removing the PG 1 protecting group from the latter.
  • Preferred embodiments are, for example, the following:
  • step a) trimethyichlorosiiane, imidazole, N, AZ-dimethylformamide, room temperature, 4 to 12 hours;
  • step c) i) sodium hydride, alkyl halide, A/,A/-dimethylformamide, 0 to 100°C, 12 to 48 hours, or
  • step a) the nitrogen atom of the benzazepine derivative of general formula (X) is protected by a protecting group (step a)) to obtain the protected benzazepine derivative of general formula (XXII) - wherein PG 1 is a protecting group ((Peter G. M. Wuts: Greene's Protective Groups in Organic Synthesis: Fifth Edition, Chapter 7. Protection for the Amino Group, pages 895-1193), preferably 4-methoxybenzyl - followed by reduction of the ester group (step b)) to obtain the hydroxy compound of general formula (XXIII)
  • step e The benzazepine-thlone derivative of general formula (I! l-b) is prepared in step e).
  • Preferred embodiments are, for example, the following:
  • step a) 4-methoxybenzyl chloride, sodium hydride, A/,A/-dimethylformamide, 0 to 25°C, 3 to 6 hours;
  • step c) i) sodium hydride, alkyl halide, L/,/V-dimethyiformamide, 0 to 100°C, 12 to 48 hours, or
  • Sis silver oxide, alkyl halide, A/,A/-dimethylformamide, room temperature, 48 to 120 hours;
  • step d) i) ammonium cerium nitrate, water, acetonitrile, 0 to 25°C, 8 to 18 hours, or ii) trifiuoroacetic acid, dich!oromethane, room temperature, 12 to 24 hours, or US) trifluoromethanesulfonic acid, dichioromethane, room temperature, 2 to 12 hours;
  • step e) i) Lawesson reagent, pyridine, reflux temperature, 2 to 10 hours, or
  • the compounds of genera! formula (l-b) can be prepared by reacting the compounds of general formula (II) with the compounds of genera! formula (ll!-a) ( Scheme 7)
  • ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y.
  • Preferred embodiments are, for example, the following:
  • the nitriles of general formula ( e) can be prepared from the acid amides of general formula (l-d) (step c)) from which the tetrazoles of general formula (i-f) are obtained (step d)).
  • the oxadiazole derivatives of general formula (l-h) can also be prepared from the acids of general formula (i-c) (step f)).
  • Preferred embodiments are, for example, the following:
  • step a) methanol, sodium hydroxide, room temperature, 1 to 20 hours;
  • step b) ammonium chloride, A/-(3-dimethylaminopropyl)-A/'-ethylcarbodiimide hydrochloride, A/,A/ ⁇ dimethy!formam!de, A/,A/-diisopropylethylamine or triethylamine, 1-hydroxybenzotriazole hydrate, room temperature, 4 to 20 hours; step c) pyridine, phosphorous oxychloride, room temperature, 2 to 20 hours;
  • step d) sodium azide, ammonium chloride, A/,A/-dimethylformamide, 100 to 130°C, 2 to 8 hours;
  • step e) /) the appropriate amine derivative, /V-(3-dimethylaminopropyl)-/V- ethylcarbodiimide hydrochloride, V,/V-dimethyiformamide, N,N- diisopropyiethylam!ne or triethylamine, 1-hydroxybenzotriazoie hydrate, room temperature, 4 to 20 hours or
  • step f) A/-(3 ⁇ dimethy!aminopropyl)-A -ethyicarbodiimide hydrochloride, N,N- dimethylformamide, 1-hydroxybenzotriazole hydrate, A/ ⁇ hydroxyacetamide, 80 to 120°C, 4 to 20 hours.
  • hydroxymethyl derivatives of general formula (i-i) can be prepared by reduction of compounds of general formula (l-b) (step a) of Scheme 9 ⁇
  • ring A is a cycioa!ky! or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y.
  • the compounds of genera! formula (l-i) if desired can a!so be converted to another compound of the genera! formu!a (I) by known methods with the introduction of new substituents and/or with the modification, removal of the existing substituents and/or with salt-formation and/or with releasing the base from salts and/or with the preparation of the enantiomers from the racemic mixtures.
  • compounds may be prepared wherein R 1 is a hydrogen atom (not shown in Scheme). Further derivatives can be prepared by alkylation or acylation to obtain the compounds of genera!
