- Synthesis and biological investigation of new equatorial (β) stereoisomers of 3-aminotropane arylamides with atypical antipsychotic profile
-
A series of novel 3β-aminotropane derivatives containing a 2-naphthalene or a 2-quinoline moiety was synthesised and evaluated for their affinity for 5-HT1A, 5-HT2Aand D2receptors. Their affinity for the receptors was in the nanomolar to micromolar range. p-Substitution (6c, 6f, 6i, 6l, 6o), as well as substitution with chlorine atoms (6g, 6h, 6i), led to a significant increase in binding affinity for D2receptors with compounds 6f (Ki?=?0.6?nM), 6c and 6i (Ki?=?0.4?nM), having the highest binding affinities. m-Substituted derivatives were the most promising ligands in terms of 5-HT2Areceptor binding affinity whereas 2-quinoline derivatives (10a, 10b) displayed the highest affinity for 5-HT1AR and were the most selective ligands with Ki?=?62.7?nM and Ki?=?30.5?nM, respectively. Finally, the selected ligands 6b, 6d, 6e, 6g, 6h, 6k, 6n and 6o, with triple binding activity for the D2, 5-HT1Aand 5-HT2Areceptors, were subjected to in vivo tests, such as those for induced hypothermia, climbing behaviour and the head twitch response, in order to determine their pharmacological profile. The tested ligands presented neither agonist nor antagonist properties for the 5-HT1Areceptors in the induced hypothermia and lower lip retraction (LLR) tests. All tested compounds displayed antagonistic activity against 5-HT2A, with 6n and 6o being the most active. Four (6b, 6k, 6n and 6o) out of eight tested compounds could be classified as D2antagonists. Additionally, evaluation of metabolic stability was performed for selected ligands, and introduction of halogen atoms into the benzene ring of 6h, 6k, 6n and 6o improved their metabolic stability. The project resulted in the selection of the lead compounds 6n and 6o, which had antipsychotic profiles, combining dopamine D2-receptor and 5-HT2Aantagonism and metabolic stability.
- Stefanowicz, Jacek,S?owiński, Tomasz,Wróbel, Martyna Zofia,Herold, Franciszek,Gomó?ka, Anna Edyta,Weso?owska, Anna,Jastrz?bska-Wi?sek, Magdalena,Partyka, Anna,Andres-Mach, Marta,Czuczwar, Stanis?aw Jerzy,?uszczki, Jarogniew Jacek,Zagaja, Miros?aw,Siwek, Agata,Nowak, Gabriel,?o?nierek, Maria,B?czek, Tomasz,Ulenberg, Szymon,Belka, Mariusz,Tur?o, Jadwiga
-
-
Read Online
- Structure-Based Design of 1-Heteroaryl-1,3-propanediamine Derivatives as a Novel Series of CC-Chemokine Receptor 5 Antagonists
-
CC-chemokine receptor 5 (CCR5) is an attractive target for preventing the entry of human immunodeficiency virus 1 (HIV-1) into human host cells. Maraviroc is the only CCR5 antagonist, and it was marketed in 2007. To overcome the shortcomings of maraviroc, structure-based drug design was performed to minimize CYP450 inhibition and to enhance anti-HIV potency and bioavailability. Thirty-four novel 1-heteroaryl-1,3-propanediamine derivatives (1-34) were synthesized, displaying CCR5-antagonist activities in the 2.3-296.4 nM range. Among these, compounds 21 and 34 were the most potent CCR5 antagonists, with excellent in vitro anti-HIV-1 activity, low cytotoxicity, and an acceptable pharmacokinetic profile. Furthermore, the X-ray crystal structures of compounds 21 and 34 bound to CCR5 were determined at 2.8 ? resolution. Compound 34 exhibited no CYP450-inhibition activity at 25 μM, which overcomes the potential drug-drug interaction of maraviroc. Compound 34 represents a promising drug candidate for HIV-infection treatment.
