Pharmaceutically useful carbostyril derivatives

• US 4,734,416 A
• Filed: 03/28/1979
• Issued: 03/29/1988
• Est. Priority Date: 03/30/1978
• Status: Expired due to Term

• Current Assignee: Otsuka Pharmaceutical Company Limited (Otsuka Holdings Company Limited)
• Original Assignee: Otsuka Pharmaceutical Company Limited (Otsuka Holdings Company Limited)
• Inventors: Fujioka, Takafuni, Nakagawa, Kazuyuki, Oshiro, Yasuo, Banno, Kazuo
• Primary Examiner(s): TURNIPSEED, JAMES
• Assistant Examiner(s): Rivers, Diana G.
• Application Number:
  US06/024,602
• Time in Patent Office: 3,289 Days
• Field of Search: 544/363, 424/250, 514/253
• US Class Current: 514/253.07
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 215/16 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 215/22 attached in position 2 or 4
• CPC Class Codes: C07D 215/227 only one oxygen atom which is attached in position 2
• CPC Class Codes: C07D 215/28 with halogen atoms or nitro radicals in positions 5, 6 or 7

Abstract

Carbostyril derivatives having antihistamic action and central nervous controlling action are useful as antihistamic agents or central nervous controlling agents. The derivatives are represented by the general formula, ##STR1## wherein R¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms or a phenylalkyl group having an alkylene group containing 1 to 4 carbon atoms; R² is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a phenyl group; R³ is a hydrogen atom, a hydroxy group, an alkyl group having 1 to 4 carbon atoms, an alkanolyoxy group having 1 to 4 carbon atoms or a 3,4,5-trimethoxybenzoyloxy group; R⁴ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R⁵ is a cycloalkyl group having 3 to 8 carbon atoms, a phenyl group (which may have 1 to 3 substituted groups selected from the group consisting of halogen atoms, alkyl groups having 1 to 4 carbon atoms and alkoxy groups having 1 to 4 carbon atoms), an alkyl group having 1 to 4 carbon atoms (having one substituted group such as a hydroxy group, a phenyl group or an alkanoyloxy group having 1 to 4 carbon atoms), an alkanoyl group having 1 to 4 carbon atoms or benzoyl group; X is a halogen atom; n is 0, or an integer of 1 or 2; Q is an integer of 2 or 3, l and m are respectively an integer of 0 or 1-6, but the sum of l and m should not exceed 6; the carbon-carbon bond at the 3- and 4-positions in the carbostyril skeleton is a single or double bond; and the substituted position of the side chain of ##STR2## is any one of the 4-, 5-, 6-, 7- or 8-positions.

Claims

1. A carbostyril derivative represented by the formula, ##STR25## wherein R¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon alkynyl group having 2 to 4 carbon atoms or a phenyl alkyl group having an alkylene group having 1 to 4 carbon atoms;

R² is a hydrogen atom;

R³ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;

R⁴ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms;

R⁵ is a phenyl group which may be substituted by 1 to 3 identical or different groups selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms;

X is a halogen atom;

n is 0 or an integer of 1 or 2;

Q is an integer of 2;

l and m are respectively 0 or an integer of 1 to 6, but the sum of l and m should not exceed 6;

the carbon-carbon bond at the 3- and 4-positions in the carbostyril skeleton in a single or double bond;

the substituted position of the side chain of ##STR26## is any one of the 4-, 5-, 6-, 7- or 8-positions;

or an acid addition salt thereof, with the proviso that when said side chain is substituted at the 4-position and said carbon-carbon bond at the 3- or 4-positions is a double bond, then R² does not exist.

2. A carbostyril derivative or an acid addition salt thereof according to claim 1, wherein the substituted position of the side chain represented by the formula, ##STR27## is 5- or 7-position in the carbostyril skeleton.

3. A carbostyril derivative or an acid addition salt thereof according to claim 1, wherein the substituted position of the side chain represented by the formula, ##STR28## is 4-, 6- or 8-position in the carbostyril skeleton.

4. A carbostyril derivative or an acid addition salt thereof according to claim 2, wherein the substituted position of the side chain represented by the formula, ##STR29## is 5-position in the carbostyril skeleton.

5. A carbostyril derivative or an acid addition salt thereof according to claim 2, wherein the substituted position of the side chain represented by the formula, ##STR30## is 7-position in the carbostyril skeleton.

