Pyrimidine derivatives and processes for the preparation thereof

• US 5,750,531 A
• Filed: 01/23/1997
• Issued: 05/12/1998
• Est. Priority Date: 08/13/1994
• Status: Expired due to Term

• Current Assignee: NEC Corporation
• Original Assignee: Yuhan Corporation
• Inventors: Choi, Yeon Shik, Lee, Sang Ho, Kim, Chang Seop, Kim, Jae Kyu, Shon, Moon Kyu, Lim, Dae Sung, Chae, Jeong Seok, Lee, Jong Wook
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US08/776,220
• Time in Patent Office: 474 Days
• Field of Search: 514/256, 514/258, 514/275, 544/253, 544/297, 544/326, 544/328, 544/334
• US Class Current: 514/256
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 495/04 Ortho-condensed systems

Abstract

The present invention relates to novel pyrimidine derivatives of the formulae (I-1) and (I-2) and pharmaceutically acceptable salts thereof which possess an excellent anti-secretory activity, pharmaceutical compositions containing same as an active ingredient, their novel intermediates, and processes for the preparation thereof: ##STR1## wherein: R₄ and R₅, which may be the same or different, are independently hydrogen or a C₁ -C₃ alkyl group, or jointly form a cyclopentyl or cyclohexyl ring;

A is a group of formula(II): ##STR2## wherein R₁ and R₂ are, independently of each other, hydrogen or a C₁ -C₃ alkyl group, and R₃ is hydrogen, a C₁ -C₃ alkyl group or a halogen; and

B is 1-(substituted)-1,2,3,4-tetrahydroisoquinolin-2-yl of formula (III-1) or 7-(substituted)-4,5,6,7-tetrahydrothieno 2,3-c!pyridin-6-yl of formula (III-2) ##STR3## wherein R₆ is hydrogen or a C₁ -C₃ alkyl group.

Claims

1. Pyrimidine derivative compounds of formulae (I-1) and (I-2) inclusive of pharmaceutically acceptable salts thereof:

##STR9## wherein;

R₄ and R₅, which may be the same or different, are independently hydrogen or a C₁ -C₃ alkyl group, or jointly form a cyclopentyl or cyclohexyl ring;

A is a group of formula(II);

##STR10## wherein R₁ and R₂ are, independently of each other, hydrogen or a C₁ -C₃ alkyl group, and R₃ is hydrogen, a C₁ -C₃ alkyl group or a halogen; and

B is 1-(substituted)-1,2,3,4-tetrahydroisoquinolin-2-yl of formula (III-1) or 7-(substituted)-4,5,6,7-tetrahydrothieno 2,3-c!pyridin-6-yl of formula (III-2) ##STR11## wherein R₆ is hydrogen or a C₁ -C₃ alkyl group.

2. The compound of claim 1, which is selected from the group consisting of:

2-(2-methyl-4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

6-methyl-2-(2-methyl-4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

6-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-(4-fluorophenylamino)pyrimidine hydrochloride;

6-methyl-2-(N-methylphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

6-ethyl-2-(2-methyl-4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

6-ethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

6-ethyl-2-(N-methylphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

6-ethyl-2-(2-methylphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

2-(2-methyl-4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-6-propylpyrimidine hydrochloride;

4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-6-propyl-2-(4-fluorophenylamino)pyrimidine hydrochloride;

2-(N-methylphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-6-propylpyrimidine hydrochloride;

5,6-dimethyl-2-(2-methyl-4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

(R)-5,6-dimethyl-2-(2-methyl-4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

(S)-5,6-dimethyl-2-(2-methyl-4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

(R)-5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl )pyrimidine hydrochloride;

(S)-5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

5,6-dimethyl-2-(N-methylphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl )pyrimidine hydrochloride;

(R)-5,6-dimethyl-2-(N-methylphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

(S)-5,6-dimethyl-2-(N-methylphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

5,6-dimethyl-2-(phenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

(R)-5,6-dimethyl-2-(4-phenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

(S)-5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

5,6-dimethyl-2-(2-methylphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

5,6-dimethyl-2-(4-methylphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

5-methyl-6-ethyl-2-(2-methyl-4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

5-methyl-6-ethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

5-methyl-6-ethyl-2-(N-methylphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

2-(2-methyl-4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)cyclopenta d!pyrimidine hydrochloride;

2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)cyclopenta d!pyrimidine hydrochloride;

