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SUBSTITUTED SPIROPYRIDO[1,2-a]PYRAZINE DERIVATIVE AND PHARMACEUTICAL USE OF SAME AS HIV INTEGRASE INHIBITOR

a technology of spiropyrido[1,2-a]pyrazine and derivative, which is applied in the direction of heterocyclic compound active ingredients, drug compositions, biocide, etc., can solve the problems of side effects and liver function failure, and achieve the effects of fewer side effects, effective anti-hiv agents, and high inhibitory activity

Inactive Publication Date: 2014-08-07
JAPAN TOBACCO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a compound that can be used as medicine to prevent or treat HIV infections and AIDS. This compound is effective as an anti-HIV agent, specifically by inhibiting the activity of HIV integrase. It can be used in combination with other anti-HIV agents, such as protease inhibitors and reverse transcriptase inhibitors, making it more effective. Additionally, the compound has high specificity for integrase, making it safer for human use with fewer side effects.

Problems solved by technology

However, some of these medicaments are known to cause side effects such as liver function failure, central nervous disorders (e.g., vertigo), and the like.
In addition, acquisition of resistance to a medicament causes a problem.

Method used

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  • SUBSTITUTED SPIROPYRIDO[1,2-a]PYRAZINE DERIVATIVE AND PHARMACEUTICAL USE OF SAME AS HIV INTEGRASE INHIBITOR
  • SUBSTITUTED SPIROPYRIDO[1,2-a]PYRAZINE DERIVATIVE AND PHARMACEUTICAL USE OF SAME AS HIV INTEGRASE INHIBITOR
  • SUBSTITUTED SPIROPYRIDO[1,2-a]PYRAZINE DERIVATIVE AND PHARMACEUTICAL USE OF SAME AS HIV INTEGRASE INHIBITOR

Examples

Experimental program
Comparison scheme
Effect test

reference example 1

Step R1-1

[0938]

[0939]Under nitrogen, a solution of 1M lithium bis(trimethylsilyl)amide-THF / ethylbenzene (100 mL) in THF (100 mL) was cooled to −70° C. and, under stirring, tert-butyl acetate (13.5 mL) was added dropwise. After stirring for 15 min, benzyloxyacetyl chloride (7.52 mL) was added dropwise. After stirring for 1 hr, 2N aqueous hydrochloric acid solution was added until the reaction mixture became pH=3 and the mixture was allowed to warm to room temperature. The mixture was extracted with ethyl acetate, and the organic layer was washed with 2N aqueous hydrochloric acid solution and saturated brine, dried over sodium sulfate and concentrated. The above operation was repeated again, and the both were combined to give compound R1-1 (40.3 g) as a crude product.

Step R1-2

[0940]

[0941]To a solution of compound R1-1 (38 g) obtained in step R1-1 in toluene (80 mL) was added dimethylformamide dimethyl acetal (38 mL), and the mixture was stirred at 100° C. for 1 hr. The mixture was all...

example 1

Production of N-(3-chloro-2-fluorobenzyl)-9′-hydroxy-cis-3-methoxy-2′-methyl-1′,8′-dioxo-1′,2′,3′,8′-tetrahydrospiro[cyclobutane-1,4′-pyrido[1,2-a]pyrazine]-7′-carboxamide hydrochloride

Step 1

[0949]

[0950]To a mixed solution of commercially available 3-benzyloxycyclobutane-1,1-dicarboxylic acid diethyl ester (5.00 g) in ethanol-water (42 mL-10.5 mL) was added potassium hydroxide (981 mg, 85%), and the mixture was stirred at 100° C. for 16 hr. The reaction mixture was concentrated, water was added, and the mixture was extracted 3 times with diethyl ether to give organic layer 1-1 and aqueous layer 1-1.

[0951]The organic layer 1-1 was dried over magnesium sulfate, and concentrated to give a residue 1-1-1 (949 mg).

[0952]To aqueous layer 1-1 was added potassium hydrogen sulfate (7.67 g), and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. Toluene was added and the mixture was concentrat...

example 2

Production of N-(3-chloro-2-fluorobenzyl)-9′-hydroxy-trans-3-methoxy-2′-methyl-1′,8′-dioxo-1′,2′,3′,8′-tetrahydrospiro[cyclobutane-1,4′-pyrido[1,2-a]pyrazine]-7′-carboxamide hydrochloride

Step 1

[0987]

[0988]From compound 1-7b (115 mg) obtained in Example 1, step 7, and by a method similar to that in Example 1, step 8, a crude product of compound 2-1 was obtained. The obtained crude product of compound 2-1 was directly used in the next step.

step 2

[0989]From a crude product of compound 2-1 obtained in the above-mentioned step, and by a method similar to that in Example 1, step 9, compound 2-2 (112 mg) was obtained.

[0990]1H-NMR (CDCl3) δ: 10.56 (br s, 1H), 8.65 (s, 1H), 7.62-7.59 (m, 2H), 7.37-7.28 (m, 5H), 7.06-7.00 (m, 1H), 5.31 (s, 2H), 4.74-4.70 (m, 3H), 3.79 (s, 2H), 3.20 (s, 3H), 2.95-2.88 (m, 2H), 2.33-2.31 (m, 1H), 2.30-2.28 (m, 1H), 2.17-2.15 (m, 1H).

Step 3

[0991]

[0992]From compound 2-2 (24 mg) obtained in the above-mentioned step, and by a method similar to that in Example 1, st...

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Abstract

[Summary][Problem] Provided is a substituted spiropyrido[1,2-a]pyrazine derivative or a pharmaceutically acceptable salt thereof, which is useful as an anti-HIV agent.[Solving Means] The present invention relates to a compound represented by the following formula [I] or [II] or a pharmaceutically acceptable salt thereof:wherein each symbol is as defined in the specification.

Description

TECHNICAL FIELD[0001]The present invention relates to a substituted spiropyrido[1,2-a]pyrazine derivative useful as an anti-HIV agent and a pharmaceutically acceptable salt thereof. In addition, the present invention relates to a pharmaceutical composition comprising the derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; an anti-HIV agent, an HIV integrase inhibitor and the like, comprising the derivative or a pharmaceutically acceptable salt thereof as an active ingredient; an anti-HIV agent comprising a combination of the derivative or a pharmaceutically acceptable salt thereof, and one or more kinds of other anti-HIV active substances; and the like.BACKGROUND ART[0002]HIV (Human Immunodeficiency Virus (type 1)) belonging to retrovirus is a causative virus of AIDS (Acquired Immunodeficiency Syndrome).[0003]HIV targets CD4 positive cell groups such as helper T cell, macrophage and dendritic cell and destroys these immunocompetent ce...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D471/04A61K45/06A61K31/499
CPCC07D471/04A61K31/499A61K45/06C07D471/10A61P31/18A61P43/00C07D487/10
Inventor MIYAZAKI, SUSUMUISOSHIMA, HIROTAKAOSHITA, KENGOKAWASHITA, SEIJINAGAHASHI, NOBORUTERASHITA, MASAKAZU
Owner JAPAN TOBACCO INC
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