AT376973B - METHOD FOR PRODUCING NEW CARBOSTYRILE DERIVATIVES AND ACID ADDITIONAL SALTS AND QUATERNAUS SALTS HIEVON AND THEIR OPTICAL ISOMERS - Google Patents

Description

  

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   The invention relates to a process for the preparation of new carbostyril derivatives of the general formula
 EMI1.1
 in which R 'represents a hydrogen atom, a lower alkenyl group, a lower alkynyl group or a lower alkyl group which may have one or more phenyl groups as substituents, R2 represents a hydrogen atom, a lower alkyl group or a phenyl group, R3 represents a lower alkyl group , which has one or more phenyl groups as substituents, or a phenyl group which may have 1 to 3 substituents from the group consisting of halogen atoms, lower alkyl groups and lower alkoxy groups, R "represents a hydrogen atom, a hydroxyl group or a lower alkanoyl group, X represents represents a halogen atom, Y represents a lower alkylene group,

   which may have one or more hydroxyl groups as substituents, n has the value 0, 1 or 2, the carbon-carbon bond between the 3 and 4 positions in the carbostyril skeleton is a single or double bond, with the proviso that when R3 is a lower alkyl group with one or more phenyl groups as substituents, then R '* represents neither a hydroxyl group nor a lower alkanoyl group, and pharmaceutically acceptable acid addition salts and quaternary salts thereof and their optical isomers.



   Extensive animal studies have shown that the carbostyril derivatives which can be prepared according to the invention have excellent antihistamine effects with fewer side effects, e.g. B. a CNS control effect or an ss-adrenergic nerve blocking effect.



   In various medical and pharmaceutical publications, e.g. B. Goodman-Gilman's "YAKURI SHO" (Textbook of Pharmacology) (first volume) - "YAKUBUTSU CHIRYO NO KISO TO RINSHO" (Fundamental and Clinic of Pharmacotherapy), pages 781-835 (published by Hirokawa Shoten Co.
 EMI1.2
 
YAKURI-GAKU "nic), volume 20, No. 11, pages 129-133 [1971], and" KISO TO RINSHO "(Laboratory and Clinic), volume 10, No. 10, pages 17-27 [1976] described that in general the antihistamines
Isolation of a combined type histamine formed in allergies by the antigen-antibody reaction does not inhibit, but inhibits the combination (a competitive antagonism) of an active type histamine with a histamine acceptor to produce an antihistamine effect.

   The antihistaminic agents containing compounds which can be prepared according to the invention are therefore suitable as treatment agents and prophylactic agents for various allergic diseases and symptoms which are brought about by the combination of histamine and histamine acceptor. Examples of these are allergic symptoms in the respiratory tract, e.g. B. sneezing, runny nose, stinging of the eyes, nose and throat, hay fever, pollinosis, acute urticaria (itching, edema, inflammation and the like), vascular edema, pruritus, atopic dermatitis, insect bites, contact dermatitis, e.g. B. "urushi kabure" (ivy poisoning), urticaria and edema disorders in serum diseases, allergic rhinitis, allergic conjunctivitis or corneitis.

   Furthermore, the antihistamines according to the invention can also be used as supplements for the treatment of systematic anaphylaxis, in which autacoids other than histamine can play an important role. Furthermore, the carbostyril derivatives which can be prepared according to the invention can also be used as diagnostics for measuring the activity of the gastric acid deposition, in particular the effect of the gastric acidity.

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   Some carbostyril derivatives with usable pharmacological effects, e.g. B. anti-inflammatory effects, inhibitory effects on platelet aggregation, CNS control effect and ss-adrenergic nerve blocking effect are known in the literature, for. B. from the US-PS
No. 3, 994, 900, No. 4, 147, 869, DE-OS 2302027 and 2711719, and JP-AS 106977/1975 and
142576/1975. However, these references do not describe that these carbostyril derivatives have antihistaminic effects.



   On the other hand, other carbostyril derivatives with antihistamine effects are known from other publications, e.g. B. from DE-OS 2912105 and JP-AS 16478 / 1979,2693 / 1980,
89221 / 1980.89222 / 1980. However, these known carbostyril derivatives with antihistamine effects differ from the carbostyril derivatives according to the invention with regard to the type and the substituted positions of the substituted groups.



   Furthermore, the carbostyril derivatives which can be prepared according to the invention have selective antihistamine effects, but lower CNS control effects and ss-adrenergic nerve blocking effects in comparison to the known carbostyril derivatives.



   Specific examples of groups R ', R, R ", R", X and Y of the general formula (I) are given below.



   The term "lower alkenyl group" means a straight-chain or branched alkenyl group with 2 to 6 carbon atoms. Examples of these are the vinyl group, allyl group,
2-butenyl group, 1-methyl-2-butenyl group, 2-pentenyl group, 2-hexenyl group and the like. the like



   The term "lower alkynyl group" means a straight-chain or branched alkynyl group with 2 to 6 carbon atoms. Examples include the ethynyl group, propargyl group,
2-butynyl group, 1-methyl-2-propargyl group, 2-pentynyl group, 2-hexynyl group and the like. the like



   The term "lower alkyl group, which may have one or more phenyl groups as substituents" means a straight-chain or branched alkyl group having 1 to 6 carbon atoms, which may have one or more phenyl groups as substituents. Examples of this are
Methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert. Butyl group, pentyl group, hexyl group, benzyl group, 1-phenylethyl group, 2-phenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group, 1, 1-dimethyl-2-phenylethyl group, 5-phenylpentyl group, 6-phenylhexyl group, diphenylmethyl group and the like. the like



   The term "lower alkyl group" means a straight-chain or branched alkyl group having 1 to 6 carbon atoms. Examples of these are the methyl group, ethyl group, propyl group,
Isopropyl group, butyl group, tert. Butyl group, pentyl group, hexyl group and the like. the like



   The term "lower alkyl group with one or more phenyl groups as substituents" means a straight-chain or branched alkyl group with 1 to 6 carbon atoms, which has one or more phenyl groups as substituents. Examples include the benzyl group, 1-phenylethyl group, 2-phenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group, 1, 1-dimethyl-2-phenylethyl group, 5-phenylpentyl group, 6-phenylhexyl group, diphenylmethyl group and the like. the like



   The term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.



   The term "lower alkoxy group" means a straight-chain or branched alkoxy group having 1 to 6 carbon atoms. Examples of these are the methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, tert. Butoxy group, pentyloxy group, hexyloxy group and the like. the like



   The term "lower alkanoyl group" means a straight-chain or branched alkanoyl group having 1 to 6 carbon atoms. Examples include the formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, pentanoyl group, tert. Butylcarbonylgruppe, Hexanoylgruppe u. the like



   The term "lower alkylene group, which may have one or more hydroxyl groups as substituents" means a straight-chain or branched alkylene group having 1 to 6 carbon atoms, which may have one or more hydroxyl groups as substituents, examples of which are the methylene group, ethylene group, trimethylene group, 2- Methyltrimethylene group, 1-methyltrimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, 2-ethylethylene

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 EMI3.1
 

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    2,2-dimethyltrimethylene group, l-benzyl-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril and its 3,4-dehydro compound
 EMI4.1
 dung 7- [6- (4-benzyl-l-piperidyl) hexyloxy] -3, 4-dihydrocarbostyril and its 3,

   4-dehydro compound 1-methyl-5- [3- (4-benzyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro - compound 1-methyl-7- [3- (4-benzyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3, 4-dehydro - compound
 EMI4.2
   [3- (4-benzyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril compound 1-allyl-5- [3- (4-benzyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro- compound 1-allyl-7- [3- (4-benzyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro- compound

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   1- (1-Methylallyl) -7- [3- (4-benzyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound 1-propargyl-7 - [3- ( 4-benzyl-1-piperidyl) propoxy] -3, 4-dihydrocarbostyril and its 3,

