- Loratadine analogues as MAGL inhibitors Dedicated to Dr. Sameer Agarwal, principal scientist at Zydus Research Centre (ZRC, India)
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Compound 12a (JZP-361) acted as a potent and reversible inhibitor of human recombinant MAGL (hMAGL, IC50 = 46 nM), and was found to have almost 150-fold higher selectivity over human recombinant fatty acid amide hydrolase (hFAAH, IC50 = 7.24 μM) and 35-fold higher selectivity over human α/β-hydrolase-6 (hABHD6, IC50 = 1.79 μM). Additionally, compound 12a retained H1 antagonistic affinity (pA2 = 6.81) but did not show cannabinoid receptor activity, when tested at concentrations ≤10 μM. Hence, compound 12a represents a novel dual-acting pharmacological tool possessing both MAGL-inhibitory and antihistaminergic activities.
- Patel, Jayendra Z.,Ahenkorah, Stephen,Vaara, Miia,Staszewski, Marek,Adams, Yahaya,Laitinen, Tuomo,Navia-Paldanius, Dina,Parkkari, Teija,Savinainen, Juha R.,Walczyński, Krzysztof,Laitinen, Jarmo T.,Nevalainen, Tapio J.
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Read Online
- A new addition compound of desloratadine with carbon dioxide
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The addition compound of 8-chloro-6,11-dihydro-11-(4-pip-eridylidene)-5H- benzo[5,6]cyclohepta[1,2-b]pyridine (descarboet-hoxyloratadine, desloratadine) with CO2, in molar ratio 2:1, is described. This unique form of desloratadine drug substance can be prepared in exceedingly high purity by a simple process from crude desloratadine. The addition compound is a useful intermediate in the manufacturing process of desloratadine Form I polymorph. An improved, environmental friendly manufacturing process for the synthesis of desloratadine starting from loratadine is also disclosed here.
- Mezei, Tibor,Volk, Balazs,Kiraly, Imre,Simig, Gyula
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Read Online
- Desloratadine preparation method
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The invention discloses a desloratadine preparation method. The method comprises the following steps: firstly reacting methyl desloratadine with chloroethyl chloroformate to prepare chloroethoxycarbonyl desloratadine, and then heating in methanol to remove chloroethoxycarbonyl to obtain desloratadine. The method is mild in reaction condition, simple and easy to implement, and the obtained product is high in purity and few in impurity, and can be used for industrial mass production.
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Paragraph 0003
(2021/06/23)
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- Preparation method of desloratadine
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The invention discloses a preparation method of desloratadine, according to the preparation method, loratadine is taken as a raw material, reaction is carried out at a mild temperature, the reaction time is short, especially the yield can reach 98% or above, and the purity can reach 99.90% or above.
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Paragraph 0015; 0040-0091
(2021/07/17)
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- Preparation method of desloratadine
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The invention provides a preparation method of desloratadine. The preparation method comprises the following steps: dissolving desloratadine in an ionic liquid, and reacting while stirring to obtain desloratadine; the ionic liquid is a mixture of 1-butyl-3-methylimidazolium propionate ionic liquid and ionic liquid shown as a formula I in the specification. The method is simple, easy to operate, high in yield, simple in aftertreatment, environmentally friendly and high in safety.
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Paragraph 0022-0055
(2020/12/29)
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- Late-Stage Lead Diversification Coupled with Quantitative Nuclear Magnetic Resonance Spectroscopy to Identify New Structure-Activity Relationship Vectors at Nanomole-Scale Synthesis: Application to Loratadine, a Human Histamine H1Receptor Inverse Agonist
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An experimental approach is described for late-stage lead diversification of frontrunner drug candidates using nanomole-scale amounts of lead compounds for structure-activity relationship development. The process utilizes C-H bond activation methods to explore chemical space by transforming candidates into newly functionalized leads. A key to success is the utilization of microcryoprobe nuclear magnetic resonance (NMR) spectroscopy, which permits the use of low amounts of lead compounds (1-5 μmol). The approach delivers multiple analogues from a single lead at nanomole-scale amounts as DMSO-d6 stock solutions with a known structure and concentration for in vitro pharmacology and absorption, distribution, metabolism, and excretion testing. To demonstrate the feasibility of this approach, we have used the antihistamine agent loratadine (1). Twenty-six analogues of loratadine were isolated and fully characterized by NMR. Informative SAR analogues were identified, which display potent affinity for the human histamine H1 receptor and improved metabolic stability.