21. A central nervous controlling agent, containing a suitable amount of a carbostyril derivative or acid addition salt thereof according to claim 1 as an active ingredient and a pharmaceutically acceptable carrier.

22. A carbostyril derivative or an acid addition salt thereof according to claim 1 or 2, wherein R¹ is a hydrogen atom.

23. A carbostyril derivative or an acid addition salt thereof according to claim 1, wherein R¹ is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms or a phenyl alkyl group having an alkylene group having 1 to 4 carbon atoms.

24. A carbostyril derivative or an acid addition salt thereof according to claim 1 or 2, wherein R¹ is a hydrogen atom and n is 0.

25. A carbostyril derivative or a salt thereof as claimed in claim 1, wherein the carbon-carbon bond at the 3- and 4-positions in the carbostyril skeleton is a single bond, the substituted position of the side chain of ##STR31## is the 6-position, l and m are each 1, R⁴ is hydrogen, n is 0, R¹ denotes a hydrogen atom or a C₁ -C₆ alkyl group, R⁵ denotes a phenyl group having one to three, identical or different substituents selected from the group consisting of a C₁ -C₄ -alkyl group, a C₁ -C₄ -alkoxy group and a halogen atom and R³ denotes a hydrogen atom.

26. A carbostyril derivative or a salt thereof as claimed in claim 25, wherein R⁵ is a phenyl group which is substituted by a group selected from the group consisting of a halogen atom, an alkyl group having 1 to 3 carbon atoms and an alkoxy group having 1 to 3 carbon atoms.

27. A composition having a central nervous controlling effect comprising a compound as defined in claim 26.

28. The method of treating a human patient to produce a central nervous controlling effect which comprises orally administering to said patient a dosage of about 40 ug to 2 mg/kg day of a compound as defined in claim 26.

29. The method of treating a human patient to produce a central nervous controlling effect which comprises intravenously administering to said patient a dosage of about 40 ug to 2 mg/kg day of a compound as defined in claim 26.

30. The compound of claim 1 wherein R⁵ is a phenyl group substituted by two halogen atoms.

32. A carbostyril derivative in accordance with claim 1 consisting of:

7-{3-[4-(3-Fluorophenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril.

34. A carbostyril derivative or a salt thereof as claimed in claim 1, wherein R¹ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;

R³ is a hydrogen atom;

R⁴ is a hydrogen atom;

R⁵ is a phenyl group which may be substituted by a group selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, and an alkoxy group having 1 to 4 carbon atoms;

n is 0;

l and m are respectively 0 or an integer, wherein the sum of l and m is from 1 to 4;

the carbon-carbon bond at the 3- and 4-positions in the carbostyril skeleton is a double bond; and

the substituted position of the side chain of ##STR33## is any one of the 5-, 6-, 7- or 8-positions.

35. A compound or salt thereof according to claim 34 in which R¹ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms;

R² is a hydrogen atom; and

R⁵ is a phenyl group which may be substituted by a group selected from the group consisting of a chlorine atom, an alkyl group having 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms.

40. A composition having an antihistaminic and a central nervous controlling effect comprising an effective amount of a compound or salt as defined in claim 34.

41. A method of treating a patient to produce a central nervous controlling effect or an antihistaminic effect comprising the step of administering to said patient an effective amount of a compound or salt according to claim 34.

74. The method of treating a human patient to produce a central nervous controlling effect which comprises administering to said patient an effective dosage of a compound or salt thereof as defined in claim 26.

75. The method of treating a human patient to produce a central nervous controlling effect which comprises orally administering to said patient an effective dosage of a compound or salt thereof as defined in claim 26.

76. The method of treating a human patient to produce a central nervous controlling effect which comprises intravenously administering to said patient an effective dosage of a compound or salt thereof as defined in claim 26.

77. A composition having an antihistaminic and a central nervous controlling effect comprising an effective amount of a compound or salt as defined in claim 26.

78. A method of treating a patient to produce a central nervous controlling effect or an antihistaminic effect comprising the step of administering to said patient an effective amount of a compound or salt according to claim 26.