- Peng, Panfeng,Chen, Huan,Zhu, Ya,Wang, Zhilong,Li, Jian,Luo, Rong-Hua,Wang, Jiang,Chen, Liang,Yang, Liu-Meng,Jiang, Hualiang,Xie, Xin,Wu, Beili,Zheng, Yong-Tang,Liu, Hong
-
-
Read Online
- Synthesis and biological investigations of 3β-aminotropane arylamide derivatives with atypical antipsychotic profile
-
This work is a continuation of our previous research, concentrating this time on lead structure modification to increase the 5-HT1A receptor affinity and water solubility of designed compounds. Therefore, the compounds synthesised within the present project included structural analogues of 3β-acylamine derivatives of tropane with the introduction of a methyl substituent in the benzyl ring and a 2-quinoline, 3-quinoline, or 6-quinoline moiety. A series of novel 3β-aminotropane derivatives was evaluated for their affinity for 5-HT1A, 5-HT2A, and D2 receptors, which allowed for the identification of compounds 12e, 12i, and 19a as ligands with highest affinity for the tested receptors; they were then subjected to further evaluation in preliminary in vivo studies. Selected compounds 12i and 19a displayed antipsychotic properties in the d-amphetamine-induced and MK-801-induced hyperlocomotor activity test in mice. Moreover, compound 19a showed significant antidepressant-like activity in the forced swim test in mice.
- Stefanowicz, Jacek,S?owiński, Tomasz,Wróbel, Martyna Z.,?lifirski, Grzegorz,Dawidowski, Maciej,Stefanowicz, Zdzis?awa,Jastrz?bska-Wi?sek, Magdalena,Partyka, Anna,Weso?owska, Anna,Tur?o, Jadwiga
-
-
Read Online
- Efficient, two-step synthesis of N-substituted nortropinone derivatives
-
We describe a novel strategy for the synthesis of N-substituted nortropinone derivatives starting from tropinone. The key step of our synthesis is a reactivity umpolung of tropinone, which yields 8,8-dimethyl-3-oxo-8-azonia-bicyclo[3.2.1]octane iodide (IDABO) as a stable and convenient synthetic equivalent of cycloheptadienone.
- Willand, Nicolas,Folléas, Benoit,Boutillon, Christophe,Verbraeken, Liesbeth,Gesquière, Jean-Claude,Tartar, André,Deprez, Benoit
-
-
Read Online
- Enantioselective Total Syntheses of the Proposed and Revised Structures of Methoxystemofoline: A Stereochemical Revision
-
This article describes the full details of our synthetic efforts toward the enantioselective total synthesis of the complex alkaloid methoxystemofoline. The enantioselective construction of the tetracyclic core features: (1) the Keck allylation at the N-α bridgehead carbon to forge the tetrasubstituted stereocenter; (2) an olefin cross-metathesis reaction for the side-chain elongation that is amenable for the synthesis of congeners and analogues; and (3) a regioselective aldol addition reaction with methyl pyruvate that ensured the subsequent regioselective cyclization reaction to construct the fourth ring. Overman's method was employed to install the 5-(alkoxyalky1idene)-3-methyl-tetronate moiety. In the last step, a nonstereoselective reaction resulted in the formation of both the proposed structure of methoxystemofoline and its E-stereoisomer, the natural product (revised structure), in a 1:1 ratio. We suggest to rename the natural product as isomethoxystemofoline, and report for the first time the complete 1H NMR data for this natural product.
- Huang, Su-Yu,Gao, Long-Hui,Huang, Xiong-Zhi,Huang, Pei-Qiang
-
p. 11053 - 11071
(2021/02/01)
-
- 3-aryl azabicyclo derivative as well as preparation and application thereof in nematode killing
-
The invention relates to preparation of a 3-aryl azabicyclo derivative and application of the derivative in nematode killing. Specifically, the invention discloses application of a compound with a structure as shown in a formula (I) or a composition, an optical isomer, a cis-trans-isomer and an agricultural pharmacologically acceptable salt of the compound in the field of nematode killing.
