- Developing pyridazine-3-carboxamides to be CB2 agonists: The design, synthesis, structure-activity relationships and docking studies
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Herein, we described the design and synthesis of a series of pyridazine-3-carboxamides to be CB2-selective agonists via a combination of scaffold hopping and bioisosterism strategies. The compounds were subjected to assessment of their potential activities through calcium mobilization assays. Among the tested derivatives, more than half of these compounds exhibited moderate to potent CB2 agonist activity. Six compounds showed EC50 values below 35 nM, and several derivatives also exhibited significantly enhanced potency and high selectivity at the CB2 receptor over the CB1 receptor. Specifically, compound 26 showed the highest CB2 agonist activity (EC50 = 3.665 ± 0.553 nM) and remarkable selectivity (Selectivity Index > 2729) against CB1. In addition, logPs of some representative compounds were measured to display significantly decreased values in comparison with GW842166X. Furthermore, docking simulations were conducted to explain the interaction mode of this series.
- Qian, Hai-Yan,Wang, Zhi-Long,Xie, Xiao-Yu,Pan, You-Lu,Li, Gang-Jian,Xie, Xin,Chen, Jian-Zhong
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Read Online
- INHIBITOR COMPOUNDS
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The disclosure relates to heterocyclic compounds and methods for their preparation. The disclosure provides compounds that may have beneficial therapeutic activity in the treatment of a disease or condition mediated by excessive or otherwise undesirable Des1 and/or fibrotic activity.
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Page/Page column 63; 146-147
(2021/01/29)
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- Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}- N-methylpyridine-2-carboxamide (AZD5305): A PARP1-DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs
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Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1-DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure- and property-based design of 25 (AZD5305), a potent and selective PARP1 inhibitor and PARP1-DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25 is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro.
- Balazs, Amber,Barratt, Derek,Bista, Michal,Chuba, Matthew D.,Cosulich, Sabina,Critchlow, Susan E.,Degorce, Sébastien L.,Di Fruscia, Paolo,Edmondson, Scott D.,Embrey, Kevin,Fawell, Stephen,Ghosh, Avipsa,Gill, Sonja J.,Gunnarsson, Anders,Hande, Sudhir M.,Heightman, Tom D.,Hemsley, Paul,Illuzzi, Giuditta,Johannes, Jeffrey W.,Lane, Jordan,Larner, Carrie,Leo, Elisabetta,Liu, Lina,Madin, Andrew,Martin, Scott,McWilliams, Lisa,O'Connor, Mark J.,Orme, Jonathan P.,Pachl, Fiona,Packer, Martin J.,Pei, Xiaohui,Pike, Andrew,Schimpl, Marianne,She, Hongyao,Staniszewska, Anna D.,Talbot, Verity,Underwood, Elizabeth,Varnes, Jeffrey G.,Xue, Lin,Yao, Tieguang,Zhang, Andrew X.,Zhang, Ke,Zheng, Xiaolan
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supporting information
p. 14498 - 14512
(2021/10/20)
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- FLAVONE COMPOUNDS FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS DISEASE
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The present invention provides flavone derivatives having the general formula (I) which are useful for the treatment of Hepatitis B Virus infection (HBV). The compounds act as cccDNA (covalently closed circular DMA) inhibitors.
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Page/Page column 84-85
(2020/05/06)
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- BENZAMIDE DERIVATIVE
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The present invention relates to a benzamide derivative of general formula I, a drug composition containing same and a use thereof as a drug, wherein the definitions of R1, Z and Q are as described in the description.
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Paragraph 0083
(2018/08/20)
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- Piperazin-1-ylpyridazine Derivatives Are a Novel Class of Human dCTP Pyrophosphatase 1 Inhibitors
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The dCTP pyrophosphatase 1 (dCTPase) is a nucleotide pool “housekeeping” enzyme responsible for the catabolism of canonical and noncanonical nucleoside triphosphates (dNTPs) and has been associated with cancer progression and cancer cell stemness. We have identified a series of piperazin-1-ylpyridazines as a new class of potent dCTPase inhibitors. Lead compounds increase dCTPase thermal and protease stability, display outstanding selectivity over related enzymes and synergize with a cytidine analogue against leukemic cells. This new class of dCTPase inhibitors lays the first stone toward the development of drug-like probes for the dCTPase enzyme.
