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(51) International Patent Classification: C07D 223/06 (2006.01) A61K 31

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( (51) International Patent Classification: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, C07D 223/06 (2006.01) A61K 31/55 (2006.01) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. C07D 223/10 (2006.01) A61P 25/00 (2006.01) (84) Designated States (unless otherwise indicated, for every C07D 487/04 (2006.01) A61P 25/24 (2006.01) kind of regional protection available) . ARIPO (BW, GH, C07D 487/14 {2006.01) GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (21) International Application Number: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, PCT/IB20 18/060078 TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (22) International Filing Date: MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 14 December 2018 (14. 12.2018) TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, (25) Filing Language: English KM, ML, MR, NE, SN, TD, TG). (26) Publication Language: English Declarations under Rule 4.17: (30) Priority Data: — as to applicant's entitlement to apply for and be granted a P1700522 15 December 2017 (15. 12.2017) HU patent (Rule 4.17(H)) P1800332 28 September 2018 (28.09.2018) HU Published: (71) Applicant: RICHTER GEDEON NYRT. [HU/HU]; — with international search report (Art. 21(3)) Gydmrdi t 19-21., 1103 Budapest (HU). (72) Inventors: BATA, Imre; Frankel Leo lit 7., 1027 Budapest (HU). SZELECZKY, Zsolt; Kanizsai u . 1., 1114 Budapest (HU). SZONDINE KORDAS, Krisztina; Rakosi lit 163., 1162 Budapest (HU). SZANT0, Gabor; Ormester u . 27, 1163 Budapest (HU). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (54) Title: TRICYCLIC COMPOUNDS AS VASOPRESSIN VIA RECEPTOR ANTAGONISTS (57) Abstract: The present invention relates to 5,6-dihydro-4H-[l,2,4]triazolo[4,3-a][l]benzazepine derivatives of 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 or together with one or more other active substances, as well as to the use in the treatment and/or prophylaxis of a disease or condition associated with Via receptor function. TRICYCLIC COMPOUNDS AS VASOPRESSIN V1 RECEPTOR ANTAGONISTS THE FIELD OF THE INVENTION The present invention relates to 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine derivatives of the general formula ( ) 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 THE BACKGROUND OF THE INVENTION The vasopressin (antidiuretic hormone, ADH, CYIQNCPRG) is 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. For this reason, the conditions due to inappropriate secretion of vasopressin thus the lack of 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 a ., BMC Neuroscience 2008, 9:1 11). 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. Similarly, 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. Three vasopressin receptors are distinguished, all of them are G-protein coupled receptors. The Via receptor (V1aR) is expressed centrally in the cerebral cortex, hippocampus and pituitary gland, furthermore peripherally in the liver, vascular smooth muscle, lung, uterus and testes (Frank et a , Eur J Pharmacol 2008, 583:226-42) The V 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. In contrast to this, the V2 receptor (V2R) 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). Thus, due to changes in the regulation of water balance the effect on the V2 receptor may cause undesirable side effect. The secondary signalling pathway of Via and V1b receptors include the change of intracellular Ca2 concentration through phosphatidylinositol, whereas the V2 receptors activate adenylate cyclase enzyme and influence cAMP levels (Gouzenes et a ., J Physiol 1999, 5 17(Pt3):771-9; Tahara et a ., Pf!ugers Arch 1999, 437(2):219-26). An important role is attached to the Via receptors in the regulation of the circadian rhythm. One-third of the neurons in the suprachiasmatic nucleus (SCN) express vasopressin and the mRNA of Via receptors exhibit daily fluctuations in this brain region of which the highest values can be observed during night hours (de Vries and Miller, Prog Brain Res 1998, 119:3-20). 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 a ., 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). 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 a , Behav Brain Res 2005, 164(1):132-6). The male V1aR knockout mice did not show any phenotypic difference in motor performances. In normal light-dark-cycle experiments, 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 Via knockout mice was shifted significantly (Egashira et al., Behav Brain Res 2007, 178(1):123-7). The V1aR 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 a have shown decreased function in the social interaction test, which is suitable to measure socio-cognitive behaviour of the V1aR KO mice in both sexes, but it was not observed after the treatment with antagonist (Bleickard et a , Psychopharmacology (Berl) , 2009, 202:71 1-18).
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    0022-3565/07/3221-172–179$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 322, No. 1 Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics 118869/3215703 JPET 322:172–179, 2007 Printed in U.S.A. In Vitro Pharmacology of Clinically Used Central Nervous System-Active Drugs as Inverse H1 Receptor Agonists R. A. Bakker,1 M. W. Nicholas,2 T. T. Smith, E. S. Burstein, U. Hacksell, H. Timmerman, R. Leurs, M. R. Brann, and D. M. Weiner Department of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (R.A.B., H.T., R.L.); ACADIA Pharmaceuticals Inc., San Diego, California (R.A.B., M.W.N., T.T.S., E.S.B., U.H., M.R.B., D.M.W.); and Departments of Pharmacology (M.R.B.), Neurosciences (D.M.W.), and Psychiatry (D.M.W.), University of California, San Diego, California Received January 2, 2007; accepted March 30, 2007 Downloaded from ABSTRACT The human histamine H1 receptor (H1R) is a prototypical G on this screen, we have reported on the identification of 8R- protein-coupled receptor and an important, well characterized lisuride as a potent stereospecific partial H1R agonist (Mol target for the development of antagonists to treat allergic con- Pharmacol 65:538–549, 2004). In contrast, herein we report on jpet.aspetjournals.org ditions. Many neuropsychiatric drugs are also known to po- a large number of varied clinical and chemical classes of drugs tently antagonize this receptor, underlying aspects of their side that are active in the central nervous system that display potent effect profiles.