- -
-
Paragraph 0128; 0130-0131
(2021/08/06)
-
- Structure-Based Design and Development of Chemical Probes Targeting Putative MOR-CCR5 Heterodimers to Inhibit Opioid Exacerbated HIV-1 Infectivity
-
Crystal structures of ligand-bound G-protein-coupled receptors provide tangible templates for rationally designing molecular probes. Herein, we report the structure-based design, chemical synthesis, and biological investigations of bivalent ligands targeting putative mu opioid receptor C-C motif chemokine ligand 5 (MOR-CCR5) heterodimers. The bivalent ligand VZMC013 possessed nanomolar level binding affinities for both the MOR and CCR5, inhibited CCL5-stimulated calcium mobilization, and remarkably improved anti-HIV-1BaL activity over previously reported bivalent ligands. VZMC013 inhibited viral infection in TZM-bl cells coexpressing CCR5 and MOR to a greater degree than cells expressing CCR5 alone. Furthermore, VZMC013 blocked human immunodeficiency virus (HIV)-1 entry in peripheral blood mononuclear cells (PBMC) cells in a concentration-dependent manner and inhibited opioid-accelerated HIV-1 entry more effectively in phytohemagglutinin-stimulated PBMC cells than in the absence of opioids. A three-dimensional molecular model of VZMC013 binding to the MOR-CCR5 heterodimer complex is constructed to elucidate its mechanism of action. VZMC013 is a potent chemical probe targeting MOR-CCR5 heterodimers and may serve as a pharmacological agent to inhibit opioid-exacerbated HIV-1 entry.
- Huang, Boshi,Wang, Huiqun,Zheng, Yi,Li, Mengchu,Kang, Guifeng,Barreto-De-Souza, Victor,Nassehi, Nima,Knapp, Pamela E.,Selley, Dana E.,Hauser, Kurt F.,Zhang, Yan
-
p. 7702 - 7723
(2021/06/28)
-
- CERAMIDE GALACTOSYLTRANSFERASE INHIBITORS FOR THE TREATMENT OF DISEASE
-
Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with the enzyme ceramide galactosyltransferase (CGT), such as, for example, lysosomal storage diseases. Examples of lysosomal storage diseases include, for example, Krabbe disease and Metachromatic Leukodystrophy.
- -
-
Paragraph 00269-00270
(2019/06/11)
-
- Discovery of N-substituted-endo-3-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenol and -phenyl carboxamide series of μ-opioid receptor antagonists
-
Gastrointestinal dysfunction as a consequence of the use of opioid analgesics is of significant clinical concern. First generation drugs to treat these opioid-induced side-effects were limited by their negative impact on opioid receptor agonist-induced analgesia. Second generation therapies target a localized, peripherally-restricted, non-CNS penetrant drug distribution of opioid receptor antagonists. Herein we describe the discovery of the N-substituted-endo-3-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenol and -phenyl carboxamide series of μ-opioid receptor antagonists. This report highlights the discovery of the key μ-opioid receptor antagonist pharmacophore and the optimization of in vitro metabolic stability through the application of a phenol bioisostere. The compounds 27a and 31a with the most attractive in vitro profile, formed the basis for the application of Theravance Biopharma's multivalent approach to drug discovery to afford the clinical compound axelopran (TD-1211), targeted for the treatment of opioid-induced constipation.
- Jiang, Lan,Beattie, David T.,Jacobsen, John R.,Kintz, Samuel,Obedencio, Glenmar P.,Saito, Daisuke,Stergiades, Ioanna,Vickery, Ross G.,Long, Daniel D.
-
p. 2926 - 2930
(2017/06/05)
-
- Azabicyalo derivative as well as preparation and application thereof
-
The invention relates to an azabicyalo derivative as well as preparation and application thereof, and particularly discloses a compound with a structure shown in to the formula (A) or salt thereof acceptable in agricultural pharmacology. The compound in the formula (A) is described in the description in detail, and has an excellent killing effect on nematode.
- -
-
Paragraph 0163; 0164; 0165
(2016/10/07)
-
- Versatile construction of functionalized tropane ring systems based on lactam activation: Enantioselective synthesis of (+)-pervilleine B
-
The halo-assisted intramolecular addition of silyl enol ethers with in situ activated lactams yielded (hydroxylated) 1-halo-8-azabicyclo[3,2,1]octane and 1-halo-9-azabicyclo[3,3,1]nonane ring systems, which provided an easy enantioselective access to 6β-s
- Huang, Su-Yu,Chang, Zong,Tuo, Shi-Chuan,Gao, Long-Hui,Wang, Ai-E,Huang, Pei-Qiang
-
p. 7088 - 7090
(2013/09/02)
-
- INDOLYLPYRIMIDINES AS MODULATORS OF GPR119
-
The present invention relates to compounds of Formula (I) that are useful for treating, preventing and/or managing the diseases, disorders, syndromes or conditions modulated by GPR119 receptor activity. The invention also relates to the process for preparation of the compounds, pharmaceutical compositions thereof. The invention further relates to methods of treating, preventing and/or managing diseases, disorders syndromes or conditions associated with the modulation of GPR119 receptor by using either alone or in combinations of Formula (I).
