Esters and amides of pyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylic acids as antiulcer agents

• US 4,011,324 A
• Filed: 01/20/1976
• Issued: 03/08/1977
• Est. Priority Date: 01/20/1976
• Status: Expired due to Term

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Althuis, Thomas H.
• Primary Examiner(s): Daus, Donald G.
• Assistant Examiner(s): Turnipseed, James H.
• Application Number:
  US05/650,714
• Time in Patent Office: 413 Days
• Field of Search: 424/251
• US Class Current: 514/267
• 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 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

A series of alkyl ester and amide derivatives of pyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylic acids, salts thereof and their preparation and use as antiulcer agents.

Claims

1. A compound of the formula ##STR14## wherein Z is selected from the group consisting of hydroxyalkyl having from two to four carbon atoms, aminoalkyl having from two to four carbon atoms;

and

space="preserve" listing-type="equation">--(alk).sub.m --(O).sub.n --W

wherein

each of m and n is 0 or 1, provided that when n is 1, m is 1;

(alk) is alkylene having from one to four carbon atoms, provided that when n is 1, (alk) is alkylene having from two to four carbon atoms;

W is selected from the group consisting of pyridyl, imidazolyl and ##STR15## wherein X is selected from the group consisting of hydrogen, amino, carboxy, hydroxy, alkyl having from one to four carbon atoms and alkoxy having from one to four carbon atoms;

Y is selected from the group consisting of hydrogen, methyl, carboxyalkyl having from one to four carbon atoms in the alkyl group and carbalkoxyalkyl having from one to four carbon atoms in each of the alkyl and alkoxy groups;

R₁ is selected from the group consisting of hyrogen, alkyl having from one to four carbon atoms and phenyl;

each of R₂, R₃ and R₄ when taken separately is selected from the group consisting of hydrogen, alkyl having from one to four carbon atoms, alkoxy having from one to four carbon atoms, halo, hydroxy, benzyloxy, benzoyloxy, alkanoyloxy having from one to four carbon atoms, thiol, methylthio, methylsulfinyl, benzylthio and benzylsulfinyl;

with the proviso that no more than two of R₂, R₃ and R₄ are branched alkyl or alkoxy, and when two of R₂, R₃ and R₄ are branched chain alkyl or alkoxy, said groups are located on non-adjacent carbon atoms;

R₂ and R₃ or R₃ and R₄ when taken together are alkylenedioxy and are selected from the group consisting of methylenedioxy and ethylenedioxy;

with the proviso that only one of said pairs is alkylenedioxy; and

the pharmaceutically acceptable acid addition salts thereof, and the pharmaceutically acceptable cationic salts of those compounds wherein W is carboxyphenyl or Y is carboxyalkyl.

2. A compound according to claim 1 wherein each of R₁, R₂, R₃, R₄ and Y is hydrogen, and Z is --(alk)_m --(O)_n --W.

3. A compound according to claim 2 wherein W is ##STR16## and each of m and n is 1.

4. The compound according to claim 3 wherein X is hydrogen and --(alk)-- is --CH₂ CH₂ --.

5. The compound according to claim 3 wherein X is 3-amino and --(alk)-- is --(CH₂ CH₂ --.

6. A compound according to claim 1 wherein each of R₁, R₂ and Y is hydrogen;

each of R₃ and R₄ is alkoxy; and

Z is --(alk)_m --(O)_n --W.

7. A compound according to claim 6 wherein each of m and n is 1;

--(alk)-- is --CH₂ CH₂ --;

each of R₃ and R₄ is methoxy; and

W is ##STR17##

8. The compound according to claim 7 wherein X is hydrogen.

9. The compound according to claim 7 wherein X is 3-amino.

10. A compound according to claim 6 wherein W is 2-pyridyl.

11. The compound according to claim 10 wherein each of R₃ and R₄ is methoxy;

each of m and n is 1; and

--(alk)-- is --CH₂ CH₂ --.

12. The compound according to claim 1 wherein each of R₁, R₂ and Y is hydrogen;

each of R₃ and R₄ is methoxy; and

Z is hydroxyethyl.

