Indole, azaindole and related heterocyclic pyrrolidine derivatives

a heterocyclic pyrrolidine and derivative technology, applied in the field of compounds with drug and bioaffecting properties, can solve the problems of 30 to 50% of patients ultimately failing combination drug therapies, each of these drugs can only transiently restrain viral replication if used alone, and the effect of viremia and disease progression

Inactive Publication Date: 2006-12-21
VIIV HEALTHCARE UK (NO 5) LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

HIV-1 (human immunodeficiency virus-1) infection remains a major medical problem, with an estimated 33.6 million people infected worldwide.
Each of these drugs can only transiently restrain viral replication if used alone.
However, when used in combination, these drugs have a profound effect on viremia and disease progression.
However, despite these impressive results, 30 to 50% of patients ultimately fail combination drug therapies.
Furthermore, the high replication rate and rapid turnover of HIV-1 combined with the frequent incorporation of mutations, leads to the appearance of drug-resistant variants and treatment failures when sub-optimal drug concentrations are present (Larder and Kemp; Gulick; Kuritzkes; Morris-Jones et al; Schinazi et al; Vacca and Condra; Flexner; Berkhout and Ren et al; (Ref. 6-14)).
However, the major drawback to the development and application of NNRTIs is the propensity for rapid emergence of drug resistant strains, both in tissue cell culture and in treated individuals, particularly those subject to monotherapy.
However, these structures differ from those claimed herein in that they are aza-indole mono-amide rather than unsymmetrical aza-indole piperazine diamide derivatives, and there is no mention of the use of these compounds for treating viral infections, particularly HIV.

Method used

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  • Indole, azaindole and related heterocyclic pyrrolidine derivatives
  • Indole, azaindole and related heterocyclic pyrrolidine derivatives
  • Indole, azaindole and related heterocyclic pyrrolidine derivatives

Examples

Experimental program
Comparison scheme
Effect test

example 1

N-(1-Benzoyl-pyrrolidin-3-ylmethyl)-2-(4-fluoro-1H-indol-3-yl)-2-oxo-acetamide

[0269]

[0270] The acid chloride (1 mmol, 225 mg) was added to a solution of the amine hydrochloride (1 mmol, 240 mg) and diisopropyl ethyl amine (10 mmol, 1.74 mL) in 5 mL of anhydrous THF under a nitrogen atmosphere. The reaction was stirred for 16 h at ambient temperature and then poured into ethyl acetate. The organic layer was washed with water and then sat aq NaCl and then dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo provided a crude product which was purified by flash chromatography over silica gel to provide 208 mg of the desired N-(1-Benzoyl-pyrrolidin-3-ylmethyl)-2-(4-fluoro-1H-indol-3-yl)-2-oxo-acetamide.

[0271] 1H NMR (500 MHz, CD3OD): 8.69 (s), 8.56 (s), 1H. 7.55˜7.40 (m, 5H), 7.31˜7.20 (m, 2H), 6.96˜6.87 (m, 1H), 3.81˜3.29 (m, 6H), 2.70˜1.73 (m, 3H).

[0272] LC / MS: (ES+) m / z (M+H)+=394, RT=1.06.

example 2

{1-[2-(4-Fluoro-1H-indol-3-yl)-2-oxo-acetyl]-pyrrolidin-3-ylmethyl}-carbamic acid tert-butyl ester

[0273]

[0274] The acid chloride (2 mmol, 453 mg) was added to a solution of the amine hydrochloride (2 mmol, 400 mg) and diisopropyl ethyl amine (4 mmol, 0.7 mL) in 12 mL of anhydrous THF under a nitrogen atmosphere. The reaction was stirred for 18 h at ambient temperature and then poured into ethyl acetate. The organic layer was washed with water and then sat aq NaCl and then dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo provided a crude product which was purified by flash chromatography over silica gel to provide 475 mg of the desired 3-{[2-(4-Fluoro-1H-indol-3-yl)-2-oxo-acetylamino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester.

[0275] 1H NMR (500 MHz, CD3OD): 8.17(s), 8.14(S), 1H. 7.32˜7.24(m, 2H), 6.97˜6.93(m, 1H), 3.73˜3.04(m, 6H), 2.46˜2.43(m, 1H), 2.09˜2.01(m, 1H), 1.74˜1.73(m, 1H), 1.44(s, 9H).

Intermediate 8

[0276]

[0277] The carbamate wa...

example 3

N-{1-[2-(4-Fluoro-1H-indol-3-yl)-2-oxo-acetyl]-pyrrolidin-3-ylmethyl}-benzamide and Example 4N-{1-[2-(1-Benzoyl-4-fluoro-1H-indol-3-yl)-2-oxo-acetyl]-pyrrolidin-3-ylmethyl}-benzamide

[0278]

[0279] Benzoyl chloride (0.46 mmol, 54 μL) and then diisopropyl ethyl amine (0.92 mmol, 0.16 mL) were added to a stirring solution of amine hydrochloride (0.46 mmol, 150 mg) in 5 mL of THF under an atmosphere of nitrogen at ambient temperature. The reaction was stirred for 18 h and then the THF was removed in vacuo. The residue was dissolved in ethyl acetate and washed with water and then sat aq NaCl. The organic extract was dried, filtered, concentrated, and purified via flash chromatography to the desired product of example 3:

[0280] 1H NMR (500 MHz, CD3OD): 8.18 (s), 8.14 (s), 1H. 7.85˜7.82 (m, 1H), 7.72˜7.68 (m, 1H), 7.54˜7.24 (m, 5H), 6.97˜6.90 (m, 1H), 3.80˜3.29 (m, 6H), 2.67˜2.61 (m, 1H), 2.20˜2.05(m, 1H), 1.87˜1.81(m, 1H).

[0281] LC / MS: (ES+) m / z (M+H)+=394, RT=1.74.

and the bis benzylate...

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Abstract

This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with amido piperazine derivatives. These compounds possess unique antiviral activity, whether used alone or in combination with other antivirals, antiinfectives, immunomodulators or HIV entry inhibitors. More particularly, the present invention relates to the treatment of HIV and AIDS.

Description

REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application Ser. No. 60 / 356,977 filed Feb. 14, 2002.FIELD OF THE INVENTION [0002] This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with new heterocyclic amidopiperazine derivatives that possess unique antiviral activity. More particularly, the present invention relates to compounds useful for the treatment of HIV and AIDS. BACKGROUND ART [0003] HIV-1 (human immunodeficiency virus-1) infection remains a major medical problem, with an estimated 33.6 million people infected worldwide. The number of cases of HIV and AIDS (acquired immunodeficiency syndrome) has risen rapidly. In 1999, 5.6 million new infections were reported, and 2.6 million people died from AIDS. Currently available drugs for the treatment of HIV include six nucleoside reverse transcriptase (RT) inhibito...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D471/02C07D209/42C07D403/06C07D403/12C07D403/14C07D471/04
CPCC07D403/12C07D403/14C07D403/06C07D403/04C07D471/04A61P31/12A61P31/18
Inventor KADOW, JOHN F.XUE, QIUFEN MAYWANG, TAOZHANG, ZHONGXINGMEANWELL, NICHOLAS A.
Owner VIIV HEALTHCARE UK (NO 5) LTD
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