94. The compound of claim 1, wherein R¹, R², R³ and R⁴ are hydrogen atoms;

l and m are each 1;

Q is 2;

R⁵ is a phenyl group containing 1 to 3 identical or different substituents selected from an alkyl group having 1 to 4 carbon atoms; and

the side chain on the carbostyril skeleton is in the 7-position.

95. The compound of claim 94, wherein the R⁵ substituted phenyl group contains two methyl groups as the substituents.

96. The compound of claim 94, wherein the R⁵ substituted phenyl group contains one methyl group as the substituent.

97. The compound of claim 95, wherein n is 0.

98. The compound of claim 96, wherein n is 0.

99. An acid-addition salt of the compound of claim 94.

100. The compound of claim 1, wherein R¹, R², R³ and R⁴ are hydrogen atoms;

l and m are each 1;

n is 0;

Q is 2;

R⁵ is a phenyl group containing one halogen atom;

the side chain on the carbostyril skeleton is in the 7-position; and

there is a single bond between the 3- and 4-positions in the carbostyril skeleton.

101. The compound of claim 100, wherein the R⁵ halogen substituent is a chlorine atom.

102. The compound of claim 100, wherein the R⁵ halogen substituent is a fluorine atom.

103. The compound of claim 1, wherein R¹, R², R³ and R⁴ are hydrogen;

l and m are each 1;

n is 0;

Q is 2;

R⁵ is a phenyl group containing 1 to 3 identical or different substituents selected from the group consisting of a halogen atom and an alkyl group having 1 to 4 carbon atoms;

the side chain on the carbostyril skeleton is in the 7-position and there is a single bond between the 3- and 4-positions in the carbostyril skeleton.

104. The compound of claim 103, wherein the R⁵ substituted phenyl group is 4-chloro-3-methylphenyl group.

105. The compound of claim 1, wherein R¹, R², R³ and R⁴ are hydrogen atoms;

l and m are each 1;

Q is 2;

n is 0;

R⁵ is a phenyl group containing 1 to 3 identical or different substituents selected from a halogen atom;

the side chain on the carbostyril skeleton is in the 5-position; and

the carbon-carbon bond between the 3- and 4-positions in the carbostyril skeleton is a single bond.

106. The compound of claim 105, wherein the R⁵ halogen substituent is a fluorine atom.

110. The compound of claim 95, wherein the carbon-carbon bond at the 3- and 4-positions in the carbostyril skeleton is a double bond.

111. A phenylpiperazine compound in accordance with claim 25, wherein said compound is selected from the group consisting of 6-{3-[4-(4-methylphenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril,

6-{3-[4-(4-bromophenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril, and

1-methyl-6-{3-[4-(4-methylphenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril.

6. 7-[3-(4-Phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril.

7. 7-{3-[4-(2-Methoxyphenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril.

8. 7-{3-[4-(3-Chlorophenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril.

9. 7-{3-[4-(2-Fluorophenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril.

10. 7-[3-(4-Phenylpiperazinyl)propoxy]carbostyril.

11. 7-{3-[4-(2-Ethoxyphenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril.

12. 1-Methyl-7-[3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril.

13. 7-[4-(4-Phenylpiperazinyl)butoxy]-3,4-dihydrocarbostyril.

14. 5-[3-(4-Phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril.

15. 6-[3-(4-Phenylpiperazinyl)propoxy]carbostyril.

16. 7-{3-[4-(2-Chlorophenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril.

17. 8-Bromo-5-[3-(4-phenylpiperazinyl)propoxy]carbostyril.

18. 7-{3-[4-(2-Methoxyphenyl)piperazinyl]propoxy}carbostyril.

19. 7-{3-[4-(4-Methylphenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril.

20. 1-Benzyl-5-[3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril.

31. 5-{3-[4-(2-Ethoxyphenyl)piperazinyl]propoxy}3,4-dihydrocarbostyril.

33. A (4-substituted-piperazin-1-yl)alkoxy-2-oxo-1,2-dihydroquinoline of the formula:

##STR32## in which R₁ is a hydrogen atom or an alkyl radical with 1 to 6 carbon atoms, R³ is a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms, R₄ is a hydrogen atom, a halogen atom, or an alkyl or alkoxy radical with 1 to 4 carbon atoms, n is 2, 3, 4 or 5 and A is a valency bond or a methylene radical with the proviso that when A is a methylene radical, R₄ is a hydrogen atom;

or a salt thereof with a pharmacologically acceptable acid.

