Medicaments against viral diseases

• US 20030232842A1
• Filed: 03/10/2003
• Published: 12/18/2003
• Est. Priority Date: 03/16/2000
• Status: Active Grant

• Current Assignee: Arnold Paessens, Sunshine Lake Pharma Co Ltd (Shenzhen Dongyangguang Industry Co., Ltd.), Siegfried Goldmann
• Original Assignee: Arnold Paessens, Siegfried Goldmann
• Inventors: Schlemmer, Karl-Heinz, Weber, Olaf, Paessens, Arnold, Keldenich, Jorg, Niewohner, Ulrich, Deres, Karl, Graef, Erwin, Goldmann, Siegfried, Stoltefuss, Jurgen
• Granted Patent: US 7,074,784 B2
• Time in Patent Office: Days
• US Class Current: 514/256
• 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: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond

Abstract

Novel dihydropyrimidines and combinations thereof with other antiviral agents, suitable for combating HBV infections.

Claims

1. A compound of the formula

2. A compound as claimed in claim 1, in which

R⁴ and R⁵ together with the nitrogen atom to which they are bonded form a morpholinyl or thiomorpholinyl ring,

and the salts thereof.

3. A compound as claimed in claim 1, in which

R¹, R² are, independently of one another, fluorine, chlorine or bromine,

and the salts thereof.

4. A compound as claimed in claim 1, in which

R¹, R² are, independently of one another, fluorine, chlorine or bromine, and

R⁴ and R⁵ together with the nitrogen atom to which they are bonded form a morpholinyl or thiomorpholinyl ring,

and the salts thereof.

6. A process for preparing the compounds as claimed in claims 1 to 5, by

[A] reacting compounds of the formula

 

in which

R¹ to R³, X and Z have the meanings indicated in claims 1 to 5,

with amidines of the formula

 

in which

R⁶ has the meaning indicated in claims 1 to 5,

or the salts thereof, or

[B] reacting compounds of the formula

 

in which

R³, X and Z have the meanings indicated in claims 1 to 5,

in a one-stage process with aldehydes of the formula

 

in which

R¹ and R² have the meanings indicated in claims 1 to 5,

and amidines of the formula

 

in which

R⁶ has the meanings indicated in claims 1 to 5,

or the salts thereof, or else

[C] where X in formula (I) is a methylene group, reacting compounds of the formula

 

in which

R¹ to R³ and R⁶ have the meanings indicated in claims 1 to 5, and

Y is a nucleophilically replaceable group,

with compounds of the formula

 

in which

R⁴ and R⁵ have the meanings indicated claims 1 to 5, or else

[D] where X in formula (I) is an ethylene group, reacting compounds of the formula

 

in which

R¹ to R⁵ have the meanings indicated in claims 1 to 5, with amidines of the formula

 

in which

R⁶ has the the meanings indicated in claims 1 to 5,

or the salts thereof.

7. A process for preparing the compounds as claimed in claims 1 to 5, by

[A] firstly converting aldehydes of the formula

 

in which

R¹ and R² have the meanings indicated in claims 1 to 5,

with β

-keto esters of the formula

 

in which

R³, X and Z have the meanings indicated in claims 1 to 5, into benzylidene compounds of the formula

and then reacting the latter with amidines of the formula

 

in which

R⁶ has the meaning indicated in claims 1 to 5,

or the salts thereof, or

[B] reacting compounds of the formula (III) in a one-stage process with aldehydes (II) and amidines (V) or the salts thereof, or else

[C] where X in formula (I) is a methylene group, reacting compounds of the formula

 

in which

R¹ to R³ and R⁶ have the meanings indicated in claims 1 to 5, and

Y is a nucleophilically replaceable group,

with compounds of the formula

 

in which

R⁴ and R⁴ have the meanings indicated in claims 1 to 5, or else

[D] where X in formula (I) is an ethylene group, converting compounds of the formula

 

in which

R¹ to R³ have the meanings indicated in claims 1 to 5,

with immonium salts of the formula

 

in which

R⁴ and R⁵ have the meanings indicated in claims 1 to 5,

into compounds of the formula

 

and then reacting the latter with amidines of the formula (V) or the salts thereof.

8. A compound of the formula

9. A compound as claimed in any of claims 1 to 5 for controlling diseases.

10. A medicament comprising at least one compound as claimed in claims 1 to 5 and, where appropriate, other active pharmaceutical ingredients.

11. The use of compounds of claims 1 to 5 for producing a medicament for the treatment and prophylaxis of viral diseases.

12. The use of compounds of claims 1 to 5 for producing a medicament for the treatment and prophylaxis of heptatitis B infections.

13. A combination of

A) at least one dihydropyrimidine as claimed in claims 1 to 5,

B) at least one HBV antiviral agent different from A and, where appropriate,

C) at least one immunomodulator.

14. A combination as claimed in claim 13, in which component B is an HBV polymerase inhibitor.

15. A combination as claimed in claim 13, in which component B is lamivudine.

16. A combination as claimed in claim 13, in which component B is selected from compounds of the formula

17. A combination as claimed in claim 16, in which

X is chlorine, A is 1-piperidinyl and Y and Z are each phenyl.

18. A combination as claimed in claims 13 to 17, in which the immunomodulator C comprises interferons.

19. A combination of A) dihydropyrimidine as claimed in claims 1 to 5, B) lamivudine and, where appropriate, C) interferon.

20. A process for producing the combinations as claimed in claims 13 to 19, characterized in that components A, B and, where appropriate, C are combined or prepared in a suitable way.

21. A combination as claimed in claims 13 to 19 for controlling diseases.

22. A medicament comprising at least one combination as claimed in claims 13 to 19 and, where appropriate, other active pharmaceutical ingredients.

23. The use of combinations of claims 13 to 19 for producing a medicament for the treatment and prophylaxis of viral diseases.

24. The use of combinations of claims 13 to 19 for producing a medicament for the treatment and prophylaxis of hepatitis B infections.

5. A compound of Example 5, 7, 9, 11, 12, 15, 24, 31, 34, 45.