   4-dehydro compound 1-propargyl-5- [3- (4-benzyl-1-piperidyl) propoxY] -3, 4-dihydrocarbostyril and its 3,4-dehydro compound 1-benzyl-5- [3- (4-benzyl-1-piperidyl) propoxy] -3, 4-dihydrocarbostyril and its 3,4-dehydro- - compound 1- (4-phenylbutyl) -7- [3- (4-benzyl-1-piperidyl) -propoxy] -3, 4-dihydrocarbostyril and 3,4-dehydro compound 1-benzyl-7- [3- (4-benzyl-1-piperidyl) -propoxy] -3, 4-dihydrocarbostyril and its 3,4- Dehydro- - compound
 EMI5.1
   {3- [4- (2-phenylethyl) -l-piperidyl] propoxy} -3, 4-dihydrocarbostyril3, 4-dehydro compound 6-fluoro-7- [3- (4-benzyl-1-piperidyl) - propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro- - compound 1-benzyl-6-chloro-5- [3- (4-benzyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and his 3,

   4-dehydro compound 1-benzyl-5-chloro-8- [3- (4-benzyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound 1-benzyl-6 -chloro-7- [3- (4-benzyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound 6,8-dichloro-5- [3- (4-benzyl -1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound 6-chloro-8-bromo-7- [3- (4-benzyl-1-piperidyl) propoxy] -3 , 4-dihydrocarbostyril and its 3, 4-dehydro compound
 EMI5.2
 [3- (4-phenyl-1-piperidyl) propoxy] -3, 4-dihydrocarbostyril1-methyl-5- [3- (4-benzyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3rd , 4-Dehydro- - Compound 1-benzyl-7- [3- (4-benzyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3, 4-dehydro- - Compound
 EMI5.3
   3- (4-phenyl-l-piperidyl) propoxy] -3,

   4-dihydrocarbostyril compound 1-methyl-7- [3- (4-benzyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro- compound

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   1-propargyl-7- [3- (4-phenyl-1-piperidyl) propoxy] -3, 4-dihydrocarbostyril and its 3,4-dehydro compound 1-benzyl-6-chloro-5- [3- ( 4-phenyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril and its 3,4-dehydro compound 6,8-dichloro-5- [3- (4-phenyl-l-piperidyl) propoxy] - 3,4-dihydrocarbostyril and its 3,4-dehydro compound 1-benzyl-6,8-dichloro-5- [3- (4-phenyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3rd , 4-dehydro compound l-methyl-6-chloro-7- [3- (4-phenyl-l-piperidyl) propoxy] -3,

   4-dihydrocarbostyril and its 3,4-dehydro compound l-hexyl-7- [3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro- compound 1 - (3-Phenylpropyl) -7- [3- (4-benzyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound
 EMI6.1
   2-methyl-3- (4-benzyl-1-piperidy1) propoxy] -3, 4-dihydrocarbostyril compound 7- [2-methyl-3- (4-benzyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril and its 3,4-dehydro- - Compound 7- [2,2-dimethyl-3- (4-benzyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro- Compound 1-methyl-5- [2-methyl-3- (4-benzyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound
 EMI6.2
   (4-benzyl-1-piperidyl)

   -propoxy] -3, 4-dihydrocarbostyril3, 4-dehydro compound 5- [2-methyl- (4-phenyl-l-piperidyl) -propoxy] -3, 4-dihydrocarbostyril and its 3,4-dehydro- compound 7- [2-Methyl-4- (phenyl-l-piperldyl) propoxy] -3, 4-dihydrocarbostyril and its 3,4-dehydro- - compound 1-methyl-5- [2-methyl-3- (4th -benzyl-1-piperidyl) -propoxy] -3,4-dihydrocarbostyril and its 3, 4-dehydro compound
 EMI6.3
   [2-methyl-3- (4-phenyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril compound 4-methyl-7- [3- (4-benzyl-l-piperidyl) propoxy] -3 , 4-dihydrocarbostyril and its 3, 4-dehydro- - Compound 1,4-dimethyl-5- [3- (4-benzyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3, 4-dehydro Compound 1-benzyl-4-methyl-7 [3- (4-benzyl-l-piperidyl)

  -propoxy] -3, 4-dihydrocarbostyril and its 3, 4-dehydro compound
 EMI6.4
   [3- (4-phenyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril compound 4-methyl-7- [3- (4-phenyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril and its 3,4-dehydro- compound 1,4-dimethyl-7- [3- (4-benzyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound 4- Methyl 5- [2-hydroxy-3- (4-benzyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

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   1-Benzyl-7- [2-hydroxy-3- (4-benzyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound
 EMI7.1
   4-dimethyl-5- [2-hydroxy -3- (4-phenyl-l-piperidyl) propoxy] -3,

   4-dihydrocarbostyril compound
6- {3- [4- (4-Clorphenyl) -1-piperidyl) propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro- - compound 7- {3- [4- (3,4- Dichlorophenyl) -1-piperidyl) propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro compound 7- {3- [4- (2-fluorophenyl) -1-piperidyl] propoxy} -3,4 dihydrocarbostyril and its 3,4-dehydro compound 5- {3- [4- (2-methylphenyl) -1-piperidyl) propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro compound 6- {3- [4- (3-ethylphenyl) -1-piperidyl) propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro- - compound 7- {3- [4- (4-methylphenyl) -1 -piperidyl) -propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro- - compound 7- {3- [4- (2,3-dimethylphenyl) -1-piperidyl) -propoxy} -3,4- dihydrocarbostyril and its 3,4-dehydro compound 5- {3- [4- (4-methoxyphenyl) -1-piperidyl) propoxy} -3,

  4-dihydrocarbostyril and its 3,4-dehydro compound 7- {3- [4- (2-ethoxyphenyl) -1-piperidyl) propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro- compound 8 - {3- [4- (3-methoxyphenyl) -1-piperidyl) propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro compound 7- {3- [4- (3,4-dimethoxyphenyl) -1-piperidyl) propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro compound 7- {3- [4- (3,4,5-trimethoxyphenyl) -1-piperidyl) propoxy} -3 , 4-dihydrocarbostyril and its 3, 4-dehydro compound

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   7- {3- [4- (2-chlorophenyl) -1-piperidyl] propoxy} -3, 4-dihydrocarbostyril and its 3,4-dehydro- - compound 5- {3- [4- (4-fluorophenyl) -1-piperidyl] -propoxy} -3, 4-dihydrocarbostyril and its 3, 4-dehydro - compound
 EMI8.1
   {3- [4- (3-methylphenyl) -1-piperidyl] propoxy} -3,

   4-dihydrocarbostyril compound 5- {3- [4- (3-methylphenyl) -1-piperidyl) propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro- compound 7- {3- [4- (3-methoxyphenyl) -1-piperidyl) propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro compound 5- {2-hydroxy-3- [4- (2-fluorophenyl) -1-piperidyl) -propoxy} -3,4-dihydrocarbostyril and its 3, 4-dehydro compound
 EMI8.2
 nium chloride 4-phenyl-1- [3- (1-propargyl-2-oxo-1,2,3,4-tetrahydroquinolin-5-yl-oxy) propyl] -1-methylpiperidinium chloride

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   4-phenyl-1- [3- (6-chloro-2-oxo-1, 2, 3, 4-tetrahydroquinolin-7-yl-oxy) propyl] -l-methylpiperidium chloride
 EMI9.1
   (2-fluorophenyl) -1- [3- (2-oxo-1, 2, 3, 4-tetrahydroquinolin-5-yl-oxy) -propyl] -l-methylpiperidylthylpiperidinium-iodide 4-phenyl-1- [2-hydroxy-3- (1-benzyl-2-oxo-1,2,3,

  4-tetrahydroquinolin-5-yl-oxy) propyl] -1-methylpiperidinium iodide 4-phenyl-1- [2-hydroxy-3- (6-chloro-2-oxo-1,2,3,4-tetrahydroquinoline -5-yl-oxy) -propyl] -1-methylpiperidinium-i odid
 EMI9.2
   (6, 8-dibromo-2-oxo-1, 2, 3, 4-tetrahydroquinolin-5-yl-oxy) -propyl] -l-me-- 1-methylpiperidinium chloride 4- (3-chlorophenyl) -1 - [2-hydroxy-3- (2-oxo-1,2-dihydroquinolin-7-yl-oxy) propyl] -1-methylpiperidinium iodide

