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

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 compound described in this patent can be used as a medication to prevent or treat HIV infections and AIDS. It works by inhibiting the action of a protein called HIV integrase, which is necessary for the virus to reproduce and spread in the body. When used on its own, this compound can be effective in fighting HIV, but it can also be combined with other anti-HIV agents such as protease inhibitors or reverse transcriptase inhibitors to make it more effective. Additionally, this compound is relatively safe for humans as it has a high degree of specificity towards integrase, meaning it has fewer side effects as a treatment.

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

[1349]

[1350]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

[1351]

[1352]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

[1360]

[1361]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.

[1362]The organic layer 1-1 was dried over magnesium sulfate, and concentrated to give a residue 1-1-1 (949 mg).

[1363]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

[1398]

[1399]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

[1400]

[1401]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.

[1402]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

[1403]

[1404]From compound 2-2 (24 mg) obtained in the above-mentioned step, and by a method similar to that in Example...

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Abstract

Provided is a substituted spiropyrido[1,2-a]pyrazine derivative or a pharmaceutically acceptable salt thereof, which is useful as an anti-HIV agent. 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 OF THE INVENTION[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 i...

Claims

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Application Information

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