2-(N-methylphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)cyclopenta d!pyrimidine hydrochloride;

2-(2-methyl-4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-5,6,7,8-tetrahydroquinazoline hydrochloride;

2-(N-methylphenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)-5,6,7,8-tetrahydroquinazoline hydrochloride;

6-methyl-2-(2-methyl-4-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

6-methyl-2-(4-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinoline-2-yl )pyrimidine hydrochloride;

6-methyl-2-(N-methylphenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

6-ethyl-2-(2-methyl-4-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

6-ethyl-2-(4-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

6-ethyl-2-(N-methylphenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

6-ethyl-2-(2-methylphenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

5,6-dimethyl-2-(2-methyl-4-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

5,6-dimethyl-2-(4-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

5,6-dimethyl-2-(N-methylphenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

5-methyl-6-ethyl-2-(2-methyl-4-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

5-methyl-6-ethyl-2-(4-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

5-methyl-6-ethyl-2-(N-methylphenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

2-(2-methyl-4-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)cyclopenta d!pyrimidine hydrochloride;

2-(2-methyl-4-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-5,6,7,8-tetrahydroquinazolinehydrochloride;

2-(4-fluorophenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-5,6,7,8-tetrahydroquinazoline hydrochloride;

2-(N-methylphenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-5,6,7,8-tetrahydroquinazoline hydrochloride;

2-(2-methylphenylamino)-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-5,6,7,8-tetrahydroquinazoline hydrochloride;

6-methyl-2-(2-methyl-4-fluorophenylamino)-4-(7-methyl-4,5,6,7-tetrahydrothieno 2,3-c!pyridin-6-yl)pyrimidine hydrochloride;

6-methyl-4-(7-methyl-4,5,6,7-tetrahydrothieno 2,3-c!pyridin-6-yl)-2-(4-fluorophenylamino)pyrimidine hydrochloride;

6-methyl-2-(N-methylphenylamino)-4-(7-methyl-4,5,6,7-tetrahydrothieno 2,3-c!pyridin-6-yl)pyrimidine hydrochloride;

5,6-dimethyl-2-(2-methyl-4-fluorophenylamino)-4-(7-methyl-4,5,6,7-tetrahydrothieno 2,3-c!pyridin-6-yl)pyrimidine hydrochloride;

5-methyl-2-(2-methyl-4-fluorophenylamino)-4-(7-methyl-4,5,6,7-tetrahydrothieno 2,3-c!pyridin-6-yl)-6-ethylpyrimidine hydrochloride;

6-methyl-4-(2-methyl-4-fluorophenylamino)-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

6-methyl-4-(4-fluorophenylamino)-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

6-methyl-4-(2-methyl-4-fluorophenylamino)-2-(7-methyl-4,5,6,7-tetrahydrothieno 2,3-c!pyridin-6-yl)pyrimidine hydrochloride;

6-methyl-4-(4-fluorophenylamino)-2-(7-methyl-4,5,6,7-tetrahydrothieno 2,3-c!pyridin-6-yl)pyrimidine hydrochloride;

6-ethyl-2-(2-methyl-4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

6-ethyl-4-(2-methyl-4-fluorophenylamino)-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

6-ethyl-4-(4-fluorophenylamino)-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

6-ethyl-4-(N-methylphenylamino)-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

5,6-dimethyl-4-(2-methyl-4-fluorophenylamino)-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

(R)-5,6-dimethyl-4-(2-methyl-4-fluorophenylamino)-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

(S)-5,6-dimethyl-4-(2-methyl-4-fluorophenylamino)-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

5,6-dimethyl-4-(4-fluorophenylamino)-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl )pyrimidine hydrochloride;

(R)-5,6-dimethyl-4-(4-fluorophenylamino)-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

(S)-5,6-dimethyl-4-(4-fluorophenylamino)-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

5,6-dimethyl-4-(N-methylphenylamino)-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

(R)-5,6-dimethyl-4-(N-methylphenylamino)-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

(S)-5,6-dimethyl-4-(N-methylphenylamino)-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

5,6-dimethyl-4-(2-methyl-4-fluorophenylamino)-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

5,6-dimethyl-4-(4-fluorophenylamino)-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

5,6-dimethyl-4-(N-methylphenylamino)-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

5,6-dimethyl-4-(2-methyl-4-fluorophenylamino)-2-(7-methyl-4,5,6,7-tetrahydrothieno 2,3-c!pyridin-6-yl)pyrimidine hydrochloride;