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   4- (4-methoxyphenyl) -1- [2-hydroxy-3- (2-oxo-1,2-dihydroquinolin-5-yl-oxy) propyl] -1-methylpiperidinium iodide
 EMI10.1
 (2-methylphenyl) -1- [2-hydroxy-3- (2-oxo-1, 2-dihydroquinoline-7-yl-oxy) propyl] -l-methyl-methylpiperidinium iodide 4-acetyl-4-phenyl -2- [3- (2-oxo-1, 2, 3, 4-tetrahydroquinolin-7 -yl-oxy)

   -propyl] -l-methylpiperidium iodide 5- [3- (4-hydroxy-4-phenyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro- - compound 5- {3- [4-Hydroxy-4- (4-chlorophenyl) -l-piperidyl] propoxy} -3, 4-dihydrocarbostyril and its 3,4-dehydro compound
 EMI10.2
   {3- [4-Hydroxy-4- (4-fluorophenyl) -l-piperidyl] propoxy} -3, 4-dihydrocarbostyril3, 4-dehydro compound 5- {3- [4-Hydroxy-4- (4- iodophenyl) -1-piperidyl] -propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro compound 5- [1- (4-hydroxy-4-phenyl-1-piperidyl) propoxy] -3.4 dihydrocarbostyril and its 3,4-dehydro- compound 5- [2- (4-hydroxy-4-phenyl-1-piperidyl) -ethoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro- compound 5 - [3- (4-acetyl-4-phenyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,

   4-dehydro- - Compound 5- [3- (4-propionyl-4-phenyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound 5- [3- (4- Hexanoyl-4-phenyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound 1-benzyl-5- [2- (4-hydroxy-4-phenyl-1-piperidyl) -ethoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound 5- [4- (4-hydroxy-4-phenyl-l-piperidyl) butoxy] -3,4-dihydrocarbostyril and its 3,4 -Dehydro- - Compound 6- [3- (4-Hydroxy-4-phenyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

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   6- {3- [4-Hydroxy-4- (4-chlorophenyl) -l-piperidyl] propoxy} -3, 4-dihydrocarbostyril and its 3,4-dehydro compound
 EMI11.1
   {3- [4-Hydroxy-4- (4-fluorophenyl) -1-piperidyl] propoxy} -3, 4-dihydrocarbostyril3,

   4-dehydro compound 6- {3- [4-hydroxy-4- (2-chlorophenyl) -1-piperidyl] propoxy} -3, 4-dihydrocarbostyril and its 3,4-dehydro compound 6- {3- [4-Hydroxy-4- (3-chlorophenyl) -1-piperidyl] propoxy} -3, 4-dihydrocarbostyril and its 3,4-dehydro compound 6-13- [4-hydroxy-4- (4-bromophenyl ) -l-piperidyl] -propoxy} -3, 4-dihydrocarbostyril and its 3, 4-dehydro compound
 EMI11.2
    {3- [4-Hydroxy-4- (2, 6-dichlorophenyl) -1-piperidyl] propoxy} -3, 4-dihydrocarbostyril3, 4-dehydro compound 6- [3- (4-acetyl-4-phenyl -1-piperidy1) -propoxy] -3, 4-dihydrocarbostyril and its 3,4-dehydro- - compound 6- [3- (4-propionyl-4-phenyl-l-piperidyl) propoxy] -3,

   4-dihydrocarbostyril and its 3,4-dehydro compound 6- [3- (4-hexanoyl-4-phenyl-1-piperidyl) propoxy] -3, 4-dihydrocarbostyril and its 3,4-dehydro compound 7- [3- (4-Hydroxy-4-phenyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril and its 3,4-dehydro compound 7- {3- [4-Hydroxy-4- (4-chlorophenyl ) -l-piperidyl] -propoxy} -3, 4-dihydrocarbostyril and its 3, 4-dehydro compound
 EMI11.3
    {3- [4-Hydroxy-4- (4-fluorophenyl) -1-piperidyl] propoxy} -3, 4-dihydrocarbostyril3, 4-dehydro compound 7- {3- [4-Hydroxy-4- (2- fluorophyenyl) -1-piperidyl] propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro compound 7- {3- [4-hydroxy-4- (2-chlorophenyl) -1-piperidyl] propoxy} -3,4-dihydrocarbostyril and its 3,

   4-dehydro compound 7- {3- [4-hydroxy-4- (3-chlorophenyl) -1-piperidyl] propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro compound 7- {3- [4-Hydroxy-4- (4-bromophenyl) -1-piperidyl] propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro compound 6- [2- (4-acetyl-4-phenyl-l -piperidyl) -ethoxy] -3, 4-dihydrocarbostyril and its 3,4-dehydro- - Compound 7- {3- [4-Hydroxy-4- (2,6-dichlorophenyl) -1-piperidyl] -propoxy} - 3,4-dihydrocarbostyril and its 3, 4-dehydro compound
 EMI11.4
   - {3- [4-Hydroxy-4- (3-fluorophenyl) -l-piperidyl] propoxy} -3, 4-dihydrocarbostyril3, 4-dehydro compound 7- {3- [4-Hydroxy-4- (3rd -bromophenyl) -1-piperidyl] -propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro compound 7- {3- [4-hydroxy-4- (2-bromophenyl)

  -1-piperidyl] -propoxy} -3,4-dihydrocarbostyril and its 3, 4-dehydro compound

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   7- {3- [4-Hydroxy-4- (4-iodophenyl) -l-piperidyl] propoxy} -3, 4-dihydrocarbostyril and its 3,4-dehydro compound 8- [3- (4-hydroxy- 4-phenyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril and its 3,4-dehydro compound 8- {3- [4-hydroxy-4- (4-chlorophenyl) -l-piperidyl] -propoxy} -3, 4-dihydrocarbostyril and its 3, 4-dehydro compound
 EMI12.1
   -4- (4-fluorophenyl) -l-piperidyl] -propoxy} -3, 4-dihydrocarbostyril3, 4-dehydro compound 8- {3- [4-hydroxy -4- (2-chlorophenyl) -l-piperidyl] -propoxy} -3,

   4-dihydrocarbostyril and its 3,4-dehydro compound 8- {3- [4-Hydroxy-4- (3-chlorophenyl) -1-piperidyl] propoxy} -3, 4-dihydrocarbostyril and its 3,4-dehydro -Connection
 EMI12.2
   {3- [4-Hydroxy-4- (4-bromophenyl) -l-piperidyl] propoxy} -3, 4-dihydrocarbostyril3, 4-dehydro compound 7- [3- (4-acetyl-4-phenyl-l -piperidyl) -propoxy] -3, 4-dihydrocarbostyril and its 3,4-dehydro- - compound 7- [3- (4-propionyl-4-phenyl-1-piperidyl) -propoxy] -3, 4-dihydrocarbostyril and its 3,4-dehydro compound 7- [3- (4-hexanoyl-4-phenyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound 7- [2- ( 4-hydroxy-4-phenyl-1-piperidyl) ethoxy] -3,4-dihydrocarbostyril and its 3,

   4-dehydro compound 7- [6- (4-hydroxy-4-phenyl-l-piperidyl) hexyloxy] -3, 4-dihydrocarbostyril and its 3,4-dehydro compound 8- {3- [4-hydroxy -4- (2, 6-dichlorophenyl) -l-piperidyl] -propoxy} -3, 4-dihydrocarbostyril and its 3, 4-dehydro compound
 EMI12.3
   8- {3- [4-Hydroxy-4- (3-fluoropheny1) -1-piperidyl] propoxy} -3, 4-dihydrocarbostyril3, 4-dehydro compound 8- {3- [4-Hydroxy-4- ( 3-bromophenyl) -1-piperidyl] -propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro compound 8- {3- [4-hydroxy-4- (2-bromophenyl) -1-piperidyl] - propoxy} -3,4-dihydrocarbostyril and its 3, 4-dehydro compound 8- {3- [4-Hydroxy-4- (4-iodophenyl) -1-piperidyl] propoxy} -3,4-dihydrocarbostyril and its 3,

   4-dehydro compound 8- [3- (4-acetyl-4-phenyl-1-piperidyl] propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro- - compound 8- [3- (4- Propionyl-4-phenyl-1-piperidyl] propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro compound 8- [3- (4-hexanoyl-4-phenyl-1-piperidyl] propoxy} - 3,4-dihydrocarbostyril and its 3,4-dehydro compound 7- [2-hydroxy-3- (4-acetyl-4-phenyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4 -Dehydro connection
 EMI12.4
 

  <Desc / Clms Page number 13>

 
 EMI13.1
 (4-acetyl-4-phenyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril3, 4-dehydro compound
1-Crotyl-7- [3- (4-hydroxy-4-phenyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound.



