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N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-3-(7-tert-butylpyrazolo[1,5-A][1,3,5]triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide, a dual modulator of chemokine receptor activity, crystalline forms and processes

A technology of N-1, crystal form, applied in N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-3-(7-tert-butylpyrazolo [1,5-A][1,3,5]Triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide, dual modulator of chemokine receptor activity , crystal form and domain

Active Publication Date: 2012-08-22
BRISTOL MYERS SQUIBB CO
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although MCP-1 is not involved in these processes, MCP-1 antagonists acting via binding to CCR-2 in HIV-infected patients may be beneficial therapeutically for delaying disease progression to AIDS

Method used

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  • N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-3-(7-tert-butylpyrazolo[1,5-A][1,3,5]triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide, a dual modulator of chemokine receptor activity, crystalline forms and processes
  • N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-3-(7-tert-butylpyrazolo[1,5-A][1,3,5]triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide, a dual modulator of chemokine receptor activity, crystalline forms and processes
  • N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-3-(7-tert-butylpyrazolo[1,5-A][1,3,5]triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide, a dual modulator of chemokine receptor activity, crystalline forms and processes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0064] In one embodiment, the present invention relates to N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-3-(7-tert-butylpyrazolo[1, 5-a][1,3,5]triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide:

[0065]

[0066] and its medicinal salts.

[0067] Another embodiment is N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-3-(7-tert-butylpyrazolo[1,5-a] Crystalline form of [1,3,5]triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide.

[0068] Another embodiment is N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-3-(7-tert-butylpyrazolo[1,5-a] A crystal form of [1,3,5]triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide, wherein the crystal form comprises N-1 and / or P-1 crystal form.

[0069] Another embodiment is N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-3-(7-tert-butylpyrazolo[1,5-a] A crystal form of [1,3,5]triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide, wherein the crystal form comprises N-1 crystal form.

[0070] Another embodiment is N-((1R,2S,5R)-5-(ter...

Embodiment 1

[0247] N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-3-(7-tert-butylpyrazolo[1,5-a][1,3, 5] Triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide

[0248]

[0249] Example 1, Step 1: Add hemicarbazide hydrochloride (100.0 g, 0.89 mol), pivaloyl acetonitrile (112.2 g, 0.89 mol) and ethanol (1 L ). After the addition was complete, the reaction mixture was cooled to 12-15°C and anhydrous sodium acetate (73.5 g, 0.89 mol) was added. The addition of anhydrous sodium acetate is endothermic, raising the temperature to 22-25°C. The reaction mixture was maintained at 22-25°C and stirred for 60-90 minutes. Then, analysis of the reaction mixture by HPLC indicated complete formation of the hydrazone intermediate.

[0250] Example 1, Step 2: The reaction mixture was then heated to 68 to 72°C and trimethyl orthoformate (475.7 g, 4.48 mol) was added over a period of 5-10 minutes. The reaction mixture was cooled to 40-45°C, then acetic acid (53.8 g, 0.89 mol) was added over a period...

Embodiment 2

[0255] Tritiated N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-3-(7-tert-butylpyrazolo[1,5-a][ 1,3,5]triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide

[0256]

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Abstract

The present invention provides a novel antagonist: N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-3-(7-tert-butylpyrazolo[1,5-a][1,3,5]triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide: or a pharmaceutically acceptable salt, solvate or prodrug, thereof, having unexpected dual CCR-2 and CCR-5 receptor activity. Crystalline forms, metabolites, pharmaceutical compositions containing the same and methods of using the same as agents for the treatment of inflammatory diseases, allergic, autoimmune, metabolic, cancer and / or cardiovascular diseases are also disclosed. The present disclosure also provides processes for preparing compounds of Formula (I) as provided herein, including N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-3-(7-tert-butylpyrazolo[1,5-a][1,3,5]triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide. Compounds that are useful intermediates of the process are also provided herein.

Description

technical field [0001] The present invention provides N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-3-(7-tert-butylpyrazolo[1,5-a][1 ,3,5] triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide, or pharmaceutically acceptable salts, solvates or prodrugs thereof, which have unexpected Dual activity required. Crystalline forms of the invention are also provided. Pharmaceutical compositions containing them and their methods of use as medicines for the treatment of inflammatory diseases, allergic diseases, autoimmune diseases, metabolic diseases, cancer and / or cardiovascular diseases are also objects of the present invention. The present invention also provides the preparation of compounds of formula (I), including N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-3-(7-tert-butylpyrazolo [1,5-a][1,3,5]triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide method: [0002] [0003] where R 1 , R 8 , R 9 , R 10 and as described in this article. Compounds useful as interm...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/53A61P37/00
CPCC07D487/04A61P1/00A61P1/04A61P11/00A61P11/06A61P13/12A61P17/00A61P17/06A61P19/02A61P25/00A61P25/04A61P25/28A61P29/00A61P29/02A61P3/00A61P3/04A61P31/18A61P35/00A61P3/06A61P37/00A61P37/02A61P37/06A61P43/00A61P7/02A61P9/00A61P9/04A61P9/10A61P9/12A61P9/14A61P3/10A61K31/53A61K45/06C07D403/12A61K2300/00C07B2200/13
Inventor P.H.卡特R.J.彻尼V.W.罗索李俊
Owner BRISTOL MYERS SQUIBB CO
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