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

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

Inactive Publication Date: 2005-04-27
NEUROCRINE BIOSCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, like the use of barbiturates, benzodiazepines have some 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)a cetamide and compositions and methods related thereton
  • Polymorphs of N-methyl-N-(3-3-{2-thienylcarbonyl]-pyrazol -[1,5-alpha]-pyrimidin-7-yl}phenyl)a cetamide and compositions and methods related thereton
  • Polymorphs of N-methyl-N-(3-3-{2-thienylcarbonyl]-pyrazol -[1,5-alpha]-pyrimidin-7-yl}phenyl)a cetamide and compositions and methods related thereton

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0133] Synthesis of compound 1

[0134]This example illustrates the synthesis of Compound 1 by known techniques, resulting in Compound 1 being a mixture of the Form I polymorph and the Form II polymorph, according to figure 1 confirmed by the DSC thermogram.

[0135]

[0136] β-Dimethylamino-1-(2-thienyl)-2-propen-1-one (3).

[0137] 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 give a dark orange-red solid. The solid was collected by filtration and triturated with a solution of dichloromethane and ether (1:10, 200 mL). The resulting compound 3 was 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.

[0138] 5-(2-Thienyl)isoxazole (4).

[0139] A mixture of compound 3 (18.1 g, 100 mmol) and hydroxylamine hydrochloride (7.0 g, 101 mmol) was refluxed in 100 mL of...

Embodiment 2

[0152] Synthesis of Substantially Pure Form I Polymorph

[0153] 100 mL of acetone was added to 1.5 g of compound 1 prepared as in Example 1. Heat to reflux until the solution is homogeneous. The solution was quickly passed through a molten glass funnel. The solution was then slowly cooled to room temperature, which took approximately 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 yield 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 yield an additional 0.5 g of Form I polymorph.

Embodiment 3

[0155] basically pure II Synthesis of polymorphs

[0156] 75 mL of methanol was added to 1.4 g of compound 1 prepared as in Example 1. Heat to reflux until the solution is homogeneous. The solution was quickly passed through a molten glass funnel. The solution was then slowly cooled to room temperature, which took approximately 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 yield 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 yield an additional 0.4 g of Form II polymorph.

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Abstract

Polymorphs of N-methyl-N-(3-ä3-Ä2-thienylcarbonylÜ-pyrazol-Ä1,5- alpha Ü-pyrimidin-7-ylüphenyl)acetamide (Compound (1)), and use of the same as a sedative-hypnotic, anxiolytic, anticonvulsant, and skeletal muscle relaxant agent. Processes for making the same, as well as related compositions and methods are also disclosed, particularly with regard to treatment of insomnia. A polymorph Form I possessing exception physical and heat stability is provided. A polymorph Form II, is also provided.

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 is active in many 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 all states of discomfort associated with a patient's sleep deprivation or non-resting sleep sensations (Dement, International Pharmacopsychiatry 17:3-38, 1982). Insomnia is the most frequent disorder reported to be present in approximately 32% of adults surveyed in Los Angeles (Bixler et al., Amer. Journal of Psychiatry 136:1257-1262, 1979 ), about 13% of the population surveyed in San Marino, Italy, suffered from insomnia (Lugaresi et al., Psychiatric Annals 17:446-453, 1987). At least 45% of the surveyed ad...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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