  • Preferred embodiments are, for example, the following:
  • step a) dichloromethane, diethyl ether, lithium aluminium hydride, (-30) to (-10)°C, 15 to 60 minutes;
  • step b) i) sodium hydride, alkyl halide, / ⁇ /,/V-dimethylformamide or tetrahydrofuran, (-5) to 40°C, 2 to 10 hours, or
  • acyl chloride iv) acyl chloride, dichloromethane, triethylamine or A/,A/-diisopropylethylamine, room temperature, 4 to 20 hours, or
  • step c) methanesuifonyi chloride, dichloromethane, triethylamine 4 ⁇ dimethy!aminopyridine, room temperature, 2 to 20 hours;
  • step d) sodium cyanide, A/,A/-dimethyiformamide, 70 to 100°C, 3 to 20 hours;
  • step e tetrabutylammonium fluoride, tetrahydrofuran, 50 to 70°C, 4 to 20 hours;
  • step f) amine, A/,A/-dimethylformamide, A/,A/-diisopropylethyiamine, 80 to 120°C, 3 to 20 hours;
  • step g) secondary amine, A/,A/-dimethy!formamide, triethylamine, cesium carbonate, 100°C, 12 to 48 hours.
  • Step a) yields the azide compound of general formula (l-o) - wherein ring B, Y, R 1 are as defined above for general formula (l), ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y - from which the amine derivatives of general formula (l-p) can be prepared by reduction (step b)).
  • the amine derivatives of general formula (l-p) are the starting materials of the alkyl compounds of general formula (l-q) (step c)) and the acyl compounds of general formula (I- r) (step d)) - wherein ring B, Y, R 1 are as defined above for formula (l), ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y, R”’ represents an optionally substituted Ci -4 alkyl or Cy 3 as defined above for R 10 and R 11 in general formula (I), and acyl is C(G)R 13 as defined above for R 10 and R 11 in general formula (I).
  • Compounds of general formula (l-n) wherein R 10 and R 11 are optionally substituted C h alky! can also be prepared from compounds of general formula (I- p) according to step e).
  • Preferred embodiments are, for example, the following:
  • step b) triphenyiphosphine, tetrahydrofuran, water, room temperature, 4 to 20 hours; step c) i) sodium hydride, alkyl halide, /V, V ⁇ dimethylformamide or tetrahydrofuran, (-5) to 40°C, 2 to 10 hours, or
  • step d) S) acyl chloride, pyridine, room temperature, 4 to 20 hours, or
  • acyl chloride dlchloromethane, triethyiamine or /V,A -diisopropylethylamine, room temperature, 4 to 20 hours, or
  • step e) aldehyde, 1 ,2-dichloroethane, acetic acid, sodium triacetoxyborobydride, room temperature, 4 to 20 hours.
  • Preferred embodiments are, for example, the following:
  • step a) dichioromethane, trifluoroacetic acid or potassium carbonate, trimethyloxonium tetrafluoroborate, room temperature, 20 to 25 hours;
  • step b) acid hydrazide of general formula (II), dichioromethane or acetonitrile, 50°C, 6 to 20 hours;
  • step c) methanol, concentrated hydrochloric acid, 70°C, 2 to 8 hours;
  • step d) sodium borohydride, ethanol or methanol, room temperature, 1 to 2 hours
  • step e) Dess-Martin periodinane, dichioromethane, 0°C to room temperature, 1 to 5 hours;
  • step f) appropriate amine, 1 ,2-dichloroethane, sodium triacetoxyborohydride, acetic acid, room temperature, 4 to 20 hours.
  • Preferred embodiments are, for example, the following:
  • the benzazepine-thione derivative of general formula (l!!-c) is prepared from the difluoro derivative of general formula (XIII) (step a) of Scheme 13) - wherein R 1 is as defined above for general formula (I) - and the latter is reacted with an acid hydrazide of general formula (II) (step b)) to obtain the compound of general formula (i-v) - wherein ring B, Y, R 1 are as defined above for general formula (I), ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y.
  • Preferred embodiments are, for example, the following:
  • step a) i) Lawesson reagent, pyridine, reflux temperature, 2 to 10 hours, or
  • step b) i) reaction of (II) and (lli-c) in xylene at 140°C for 20 to 120 hours, or
  • reaction of (II) and (ll! ⁇ c) in n-butanol at 110°C for 20 to 50 hours or Hi) reaction of (II) and (!i!-c) in 1 ,4-dioxane at 110°C for 20 to 50 hours.
  • the benzazepine-thione derivative of general formula (! I i-d) - wherein R is as defined above for general formula (I) - is prepared from the monofiuoro derivative of general formula (XVI I) (step a) of Scheme 14) and the latter is reacted with an acid hydrazide of general formula (II) (step b) to obtain the compound of general formula (! ⁇ w) - wherein ring B, Y, R 1 are as defined above for general formula (I), ring A is a cycloalky! or a 4- to 7-membered saturated heferocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y.
  • Preferred embodiments are, for example, the following:
  • step a) i) Lawesson reagent, pyridine, reflux temperature, 2 to 10 hours, or
  • step b) i) reaction of (II) and (i!l-d) in xylene at 140°C for 20 to 120 hours, or
  • reaction of (II) and (lii-d) in n-butanol at 110°C for 20 to 50 hours or Hi) reaction of (II) and (!!l-d) in 1 ,4-dioxane at 110°C for 20 to 50 hours.
