Dihydropyrimidine compounds and their application in pharmaceuticals

• US 9,498,479 B2
• Filed: 11/18/2014
• Issued: 11/22/2016
• Est. Priority Date: 11/19/2013
• Status: Active Grant

• Current Assignee: Ruyuan HEC Enterprise Management Company Limited
• Original Assignee: Sunshine Lake Pharma Co Ltd (Shenzhen Dongyangguang Industry Co., Ltd.)
• Inventors: Zou, Zhifu, Liang, Jinsheng, Zhang, Yingjun, Liu, Xinchang, Goldmann, Siegfried, Ren, Qingyun
• Primary Examiner(s): RAO, DEEPAK R
• Application Number:
  US15/022,562
• Publication Number:
  US 20160206616A1
• Time in Patent Office: 735 Days
• Field of Search: 544/60, 544/333, 514/227.8, 514/256
• US Class Current: 1/1
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/541 Non-condensed thiazines containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

Provided herein are dihydropyrimidine compounds and their pharmaceutical applications, especially for use in treating and preventing HBV diseases. Specifically, provided herein are compounds having Formula (I) or (Ia), or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, wherein the variables of the formulas are as defined in the specification. Also provided herein is the use of the compounds having Formula (I) or (Ia), or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof for treating and preventing HBV diseases.

Claims

1. A compound having Formula (I) or (Ia), or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, a stereoisomer, an N-oxide, or a pharmaceutically acceptable salt thereof,

2. The compound according to claim 1, wherein

R is

3. The compound according to claim 2, wherein

R is

4. The compound according to claim 1, wherein

R¹ is phenyl;

R³ is thiazolyl or 1-methyl-1H-imidazolyl; and

each of R², R⁴ and R⁵ is independently hydrogen, methyl or ethyl;

wherein each thiazolyl and 1-methyl-1H-imidazolyl described in R³, phenyl described in R¹, and methyl and ethyl described in R², R⁴ and R⁵, is optionally and independently substituted with one or more substituents independently selected from hydrogen, C_1-4 alkyl, fluoro, chloro or bromo.

5. The compound according to claim 1 having Formula (II) or (IIa), or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, a stereoisomer, an N-oxide or a pharmaceutically acceptable salt thereof,

6. The compound according to claim 1 or 5, wherein

R is

7. The compound according to claim 1 having one of the following structures, or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, a stereoisomer, an N-oxide, or a pharmaceutically acceptable salt thereof,

9. A pharmaceutical composition comprising the compound according to claim 1;

and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

10. The pharmaceutical composition according to claim 9 further comprising an anti-HBV agent.

11. The pharmaceutical composition according to claim 10, wherein the anti-HBV agent is a HBV polymerase inhibitor, immunomodulator or interferon.

12. The pharmaceutical composition according to claim 10, wherein the anti-HBV agent comprises at least one selected from the group consisting of lamivudine, telbivudine, tenofovir, entecavir, adefovir dipivoxil, alfaferone, alloferon, celmoleukin, clevudine, emtricitabine, famciclovir, interferon, hepatect CP, intefen, interferon α

-1b, interferon α

, interferon α

-2a, interferon β

-1a, interferon α

-2, interleukin-2, mivotilate, nitazoxanide, peginterferon alfa-2a, ribavirin, roferon-A, sizofiran, euforavac, ampligen, phosphazid, heplisav, interferon α

-2b, levamisole and propagermanium.

13. A method for treating a HBV disease comprising administering to a patient a therapeutically effective amount of the compound according to claim 1.

14. The method according to claim 13, wherein the viral disease or HBV disease is hepatitis B infection or a disease caused by hepatitis B infection.

15. The method according to claim 14, wherein the disease caused by hepatitis B infection is cirrhosis or hepatocellular carcinoma.

16. A method for treating a HBV disease comprising administering to a patient a therapeutically effective amount of the pharmaceutical composition according to claim 9.

17. The method according to claim 16, wherein the viral disease or HBV disease is hepatitis B infection or a disease caused by hepatitis B infection.

18. The method according to claim 17, wherein the disease caused by hepatitis B infection is cirrhosis or hepatocellular carcinoma.

8. A compound having one of the following structures, or an enantiomer, a diastereoisomer, a tautomer, a hydrate, a solvate, a stereoisomer, an N-oxide, or a pharmaceutically acceptable salt thereof,