- Llona-Minguez, Sabin,H?glund, Andreas,Ghassemian, Artin,Desroses, Matthieu,Calderón-Monta?o, José Manuel,Burgos Morón, Estefanía,Valerie, Nicholas C. K.,Wiita, Elisee,Alml?f, Ingrid,Koolmeister, Tobias,Mateus, André,Cazares-K?rner, Cindy,Sanjiv, Kumar,Homan, Evert,Loseva, Olga,Baranczewski, Pawel,Darabi, Masoud,Mehdizadeh, Amir,Fayezi, Shabnam,Jemth, Ann-Sofie,Warpman Berglund, Ulrika,Sigmundsson, Kristmundur,Lundb?ck, Thomas,Jenmalm Jensen, Annika,Artursson, Per,Scobie, Martin,Helleday, Thomas
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p. 4279 - 4292
(2017/06/05)
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- BICYCLIC COMPOUND
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Provided is a bicyclic compound having an acetyl-CoA carboxylase inhibitory action. A compound represented by the formula: wherein each symbol is as described in the DESCRIPTION, or a salt thereof has an acetyl-CoA carboxylase inhibitory action, is useful for the prophylaxis or treatment of cancer, inflammatory diseases and the like, and has superior efficacy.
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Paragraph 1206
(2017/12/28)
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- Pyridazine derivative and preparation method and application thereof
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The invention provides a pyridazine derivative and a pharmaceutically acceptable salt or hydrate of the pyridazine derivative. The compound is an active ligand of a novel cannabinoid II type receptor CB2. The compound and the pharmaceutically acceptable salt or hydrate of the compound generally have high calcium current activity and quite good selectivity for anthropogenic marijuana receptors CB2. The compound is a specificity agonist of the cannabinoid receptor CB2, and can be used for treating, preventing and inhibiting diseases mediated by CB2 receptors. The compound I has the general formula shown in the description.
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- 1 -(PYRIDAZIN-3-YL)-IMIDAZOLIDIN-2-ONE DERIVATIVES AS HERBICIDES
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The invention relates to pyrrolone compounds of the formula (I) wherein R1, R2, R3, Rb, Rc and Rd are as defined in the specification. Furthermore, the present invention relates to processe
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Page/Page column 44; 45
(2015/05/26)
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- TrkA KINASE INHIBITORS,COMPOSITIONS AND METHODS THEREOF
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The present invention is directed to substituted five membered heteroaryl benzamide compounds compounds of formula (I), which are tropomyosin-related kinase (Trk) family protein kinase inhibitors, and hence are useful in the treatment of pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, a disease, disorder, injury, or malfunction relating to dysmyelination or demyelination or a disease or disorder associated with abnormal activities of nerve growth factor (NGF) receptor TrkA.
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Page/Page column 49
(2015/12/08)
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- CXCR7 ANTAGONISTS
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Compounds having formula I, or pharmaceutically acceptable salts, hydrates or N-oxides thereof are provided and are useful for binding to CXCR7, and treating diseases that are dependent, at least in part, on CXCR7 activity. Accordingly, the present invention provides in further aspects, compositions containing one or more of the above-noted compounds in admixture with a pharmaceutically acceptable excipient.
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Paragraph 0333; 0334
(2014/06/23)
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- SUBSTITUTED BICYCLIC AZA-HETEROCYCLES AND ANALOGUES AS SIRTUIN MODULATORS
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Provided herein are novel substituted bicyclic aza-heterocycle sirtuin-modulating compounds and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity. Also provided, are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.
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Page/Page column 80
(2013/05/09)
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- Discovery of piperazin-1-ylpyridazine-based potent and selective stearoyl-CoA Desaturase-1 inhibitors for the treatment of obesity and metabolic syndrome
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Stearoyl-CoA desaturase-1 (SCD1) catalyzes de novo synthesis of monounsaturated fatty acids from saturated fatty acids. Studies have demonstrated that rodents lacking a functional SCD1 gene have an improved metabolic profile, including reduced weight gain, lower triglycerides, and improved insulin response. In this study, we discovered a series of piperazinylpyridazine-based highly potent, selective, and orally bioavailable compounds. Particularly, compound 49 (XEN103) was highly active in vitro (mSCD1 IC50 = 14 nM and HepG2 IC50 = 12 nM) and efficacious in vivo (ED50 = 0.8 mg/kg). It also demonstrated striking reduction of weight gain in a rodent model. Our findings with small-molecule SCD1 inhibitors confirm the importance of this target in metabolic regulation, describe novel models for assessing SCD1 inhibitors for efficacy and tolerability and demonstrate an opportunity to develop a novel therapy for metabolic disease.
