Quinoline amino acid derivatives of carbostyril compounds

Abstract

Disclosed are carbostyril derivatives and their salts of the formulas ##STR1## The compounds have anti-peptic ulcer effects, and are useful as a treating agent for curing peptic ulcers in the digestive system, such as ulcers in the stomach and in the duodenum. The compounds particularly have prophylaxis and curing effects for treating chronic ulcers, for example experimental acetic acid-induced ulcers and cautery ulcers, with both low toxicity and few side-effects. Also disclosed are processes for preparing the compounds and for preparing pharmaceutical compositions containing them.

What is claimed is: 
     
       1. (a) A carbostyril derivative or .Iadd.a pharmaceutically acceptable .Iaddend.salt thereof represented by the formula ##STR574## wherein: R 1  is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a phenyl-lower alkyl group; R 2  is a hydrogen atom, .[.a halogen atom, a benxoyloxy group, said benzoyloxy group having a halogen atom substituent,.]. a hydroxyl group, a lower alkyl group or a lower alkoxy group;   R 3  is a hydroxyl group, an amino group, said amino group having a cycloalkyl-lower alkyl group substituent, .Iadd.or .Iaddend.said amino group having a cycloalkyl-lower alkyl group substituent having a carboxy group or a lower alkoxycarbonyl group substituent on the cycloalkyl ring.[.a lower alkoxy group, a lower alkoxycarbonyl-lower alkoxy group, a benzoyl-lower alkoxy group or a lower alkanoyloxy-lower alkoxy group.].;   R 4  is .[.a hydrogen atom,.]. a phenylsulfonyl group, said phenylsulfonyl group having lower alkyl group or halogen atom substituents, .[.a lower alkyl group, a phenyl-lower alkyl group, said phenyl-lower alkyl group having halogen atom substituents on the phenyl ring,.]. or a group of the formula --COR 5  wherein R 5  is .[.a lower alkyl group, said lower alkyl group having amino group or phenyl-lower alkoxycarbonylamino group substituents,.]. a cycloalkyl group, said cycloalkyl group having an amino-lower alkyl group or a phenyl-lower alkoxycarbonylamino-lower alkyl group substituent on the cycloalkyl ring, a phenyl group, said phenyl group having 1 to 3 halogen atom, lower alkyl group, lower alkoxy group, nitro group, amino group or hydroxyl group substituents on the phenyl ring, or a 5- or 6-membered unsaturated heterocyclic ring selected from the group consisting of pyridyl, 2-methylpyridyl, 3-ethylpyridyl, 4-butylpyridyl, .[.thienyl, 2-methylthienyl, 3-propylthienyl, pyrimidyl, 2-pentylpyrimidinyl, pyrrolyl, 3-methyl-pyrrolyl, 1-pyrazinyl, 4-pentyl-1-pyraxinyl, pyrazoylyl, 3-methylpyrazolyl, 4-ethylpyrazolyl, imidazolyl, 2-propylimidazolyl, 4-pentylimidazolyl, pyridazinyl, 4-methylpyridazinyl, pyrazinyl, 2-ethylpyrazinyl, oxazolyl, 4-butyloxazolyl, isoxazolyl, 4H-1,4-oxazinyl,.]. thiazolyl, 4-methylthiazolyl, 2-ethylthiazolyl, 5-propylthiazolyl, isothiazolyl, 3-methylisothiazolyl, furyl, 3-methylfuryl, .Iadd.and .Iaddend.2-ethylfuryl.[., 2-methylthianyl, 4-methylthianyl and 4-methylthianyl.]. groups;   R 0  is a hydrogen atom.[., a phenylsulfonyl group or said phenylsulfonyl group having lower alkyl group or halogen atom substituents.].;   A is a lower alkylene group;   n is 0 or 1;   the carbon-carbon bond of --CH  C< is a single or double carbon-carbon .Iadd.bond, wherein the dashed bond becomes two hydrogen atoms when the carbon-carbon bond is a single .Iaddend.bond;   the carbon-carbon bond between the 3- and 4-positions in the carbostyril skeleton is a single or double bond; and   the substitution position of the side-chain of the formula ##STR575## is any one of the 3-, 4-, 5-, 6-.[.7-.]. or 8-positions in the carbostyril skeleton.[.;   (b) a carbostyril derivative represented by the formula ##STR576## wherein: R 1  is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or phenyl-lower alkyl group;   R 2  is a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a halogen atom, a benzoyloxy group or said benzoyloxy group having halogen atom substituents;   R 9  is a group of the formula ##STR577## wherein R 4  and R 6  are lower alkyl groups and R 5  is a lower alkanoyl group;   A is a lower alkylene group;   n is 0 or 1;   the carbon-carbon bond between the 3- and 4- positions in the carbostyril skeleton is a single or double bond; and   the substitution position of the side-chain of the formula --(A) n  --CH 2  --R 9  is any one of the 3-, 4-, 5-, 6-, 7-, or 8-positions in the carbostyril skeleton;   provided that when R 2  is a hydrogen atom and n is 1, and R 9  is a halogen atom, then the substitution position of the side chain of the formula --(A) n  --CH 2  --R 9  is the 3- or 4-position in the carbostyril skeleton.].. .[.   
     