  • PG 1 is a protecting group (Peter G. M. Wuts: Greene's Protective Groups in Organic Synthesis: Fifth Edition, Chapter 2 Protection for the Hydroxyl Group, Including 1 ,2- and 1 ,3-Dio!s, pages 17-471), preferably a silyl protecting group - is prepared from the protected hydroxy compound of general formula (XIX) (step a) of Scheme 15) and the latter is reacted with an acid hydrazide of general formula (II) (step b) to obtain the compound of general formula (l-x) - wherein ring B, Y, R 1 are as defined above for general formula (I), ring A is a cycloalkyl or a 4 ⁇ to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y.
  • ring A is a cycloalkyl or a 4 ⁇ to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached
  • Preferred embodiments are, for example, the following:
  • step a) i) Lawesson reagent, pyridine, reflux temperature, 2 to 10 hours, or
  • step b) i) reaction of (II) and (lll-e) in xylene at 140°C for 20 to 120 hours, or
  • the benzazepine-thione derivative of general formula (ll!-f) - wherein R 1 is as defined above for general formula (I) and alkyl represents a C h alky! group - is prepared from the alkyl derivative of general formula (XXI) (step a) of Scheme 16) and the latter is reacted with an acid hydrazide of general formula (II) (step b) to obtain the compound of general formula (l-y) - wherein ring B, Y, R 1 are as defined above for general formula (I), ring A is a eycioa!ky! or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y.
  • Preferred embodiments are, for example, the following:
  • step a) i) Lawesson reagent, pyridine, reflux temperature, 2 to 10 hours, or
  • step b) i) reaction of (II) and (ill-f) in xylene at 140°C for 20 to 120 hours, or
  • R 2 is a C h alky! group
  • R 3 is a C(0)R s group
  • R 5 is Ci-4alkoxy group
  • ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y
  • the compounds of general formula (I) of the present invention are prepared by reacting the compounds of general formula (II)
  • ring A is a eyc!oalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y - and the compounds of general formula (XXVil)
  • R 1 is as defined above for general formula (I)
  • R 2 is a Ci-4alkyl group
  • R 3 is a C(0)R 5 group
  • R 5 is Ci-4alkoxy group.
  • step a) of Scheme 17 are, for example, the following:
  • the ketone group of the compound of general formula (VIII) is protected by a dioxolane ring (step a)), and the resulting compound of general formula (XXVIII) is alkylated (step b)) to obtain the compound of general formula (XXIX) - wherein R 1 is as defined above for general formula (!) and R 2 is a C h alky! group.
  • the latter is deprotected (step c)) and from the resulting derivative of general formula (XXX) the oxime compound of general formula (XXXI) is prepared (step d)).
  • the oxime of general formula (XXXI) is converted by Beckmann rearrangement to the benzazepine compound of genera! formula (XXXII) (step e)).
  • Preferred embodiments are, for example, the following:
  • step a) ethylene glycol, toluene, p-toluenesulfonic add, reflux temperature, 2 to 12 hours;
  • step b) lithium diisopropylamide, alkyl iodide, tetrahydrofuran, ( ⁇ 78)°C, 0.5 to 2 hours; step c) i) methanol, concentrated hydrochloric acid, 70°C, 2 to 6 hours, or
  • step d) methanol, sodium acetate, hydroxylamine hydrochloride, reflux temperature, 3 to 6 hours;
  • step e poiyphosphoric acid, 100 to 120°C, 15 to 60 minutes.
  • Preferred embodiments are, for example, the following:
  • step a) i) sodium hydride, A/,A/-dimethylformamide, alkyl iodide, O to 100°C, 1 to 12 hours, or
  • step b) i) lithium diisopropylamide, alkyl iodide, tetrahydrofuran, (-78)°C, 0.5 to 2 hours; step b) i) ammonium cerium nitrate, water, acetonitrile, 0 to 25°C, 8 to 18 hours, or ii) trifluoroacetic acid, dichioromethane, room temperature, 12 to 24 hours, or iii) trifluoromethanesulfonic acid, dichioromethane, room temperature, 2 to 12 hours.
  • Preferred embodiments are, for example, the following:
  • step b) methanol, sodium hydroxide, room temperature, 3 to 6 hours;
  • step c) sulphuric add, room temperature, 0 5 to 1 5 hours;
  • step d) thionyl chloride, methanol, 80°C, 8 to 8 hours.
  • the benzazepine-thione derivative of general formula (XXVI I -a) is prepared from the key intermediate of general formula (XXXII) (step a) of Scheme 21) and the latter is reacted with the add hydrazide of formula (II) to obtain the compounds of general formula (l-z) (step b)) - wherein ring B, Y, R 1 are as defined above for general formula (I), ring A is a cycloaikyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y and R 2 is a C h alky! group.
  • the compounds of general formula (l-z) can also be synthesized from the compound of general formula (XL-a) (step d)) and the latter can be obtained from the compound of general formula (XXVI l-a) by methylation (step c)).
