Tetrahydrothiopyranopyrimidine derivatives as anti-HIV agent

Patent metadata

Field	Value
Publication number	US-10590145-B2
Application number	US-201615735135-A
Country	US
Kind code	B2
Filing date	Jul 12, 2016
Priority date	Jun 27, 2016
Publication date	Mar 17, 2020
Grant date	Mar 17, 2020

Abstract

The invention relates the tetrahydrothiopyranopyrimidine derivatives, the preparation, and the use thereof. The invention contained tetrahydrothiopyranopyrimidine derivatives, and pharmaceutical acceptable salt and prodrug with the formula I or II. Also described here are preparation of tetrahydrothiopyranopyrimidine derivatives, pharmaceutical compositions comprising these compounds as therapy and prevention for HIV.

First claim

The invention claimed is:

1. A compound of tetrahydrothiopyranopyrimidine, or pharmaceutically acceptable salt thereof, the compound having a general formula I or II shown as following:

wherein
A is S(═O) n or CH 2 ; B is S(═O) n or CH 2 , while either A or B is S(═O) n in the compound; n=0, 1 or 2;
X is O or NH;
R 1 , R 2 and R 3 are independently selected from a group consisting of H, halo, CN, CF 3 , NH 2 , OH, C 1-6 alkyl, C 1-6 alkyloxy, C 2-6 alkenyl, trifluoromethyl, amino, hydroxy, cyanovinyl, cyanoethyl and cyclopropyl;
Ar is selected from a group consisting of an optionally substituted benzyl ring, an optionally substituted benzene ring, an optionally substituted naphthalene ring, a substituted 6-membered heterocyclic ring, a substituted 5-membered heterocyclic ring, a substituted 6-membered and 5-membered heterocyclic ring, a substituted 6- and 6-membered heterocyclic ring, a substituted five-membered and five-membered heterocyclic ring, a substituted benzo five-membered heterocyclic ring and a substituted benzo-six-membered heterocyclic ring.

2. The compound of claim 1 , wherein R 1 and R 3 are CH 3 , R 2 is selected from a group consisting of CN, Me and CH═CHCN.

3. The compound of claim 1 , wherein the Ar has a general formula (a) or (b) shown as following:

wherein R 4 is selected from a group consisting of H, CN, Me, COR 5 , COOR 5 , CONH 2 , CONHR 5 , SO 2 R 5 , SO 2 NH 2 , SO 2 NHR 5 , NO 2 , NH 2 , NHR 5 , NHCOR 5 and NHSO 2 R 5 ; R 5 is selected from a group consisting of C 1-10 alkyl, C 1-10 cyclicalkyl, C 1-10 haloalkyl, C 1-10 alkenyl and C 1-10 aromatic alkyl.

4. The compound of claim 3 , wherein the R 5 is Me or CH 3 CO.

5. The compound of claim 3 , wherein the compound have a formula (IA-1), (IA-2), (IB-1), (IB-2), (IIA-1), (IIA-2), (IIB-1), (IIB-2), (IIC-1), (IIC-2), (IID-1) or (IID-2) shown as following:

wherein, R 1 , R 2 , R 3 , R 4 are independently selected from a group consisting of H, halo, CN, CF 3 , NH 2 , OH, C 1-6 alkyl, C 1-6 alkyloxy, C 2-6 alkenyl, trifluoromethyl, amino, hydroxy, cyanovinyl, cyanoethyl and cyclopropyl.

6. The compound of claim 5 , the compound is selected from a group consisting of

7. The compound of claim 1 , wherein the compound is prepared by the following steps:
methyl mercaptoacetate (A) reacting with methyl 4-chlorobutanoate (B) to give methyl 4-((2-methoxy-2-oxoethyl) thio) butyrate (C) in sodium methoxide; the intermediate C being converted to oxotetrahydropyranyl ester (D) by Dieckmann condensation under sodium methoxide; the intermediate D being cyclized with methyl isothiourea into 2-methylmercaptothiopyranopyrimidine-2-ol (E) in potassium hydroxide; the intermediate E being hydrolyzed into tetrahydrothiopyrano pyrimidine-2,4-diol (F) in acetic acid; the intermediate F being base chlorinated with N, N-dimethylaniline into 2,4-dichloro tetrahydrothiopyranopyrimidine (G) in phosphorus oxychloride; the intermediate G being reacted by substituting phenol or aniline to give an intermediate H under alkaline condition; the intermediate H being reacted with the corresponding substituted aniline to obtain a final compound; or the intermediate H being reacted with 1-boc-4-aminopiperidine, deprotected with boc, then reacted with corresponding benzyl chloride or benzyl bromide to obtain the final compound; above reactions shown as the

