- C(sp2)-H Bond Multiple Functionalization in Air for Construction of Tetrahydrocarbazoles with Continuous Quaternary Carbons and Polycyclic Diversification
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The C(sp2)-H function of indole ketone with diazo compound via a rhodium(II)-catalyzed intramolecular electrophilic trapping reaction under mild conditions in air was demonstrated. The established methodology provided a highly efficient approach for direct synthesis of mutisubstituted tetrahydrocarbazoles with continuous quaternary carbons. The resulting products facilitate further modification to conveniently construct tetrahydrocarbazoles with additional fused heterocyclic rings. By phenotypic screening, several products exhibit good anticancer bioctivities in osteosarcoma cell lines.
- Dong, Suzhen,Jia, Shikun,Liu, Shunying,Ni, Dan,Pi, Rou,Song, Longlong,Tang, Jie,Yang, Fan
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- IMIDAZOLYL MODULATORS OF 5-HT3 RECEPTORS
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The present invention relates to new imidazolyl modulators of 5-HT3 receptors, pharmaceutical compositions thereof, and methods of use thereof.
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- A ONE-POT PROCESS FOR THE PREPARATION OF ANTIEMETIC AGENT, 1,2,3,9-TETRAHYDRO-9-METHYL-3[(2-METHYL)-1H-IMIDAZOLE-1-YL)METHYL]-4H-CARBAZOL-4-O
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A one-pot industrial process for preparing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazole-1-yl)methyl]-4H-carbazol-4-one of Formula-(I) from 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one of Formula-(IV) involves reaction of Formula (IV) with HNR1R2 salt and paraformaldehyde, where R1,R2 are independently alkyl groups or together forms a cyclic alkyl group, in a solvent system of acetic acid and hydrocarbon solvent to form a crude mixture of intermediate compounds of Formula (III) and (VIII), which is converted to ondansetron (Formula (I)) without isolation by reaction with 2-methyimidazole in a suitable solvent system in the same pot.
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Page/Page column 18-19
(2008/06/13)
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- Process for preparing 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one and ondansetron therefrom
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The present invention provides a rapid, high-yielding process for preparing 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one from 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one without using a secondary amine as a catalyst, and without using glacial acetic acid as a solvent. The present invention further provides a rapid, high-yielding process for preparing ondansetron from 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one without using alumina as a catalyst.
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Page/Page column 8
(2008/06/13)
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- NEW POLYMORPHIC FORMS OF ONDANSETRON, PROCESSES FOR PREPARING THEM, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR USE AS ANTIEMETICS
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This invention relates to new polymorphs of (±)1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-il)methyl]-4H-carbazol-4-one, known under the INN of ondansetron, to processes for preparing said polymorphs, to pharmaceutical compositions containing them and to their use in the treatment and prophylaxis of nausea and vomiting. The invention provides new stable polymorphic forms of ondansetron and processes for manufacturing them at an industrial scale.
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Page/Page column 17-18
(2008/06/13)
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- PROCESS FOR PREPARING 1,2,3,9-TETRAHYDRO-9-METHYL-3-[(2-METHYL-1H-IMIDAZOLE-1-YL)METHYL]-4H-CARBAZOL-4-ONE OR ITS SALT
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The present invention provides an improved process for preparing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one or its salt, which is useful as an anti-vomiting agent, in a high yield under a mild condition, so as to be favorably applied to a large-scale mass production thereof.
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Page/Page column 14-15
(2008/06/13)
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- PROCESS FOR PREPARING 1,2,3,9-TETRAHYDRO-9-METHYL-3-[(2-METHYL-1H-IMIDAZOLE-1-YL)METHYL]-4H-CARBAZOL-4-ONE OR ITS SALT
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1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]- 4H-carbazol-4-one or its salt is prepared in high yield by reacting a compound of formula 2 with a compound of formula 3 and a compound of formula 4 in the presence of an acid, an alkylsilylhalide compound or an acylhalide compound, in an solvent, and thus, such an inventive process can be favorably applied to a large-scale mass production thereof.
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Page/Page column 9
(2008/06/13)
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- ONDANSETRON FORMS AND PROCESSES OF MAKING THE SAME
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The invention relates to a solid crystalline ondansetron having at least one of the following characteristics: a melting endotherm peak greater than or equal to 240°C; a trace amount of a base or residue thereof comprising an alkali metal, an amine, an ammonium or an ion thereof; or a water content of 1.3 to 1.5 wt%, and to a composition comprising same and a pharmaceutically acceptable excipient, and to a process, which comprises: neutralizing an acid addition salt of ondansetron to liberate ondansetron free base; and precipitating said ondansetron free base from a liquid media, and to a process, which comprises dissolving ondansetron free base in a solvent and precipitating said dissolved ondansetron free base to form ondansetron having a melting endotherm peak of greater than or equal to 240°C measured on DSC at 5°C/min.