13. A compound according to claim 1 wherein each of R₁ and R₂ is hydrogen;

each of R₃ and R₄ is alkoxy;

Y is carbalkoxyalkyl, and Z is --(alk)_m --(O)_n --W.

14. The compound according to claim 13 wherein each of R₃ and R₄ is methoxy;

Y is carbethoxymethyl;

each of m and n is 1 and W is 2-pyridyl.

15. A compound according to claim 6 wherein W is 2-pyridyl.

16. A method for the control of peptic ulcers in animals in need of said treatment which comprises administering, by either the intraperitoneal or oral route to the animals an antipeptic ulcer amount of a compound having the formula ##STR18## wherein R₀ is selected from the group consisting of alkoxy having from one to four carbon atoms, and NHZ wherein Z is selected from the group consisting of hydrogen, hydroxyalkyl having from two to four carbon atoms, aminoalkyl having from two to four carbon atoms;

alkyl having from one to four carbon atoms and;

space="preserve" listing-type="equation">--(alk).sub.m --(O).sub.n --W

wherein

each of m and n is 0 or 1, provided that when n is 1, m is 1;

(alk) is alkylene having from one to four carbon atoms, with the proviso that when n is 1, (alk) is alkylene having from two to four carbon atoms;

W is selected from the group consisting of pyridyl, imidazolyl and ##STR19## wherein X is selected from the group consisting of hydrogen, amino, carboxy, hydroxy, alkyl having from one to four carbon atoms and alkoxy having from one to four carbon atoms;

Y is selected from the group consisting of hydrogen, methyl, carboxyalkyl having from one to four carbon atoms in the alkyl group and carboxyalkyl having from one to four carbon atoms in each of the alkyl and alkoxy groups;

R₁ is selected from the group consisting of hydrogen, alkyl having from one to four carbon atoms and phenyl;

each of R₂, R₃ and R₄ when taken separately is selected from the group consisting of hydrogen, alkyl having from one to four carbon atoms, alkoxy having from one to four carbon atoms, halo, hydroxy, benzyloxy, benzoyloxy, alkanoyloxy having from one to four carbon atoms, thiol, methylthio, methylsulfinyl, benzylthio and benzylsulfinyl;

with the proviso that no more than two of R₂, R₃ and R₄ are branched alkyl or alkoxy, and when two of R₂, R₃ and R₄ are branched chain alkyl or alkoxy, said groups are located on non-adjacent carbon atoms;

R₂ and R₃ or R₃ and R₄ when taken together are alkylenedioxy and are selected from the group consisting of methylenedioxy and ethylenedioxy;

with the proviso that only one of said pairs is alkylenedioxy; and

the pharmaceutically acceptable acid addition salts thereof, and the pharmaceutically acceptable cationic salts of those compounds wherein W is carboxyphenyl or Y is carboxyalkyl.

17. The method of claim 16 wherein each of R₁, R₂, R₃, R₄ and Y is hydrogen;

and Z is --(alk)_m --(O)_n --W.

18. The method of claim 17 wherein each of m and n is 1 and W is ##STR20##

19. The method of claim 18 wherein X is hydrogen and --(alk)-- is --CH₂ CH₂ --.

20. The method of claim 17 wherein X is 3-amino and --(alk)-- is --CH₂ CH₂ --.

21. The method of claim 16 wherein each of R₁, R₂ and Y is hydrogen;

each of R₃ and R₄ is alkoxy; and

Z is --(alk)_m --(O)_n --W.

22. The method of claim 21 wherein each of m and n is 1;

--(alk)-- is --CH₂ CH₂ --;

each of R₃ and R₄ is methoxy; and

W is ##STR21##

23. The method of claim 22 wherein X is 3-amino.

24. The method of claim 21 wherein each of m and n is 1;

--(alk)-- is --CH₂ CH₂ --;

each of R₃ and R₄ is methoxy; and

W is 2-pyridyl.

25. The method of claim 16 wherein each of R₁, R₂ and Y is hydrogen;

each of R₃ and R₄ is methoxy; and

Z is hydroxyethyl.

26. The method of claim 16 wherein each of R₁, R₂ and Y is hydrogen;

each of R₃ and R₄ is methoxy and R₀ is alkoxy.

27. The method of claim 26 wherein R₀ is ethoxy.