     
       2.  A carbostyril derivative represented by the formula ##STR578## wherein R 0 , R 1 , R 2 , R 3 , R 4 , A, n, the carbon-carbon bond in the side-chain, the carbon-carbon bond between the 3- and 4-positions in the carbostyril skeleton and the substitution position of the side-chain are the same as defined in claim 1(a)..]. .[. 
     
     
       3.  A carbostyril derivative represented by the formula ##STR579## wherein R 1 , R 2 , R 9 , A, n, the carbon-carbon bond in the side-chain, the carbon-carbon bond between the 3- 4-positions in the carbostyril skeleton, and the substituted position of the side-chain are the same as defined in claim 1(b)..]. 
     
     
       4. The carbostyril derivative according to claim .[.2.]. .Iadd.1.Iaddend., wherein n is 0. 
     
     
       5. The carbostyril derivative according to claim .[.2.]. .Iadd.1.Iaddend., wherein n is 1. .[.6. The carbostyril derivative according to claim 4, 
     
     
        wherein R o  is a hydrogen atom..]. .[.7.  The carbostyril derivative according to claim 4, wherein R 0  is a phenylsulfonyl group or said phenylsulfonyl group having lower alkyl group or halogen atom 
     
     
        substituents..]. 8. The carbostyril derivative according to claim .[.6.]. .Iadd.1.Iaddend., wherein R 3  is a hydroxyl group. .[.9. The carbostyril derivative according to claim 6, wherein R 3  is a lower alkoxy group, a lower alkoxycarbonyl-lower alkoxy group, a benzoyl-lower 
     
     
        alkoxy group or a lower alkanoloxy-lower alkoxy group..]. 10. The carbostyril derivative according to claim .[.6.]. .Iadd.1.Iaddend., wherein R 3  is an amino group. .[.11. The carbostyril derivative 
     
     
        according to claim 8, 9 or 10, wherein R 4  is a hydrogen atom..]. 12. The carbostyril derivative according to claim 8.[., 9.]. or 10, wherein R 4  is .[.a lower alkyl group, a phenyl-lower alkyl group, said phenyl-lower alkyl group having halogen atom substituents on the phenyl ring,.]. a phenylsulfonyl group or said phenylsulfonyl group having 
     
     
        lower alkyl group or halogen atom substituents. 13. The carbostyril derivative according to claim 8, wherein R 4  is a group of the formula --COR 5 . .[.14. The carbostyril derivative according to claim 9, 
     
     
        wherein R 4  is a group of the formula --COR 5 ..]. 15. The carbostyril derivative according to claim 10, wherein R 4  is a group 
     
     
        of the formula --COR 5 . 16. The carbostyril derivative according to claim 13 .[.or 14.]., wherein R 5  is a phenyl group or said phenyl group having 1 to 3 halogen atom, lower alkyl group, lower alkoxy group, nitro group, amino group or hydroxyl group substituents on the phenyl 
     
     
        ring. 17. The carbostyril derivative according to claim 16, wherein R 5  is a phenyl group having 1 to 3 halogen atom substituents on the 
     
     
        phenyl ring. 18. The carbostyril derivative according to claim 13 .[.or 14.]., wherein R 5  is a cycloalkyl group or said cycloalkyl group having an amino-lower alkyl group or a phenyl-lower alkoxycarbonylamino-lower alkyl group substituent on the cycloalkyl ring. .[.19. The carbostyril derivative according to claim 13 or 14, wherein R 5  is a lower alkyl group or said lower alkyl group having an amino 
     
     
        group or a phenyl-lower alkoxycarbonylamino group substituent..]. 20. The carbostyril derivative according to claim 16, wherein R 2  is a 
     
     
        hydrogen atom. 21. The carbostyril derivative according to claim 16, wherein R 2  is a hydroxyl group.[., a lower alkyl group, a benzoyloxy group, said benzoyloxy group having halogen atom substituents, a halogen 
     
     
        atom.]. or a lower alkoxy group. 22. The carbostyril derivative according to claim 20, wherein R 1  is a hydrogen atom or a lower alkyl group. 
     
