JPS6132286B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to antihistamines. More specifically, the present invention relates to the general formula [In the formula, R ¹ is a hydrogen atom, a lower alkyl group, or a phenylalkyl group, and R ² is a hydrogen atom, a lower alkyl group, a phenylalkyl group, a lower alkenyl group, a lower alkynyl group, an alkoxyalkyl group,
hydroxyalkyl group, carboxyalkyl group,
a lower alkanoyl group, a cycloalkylcarbonyl group, an alkylcarbonylalkyl group, an alkoxycarbonylalkyl group, or a carbamoylalkyl group, R ³ and R ⁴ are hydrogen atoms, lower alkyl groups,
Indicates a cycloalkyl group, an alkoxyalkyl group, a lower alkenyl group, a phenylalkyl group, a phenoxyalkyl group, a 6-membered saturated heterocyclic alkyl group, or a phenyl group. In addition, R ³ and R ⁴ may form a six-membered saturated heterocycle that may have a C _1-4 alkyl group or a phenyl group together with the nitrogen atom to which they are bonded, and the heterocycle is other than the above nitrogen atom. may have a nitrogen atom or an oxygen atom as a hetero atom. The carbon-carbon bond between the 3rd and 4th positions of the carbostyril skeleton represents a single bond or a double bond. However, the phenyl alkyl group, phenoxyalkyl group, and phenyl group substituted on a six-membered saturated heterocycle defined in R ³ and R ⁴ are C 1-4 alkyl group, C _1-4 alkyl group, C
It may have 1 to 3 identical or different substituents selected from the group consisting of _{1 to 4} alkoxy groups, halogen atoms, methylenedioxy groups, and carbamoyl groups. ] The present invention relates to an antihistamine agent characterized by containing a carbostyril derivative represented by the following or an acid addition salt thereof as an active ingredient. The compound represented by the above general formula [1] is a known compound, and is known to have β-adrenergic nerve blocking action and to be useful as a therapeutic agent for arrhythmia and angina pectoris [West German Published Publication No.
See Publication No. 2711719 and Publication No. 2549889]. As a result of extensive research into the compound represented by the above general formula [1], the present inventors found that such compounds were not described at all in the above publications, and that they did not have the above β-adrenergic neuroblocking action. It has been found that it has a completely unpredictable antihistamine effect and is therefore useful as an antihistamine.
The present invention was completed based on this new knowledge. Antihistamines are described in Gutsman Gilman, Pharmacology Book [1] Fundamentals and Clinical Practice of Drug Treatment, Nos. 781-835.
p., published by Hirokawa Shoten (1974), New Applied Pharmacology by Hisashi Hano, pp. 307-319, Nagai Shoten (1970), New Drugs and Clinical Practice, Vol. 20, No. 11, pp. 129-133 (1971)
As also described in Basic and Clinical Studies, Vol. 10, No. 10, pp. 17-27 (1976), rather than suppressing the release of bound histamine due to allergic antigen-antibody reactions, the release activity Blocks the binding of type histamine to histamine receptors (competitive antagonism)