- Zhang, Zaihui,Sun, Shaoyi,Kodumuru, Vishnumurthy,Hou, Duanjie,Liu, Shifeng,Chakka, Nagasree,Sviridov, Serguei,Chowdhury, Sultan,McLaren, David G.,Ratkay, Leslie G.,Khakh, Kuldip,Cheng, Xing,Gschwend, Heinz W.,Kamboj, Rajender,Fu, Jianmin,Winther, Michael D.
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p. 568 - 583
(2013/04/23)
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- OXADIAZOLE INHIBITORS OF LEUKOTRIENE PRODUCTION
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The present invention relates to compound of formula (I) and pharmaceutically acceptable salt thereof, wherein R1-R5 are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.
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Page/Page column 127
(2012/03/26)
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- NOVEL COMPOUNDS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES
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This invention provides novel compounds and the novel compounds for use as a medicine, more in particular for the prevention or treatment of neurodegenerative disorders, more specifically certain neurological disorders, such as disorders collectively known as tauopathies, and disorders characterised by cytotoxic α-synuclein amyloidogenesis. The present invention also relates to the use of said novel compounds for the manufacture of medicaments useful for treating such neurodegenerative disorders. The present invention further relates to pharmaceutical compositions including said novel compounds and to methods for the preparation of said novel compounds. The compounds have the formula (A1), wherein R1, R2, R4, R5, R6, E, n, Y1, Y2, Y3, Y4, Y5, B, R8, and m are as defined in the claims.
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Page/Page column 73-74
(2012/06/30)
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- Biological activity and preclinical efficacy of azetidinyl pyridazines as potent systemically-distributed stearoyl-CoA desaturase inhibitors
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Potent and orally bioavailable SCD inhibitors built on an azetidinyl pyridazine scaffold were identified. In a one-month gDIO mouse model of obesity, we demonstrated that there was no therapeutic index even at low doses; efficacy in preventing weight gain
- Isabel, Elise,Powell, David A.,Black, W. Cameron,Chan, Chi-Chung,Crane, Sheldon,Gordon, Robert,Guay, Jocelyne,Guiral, Sebastien,Huang, Zheng,Robichaud, Jo?l,Skorey, Kathryn,Tawa, Paul,Xu, Lijing,Zhang, Lei,Oballa, Renata
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scheme or table
p. 479 - 483
(2011/02/28)
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- NOVEL SUBSTITUTED BIPYRIDINE DERIVATIVES AND THEIR USE AS ADENOSINE RECEPTOR LIGANDS
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The present invention relates to novel substituted 2,4′- and 3,4′-bipyridine derivatives, to processes for their preparation, to their use for the treatment and/or prophylaxis of diseases and to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, preferably for the treatment and/or prevention of hypertension and other cardiovascular disorders.
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Page/Page column 18
(2010/04/30)
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- Novel spiropiperidine-based stearoyl-CoA desaturase-1 inhibitors: Identification of 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4′-piperidine]
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Cyclization of the benzoylpiperidine in lead compound 2 generated a series of novel and highly potent spiropiperidine-based stearoyl-CoA desaturase (SCD)-1 inhibitors. Among them, 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4′-piperidine] (19) demonstrated the most powerful inhibitory activity against SCD-1, not only in vitro but also in vivo (C57BL/6 J mice). With regard to the pharmacological evaluation, 19 showed powerful reduction of the desaturation index in the plasma of C57BL/6 J mice on a non-fat diet after a 7-day oral administration (q.d.) without causing notable abnormalities in the eyes or skin up to the highest dose (3 mg/kg) in our preliminary analysis.
