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Benzophenones as inhibitors of reverse transcriptase

a reverse transcriptase and benzophenone technology, applied in the direction of capsule delivery, organic active ingredients, organic chemistry, etc., can solve the problem of reducing the sensitivity of other reverse transcriptas

Inactive Publication Date: 2006-01-12
CHAN JOSEPH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0005] A first aspect of the invention features compounds of formulas IA, IA′, and IB (hereinafter known as compounds of formula I). These compounds are useful as prodrugs that, when administered in vivo, provide compounds that are useful in the inhibition of HIV reverse transcriptase, particularly its resistant varieties, the prevention of infection by HIV, the treatment of infection by HIV and in the treatment of AIDS and / or ARC, either as pharmaceutically acceptable salts or pharmaceutical composition ingredients. A second aspect of the invention features methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV as monotherapy or in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. A third aspect of the invention features pharmaceutical compositions comprising the above-mentioned compounds and which are suitable for the prevention or treatment of HIV infection. A fourth aspect of the invention features processes for making the above-mentioned compounds.

Problems solved by technology

Moreover, the mutations that appear in the reverse transcriptase enzyme frequently result in a decreased sensitivity to other reverse transcriptase inhibitors, which results in cross-resistance.
However, these compounds were primarily active against wild-type HIV-1 reverse transcriptase, rapidly induced resistant virus, and were inactive against a common resistant strain.

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

example 1

N-{4-[(acetylamino)sulfonyl]-2-methylphenyl}-2-[4-chloro-2-(3-cyano-5-methylbenzoyl)phenoxy]acetamide, Sodium Salt

[0308]

Step A:

[0309] Into a round-bottom flask were placed 2-aminotoluene-5-sulfonic acid (50.0 g, 267 mmol), and pyridine (300 mL). Acetic anhydride (38 mL, 403 mmol) was added dropwise from an addition funnel and the resulting mixture was allowed to stir for 2 h at rt. The solvents were removed under reduced pressure, leaving a brown solid. Several portions of ethyl alcohol were added to the solid and subsequently removed under reduced pressure, to afford a brown solid which was filtered and washed with several additional portions of ethyl alcohol and dried under vacuum (67.03 g, 81%). 1H NMR (DMSO-d6,) δ 2.08 (s, 3H), 2.22 (s, 3H), 7.39 (s, 2H), 7.45 (s, 1H), 8.02 (t, J=6 Hz, 2H), 8.53 (t, J=6 Hz, 1H), 8.92 (d, J=6 Hz, 2H), 9.31 (s, 1H).

Step B:

[0310] The compound from step A (67.03 g, 217 mmol) was added to a round-bottom flask containing 1N NaOH (225 mL) and t...

example 2

2-[4-chloro-2-(3-cyano-5-methylbenzoyl)phenoxy]-N-{4-[(isobutyrylamino)sulfonyl]-2-methylphenyl}acetamide, Sodium Salt

[0323]

Step A:

[0324] Following the procedure for the synthesis of 6 and using 12 (1 g, 5.4 mmol), isobutyric acid (0.6 mL, 5.9 mL) and fuming sulfuric acid (5 mL), 15 (0.67 g, 48%) was obtained as an off-white solid.

Step B:

[0325] Following the procedure for the synthesis of 13 and using 15 (0.2 g, 0.6 mmol), 16 (0.12 g, 33%) was obtained as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 1.9 (d, 6H), 2.2 (s, 3H), 2.4 (s, 3H), 2.3-2.5 (m, 1H), 4.8 (s, 2H), 7.2 (d, 1H), 7.5 (s, 1H), 7.6-7.8 (m, 4H), 7.8-8 (m, 3H), 9.4 (s, 1H), 12 (s,.67 (s, 2H).

Step C:

[0326] Following the procedure used for the synthesis of 1 and using 16 (0.12 g, 0.2 mmol) and 1 equivalent of NaOH, 14 (0.13 g, 100%) was obtained as a white fluffy solid. 1H NMR (DMSO-d6, 300 MHz) δ 1.9 (d, 6H), 2.2 (s, 3H), 2.4 (s, 3H), 2.3-2.5 (m, 1H), 4.8 (s, 2H), 7.2 (d, 1H), 7.5 (s, 1H), 7.6-7.8 (m, 4H), 7.8-8...

example 3

2-[4-chloro-2-(3-cyano-5-methylbenzoyl)phenoxy]-N-{2-methyl-4-[(propionylamino)sulfonyl]phenyl}acetamide, Sodium Salt

[0327]

Step A:

[0328] Propionic acid (Aldrich, 1.87 mL, 25 mmol) was added dropwise to fuming sulfuric acid (5 mL) in a round bottomed flask cooled in a water bath. The solution was stirred for 1 h at rt then 4-amino-3-methylbenzenesulfonamide (5) (3.26 g, 17.4 mmol) was added in one portion. The reaction was heated to 40° C. and stirred for an additional 4 h. The syrup was poured into ice water and the pH was adjusted to 4-5 with concentrated ammonium hydroxide. The resulting suspension was stirred vigorously for 2 h. The suspension was filtered and the solid was further purified on silica gel by flash chromatography using 95:5 methylene chloride (CH2Cl2):methanol (CH3OH) as eluant to afford an orange oil (1.86 g, crude). The crude oil was triturated with diethyl ether and the resulting solid was filtered and air-dried to afford 18 as a pale yellow solid (1.46 g, 3...

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Abstract

The present invention is directed to benzophenone compounds useful in the inhibition of HIV reverse transcriptase, particularly its resistant varieties.

Description

BACKGROUND OF THE INVENTION [0001] The human immunodeficiency virus (“HIV”) is the causative agent for acquired immunodeficiency syndrome (“AIDS”), a disease characterized by the destruction of the immune system, particularly of CD4+ T-cells, with attendant susceptibility to opportunistic infections, and its precursor AIDS-related complex (“ARC”), a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss. HIV is a retrovirus; the conversion of its RNA to DNA is accomplished through the action of the enzyme reverse transcriptase. Compounds that inhibit the function of reverse transcriptase inhibit replication of HIV in infected cells. Such compounds are useful in the prevention or treatment of HIV infection in humans. [0002] Non-nucleoside reverse transcriptase inhibitors (NNRTIs), in addition to the nucleoside reverse transcriptase inhibitors gained a definitive place in the treatment of HIV-1 infections. The NNRTIs interact with a sp...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07C235/70C07C255/56A61K9/08C07D295/14A61K9/20A61K9/48A61K31/63A61P31/12A61P31/18C07C303/40C07C311/46C07C311/51C07C311/53C07D207/16C07D295/15
CPCC07C311/46C07C311/51C07D295/15C07D207/16C07C311/53A61P31/12A61P31/18
Inventor CHAN, JOSEPH
Owner CHAN JOSEPH
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