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Indole, azaindole and related heterocyclic N-substituted piperazine derivatives

Inactive Publication Date: 2005-04-07
VIIV HEALTHCARE UK (NO 5) LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

HIV-1 (human immunodeficiency virus-1) infection remains a major medical problem, with an estimated 42 million people infected worldwide at the end of 2002.
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 oxoacetamide 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 N-substituted piperazine derivatives
  • Indole, azaindole and related heterocyclic N-substituted piperazine derivatives
  • Indole, azaindole and related heterocyclic N-substituted piperazine derivatives

Examples

Experimental program
Comparison scheme
Effect test

example 4

LC / MS: (ES+) m / z (M+H)+=493, 495; HPLC Rt=1.128.

A mixture of Example 4 (50 mg, 0.101 mmol), imidazole (69 mg, 1.01 mmol) cesium carbonate (66 mg, 0.203 mmol) and copper bromide (30 mg, 0.212 mmol) was heated at 145° C. for 4 h. The reaction mixture was then cooled to r.t., diluted with MeOH (2 ml) and filtered. The residue was further washed with 3×2 ml MeOH. The filtrate was evaporated in vacuo to give the crude product, which was purified by preparative TLC (10% MeOH / CH2Cl2) to give Example 5; LC / MS: (ES+) m / z (M+H)+=481; HPLC Rt=0.867.

example 6

Example 6 was prepared in the same manner as Example 5.

LC / MS: (ES+) m / z (M+H)+=480, 495; HPLC Rt=1.233.

The following HPLC conditions for the LCMS were used for Example 7, Example 8 and Example 9: Column: G; Gradient Time=3 min; Flow rate=4 ml / min.

Preparation of Example 7:

To a mixture of 4ab (crude, about 1.94 mmol), DEPBT (1.161 g, 3.88 mmol), intermediate 2 (952 mg, 2.91 mmol) in DMF (5 ml) was added N,N-diisopropylethylamine (3.0 ml, 17 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with MeOH (6 ml) and filtered. The filtrate was purified by preparative reverse phase HPLC using the method: Start % B=20, Final % B=60, Gradient time=15 min, Flow Rate=40 ml / min, Column: XTERRA C18 5 μm 30×50 mm, Fraction Collection: 6.169-6.762 min. 1H NMR: (DMSO-d6) 13.71 (s, 1H), 8.50 (d, J=3.0, 1H), 8.27 (s, 1H), 8.23 (d, J=8.5, 1H), 8.06 (d, J=6.0, 1H), 7.97 (d, J=8.0, 1H), 7.82 (app t, J=7.5, 1H), 7.69 (d, J=7.5, 1H), 7.5...

example 43

A mixture of intermediate 4ab (0.671 g, 2.7 mmol), intermediate 2 (0.869 g, 4.1 mmol), EDC (0.928 g, 4.8 mmol), dimethylaminopyridine (0.618 g, 5.1 mmol) and N-methylmorpholine (2.4 ml, 21.6 mmol) in DMF (20 ml) was stirred at room temperature for 17 hr. The reaction mixture was then quenched with 1N HCl and extracted with ethyl acetate (6 times). The combined organic extracts were evaporated in vacuo and purified by flash columatography (0%→5% MeOH / CH2Cl2) to provide Example 43 as a dark solid; 1H NMR (CDCl3) δ 9.64 (b s, 1H), 8.15 (d, J=5.5, 1H), 8.11 (d, J=8.0, 1H), 8.05 (d, J=3.0, 1H), 7.79 (d, J=8.0, 1H), 7.65 (app t, J=9.0, 1H), 7.57 (d, J=8.5, 2H), 7.32 (d, J=6.0, 1H), 6.74 (d, J=8.5, 1H), 4.05 (s, 3H, overlapping with m), 4.05-4.00 (m, 2H), 3.79 (b s, 2H), 3.56 (b s, 2H), 3.48 (b s, 2H); LC / MS (ES+) m / z (M+H)+=440, HPLC Rt=0.993.

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Abstract

This invention provides compounds of Formula I, including pharmaceutically accceptable salts thereof, having drug and bio-affecting properties, their pharmaceutical compositions and method of use. 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. The compounds of Formula I have the formula wherein: Z is Q is selected from the group consisting of m is 2; A is selected from the group consisting of cinnolinyl, napthyridinyl, quinoxalinyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, azabenzofuryl, and phthalazinyl each of which may be optionally substituted with one or two groups independently selected from methyl, methoxy, hydroxy, amino and halogen; and —W— is

Description

FIELD OF THE INVENTION 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 N-heteroaryl and N-aryl piperazine derivatives that possess unique antiviral activity. More particularly, the present invention relates to compounds useful for the treatment of HIV and AIDS. BACKGROUND ART HIV-1 (human immunodeficiency virus-1) infection remains a major medical problem, with an estimated 42 million people infected worldwide at the end of 2002. The number of cases of HIV and AIDS (acquired immunodeficiency syndrome) has risen rapidly. In 2002, ˜5.0 million new infections were reported, and 3.1 million people died from AIDS. Currently available drugs for the treatment of HIV include ten nucleoside reverse transcriptase (RT) inhibitors or approved single pill combinations(zidovudine or AZT (or Retrovir®), didanosine (or Videx®), stavudine (or Zerit®), lamivudine (or 3T...

Claims

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Application Information

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IPC IPC(8): A61K31/405A61K31/4745A61K31/496A61K31/497A61K31/498A61K31/502A61K31/517C07D401/12C07D401/14C07D403/12C07D403/14C07D413/14C07D471/02C07D471/04C07D487/04C07D491/04
CPCC07D401/12C07D401/14C07D491/04C07D413/14C07D471/04C07D403/12A61P31/00A61P31/18A61P37/02
Inventor YEUNG, KAP-SUNFARKAS, MICHELLEKADOW, JOHN F.MEANWELL, NICHOLAS A.TAYLOR, MALCOLMJOHNSTON, DAVIDCOULTER, THOMAS STEPHENWRIGHT, J. J. KIM
Owner VIIV HEALTHCARE UK (NO 5) LTD
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