   The compounds of the general formula (I) are prepared according to the invention in that a hydroxycarbostyril of the general formula
 EMI13.2
 in which R ', R', X, n and the carbon-carbon bond between the 3- and the 4-position of the carbostyril skeleton have the above meanings, with a piperidyl compound of the general formula

  <Desc / Clms Page number 14>

 
 EMI14.1
 in which R3 and R "have the meanings given above and R is a group of the general formula Y-X 'with the above meaning for Y and with the meaning of a halogen for X or a group of the formula
 EMI14.2
 
 EMI14.3
 addition salt or with a compound of the general formula R'-Q, (IV)

      with the meaning of a lower alkyl group for Rs and the meaning of a halogen for Q is converted into a quaternary salt and / or, if desired, a carbostyril obtained
 EMI14.4
 is converted into a compound of the general formula (I) with one of the other meanings of Rl and / or a mixture of optical isomers obtained is split into the individual optical isomers.



   The process according to the invention can be illustrated by the following reaction schemes 1, 2, 3 and 4.



   Reaction scheme 1
When working according to reaction scheme 1
 EMI14.5
 wherein R ', R ", R, R", X, X', Y, n and the carbon-carbon bond between the 3- and 4-positions in the carbostyril skeleton can assume all of the meanings given above, the compound of the general formula (II) with the compound of the general formula (IIIa)
 EMI14.6
 

  <Desc / Clms Page number 15>

 Restrictions. Examples of useful solvents are ethers such as dioxane, tetrahydrofuran (THF), ethylene glycol dimethyl ether, etc., aromatic hydrocarbons such as benzene, toluene, xylene etc., lower alcohols such as methanol, ethanol, isopropanol, etc., and aprotic polar solvents such as dimethylformamide ( DMF), dimethyl sulfoxide (DMSO) and ketones such as acetone, methyl ethyl ketone or the like.

   There are also no particular restrictions with regard to the dehydrohalogenating agent either, with conventional basic compounds, e.g. B. the above-mentioned basic compounds and further sodium methoxide, sodium ethoxide, potassium ethoxide, metallic potassium or the like can be used. In the above reaction, an alkali metal iodide such as sodium iodide, potassium iodide or the like can be used as a reaction accelerator.

   The ratio of the amount of the compound of the formula (II) to the amount of the compound of the formula (IIa) is not particularly limited, but it is desirable that the latter in an equimolar amount or in a higher amount, usually in the 1 to 1.5 times , preferably 1 to 1, 2 times, molar amount of the former compound is used.



   Reaction scheme 2
When working according to reaction scheme 2
 EMI15.1
 wherein R ', R2, R3, R ", n and the carbon-carbon bond between the 3-position and the 4-position in the carbostyril skeleton have the meanings given above and Z for a group of the formula
 EMI15.2
 
 EMI 15.3
 

  <Desc / Clms Page number 16>

 
 EMI16.1
 is prepared and is accordingly obtained in the form of a mixture of the two possible compounds with regard to the meaning of Z, in the presence or in the absence of a suitable one
 EMI16.2
 hours to 24 hours is completed. In this reaction, the solvent is not particularly limited, and any solvents which do not interfere with the reaction can be used.

   Examples of these are the above-mentioned ethers, aromatic hydrocarbons, lower alcohols, dimethylformamide, dimethyl sulfoxide or the like.



   Furthermore, a conventional basic compound can be added to the reaction system, if necessary. As the basic compound, inorganic compounds such as potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium amide, sodium hydride or the like, organic tertiary amines such as triethylamine, tripropylamine, pyridine, quinoline or the like can be used.



   The ratio of the amount of the compound of formula (VI) to the amount of the compound of formula (V) is usually an equimolar to excess amount, preferably an equimolar to 5 times the molar amount, most preferably an equimolar to 1, 2 times the molar amount the latter.



   A carbostyril derivative of the general formula (Ib), in which RI has a meaning other than a hydrogen atom, can be prepared from a compound (Ia) obtained, in which R 'is a hydrogen atom, in accordance with reaction scheme 3.



   Reaction scheme 3
 EMI 16.3
 
 EMI 16.4
 and the 4-position of the carbostyril skeleton has the meanings given above, while X4 represents a halogen atom and R11 represents a lower alkenyl group, a lower alkynyl group or a lower alkyl group which may have one or more phenyl groups as substituents.



   The reaction conditions are similar to the reaction conditions given in connection with reaction scheme 1, a compound of the general formula (IVa) being used in the equimolar to about 3 times the molar amount, preferably an equimolar amount, of a compound of the general formula (Ia).

  <Desc / Clms Page number 17>

 



  Reaction Scheme 4 In Reaction Scheme 4
 EMI17.1
 wherein R ', R2, R3, R ", R, Q, X, Y, n and the carbon-carbon bond between the 3- and 4-positions in the carbostyril skeleton have the meanings given above, is advantageously carried out in an inert solvent , a lower alcohol such as
Methanol, ethanol, propanol or the like, an aromatic hydrocarbon such as benzene, toluene, xylene or the like, an ether such as tetrahydrofuran, dioxane or the like, chloroform, trichlorethylene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoryl triamide or the like can be used.



   The ratio of the amount of compound of formula (IV) to the amount of compound of
Formula (I) is usually at least the equimolar amount, preferably the equimolar to 5 times the molar amount, of the latter compound. The reaction is usually carried out at a temperature of from 0 to about 200 ° C., preferably from room temperature to 80 ° C., and for a period of from 1 to about 8 hours.



   Among the compounds of the general formula (Ic) which have been prepared by the process according to reaction scheme 4, if Q denotes a halogen atom with an atomic number which is greater than that of the chlorine atom, the compound mentioned can be converted into another compound, in the Q is a chlorine atom can be converted by reacting the compound with silver chloride. Similarly, when Q represents a halogen atom having an atomic number larger than that of the bromine atom, the compound can be converted into another compound in which Q is a bromine atom by reacting the compound with silver bromide. Such a conversion reaction of the halogen atom can advantageously in the presence of a solvent, e.g.

   B. an above-mentioned lower alcohol, of dimethylformamide, dimethyl sulfoxide or water. The ratio of the amount of silver halide to the amount of starting material is at least an equimolar amount, preferably an equimolar to 6 times the molar amount of the latter. The reaction can be carried out at a temperature of from 0 to about 80 ° C., preferably at room temperature to 50 ° C., over a period of from 5 to about 24 hours.



   The carbostyril derivatives thus produced according to the invention can easily be converted into their acid addition salts by reaction with pharmaceutically acceptable acids. Examples of suitable acids are inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like. Like. And organic acids such as acetic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, malonic acid, methanesulfonic acid, benzoic acid and the like. the like



   Among the carbostyril derivatives which can be prepared according to the invention, compounds in which the carbon-carbon bond between the 3 and 4 positions in the carbostyril skeleton is a double bond easily form their salts by reacting with basic compounds such as metal oxides, e.g. B.



  Potassium hydroxide, sodium hydroxide, calcium hydroxide or the like.

  <Desc / Clms Page number 18>

 



   The desired compounds, such as those prepared by the processes according to the above reaction scheme, can easily be separated by conventional separation measures such as solvent extraction,
Dilution, recrystallization, column chromatography, preparative thin layer chromatography, etc. can be isolated and purified.



   For agents having an antihistamine action, the compounds of the general formula (I) can be used in the form of a pharmaceutical preparation together with the customary, pharmaceutically acceptable carriers. Examples of carriers which are used according to the desired form of the pharmaceutical preparation are diluents or excipients, e.g. B. fillers, diluents, binders, humectants, disintegrants, surface-active agents and lubricants.