  • Preferred embodiments are, for example, the following:
  • step a) i) Lawesson reagent, pyridine, reflux temperature, 2 to 10 hours, or
  • step b) i) reaction of (II) and (XXVI l-a) In xylene at 140°C for 20 to 120 hours, or
  • the compounds of general formula (l-z) - in a manner similar to the compounds of general formulae (l-b) or (l-i) ⁇ if desired can also be converted to another compound of the general formula (!) by known methods with the introduction of new substituents and/or with the modification, removal of the existing substituents and/or with salt-formation and/or with releasing the base from salts and/or with the preparation of the enantiomers from the racemic mixtures, for example with any of the methods shown in Scheme 8 to 10.
  • R 2 is a hydrogen
  • R 3 is a
  • ring A is a 4- to 7- membered saturated heterocycie containing 1 or 2 N, wherein ring A is attached via a ring nitrogen to the triazole ring of the 5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine core - and the compounds of genera! formula (XXX!X)
  • R 1 is as defined above for general formula (!)
  • R 2 is a hydrogen
  • R 3 is C(0)NH 2 group.
  • step a) of Scheme 22 are, for example, the following:
  • the compounds of general formula (lll-a) are methylated (step a)) and the resulting compound of general formula (XL-b) is reacted with formyl hydrazine (step b)) to obtain the compounds of general formula (XLI) - wherein R 1 is as defined above for general formula (I)
  • the latter is brominated (step c)) to obtain the bromo derivative of general formula (XLI! - wherein R 1 is as defined above for general formula (I).
  • the compounds of general formula (XLI! I) is prepared by hydrolysis (step d)) and then the acid amide of general formula (XXXIX) is formed in step e).
  • the acid amide of general formula (XXXIX) the nitril derivative of general formula (LI I) can also be synthesized (step f)) and the latter can be reacted with the compounds of general formula (XXXVI 11)
  • ring A is a 4- to 7 ⁇ membered saturated heterocycle containing 1 or 2 N, wherein ring A is attached via a ring nitrogen to the triazole ring of the 5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine core - to yield the compounds of general formula (l-ac).
  • Preferred embodiments are, for example, the following:
  • step a) iodomethane, potassium carbonate, acetone, room temperature, 4 to 24 hours; step b) formyihydrazine, 1 ,4-dioxane, 90°C, 3 to 10 hours;
  • step c) A/-bromosuccinimide, tetrahydrofuran, 70°C, 10 to 60 minutes;
  • step d methanol, sodium hydroxide, room temperature, 1 to 20 hours;
  • step e ammonium chloride, A/ ⁇ (3 ⁇ dimethylaminopropyi)-A '-ethyicarbodiimide hydrochloride, A/,A/-dimethylformamide, A/,A/-diisopropylethyla ine or triethylamine, 1-hydroxybenzotriazole hydrate, room temperature, 4 to 20 hours
  • step g) i) melt (without solvent), 120 to 150°C, 3 to 72 hours, or
  • si sulfolane, 140 to 180°C, 3 to 72 hours.
  • the compounds of general formula (l-aa) prepared according to Scheme 22 if desired can also be converted to another compound of the general formula (I) by known methods with the introduction of new substituents and/or with the modification, removal of the existing substituents and/or with salt-formation and/or with releasing the base from salts and/or with the preparation of the enantiomers from the racemic mixtures, for example using steps c) and d) shown in Scheme 8.
  • R 1 is as defined above for general formula (I)
  • R 2 is a hydrogen or Ci ⁇ alkyl
  • R 3 is a Ci. 4 alkyl group
  • R 2 and R 3 jointly represent -(CH 2 )p-0-(CH 2 )q- or-(CH 2 )r group (p is 1 , 2 or 3; q is 1 , 2 or 3; r Is 4, 5 or 6) can be prepared by the procedures described in detail in Scheme 24:
  • step c) Decarboxylation (step c)) of compound of genera! formula (XLVi) yields compound of general formula (XLVi I), from which compound of general formula (XLVI 11) is prepared by treatment with concentrated sulfuric acid (step d)).
  • Oxime derivative of general formula (XLIX) is then prepared (step e)) from compound of general formula (XLVI 11), which is converted by Beckmann rearrangement (step fj) to the benzazepine compound of general formula (L).
  • R 3 is a hydrogen
  • compound of general formula (L) is chlorinated or brominated (step g)) to obtain the compound of genera!