36. A compound or salt thereof according to claim 33 wherein such compound is ##STR34## in which R³ is a hydrogen atom or a methyl radical,

R⁴ is a hydrogen atom or a chlorine atom, and

A is a valency bond or methylene radical, with the proviso that when A is a methylene radical, R₄ is a hydrogen atom.

37. A compound or salt thereof according to claim 33 wherein such compound is ##STR35## in which R₃ is a hydrogen atom or a methyl radical, and

A is a valency bond.

38. A compound or salt thereof according to claim 33 wherein such compound is:

##STR36## in which R₃ is a hydrogen atom or a methyl radical, and

A is a valency bond or a methylene radical.

39. A compound or salt thereof according to claim 33 wherein such compound is:

##STR37## in which R₃ is a hydrogen atom or a methyl radical, and

A is a valency bond.

79. A (4-substituted-piperazin-1-yl)alkoxy-2-oxo,1,2-dihydroquinoline or a salt thereof as claimed in claim 33, wherein

R₄ is a hydrogen atom, a halogen atom, or an alkyl or alkoxy group having 1 to 3 carbon atoms.

80. A composition having an antihistaminic and a central nervous controlling effect comprising an effective amount of a compound or salt as defined in claim 79.

81. A method of treating a patient to produce a central nervous controlling effect or an antihistaminic effect comprising the step of administering to said patient an effective amount of a compound or salt according to claim 79.

82. A (4-substituted-piperazin-1-yl)alkoxy-2-oxo-1,2-dihydroquinoline or a salt thereof as claimed in claim 33, in which

R₄ is a hydrogen atom, and A is a methylene radical.

83. A compound or salt thereof according to claim 82, in which

R₁ is a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms.

84. A compound or salt thereof according to claim 82, wherein such compound is ##STR56## in which R³ is a hydrogen atom or a methyl radical, and

R⁴ is a hydrogen atom.

85. A compound or salt thereof according to claim 82 wherein such compound is ##STR57## in which R₃ is a hydrogen atom or a methyl radical.

86. A compound or salt thereof according to claim 82 wherein such compound is:

##STR58## in which R₃ is a hydrogen atom or a methyl radical.

87. A compound or salt thereof according to claim 82 wherein such compound is:

##STR59## in which R₃ is a hydrogen atom or a methyl radical.

88. A composition having an antihistaminic and a central nervous controlling effect comprising an effective amount of a compound or salt as defined in claim 82.

89. A method of treating a patient to produce a central nervous controlling effect or an antihistaminic effect comprising the step of administering to said patient an effective amount of a compound or salt according to claim 82.

90. The method according to claim 89, wherein said compound is:

##STR60## in which R₃ is a hydrogen atom or a methyl radical, and

R₄ is a hydrogen atom.

91. A (4-substituted-piperazin-1-yl)alkoxy-2-oxo-1,2-dihydroquinoline or a salt thereof as claimed in claim 33, in which A is a valency bond.

92. A composition having an antihistaminic and a central nervous controlling effect comprising an effective amount of a compound or salt as defined in claim 91.

93. A method of treating a patient to produce a central nervous controlling effect or an antihistaminic effect comprising the step of administering to said patient an effective amount of a compound or salt according to claim 91.

112. A compound in accordance with claim 33, wherein said compound is selected from the group consisting of,

5-[2-(4-phenylpiperazinyl)ethoxy]carbostyril,

7-[2-(4-phenylpiperazinyl)ethoxy]carbostyril,

8-[2-(4-phenylpiperazinyl)ethoxy]carbostyril,

5-[3-(4-phenylpiperazinyl)propoxy]carbostyril,

5-[4-(4-phenylpiperazinyl)propoxy]carbostyril,

7-[4-(4-phenylpiperazinyl)butoxy]carbostyril,

6-[5-(4-phenylpiperazinyl)pentyloxy]carbostyril,

8-[5-(4-phenylpiperazinyl)pentyloxy]carbostyril.