   There are no particular restrictions on the form of administration, and the compounds which can be prepared according to the invention can be used in any desired unit form as antihistamines. Typical unit forms are e.g. B. tablets, pills, powders, liquids,
Suspensions, emulsions, granules, capsules, suppositories, injection liquids (solutions and suspensions) and ointments. For deformation in the form of tablets, carriers which are commonly used in this field can also be used, e.g. B.

   Excipients like
Lactose, sucrose, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silica, binders such as water, ethanol, propanol, simple syrup,
Glucose, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, calcium phosphate and polyvinyl pyrrolidone, disintegrants such as dried starch, sodium alginate,
Agar-agar powder, laminalia powder, sodium hydrogen carbonate, calcium carbonate, tween wetting agent,
Sodium lauryl sulfate, monoglycerides of stearic acid, starch, lactose, disintegration inhibitors such as sucrose, stearin, coconut butter, hydrogenated oil, absorption accelerators such as quaternary ammonium bases, sodium lauryl sulfate, humectants such as glycerol or starch, adsorbent agents such as starch, lactose, lactose, lactose, lactone, lactose, lactose, lactose, lactose, lactose, lactose, lactose, lactose, lactose, lactose

   Lubricants like cleaned ones
Talc, stearic acid salt, boric acid powder, macrogol, solid polyethylene glycol, etc. In the case of tablets, it is also possible to coat with the usual coating materials, tablets coated with sugar, tablets coated with gelatin film, tablets coated with intestine, tablets coated with films, or double-layer tablets and to make multi-layer tablets.



   Carriers which are known and are widespread in this field can be used to deform into pills, e.g. B. excipients such as glucose, lactose, starch, coconut butter, hydrogenated vegetable oils, kaolin and talc, binders such as powdered gum arabic, powdered tragacanth, gelatin and ethanol, disintegrators such as laminaria and agar.



   Carriers which are known and widely used in this field can be used for deformation into suppositories, such as, for. B. polyethylene glycols, coconut butter, higher alcohols, esters of higher alcohols, gelatin and semi-synthesized glycerides.



   Solutions and suspensions are sterilized to produce injectable preparations. They are preferably isotonic with blood. In the preparation of injectable preparations, all carriers which are usually used therefor can be used, such as, for. B. water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters. In these cases, adequate amounts of sodium chloride, glucose or glycerin can be added to the desired preparations to make them isotonic. Furthermore, the usual dissolving agents, buffering agents, analgesics, preservatives as well as coloring materials, preservatives, flavoring agents, seasonings, sweeteners and other drugs can be added.



   For the preparation of pastes and creams, customary diluents can be used, such as, for. B. white petroleum jelly, paraffin, glycerin, cellulose derivatives, polyethylene glycols, silicones and bentonite.



   The amount of compounds of the general formula (I) or their acid addition salts in the antihistaminic agents is not particularly limited. It can be appropriately selected within a wide range. However, 1 to 70% by weight, based on the total composition, is usually preferred.

  <Desc / Clms Page number 19>

 



   The above-mentioned antihistamines and CNS control agents can be used in various forms, depending on the application, without any restrictions. So z. B. orally administered tablets, pills, solutions, suspensions, emulsions, granules and capsules. Injectable preparations are either administered intravenously individually or mixed with injectable transfusion preparations such as glucose solutions and amino acid solutions. If necessary, the injectable preparations can be administered individually intramuscularly, intracutaneously, subcutaneously or intraperitoneally. Suppositories are administered into the rectum and ointments are administered by application.



   The dose of the antihistamines which can be prepared according to the invention is suitably selected depending on the use, the purpose and the condition of the symptoms. Usually a drug
 EMI19.1
 
According to the usual procedures, tablets with the following composition are produced.
 EMI19.2
 
 <tb>
 <tb>



  1-methyl-7- [3- <SEP> (4-benzyl-1-piperidyl) <SEP> -propoxy] <SEP> - <SEP>
 <tb> - <SEP> 3, <SEP> 4-dihydrocarbostyril. <SEP> monooxalate <SEP> 5 <SEP> mg
 <tb> cornstarch <SEP> 132 <SEP> mg
 Magnesium stearate <SEP> 18 <SEP> mg
 <tb> lactose <SEP> 45 <SEP> mg
 <tb> overall <SEP> 200 <SEP> mg
 <tb>
 
Example of preparation of tablets - 2
Tablets with the following composition were produced according to the usual procedures.
 EMI 19.3
 
 <tb>
 <tb>



  1-methyl-5- <SEP> [3- <SEP> (4-benzyl-l-piperidyl) propoxy] <SEP> - <SEP>
 <tb> - <SEP> 3, <SEP> 4-dihydrocarbostyril. <SEP> monooxalate <SEP> 5 <SEP> mg
 <tb> cornstarch <SEP> 132 <SEP> mg
 Magnesium stearate <SEP> 18 <SEP> mg
 <tb> lactose <SEP> 45 <SEP> mg
 <tb> overall <SEP> 200 <SEP> mg
 <tb>
 
Example of preparation of tablets - 3
Tablets with the following composition were produced according to the usual procedures.
 EMI 19.4
 
 <tb>
 <tb>



  7- <SEP> [2-hydroxy-3- <SEP> (4-phenyl-l-piperidyl) propoxy] - <SEP>
 <tb> - <SEP> 3, <SEP> 4-dihydrocarbostyril <SEP> 5 <SEP> mg
 <tb> cornstarch <SEP> 132 <SEP> mg
 Magnesium stearate <SEP> 18 <SEP> mg
 <tb> lactose <SEP> 45 <SEP> mg
 <tb> overall <SEP> 200 <SEP> mg
 <tb>
 

  <Desc / Clms Page number 20>

 
Example of preparation of tablets - 4
Tablets with the following composition were produced according to the usual procedures.
 EMI20.1
 
 <tb>
 <tb>



  4-phenyl-l- <SEP> 3- <SEP> (2-oxo-1, <SEP> 2, <SEP> 3, <SEP> 4-tetrahydroquinoline-7 <SEP> -yl- <SEP>
 <tb> - <SEP> oxy) -propyl] -1-methylpiperidinium chloride. <SEP> semihydrate <SEP> 5 <SEP> mg
 <tb> cornstarch <SEP> 132 <SEP> mg
 Magnesium stearate <SEP> 18 <SEP> mg
 <tb> lactose <SEP> 45 <SEP> mg
 <tb> overall <SEP> 200 <SEP> mg
 <tb>
 
Example of preparation of tablets - 5
Tablets with the following composition were produced according to the usual procedures.
 EMI20.2
 
 <tb>
 <tb>



  5- [3- <SEP> (4-hydroxy-4-phenyl-1-piperidyl) <SEP> -propoxy] - <SEP>
 <tb> - <SEP> 3, <SEP> 4-dihydrocarbostyril <SEP> 5 <SEP> mg
 <tb> cornstarch <SEP> 132 <SEP> mg
 Magnesium stearate <SEP> 18 <SEP> mg
 <tb> lactose <SEP> 45 <SEP> mg
 <tb> overall <SEP> 200 <SEP> mg
 <tb>
 
Pharmacological test 1
Test of antihistamine activity
As a test method for determining the antihistamine activity of a compound in vitro, a method using a peeled ileum of the guinea pig is generally used. The pharmacological test of the compounds which can be prepared according to the invention was carried out according to this method as follows.



   A male guinea pig weighing 300 to 500 g was killed by bleeding. An ileum with a length of 15 cm was peeled out of the ileocecal area and immersed in a Tyrode solution (the latter was made from 8.0 g NaCl, 0.2 g KC1.0, 2 g
 EMI20.3
 cut to a length of 2.5 to 3.0 cm and hung in an organ bath which was filled with 30 ml of Tyrode solution. The organ bath was kept at a temperature of 36 C and a mixed gas consisting of 5% CO 2 and 95% 02 was blown into the bath. Ten minutes after the injection, 10-6 M histamine was added to the bath to examine the sensitivity of the tissue. A response curve (control) regarding the dose of histamine was obtained.