  • formula (LI) Compound of general formulae (LI) or (L) are converted to compound of general formula (l-ad) (step h)), wherein R 1 as defined above for genera! formula (I), R 2 is a hydrogen or Ci- 4 alkyl, R 3 is a Ci -4 alkyl group, or R 2 and R 3 jointly represent -(CHsj p -O- (CH2) q - or -(Ch )r group (p is 1 , 2 or 3; q is 1 , 2 or 3; r is 4, 5 or 6), ring B and Y are as defined above for general formula (! and ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the ring nitrogen to Y
  • Preferred embodiments of the synthesis of Scheme 24 are, for example, the following: step a) benzylmagnesium chloride or 3-fluorobenzy!magnesium chloride, diethyl ether, room temperature, 2 to 12 hours;
  • step b) 2 M aqueous sodium hydroxide, ethanol, reflux temperature, 2 hours;
  • step c) heating at 180-200°C, 3-5 minutes;
  • step d) sulfuric acid, 35 to 40°C, 80 minutes
  • step e) methanol, sodium acetate, hydroxy!amine hydrochloride, reflux temperature, 2 to 6 hours;
  • step g) bromine, acetic acid/water, room temperature, 30 to 90 minutes or N- chlorosuccimide, D F, room temperature, 30 to 90 minutes
  • step h) i) Lawesson reagent, pyridine, reflux temperature, 2 to 10 hours,
  • the acid hydrazides of general formula (II), wherein ring B and Y are as defined above for general formula (I) and ring A is a cycloalkyl or a 4- to 7-membered saturated heferocycie containing 1 N, wherein ring A is attached via the ring nitrogen to Y, can be synthesized in various ways as described in Scheme 2.
  • a compound of general formula (X) - wherein R 1 is as defined above for general formula (!) - is reduced (step a)) and the obtained hydroxy compound of general formula (Llll) is converted to a fluorine derivative of general formula (LIV) (step b)).
  • the compound of general formula (l- ) can be synthesized either directly from the benzazepine-thione of general formula (LV) (step e)), which is obtained from a compound of general formula (LIV) in step c), or from the methylsulfanyi derivative of general formula (LVI I) in step h).
  • the latter can be prepared from the benzazepine-thione of general formula (LV) by methy!ation (step f)).
  • An alternative synthetic pathway is to methylate the compound of general formula (LIV) (step d)) and reacting the obtained methoxy derivative of general formula (LVI) in situ with a compound of general formula (II) (step g) to yield compound of general formula (l-m).
  • Preferred embodiments of the synthesis of Scheme 25 are, for example, the following: step a) lithium aluminum hydride, diethyl ether, tetrahydrofuran, (-40) to 0°C, 0.1 to 2 hours;
  • step b) diethylamino sulphur trifluoride, dichloromethane; (-78) to 10°C, 4 to 12 hours; step c) i) Lawesson reagent, pyridine, reflux temperature, 2 to 10 hours, or
  • step d) trimethyloxonium tetrafluoroborate, trifluoroacetic acid or potassium carbonate, dichloromethane, room temperature, 2 to 4 hours;
  • step e) i) reaction of acid hydrazide of formula (II) and (LV) in xylene at 140°C for 20 to 120 hours, or
  • step f) iodomethane, potassium carbonate, acetone, room temperature, 4 to 24 hours;
  • step h) reaction of acid hydrazide of formula (II) and (LVII) in 1 ,4 ⁇ dioxane at 110°C for 2 to 20 hours.
  • R 1 as defined above for general formula (I) R 2 is a hydrogen or Ci-4alkyl
  • R 3 is a Ci ⁇ aikyi group
  • R 2 and R 3 jointly represent -(CH 2 ) P -0-(GH 2 )q- or -(CH2) r - group
  • p is 1 , 2 or 3
  • q is 1 , 2 or 3
  • r is 4, 5 or 6
  • ring A is a 4 ⁇ to 7-membered saturated heterocycle containing 1 or 2 N, wherein ring A is attached via a ring nitrogen to the triazole ring of the 5,8-dihydro-4H- [1 ,2,4]triazo!o[4,3-a][1]benzazepine core, can be prepared according to the methods described in Scheme 26.
  • ring A is a 4- to 7 ⁇ membered saturated heterocycle containing 1 or 2 N, wherein ring A is attached via a ring nitrogen to the triazole ring of the 5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine core - to yield the compounds of general formula (l-ae).
  • Preferred embodiments of the synthesis of Scheme 26 are, for example, the following: step a) i) Lawesson reagent, pyridine, reflux temperature, 2 to 10 hours, or
  • step b) iodomethane, potassium carbonate, acetone, room temperature, 4 to 24 hours; step c) formylhydrazine, 1 ,4-dioxane, 90°C, 3 to 10 hours;
  • step d) A/-bromosuccinimide, tetrahydrofuran, 70°C, 10 to 80 minutes;
  • step e) i) melt (without solvent), 120 to 150°C, 3 to 72 hours, or
  • An aspect of the present invention is novel intermediates represented by the general formulae (lli-a), (X), (XL! I), (LI) and (LIV) synthesised in the process for preparing the compound of formula (I) wherein R 1 is as defined above for general formula (I), especially methyl 7-chloro-2-oxo-2,3,4,5-tetrahydro-1 H-1-benzazepine-4-carboxylate (Intermediate 3), methyl 7-chloro-2-thioxo-2,3,4,5-tetrahydro-1 H-1-benzazepine-4-carboxylate (Intermediate 4), methyl 1-bromo-8-chloro-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5- carboxyiate (Intermediate 24), 7 ⁇ chioro-4-(fiuoromethyl)-1 ,3,4,5 ⁇ tetrahydro-2H ⁇ 1 ⁇ benzazepin-2
  • the immortalized 1321 N1 cell line (Perkin Elmer, ES-361-M400-UA) constitutive!y and stably expressing human vasopressin Via receptor and vasopressin (8-L-Arginine), [Phenyialanyl-3,4,5- 3 H(N)] labelled compound (Perkin Elmer Life and Analytical Sciences) as radioligand were used to determine the affinity of the prepared compounds.