5,6-dimethyl-2-(7-methyl-4,5,6,7-tetrahydrothieno 2,3-c!pyridin-6-yl)-4-(4-fluorophenylamino)pyrimidine hydrochloride;

5,6-dimethyl-4-(N-methylphenylamino)-2-(7-methyl-4,5,6,7-tetrahydrothieno 2,3-c!pyridin-6-yl)pyrimidine hydrochloride;

5-methyl-6-ethyl-4-(2-methyl-4-fluorophenylamino)-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine hydrochloride;

4-(2-methyl-4-fluorophenylamino)-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)cyclopenta d!pyrimidine hydrochloride;

2-(2-methyl-4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-5,6,7,8-tetrahydroquinazoline hydrochloride; and

4-(2-methyl-4-fluorophenylamino)-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-5,6,7,8-tetrahydroquinazoline hydrochloride.

3. The compound of claim 1, wherein the pharmaceutically acceptable salts are hydrochlorides, sulfates, phosphates, nitrates, tartrates, fumarates, citrates, mesylates or acetates of the pyrimidine derivative compounds of formulae (I-1) and (I-2).

4. A process for preparing a pyrimidine derivative compound of formula (I-1), which comprises reacting a compound of formula(IV) with a compound of formula (V-1) or (V-2) to give a compound of formula(VI-1);

and reacting the compound of formula(VI-1) with a compound of formula(VII);

##STR12## wherein B, R₁, R₂, R₃, R₄, R₅ and R₆ are the same as defined in claim 1.

5. The process of claim 4, wherein the reaction of the compound of formula (IV) with the compound of formula (V-1) or (V-2) is carried out in the presence of a solvent selected from the group consisting of dichloromethane, acetone, acetonitrile and dimethylformamide, and a base selected from the group consisting of triethylamine, N,N-dimethylaniline and pyridine.

6. A process for preparing a pyrimidine derivative compound of formula (I-2), which comprises:

hydrolyzing a compound of formula(IV) at its 4-position to give a compound of formula(VIII);

reacting the compound of formula(VIII) with a compound of formula (V-1) or (V-2) to give a compound of formula(IX);

chlorinating the compound of formula(IX) at its 4-position to give a compound of formula (VI-2); and

then reacting the compound of formula (VI-2) with a compound of formula (VII);

##STR13## wherein B, R₁, R₂, R₃, R₄, R₅ and R₆ are the same as defined in claim 1.

7. The process of claim 6, where the reaction of the compound of formula (VIII) with the compound of formula (V-1) or (V-2) is carried out in the presence of a solvent selected from the group consisting of dichloromethane, acetone, acetonitrile and dimethylformamide, and a base selected from the group consisting of triethylamine, N,N-dimethylaniline and pyridine.

8. Pyrimidine derivative compounds of formulae (VI-1) and (VI-2):

##STR14## wherein B, R₄ and R₅ are the same as defined in claim 1.

9. A process for preparing a compound of formula (VI-1), which comprises reacting a compound of formula(IV) with a compound of formula (V-1) or (V-2):

##STR15## wherein R₄, R₅ and R₆ are the same as defined in claim 1.

10. The process of claim 9, wherein the reaction of the compound of formula (IV) with the compound of formula (V-1) or (V-2) is carried out in the presence of a solvent selected from the group consisting of dichloromethane, acetone, acetonitrile and dimethylformamide, and a base selected from the group consisting of triethylamine, N,N-dimethylaniline and pyridine.

11. A process for preparing a compound of formula (VI-2), which comprises:

hydrolyzing a compound of formula(IV) at its 4-position to give a compound of formula(VIII);

reacting the compound of formula(VIII) with a compound of formula (V-1) or (V-2) to give a compound of formula(IX); and

then chlorinating the compound of formula(IX) at its 4-position;

##STR16## wherein B, R₄, R₅ and R₆ are the same as defined in claim 1.

12. The process of claim 11, wherein the reaction of the compound of formula (VIII) with the compound of formula (V-1) or (V-2) is carried out in the presence of a solvent selected from the group consisting of dichloromethane, acetone, acetonitrile and dimethylformamide, and a base selected from the group consisting of triethylamine, N,N-dimethylaniline and pyridine.

13. A pharmaceutical composition comprising a therapeutically effective amount of any of the pyrimidine derivative compounds of claim 1 and a pharmaceutically acceptable carrier.