113. A compound in accordance with claim 33, wherein said compound is selected from the group consisting of,

1-methyl-5-[2-(4-phenylpiperazinyl)ethoxy]carbostyril,

1-methyl-6-[3-(4-phenylpiperazinyl)propoxy]carbostyril,

1-methyl-7-[3-(4-phenylpiperazinyl)propoxy]carbostyril,

1-hexyl-6-[3-(4-phenylpiperazinyl)propoxy]carbostyril,

1-methyl-5-{3-[4-(4-chlorophenyl)piperazinyl]propoxy}-carbostyril,

1-methyl-6-{3-[4-(4-methylphenyl)piperazinyl]propoxy}-carbostyril, and

1-methyl-7-{3-[4-(4-methoxyphenyl)piperazinyl]propoxy}-carbostyril.

114. A compound or salt thereof in accordance with claim 33, wherein said compound or salt is selected from the group consisting of,

5-{3-[4-(2-methoxyphenyl)piperazinyl]propoxy}carbostyril,

5-{3-[4-(3-methylphenyl)piperazinyl]propoxy}carbostyril,

6-{3-[4-(4-methylphenyl)piperazinyl]propoxy}carbostyril,

7-{2-[4-(4-propylphenyl)piperazinyl]ethoxy}carbostyril,

5-{3-[4-(4-chlorophenyl)piperazinyl]propoxy}carbostyril,

6-{3-[4-(4-bromophenyl)piperazinyl]propoxy}carbostyril,

7-{2-[4-(2-chlorophenyl)piperazinyl]ethoxy}carbostyril,

6-{3-[4-(2-methoxyphenyl)piperazinyl]propoxy}carbostyril.dihydrochloride,

8-{3-[4-(2-methoxyphenyl)piperazinyl]propoxy}carbostyril.dihydrochloride, and

7-{3-[4-(3-chlorophenyl)piperazinyl]propoxy}carbostyril.

42. A carbostyril derivative represented by the formula, ##STR38## wherein R¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms or a phenyl alkyl group having an alkylene group having 1 to 4 carbon atoms;

R² is an alkyl group having 1 to 4 carbon atoms or a phenyl group;

R³ is a hydrogen atom, a hydroxy group, an alkyl group having 1 to 4 carbon atoms, an alkanoyloxy group having 1 to 4 carbon atoms or a 3,4,5-trimethoxybenzoyloxy group;

R⁴ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms;

R⁵ is a phenyl group which may be substituted by 1 to 3 identical or different groups selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms;

X is a halogen atom;

n is 0 or an integer of 1 to 2;

Q is an integer of 2, l and m are respectively 0 or an integer of 1 to 6, but the sum of l and m should not exceed 6;

the carbon-carbon bond at the 3- and 4-positions in the carbostyril skeleton is a single or double bond;

the substituted position of the side chain of ##STR39## is any one of the 5-, 6-, 7- or 8-positions;

or an acid addition salt thereof.

43. A carbostyril derivative or an acid addition salt thereof according to claim 42, wherein R³ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

44. A carbostyril derivative or an acid addition salt thereof according to claim 42, wherein R³ is a hydroxy group, an alkanoyloxy group having 1 to 4 carbon atoms or a 3,4,5-trimethoxybenzoyloxy group.

45. A carbostyril derivative or an acid addition salt thereof according to claim 43, wherein the substituted position of the side chain represented by the formula, ##STR40## is 5- or 7-position in the carbostyril skeleton.

46. A carbostyril derivative or an acid addition salt thereof according to claim 43, wherein the substituted position of the side chain represented by the formula, ##STR41## is 6- or 8-position in the carbostyril skeleton.

47. A carbostyril derivative or an acid addition salt thereof according to claim 45, wherein the substituted position of the side chain represented by the formula, ##STR42## is 5-position in the carbostyril skeleton.

48. A carbostyril derivative or an acid addition salt thereof according to claim 45, wherein the substituted position of the side chain represented by the formula, ##STR43## is 7-position in the carbostyril skeleton.

49. A pharmaceutical composition useful as an antihistaminic agent, containing a suitable amount of carbostyril derivative or an acid addition salt thereof according to claim 42 as an active ingredient and a pharmaceutically acceptable carrier.