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- NOVEL PROCESS FOR THE PREPARATION OF IMIDAZOLYL COMPOUNDS
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The present invention relates to a method for the preparation of an imidazolyl compound of the general formula (I), wherein: Ra and Rb each separately are (C1-C6)alkyl, (C1-C6)alkoxyalkyl, optionally substituted aryl or heteroaryl; or wherein Ra and Rb together form a further homocyclic or heterocyclic system comprising one or more rings; Ra’ and Rb’ each are hydrogen or together form a carbon-carbon double bond, said carbon-carbon double bond optionally being part of an aromatic system; Rc is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1,-C6)alkoxyalkyl or halogen; Rd is hydrogen or (C1-C4)aIkyl; Re is hydrogen or (C1-C4)aIkyl; m is 1 or 2; and R1, is hydrogen or (C1-C4)aIkyl; as well as its acid addition salt;characterized in that a compound of the general formula (II) is reacted with a compound of the formula (III), wherein: R is a hydrogen, a (C1-C4)alkyl group optionally substituted with a hydroxygroup or an optionally substituted aryl group, R', R", R'" and R"" each individually are a hydrogen or a (C1-C4)aIkyl group; followed by a reaction with a compound of the formula (IV), wherein R1, Rd and Re have the meanings defined above; and optionally followed by a reaction with a suitable acid. De method according to the present invention is especially useful for the preparation of ondansetron and cilansetron.
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- PROCESS FOR PREPARING 1,2,3,9-TETRAHYDRO-9-METHYL-3-[(2-METHYL-1H-IMIDAZOL-1-YL)METHYL]-4H-CARBAZOL-4-ONE
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A process for preparing ondansetron by transamination of an ondansetron structural analog that can be readily prepared conveniently by a Mannich reaction is provided. The process represents an improvement upon known procedures for making ondansetron by transamination because of its rapid rate, selectivity and the ease with which the product can be isolated from the reaction mixture.
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Page/Page column 15; 16
(2008/06/13)
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- Medicaments for gastrointestinal disorders
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The invention relates to the co-administration in human or veterinary medicine of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one or a physiologically acceptable salt or solvate thereof and dexamethasone or a physiologically acceptable salt or ester thereof. The two active ingredients, which may be administered separately either simultaneously or sequentially, or may be combined in a single pharmaceutical preparation, are useful in the relief and/or prevention of nausea and vomiting.
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- Process for the preparation of 1,2,3,9-tetrahydro-9-methyl-3-((2-methyl-1H-imidazol-1-yl)-methyl)-4H-carbazol-4-one
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Pure 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one or a pharmaceutically acceptable salt thereof is prepared in a high yield by a simple process which reacts 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one with a 2-methylimidazole derivative in an organic solvent or in a mixture of an organic solvent and water in the presence of a halosilane compound.
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- Process for the preparation of 1,2,3,9-tetrahydro-9-methyl-3-{(2-methyl-1H-imidazol-1-yl)methyl}-4H-carbazol-4-one
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Pure -1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one or a pharmaceutically acceptable salt thereof is prepared in a high yield by a simple process which reacts 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one with a 2-methylimidazole derivative in an organic solvent or in a mixture of an organic solvent and water in the presence of a halosilane compound.
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- Novel crystal and solvate forms of ondansetron hydrochloride and processes for their preparation
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The present invention provides novel ondansetron hydrochloride crystalline polymorphic forms and solvates. Processes for making and interconverting the polymorphic forms are also provided. Further provided are pharmaceutical compositions and therapeutic methods using the novel polymorphic forms and hydrates.
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- Process for preparing pure ondansetron hydrochloride dihydrate
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An improved method for preparing dimethylamino-methyl-carbazolone and ondansetron base. A recrystallization process for preparing pure ondansetron hydrochloride dihydrate with a purity of at least 99.0% is also disclosed.
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- Use of serotonin antagonists for treating fibromyalgia
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The invention is directed to the use of 5HT3 antagonists of formula I STR1 wherein the substituents are as defined herein.
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- An efficient process of ondansetron synthesis
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An efficient and practical two-step synthesis of ondansetron (1) was accomplished from readily available N-methyltetrahydrocarbazolone (2) via direct Mannich a-methylenation and alumina catalyzed Michael addition resulting in a 70% overall yield.