  • Membrane-preparation Membrane preparation of immortalized 1321 N1 cells expressing the propagated human Vasopressin Via receptor was made according to Jarvis's method (Jarvis ei al., J Pharmacol Exp Ther 2004, 310:407-16). Cells were suspended in preparative buffer (50 mM Tris, 1 mM EDTA, 0.1 mM PMSF) and homogenized with glass homogenizing potter. To separate the raw membrane fraction two consecutive centrifugation procedures (40,000 g for 20 minutes at 4°C) were executed, then the membrane was taken into the preparatory buffer during a final washing step, it was divided into aliquots which were stored at -80°C until the time of measurement.
  • preparative buffer 50 mM Tris, 1 mM EDTA, 0.1 mM PMSF
  • the protein content of the prepared membrane was determined according to Lowry’s method using standard dilution line of bovine serum albumin (BSA) (Lowry et al., JBioi Chem 1951 , 193:265-75).
  • BSA bovine serum albumin
  • Receptor binding test In the receptor binding assay, the substances with unknown affinity were used at a minimum of 8 different concentrations, with 3 parallels at each concentration. To determine the final affinity value, the results of at least two independent experiments were taken info account.
  • the assay mixture included the incubation buffer (50 mM Tris-HCI, pH 7.4 + 3% BSA), membrane preparation of 1321 N1 cells expressing the human Vasopressin Via receptor (167 pg/m! and Vasopressin (8-L-Arginine), [Phenyialanyl-3,4,5- 3 H(N)j as radioligand (1 nM).
  • Non-specific binding values were determined in the presence of unlabelled 1.2x1 O 6 M (Arg 8 )-vasopressin Samples were incubated in a total volume of 0.33 ml for 60 minutes at 27°C. Membrane-bound and free ligands were separated by filtration through a 0.5% polyethyleneimine-impregnated UniFi!tert® GF/BTM. After drying the filter plates, 40 mI Microscint ⁇ 20 (Packard) scintillation cocktail was added to the samples. Finally, radioactivity was measured using MicroBeta 2 Microplate Counter (Perkin Elmer).
  • the ICso data i.e. the concentration of the unknown substance which displaces 50% of specific bound radioligand
  • y (A1-A2)/(1+(x/x 0 )p)+A2 with Origin 7.5. software (OriginLab Corporation, Northampton, USA).
  • the K D is determined beforehand using the Scatchard curve.
  • the immortalized 1321 N1 cell line (Perkin Elmer, ES-361-M400-UA) constitutiveiy and stably expressing human vasopressin Via receptor were used to measure the prepared compounds.
  • the ordinary secondary messenger pathway of the measured GPCR receptor was used, the endogenous G q ⁇ associated system.
  • FLIPR Calcium 5 kit (Molecular Devices) was used as fluorescent dye, the medium was not removed prior to filling with the dye and the cells were not washed out either before or after. The incubation was performed at room temperature, the final concentration of DMSO was 1 %.
  • the materials to be measured were administered in 15 to 20 minutes pretreatment, at least two parallels of each compound in each concentration was measured.
  • Fluorescence signal was used to determine the intracellular Ca 2+ level, the reader was FlexStation II96. Cytoplasmic Ca 2+ concentrations were measured by fluorometry using the FlexStation M98 plate reader (excitation: 485 nm, emission: 525 nm). The fluorescence signal was logged in every 1.4 seconds for 1 minute.
  • the reference compounds used were the following: (Arg 8 )-vasopressin as agonist at concentration of ECeo, determined for each plate, and relcovaptan as antagonist at 1 mM. The % of inhibition at each concentration and the ICso value of the compounds were determined where a concentration line was also measured.
  • the total AVP concentration-response curve was recorded on each plate.
  • the effect of compounds measured was expressed by percentage of relative inhibition compared to control response.
  • the average ICso values were calculated from at least three independent measurements in all cases.
  • Table 1 The effectiveness of the compounds of the present invention measured in human vasopressin Via receptor binding assay and functional assay
  • the immortalized 1321 N1 cell line (B9/1321 N1 clone) constitutively and stably expressing mouse vasopressin Via receptor vasopressin (8-L-Arginine), [Phenylaianyi- 3,4,5- 3 H(N)j labelled compound (Perkin Elmer Life and Analytical Sciences) as radioligand were used to determine the affinity of the prepared compounds.