- Lall, Manjinder S.,Bassyouni, Asser,Bradow, James,Brown, Maria,Bundesmann, Mark,Chen, Jinshan,Ciszewski, Gregory,Hagen, Anne E.,Hyek, Dennis,Jenkinson, Stephen,Liu, Bo,Obach, R. Scott,Pan, Senliang,Reilly, Usa,Sach, Neal,Smaltz, Daniel J.,Spracklin, Douglas K.,Starr, Jeremy,Wagenaar, Melissa,Walker, Gregory S.
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p. 7268 - 7292
(2020/08/19)
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- Desloratadine crystal form IV and preparation method thereof (by machine translation)
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The invention provides a novel crystal form of desloratadine and a preparation method thereof. The preparation method comprises the following steps: dissolving desloratadine in tetrahydrofuran, adding water dropwise to the system, filtering the dropwise addition, obtaining a filter cake, and drying to obtain the desloratadine crystal. The crystal form has the advantages of high purity and good stability, has superiority in the production of the process, and is suitable for long-term storage of the preparation process. (by machine translation)
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Paragraph 0035-0037
(2020/11/12)
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- Method of preparing rupatadine fumarate through microchannel reaction device
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The invention discloses a method of preparing rupatadine fumarate through a microchannel reaction device. A process is optimized on a known path of synthesis for rupatadine fumarate; the microchannelreaction device helps greatly shorten the reaction time and provide high throughput and good product quality stability; high continuity is good for continuous scaled production; operating is simple, safety is high, and separating is easy; the defects of the traditional synthetic path can be effectively overcome; the yield is significantly increased, up to 90%. Desloratadine prepared in the production process is subjected to continuous separation and continuous liquid separation; the solution is added directly to next reaction to obtain rupatadine; the yield is not reduced, and the operation issimplified.
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Paragraph 0025; 0034-0039
(2019/05/22)
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- Preparation method for desloratadine
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The invention provides a green synthesis method for desloratadine, which achieves a yield of more than 90% and a purity of more than 99.9%. A reaction is carried out in a specific medium, that is, an ionic liquid with a specific structure. The ionic liquid can be used as a medium independently or be used in combination with other component solvents, and can be recovered and cyclically used, and therefore is green and environment-friendly. After-treatment is simple and convenient.
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Paragraph 0018
(2017/08/28)
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- A ground of loratadine preparation method (by machine translation)
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The present invention provides a yield of 90% or more, purity 99.9% or more green synthetically loratadine method. In a specific medium, i.e. a particular structure of the reaction is carried out in the ionic liquid. The ionic liquid may be used alone as the media, can also be combined with other component solvent use, and can be recycled, and environmental protection. After treatment is simple, post-processing is simple and convenient. (by machine translation)
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Paragraph 0015; 0019; 0020
(2017/05/05)
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- Desloratadine preparation method
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The invention provides a green desloratadine synthesis method with the yield of 90% or above and the purity of 99.9% or above. A reaction is carried out in a specific medium which is an ionic liquid with a specific structure. The ionic liquid can be individually used as a medium, also can be used together with other component solvents, and can be recovered and reused, so the ionic liquid is green and environmentally-friendly. The method allows post-treatment to be simple and convenient.
