US RE34,722 EGranted

Quinoline amino acid derivatives of carbostyril compounds

AssigneeOtsuka Pharmaceutical Co., Ltd.

InventorsMinoru Uchida, Makoto Komastu, Kazuyuki Nakagawa

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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.

Claims11

Dependent claims

(a) A carbostyril derivative or a pharmaceutically acceptable salt thereof represented by the formula ##STR574## wherein:

R.sup.1 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a phenyl-lower alkyl group;
R.sup.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.sup.3 is a hydroxyl group, an amino group, said amino group having a cycloalkyl-lower alkyl group substituent, or 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.sup.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.sup.5 wherein R.sup.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, and 2-ethylfuryl[, 2-methylthianyl, 4-methylthianyl and 4-methylthianyl] groups;
R.sup.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 bond, wherein the dashed bond becomes two hydrogen atoms when the carbon-carbon bond is a single 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.sup.1 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or phenyl-lower alkyl group;
R.sup.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.sup.9 is a group of the formula ##STR577## wherein R.sup.4 and R.sup.6 are lower alkyl groups and R.sup.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).sub.n --CH.sub.2 --R.sup.9 is any one of the 3-, 4-, 5-, 6-, 7-, or 8-positions in the carbostyril skeleton;
provided that when R.sup.2 is a hydrogen atom and n is 1, and R.sup.9 is a halogen atom, then the substitution position of the side chain of the formula --(A).sub.n --CH.sub.2 --R.sup.9 is the 3- or 4-position in the carbostyril skeleton]. [

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[19. The carbostyril derivative according to claim 13 or 14, wherein R.sup.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.sup.2 is a
hydrogen atom. 21. The carbostyril derivative according to claim 16, wherein R.sup.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.sup.1 is a hydrogen atom or a lower alkyl group.
The carbostyril derivative according to claim 20, wherein R.sup.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.sup.2 is a hydrogen atom, R.sup.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.sup.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.

30 more elements

Dependencies are inferred from the claim text.

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Abstract

(a) A carbostyril derivative or a pharmaceutically acceptable salt thereof represented by the formula ##STR574## wherein:

R.sup.1 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a phenyl-lower alkyl group;
R.sup.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.sup.3 is a hydroxyl group, an amino group, said amino group having a cycloalkyl-lower alkyl group substituent, or 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.sup.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.sup.5 wherein R.sup.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, and 2-ethylfuryl[, 2-methylthianyl, 4-methylthianyl and 4-methylthianyl] groups;
R.sup.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 bond, wherein the dashed bond becomes two hydrogen atoms when the carbon-carbon bond is a single 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.sup.1 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or phenyl-lower alkyl group;
R.sup.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.sup.9 is a group of the formula ##STR577## wherein R.sup.4 and R.sup.6 are lower alkyl groups and R.sup.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).sub.n --CH.sub.2 --R.sup.9 is any one of the 3-, 4-, 5-, 6-, 7-, or 8-positions in the carbostyril skeleton;
provided that when R.sup.2 is a hydrogen atom and n is 1, and R.sup.9 is a halogen atom, then the substitution position of the side chain of the formula --(A).sub.n --CH.sub.2 --R.sup.9 is the 3- or 4-position in the carbostyril skeleton]. [

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