- Kim, Moohi Yoo,Lim, Geun Jho,Lim, Joong In,Kim, Dong Sung,Kim, Ik Yon,Yang, Jae Sung
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p. 2041 - 2043
(2007/10/03)
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- Benzimidazole derivative, process for preparing the same, antiemetic agent containing the same as active ingredient and intermediate compound for preparing the same
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A benzimidazole derivative having the following formula (I): STR1 or a pharmaceutically acceptable acid addition salt thereof, a process for preparing the same, an antiemetic agent containing the same as an active ingredient and an intermediate compound for preparing the same. The above novel benzimidazole derivative has a continuous 5-HT3 antagonistic activity, shows preventive and therapeutic effects against vomiting caused by cisplatin and has a low toxicity, and hence, is useful as an antiemetic agent against vomiting due to chemotherapeutic treatment with cisplatin etc.
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- Carbazolone derivatives
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The invention relates to carbazolone derivatives of the formula STR1 wherein A stands for a group of formula wherein R means a hydroxyl or 2-methyl-1H-imidazol-1-yl group; B represents a group of formula STR2 wherein R1 means hydrogen or a methyl or ethyl group; or A and B together form a group of formula STR3 wherein R2 means a methyl or ethyl group; or A and B together form a group of formula STR4 The above compounds are useful intermediates in the synthesis of ondansetron of formula STR5 chemically 9-methyl-3-[(2-methyl)-1H-imidzol-1-yl)methyl]1,2,3,9-tetrahydro-4H-carbazol-4-one. The invention further relates to a novel process for the preparation of compounds of the formula (I), wherein A and B are the same as in formula (I) but B may be also hydrogen. Thus, this novel process is suitable for the preparation of ondansetron itself.
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- Carbazolone derivatives and process for preparing the same
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The invention relates to carbazolone derivatives of the formula wherein Astands for a group of formula -CH2-Rwherein R means a hydroxyl or 2-methyl-1H-imidazol-1-yl group; Brepresents a group of formula wherein R1means hydrogen or a methyl or ethyl group; or A and Btogether form a group of formula wherein R2means a methyl or ethyl group; or A and Btogether form a group of formula The above compounds are useful intermediates in the synthesis of ondansetron of formula chemically 9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one. The invention further relates to a novel process for the preparation of compounds of the formula (I), wherein A and B are the same as in formula (I).
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- MEDICAMENTS
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The invention relates to the co-administration in human or veterinary medicine of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one or a physiologically acceptable salt or solvate thereof and a cyclo-oxygenase inhibitor such as indomethacin or piroxicam. The two active ingredients, which may be administered separately either simultaneously or sequentially, or may be combined in a single pharmaceutical preparation, are useful in the relief and/or prevention of nausea and vomiting
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- Medicaments for the treatment of bulimia
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The invention relates to the use of ondansetron or a physiologically acceptable salt or solvate thereof, particularly ondansetron hydrochloride dihydrate, in the treatment of bulimia or a related disorder.
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- Process for preparing N-heterocyclic compounds
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The invention relates to a process for the preparation of compounds of general formula (I) STR1 wherein R 1 represents a hydrogen atom or a C 1-10 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-(C 1-4)alkyl, C 3-6 alkenyl, C 3-10 alkynyl, phenyl or phenyl-(C 1-3)alkyl group, and one of the groups represented by R 2, R 3 and R 4 is a hydrogen atom or a C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl or phenyl-phenyl-(C 1-3)alkyl group and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C 1-6 alkyl group; or a salt or protected derivative thereof by cyclization of a compound of general formula (II) STR2 wherein X represents a hydrogen atom or a halogen atom and R 1, R 2, R 3 and R 4 are as defined above, or a salt or a protected derivative thereof.The compounds of formula (I) are potent and selective antagonists at ""neuronal"" 5-hydroxytryptamine receptors.
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- Method of medical treatment
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The invention relates to the use of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one and physiologically acceptable salts and solvates thereof in the treatment of depression.
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- Method of medical treatment of addiction
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The invention relates to the use of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one and physiologically acceptable salts and solvates thereof in the relief or prevention of a withdrawal syndrome resulting from addiction to a drug or substance of abuse and/or for the suppression of dependence on drugs or substances of abuse.