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Paragraph 0018
(2017/05/18)
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- A compound Rupatadine fumarate, its synthetic method and its pharmaceutical composition
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The invention relates to the field of compounds, and in particular relates to a rupatadine fumarate compound as well as a synthesis method and a pharmaceutical composition thereof. An X-ray powder diffraction diagram of the rupatadine fumarate compound measured through a Cu-K alpha ray is represented as Drawing 1 described in the specification. Furthermore, the invention relates to a synthesis method of the rupatadine fumarate. The method, which takes 3-methyl-5-chloromethylpyridine hydrochloride as an initial raw material, simplifies synthesis steps and avoids complex processes such as extraction; therefore the method is quite suitable for industrial production. The rupatadine fumarate compound disclosed by the invention is high in purity, good in stability, high in bioavailability and quite suitable for clinical application.
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Paragraph 0041-0042
(2017/01/19)
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- HETEROCYCLIC COMPOUND AND H1 RECEPTOR ANTAGONIST
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A heterocyclic compound useful as an antiallergic agent is provided. A compound represented by the following formula (1) or a salt thereof: wherein the ring A is a homocyclic or heterocyclic ring; the ring B is a heterocyclic ring which contains G and nitrogen atom N as constituent atoms thereof, wherein G is CH or N; R1 is a carbonyl group or an alkylene group; R2a and R2b are an alkyl group, a cycloalkyl group, an aryl group, or a heterocyclic group; X is an oxygen atom or a sulfur atom; Z is a hydroxyl group, an alkoxy group, a cycloalkyloxy group, an aryloxy group, an aralkyloxy group, an amino group, or an N-substituted amino group; and n is 0 or 1; with the proviso that when the ring A is a benzene ring or when the ring B is a piperazine ring, R1 is an alkylene group which may have a substituent.
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Paragraph 0286; 0287; 0288
(2013/04/13)
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- Design and synthesis of thiourea derivatives containing a benzo[5,6]cyclohepta[1,2-b]pyridine moiety as potential antitumor and anti-inflammatory agents
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Thiourea derivatives (6a-e) were developed and screened for antitumor and anti-inflammatory activity. Most of the compounds exhibited growth inhibitory effects comparable to 5-fluorouracil in vitro against mammary (MCF-7 and MDA-MB 231) as well as colon (HT-29) carcinoma cells. They also showed stronger anti-inflammatory activity than ibuprofen in vivo in the xylene-induced ear swelling assay in mice.
- Liu, Wukun,Zhou, Jinpei,Zhang, Tong,Zhu, Haiyang,Qian, Hai,Zhang, Huibin,Huang, Wenlong,Gust, Ronald
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p. 2701 - 2704
(2012/05/20)
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- PROCESS FOR THE PREPARATION OF DESLORATADINE
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The present invention provides a process for the preparation of desloratadine comprising contacting loratadine with a mixture of a weak inorganic base and sodium or potassium hydroxide in a ratio, ranging from 0.01 to 0.15 equivalents of sodium or potassium hydroxide per equivalent of weak inorganic base, in one or more suitable solvents) followed by isolation.
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Page/Page column 2
(2012/05/04)
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- Stereoselective synthesis of desloratadine derivatives as antagonist of histamine
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A series of desloratadine derivatives were stereoselectively synthesized and evaluated for H1 antihistamine activity. For the evaluation of H1 antihistamine activity, the in vitro histamine-induced contraction of the guinea-pig ileum assay (HC) was used. The synthesized desloratadine derivatives 7, 8 and 9 are structurally related to rupatadine and were generated by replacement of the 5-methyl-3-pyridine group of rupatadine with γ-alkylidene butenolide. Their H1 antihistamine activities have shown a high dependence on the exact nature of the substituent in the lactone ring. Optimum structures 7, 8a and 8g display potent activity inhibiting histamine-induced effects.
- Liu, Gai-Zhi,Xu, Hai-Wei,Chen, Guang-Wei,Wang, Peng,Wang, Ya-Na,Liu, Hong-Min,Yu, De-Quan
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experimental part
p. 1626 - 1632
(2010/04/26)
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- PROCESS FOR THE PREPARATION OF DESLORATADINE
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The present invention provides a process for the preparation of desloratadine comprising contacting loratadine with a mixture of a weak inorganic base and sodium or potassium hydroxide in a ratio, ranging from 0.01 to 0.15 equivalents of sodium or potassium hydroxide per equivalent of weak inorganic base, in one or more suitable solvents) followed by isolation.