following:
wherein reagents and conditions are (i) sodium methoxide, potassium iodide, methanol, reflux; (ii) sodium methoxide, toluene, 105° C.; (iii) methylisothiourea sulfate, potassium hydroxide, (V) phosphorus oxychloride, N, N-dimethylaniline at 90° C.; (vi) potassium carbonate, N, N-dimethylformamide, substituted phenol or aniline; 1-Boc-4-aminopiperidine, N, N-diisopropylethylamine, N-methylpyrrolidone at 120-130° C.; b) trifluoroacetic acid in dichloromethane at room temperature; c) (Viii) 1-Substituted-4-aminopiperidine, N, N-diisopropylethylamine, N-methylpyrrolidone, 130° C.; (ix) 4-aminobenzonitrile, 2,2′-bis-(diphenylphosphino)-1,1′-binaphthyl, tris (dibenzylideneacetone) dipalladium, dioxane;
wherein, the 2,4,6-trisubstituted phenol/aniline is selected from a group consisting of 2,4,6-trimethylphenol, 4-hydroxy-3,5-dimethylbenzonitrile, (E)-3-(4-hydroxy-3,5-dimethylphenyl)acrylonitrile, 2,4,6-trimethylaniline, 4-amino-3,5-dimethylbenzonitrile, and (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile;
wherein, the substituted benzyl chloride/bromide is selected from a group consisting of 1-chloro-2-(chloromethyl)benzene, 1-chloro-3-(chloromethyl)benzene, 1-chloro-4-(chloromethyl)benzene, 1-bromo-2-(bromomethyl)benzene, 1-bromo-3-(bromomethyl)benzene, 1-bromo-4-(bromomethyl)benzene, 1-(chloromethyl)-2-fluorobenzene, 1-(chloromethyl)-3-fluorobenzene, 1-(chloromethyl)-4-fluorobenzene, 1-(bromomethyl)-2,4-difluorobenzene, 1-(bromomethyl)-3,4-difluorobenzene, 2-(chloromethyl)benzonitrile, 3-(chloromethyl)benzonitrile, 4-(chloromethyl)benzonitrile, 1-(cholomethyl)-2-nitrobenzene, 1-(chloromethyl)-3-nitrobenzene, 1-(chloromethyl)-4-nitrobenzene, 1-(chloromethyl)-2-methoxybenzene, 1-(chloromethyl)-3-methoxybenzene, 1-(chloromethyl)-4-methoxybenzene, 1-(bromomethyl)-4-(methylsulfonyl)benzene, 4-(bromomethyl)benzenesulfonamide, 3-(bromomethyl)benzenesulfonamide, 2-(bromomethyl)benzamide, N-(4-(bromomethyl)phenyl)formamide, ethyl 4-(bromomethyl)benzoate, 4-(bromomethyl)benzamide, 3-(bromomethyl)benzamide and N-(4-(bromomethyl)phenyl)methanesulfonamide;

wherein
A is S(═O) n or CH 2 ; B is S(═O) n or CH 2 , while either A or B is S(═O) n in one compound; n=0, 1 or 2;
X is O or NH;
R 1 , R 2 and R 3 are independently selected from a group consisting of H, halo, CN, CF 3 , NH 2 , OH, C 1-6 alkyl, C 1-6 alkyloxy, C 2-6 alkenyl, trifluoromethyl, amino, hydroxy, cyanovinyl, cyanoethyl and cyclopropyl.

8. A method for preventing HIV infection or treating HIV-infected patient comprising a step of administrating to a subject in need a therapeutically effective amount of the compound of claim 1 or its pharmaceutically acceptable salt.

9. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or its pharmaceutically acceptable salt and one or more pharmaceutical acceptable carrier or excipient.

Assignees

• Univ Shandong

Inventors

• Liu Xinyong
• Zhang Heng
• Zhan Peng
• Zhou Zhongxia
• Kang Dongwei

Classifications

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• A61P31/18

  for HIV · CPC title