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- Method for treating nausea and vomiting
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The invention relates to the use of compounds of the general formula (I) STR1 wherein R1 represents a hydrogen atom or a C1-10 alkyl, C3-7 cycloalkyl, C3-7 cycoalkyl-(C1-4) alkyl, C3-6 alkenyl, C3-10 alkynyl, phenyl or phenyl-C1-3 alkyl group, and one of the groups represented by R2,R3 and R4 is a hydrogen atom or a C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl or phenyl - C1-3 alkyl group and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C1-6 alkyl group; and physiologically acceptable salts and solvates thereof, for the relief of nausea and vomiting and/or the promotion of gastric emptying and for the manufacture of a medicament for this purpose. Promotion of gastric emptying may be for the relief of gastro-intestinal disorders associated with gastric stasis or may be of advantage of radiological examination procedures. The invention also relates to a product containing a therapeutic agent liable to induce nausea and vomiting, e.g. a cytostatic agent such as a cyclophosphamide, an alkylating agent or a platinum complex, and a compound of the general formula (I) as a combined preparation for simultaneous separate or sequential use in therapy.
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- Use of ketone derivatives for the manufacture of medicaments
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A medicament for use in the treatment of gastrointestinal disorders comprising 1,2,3,9-tetrahydro-9--methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4--one or a physiologically acceptable salt or solvate thereof and sufotidine or a physiologically acceptable salt thereof.
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- Method of treating emesis, anxiety and/or IBS
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A method of treatment of emesis, anxiety and/or IBS in mammals, including humans, which method comprises administering an effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof: wherein Ar is a group of formula (a): STR1 wherein: R1 and R2 are independently selected from hydrogen, halogen, C1-6 alkyl, C1-4 alkoxy, hydroxy, amino optionally substituted by one or two C1-4 alkyl groups, thiol, C1-4 alkylthio; X is CH2, NR3, --O-- or --S-- wherein R3 is hydrogen, C1-4 alkyl, C3-5 alkenyl, phenyl or phenyl C1-4 alkyl; or Ar is a group of formula (b): STR2 wherein R4 to R7 are independently hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, hydroxy, amino optionally substituted by one or two C1-4 alkyl, by C1-4 alkanoylamino or pyrrolyl, one of R4 to R7 being other than hydrogen; Y is --O-- or --NH--; and Z is a group of formula (c), (d) or (e): STR3 wherein n is 2, 3 or 4; R8 is hydrogen, C1-7 alkyl, C3-5 alkenyl or phenyl C1-4 alkyl optionally substituted by one or two halogen, C1-4 alkoxy or C1-4 alkyl; STR4 wherein: p is 1, 2 or 3; and R9 is as defined above for R8 ; and with the proviso that, when Ar is of formula (b) and Y is --NH--, Z is a group of formula (d) or (e); STR5 wherein R10 is hydrogen, C1-10 alkyl, C3-7 cycloalkyl, C3-6 alkenyl, phenyl or phenyl-C1-3 alkyl; and one of the groups represented by R11, R12 and R13 is hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl or phenyl-C1-3 alkyl and each of the other groups, which may be the same or different, is hydrogen or C1-6 alkyl.
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- Process for preparing tetrahydrocarbazolones
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The invention relates to a process for the preparation of a compound of general formula (I) STR1 wherein R 1 represents a hydrogen atom or a C 1-10 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-(C 1-4)alkyl, C 3-6 alkenyl, C 3-10 alkynyl, phenyl or phenyl-(C 1-3)alkyl group, and one of the groups represented by R 2, R 3 and R 4 is a hydrogen atom or a C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl or phenyl-(C 1-3)alkyl group and each of the other two groups, which may be the same or different, represent a hydrogen atom or a C 1-6 alkyl group;or a salt or protected derivative thereof, by cyclization of a compound of general formula (II) STR2 wherein R 1, R 2, R 3 and R 4 are as defined above, or a salt or a protected derivative thereof.The compounds of formula (I) are potent and selective antagonists at ""neuronal"" 5-hydroxytryptamine receptors.
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- 1,2,3,9-tetrahydro-3-imidazol-1-ylmethyl-4H-carbazol-4-ones, composition containing them, and method of using them to treat neuronal 5HT function disturbances
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The invention relates to compounds of formula (I). STR1 wherein R 1 represents a hydrogen atom or a C 1-10 alkyl, C 3-7 cycloalkyl, C 3-6 alkenyl, C 3-7 cycloalkyl-(C 1-4) alkyl, C 3-10 alkynyl, phenyl or phenyl-C 1-3 alkyl group, and one of the groups represented by R 2, R 3 and R 4 is a hydrogen atom or a C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl or phenyl-(C 1-3) alkyl group and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C 1-6 alkyl group; and physiologically acceptable salts and solvates, e.g. hydrates thereof.The compounds are potent selective antagonists at ""neuronal"" 5-hydroxytryptamine receptors and are useful in the treatment of migraine and psychotic disorders such as schizophrenia.
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