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: 2004-07-28
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Certain crystalline, i.e., morphological forms of pharmaceutical compounds may assist in the development of suitable dosage forms, 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

[0242] Preparation of type I 1-[4-(5-cyanindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride

[0243] method 1:

[0244] 1 g of 1-[4-(5-cyanindol-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 in vacuo at room temperature to constant weight gave 1-[4-(5-cyanindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piper Oxazine hydrochloride acetonide type I.

[0245] Method 2:

[0246] Disperse 2.25 g of 1-[4-(5-cyanindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride Type III in 200ml acetone. After stirring for 14 days, the precipitated crystals were recovered by filtration and dried in vacuum a...

Embodiment 2

[0248] Preparation of type II 1-[4-(5-cyanindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride

[0249] method 1:

[0250] 1g 1-[4-(5-cyanindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine was dissolved in 46.6g tetrahydrofuran, and To the reaction mixture was added 2.2 g of 1N hydrochloric acid. After settling and stirring for 30 minutes, the precipitated crystals were filtered with suction. Drying in vacuo at room temperature to constant weight gave 1-[4-(5-cyanindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piper A solvate type II of oxazine hydrochloride and tetrahydrofuran, which presents figure 2 The IR absorption spectrum and Figure 13 X-ray diffraction spectrum.

[0251] Method 2:

[0252] Disperse 3 g of 1-[4-(5-cyanindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride type III in 400ml tetrahydrofuran. After stirring for 20 days, the precipitated crystals were recovered by filtration. Drying in vacuo a...

Embodiment 3

[0254] Preparation of Type XV 1-[4-(5-cyanindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride

[0255]At 0°C, to 1-[4-(5-cyanindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride A solution of tetrahydrofuran (200ml) (molar ratio of base to tetrahydrofuran = 1:48) was added to 10ml of 1N hydrochloric acid. After stirring for 30 minutes, the precipitated crystals were recovered by filtration. Drying in vacuo at room temperature to constant weight gave 1-[4-(5-cyanindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piper The solvate type XV of oxazine hydrochloride and tetrahydrofuran, which presents image 3 The IR absorption spectrum and Figure 14 X-ray diffraction spectrum.

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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

field of invention [0001] The present invention relates to novel compounds, processes for their preparation and their use in the treatment of medical conditions. Background of the invention [0002] 1-[4-(5-cyanindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl) is known from US patent US 5,532,241 and WO 00 / 72832 - piperazine, its physiologically acceptable salts (US 5,532,241 column 7, lines 30 to 58), the process 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-cyanindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine The preparation of hydrochloride, first make 1-[4-(5-cyanoindol-3-yl) butyl]-4-(2-carboxybenzofuran-5-yl)-piperazine and 2-chloro -1-Methylpyridine mesylate was reacted in N-Methylpyrrolidine, and then with dry NH 3 reaction. Conventional work-up affords the free base 1-[4-(5-cyanindol-3-yl)butyl]-4-(2-carb...

Claims

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Application Information

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IPC IPC(8): C07D405/00A61K31/496A61P1/14A61P3/04A61P9/10A61P9/12A61P15/00A61P15/10A61P21/00A61P25/04A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P29/02C07D405/12
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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