  After the dose of the histamine reaction curve (control) became constant, 10-6 g / ml of the test compound was added to the bath, and further, histamine was added 5 minutes later to obtain a dose reaction curve. The response of the ileum was recorded on a recorder by an isotonic transducer (TD-112S, manufactured by Nihon Koden). The antihistamine activity of the test compound was determined as pA2 value according to the "Van Rossam" method (JM Van Rossam, Arch. Inst. Pharmacodyn., 143, 299 [1963]), the maximum retraction of the ileum by histamine according to the control curve was effected when 100% was estimated.

   The results obtained are summarized in Table 1.

  <Desc / Clms Page number 21>

 Test compounds [compounds that can be produced according to the invention (No. 1 to 15)]
Connection Name of the connection
 EMI21.1
 8 8-bromo-5- [2-hydroxy-3- (4-benzyl-1-piperidyl) propoxy] - - 3,4-dihydrocarbostyril 9 7- [2-hydroxy-3- (4-phenyl-1- piperidyl) propoxy] -3,4-di-hydrocarbostyril
 EMI21.2
 [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxystyril. Monohydrochloride
14 5- {3- [4- (4-Hydroxy-4-phenyl) -1-piperidyl] propoxy} - - 3,4-dihydrocarbostyril
15 7- {3- [4- (4-Acetyl-4-phenyl) -1-piperidyl] propoxy} -3,4-di-hydrocarbostyril.



  [Reference compounds A and B]
A diphenylhydramine hydrochloride
B chlorpheniramine maleate
Table 1
 EMI21.3
 
 <tb>
 <tb> connection <SEP> no. <SEP> pAs value
 <tb> (according to the invention <SEP> producible <SEP> connections)
 <tb> 1 <SEP> 9, <SEP> 52 <SEP>
 <tb> 2 <SEP> 10, <SEP> 70 <SEP>
 <tb> 3 <SEP> 9, <SEP> 73 <SEP>
 <tb> 4 <SEP> 11, <SEP> 00 <SEP>
 <tb> 5 <SEP> 9, <SEP> 59 <SEP>
 <tb>
 

  <Desc / Clms Page number 22>

 Table 1 (continued)
 EMI22.1
 
 <tb>
 <tb> connection <SEP> no.

    <SEP> pA2 <SEP> value <SEP>
 <tb> (according to the invention <SEP> producible <SEP> connections)
 <tb> 6 <SEP> 9, <SEP> 54 <SEP>
 <tb> 7 <SEP> 9, <SEP> 65 <SEP>
 <tb> 8 <SEP> 8, <SEP> 39 <SEP>
 <tb> 9 <SEP> 9, <SEP> 89 <SEP>
 <tb> 10 <SEP> 9, <SEP> 62 <SEP>
 <tb> 11 <SEP> 8, <SEP> 23 <SEP>
 <tb> 12 <SEP> 10, <SEP> 70 <SEP>
 <tb> 13 <SEP> 9, <SEP> 73 <SEP>
 <tb> 14 <SEP> 9, <SEP> 30 <SEP>
 <tb> 15 <SEP> 9, <SEP> 92 <SEP>
 <tb> (reference connections)
 <tb> A <SEP> 8, <SEP> 15 <SEP>
 <tb> B <SEP> 9, <SEP> 00 <SEP>
 <tb>
 
Pharmacological test 2
Acute toxicity test
The individual compounds were administered orally to male rats to determine acute toxicity. The results obtained are shown in Table 2.



   Table 2
 EMI22.2
 
 <tb>
 <tb> test connections <SEP> Acute <SEP> toxicity <SEP> (LD5 <SEP> 0 <SEP> mg / kg)
 <tb> 1 <SEP>> <SEP> 1000 <SEP>
 <tb> 2 <SEP>> <SEP> 1000 <SEP>
 <tb> 3 <SEP>> <SEP> 1000 <SEP>
 <tb> 4 <SEP>> <SEP> 1000 <SEP>
 <tb> 5 <SEP>> <SEP> 1000 <SEP>
 <tb> 6 <SEP>> <SEP> 1000 <SEP>
 <tb> 7 <SEP>> <SEP> 1000 <SEP>
 <tb> 8 <SEP>> <SEP> 1000 <SEP>
 <tb> 9 <SEP>> <SEP> 1000 <SEP>
 <tb> 10 <SEP>> <SEP> 1000 <SEP>
 <tb> 11 <SEP>> <SEP> 1000 <SEP>
 <tb> 12 <SEP>> <SEP> 1000 <SEP>
 <tb> 13 <SEP>> <SEP> 1000 <SEP>
 <tb> 14 <SEP>> <SEP> 1000 <SEP>
 <tb> 15 <SEP>> <SEP> 1000 <SEP>
 <tb>
 

  <Desc / Clms Page number 23>

 
The invention is illustrated in the examples. The preparation of the compounds as
Starting materials are used, is described in the reference examples.

   The method according to the invention is explained in the examples.



   Reference Example 1: 24 g of 4-phenylpiperidine, 14 g of 1-chloro-3-bromopropane and 15 g of triethylamine were mixed with 100 ml of dimethylformamide and the mixture was stirred at 50 to 60 ° C. for 1 hour. The reaction mixture was poured into 200 ml of saturated sodium chloride aqueous solution and the organic layer was extracted with chloroform. The chloroform layer was then washed with water, dried and the chloroform was distilled off. The residue thus obtained was purified by silica gel column chromatography (only the main product being the top one)
Part of the column was won). 15.3 g of 1-chloro-3- (4-phenylpiperidinyl) propane were obtained in the form of a colorless, oily substance.

   Then this oily substance was reduced
Distilled pressure, whereby 11 g of a fraction of a distillate with a boiling point of 112 to 115 C / 0.13 mbar were obtained. A portion of this distillate was converted to the hydrochloride and recrystallized from ethanol to give 1-chloro-3- (4-phenyl-1-piperidyl) propane. Monohydrochloride with mp = 167 to 169 C, was obtained in the form of colorless, needle-shaped crystals.



   Reference example 2: Using a method similar to reference example 1, 1-chloro-2-methyl-3- (4-phenyl-l-piperidyl) propane was obtained in the form of a colorless, oily substance, bp = 114 to 116 ° C / 0 , 13 mbar.



   Reference example 3: 16.0 g of 4-hydroxy-4-phenylpiperidine, 24 g of 1-chloro-3-bromopropane and
15 g of triethylamine were mixed with 100 ml of dimethylformamide and the mixture was stirred at 50 to 60 C for 1 h. The reaction mixture was poured into 200 ml of saturated sodium chloride aqueous solution. The organic layer was extracted with chloroform. The chloroform layer was then washed with water, dried and the chloroform was distilled off. The residue thus obtained was purified by silica gel column chromatography (whereby only the main product was obtained as the uppermost part in the column). 14.3 g of 1-chloro-3- (4-hydroxy-4-phenyl-1-piperidyl) propane were obtained in the form of a colorless, oily substance.

   Then, this oily substance was distilled under reduced pressure, whereby a fraction of the distillate was obtained. The fraction of the distillate was converted to the form of the hydrochloride and the product was recrystallized from ethanol. 1-Chloro-3- (4-hydroxy-4-phenyl-1-pipe-ridy1) propane was obtained. Monohydrochloride, mp = 192 to 195 C, in the form of colorless, needle-shaped crystals.



   Example 1: 2.4 g of 7-hydroxy-4-phenylcarbostyril and 0.8 g of potassium hydroxide were mixed with 60 ml of methanol and the mixture was concentrated to dryness under reduced pressure. To the residue obtained was added 60 ml of dimethylformamide and mixed thoroughly. The mixture was then mixed with 5 g of 1- (3-chloropropy1) -4-phenylpiperidine and heated to 70 to 80 ° C. for 8 hours with stirring. The reaction mixture was concentrated to dryness under reduced pressure, 60 ml of aqueous 5% sodium hydrogen carbonate solution were added to the residue obtained, and the mixture was extracted with chloroform. The chloroform layer was washed with water, dried and the chloroform was removed by distillation.

   30 ml of methanol and 5 ml of concentrated hydrochloric acid were added to the residue obtained, and the mixture was concentrated under reduced pressure. The residue was crystallized with ethanol and the methanol was recrystallized. One
 EMI23.1
 Form of colorless, needle-shaped crystals, mp = 238 to 241 C.