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Page/Page column 5-6
(2010/11/04)
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- NOVEL CRYSTALLINE FORM OF RUPATADINE FREE BASE
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The present invention relates to a novel crystalline form of rupatadine free base, process for its preparation and to a pharmaceutical composition containing it. In accordance with the present invention rupatadine is suspended in n-hexane, n-heptane, cyclohexane, diethyl ether or diisopropyl ether, stirred for at least 1 hour, filtered the solid and dried to give crystalline rupatadine form-B. The isolation of novel rupatadine free base as crystalline form-B may be useful as a purification of rupatadine or a salt thereof.
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Page/Page column 2
(2009/08/16)
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- PROCESS FOR THE PREPARATION OF DESLORATADINE ADDUCT FORMED WITH CARBON DIOXIDE
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Process for the preparation of a desloratadine adduct forme with carbon dioxide of the formula: (I)
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Page/Page column 20-21
(2008/12/05)
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- IMPROVED METHOD FOR THE PREPARATION OF DESLORATADINE WITH REDUCED LEVELS OF ORGANIC SOLVENTS
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The present invention relates to an improved method for the preparation of Desloratadine with reduced levels of organic solvents. Further the invention also relates to a process for the preparation of Desloratadine containing reduced level of chloroform and hexane in Desloratadine to meet ICH specifications. The invention also relates to provide Desloratadine in mixture of polymorphic form 1 and form 2.
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Page/Page column 6
(2008/12/07)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF DESLORATADINE
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The present invention relates to an improved process for the preparation of compound of formula (I), 8-chloro-6,l l-dihydro-l l-(4-piperidinylidene)-5H- benzo[5,6]cyclohepta[l,2-b]pyridine (Desloratadine) or its pharmaceutically acceptable salts thereof, by reacting a compound of formula (II), 4-(8-Chloro-5,6-dihydro-l IH- benzo[5,6]cyclohepta[l,2-b]pyridin-l l-ylidene)-l piperidinecarboxylic acid ethyl ester (Loratadine) with sodium hydroxide in a solvent mixture of toluene and polyethylene glycol (PEG 400) at reflux temperature.
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Page/Page column 4-5
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF DESLORATADINE POLYMORPH MIXTURES
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The present application provides a process for the preparation of mixture of polymorphic Form I and Form II of desloratadine in any desired ratio.
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Page/Page column 5
(2008/12/09)
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- Process for the preparation of desloratadine
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The present invention relates to an improved process for the preparation of compound of formula (I), 8-chloro-6,11-dihydro-11-(4-piperidinylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (Desloratadine) or its pharmaceutically acceptable salts thereof, by reacting a compound of formula (II), 4-(8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1 piperidinecarboxylic acid ethyl ester (Loratadine) with sodium hydroxide in a solvent mixture of toluene and polyethylene glycol (PEG 400) at reflux temperature.
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Page/Page column 3
(2008/06/13)
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- Hybrid approach for the design of highly affine and selective dopamine D3 receptor ligands using privileged scaffolds of biogenic amine GPCR ligands
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A series of compounds containing privileged scaffolds of the known histamine H1 receptor antagonists cetirizine, mianserin, ketotifen, loratadine, and bamipine were synthesized for further optimization as ligands for the related biogenic amine binding dopamine D3 receptor. A pharmacological screening was carried out at dopamine D2 and D3 receptors. In the preliminary testing various ligands have shown moderate to high affinities for dopamine D3receptors, for example, N-(4-{4-[benzyl(phenyl)amino]piperidin-1-yl}butylnaphthalen-2-carboxamide (19a) (hD3 Ki = 0.3 nM; hD2 Ki = 703 nM), leading to a selectivity ratio of 2343.