It exerts antihistamine action. Therefore, the antihistamine of the present invention can be used to treat various diseases caused by the binding of histamine to histamine receptors, such as allergic symptoms of the respiratory tract such as combing, nasal discharge, itching of the eyes, nose, and throat, hay fever, hay fever, and acute Ging machine (itching, floating dust, redness, etc.), angioedema, hemorrhoids, atopic dermatitis, contact dermatitis such as insect stings, sumac rash, gin machine and edema disorders during serum sickness, allergic rhinitis, allergies It is effective as a treatment or preliminary medicine for allergic diseases such as sexual conjunctivitis and keratitis. Furthermore, the antihistamine of the present invention can be used as an adjunct in treating systemic anaphylaxis, in which autacoids other than histamine are thought to play an important role. Furthermore, the antihistamine of the present invention can also be used as a diagnostic agent for measuring the acid secretion ability of the stomach. More specifically, each group represented by R ¹ to ^{R 4} in the above general formula [1] is as follows. Lower alkyl group...straight chain or branched alkyl group having 1 to 6 carbon atoms, e.g. methyl, ethyl, propyl, butyl, sec-butyl, tert-butyl,
Pentyl, hexyl groups, etc. Cycloalkyl group...Cycloalkyl group having 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl, cycloheptyl groups, etc. Phenyl alkyl group...one or two phenyl groups
A straight-chain or branched alkyl group having 1 to 6 carbon atoms as a substituent, e.g. benzyl, 2-
Phenylethyl, 1-phenylethyl, 2-methyl-2-phenylpropyl, diphenylmethyl, 2,2-diphenylethyl, 4-phenylbutyl, 6-phenylhexyl, 1,1-dimethyl-2-phenylethyl, 2-methyl-4-
phenylbutyl, 2-methyl-3-phenylpropyl group, etc. Lower alkenyl group: Straight chain or branched alkenyl group having 2 to 6 carbon atoms, e.g. vinyl, 2-propenyl, 2-butenyl, 2-pentenyl, 3
-pentenyl, 1-methyl-2butenyl, 2-
hexenyl, 4-hexenyl group, etc. Lower alkynyl group...C2-C6 linear or branched alkynyl group, examples: 2-propynyl, 1-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-
pentynyl, 2-methyl-3-butynyl, 1-
Methyl-3-butynyl, 2-hexynyl, 3-
hexynyl, 4-hexynyl, 5-hexynyl, 2-methyl-4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 1-methyl-3-pentynyl groups, etc. Alkoxyalkyl group...C1-6 straight-chain or branched alkyl group having a C1-6 straight-chain or branched alkoxy as a substituent, examples: ethoxymethyl, 2-methoxyethyl, 2- Isopropoxyethyl, 3-butoxypropyl, 5-sec-butoxypentyl, 4-
Hexyloxybutyl, 6-pentyloxyhexyl, 3-ethoxybutyl groups, etc. Hydroxyalkyl group...C 1-6 straight chain or branched alkyl group having a hydroxyl group as a substituent, examples: hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3-
Hydroxybutyl, 2-methyl-3-hydroxypropyl, 5-hydroxypentyl, 4-hydroxypentyl, 2-methyl-4-hydroxybutyl, 2-methyl-3-hydroxybutyl, 6-hydroxyhexyl, 5-hydroxyhexyl, 2-methyl-5-hydroxypentyl, 2-methyl-4-hydroxypentyl group, etc. Carboxyalkyl group...C 1-6 straight chain or branched alkyl group having a carboxyl group as a substituent, e.g. carboxymethyl, 2-
Carboxyethyl, 3-carboxypropyl,
4-carboxybutyl, 2-carboxyhexyl, 3-carboxy-2-methylbutyl groups, etc. Lower alkanoyl group: Straight chain or branched alkanoyl group having 2 to 6 carbon atoms, such as acetylpropionyl, butyryl, isobutyryl, pentanoyl, hexanoyl group, etc. Cycloalkylcarbonyl group: A cycloalkylcarbonyl group having a cycloalkyl group having 3 to 7 carbon atoms, such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl group, etc. Alkylcarbonylalkyl group...C2-7
