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Benzophenones as inhibitors of reverse transcriptase

An alkyl and heterocycle technology, applied in the field of benzophenone as a reverse transcriptase inhibitor, can solve the problem of inactivity of drug-resistant strains

Inactive Publication Date: 2005-07-13
GLAXO GRP LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these compounds are mainly active against wild-type HIV-1 reverse transcriptase but rapidly develop drug-resistant virus and are therefore inactive against common drug-resistant strains

Method used

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  • Benzophenones as inhibitors of reverse transcriptase
  • Benzophenones as inhibitors of reverse transcriptase

Examples

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preparation example Construction

[0317] The following is a flow chart showing the preparation of the compound of formula VI, where R 1 And R 5 As defined above, R 7 It is hydrogen or methyl. Where R 1 And R 5 As defined above and R 7 Compounds of formula VI that are methyl can be obtained by making R 5 As defined above and R 7 The compound of formula IX which is methyl and wherein R 1 And R 10 The compound of formula X as defined above is prepared by reaction, but with the further condition that these groups are chemically compatible with the reaction conditions, R 7 Is methyl, R 9 Is halogen, preferably bromine or iodine, and R 10 It is N, O-dimethylhydroxyamino.

[0318]

[0319] The compound of formula IX is usually treated with a reagent capable of carrying out a halogen-metal exchange reaction, such as sec-butyl lithium, methyl lithium, tert-butyl lithium, or more preferably n-butyl lithium. The halogen-metal exchange can be performed in an ether solvent, such as THF, dioxane or more preferably diethyl eth...

Embodiment 1

[0488]

[0489] Step A:

[0490]

[0491] The 2-bromo-4-chloroanisole (8.98g, 40.54mmol) in diethyl ether (65ml) was cooled to -78°C, and n-butyllithium (26ml of 1.6M solution in hexane was added via syringe, 41.6mmol). The resulting orange solution was stirred at -78°C for 30 minutes, after which only 2-thiazolecarboxaldehyde (4.53 g, 40.04 mmol) was added to form a reddish purple solution. The mixture was stirred at -78°C for 15 minutes, after which time water (50 ml) was added and the mixture was allowed to warm to room temperature. The mixture was poured into a separatory funnel containing ether and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure to obtain a white solid. The solid was washed with hexane and dried under vacuum to obtain white needles (5.21 g, 51%). 1 H NMR(CDCl 3 , 400 MHz) δ 7.70 (d, J = 4 Hz, 1H), 7.38 (d, J = 4 Hz, 1H), 7.28 (d, J = 4 Hz, 1H), 7.23...

Embodiment 2

[0501]

[0502] Step A:

[0503]

[0504] According to general method II, phenol 4 (2.31 g, 9.64 mmol), potassium carbonate (6.95 g, 50.3 mmol), ethyl bromoacetate (1.1 ml, 1.7 g, 9.9 mmol) and acetone (150 ml) were used. The product was used in the next reaction without any further purification. 1 H NMR(CDCl 3 , 300MHz) δ 8.05 (d, J = 3Hz, 1H), 7.76 (d, J = 3Hz, 1H), 7.66 (d, J = 3Hz, 1H), 7.48 (dd, J = 9, 3Hz, 1H) , 6.93 (d, J = 9 Hz, 1H), 4.61 (s, 2H), 4.21 (q, J = 6 Hz, 2H), 1.26 (t, J = 6 Hz, 3H).

[0505] Step B:

[0506]

[0507] According to general method III, ester 6 (3.1 g, 9.6 mmol), THF (30 ml), water (10 ml), ethanol (10 ml) and lithium hydroxide (1.0 g, 23.8 mmol) were used. The product was used in the next reaction without any further purification. 1 H NMR(DMSO-d 6, 300 MHz) δ 8.30 (d, J = 3Hz, 1H), 8.15 (d, J = 3Hz, 1H), 7.63 (d, J = 3Hz, 1H), 7.57 (dd, J = 9, 3Hz, 1H) ), 7.05 (d, J=9 Hz, 1H), 4.45 (s, 2H).

[0508] Step C:

[0509] According to general meth...

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Abstract

The present invention includes benzophenone compounds (I) for use in the treatment of HIV infection.

Description

[0001] This application is a divisional application of the application filed on August 31, 2000 with the application number 00815249.7 (PCT / EP00 / 08487) and the invention title "benzophenone as a reverse transcriptase inhibitor". Background of the invention [0002] Human immunodeficiency virus ("HIV") is the pathogen of acquired immunodeficiency syndrome ("AIDS"), which is characterized by the immune system, especially CD4 + The destruction of T-cells is accompanied by susceptibility to opportunistic infections, and the predecessor of the disease, AIDS-related complications ("ARC"), a syndrome characterized by persistent systemic lymphadenopathy, fever, and weight loss. HIV is a retrovirus; the conversion of its RNA to DNA is achieved through the action of reverse transcriptase. Compounds that inhibit the function of reverse transcriptase inhibit HIV replication in infected cells. Such compounds are used to prevent or treat human HIV infection. [0003] In ad...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/08A61K9/08A61K9/20A61K9/48A61K31/167A61K31/17A61K31/18A61K31/245A61K31/277A61K31/341A61K31/381A61K31/40A61K31/404A61K31/416A61K31/421A61K31/425A61K31/426A61K31/427A61K31/428A61K31/433A61K31/437A61K31/44A61K31/45A61K31/47A61K31/495A61K31/498A61K31/5375A61K31/541A61K31/63A61P31/00A61P31/12A61P31/18A61P43/00C07C235/24C07C237/42C07C255/40C07C255/44C07C255/56C07C259/06C07C275/10C07C311/08C07C311/24C07C311/46C07C317/24C07C317/40C07C323/22C07D207/09C07D207/20C07D207/32C07D207/333C07D209/08C07D209/48C07D211/74C07D213/42C07D213/50C07D213/61C07D213/75C07D213/84C07D213/85C07D215/08C07D217/04C07D231/56C07D233/22C07D233/60C07D233/84C07D235/04C07D235/08C07D235/26C07D235/28C07D241/42C07D249/18C07D261/08C07D261/16C07D263/32C07D275/04C07D277/04C07D277/20C07D277/24C07D277/28C07D277/36C07D277/62C07D277/64C07D279/34C07D285/06C07D295/08C07D295/092C07D295/12C07D295/13C07D295/135C07D295/15C07D295/18C07D295/22C07D295/26C07D295/28C07D307/14C07D307/46C07D307/80C07D333/20C07D333/22C07D333/32C07D333/38C07D333/54C07D333/56C07D333/72C07D401/12C07D405/12C07D409/04C07D409/12C07D417/12C07D471/04
CPCC07C255/44C07C255/56C07C311/24C07C311/46C07C317/24C07C317/40C07C323/22C07D207/333C07D233/22C07D277/24C07D277/62C07D279/34C07D295/088C07D295/13C07D295/135C07D295/15C07D295/26C07D295/30C07D307/80C07D333/56C07C2601/02C07C2601/08A61P31/00A61P31/12A61P31/18A61P43/00
Inventor C·W·安德鲁斯J·H·陈G·A·弗雷曼K·R·罗米尼斯J·H·蒂维尔P·M·C·皮尔尼蒂
Owner GLAXO GRP LTD
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