Pyrimidine derivatives and processes for the preparation thereof

• US 6,352,993 B1
• Filed: 09/24/1999
• Issued: 03/05/2002
• Est. Priority Date: 03/27/1997
• Status: Expired due to Fees

• Current Assignee: Yuhan Corporation
• Original Assignee: Yuhan Corporation
• Inventors: Lee, Seung Kyu, Lee, Bong Yong, Lee, Song Jin, Kim, Chang Seop, Hwang, Man Soon, Song, Keun Seog, Shim, Woo Jeon, Lee, Jong Wook
• Primary Examiner(s): Ford, John M.
• Application Number:
  US09/381,814
• Time in Patent Office: 893 Days
• Field of Search: 544/332, 544/298, 544/330, 514/275, 514/269, 514/272
• US Class Current: 514/275
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• 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 417/14 containing three or more hetero rings

Abstract

The present invention relates to novel pyrimidine derivatives of formula (I) or pharmaceutically acceptable salts thereof which possess an excellent anti-secretory activity, pharmaceutical compositions containing the same as an active ingredient, their novel intermediates, and processes for the preparation thereof wherein: when A is piperidin-1-yl or —NH—B, wherein B is C₃-C₄ alkyl, C₃-C₄ alkenyl, C₃-C₇ cycloalkyl, C₁-C₃ alkoxyethyl, phenylethl which may be substituted or unsubstituted, 3-trifluoromethylphenylmethyl, 1-naphthylmethyl, 4-methylthiazol-2-yl or 4-phenylthiazol-2-yl, R₁ is hydrogen or methyl; and R₂, R₃, R₄ and R₅ are hydrogen; or when A is a group of formula (II); when R₁ is hydroxymethyl or C₁-C₃ alkoxymethyl, R₂, R₃, R₄, R₅ and R₆ are hydrogen; and R₇ is hydrogen or halogen; or when R₁ is hydrogen or methyl, R₇ is hydrogen or halogen; and one or two of R₂, R₃, R₄, R₅ and R₆ is hydroxy, methoxy, or a group of formula (III) wherein Z is C₁-C₄ alkyl, substituted or unsubstituted C₁-C₄ alkenyl, cyloalkyl, benzyloxyalkyl, alkoxycarbonylalkyl, morpholinomethyl, piperidinomethyl, 4-substituted-piperazinomethyl, substituted or unsubstituted phenyl, naphthyl, substituted or unsubstituted benzyl, thiophen-2-yl-methyl, 1-substituted-pyrrolidin-2-yl or —CHR₈NHR₉, wherein R₈ is hydrogen, methyl, isopropyl, benzyl, benzyloxymethyl, methylthioethyl, benzyloxycarbonylmethyl, carbamolymethyl, carbamoylethyl, or 1-benzylimidazol-4-ylmethyl and R₉ is hydrogen or t-butoxycarbonyl; and the others are hydrogen or methyl.

Claims

1. Pyrimidine derivative of the following formula (I):

wherein

B is C₃-C₇ cycloalkyl;

C₁-C₃ alkoxyethyl;

1-naphthylmethyl, 4-methylthiazol-2-yl or 4-phenylthiazol-2-yl or a group of formula (II);

wherein R₆ is hydrogen, methyl, hydroxy, methoxy, or a group of formula (III);

wherein Z is C₁-C₄ alkyl;

C₂-C₄ alkenyl optionally substituted by phenyl;

cycloalkyl;

benzyloxyalkyl;

alkoxycarbonylalkyl;

morpholinomethyl;

piperidinomethyl;

4-benzyl-piperazinomethyl;

phenyl optionally mono- or polysubstituted by nitro, halogen, C₁-C₅ alkyl, C₁-C₄ alkoxy, cyano or trifluoromethyl;

naphthyl;

benzyl optionally substituted by alkoxy;

thiophen-2-yl-methyl;

1-alkoxycarbonyl-pyrrolidin-2-yl or —

CHR₈NHR9, wherein R₈ is hydrogen, methyl, isopropyl, benzyl, benzyloxymethyl, methylthioethyl, benzyloxycarbonylmethyl, carbamoylmethyl, carbamoylethyl, or 1-benzylimidazol-4-ylmethyl and R₉ is hydrogen or t-butoxycarbonyl; and

R₇ is hydrogen or halogen;