115. A carbostyril derivative in accordance with claim 42, wherein said compound is selected from the group consisting of,

4-methyl-7-[3-(4-phenylpiperazinyl)propoxy]-3,4-dihydro-carbostyril

4-phenyl-7-[3-(4-phenylpiperazinyl)propoxy]carbostyril,

4-phenyl-7-[3-(4-phenylpiperazinyl)propoxy]-3,4-dihydro-carbostyril,

4-phenyl-7-{3-[4-(2-methoxyphenyl)piperazinyl]propoxy}-carbostyril, and

4-methyl-7-[3-(4-phenylpiperazinyl)propoxy]carbostyril.

50. A method for producing an antihistaminic effect in a mammal comprising the step of administering to the mammal for producing said antihistaminic effect a pharmaceutical composition containing a suitable amount of a carbostyril derivative represented by the formula, ##STR44## wherein R¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms or a phenyl alkyl group having an alkylene group having 1 to 4 carbon atoms;

R² is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a phenyl group;

R³ is a hydrogen atom, a hydroxy group, an alkyl group having 1 to 4 carbon atoms, an alkanoyloxy group having 1 to 4 carbon atoms or a 3,4,5-trimethoxybenzoyloxy group;

R⁴ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms;

R⁵ is a cycloalkyl group having 3 to 8 carbon atoms, a phenyl group which may be substituted by 1 to 3 identical or different groups selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms, a substituted alkyl group having 1 to 4 carbon atoms, having one hydroxy group, phenyl group or alkanoyloxy group having 1 to 4 carbon atoms as the substituent, an alkanoyl group having 1 to 4 carbon atoms or a benzoyl group;

X is a halogen atom;

n is 0 or an integer of 1 or 2;

Q is an integer of 2;

l and m are respectively 0 or an integer of 1 to 6, but the sum of l and m should not exceed 6;

the carbon-carbon bond at the 3- and 4-positions in the carbostyril skeleton is a single or double bond;

the substituted position of the side chain of ##STR45## is any one of the 4-, 5-, 6-, 7-, or 8-positions;

or an acid addition salt thereof, with the proviso that when said side chain is substituted at the 4-position and said carbon-carbon bond at the 3- and 4-positions is a double bond, then R² does not exist.

51. The method of claim 50, wherein R³ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

52. The method of claim 50, wherein R³ is a hydroxy group, an alkanoyloxy group having 1 to 4 carbon atoms or a 3,4,5-trimethoxybenzoyloxy group.

53. The method of claim 51, wherein R⁵ is a phenyl group which may be substituted by 1 to 3 identical or different groups selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms.

54. The method of claim 51, wherein R⁵ is a substituted alkyl group having 1 to 4 carbon atoms, having one phenyl group as the substituent.

55. The method of claim 51, wherein R⁵ is a cycloalkyl group having 3 to 8 carbon atoms;

a substituted alkyl group having 1 to 4 carbon atoms having one hydroxy group or alkanoyloxy group having 1 to 4 carbon atoms as the substituent;

an alkanoyl group having 1 to 4 carbon atoms or a benzoyl group.

56. The method of claim 52, wherein R⁵ is a phenyl group which may be substituted by 1 to 3 identical or different groups selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms.

57. The method of claim 52, wherein R⁵ is a cycloalkyl group having 3 to 8 carbon atoms;

a substituted alkyl group having 1 to 4 carbon atoms having one hydroxy group, phenyl group or alkanoyloxy group having 1 to 4 carbon atoms as the substituent;

an alkanoyl group having 1 to 4 carbon atoms or a benzoyl group.

58. The method of claim 53, wherein the substituted position of the side chain represented by the formula, ##STR46## is 5- or 7-position in the carbostyril skeleton.

59. The method of claim 53, wherein the substituted position of the side chain represented by the formula, ##STR47## is 4-, 6- or 8-position in the carbostyril skeleton.

60. The method of claim 58, wherein the substituted position of the side chain represented by the formula, ##STR48## is 5-position in the carbostyril skeleton.

61. The method of claim 58, wherein the substituted position of the side chain represented by the formula, ##STR49## is 7-position in the carbostyril skeleton.

116. The method of claim 50, wherein the carbostyril derivative is selected from the group consisting of:

7-[3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostryril,

7-[3-(4-phenylpiperazinyl)propoxy]carbostyril,

1-Methyl-7-[3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril,

7-[4-(4-phenylpiperazinyl)butoxy]-3,4-dihydrocarbostyril,

5-[3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril,

6-[3-(4-phenylpiperazinyl)propoxy]carbostyril,

8-bromo-5-[3-(4-phenylpiperazinyl]propoxy]carbostyril,

7-[3-(4-benzylpiperazinyl)propoxy]-3,4-dihydrocarbostyril, and

1-benzyl-5-[3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril.

