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Phenylindoles for the treatment of HIV

Inactive Publication Date: 2007-12-20
LACOLLA PAULO +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0028] A novel class of phenylindoles has been discovered that display significant antiviral activity against HIV, and in particular, strains of the HIV that have developed cross resistance to other anti-HIV drugs. It has surprisingly been discovered that HIV activity can be enhanced, and in certain cases cross resistance can be substantially overcome, by incorporating into the molecule at least two moieties other than hydrogen on either the phenyl ring or the benzyl ring of the

Problems solved by technology

However, this work was not pursued, perhaps because HIV virus that had been exposed to other drugs was shown to be cross resistant to these indoles (Williams et al., Journal of Medicinal Chemistry, 1993, 36(9), 1291-94).
It is known that over a period of time, antiviral agents that are active against HIV induce mutations in the virus that reduce the efficacy of the drug.
However, one cannot predict which mutations will be induced in the HIV-1 genome by a given drug, whether the mutations are permanent or transient, or how an infected cell with a mutated HIV-1 sequence will respond to therapy with other agents in combination or alternation.
These factors are exacerbated by the fact that there is a paucity of data on the kinetics of drug resistance in long-term cell cultures treated with modern antiretroviral agents.

Method used

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  • Phenylindoles for the treatment of HIV
  • Phenylindoles for the treatment of HIV
  • Phenylindoles for the treatment of HIV

Examples

Experimental program
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Effect test

example 1

Synthesis of Ethyl Pyruvate 4-Chloro-3-Fluorophenylhydrazone

[0449] A solution of sodium nitrite (4.76 g, 0.069 mol) in water (6.3 mL) was added dropwise to an ice cooled mixture of 4-chloro-3-fluoroaniline (J. Am. Chem. Soc., 1996, 61, 5130-5133) (10.00 g, 0.069 mol), water (167 mL) and 37% hydrochloric acid (167 mL). After 20 minutes potassium acetate (9.81 g, 0.10 mol) was added, and then a solution of ethyl 2-methylacetoacetate (9.95 g, 0.069 mol), potassium acetate (9.81 g, 0.10 mol) in methanol (67 mL) was dropped while cooling on the ice bad. Reaction was stirred at 0° C. for 3 hours, then extracted with diethyl ether. Organic layer was washed with brine and dried. Removal of the solvent furnished a red oily residue that was treated with ethanol (100 mL) and stirred at room temperature overnight. The solid which formed was filtered a recrystallized from ethanol to give 5.4 g (30%) of title compound, mp 161-163° C. (from ethanol). [0450] Ethyl pyruvate 2,4-difluorophenylhydraz...

example 2

Synthesis of Ethyl pyruvate 2,4-dichlorophenylhydrazone

[0453] A mixture of 2,4-dichlorophenylhydrazine (16.00 g, 0.075 mol), ethyl pyruvate (14.47 g, 10.3 mL, 0.12 mol), glacial acetic acid (0.9 mL), absolute ethanol (105 mL) was refluxed for 2 hours. After cooling at room temperature, the solid which formed was filtered and recrystallized from ethanol to give 17.0 g (83%) of the title compound, mp 118-120° C. (from ethanol).

example 3

Synthesis of Ethyl 5-chloro-6-fluoroindole-2-carboxylate (2j) and ethyl 5-chloro-4-fluoroindole-2-carboxylate (2 g)

[0454] Ethyl pyruvate 4-chloro-3-fluorophenylhydrazone (5.00 g, 0.0193 mol) was added by portions to PPA (50 g) pre-heated at 110° C., then reaction was stirred for 30 minutes. After cooling at room temperature, ice water was added while stirring. The solid which formed was filtered, washed with water, dried and passed by a silica gel column chromatography (n-hexane:ethyl acetate 1:2 as eluent). First fractions furnished ethyl 5-chloro-6-fluoroindole-2-carboxylate (2f), (1.85 g, 40%), mp 160-164° C.° (ethanol). Further elution with the same eluent gave ethyl 5-chloro-4-fluoroindole-2-carboxylate (2 g) (0.9 g, 19%), mp 186-190° C. (ethanol). [0455] Ethyl 5,7-dichloroindole-2-carboxylate (2b), yield 37%, mp 143-145° C. (from ethanol). [0456] Ethyl 4,5-difluoroindole-2-carboxylate (2c), yield 15%, mp 166-168° C. (from ethanol). [0457] Ethyl 4,5-difluoroindole-2-carboxylat...

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Abstract

The invention as disclosed herein is a method and composition for the treatment of HIV in humans and other host animals, that includes the administration of an effective HIV treatment amount of a phenylindole as described herein or a pharmaceutically acceptable salt or prodrug thereof, optionally in a pharmaceutically acceptable carrier. The compounds of this invention either possess antiviral (i.e., anti-HIV) activity, or are metabolized to a compound that exhibits such activity.

Description

[0001] This application claims priority to U.S. Provisional Application No. 60 / 283,393, filed on Apr. 11, 2001.FIELD OF THE INVENTION [0002] This invention is in the area of phenylindoles that are useful for the treatment of HIV infection, and, in particular, phenylindoles that exhibit significant activity against resistant strains of HIV. BACKGROUND OF THE INVENTION [0003] In 1983, the etiological cause of AIDS was determined to be the human immunodeficiency virus (HIV). Numerous compounds have since been synthesized to combat the virus, designed to inhibit progression beyond various stages of the virus's lifecycle. A focal point in AIDS research efforts has been the development of inhibitors of human immunodeficiency virus (HIV-1) reverse transcriptase (RT), an enzyme responsible for the reverse transcription of the retroviral RNA to proviral DNA (Greene, W. C., New England Journal of Medicine, 1991, 324, 308-317; Mitsuya, H. et al., Science, 1990, 249, 1533-1544; De Clercq, E., J...

Claims

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Application Information

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IPC IPC(8): C07D209/36C07D413/02A61K31/404A61K31/4178A61K45/06C07D209/20C07D209/42C07D403/12
CPCA61K31/404A61K31/4178A61K45/06C07D413/12C07D209/42C07D401/04C07D403/12C07D209/20A61P31/18
Inventor LACOLLA, PAULOARTICO, MARINOSOMMADOSSI, JEAN-PIERRE
Owner LACOLLA PAULO
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