Straight chain or branched alkyl group having 1 to 6 carbon atoms as a substituent, e.g. methylcarbonylmethyl, ethylcarbonylmethyl, 2-ethylcarbonylethyl, 2-isopropylcarbonyl Ethyl, 3-sec-butylcarbonylpropyl, 6-hexylcarbonylhexyl, 3-ethylcarbonyl-2-methylpropyl groups, etc. Alkoxycarbonylalkyl group...C2 or more
Straight chain or branched alkyl group having 1 to 6 carbon atoms having 7 straight chain or branched alkoxycarbonyl groups as a substituent, e.g. methoxycarbonylmethyl, ethoxycarbonylmethyl, isopropoxycarbonylmethyl, 2-ethoxycarbonyl Ethyl, 3-sec-butoxycarbonylpropyl, 5-isobutoxycarbonylpentyl, 6-hexyloxycarbonylhexyl, 3-ethoxycarbonyl-2-methylbutyl group, etc. Carbamoyl alkyl group...A carbamoyl alkyl group that may have a straight chain or branched alkyl group having 1 to 6 carbon atoms or a phenyl alkyl group having the alkyl group as a substituent on the nitrogen atom, e.g. carbamoylmethyl, 3 -carbamoylpropyl, 4-carbamoylbutyl, 6-
Carbamoylhexyl, 2-(N,N-diethylcarbamoyl)ethyl, N-(β-3,4-
dimethoxyphenethyl) carbamoylmethyl group, etc. Phenoxyalkyl group...C 1-6 straight chain or branched alkyl group having a phenoxy group as a substituent, e.g. phenoxymethyl, 2-phenoxyethyl, 1-phenoxyethyl, 2-
Methyl-2-phenoxypropyl, diphenoxymethyl, 2,2-diphenoxyethyl, 4-
Phenoxybutyl, 6-phenoxyhexyl,
1,1-dimethyl-2-phenoxyethyl, 2
-Methyl-4-phenoxybutyl, 2-methyl-3-phenoxypropyl groups, etc. 6-membered saturated heterocyclic alkyl group: A 6-membered saturated heterocyclic ring in which one nitrogen atom is a heteroatom and may have a nitrogen atom or an oxygen atom as another heteroatom, and a carbon bonded to the nitrogen atom of the ring. A group composed of a linear or branched alkyl group of numbers 1 to 6, the other hetero atoms of the six-membered saturated heterocycle may be substituted with a phenyl group, e.g. 2-(1 -piperazinyl)ethyl, 3
-morpholinopropyl, 2-(1-piperazinyl)propyl, 3-(1-piperazinyl)butyl, 6-morpholinohexyl, 2-piperidinoethyl, 2-(4-phenyl-1-piperazinyl)ethyl group, etc. A six-membered saturated heterocycle represented by R ³ and R ⁴ formed together with the nitrogen atom to which they are bonded, the six-membered saturated heterocycle having a C _1-4 alkyl group or a phenyl group; Good too. ...Example: piperidino, morpholino, piperazinyl, 4-ethyl-
1-piperazinyl, 4-(tert-butyl)-1-
piperazinyl, 3-isopropyl-1-piperazinyl, 4-phenyl-1-piperazinyl groups, etc. Among the above groups, the phenylalkyl group, phenoxyalkyl group, and phenyl group substituted on a six-membered saturated heterocycle defined in R ³ and R ⁴ have 1 to 3 same or different substituents. Compounds having such substituents are also included within the scope of the present invention. Examples of the substituent include the following. C ₁ such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl group, etc.
_-4 alkyl group; _C1-4 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy group; halogen atom such as fluorine atom, chlorine atom, bromine atom, iodine atom; methylenedioxy ; Carbamoyl group. Examples of the groups having the above-mentioned substituents include the following. Phenyl alkyl group having a substituent...2-(4
-fluorophenyl)ethyl, 2-(3,4-
dibromophenyl)ethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(3,4-methylenedioxyphenyl)ethyl, 3-(3,
5-dichlorophenyl)propyl, 2-(4-
carbamoylphenyl)ethyl, 2-(4-chloro-3,5-dimethoxyphenyl)ethyl,
2-(2-isopropoxyphenyl)ethyl group, etc. Phenoxyalkyl group having a substituent...2-