117. The method of claim 50, wherein the carbostyril derivative is selected from the group consisting of:

7-{3-[4-(2-methoxyphenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril,

7-{3-[4-(3-chlorophenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril,

7-{3-[4-(2-fluorophenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril,

7-{3-[4-(2-ethyoxyphenyl)piperazinyl]propoxy}-3,4-hydrocarbostyril,

7-{3-[4-(2-chlorophenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril,

7-{3-[4-(2-methoxyphenyl)piperazinyl]propoxy}carbostyril and

7-{3-[4-(4-methylphenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril.

118. The method of claim 50, wherein the carbostyril derivative is selected from the group consisting of:

7-[2-hydroxy-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril, and

1-benzyl-5-[2-hydroxy-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril.

62. A carbostyril derivative represented by the formula, ##STR50## wherein R¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms or a phenyl alkyl group having an alkylene group having 1 to 4 carbon atoms;

R² is a hydrogen atom, a C₁ -C₄ alkyl group;

R³ is a hydrogen atom, a hydroxy group, an alkyl group having 1 to 4 carbon atoms, an alkanoyloxy group having 1 to 4 carbon atoms or a 3,4,5-trimethoxybenzoyloxy group;

R⁴ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms;

R⁵ is a cycloalkyl group having 3 to 8 carbon atoms, a substituted alkyl group having 1 to 4 carbon atoms, having one phenyl group as the substituent, an alkanoyl group having 1 to 4 carbon atoms or a benzoyl group;

X is a halogen atom;

n is 0 or an integer of 1 or 2;

Q is an integer of 2;

l and m are respectively 0 or an integer of 1 to 6, but the sum of l and m should not exceed 6;

the carbon-carbon bond at the 3- and 4-positions in the carbostyril skeleton is a single or double bond;

the substituted position of the side chain of ##STR51## is any one of the 4-, 5-, 6-, 7-, or 8-positions;

or an acid addition salt thereof, with the proviso that when said side chain is substituted at the 4-position and said carbon-carbon bond at the 3- and 4-positions is a double bond, then R² does not exist.

63. A carbostyril derivative or an acid addition salt thereof according to claim 62, wherein R³ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

64. A carbostyril derivative or an acid addition salt thereof according to claim 62, wherein R³ is a hydroxy group, an alkanoyloxy group having 1 to 4 carbon atoms or a 3,4,5-trimethoxybenzoyloxy group.

65. A carbostyril derivative or an acid addition salt thereof according to claim 63, wherein the substituted position of the side chain represented by the formula, ##STR52## is 5- or 7-position in the carbostyril skeleton.

66. A carbostyril derivative or an acid addition salt thereof according to claim 63, wherein the substituted position of the side chain represented by the formula, ##STR53## is 4-, 6- or 8-position in the carbostyril skeleton.

67. A carbostyril derivative or an acid addition salt thereof according to claim 63, wherein the substituted position of the side chain represented by the formula, ##STR54## is 5-position in the carbostyril skeleton.

68. A carbostyril derivative or an acid addition salt thereof according to claim 63, wherein the substituted position of the side chain represented by the formula, ##STR55## is 7-position in the carbostyril skeleton.

69. A pharmaceutical composition usable as an antihistaminic agent, containing a suitable amount of the carbostyril derivative or acid addition salt thereof of claim 62 as an active ingredient and a pharmaceutically acceptable carrier.

70. 7-[3-(4-Benzylpiperazinyl)propoxy]-3,4-dihydrocarbostyril.

71. 7-[3-(4-Cyclohexylpiperazinyl)propoxy]-3,4-dihydrocarbostyril.

72. 5-[3-(4-Benzylpiperazinyl)propoxy]-3,4-dihydrocarbostyril.

73. 5-[3-(4-Benzoylpiperazinyl)propoxy]-3,4-dihydrocarbostyril.

107. 7-{3-[4-(4-Chlorophenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril.

108. 7-{3-[4-(3,4-Dimethylphenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril.

109. 5-{3-[4-(2-Fluorophenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril.