JP2006096662A - New 6-substituted urasil derivative, and therapeutic agent for allergic disease - Google Patents

New 6-substituted urasil derivative, and therapeutic agent for allergic disease Download PDF

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JP2006096662A
JP2006096662A JP2002271030A JP2002271030A JP2006096662A JP 2006096662 A JP2006096662 A JP 2006096662A JP 2002271030 A JP2002271030 A JP 2002271030A JP 2002271030 A JP2002271030 A JP 2002271030A JP 2006096662 A JP2006096662 A JP 2006096662A
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group
substituted
1h
2h
ar
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Inventor
Yoshifumi Inoue
Yoshiaki Isobe
Ikuhiro Obara
Masanori Tobe
善文 井上
郁博 小原
雅則 戸辺
義明 磯部
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Sumitomo Pharmaceut Co Ltd
住友製薬株式会社
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46Two or more oxygen, sulfur or nitrogen atoms
    • C07D239/52Two oxygen atoms
    • C07D239/54Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new compound having not only antihistamine effects but also antiinflammatory effects. <P>SOLUTION: A urasil derivative represented by general formula (I) or a pharmacologically acceptable salt thereof is used for medicinal applications. In formula (I), R<SP>1</SP>is a hydrogen atom, a substituted or unsubstituted 1-4C alkyl group, or a substituted or unsubstituted 7-10C aralkyl group; R<SP>2</SP>is a hydrogen atom or a 1-4C alkyl group; Ar<SP>1</SP>is a substituted or unsubstituted aromatic group, or a substituted or unsubstituted aromatic heterocyclic group; Ar<SP>2</SP>and Ar<SP>3</SP>are each a substituted or unsubstituted phenyl group, or a substituted or unsubstituted monocyclic aromatic heterocyclic group, and may form a third ring by a group linking to both Ar<SP>2</SP>and Ar<SP>3</SP>; X is a methine (CH) group or a nitrogen atom; Y is a single bond or an oxygen atom when X is a methine group, and is a single bond when X is a nitrogen atom; Z is a hydrogen atom or a hydroxy group when X is a methine group and Y is a single bond, and is a hydrogen atom when X is a methine group and Y is an oxygen atom or when X is a nitrogen atom (and Y is a single bond); and m is 2-6. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention has a novel antiallergic action, antihistamine action, anti-inflammatory action and the like, and is useful as a preventive / therapeutic agent for atopic dermatitis, allergic rhinitis, bronchial asthma, allergic conjunctivitis, chronic urticaria, etc. Relates to a novel uracil derivative and its pharmaceutical use.
[0002]
[Prior art]
Allergic diseases such as allergic conjunctivitis, allergic rhinitis, chronic urticaria, and atopic dermatitis are mainly caused by type I allergies. Cells infiltrate the affected area and become inflammatory. For these diseases, antihistamines are widely used as symptomatic therapeutic agents. However, antihistamines are ineffective against inflammation itself and cannot be a radical treatment. Therefore, in addition to antihistamines, treatments that use steroids that are anti-inflammatory agents are performed. However, steroid drugs have side effects that cause problems such as infection, adrenal atrophy, osteoporosis, diabetes, and growth disorders in children.
[0003]
[Problems to be solved by the invention]
Since conventional antihistamines do not have an anti-inflammatory action, it is desired to develop a new compound that has an anti-inflammatory action in addition to an antihistamine action and is more satisfactory in terms of safety.
[0004]
[Means for Solving the Problems]
In order to solve the above-mentioned problems, the present inventors have conducted various studies, and as a result, obtained a spacer from the 6-position of the 1- (substituted or unsubstituted) aryl-2,4 (1H, 3H) -pyrimidinedione skeleton. And a novel uracil derivative having a large chemical structure in the presence of a substituted piperidine or piperazine via an anti-histamine action and a remarkable suppression of late-onset inflammatory reaction, thereby completing the present invention It came to.
[0005]
That is, the present invention includes the following inventions.
(1) General formula (I):
[Chemical 2]
(Where R 1 Represents a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms or a substituted or unsubstituted aralkyl group having 7 to 10 carbon atoms, R 2 Represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, Ar 1 Represents a substituted or unsubstituted aromatic group or a substituted or unsubstituted aromatic heterocyclic group, Ar 2 , Ar Three Each represents a substituted or unsubstituted phenyl group or a substituted or unsubstituted monocyclic aromatic heterocyclic group, Ar 2 And Ar Three A third ring may be formed by a group bonded to both, X represents a methine group (CH) or a nitrogen atom, Y represents a single bond or an oxygen atom when X is a methine group, X Represents a single bond when Z is a nitrogen atom, Z represents a hydrogen atom or a hydroxyl group when X is a methine group and Y is a single bond, X represents a methine group and Y represents an oxygen atom and X represents a nitrogen atom ( Y represents a hydrogen atom, and m represents 2-6. )
Or a pharmaceutically acceptable salt thereof.
[0006]
(2) In general formula (I), Ar 1 The uracil derivative or the pharmaceutically acceptable salt thereof according to (1), wherein is a substituted or unsubstituted aromatic group.
(3) In general formula (I), Ar 2 , Ar Three The uracil derivative or the pharmaceutically acceptable salt thereof according to (1) or (2), wherein each represents a substituted or unsubstituted phenyl group.
(4) In general formula (I), Ar 2 , Ar Three Are each (1) a phenyl group optionally substituted with a halogen atom or an alkyl group having 1 to 4 carbon atoms, or (2) 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to the carbon atom. The uracil derivative or the pharmaceutically acceptable salt thereof according to the above (1) or (2), which is a 5- to 8-membered aromatic heterocyclic group containing an atom.
(5) The uracil derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (4), wherein X is a methine group in general formula (I).
(6) The uracil derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (4), wherein X is a nitrogen atom in general formula (I).
(7) An antihistamine containing the uracil derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (6) as an active ingredient.
(8) An antiallergic agent containing the uracil derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (6) as an active ingredient.
(9) Allergic conjunctivitis, allergic rhinitis, chronic urticaria, atopic dermatitis containing the uracil derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (6) as an active ingredient , A prophylactic / therapeutic agent for asthma or chronic bronchitis.
[0007]
DETAILED DESCRIPTION OF THE INVENTION
The compound of the present invention will be described in more detail. 1 Examples of the unsubstituted alkyl group having 1 to 4 carbon atoms represented by: methyl group, ethyl group, propyl group (1-propyl group), isopropyl group (2-propyl group), butyl group (1-butyl group), Examples include sec-butyl group (2-butyl group), isobutyl group (2-methyl-1-propyl group), and t-butyl group (2-methyl-2-propyl group). R 1 Substituents allowed on the alkyl group having 1 to 4 carbon atoms represented by the following are halogen atoms such as fluorine atoms and chlorine atoms, hydroxyl groups, alkoxy groups having 1 to 4 carbon atoms, and acyloxy groups having 1 to 5 carbon atoms. Group, carboxyl group, alkoxycarbonyl group having 2 to 5 carbon atoms, and specific R 1 As the substituted alkyl group having 1 to 4 carbon atoms, trifluoromethyl group, 2-chloroethyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, 2-methoxyethyl group, 2-ethoxyethyl group, 3 -Methoxypropyl group, 2-acetoxyethyl group, carboxymethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group and the like can be mentioned. Also R 1 The unsubstituted aralkyl group having 7 to 10 carbon atoms represented by benzyl group, 1-phenylethyl group, 2-phenylethyl group (phenethyl group), 1-phenylpropyl group, 2-phenylpropyl group, 2- Examples thereof include a phenyl-2-propyl group, a 3-phenylpropyl group, a 2-methylbenzyl group, a 3-methylbenzyl group, a 4-methylbenzyl group, and a 4-methylphenethyl group. R 1 Substituents allowed on the aralkyl group having 7 to 10 carbon atoms represented by the following are halogen atoms such as fluorine atoms and chlorine atoms, hydroxyl groups, alkoxy groups having 1 to 4 carbon atoms, and acyloxy groups having 1 to 5 carbon atoms. Group, carboxyl group, alkoxycarbonyl group having 2 to 5 carbon atoms, and specific R 1 As the substituted aralkyl group having 7 to 10 carbon atoms, represented by 4-fluorobenzyl group, 3-chlorobenzyl group, 4-hydroxybenzyl group, 3-methoxybenzyl group, 4-methoxybenzyl group, 4-ethoxybenzyl group , 4-acetoxybenzyl group, 4-carboxybenzyl group, 4-methoxycarbonylbenzyl group and the like. Preferred R among the above 1 Examples thereof include a hydrogen atom, a methyl group, an ethyl group, a propyl group, a butyl group, a benzyl group and a 2-phenylethyl group, and among them, a hydrogen atom, a methyl group and an ethyl group are particularly preferable.