- -
-
Page/Page column 59-60
(2012/03/26)
-
- An imidazopiperidine series of CCR5 antagonists for the treatment of HIV: The discovery of N -{(1 S)-1-(3-fluorophenyl)-3-[(3- endo)-3-(5-isobutyryl-2- methyl-4,5,6,7-tetrahydro-1 H -imidazo[4,5- c ]pyridin-1-yl)-8-azabicyclo[3.2.1] oct-8-yl]propyl}acetamide (PF-232798)
-
Preventing entry of HIV into human host cells has emerged as an attractive approach to controlling viral replication. Maraviroc 1 is an approved antagonist of the human CCR5 receptor which prevents the entry of HIV. Herein, we report the design and discovery of a series of imidazopiperidine CCR5 antagonists which retain the attractive antiviral profile and window over hERG activity of maraviroc 1, combined with improved absorption profiles in rat and dog. Furthermore, this series of compounds has been shown to retain activity against a laboratory generated maraviroc-resistant HIV-1 strain, which indicates an alternative resistance profile to that of maraviroc 1. Compound 41f (PF-232798) was selected as a clinical candidate from the imidazopiperidine series and is currently in phase II clinical trials.
- Stupple, Paul A.,Batchelor, David V.,Corless, Martin,Dorr, Patrick K.,Ellis, David,Fenwick, David R.,Galan, Sébastien R. G.,Jones, Rhys M.,Mason, Helen J.,Middleton, Donald S.,Perros, Manos,Perruccio, Francesca,Platts, Michelle Y.,Pryde, David C.,Rodrigues, Deborah,Smith, Nicholas N.,Stephenson, Peter T.,Webster, Robert,Westby, Mike,Wood, Anthony
-
experimental part
p. 67 - 77
(2011/03/19)
-
- Anti-prion activities and drug-like potential of functionalized quinacrine analogs with basic phenyl residues at the 9-amino position
-
In this paper, we report the synthesis and cell-based anti-prion activity of quinacrine analogs derived by replacing the basic alkyl side chain of quinacrine with 4-(4-methylpiperazin-I-yl)phenyl, (1-benzylpiperidin-4-yl) and their structural variants. Several promising analogs were found that have a more favorable anti-prion profile than quinacrine in terms of potency and activity across different prion-infected murine cell models. They also exhibited greater binding affinities for a human prion protein fragment (hPrP121-231) than quinacrine, and had permeabilities on the PAMPA-BBB assay that fall within the range of CNS permeant candidates. When evaluated on bidirectional assays on a Pgp overexpressing cell line, one analog was less susceptible to Pgp efflux activity compared to quinacrine. Taken together, the results point to an important role for the substituted 9-amino side chain attached to the acridine, tetrahydroacridine and quinoline scaffolds. The nature of this side chain influenced cell-based potency, PAMPA permeability and binding affinity to hPrP121-231.
- Nguyen, Thuy,Sakasegawa, Yuji,Doh-Ura, Katsumi,Go, Mei-Lin
-
p. 2917 - 2929
(2011/07/08)
-
- AMIDE COMPOUNDS, THEIR PHARMACEUTICAL COMPOSITIONS, THEIR PREPARATION METHOD AND THEIR USES
-
The present invention pertains to the field of pharmaceutical chemistry and discloses 8-(3-aminopropyl)-3-exo-8-azabicyclo[3.2.1]octane-3-amino amide compounds represented by formula I, the pharmaceutical compositions, the preparation method and the use thereof. Such compounds or pharmaceutically acceptable salts thereof can be used as an antagonist of CCR5 in preparing medicaments for treating diseases mediated by CCR5, particularly HIV infection, asthma, rheumatoid arthritis, autoimmune diseases and chronic obstructive pulmonary diseases (COPD).
- -
-
Page/Page column 20
(2011/10/19)
-
- Histamine H3 Inverse Agonists and Antagonists and Methods of Use Thereof
-
Provided herein are fused imidazolyl compounds, methods of synthesis, and methods of use thereof. The compounds provided herein are useful for the treatment, prevention, and/or management of various disorders, including, e.g., neurological disorders and metabolic disorders. Compounds provided herein inhibit the activity of histamine H3 receptors and modulate the release of various neurotransmitters, such as, e.g., histamine, acetylcholine, norepinephrine, and dopamine (e.g. at the synapse). Pharmaceutical compositions containing the compounds and their methods of use are also provided herein.