  • Membrane-preparation Membrane preparation of immortalized 1321 N1 cells expressing the propagated mouse Vasopressin Via receptor was made according to Jarvis's method (Jarvis ef ai., J Pharmacol Exp Ther 2004, 310:407-16). Cells were suspended in preparative buffer (50 mM Tris, 1 mM EDTA, 0.1 mM PMSF) and homogenized with glass homogenizing potter. To separate the raw membrane fraction two consecutive centrifugation procedures (40,000 g for 25 minutes at 4°C) were executed, then the membrane was taken into the preparatory buffer during a final washing step, it was divided into aliquots which were stored at -80°C until the time of measurement.
  • preparative buffer 50 mM Tris, 1 mM EDTA, 0.1 mM PMSF
  • the assay mixture included the incubation buffer (50 mM Tris-HCI, pH 7.4 + 3% BSA), membrane preparation of 1321 N1 cells expressing the mouse vasopressin Via receptor (152 pg/ml) and vasopressin (8-L-Arginine), [Phenyla!any!- 3,4,5- 3 H(N)] as radioligand ( ⁇ 35-50% concentration of K D ).
  • Table 2 The binding affinity of certain compounds of the present invention measured in mouse vasopressin Via receptor binding assay
  • the immortalized 1321 N1 cell line (Perkin Elmer, ES-383-M400UA)(LotNo: 1765208) stably and constitutively expressing human vasopressin V2 receptor, CHO-K1 cell membrane expressing human Vasopressin V2 receptor (Perkin Elmer, 6110541400UA) and vasopressin (8-L-Arginine), [Phenylalany! ⁇ 3,4,5- 3 H(N)] labelled compound (Perkin Elmer Life and Analytical Sciences) as radioligand were used to determine the affinity of the prepared compounds.
  • the radioligand displacement ability of a substance is determined in at least two independent experiments.
  • Specific radioligand binding can be defined as the difference between total and non-specific binding in the presence of a saturation amount of the uniabel!ed ligand or different concentrations of the substance to be tested. The results are given as a percentage of inhibition of the specific binding achieved in the presence of the substance to be tested.
  • Table 3 The binding affinity of certain compounds of the present invention measured in human vasopressin V2 receptor binding assay on 1321 N1 cell line
  • Receptor binding assays were performed in at least 8 concentrations, with two or rather three parallel samples in each concentration, in at least two independent experiments using an incubation buffer (50 mM Tris-HCi, 5 mM MgGh, pH 7.4 + 0.1% BSA), membrane preparation of CHO-K1 cells (Perkin Elmer, 6110541400UA) expressing the human vasopressin V2 receptor (7 pg/mI) and Vasopressin (8-L-Arginine), [Phenylalanyl- 3,4,5- 3 H(N)] as radioligand (-concentration of KD).
  • an incubation buffer 50 mM Tris-HCi, 5 mM MgGh, pH 7.4 + 0.1% BSA
  • membrane preparation of CHO-K1 cells Perkin Elmer, 6110541400UA
  • expressing the human vasopressin V2 receptor (7 pg/mI) and Vasopressin (8-L-Arginine) [Phenylalanyl- 3,
  • Non-specific binding values can be determined in the presence of an unlabelled 1.2 x 10- 6 M (Arg 8 )-vasopressin.
  • Samples incubated in a total volume of 0.55 mL for 90 minutes at 27°C.
  • Membrane-bound and free ligands were separated by filtration through a polyethyleneimine-impregnated UniFiiter® GF/BTM.
  • the filterplates were washed three times with 0.5 mL of ice-cold washing buffer (50 mM Tris-HCI, pH 7.4). After drying the filter plates, 40 m! of Microscint20 (Packard) scintillation cocktail was added to each well. Finally, radioactivity was measured using Tri-Carb 29QQTR liquid scintillation analyzer (Perkin Elmer).
  • mice Male mice (NMRI, ToxiCoop) weighing 18-40 g were used. Animals were kept at least 5 days after delivery, during housing and measurements they could feed and drink ad libitum. The experiments were permitted by the Local Animal Protection Committee and carried out in accordance with the European Animal Protection Directives (EU Directive 2010/63/Elf ⁇ .
  • EU Directive 2010/63/Elf ⁇ European Animal Protection Directives
  • mice were pretreated with the test substance or vehicle, and after the pretreatment period scratching-inducing compound (s.c. 0.3 mg/kg oxytocin) was administered, and then the animals were individually placed into measuring cages. Their behaviour was observed for 1 hour. To reduce the exploratory activity, the animals were measured after a 1-hour habituation to the cage. The behavioural parameters were compared to the parallel measured parameters of the control animals.
  • the behavioural Inhibitory effect of the substances was calculated with average values of parallel measured vehicle treated groups and presented as the percentage of inhibition: 0% was expressed as average value of scratching behaviour of vehicle pretreated animals (and phys. saline s.c. pretreated with vehicle), while 100% was expressed as average value of scratching of vehicle pretreated animals that received oxytocin subcutaneously.
  • a NOVA one-way analysis of variance
  • Table 4 The efficacy of certain compounds of the present invention in the mouse in vivo Via functional test: the inhibition of oxytocin- induced scratching behavior response after 10 mg/kg p.o pretreatment in mice.
  • DIPEA /V,A/-diisopropyl-ethylamine
  • Lawesson reagent 2,4-bis(4-methoxyphenyl)-1 ,3,2,4-dithiadiphosphethane-2 4-disulfide
  • Meidrum’s acid 2,2-dimethyl-1 ,3-dioxane-4,6-dione
  • NaBhU sodium borohydride
  • NaHCOs sodium bicarbonate
  • reaction mixture was stirred for 20 minutes at this temperature, then 2.46 mL (39.5 mmol) of iodomethane was added dropwise over 20 minutes.
  • the mixture was stirred for a further hour at 0-5°C, allowed to warm to room temperature and stirred for 3 hours at this temperature.
  • 1 8 mL (31 mmol) of acetic acid was added dropwise over 10 minutes, after stirring for 15 minutes, the reaction mixture was concentrated and 90 mL of n-heptane was evaporated off the residue twice.
  • reaction mixture was stirred at room temperature for 2 h, then diluted with water.
  • the pH of the mixture was adjusted to 8 by addition of 10% K 2 CO 3 solution, the phases were separated and the water phase was extracted with dichioromethane.
  • the combined organic phases were successively washed with 10% K 2 CO 3 solution, water and brine, dried over Na 2 S0 4 filtered and concentrated.
  • the residue was dissolved in 40 mL of dry THF and 330 mg (2.94 mmol) of potassium tert-butoxide was added.
  • the reaction mixture was stirred at room temperature for 3 h, then neutralized by addition of solid CO 2 .
  • the THF was evaporated and the water phase was extracted with ethyl acetate.
  • the reaction mixture was transferred over 25-30 min via a cannula to an ice-cold mixture of 180 mL of ethyl acetate, 425 mL of water, 75 mL of concentrated hydrochloric acid and 100 g of crushed ice while keeping the internal temperature below 10°C.
  • the phases were separated, the organic phase was successively washed with 400 mL of water and 400 mL of brine, dried over Na 2 SG 4 , filtered and concentrated to yield 5.44 g (53%) of title compound.
  • 1 HNMR spectroscopy it was a 28:72 mixture of cis- and trans- isomers. This mixture was used in the next step without further purification.

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Abstract

La présente invention concerne des dérivés de 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1] benzazépine de formule générale (I) et/ou des sels de ceux-ci et/ou des isomères géométriques et/ou des stéréoisomères et/ou des énantiomères et/ou des racémates et/ou des diastéréomères et/ou des métabolites actifs sur le plan biologique et/ou des promédicaments et/ou des solvates et/ou des hydrates et/ou des polymorphes desdits dérivés qui sont des modulateurs du récepteur de V1a à action centrale et/ou périphérique, en particulier des antagonistes du récepteur de V1a. La présente invention concerne également un procédé de préparation des composés ainsi que des intermédiaires du procédé de préparation. L'invention concerne également des compositions pharmaceutiques contenant les composés ou conjointement avec une ou plusieurs autres substances actives, ainsi que l'utilisation dans le traitement et/ou la prophylaxie d'une maladie ou d'un état pathologique associé à la fonction du récepteur de V1a.
PCT/IB2018/060078 2017-12-15 2018-12-14 Composés tricycliques utilisés en tant qu'antagonistes du récepteur de la vasopressine v1a Ceased WO2019116325A1 (fr)

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WO2021191838A1 (fr) 2020-03-26 2021-09-30 Richter Gedeon Nyrt. DÉRIVÉS DE NAPHTYRIDINE ET DE PYRIDO[3,4-C]PYRIDAZINE SERVANT DE MODULATEURS DU RÉCEPTEUR GABAA α5
CN114644635A (zh) * 2020-12-21 2022-06-21 上海济煜医药科技有限公司 三氮唑类三并环衍生物及其制备方法和应用
WO2023053015A1 (fr) 2021-09-29 2023-04-06 Richter Gedeon Nyrt. DÉRIVÉS BICYCLIQUES D'AMINE SERVANT DE MODULATEURS DU RÉCEPTEUR GABAA α5
JP2023534713A (ja) * 2020-07-23 2023-08-10 エフ． ホフマン－ラ ロシュ アーゲー バソプレシン受容体ｖ１ａアンタゴニストとしてのシクロヘキシル置換トリアゾール

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JP2023534713A (ja) * 2020-07-23 2023-08-10 エフ． ホフマン－ラ ロシュ アーゲー バソプレシン受容体ｖ１ａアンタゴニストとしてのシクロヘキシル置換トリアゾール
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