[0008]
R 2 Examples of the alkyl group having 1 to 4 carbon atoms represented by can include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, an isobutyl group, and a t-butyl group. Preferred R 2 Examples thereof include a hydrogen atom, a methyl group, an ethyl group, a propyl group, and a butyl group. Among them, a hydrogen atom, a methyl group, and an ethyl group are particularly preferable.
[0009]
Ar 1 Examples of the unsubstituted aromatic group represented by can include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, and a biphenylyl group. Examples of the substituent that the aromatic group may have include a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms, an acyloxy group having 1 to 5 carbon atoms, and a carboxyl group. , A carboxyalkyl group having 2 to 5 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, an alkoxycarbonylalkyl group having 3 to 6 carbon atoms, a cyano group, a tetrazolyl group, and a nitro group. 1 As the substituted aromatic group represented by: 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-methylphenyl group, 3 -Methylphenyl group, 4-methylphenyl group, 2-ethylphenyl group, 3-ethylphenyl group, 2,3-dimethylphenyl group, 2,4-dimethylphenyl group, 2,5-dimethylphenyl group, 2,6 -Dimethylphenyl group, 3,4-dimethylphenyl group, 3,5-dimethylphenyl group, 4-ethylphenyl group, 2-methylnaphthyl group, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-ethoxyphenyl group, -Ethoxyphenyl group, 4-ethoxyphenyl group, 2-acetoxyphenyl group, 3-acetoxyphenyl group, 4-acetoxyphenyl group, 2-carboxyphenyl group, 3-carboxyphenyl group, 4-carboxyphenyl group, 2-carboxy Methylphenyl group, 3-carboxymethylphenyl group, 4-carboxymethylphenyl group, 2-methoxycarbonylphenyl group, 3-methoxycarbonylphenyl group, 4-methoxycarbonylphenyl group, 2-ethoxycarbonylphenyl group, 3-ethoxycarbonyl Phenyl group, 4-ethoxycarbonylphenyl group, 2-methoxycarbonylmethylphenyl group, 3-methoxycarbonylmethylphenyl group, 4-methoxycarbonylmethylphenyl group, 2-ethoxycarbonylmethylphenyl group, 3 Ethoxycarbonylmethylphenyl group, 4-ethoxycarbonylmethylphenyl group, 2-cyanophenyl group, 3-cyanophenyl group, 4-cyanophenyl group, 2-tetrazolylphenyl group, 3-tetrazolylphenyl group, 4- Examples thereof include a tetrazolylphenyl group, a 2-nitrophenyl group, a 3-nitrophenyl group, and a 4-nitrophenyl group. Ar 1 As the unsubstituted aromatic heterocyclic group represented by the formula, furyl group, thienyl group, pyrrolyl group, oxazolyl group, thiazolyl group, pyrazolyl group, imidazolyl group, tetrazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, Examples thereof include a benzo [b] furyl group, a benzo [b] thienyl group, an indolyl group, a benzoxazolyl group, a benzothiazolyl group, a benzimidazolyl group, a quinolyl group, an isoquinolyl group, a quinazolinyl group, and a quinoxalinyl group. As a substituent that may be present on the aromatic heterocyclic group, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms, an acyloxy group having 1 to 5 carbon atoms, Examples include a carboxyl group, an alkoxycarbonyl group having 2 to 5 carbon atoms, a cyano group, and a nitro group. 