(3,4-dimethoxyphenoxy)ethyl, 2
-(3,5-dimethoxyphenoxy)ethyl,
2-(4-fluorophenoxy)ethyl, 2-
(4-tert-butoxyphenoxy)ethyl, 3
-(3,5-dichlorophenoxy)propyl,
2-(4-carbamoylphenoxy)ethyl,
2-(4-chloro-3,5-dimethoxyphenoxy)ethyl, 2-(4-methoxyphenoxy)ethyl group, etc. Phenyl-substituted 6-membered saturated heterocyclic group represented by R ³ and R ⁴ ...4-phenyl-1-piperazinyl, 4-(4-methoxyphenyl)-1-piperazinyl, 4-(3-chlorophenyl)-1- Piperazinyl, 4-(2-methylphenyl)-1-
(Piperazinyl, 4-(2-chlorophenyl)-
1-piperazinyl, 4-(4-fluorophenyl)-1-piperazinyl, 4-(4-isopropylphenyl)-1-piperazinyl, 4-(2-propoxyphenyl)-1-piperazinyl, 4-
(3,4-dimethoxyphenyl)-1-piperazinyl, 4-(3,4,5-trimethoxyphenyl)-1-piperazinyl, 4-(3,4-dibromophenyl)-1-piperazinyl, 4 -(3,4
-diethylphenyl)-1-piperazinyl, 4
-(3,4-methylenedioxyphenyl)-1-
piperazinyl, 4-phenylpiperidino, 4-
(4-methylphenyl)piperidino, 4-(2-
methoxyphenyl)piperidino, 4-(4-chlorophenyl)piperidino, 4-(3,4-dimethoxyphenyl)piperidino, 4-(3,4
-methylenedioxyphenyl)piperidino group, etc. The antihistamine agent of the present invention contains a compound represented by the above general formula [1] or an acid addition salt thereof as an active ingredient. The acids capable of forming the above acid addition salts may be conventional pharmaceutically acceptable acids, such as hydrogen halides such as hydrogen chloride and hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, oxalic acid, and succinic acid. , tartaric acid, malonic acid, fumaric acid, methanesulfonic acid, etc. Further, the compound represented by the general formula [1] or its acid addition salt, which is used as an active ingredient in the antihistamine agent of the present invention, can also be used in the form of optical isomers thereof. Typical compounds that are active ingredients of the antihistamine agent of the present invention are listed below. Γ8-(2-propynyloxy)-5-[2-hydroxy-3-(β-3,4-dimethoxyphenethylamino)propoxy]-3,4-dihydrocarbostyryl hydrochloride (compound 1) Γ8-( 2-propynyloxy)-5-(2-hydroxy-3-piperidinopropoxy)-3,4
-dihydrocarbostyril hydrochloride (compound 2) Γ8-(2-propynyloxy)-5-[2-hydroxy-3-(4-phenyl-1-piperazinyl)propoxy]-3,4-dihydrocarbostyryl hydrochloride ( Compound 3) Γ8-(2-propynyloxy)-5-{2-hydroxy-3-[4-(2-methylphenyl)-1
-piperazinyl]propoxy}-3,4-dihydrocarbostyryl hydrochloride (compound 4) Γ8-(2-propynyloxy)-5-{2-hydroxy-3-[4-(4-methoxyphenyl)-
1-Piperazinyl]propoxy}-3,4-dihydrocarbostyryl hydrochloride (Compound 5) Γ8-(2-propynyloxy)-5-[2-hydroxy-3-(4-phenyl-1-piperazinyl)propoxy]carbo Styryl (compound 6) Γ8-hydroxy-5-[2-hydroxy-3-
(4-phenyl-1-piperazinyl)propoxy]-3,4-dihydrocarbostyryl hydrochloride (compound 7) Γ8-hydroxy-5-{2-hydroxy-3-
[4-(4-methoxyphenyl)-1-piperazinyl]propoxy}-3,4-dihydrocarbostyryl hydrochloride (compound 8) Γ8-hydroxy-5-{2-hydroxy-3-
[4-(2-chlorophenyl)-1-piperazinyl]propoxy}-3,4-dihydrocarbostyryl hydrochloride (compound 9) Γ8-benzyloxy-5-[2-hydroxy-
3-(4-phenyl-1-piperazinyl)propoxy]-3,4-dihydrocarbostyryl hydrochloride (compound 10) Γ8-benzyloxy-5-{2-hydroxy-
3-[4-(4-methoxyphenyl)-1-piperazinyl]propoxy}-3,4-dihydrocarbostyryl hydrochloride (compound 11) Γ8-hydroxy-5-[2-hydroxy-3-
(β-3,4-dimethoxyphenethylamino)
propoxy]-3,4-dihydrocarbostyryl hydrochloride (compound 12) Γ8-methylcarbonylmethoxy-5-[2-hydroxy-3-(β-3,4-dimethoxyphenethylamino)propoxy]-3,4 -dihydrocarbostyryl oxalate (compound 13) Γ8-(2-methoxyethoxy)-5-[2-hydroxy-3-(β-3,4-dimethoxyphenethylamino)propoxy]-3,4-dihydro Carbostyril hydrochloride (compound 14) Γ8-hydroxy-5-(2-hydroxy-3-
diphenylmethylaminopropoxy)-3,4
-dihydrocarbostyril hydrochloride (compound 15) Γ8-acetyloxy-5-[2-hydroxy-
3-(β-3,4-dimethoxyphenethylamino)propoxy]-3,4-dihydrocarbostyryl hydrochloride (compound 16) Γ1-methyl-5-{2-hydroxy-3-[N-
Methyl-N-(β-3,4-dimethoxyphenethyl)amino]propoxy}-8-benzyloxy-3,4-dihydrocarbostyryl hydrochloride (compound 17) Γ1-methyl-5-{2-hydroxy- 3-[N-
Benzyl-N-(β-3,4-dimethoxyphenethyl)amino]propoxy}-8-benzyloxy-3,4-dihydrocarbostyryl hydrochloride (compound 18) Γ8-allyloxy-5-{2-hydroxy- 3
-[N-methyl-N-(β-3,4-dimethoxyphenethyl)amino]propoxy}3,4-dihydrocarbostyryl oxalate (compound 19) Γ8-(2-propynyloxy)-5-( 2-hydroxy-3-cyclohexylaminopropoxy)3,4-dihydrocarbostyryl hydrochloride (compound 20) Γ8-(2-propynyloxy)-5-(2-hydroxy-3-allylaminopropoxy)-3,
4-dihydrocarbostyril hydrochloride (compound
21) Γ1-methyl-5-(3-benzylamino-2-
hydroxypropoxy)-8-benzyloxy-3,4-dihydrocarbostyryl hydrochloride (compound 22) Γ1-benzyl-5-(3-tert-butylamino-2-hydroxypropoxy)-8-benzyloxy-3,4- Dihydrocarbostyryl hydrochloride (compound 23) Γ8-butoxy-5-{2-hydroxy-3-[2
-(4-methoxyphenoxy)ethylamino]
Propoxy-3,4-dihydrocarbostyryl hydrochloride (compound 24) Γ8-hydroxy-5-{2-hydroxy-3-
[2-(4-carbamoylphenoxy)ethylamino]propoxy}-3,4-dihydrocarbostyryl hydrochloride (compound 25) Γ8-(2-propynyloxy)-5-[2-hydroxy-3-(2 -methoxyethylamino)propoxy]-3,4-dihydrocarbostyryl hydrochloride (compound 26) Γ8-(2-propynyloxy)-5-[2-hydroxy-3-(3-morpholinopropylamino)propoxy]-3 ,4-dihydrocarbostyryl hydrochloride (compound 27) Γ8-(2-propynyloxy)-5-[2-hydroxy-3-(N-methyl-N-phenylamino)propoxy]-3,4-dihydrocarbostyryl hydrochloride Salt (compound 28) Γ8-ethoxycarbonylmethoxy-5-[2-
Hydroxy-3-(4-phenyl-1-piperazinyl)propoxy]-3,4-dihydrocarbostyryl hydrochloride (compound 29) Γ8-cyclohexylcarbonyloxy-5-
[2-hydroxy-3-(4-phenyl-1-piperazinyl)propoxy]-3,4-dihydrocarbostyryl hydrochloride (compound 30) Γ8-carboxymethoxy-5-[2-hydroxy-3-(4-phenyl) -1-piperazinyl)
propoxy]-3,4-dihydrocarbostyryl hydrochloride (compound 31) Γ8-carbamoylmethoxy-5-[2-hydroxy-3-(β-3,4-dimethoxyphenethylamino)propoxy]-3,4- Dihydrocarbostyryl hydrochloride (compound 32) Γ8-(N-β-3,4-dimethoxyphenethylcarbamoylmethoxy)-5-[2-hydroxy-3-(β-3,4-dimethoxyphenethylamino)propoxy ]-3,4-dihydrocarbostyryl hydrochloride (compound 33) Γ8-(2-hydroxyethoxy)-5-[2-hydroxy-3-(4-phenyl-1-piperazinylpropoxy)]-3,4- Dihydrocarbostyryl hydrochloride (compound 34) Γ8-benzyloxy-5-[2-hydroxy-
3-(4-ethyl-1-piperazinyl)propoxy]-3,4-dihydrocarbostyryl hydrochloride (compound 35) Γ8-hydroxy-5-{2-hydroxy-3-
[4-(2-chlorophenyl)-1-piperazinyl]propoxy}carbostyril hydrochloride (compound 36) Γ8-benzyloxy-5-{2-hydroxy-
3-[4-(4-methoxyphenyl)-1-piperazinyl]propoxy}carbostyryl hydrochloride (compound 37) Γ8-(2-propynyloxy)-1-methyl-5
-{2-hydroxy-3-[4-(2-methylphenyl)-1-piperazinyl]propoxy}-
3,4-dihydrocarbostyril hydrochloride (compound 38) Γ8-benzyloxy-1-benzyl-5-{2
-Hydroxy-3-[4-(4-methoxyphenyl)-1-piperazinyl]propoxy}-3,4
-dihydrocarbostyril hydrochloride (compound 39) Γ8-(2-propynyloxy)-5-{2-hydroxy-3-[2-(3,5-dimethoxyphenoxy)ethylamino]propoxy}-carbostyryl hydrochloride Salt (Compound 40) Γ8-(2-methoxyethoxy)-5-[2-hydroxy-3-(β-3,4-methylenedioxyphenethylamino)propoxy]carbostyril hydrochloride (Compound 41) Γ8- (benzyloxy)-5-(2-hydroxy-3-β-phenethylaminopropoxy)-
3,4-dihydrocarbostyryl hydrochloride (compound 42) Γ8-benzyloxy-5-{2-hydroxy-
3-[2-(4-phenyl-1-piperazinyl)
ethylamino]propoxy}-3,4-dihydrocarbostyryl hydrochloride (compound 43) Γ8-hydroxy-5-{2-hydroxy-3-
[4-(3,4-dimethoxyphenyl)-1-piperazinyl]propoxy}-3,4-dihydrocarbostyryl hydrochloride (compound 44) Γ8-hydroxy-5-{2-hydroxy-3-
[4-(3,4-methylenedioxyphenyl)-
1-Piperazinyl]propoxy}-3,4-dihydrocarbostyryl hydrochloride (compound 45) Γ8-ethoxy-5-{2-hydroxy-3-[4
-(4-methoxyphenyl)-1-piperazinyl]propoxy}-3,4-dihydrocarbostyryl hydrochloride (compound 46) Γ8-allyloxy-5-[2-hydroxy-3
-(4-phenyl-1-piperazinyl)propoxy]-3,4-dihydrocarbostyryl hydrochloride (compound 47) Γ8-(2-ethoxyethoxy)-5-{2-hydroxy-3-[4-(4- Chlorophenyl)-1
-Piperazinyl]propoxy}-3,4-dihydrocarbostyryl hydrochloride (compound 48) Γ8-(2-hydroxyethoxy)-5-{2-hydroxy-3-[4-(4-methylphenyl)-
1-Piperazinyl]propoxy}-3,4-dihydrocarbostyryl hydrochloride (compound 49) Γ8-carboxymethoxy-5-{2-hydroxy-3-[4-(2-methylphenyl)-1-piperazinyl]propoxy}- 3,4-dihydrocarbostyryl hydrochloride (compound 50) Γ8-acetyloxy-5-{2-hydroxy-
3-[4-(2-chlorophenyl)-1-piperazinyl]propoxy}-3,4-dihydrocarbostyryl hydrochloride (compound 51) Γ8-carbamoylmethoxy-5-[2-hydroxy-3-(4-phenyl- 1-Piperazinyl)propoxy]-3,4-dihydrocarbostyryl hydrochloride (Compound 52) Γ8-hydroxy-1-ethyl-5-[2-hydroxy-3-(4-phenylpiperazinyl)propoxy]-3 , 4-dihydrocarbostyryl, Γ8-hydroxy-1-benzyl-5-{2-hydroxy-3-[4-(4-methoxyphenyl)
-1-piperazinyl]propoxy}-3,4-
Dihydrocarbostyryl, Γ8-(2-methoxyethoxy)-1-methyl-5
-{2-hydroxy-3-[4-(4-bromophenyl)-1-piperazinyl]propoxy}-
3,4-dihydrocarbostyryl, Γ8-ethoxy-1-benzyl-5-[2-hydroxy-3-(4-phenyl-1-piperazinyl)propoxy]-3,4-dihydrocarbostyryl, Γ8-cyclohexylcarbonyloxy -1-benzyl-5-[2-hydroxy-3-(4-phenyl-1-piperazinyl)propoxy-3,4
-dihydrocarbostyryl, Γ8-propionyloxy-1-methyl-5-
[2-hydroxy-3-(4-phenyl-1-piperazinyl)propoxy]-3,4-dihydrocarbostyryl, Γ8-carboxymethoxy-1-benzyl-5-
[2-Hydroxy-3-(4-phenyl-1-piperazinyl)propoxy]-3,4-dihydrocarbostyryl Γ8-(2-hydroxyethoxy)-1-benzyl-5-[2-hydroxy-3-(4 -Phenyl-
1-piperazinyl)propoxy]-3,4-dihydrocarbostyryl, Γ8-carbamoylmethoxy-1-methyl-5-
[2-Hydroxy-3-(4-phenyl-1-piperazinyl)propoxy]-3,4-dihydrocarbostyryl, the compound of general formula [1] and its acid addition salts are usually used as antihistamines. It is in the form of a pharmaceutical composition with a pharmaceutical carrier. Carriers include diluents or excipients such as fillers, fillers, binders, wetting agents, disintegrants, surfactants, and lubricants that are commonly used to prepare drugs according to the usage form. I can give an example. Various dosage unit forms of antihistamines can be selected depending on the therapeutic purpose, and representative examples include tablets, pills, powders, suspensions, emulsions, granules, capsules, suppositories, and injections ( (solutions, suspensions, etc.), ointments, etc. When forming tablets, a wide variety of carriers conventionally known in this field can be used, such as lactose, sucrose, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propanol, simple syrup, glucose, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binders such as polyvinylpyrrolidone, dried starch, sodium alginate, agar powder, laminaria powder , disintegrants such as sodium bicarbonate, calcium carbonate, Twin, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc.
Absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, sugar talc,
Examples include lubricants such as stearate, boric acid powder, macrogol, and solid polyethylene glycol. When forming into a pill form, a wide variety of carriers conventionally known in this field can be used, such as excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc, powdered gum arabic, Examples include binders such as tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaria and agar. Furthermore, the tablets may be coated with a conventional coating as necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric solution tablets, film-coated tablets, or double-coated tablets.
It can be a multi-layered tablet. When forming the suppository, a wide range of conventionally known carriers can be used, including polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like. When prepared as injections, solutions and suspensions are preferably sterile and isotonic with blood; when forming these into the form of solutions, emulsions and suspensions, diluents known in the art are used. All those commonly used in the art can be used, including water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, and the like. In this case, the therapeutic agent may contain a sufficient amount of salt, glucose, or glycerin to prepare an isotonic solution, and may also contain conventional solubilizing agents, buffers, soothing agents,
In addition, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc., and other pharmaceuticals may be included in the therapeutic agent, if necessary. When forming into a paste, cream or gel form, a wide variety of diluents conventionally known in this field can be used, such as white petrolatum, varafin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like. The amount of the compound of the general formula [1] or its acid addition salt to be contained in the antihistamine is not particularly limited and can be appropriately selected within a wide range, but it is usually 1 to 70% by weight based on the total composition. Furthermore, there are no particular restrictions on the use of the above-mentioned antihistamines, and they can be administered in a manner appropriate for various forms. For example, in the case of tablets, pills, solutions, suspensions, emulsions, granules, and capsules, it is administered orally, and in the case of injections, it is administered intravenously alone or mixed with normal replenishing fluids such as glucose and amino acids. If necessary, it is administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally; in the case of a suppository, it is administered rectally; and in the case of an ointment, it is applied. The dosage of the antihistamine of the present invention is appropriately selected depending on the purpose of use, symptoms, etc., and usually the compound of general formula [1] or its acid addition salt is administered at a dose of 40 μl per day.
3 to 2 mg/Kg/day
It may be administered in ~4 doses. Pharmacological Test A method using isolated guinea pig ileum (hereinafter referred to as "method A") is generally accepted as a typical method for measuring antihistamine action in vitro, and method A is also used in the present invention. The antihistamine effect was measured in vitro according to the following. Furthermore, among various methods for measuring antihistamine effects in vivo, the present invention uses basic and clinical methods.
The histamine intradermal reaction inhibitory effect was measured according to the method described in Vol. 10, No. 18 (1976) (hereinafter referred to as "Method B"). 1 Antihistamine effect test using Method A Male guinea pigs weighing 300 to 500 g were killed by exsanguination, and the ileum 15 cm proximal to the ileocecal region was removed and Tyrode's solution (NaCl 8.0 g, KCl 0.2 g, CaCl ₂ 0.2
g, glycose 1.0g, NaHCO ₃ 1.0g,
NaH ₂ PO ₄・2H ₂ O0.065g and MgCl ₂・
0.2135 g of 6H ₂ O was added with water to make a total volume of 1000 ml). The tissue was then cut into 2.5-3.0 cm pieces and suspended in a bath filled with 30 ml of Tyrode's solution. The bath was kept at 36° C. and passed through a gas mixture of 5% CO ₂ and 95% O ₂ . After 10 minutes, 10 ^-6 M of histamine was administered to examine tissue sensitivity, and a dose-response curve (control) with histamine was obtained.
After the control dose-response had stabilized, 10 ^-6 g/ml of the test compound was administered, and 5 minutes later histamine was administered to obtain a dose-response curve. Contraction is performed using an isotonic transducer [Nihon Kohden TD-
112S] and recorded on a pen recorder.
100% maximum contraction of control histamine
and Van-Rotsam's method [JMVan
Rossam, Arch.Int.Pharmacodyn., 143 , 299
(1963) _] . The results obtained are shown in Table 1 below.

[Table] As is clear from Table 1 above, the compound represented by the general formula [1] exhibits excellent antihistamine action. 2. Histamine intradermal reaction inhibitory effect test according to method B A male rabbit weighing 1.4 to 2.1 kg was fixed in a dorsal position without anesthesia, and the hair on the abdomen was removed using a hair removal cream. Compound 11 3 mg/Kg was orally administered, 2 hours later histamine 0.1% dissolved in physiological saline.
Inject the solution and saline intradermally into the abdomen.
Injected 0.1ml. At the same time, 30 mg/Kg of a 3% Evans blue solution dissolved in physiological saline was injected into the auricular vein. Thirty minutes after dye injection, the skin at the area where the dye leaked was cut off, and the dye that leaked out of the blood vessel was collected by Eda et al. [Akihide Eda et al., Allergy, Vol. 22, No. 640--
648 (1973)]. When the inhibitory effect of intradermal administration of histamine on the increase in capillary permeability was measured, the inhibition rate was 86%. It has been confirmed that all antihistamines currently on the market exhibit antihistamine effects in Method A and Method B. Therefore, it can be said that the compound of general formula [1] or its acid addition salt exhibiting an antihistamine effect in Methods A and B is effective as an antihistamine agent. Acute toxicity test The LD ₅₀ value of Compound 14 was determined by oral or intravenous administration to rats and was as follows.

[Table] LD ₅₀ values were similarly determined for compounds other than Compound 14, that is, Compounds 1 to 13 and Compounds 15 to 52. All compounds had low toxicity and were not suitable for oral administration.
The dose was 1200 mg/Kg or more, and 130 mg/Kg or more when administered intravenously. Examples of formulations are listed below. Formulation Example 1 Tablets having the following composition were manufactured in a conventional manner. Compound 11 5 mg Corn starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Formulation Example 2 Tablets with the following composition in each tablet were manufactured in a conventional manner. Compound 3 10mg Corn starch 130mg Magnesium stearate 18mg Lactose 42mg Total 200mg

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is a hydrogen atom, a lower alkyl group, or a phenylalkyl group, and R ² is a hydrogen atom, a lower alkyl group, a phenylalkyl group, a lower alkenyl group, a lower alkynyl group, an alkoxyalkyl group,
hydroxyalkyl group, carboxyalkyl group,
a lower alkanoyl group, a cycloalkylcarbonyl group, an alkylcarbonylalkyl group, an alkoxycarbonylalkyl group, or a carbamoylalkyl group, R ³ and R ⁴ are hydrogen atoms, lower alkyl groups,
Indicates a cycloalkyl group, alkoxyalkyl group, lower alkenyl group, phenylalkyl group, phenoxyalkyl group, six-membered saturated heterocyclic alkyl group, or phenyl group. In addition, R ³ and R ⁴ may form a six-membered saturated heterocycle that may have a C _1-4 alkyl group or a phenyl group together with the nitrogen atom to which they are bonded, and the heterocycle is other than the above nitrogen atom. may have a nitrogen atom or an oxygen atom as a hetero atom. The carbon-carbon bond between the 3rd and 4th positions of the carbostyril skeleton represents a single bond or a double bond. However, the phenyl alkyl group, phenoxyalkyl group, and phenyl group substituted on a six-membered saturated heterocycle defined in R ³ and R ⁴ are C 1-4 alkyl group, C _1-4 alkyl group, C
It may have 1 to 3 identical or different substituents selected from the group consisting of _{1 to 4} alkoxy groups, halogen atoms, methylenedioxy groups, and carbamoyl groups. ] An antihistamine agent characterized by containing a carbostyril derivative represented by the following or its acid addition temperature as an active ingredient.