- -
-
Page/Page column 62
(2011/04/18)
-
- Asymmetric synthesis of maraviroc (UK-427,857)
-
The asymmetric synthesis of Maraviroc (UK-427,857), a chemochine receptor 5 (CCR-5) receptor antagonist, based on an expeditious organocatalytic enantioselective assembly of the chiral βamino aldehyde key fragment is presented. The reactions were performed on a gram-scale and allow for the rapid construction of new Maraviroc analogues.
- Zhao, Gui-Ling,Lin, Shuangzheng,Korotvicka, Ales,Deiana, Luca,Kullberg, Martin,Cordova, Armando
-
supporting information; experimental part
p. 2291 - 2298
(2010/12/20)
-
- Thiazolopyridin-2-yloxy-phenyl and thiazolopyrazin-2-yloxy-phenyl amines as modulators of leukotriene A4 hydrolase
-
Thiazolopyridin-2-yloxy-phenyl and thiazolopyrazin-2-yloxy-phenyl amine compounds are described, which are useful as LTA4 hydrolase (LTA4H) modulators. Such compounds may be used in pharmaceutical compositions and methods for modulation of LTA4H and for the treatment of disease states, disorders, and conditions mediated by LTA4 hydrolase activity.
- -
-
Page/Page column 33
(2009/10/21)
-
- Prokinetic agent for bowel preparation
-
The invention provides methods of bowel preparation before a diagnostic, surgical or therapeutic procedure, in particular, bowel preparation before a colonoscopy procedure, using a 5-HT4 receptor agonist as a prokinetic agent.
- -
-
Page/Page column 4
(2008/12/09)
-
- PREPARATION AND UTILITY OF CCR5 INHIBITORS
-
Disclosed herein are substituted 8-azabicyclo[3.2.1]octane-based anti-infective agents of Formula I, processes of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.
- -
-
Page/Page column 40
(2008/12/06)
-
- TRIAZOLYL TROPANE DERIVATIVES
-
This invention relates to novel triazolyl tropane derivatives, their acceptable acid addition salts, solvates, hydrates and polymorphs thereof. The invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions beneficially treated by blocking or reducing the binding ability of the CCR5 receptor.
- -
-
Page/Page column 11-12; 25-26
(2008/12/05)
-
- INHIBITORS OF SERINE PALMITOYLTRANSFERASE
-
This invention provides compounds of the formula (I) useful in the inhibition or modulation of serine palmitoyl transferase and their use in methods of treatment or amelioration of type 2 diabetes, type 1 diabetes, insulin resistance, the effects of obesity, metabolic syndrome (sometimes referred to as Syndrome X), impaired glucose tolerance, Cushing's disease, cardiovascular disease, prothrombotic conditions, myocardial infarction, hypertension, congestive heart failure, cardiomyopathy, atherosclerosis, dyslipidemia, sepsis, liver damage, retinal degenerative disorders, cachexia, emphysema, hepatitis C infections, HIV infections and inflammatory disorders and useful in methods for raising HDL plasma levels in a mammal. The compounds of this invention can also be used to prevent damage or loss of pancreatic islet beta cells (such as in the case of pancreatic beta cell apoptosis, including those related to insulin-dependent diabetes mellitus).
- -
-
Page/Page column 100-101
(2008/12/07)
-
- UREIDE DERIVATIVE AND USE THEREOF FOR MEDICAL PURPOSES
-
This invention relates to a pharmaceutical comprising, as an active ingredient, a ureide derivative represented by formula: or a pharmaceutically acceptable salt thereof. The ureide derivative or a pharmaceutically acceptable salt thereof according to the present invention is useful for relieving pain and treating or preventing neuropathic pain.
- -
-
Page/Page column 102
(2009/01/24)
-
- Discovery of bioavailable 4,4-disubstituted piperidines as potent ligands of the chemokine receptor 5 and inhibitors of the human immunodeficiency virus-1
-
We describe robust chemical approaches toward putative CCR5 scaffolds designed in our laboratories. Evaluation of analogues in the 125I-[MIP-1β] binding and Ba-L-HOS antiviral assays resulted in the discovery of 64 and 68 in the 4,4-disubstitited piperidine class H, both potent CCR5 ligands (pIC50 = 8.30 and 9.00, respectively) and HIV-1 inhibitors (pIC50 = 7.80 and 7.84, respectively, in Ba-L-HOS assay). In addition, 64 and 68 were bioavailable in rodents, establishing them as lead molecules for further optimization toward CCR5 clinical candidates.