     
            The carbostyril derivative according to claim 20, wherein R 1  is a lower alkenyl group, a lower alkynyl group or a phenyl-lower alkyl group. 
     
     
         4. The carbostyril derivative according to claim 21, wherein the substituted position of the side-chain of the formula ##STR580## 
     
     
        is the 3- or 4-position in the carbostyril skeleton. 25. The carbostyril derivative according to claim 22, wherein the substituted position of the side-chain of the formula ##STR581## 
     
     
        is the 3- or 4-position in the carbostyril skeleton. 26. The carbostyril derivative according to claim 22, wherein the substituted position of the side-chain of the formula ##STR582## 
     
     
        is the 5-, 6-.[., 7-.]. or 8-position in the carbostyril skeleton. 27. The carbostyril derivative according to claim 23, wherein the substituted position of the side-chain of the formula ##STR583## 
     
     
        is the 3- or 4-position in the carbostyril skeleton. 28. The carbostyril derivative according to claim 24, wherein the carbon-carbon bond of --CH C< in the side-chain of the formula ##STR584## 
     
     
        is a single bond. 29. The carbostyril derivative according to claim 25, wherein the carbon-carbon bond of --CH  C< in the side-chain of the formula ##STR585## 
     
     
        is a single bond. 30. The carbostyril derivative according to claim 27, wherein the carbon-carbon bond of --CH  C< in the side-chain of the formula ##STR586## 
     
     
        is a single bond. 31. The carbostyril derivative according to claim 25, wherein the carbon-carbon bond of --CH  C< in the side-chain of the formula ##STR587## 
     
     
        is a double bond. 32. The carbostyril derivative according to claim 29, wherein the carbon-carbon bond between the 3- and 4-positions in the 
     
     
        carbostyril skeleton is a double bond. 33. The carbostyril derivative according to claim 30, wherein the carbon-carbon bond between the 3- and 
     
     
        4-positions in the carbostyril skeleton is a double bond. 34. The carbostyril derivative according to claim 29, wherein the carbon-carbon bond between the 3- and 4-positions in the carbostyril skeleton is a 
     
     
        single bond. 35. The carbostyril derivative according to claim 30, wherein the carbon-carbon bond between the 3- and 4-positions in the carbostyril 
     
     
        skeleton is a single bond. 36. The carbostyril derivative according to claim 17, wherein R 2  is a hydrogen atom, R 1  is a hydrogen atom or a lower alkyl group, and the substituted position of the side-chain of the formula ##STR588## 
     
     
        is the 3- or 4-position in the carbostyril skeleton. 37. The carbostyril derivative according to claim 35, wherein the carbon-carbon bond of --CH C< in the side-chain of the formula ##STR589## is a single bond, and the carbon-carbon bond between the 3- and 
     
     
        4-positions in the carbostyril skeleton is a double bond. 38. The carbostyril derivative according to claim 35, wherein the carbon-carbon bond of --CH  C< in the side-chain of the formula ##STR590## is a single bond, and the carbon-carbon bond between the 3- and 
     
     
        4-positions in the carbostyril skeleton is also a single bond. 
     
     
        39. 2-(4-Chlorobenzolyamino)-3-(2-quinolon-4-yl)propionic acid. 40. 2-(4-Chlorobenzolyamino)-3-(1-methyl-2-quinolon-3-yl)propionic acid. 
     
     
          . 2-(4-Chlorobenzoylamino)-3-(1-ethyl-2-quinolon-4-yl)propionic acid. 
     
     
            2-Benzolyamino-3-(1-ethyl-2-quinolon-4-yl)propionic acid. 43. A pharmaceutical composition for use in an anti-peptic ulcer agent, which contains the carbostyril derivative as claimed in claim 1(a) as the active 
     
     
        ingredient. 44. The carbostyril derivative according to claim 17 or 36, wherein R 5  is a phenyl group having a halogen atom as the substituent 
     
     
        on the phenyl ring. 45. The carbostyril derivative according to claim 44, wherein the substituted position of the halogen atom is the 2-position in 
     
     
        the phenyl ring. 46. The carbostyril derivative according to claim 44, wherein the substituted position of the halogen atom is the 3-position in 
     
     
        the phenyl ring. 47. The carbostyril derivative according to claim 44, wherein the substituted position of the halogen atom is the 4-position in the phenyl ring.