Modulators of chemokine receptor activity, crystalline forms and process

A crystalline form, compound technology, applied in the direction of organic active ingredients, non-central analgesics, anti-inflammatory agents, etc., can solve problems such as reducing the tendency of clinical drug-drug interaction

Inactive Publication Date: 2009-09-16
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0038] (e) Factors that reduce the propensity for clinical drug-drug interactions (inhibition or induction of cytochrome P450 enzymes, such as

Method used

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  • Modulators of chemokine receptor activity, crystalline forms and process
  • Modulators of chemokine receptor activity, crystalline forms and process
  • Modulators of chemokine receptor activity, crystalline forms and process

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0132] The present disclosure also provides novel methods of making compounds of Formula I:

[0133]

[0134] Including N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazoline-4- (amino)pyrrolidin-1-yl)cyclohexyl)acetamide, or a pharmaceutically acceptable salt thereof.

[0135] In the first embodiment, the present disclosure provides a novel process for preparing the compound of formula IV, the process comprising:

[0136] The amino acid derivative of structural formula III or its salt is coupled with formula II cyclohexanone or its salt (refer to the preparation in WO2005021500) to obtain the compound of structural formula IV or its salt with substituted amide side chains

[0137]

[0138] in:

[0139] R a with R b independently for C 1-6 alkoxy;

[0140] or R a with R b and the carbon to which they are both attached to form a carbonyl, thiocarbonyl, cyclic acetal or cyclic thioacetal, wherein the cyclic acetal or cyclic thioacetal is s...

Embodiment 1

[0449] N-((1R, 2S, 5R)-5-(tert-butylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-yl Amino)pyrrolidin-1-yl)cyclohexyl)acetamide

[0450]

[0451] Example 1, step 1: making (1R, 2S, 5R)-2-benzyloxycarbonylamino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester ( 89.6 g, 0.24 mol, see: P.H Carter et al., PCT application WO 2005 / 021500) was dissolved in ethyl acetate (1.5 liters), and the resulting solution was distilled with saturated NaHCO 3 (2 x 0.45 L) and saturated NaCl (1 x 0.45 L). The solution was dehydrated to dryness (Na 2 SO 4 ), then filtered directly into a 3-neck 3-liter round bottom flask. The solution was scrubbed with direct nitrogen injection and then charged with 10% Pd / C (13.65 g) under a nitrogen atmosphere. The flask was evacuated and backfilled with hydrogen; this was repeated two more times. Hydrogen was bubbled through the solution for 30 min, then the reactants were heated at 1 atm H 2 Stirring was continued for 18 ho...

Embodiment 2

[0497] N-((1R, 2S, 5R)-5-(tert-butylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-yl Crystalline form of amino)pyrrolidin-1-yl)cyclohexyl)acetamide

[0498] N-((1R, 2S, 5R)-5-(tert-butylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-yl Various crystalline forms of amino)pyrrolidin-1-yl)cyclohexyl)acetamide free base were prepared and characterized according to the following methods.

[0499] Procedures for characterization of each type

[0500] single crystal data

[0501] Data were collected on a Bruker-Nonius (BRUKER AXS Corporation, 5465 East Cheryl Parkway Madison, WI 53711 USA) CAD4 serial diffractometer. The unit cell parameters were obtained by least squares analysis with an experimental diffractometer setup of 25 high-angle reflections. Intensities are measured using Cu Kα radiation (λ=1.5418 ), at a constant temperature, measured with the θ-2θ variable scanning technique, and only corrected for the Lorentz-polarizability factor. Background coun...

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Abstract

The present invention provides a novel antagonist or partial agonists/antagonist of MCP-I receptor activity: N-((lR,2S,5R)-5-(tert-butylamino)-2- ((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-l- yl)cyclohexyl)acetamide, or a pharmaceutically acceptable salt, solvate or prodrug, thereof, having an unexpected combination of desirable pharmacological characteristics. Crystalline forms of the present invention are also provided. 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 is also an objective of this invention. The present disclosure also provides a process for preparing compounds of Formula (I), including N-((lR,2S,5R)-5-(tert-butylamino)-2-((S)-2-oxo-3-(6- (trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-l-yl)cyclohexyl)acetamide: wherein R<1>, R<8>, R<9>, R<10>, and 'HET' are as described herein. Compounds that are useful intermediates of the process are also provided herein.

Description

[0001] This application claims priority to US Provisional Application Nos. 60 / 834,235 and 60 / 896,026, filed on July 28, 2006 and March 21, 2007, respectively, the disclosures of which are incorporated herein by reference. technical field [0002] The present invention provides N-((1R, 2S, 5R)-5-(tert-butylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazoline- 4-ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide or a pharmaceutically acceptable salt, solvate or prodrug thereof, which has a surprising combination of desired pharmacological properties. Crystalline forms of the invention are also provided. [0003] Pharmaceutical compositions containing them, and methods of using them as medicaments for the treatment of inflammatory, allergic, autoimmune, metabolic, cancer and / or cardiovascular diseases are also objects of the present invention. The present invention also provides a method for preparing a compound of formula (I), which comprises N-((1R, 2S, 5R)-5-(tert-butylamino)-2-((...

Claims

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Application Information

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IPC IPC(8): C07D403/12C07D207/273C07D317/72A61K31/4025
CPCC07D317/72C07D207/273C07D403/12A61P1/04A61P17/00A61P17/06A61P19/02A61P25/04A61P25/28A61P29/00A61P3/00A61P3/04A61P31/18A61P35/00A61P3/06A61P37/00A61P37/06A61P9/00A61P9/10A61P9/12A61P3/10A61K31/4025
Inventor P·H·卡特J·V·当希亚B·M·玛卓克M·E·蓝道佐肖自力M·G·杨赵儒林
Owner BRISTOL MYERS SQUIBB CO
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