- Kazmierski, Wieslaw M.,Aquino, Christopher,Chauder, Brian A.,Deanda, Felix,Ferris, Robert,Jones-Hertzog, Deborah K.,Kenakin, Terrence,Koble, Cecilia S.,Watson, Christian,Wheelan, Pat,Yang, Hanbiao,Youngman, Michael
-
experimental part
p. 6538 - 6546
(2009/11/30)
-
- Chemical compounds
-
Compounds of formula (I): compositions comprising them, processes for preparing them and their use in medical therapy (for example modulating CCR5 receptor activity in a warm blooded animal).
- -
-
Page/Page column 40
(2008/06/13)
-
- 8-Azabicyclo[3.2.1]octane compounds as mu opioid receptor antagonists
-
The invention provides novel 8-azabicyclo[3.2.1]octane compounds of formula (I): wherein R1, R2, R3, A, and G are defined in the specification, or a pharmaceutically-acceptable salt or solvate thereof, that are antagonists at the mu opioid receptor. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat conditions associated with mu opioid receptor activity, and processes and intermediates useful for preparing such compounds.
- -
-
Page/Page column 15
(2008/06/13)
-
- CARBAMATE COMPOUNDS AS 5-HT4 RECEPTOR AGONISTS
-
The invention provides novel benzoimidazolone-carboxamide-derived carbamate 5-HT4 receptor agonist compounds of formula (I): wherein R1, R2, R3, R4, a, and b are defined in the disclosure. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds.
- -
-
Page/Page column 7; 15
(2008/06/13)
-
- PESTICIDAL SUBSTITUTED PIPERIDINES
-
The invention relates to the use of piperidine derivatives encompassed from the general formula (I) for the control of pests, including arthropods and helminths, and a method for the control of pests.
- -
-
Page/Page column 51; 70
(2008/06/13)
-
- NOVEL COMPOUNDS HAVING AN ANTI-BACTERIAL ACTIVITY
-
The present invention describes novel anti-bacterial compounds of formula (I). These compounds are, amongst others, of interest as inhibitors of DNA gyrase.
- -
-
Page/Page column 39-40
(2010/10/20)
-
- Indazole-carboxamide compounds
-
The invention provides novel indazole-carboxamide 5-HT4 receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds.
- -
-
Page/Page column 22-23
(2008/06/13)
-
- Quinolinone-carboxamide compounds
-
The invention provides novel quinolinone-carboxamide 5-HT4 receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds.
- -
-
Page/Page column 18
(2008/06/13)
-
- Quinolinone compounds as 5-HT4 receptor agonists
-
The invention provides novel quinolinone-carboxamide 5-HT4 receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds.
- -
-
Page/Page column 23
(2008/06/13)
-
- Crystalline form of a quinolinone-carboxamide compound
-
The invention provides a crystalline hydrochloride salt of 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[(R)-2-hydroxy-3-(methanesulfonyl-methyl-amino)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide or a solvate thereof. The invention also provides pharmaceutical compositions comprising such crystalline salt forms, methods of using such crystalline salt forms to treat diseases associated with 5-HT4 receptor activity, and processes useful for preparing such crystalline salt forms.
- -
-
Page/Page column 8-9
(2010/11/24)
-
- CYCLOALKANOPYRIDINE DERIVATIVE
-
Provided are cycloalkanopyridine derivatives of formula [I]: [wherein the symbols are the same as those stated in the description]. The compounds act as a nociceptin receptor antagonist, and are useful as medicines for diseases associated with a nociceptin receptor, for example, as a reliever against tolerance to a narcotic analgesic; a reliever against dependence on or addiction to a narcotic analgesic; an analgesic enhancer; an antiobesitic or appetite suppressor; a treating or prophylactic agent for cognitive impairment and dementia/amnesia; an agent for treating developmental cognitive abnormality; a remedy for schizophrenia; an agent for treating neurodegenerative diseases; an anti-depressant or treating agent for affective disorder; a treating or prophylactic agent for diabetes insipidus; a treating or prophylactic agent for polyuria; or a remedy for hypotension.
- -
-
Page/Page column 55
(2010/11/24)
-
- NOVEL PIPERIDINE/8-AZABICYCLO [3.2.1] OCTAN DERIVATIVES AS MODUILATORS OF CHEMOKINE RECEPTOR CCR5
-
Compounds of formula (I) wherein neither R4 nor R5 is hydrogen; compositions comprising them, processes for preparing them and their use in medical therapy (for example modulating CCR5 receptor activity in a warm blooded animal).
- -
-
Page/Page column 85-86
(2010/02/15)
-
- Benzoimidazolone-carboxamide compounds as 5-HT4 receptors agonists
-
The invention provides novel benzoimidazolone-carboxamide 5-HT4 receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds.
- -
-
Page/Page column 19
(2010/11/25)
-
- 5-HT4 receptor agonist compounds
-
The invention provides novel quinolinone-carboxamide 5-HT4 receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds.
- -
-
Page/Page column 20
(2008/06/13)
-
- Process for preparing substituted 8-azabicyclo[3.2.1]octan-3-ols
-
The present invention relates to a process for preparing substituted 8-azabicyclo[3.2.1]octan-3-ols having the structural formula I or a pharmaceutically acceptable salt or solvate thereof, wherein R is benzyl, R5-benzyl, allyl, —C(O)R6, —C(O)OR8 or —CH(R7)2; R1 is optionally substituted aryl or optionally substituted heteroaryl; and R5, R6, R7 and R8 are as defined in the specification; comprising a) reacting an amine of formula II [in-line-formulae]R—NH2??II [/in-line-formulae] with 2,5-dimethoxytetrahydrofuran or HC(O)(CH2)2C(O)H, and C(O)(CH2C(O)OR4)2, wherein R4 is H or alkyl, to obtain a compound of formula III b) reacting a compound of formula III with I-R1, alkyl lithium, and optionally a lithium salt, to obtain a compound of formula I; and c) optionally converting a compound of formula I wherein R is benzyl, R5-benzyl, allyl, —C(O)R6 or —C(O)OR6 to a compound of formula I wherein R is —CH(R7)2. Intermediates in the process are also claimed.
- -
-
Page/Page column 8
(2010/10/20)
-
- Chemical compounds
-
The present invention provides compounds of formula (I) wherein R1 and R2 are as defined hereinabove. The compounds of the present invention are modulators, especially antagonists, of the activity of chemokine CCR5 receptors. Modulators of the CCR5 receptor may be useful in the treatment of various inflammatory diseases and conditions, and in the treatment of infection by HIV and genetically related retroviruses.
- -
-
Page/Page column 17
(2010/02/13)
-
- IMIDAZOPYRIDINE SUBSTITUTED TROPANE DERIVATIVES WITH CCR5 RECEPTOR ANTAGONIST ACTIVITY FOR THE TREATMENT OF HIV AND INFLAMMATION
-
The present invention provides compounds of formula (I) wherein R1 and R2 are as defined hereinabove. The compounds of the present invention are modulators, especially antagonists, of the activity of chemokine CCR5 receptors. Modulators of the CCR5 receptor may be useful in the treatment of various inflammatory diseases and conditions, and in the treatment of infection by HIV and genetically related retroviruses.
- -
-
Page/Page column 37
(2010/02/11)
-
- CHEMICAL COMPOUNDS
-
Compounds of formula (I): [Chemical formula should be inserted here. Please see paper copy] compositions comprising them, processes for preparing them and their use in medical therapy (for example modulating CCR5 receptor activity in a warm blooded animal).
- -
-
Page/Page column 31
(2010/02/12)
-
- Quinolinone-carboxamide compounds as 5-HT4 receptor agonists
-
The invention provides novel quinolinone-carboxamide 5-HT4 receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds.
- -
-
Page/Page column 16
(2008/06/13)
-
- METHOD FOR PRODUCING N-SUBSTITUTED 3β-AMINONORTROPANES
-
The invention relates to a method for producing, on the basis of the corresponding 3-oxonortropane or the corresponding 3α-aminonortropane, N-substituted 3β-aminonortropanes of formula (I), wherein R1 is defined as in the claim. According to the inventive method, the starting compounds are converted to the corresponding imines by means of an arylmethylamine or an arylaldehyde, said imines are tautomerized or isomerized and then hydrolyzed. The invention also relates to the novel compounds of formula (V), wherein R1 and Ar are defined as in the claims.
- -
-
Page/Page column 11-12
(2008/06/13)
-
- INDAZOLE-CARBOXAMIDE COMPOUNDS AS 5-HT4 RECEPTOR AGONISTS
-
The invention provides novel indazole-carboxamide 5-HT4 receptor agonist compounds. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with 5-HT4 receptor activity, and processes and intermediates useful for preparing such compounds.
- -
-
Page/Page column 38-39
(2010/02/13)
-
- Modulation of selective serotonin reuptake inhibitor and 5-HT1A antagonist activity in 8-aza-bicyclo[3.2.1]octane derivatives of 2,3-dihydro-1,4-benzodioxane
-
2,3-Dihydro-1,4-benzodioxanes with aryl 8-aza-bicyclo[3.2.1]oct-3-ene attachments 2 produce compounds with potent 5-HT-T affinity, and weak 5-HT 1A affinity and α1 affinity. This compares with 2,3-dihydro-1,4-benzodioxanes containing 8-aza-bicyclo[3.2.1] octan-3-ol attachments 4 which possess potent 5-HT1A affinity, moderate to good selectivity over α1 and little 5-HT-T affinity. A 3-benzothiophene analogue of 4 (30) was synthesized which possesses potent 5-HT1A affinity and especially good selectivity over both α1 and 5-HT-T.
- Gilbert, Adam M.,Stack, Gary P.,Nilakantan, Ramaswamy,Kodah, Jason,Tran, Megan,Scerni, Rosemary,Shi, Xiaojie,Smith, Deborah L.,Andree, Terrance H.
-
p. 515 - 518
(2007/10/03)
-
- BICYCLIC PIPERIDINE DERIVATIVES AS ANTAGONISTS OF THE CCR1 CHEMOKINE RECEPTOR
-
A compound of the formula (I) wherein a, b, cR1, R2, R3, R4, R5, R6, Q, W, Y, and Z are defined as above, useful as potent and selective inhibitors of MIP-1α(CCL3) binding to its receptor CCR1 found on inflammatory and immunomodulatory cells (preferably leukocytes and lymphocytes).
- -
-
-
- CCR5 ANTAGONISTS AS THERAPEUTIC AGENTS
-
The present invention relates to compounds of formula (I) or pharmaceutically acceptable derivatives thereof, useful in the treatment or prophylaxis of CCR5-related diseases and disorders, for example, in the inhibition of HIV replication, the prevention or treatment of an HIV infection, and in the treatment of the resulting acquired immune deficiency syndrome (AIDS).
- -
-
-
- CHEMICAL COMPOUNDS
-
Compounds of formula (I): compositions comprising them, processes for preparing them and their use in medical therapy (for example modulating CCR5 receptor activity in a warm blooded animal).
- -
-
-
- Tropane derivatives useful in therapy
-
The present invention provides compounds of formula (I) wherein X, Y, R1, R2 and R3 are as defined hereinabove. The compounds of the present invention are modulators, especially antagonists, of the activity of chemokine CCR5 receptors. Modulators of the CCR5 receptor may be useful in the treatment of various inflammatory diseases and conditions, and in the treatment of infection by HIV and genetically related retroviruses.
- -
-
-
- Spiro[1,2,4-benzotriazine-3(4H),4′-(1′-substituted)piperidines] and related compounds as ligands for sigma receptors
-
As analogues of some conformationally restricted spiropiperidine derivatives which are endowed with high affinity for σ1 receptor, a set of 16 spiro[1,2,4-benzotriazine-3(4H),4′-(1′-substituted)piperidines] and congeneric compounds was prepared and tested for affinity to σ1 receptor subtype. All N-arylalkyl substituted derivatives exhibited high affinity for the relevant receptor, with Ki in the low nanomolar range. Affinity for σ2 subtype (assayed only for a few representative compounds) was from one to three order of magnitude lower. Spiro[1,2,4-benzotriazine-3(4H),4′-(1′-benzyl)piperidine] (2), with a ratio Kiσ2/Kiσ1=7000 should represent the most selective σ1 ligand so far described.
- Novelli, Federica,Sparatore, Fabio
-
p. 871 - 882
(2007/10/03)
-