R₁ is hydrogen, methyl, hydroxymethyl or C₁-C₃ alkoxymethyl, and R₂, R₃, R₄ and R₅ are respectively hydrogen, methyl, hydroxy, methoxy, or the group of formula (III) wherein Z is the same as defined above;

provided that when B is C₃-C₇ cycloalkyl, C₁-C₃ alkoxyethyl, 1-naphthylmethyl, 4-methylthiazol-2-yl or 4-phenylthiazol-2-yl, then R₁ is hydrogen or methyl, and R₂, R₃, R₄, and R₅ are hydrogen;

when B is a group of formula (II) and R₁ is hydroxymethyl or C₁-C₃ alkoxymethyl, then R₂, R₃, R₄, R₅ and R₆ are hydrogen; and

when B is a group of formula (II) and R₁ is hydrogen or methyl, then one or two of R₂, R₃, R₄, R₅ and R₆ are hydroxy, methoxy, or a group of formula (III) and the others are hydrogen or methyl, or pharmaceutically acceptable salts thereof.

2. The compound of claim 1, wherein B is C₃-C₇ cycloalkyl, C₁-C₃ alkoxyethyl, 1-naphthylmethyl, 4-methylthiazol-2-yl or 4-phenylthiazol-2-yl.

3. The compound of claim 1, wherein B is a group of formula (II);

R₁ is hydrogen or methyl; and

one or two of R₂, R₃, R₄, R₅ and R₆ are hydroxy or methoxy.

4. The compound of claim 1, wherein B is a group of formula (II);

R₁ is hydrogen or methyl; and

one or two of R₂, R₃, R₄, R₅ and R₆ are a group of formula (III).

5. The compound of claim 1, wherein B is a group of formula (II) and R₁ is hydroxymethyl or C₁-C₃ alkoxymethyl.

6. A pharmaceutical composition for treating peptic ulcer which comprises a therapeutically effective amount of the pyrimidine derivative or pharmaceutically acceptable salt thereof defined in claim 1 together with a conventionally pharmaceutically acceptable carrier.

7. A method for treating peptic ulcer comprising administering to a subject in need of such treatment a pyrimidine derivative or pharmaceutically acceptable salt thereof as defined in claim 1 in an amount effective for treating peptic ulcer.

8. A method for treating peptic ulcer comprising administering to a subject in need of such treatment a pyrimidine derivative or pharmaceutically acceptable salt thereof as defined in claim 2 in an amount effective for treating peptic ulcer.

9. A method for treating peptic ulcer comprising administering to a subject in need of such treatment a pyrimidine derivative or pharmaceutically acceptable salt thereof as defined in claim 3 in an amount effective for treating peptic ulcer.

10. A method for treating peptic ulcer comprising administering to a subject in need of such treatment a pyrimidine derivative or pharmaceutically acceptable salt thereof as defined in claim 4 in an amount effective for treating peptic ulcer.

11. A method for treating peptic ulcer comprising administering to a subject in need of such treatment a pyrimidine derivative or pharmaceutically acceptable salt thereof as defined in claim 5 in an amount effective for treating peptic ulcer.

12. The compound of claim 1, wherein the pharmaceutically acceptable salt is an inorganic acid salt.

13. The compound of claim 12, wherein the inorganic acid salt is selected from the group consisting of hydrochloride, sulfate, phosphate and nitrate salts.

14. The compound of claim 1, wherein the pharmaceutically acceptable salt is an organic acid salt.

15. The compound of claim 14, wherein the organic acid salt is selected from the group consisting of tartrate, fumarate, citrate, mesylate and acetate salts.

16. 5,6-dimethyl-2-(2-methoxyethylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine or a pharmaceutically acceptable salt thereof.

17. 6-hydroxymethyl-5-methyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine or a pharmaceutically acceptable salt thereof.

18. 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine or a pharmaceutically acceptable salt thereof.

19. 5-hydroxymethyl-6-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(4-fluorophenylamino)pyrimidine or a pharmaceutically acceptable salt thereof.

20. 5-hydroxymethyl-6-methyl-2-(4-fluorophenylamino)-4-(1-methyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine or a pharmaceutically acceptable salt thereof.

21. 5-methyl-6-(thiophen-2-yl-acetoxymethyl)-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine or a pharmaceutically acceptable salt thereof.

22. 5-methyl-6-valyloxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine or a pharmaceutically acceptable salt thereof.

23. 5-methyl-6-(phenylalanyloxymethyl)-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine or a pharmaceutically acceptable salt thereof.

24. 5,6-dimethyl-2-(4-methylthiazol-2-yl)amino-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine or a pharmaceutically acceptable salt thereof.