1 As the substituted aromatic heterocyclic group represented by the formula: 3-methyl-2-furyl group, 4-methyl-2-furyl group, 5-methyl-2-furyl group, 2-methyl-3-furyl group, 4- Methyl-3-furyl group, 5-methyl-3-furyl group, 3-methoxy-2-furyl group, 4-methoxy-2-furyl group, 5-methoxy-2-furyl group, 2-methoxy-3-furyl Group, 4-methoxy-3-furyl group, 5-methoxy-3-furyl group, 3-chloro-2-furyl group, 4-chloro-2-furyl group, 5-chloro-2-furyl group, 2-chloro -3-furyl group, 4-chloro-3-furyl group, 5-chloro-3-furyl group, 3-fluoro-2-furyl group, 4-fluoro-2-furyl group, 5-fluoro-2-furyl group 2-fluoro-3-furyl group, 4-fluoro-3-furyl group, 5-fur Rho-3-furyl group, 3-methyl-2-thienyl group, 4-methyl-2-thienyl group, 5-methyl-2-thienyl group, 2-methyl-3-thienyl group, 4-methyl-3-thienyl group Group, 5-methyl-3-thienyl group, 3-methoxy-2-thienyl group, 4-methoxy-2-thienyl group, 5-methoxy-2-thienyl group, 2-methoxy-3-thienyl group, 4-methoxy -3-thienyl group, 5-methoxy-3-thienyl group, 3-chloro-2-thienyl group, 4-chloro-2-thienyl group, 5-chloro-2-thienyl group, 2-chloro-3-thienyl group 4-chloro-3-thienyl group, 5-chloro-3-thienyl group, 3-fluoro-2-thienyl group, 4-fluoro-2-thienyl group, 5-fluoro-2-thienyl group, 2-fluoro- 3-thienyl group, 4-fluoro -3-thienyl group, 5-fluoro-3-thienyl group, 2-methyl-3-pyridyl group, 4-methyl-3-pyridyl group, 5-methyl-3-pyridyl group, 6-methyl-3-pyridyl group 3-methyl-2-pyridyl group, 4-methyl-2-pyridyl group, 5-methyl-2-pyridyl group, 6-methyl-2-pyridyl group, 2-methyl-4-pyridyl group, 3-methyl- 4-pyridyl group, 5-methyl-4-pyridyl group, 6-methyl-4-pyridyl group, 2-methoxy-3-pyridyl group, 4-methoxy-3-pyridyl group, 5-methoxy-3-pyridyl group, 6-methoxy-3-pyridyl group, 3-methoxy-2-pyridyl group, 4-methoxy-2-pyridyl group, 5-methoxy-2-pyridyl group, 6-methoxy-2-pyridyl group, 2-methoxy-4 -Pyridyl group, 3-methoxy -4-pyridyl group, 5-methoxy-4-pyridyl group, 6-methoxy-4-pyridyl group, 2-ethoxy-3-pyridyl group, 4-ethoxy-3-pyridyl group, 3-ethoxy-2-pyridyl group 4-ethoxy-2-pyridyl group, 3-ethoxy-4-pyridyl group, 2-hydroxy-3-pyridyl group, 4-hydroxy-3-pyridyl group, 3-hydroxy-2-pyridyl group, 3-hydroxy- 4-pyridyl group, 2-chloro-3-pyridyl group, 4-chloro-3-pyridyl group, 3-chloro-2-pyridyl group, 4-chloro-2-pyridyl group, 3-chloro-4-pyridyl group, 5-methyl-2-pyrazyl group, 6-methyl-2-pyrazyl group, 5-methoxy-2-pyrazyl group, 6-methoxy-2-pyrazyl group, 5-ethoxy-2-pyrazyl group, 6-ethoxy-2 -Pirazi Groups, such as 5-chloro-2-pyrazinyl group, 6-chloro-2-pyrazinyl group and the like. Preferred Ar 1 As phenyl group, 1-naphthyl group, 2-naphthyl group, 4-fluorophenyl group, 3-chlorophenyl group, 2,3-dimethylphenyl group, 2-methoxyphenyl group, 2-ethoxyphenyl group, 4-carboxyphenyl Group, 4-methoxycarbonylphenyl group, 3-cyanophenyl group, 4-cyanophenyl group, 3-tetrazolylphenyl group, 4-tetrazolylphenyl group, 4-nitrophenyl group, pyridyl group, quinolyl group, 2 -Methyl-3-pyridyl group, 2-methoxy-3-pyridyl group, 2-ethoxy-3-pyridyl group, among which phenyl group, 1-naphthyl group, 2,3-dimethylphenyl group, 2 -Methoxyphenyl group, 4-carboxyphenyl group, 4-methoxycarbonylphenyl group, 3-cyanophenyl group, 4-sia Phenyl group, 3-tetrazolyl-phenyl group, 4-tetrazolyl-phenyl group is preferred.
