Functionalized heterocycles as chemokine receptor modulators

An atomic and hydrogen atom technology, applied in the field of HIV infectivity inhibition, chemokine receptor CCR-5 modulator, can solve the problem of not finding Δ32 homozygotes

Inactive Publication Date: 2002-04-10
MILLENNIUM PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In a study of about 2700 HIV-1-infected i

Method used

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  • Functionalized heterocycles as chemokine receptor modulators

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[0312] Scheme II shows the preparation of indole intermediates. Aminocrotonate V is obtained by reaction of bromoacetic acid with nitrile in the presence of active zinc in an aprotic solvent, preferably THF, under a nitrogen atmosphere. Alternatively, the aminocrotonate V can be obtained by reacting the corresponding β-ketoester with ammonia in ethanol. This β-ketoester can be obtained from 2,2,6-trimethyl-4H-1,3-dioxin-4-one and the corresponding alcohol. Aminocrotonate V and substituted benzoquinone in a solvent, preferably acetic acid, ethanol or nitromethane, at a temperature ranging from 25°C to reflux, yields substituted 5-oxindole VI. Hydrolysis of the indole ester VI with aqueous sodium hydroxide at 50-100°C, preferably at reflux temperature, under nitrogen atmosphere gives the corresponding acid VII. In order to suppress the decarboxylation reaction, it is important to cool the reaction mixture to 0°C in an ice-water bath after completion of the reaction and acidify...

Embodiment 1

[0418] pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 3,7,8,9,10,12,13,14 , 14a, 15-Decahydro-2-methyl-, ethyl ester

[0419] Synthesized according to the method described in J. Het. Chem., 1970; 7: 1311-1319.

Embodiment 2

[0421] Pyrrolo[3',2':5,6][1]benzopyrano[3,2-i]quinazine-1-carboxylic acid, 8,9,11,12,13,13a,14,14a -Octahydro-2-methyl-, (4-fluorophenyl)methyl ester

[0422] Step A: 4-fluoro-benzyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate

[0423] To a solution of 5-hydroxy-2-methyl-1-H-indole-carboxylic acid (4.6 g, 24.1 mmol) in DMF (100 mL) was added DBU (3.67 g, 24.1 mmol) followed by 4-fluorobenzyl Bromine (5.0 g, 26.5 mmol). Under a nitrogen atmosphere, the resulting mixture was stirred at room temperature for 3 days, then partitioned between ethyl acetate (200 mL) and water (200 mL). The organic phase was separated, washed with water (2 x 100 mL), then dried over sodium sulfate and concentrated in vacuo to give a white solid. Recrystallization from ethyl acetate afforded 3.4 g (47%) of the pure title compound as a white solid: mp 209-210°C;

[0424] IR3412, 3377, 3305, 1667, 1512, 1466, 1221, 1176, 1094cm -1 ; 1 H NMR (DMSO-d 6 )δ2.53(s,...

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Abstract

The present invention is a novel series of functionalized heterocycles as chemokine receptor modulators of Formula (I) useful as modulators of chemokine receptor activity. The compounds are useful in the treatment and prevention of the AIDS virus. Intermediates useful in the prepartion of the final products, pharmaceutical compositions containing the final products are also taught.

Description

Background of the invention [0001] The present invention relates to chemokine receptors (including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR1, CXCR2, CXCR-3 and / or Functionalized heterocycles of CXCR4) modulators and pharmaceutical compositions comprising these compounds and pharmaceutically acceptable carriers. More specifically, the invention relates to methods of inhibiting HIV infectivity. [0002] Chemokines mediate a range of proinflammatory responses acting on leukocytes, such as chemotaxis, degranulation, and intigran activation (Baggiolini et al., Adv. Immunol., 1994; 55:97-179; Oppenheim et al., Annu.Rev. Immunol. ., 1991; 9: 617-48; Miller et al., Crit. Rev. Immunol., 1992; 12: 17-46). These effects are mediated by binding to seven-transmembrane-passing G protein-coupled receptors (Baggiolini et al., Adv. Immunol., 1994; 55:97-179; Murphy, Annu. Rev. Immunol., 1994; 12:593-633; Schall et al., Curr. Opin. Immunol., 1994; 6:865-73; Gerard et al., Curr...

Claims

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Application Information

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IPC IPC(8): A61K31/437A61K31/4375A61P31/18C07D455/02C07D491/14C07D491/22C07D491/147
CPCC07D491/14C07D455/02A61P31/18
Inventor G·C·哈里曼C·N·科尔兹J·R·卢利B·D·罗斯Y·宋B·K·特里维迪
Owner MILLENNIUM PHARMA INC
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