   By a method similar to that described in Example 1, the compounds of Examples 2 to 22 were obtained as follows.
 EMI23.2
 : 1-Methyl-7 - [3- (4-benzyl-1-piperidy I) propoxy] -3, 4-dihydrocarbostyril.drochloride. Monohydrate, colorless, acicular crystals (from methanol ether), mp = 172 C (dec.).



  Example 4: 1-Methyl-5- [3- (4-benzyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril. Monohydrochloride, colorless, needle-shaped crystals (from ethanol ether), mp = 130 to 133 C.

  <Desc / Clms Page number 24>

 



  Example 5: 1-Hexyl-7- [3- (4-phenyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril. Monooxalate, colorless, needle-shaped crystals (from isopropanol), mp = 168 to 170 C.



  Example 6: 1- (3-phenylpropyl) -7- [3- (4-phenyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril.



   Monooxalate, colorless, needle-shaped crystals (from methanol-water), mp = 210 to 213 C.



  Example 7: 1-Allyl-5- [2-hydroxy- (4-phenyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril. Mono oxalate, colorless, needle-shaped crystals (from ethanol), mp. 178 to 180 C.



  Example 8: 1-Methyl-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril.



   Monooxalate,
 EMI24.1
 colorless, needle-shaped crystals (from Ligroin), mp = 92 C.



  Example 14: 1-Allyl-5- [2-hydroxy-3- (4-phenyl-1-piperidyl) propoxy] -3, 4-dihydrocarbostyril.



   Monooxalate, yellowish, needle-shaped crystals (from methanol), mp = 208 C (dec.).



  Example 15: 4-methyl-6- [3- (4-benzyl-l-piperidyl) propoxy] carbostyril, yellow-brown, prism-like crystals (from methanol), mp = 177 to 178 C.
 EMI24.2
 yellowish, needle-shaped crystals (from ethanol), mp = 252 to 254 C.



  Example 19: 4-methyl-7- [3- (4-benzyl-1-piperidyl) propoxy] carbostyril. Monohydrochloride. Dihydrate, colorless, needle-shaped crystals (from ethanol), mp = 241 to 242 C.



  Example 20: 4-Methyl-6- {3- [4- (4-methylphenyl) -1-piperidyl] propoxy} carbostyril. Monohydrochloride, colorless, acicular crystals (from methanol), mp = 256 to 2590C (dec.).



  Example 21: 4-Methyl-6- {3- [4- (4-chlorophenyl) -1-piperidyl] propoxy} carbostyril. Monohydrochloride, colorless, acicular crystals (from methanol), mp = 263 to 265 C.
 EMI24.3
 colorless, flake-like crystals (from ethanol), mp = 199 to 201 C.



   Example 23: 2.4 g of 6,8-dichloro-5-hydroxy-3,4-dihydrocarbostyril and 0.8 g of granular potassium hydroxide were mixed with 60 ml of methanol and the mixture was concentrated to dryness under reduced pressure. 60 ml of dimethylformamide were added to the residue obtained, and
 EMI24.4
 reduced pressure to dryness, added 60 ml of an aqueous 5% sodium hydrogen carbonate solution and extracted with chloroform. The chloroform layer was washed with water and dried. The chloroform was removed by distillation and the residue obtained was purified by silica gel column chromatography and recrystallized from ligroin.

   1.6 g were obtained

  <Desc / Clms Page number 25>

 (Yield 35%) 6, 8-dichloro-5- [2-methyl-3- (4-phenyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril in the form of colorless, needle-shaped crystals, mp = 125 bis 126OC.



   By a method similar to that described in Example 23, the compounds of Examples 24 to 28 were obtained as follows.



   Example 24: 5- [3- (4-Benzyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril, colorless, needle-shaped crystals (from ethanol), mp = 143 to 145 C.
 EMI25.1
 colorless, needle-shaped crystals (from methanol), mp = 183 to 184 C.



   Example 28: 8-bromo-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril, colorless, needle-shaped crystals (from ethanol), mp = 165 to 166 C.



   Example 29: 1.8 g of 1-methyl-5-hydroxy-3,4-dihydrocarbostyril and 2.3 g of 4-benzyl-1- (2,3-epoxypropyl) piperidine were mixed with 30 ml of methanol and that The mixture was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was dissolved in 30 ml of acetone. Then a 5% solution of oxalic acid in acetone was added to adjust the pH to 4.5, and the mixture was allowed to stand. Then the educated
 EMI25.2
 up to 152 C.



   The compounds of Examples 30 to 40 were obtained by a method similar to that described in Example 29.



   Example 30: 1-Benzyl-5- [2-hydroxy -3- (4-benzyl-1-piperidyl) propoxy] -3, 4-dihydrocarbostyril. Monooxalate,
 EMI25.3
 : 1-ethyl-5- [2-hydroxy -3- (4-benzyl-1-piperidyl) propoxy] -3, 4-dihydrocarbostyl-ril. Monooxalate, colorless, needle-shaped crystals (from ethanol), mp = 164 to 169 C.



  Example 32: 8-bromo-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril, colorless, needle-shaped crystals (from ethanol), mp = 165 to 166 C.



  Example 33: 5- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril, colorless, needle-shaped crystals (from ethanol), mp = 207 to 208 C.



  Example 34: 6- [2-hydroxy-3- (4-phenyl-1-piperidyl) propoxy] -3, 4-dihydrocarbostyril, colorless, plate-like crystals (from ethanol), mp = 170 to 171 C.



  Example 35: 7- [2-Hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril, colorless, needle-shaped crystals (from isopropanol), mp = 149 to 150 C.



  Example 36: 1-Allyl-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril. Monooxalate, colorless, needle-shaped crystals (from ethanol), mp = 178 to 180 C.



  Example 37: 1-Allyl-5- [2-hydroxy-3- (4-phenyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril, colorless, needle-shaped crystals (from ligroin), mp = 92 C.



  Example 38: 1-Allyl-5- [2-hydroxy-3- (4-phenyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril. Monooxalate, yellowish, needle-shaped crystals (from methanol), mp = 208 C.



  Example 39: 1-Methyl-5- [2-hydroxy-3- (4-phenyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril. Monooxalate, colorless, powdery crystals (from ethanol ether), mp = 150 to 152 C.



  Example 40: 5- [2-Hydroxy-3- (3,4,5-trimethoxyphenyl) propoxy] -3,4-dihydrocarbostyril. Mono-oxalate, colorless, flake-like crystals (from ethanol), mp = 199 to 201 C.

  <Desc / Clms Page number 26>

 



   Example 41: 2.0 g of 5- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril and 3 g of methyl iodide were mixed with 30 ml of dimethylformamide and the mixture was stirred for 5 hours stirred at 50 to 60 C. The reaction mixture was concentrated under reduced pressure, the residue obtained was mixed with 50 ml of acetone and stirred. The precipitate formed was collected by filtration, washed with acetone and recrystallized from methanol-ether, 1.7 g of 4-phenyl-l- [2-hydroxy-3- (2-oxo-1, 2, 3, 4- tetrahydroquinolin-5-yl-oxy) propyl] -1-methylpiperidinium iodide in the form of a colorless, powdery substance, mp = 242 to 243 C.



   Using a method similar to that described in Example 41, the compounds of Examples 42 and 43 were obtained as follows.
 EMI26.1
 colorless, needle-shaped crystals (from isopropanol-acetone), mp = 179 to 180 C.



   Example 43: 4-Benzyl-1- [2-hydroxy-3- (1-benzyl-2-oxo-1,2,3,4-tetrahydroquinolin-5-yl-oxy) -propyl propyl] -1-methylpiperidinium -Iodide, yellowish, needle-shaped crystals (from ethanol ether), mp = 135 to 139 C.