- Sasse, Britta C.,Mach, Ulrich R.,Leppaenen, Jukka,Calmels, Thierry,Stark, Holger
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p. 7258 - 7273
(2008/03/27)
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- Novel crystalline forms of desloratadine and processes for their preparation
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Novel polymorph Forms III and V of desloratadine are provided. Pharmaceutical compositions containing such polymorphs are also provided.
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Page/Page column 6
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF DESLORATADINE
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The present invention relates to an improved process for the preparation of Form 1 of desloratadine essentially free of Form 2. The invention also relates to Form 1 of desloratadine substantially free of Form 2, process for its preparation, pharmaceutical composition comprising it and its method of use for the treatment of allergic reactions in mammals.
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Page/Page column 3
(2008/06/13)
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- NEW PSEUDOPOLYMORPH OF DESLORATADINE FORMED WITH CARBON DIOXIDE
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The pseudopolymorph of desloratadine formed with carbon dioxide of the formula (I) has valuable anti-allergic effect and can be used as pharmaceutical active ingredient. The present invention also relates to the preparation of desloratadine of high purity. The present invention also relates to the use of the pseudopolymorph of desloratadine of the formula (I) for the preparation of salts of desloratadine of the formula (VI) (wherein X stands for an anion and n is 1 or 2).
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Page/Page column 21-22; 23-24; 25-26
(2008/06/13)
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- A NOVEL CRYSTALLINE FORM OF RUPATADINE FREE BASE
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The present invention relates to a novel crystalline form of rupatadine free base, process for its preparation and to a pharmaceutical composition containing it. In accordance with the present invention rupatadine is suspended in n-hexane, n-heptane, cyclohexane, diethyl ether or diisopropyl ether, stirred for at least 1 hour, filtered the solid and dried to give crystalline rupatadine form-B. The isolation of novel rupatadine free base as crystalline form-B may be useful as a purification of rupatadine or a salt thereof.
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Page/Page column 5
(2010/11/24)
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- AN IMPROVED PROCESS FOR THE PRODUCTION OF DESLORATADINE
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An improved process for the production of Desloratadine is described wherein Loratadine is reacted with neat alcohol in presence of inorganic base, followed by isolating Desloratadine on addition of excess water in crystalline form.
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- Novel farnesyl protein transferase inhibitors as antitumor agents
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Disclosed are novel tricyclic compounds represented by the formula (1.0): and a pharmaceutically acceptable salt or solvate thereof. The compounds are useful for inhibiting farnesyl protein transferase. Also disclosed are pharmaceutical compositions comprising compounds of formula 1.0. Also disclosed are methods of treating cancer using the compounds of formula 1.0.
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- Novel farnesyl protein transferase inhibitors as antitumor agents
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Disclosed are novel tricyclic compounds represented by the formula (1.0): or a pharmaceutically acceptable salt or solvate thereof. The compounds are useful for inhibiting farnesyl protein transferase. Also disclosed are pharmaceutical compositions comprising compounds of formula 1.0. Also disclosed are methods of treating cancer using the compounds of formula 1.0.
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Page 98 - 99
(2010/02/03)
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- Substituted imidazoles as dual histamine H1 and H3 agonists or antagonists
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The present invention discloses novel substituted imidazole compounds which have dual histamine-H1 and H3 receptor antagonist activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such imidazoles as well as methods of using them to treat allergy, inflammatory and CNS-related diseases and others.
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- Tricyclic carbamate compounds useful for inhibition of G-protein function and for treatment of proliferative diseases
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A method of inhibiting Ras function and therefore inhibiting cellular growth is disclosed. The method comprises the administration of a compound of Formula 1.0 Also disclosed are novel compounds of the formulas: Also disclosed are processes for making 3-substituted compounds of the Formulas 1.1, 1.2 and 1.3. Further disclosed are novel compounds which are intermediates in the processes for making the 3-substituted compounds of Formulas 1.1, 1.2, and 1.3.
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- Tricyclic amide and urea compounds useful for inhibition of g-protein function and for treatment of proliferative diseases
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A method of inhibiting Ras function and therefore inhibiting the abnormal growth of cells is disclosed. The method comprises the administration of a compound of Formula 1.0: STR1 to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammal such as a human being. Novel compounds of formulas 5.0, 5.1 and 5.2, wherein R is --C(R20)(R21)(R46), and 5.3, 5.3A and 5.3B, wherein R is --N(R25)(R48), are disclosed. Also disclosed are processes for making 3-substituted compounds of Formulas 5.0, 5.1, 5.2 and 5.3. Further disclosed are novel compounds which are intermediates in the process for making 3-substituted compounds of Formulas 5.0, 5.1, 5.2 and 5.3.
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- Tricyclic sulfonamide compounds useful for inhibition of G-protein function and for treatment of proliferative diseases
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A method of inhibiting Ras function and therefore inhibiting cellular growth is disclosed. The method comprises the administration of a compound containing a tricyclic ring system to a biological system. In particular, the method inhibits cellular growth in a mammal such as a human being. Novel compounds of the formula: STR1 are disclosed. Also disclosed are processes for making 3-substituted compounds of Formula 4.0. Further disclosed are novel compounds which are intermediates in the processes for making the 3-substituted compounds of Formula 4.0.
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- Tricyclic amide and urea compounds useful for inhibition of G-protein function and for treatment of proliferative diseases
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Novel compounds of Formula (7.0a), (7.0b) or (7.0c): STR1 are disclosed. Also disclosed is a method of inhibiting Ras function and therefore inhibiting the abnormal growth of cells. The method comprises administering a compound of the formula (7.0a), (7.0b) or (7.0c) to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammal such as a human being.
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- Novel tricyclic aminoacetyl and sulfonamide inhibitors of ras farnesyl protein transferase
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Novel tricyclic FPT inhibitors with submicromolar FPT activity are described. Greatly enhanced FPT activity is realized with phthaloyl derivatized amino compound 2k, which showed FPT inhibitory activity of IC50 = 0.66 μM. Sulfonamides 5g and 50 were also found to be potent FPT inhibitor. SAR resulting from a variety of tricyclic amino acids and sulfonamide derivatives is discussed.
- Njoroge, F. George,Vibulbhan, Bancha,Alvarez, Carmen S.,Bishop, W. Robert,Petrin, Joanne,Doll, Ronald J.,Girijavallabhan,Ganguly, Ashit K.
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p. 2977 - 2982
(2007/10/03)
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- Bis-benzo or benzopyrido cyclohepta piperidene, piperidylidene and piperazine compounds, compositions and methods of use
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Bis-benzo or benzopyrido piperidene, piperidylidene and piperazine compounds of the formula: STR1 and pharmaceutically acceptable salts thereof are disclosed, wherein Z represents --(C(Ra)2)m --Y--(C(Ra)2)n -- or STR2 The compounds of Formula I possess anti-allergic and anti-inflammatory activity. Methods for preparing and using the compounds are also described.
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- Heterocyclic n-oxide derivatives of substituted benzo[5,6]cycloheptapyridines, compositions and methods of use
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Heterocyclic N-oxide derivatives of substituted benzo[5,6]cycloheptapyridines, and pharmaceutically acceptable salts and solvates thereof are disclosed, which possess anti-allergic and anti-inflammatory activity. Methods for preparing and using the compounds are also described.
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- 6,11-Dihydro-11-(N-substituted-4-piperidylidene)-5H-benzo(5,6)cyclohepta(1,2-B)pyridines and compositions and methods of use
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Derivatives of 6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, and pharmaceutically acceptable salts and solvates thereof are disclosed, which possess anti-allergic and anti-inflammatory activity. Methods for preparing and using the compounds are also described.
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- ANTIHISTAMINIC 8-(HALO)-SUBSTITUTED 6,11-DIHYDRO-11-(4-PIPERIDYLIDENE)-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDINES
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Disclosed are 7- and/or 8-(halo or trifluoromethyl)-substituted-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridines and the pharmaceutically acceptable salts thereof, which possess antihistaminic properties with substantially no sedative properties. Methods for preparing and using the compounds and salts are described
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