Polymorphic forms of 1-'4-(5-cyanoindol-3-yl)butyl-4-(2-carbamoylbenzofuran-5-yl)piperazine hydrochloride

A technology of cyanindole and benzofuran, which is applied in the field of treatment of medical diseases and can solve the problems of incomparability

Inactive Publication Date: 2008-03-12
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Certain crystalline, i.e., morphological forms of a pharmaceutical compound may aid in the development of a suitable dosage form, as the exact dose used or measured may differ between batches if the morphological form is not kept constant during clinical and stability studies. no comparison between

Method used

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  • Polymorphic forms of 1-'4-(5-cyanoindol-3-yl)butyl-4-(2-carbamoylbenzofuran-5-yl)piperazine hydrochloride
  • Polymorphic forms of 1-'4-(5-cyanoindol-3-yl)butyl-4-(2-carbamoylbenzofuran-5-yl)piperazine hydrochloride
  • Polymorphic forms of 1-'4-(5-cyanoindol-3-yl)butyl-4-(2-carbamoylbenzofuran-5-yl)piperazine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0243] Preparation of Type I 1-[4-(5-Cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride

[0244] method 1:

[0245] 1 g of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine was dissolved in 80 ml of acetone. The temperature of the solution was brought to 50°C, and 0.5 ml of 1N hydrochloric acid was added to the reaction mixture. After stirring for 2 to 3 minutes, the reaction mixture was cooled to room temperature and a precipitate appeared. The precipitated crystals were filtered with suction. Drying to constant weight in vacuo at room temperature gave 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperidine oxazine hydrochloride acetonate type I.

[0246] Method 2:

[0247] Disperse 2.25g of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride type III in 200ml of acetone. After stirring for 14 days, the precipitated crystals were recovered by filtration, and dried...

Embodiment 2

[0249] Preparation of Type II 1-[4-(5-Cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride

[0250] method 1:

[0251] Dissolve 1 g of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine in 46.6 g of tetrahydrofuran To the reaction mixture was added 2.2 g of 1N hydrochloric acid. After precipitation and stirring for 30 minutes, the precipitated crystals were subjected to suction filtration. Drying to constant weight in vacuo at room temperature gave 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperidine Monosolvate Form II of oxazine hydrochloride with tetrahydrofuran, which exhibits the IR absorption spectrum of FIG. 2 and the X-ray diffraction spectrum of FIG. 13 .

[0252] Method 2:

[0253] Disperse 3 g of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride type III in 400ml of tetrahydrofuran. After stirring for 20 days, the precipitated crystals were recovered by...

Embodiment 3

[0255] Preparation of Type XV 1-[4-(5-Cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride

[0256] To 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride at 0 °C 10 ml of 1N hydrochloric acid was added to a solution of tetrahydrofuran (200 ml) (molar ratio of base to tetrahydrofuran = 1:48). After stirring for 30 minutes, the precipitated crystals were recovered by filtration. Drying to constant weight in vacuo at room temperature gave 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperidine A solvate of oxazine hydrochloride with tetrahydrofuran, Form XV, which exhibits the IR absorption spectrum of FIG. 3 and the X-ray diffraction spectrum of FIG. 14 .

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Abstract

The invention relates to new crystalline modifications of the hydrochloride of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine, crystalline modification of the dihydrochloride of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine and amorphous 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride which are suitable in particular for the preparation of solid medicaments for the treatment or prevention of depressive disorders, anxiety disorders, bipolar disorders, mania, dementia, substance-related disorders, sexual dysfunctions, eating disorders, obesity, fibromyalgia, sleeping disorders, psychiatric disorders, cerebral infarct, tension, for the therapy of side-effects in the treatment of hypertension, cerebral disorders, chronic pain, acromegaly, hypogonadism, secondary amenorrhea, premenstrual syndrome and undesired puerperal lactation.

Description

[0001] This application is a divisional application of Chinese invention patent application 02812226.7, the filing date is June 5, 2002, and the priority date is June 19, 2001. Field of Invention [0002] The present invention relates to novel compounds, methods of making them and their use in the treatment of medical conditions. Background of the Invention [0003] 1-[4-(5-Cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl) is known from US Pat. No. 5,532,241 and WO 00 / 72832 - Piperazine, its physiologically acceptable salts (US 5,532,241 column 7 lines 30 to 58), methods by which it / them can be prepared (US 5,532,241 example 4) and their use in the treatment of certain medical conditions use. Example 4 of US 5,532,241 describes 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine The hydrochloride salt was prepared by first mixing 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carboxybenzofuran-5-yl)-piperazine with 2-chloro -1-Methylpyridine-methanesulfona...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12A61K31/496A61P25/00C07D405/00A61P1/14A61P3/04A61P9/10A61P9/12A61P15/00A61P15/10A61P21/00A61P25/04A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P29/02
CPCA61K31/496C07D405/14C07D405/12A61P1/14A61P15/00A61P15/08A61P15/10A61P21/00A61P25/00A61P25/04A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/30A61P29/00A61P29/02A61P3/04A61P9/00A61P9/10A61P9/12
Inventor A·巴特B·赫尔弗特S·诺恩费尔德H·克尼尔M·巴特尔斯S·鲁道夫H·波切尔
Owner MERCK PATENT GMBH
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