   Example 44: 2.0 g of 4-phenyl-1- [3- (2-oxo-1,2,3,4-tetrahydroquinolin-7-yl-oxy) propyll-1-methylpiperidinium iodide semihydrate were used dissolved in 150 ml of methanol and 100 ml of water. 3.0 g of silver chloride were added and the mixture was stirred in a dark and cool place for 24 h. The reaction mixture was filtered and the mother liquor obtained was concentrated to dryness under reduced pressure. The residue was recrystallized from isopropanol-acetone ether to give 1.0 g
 EMI26.2
 



   Example 45: 1.65 g of 6-hydroxycarbostyril and 0.75 g of granular potassium hydroxide were mixed with 50 ml of methanol and the mixture was concentrated to dryness under reduced pressure. 50 ml of dimethylformamide were added to the residue obtained and mixed well. Then 2.6 g of l- (3-chloropropyl) -4-acetyl-4-phenylpiperidine were added and the mixture was heated to 50 ° C. for 6 hours with stirring. The reaction mixture was concentrated to dryness under reduced pressure, 20 ml of an aqueous 5% sodium hydrogen carbonate solution was added and the mixture was stirred. The insolubles were collected by filtration and washed with water. After the insoluble materials had dried, they were recrystallized from ethanol.

   1.1 g of 6- [3- (4-acetyl-4-phenyl-l-piperidyl) propoxy] carbostyril were obtained in the form of colorless, prism-like crystals, mp = 192.5 to 194 C.



   Using a method similar to that described in Example 45, the compounds of Examples 46 to 56 were obtained as follows.



   Example 46: 5- [3- (4-Hydroxy-4-phenyl-l-piperidyl-propoxy] -3, 4-dihydrocarbostyril, colorless, needle-shaped crystals (from methanol), mp = 265 to 266 C.



   Example 47: 7- [3- (4-Hydroxy-4-phenyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril, colorless, flake-like crystals (from ethanol), mp = 215 C.



   Example 48: 7- {3- [4-Hydroxy-4- (4-chlorophenyl) -1-piperidyl] propoxy} -3, 4-dihydrocarbostyril, colorless, needle-shaped crystals (from ethanol), mp = 189 to 190 C.



   Example 49: 5- [3- (4-acetyl-4-phenyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril, light yellowish, prism-like crystals (from ethanol), mp = 165 C.
 EMI26.3
 

  <Desc / Clms Page number 27>

 Example 55: 1-methyl-8- [4- (3-acetyl-4-phenyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril, colorless, needle-shaped crystals (from ligroin), mp = 103 to 105 C.
 EMI27.1
 light yellowish brown, needle-shaped crystals (from methanol), mp = 212 to 213 C.



   Example 57: 2.0 g of 6- [3- (4-acetyl-4-phenyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril and
0.25 g of sodium hydride (50% in oil) was mixed in 30 ml of dimethylformamide and the mixture was stirred for 1 hour. Then 0.7 g of methyl iodide was added and the mixture was stirred for 12 h
Room temperature stirred. The reaction mixture was poured into 80 ml of saturated sodium chloride solution. The organic layer was extracted with chloroform and the chloroform layer was washed with water and dried. The chloroform was then removed by distillation and the residue was crystallized with hexane. The crude crystals were recrystallized from ligroin.

   1, 7 1-methyl-6- [3- (4-acetyl-4-phenyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril was obtained in the form of colorless, needle-shaped crystals, mp = 115 to 117 ° C. .



   By a method similar to that described in Example 57, the compounds of Examples 58 to 60 were obtained as follows.



   Example 58: 1-methyl-8- [3- (4-acetyl-4-phenyl-4-piperidyl) propoxy] -3, 4-dihydrocarbostyril, colorless, needle-shaped crystals (from ligroin), mp = 103 to 105 C.



   Example 59: 1-Allyl-5-12-hydroxy-3- [4- (4-acetyl-i-phenyl-l-piperidyl] propoxy 1-3, 4-dihydro-earbostyril, colorless, prism-like crystals (from ligroin -Benzene), mp = 141 to 142 C.



   Example 60: 1-propargyl-5- {2-hydroxy-3- [4- (4-hydroxy-4-chlorophenyl) -1-piperidyl] propoxy} - - 3,4-dihydrocarbostyril, colorless, acicular crystals (from Ligroin-benzene), mp = 132 to 134 C.



   Example 61: 1.8 g of 1-allyl-5-hydroxy-3,4-dihydrocarbostyril and 2.6 g of 4-acetyl-4-phenyl- - 1- (2,3-epoxypropyl) piperidine were added in 30 ml of methanol mixed and the mixture was heated under reflux for 3 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was dissolved in 30 ml of acetone. Then, with stirring at room temperature, a 5% solution of oxalic acid in acetone was added to adjust the pH to 4.5 and left to stand. The precipitate formed was collected by filtration, washed with acetone and then recrystallized from ligroin-benzene.

   2.62 g of 1-allyl-5- {2-hydroxy-3- [4- (4-acetyl- - 4-phenyl) -l-piperidyl] -propoxy} -3, 4-dihydrocarbostyril were obtained in the form of a colorless , powdery substance, mp = 141 to 142 C.



   Using a method similar to that described in Example 61, the compounds of Examples 62 and 63 were obtained as follows.
 EMI27.2
 hydrocarbostyril, colorless, prism-like crystals (from ethanol-water), mp = 177 to 178 C.

** WARNING ** End of DESC field may overlap beginning of CLMS **.

 

Claims (1)

 PATENT CLAIMS: 1. Process for the preparation of new carbostyril derivatives of the general formula  EMI27.3    <Desc / Clms Page number 28>  in which R 'represents a hydrogen atom, a lower alkenyl group, a lower alkynyl group or a lower alkyl group which may have one or more phenyl groups as substituents, R2 represents a hydrogen atom, a lower alkyl group or a phenyl group, R3 represents a lower alkyl group , which has one or more phenyl groups as substituents, or a phenyl group which may have 1 to 3 substituents from the group consisting of halogen atoms, lower alkyl groups and lower alkoxy groups, R '* represents a hydrogen atom, a hydroxyl group or a lower alkanoyl group, X represents a halogen atom, Y represents a lower alkylene group,  which may have one or more hydroxyl groups as substituents, n has the value 0, 1 or 2, the carbon-carbon bond between the 3 and 4 positions in the carbostyril skeleton is a single or double bond, with the proviso that when R3 is a lower alkyl group with one or more phenyl groups as substituents, then R '* represents neither a hydroxyl group nor a lower alkanoyl group, and of pharmaceutically acceptable acid addition salts and quaternary salts thereof and their optical isomers, characterized in that a hydroxycarbostyril of the general formula  EMI28.1  in which R ', R2, X, n and the carbon-carbon bond between the 3 and 4 positions of the carbostyril skeleton have the above meanings,  with a piperidyl compound of the general formula  EMI28.2  in which R3 and R '* have the meanings given above and R is a group of the general formula Y-X' with the above meaning for Y and with the meaning of a halogen for X 'or a group of the formula  EMI28.3    EMI28.4  Acid addition salt or with a compound of the general formula R5-Q, (IV) with the meaning of a lower alkyl group for R5 and the meaning of a halogen for Q is converted to a quaternary salt and / or, if desired, a carbostyril obtained  EMI28.5  a carbostyril derivative of the general formula (I) is dehydrated and / or if desired a compound of the general formula (I) obtained    with the meaning of hydrogen for R'in a  <Desc / Clms Page number 29>  Compound of general formula (I) with one of the other meanings of R 'is converted and / or a mixture of optical isomers obtained is split into the individual optical isomers.  2. The method according to claim 1, characterized in that 1-methyl-5- [3- (4-benzyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril is prepared by choosing appropriate starting materials and process steps.  3. The method according to claim 1, characterized in that 7- [3- (4-benzyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril is prepared by choosing appropriate starting materials and process steps.  EMI29.1  will be produced.  5. The method according to claim 1, characterized in that by choosing appropriate starting materials and process steps l-benzyl-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3, 4-di-hydrocarbostyril will be produced.  EMI29.2  hydrocarbostyril is produced.  7. The method according to claim 1, characterized in that 7- [2-hydroxy-3- (4-phenyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril is prepared by choosing appropriate starting materials and process steps.  8. The method according to claim 1, characterized in that by choosing appropriate starting materials and process steps l- (3-phenylpropyl) -7- [3- (4-phenyl-l-piperidyl) propoxy] -3, 4-di-hydrocarbostyril will be produced.