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Polymorphs of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide and compositions and methods related thereto

A technology of thienylcarbonyl and polymorphs, which is applied in the field of polymorphs of N-methyl-N-acetamide, can solve problems such as limiting effective use

Inactive Publication Date: 2002-10-16
NEUROCRINE BIOSCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, like barbiturates, benzodiazepines have side effects that limit their effective use in certain patient populations

Method used

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  • Polymorphs of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide and compositions and methods related thereto
  • Polymorphs of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide and compositions and methods related thereto
  • Polymorphs of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide and compositions and methods related thereto

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] Synthesis of compound 1

[0100] This example illustrates the synthesis of compound 1 by known techniques, the resulting compound 1 is a mixture of type I polymorphs and type II polymorphs, according to figure 1 It is confirmed by the DSC differential thermogram. β-Dimethylamino-1-(2-thienyl)-2-propen-1-one (3).

[0101] A mixture of 2-acetylthiophene 2 (20.0 g, 159 mmol) and dimethylformamide dimethyl acetal (39 g, 327 mmol) was refluxed under nitrogen for three hours. The reaction mixture was cooled and concentrated to obtain a dark orange-red solid. The solid was collected by filtration and triturated with a solution of dichloromethane and ether (1:10, 200 mL). Compound 3 was obtained as an orange solid (22.0 g, 121 mmol, 76%). GC / MS, m / z = 181 at tR = 11.83 min (100%). LC / MS, [M+H] = 182. 5-(2-thienyl)isoxazole (4).

[0102] A mixture of compound 3 (18.1 g, 100 mmol) and hydroxylamine hydrochloride (7.0 g, 101 mmol) was refluxed in 100 mL ...

Embodiment 2

[0109] Synthesis of Substantially Pure Form I Polymorph

[0110] 100 mL of acetone was added to 1.5 g of compound 1 prepared according to Example 1. Heat to reflux until the solution is homogeneous. The solution is passed quickly through a fused glass funnel. The solution was then cooled slowly to room temperature, which took about 1 hour. The mixture was further cooled to 5°C with an ice bath. The solid formed was collected by filtration and washed with 10 mL of cold acetone to afford 0.4 g of the Form I polymorph. The mother liquor was concentrated in vacuo to approximately 20 mL. The solution was cooled to 5°C. The solid was collected by filtration and washed with 10 mL of cold acetone to give an additional 0.5 g of Form I polymorph.

Embodiment 3

[0112] Synthesis of substantially pure Form II polymorph

[0113] 75 mL of methanol was added to 1.4 g of compound 1 prepared according to Example 1. Heat to reflux until the solution is homogeneous. The solution is passed quickly through a fused glass funnel. The solution was then cooled slowly to room temperature, which took about 1 hour. The mixture was further cooled to 5°C with an ice bath. The solid formed was collected by filtration and washed with 10 mL of cold methanol to afford 0.5 g of the Form II polymorph. The mother liquor was concentrated in vacuo to approximately 10 mL. The solution was cooled to 5°C. The solid was collected by filtration and washed with 10 mL of cold methanol to give an additional 0.4 g of the Form II polymorph.

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Abstract

The invention discloses N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazole-[1,5-α]-pyrimidin-7-yl}phenyl)acetamide (compound ( 1)), and their use as sedative-hypnotics, anxiolytics, anticonvulsants and skeletal muscle relaxants. At the same time, methods for preparing the substance and related compositions are also disclosed, especially for the treatment of insomnia. And provides the exceptional physical and thermal stability possessed by the Form I polymorph. Type II polymorphs are also contemplated.

Description

field of invention [0001] The present invention relates to polymorphic forms of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazole-[1,5-α]-pyrimidin-7-yl}phenyl)acetamide The substance has activity on numerous indications, and is particularly effective for the treatment of insomnia, and also relates to a related method, a composition containing the substance and a preparation method. Background of the invention [0002] The term "insomnia" is used to describe any uncomfortable state associated with a patient's lack of sleep or a perception of restless sleep (Dement, International Pharmacopsychiatry 17:3-38, 1982). Insomnia is the most frequently occurring disorder reported to be present in about 32% of adults surveyed in Los Angeles (Bixler et al., Amer.Journal of Psychiatry 136:1257-1262, 1979 ), about 13% of the surveyed population in San Marino, Italy suffered from insomnia (Lugaresi et al., "Psychiatric Annals" (Psychiatric Annals) 17:446-453, 1987). At ...

Claims

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Application Information

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IPC IPC(8): A61K9/20A61K9/48A61K31/505A61K31/519A61P21/02A61P25/08A61P25/20A61P25/22C07D487/02C07D487/04
CPCC07D487/04A61P21/00A61P21/02A61P25/08A61P25/20A61P25/22
Inventor W·J·瑟勒P·B·欧达尼尔
Owner NEUROCRINE BIOSCI INC
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