- Uto, Yoshikazu,Kiyotsuka, Yohei,Ueno, Yuko,Miyazawa, Yuriko,Kurata, Hitoshi,Ogata, Tsuneaki,Deguchi, Tsuneo,Yamada, Makiko,Watanabe, Nobuaki,Konishi, Masahiro,Kurikawa, Nobuya,Takagi, Toshiyuki,Wakimoto, Satoko,Kono, Keita,Ohsumi, Jun
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supporting information; experimental part
p. 746 - 754
(2010/06/11)
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- Synthesis and evaluation of novel stearoyl-CoA desaturase 1 inhibitors: 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3, 4-dihydrospiro[chromene-2,4′-piperidine] analogs
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In continuation of our investigation on novel stearoyl-CoA desaturase (SCD) 1 inhibitors, we have already reported on the structural modification of the benzoylpiperidines that led to a series of novel and highly potent spiropiperidine-based SCD1 inhibitors. In this report, we would like to extend the scope of our previous investigation and disclose details of the synthesis, SAR, ADME, PK, and pharmacological evaluation of the spiropiperidines with high potency for SCD1 inhibition. Our current efforts have culminated in the identification of 5-fluoro-1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol- 2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4′-piperidine] (10e), which demonstrated a very strong potency for liver SCD1 inhibition (ID 50 = 0.6 mg/kg). This highly efficacious inhibition is presumed to be the result of a combination of strong enzymatic inhibitory activity (IC 50 (mouse) = 2 nM) and good oral bioavailability (F >95%). Pharmacological evaluation of 10e has demonstrated potent, dose-dependent reduction of the plasma desaturation index in C57BL/6J mice on a high carbohydrate diet after a 7-day oral administration (q.d.). In addition, it did not cause any noticeable skin abnormalities up to the highest dose (10 mg/kg).
- Uto, Yoshikazu,Ueno, Yuko,Kiyotsuka, Yohei,Miyazawa, Yuriko,Kurata, Hitoshi,Ogata, Tsuneaki,Yamada, Makiko,Deguchi, Tsuneo,Konishi, Masahiro,Takagi, Toshiyuki,Wakimoto, Satoko,Ohsumi, Jun
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supporting information; experimental part
p. 4788 - 4796
(2010/12/18)
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- HETEROAROMATIC COMPOUNDS AS INHIBITORS OF STEAROYL-COENZYME A DELTA-9 DESATURASE
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Heteroaromatic compounds of structural formula (I) are selective inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD1) relative to other known stearoyl-coenzyme A desaturases. The compounds of the present invention are useful for the prevention and
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Page/Page column 43
(2008/06/13)
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- HETEROAROMATIC COMPOUNDS AS INHIBITORS OF STEAROYL-COENZYME A DELTA-9 DESATURASE
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Heteroaromatic compounds of structural formula (I) are selective inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD1) relative to other known stearoyl-coenzyme A desaturases. The compounds of the present invention are useful for the prevention and
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Page/Page column 34-35
(2008/06/13)
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- AZETIDINE DERIVATIVES AS INHIBITORS OF STEAROYL-COENZYME A DELTA-9 DESATURASE
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Azetidine derivatives of structural formula I are selective inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD1) relative to other known stearoyl-coenzyme A desaturases. The compounds of the present invention are useful for the prevention and treatment of conditions related to abnormal lipid synthesis and metabolism, including cardiovascular disease; atherosclerosis; obesity; diabetes; neurological disease; metabolic syndrome; insulin resistance; liver steatosis; and non-alcoholic steatohepatitis. (I)
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Page/Page column 36
(2008/06/13)
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- SUBSTITUTED TRIAZOLE DERIVATIVES AS OXYTOCIN ANTAGONISTS
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The present invention relates to a class of substituted 1,2,4-triazoles of formula (I) with activity as oxytocin antagonists, uses thereof, processes for the preparation thereof and compositions containing, said, inhibitors. These inhibitors have utility in a variety of therapeutic areas including sexual dysfunction, particularly premature ejaculation (P.E.).
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Page/Page column 84
(2010/02/11)
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- BENZO ‘ D!AZEPINE DERIVATIVES FOR THE TREATMENT OF NEUROLOGICAL DISORDERS
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The present invention relates to benzazepine derivatives of formula ( I ) wherein: R1 represents -C3-7 cycloalkyl optionally substituted by C1-3 alkyl; having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of neurological and psychiatric disorders.
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Page/Page column 91
(2010/02/07)
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