[0010]
Ar 2 , Ar Three As a substituent which may be present on the phenyl group represented by formula (1), a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms, an acyloxy group having 1 to 5 carbon atoms, carboxyl Groups, C2-C5 alkoxycarbonyl groups, cyano groups, tetrazolyl groups, nitro groups, and specific Ar 2 , Ar Three As the substituted phenyl group represented by the formula: 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-methylphenyl group, 3- Methylphenyl group, 4-methylphenyl group, 2-ethylphenyl group, 3-ethylphenyl group, 2,3-dimethylphenyl group, 2,4-dimethylphenyl group, 2,5-dimethylphenyl group, 2,6- Dimethylphenyl group, 3,4-dimethylphenyl group, 3,5-dimethylphenyl group, 4-ethylphenyl group, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-ethoxyphenyl group, 3-ethoxyphenyl 4-ethoxyphenyl group, 2-acetoxyphenyl group, 3-acetoxyphenyl group, 4-acetoxyphenyl group, 2-carboxyphenyl group, 3-carboxyphenyl group, 4-carboxyphenyl group, 2-methoxycarbonylphenyl group, 3-methoxycarbonylphenyl group, 4-methoxycarbonylphenyl group, 2-cyanophenyl group, 3-cyanophenyl group, 4-cyanophenyl group, 2-tetrazolylphenyl group, 3-tetrazolylphenyl group, 4- Examples thereof include a tetrazolylphenyl group, a 2-nitrophenyl group, a 3-nitrophenyl group, and a 4-nitrophenyl group. Ar 2 , Ar Three Examples of the unsubstituted aromatic heterocyclic group represented by are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. Can be mentioned. As a substituent that may be present on the aromatic heterocyclic group, a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms, an acyloxy group having 1 to 5 carbon atoms, Examples include a carboxyl group, an alkoxycarbonyl group having 2 to 5 carbon atoms, a cyano group, and a nitro group. 2 , Ar Three As the substituted aromatic heterocyclic group represented by the formula: 3-methyl-2-furyl group, 4-methyl-2-furyl group, 5-methyl-2-furyl group, 2-methyl-3-furyl group, 4- Methyl-3-furyl group, 5-methyl-3-furyl group, 3-methoxy-2-furyl group, 4-methoxy-2-furyl group, 5-methoxy-2-furyl group, 2-methoxy-3-furyl Group, 4-methoxy-3-furyl group, 5-methoxy-3-furyl group, 3-chloro-2-furyl group, 4-chloro-2-furyl group, 5-chloro-2-furyl group, 2-chloro -3-furyl group, 4-chloro-3-furyl group, 5-chloro-3-furyl group, 3-fluoro-2-furyl group, 4-fluoro-2-furyl group, 5-fluoro-2-furyl group 2-fluoro-3-furyl group, 4-fluoro-3-furyl group, 5-fur Rho-3-furyl group, 3-methyl-2-thienyl group, 4-methyl-2-thienyl group, 5-methyl-2-thienyl group, 2-methyl-3-thienyl group, 4-methyl-3-thienyl group Group, 5-methyl-3-thienyl group, 3-methoxy-2-thienyl group, 4-methoxy-2-thienyl group, 5-methoxy-2-thienyl group, 2-methoxy-3-thienyl group, 4-methoxy -3-thienyl group, 5-methoxy-3-thienyl group, 3-chloro-2-thienyl group, 4-chloro-2-thienyl group, 5-chloro-2-thienyl group, 2-chloro-3-thienyl group 4-chloro-3-thienyl group, 5-chloro-3-thienyl group, 3-fluoro-2-thienyl group, 4-fluoro-2-thienyl group, 5-fluoro-2-thienyl group, 2-fluoro- 3-thienyl group, 4-fluoro -3-thienyl group, 5-fluoro-3-thienyl group, 2-methyl-3-pyridyl group, 4-methyl-3-pyridyl group, 5-methyl-3-pyridyl group, 6-methyl-3-pyridyl group 3-methyl-2-pyridyl group, 4-methyl-2-pyridyl group, 5-methyl-2-pyridyl group, 6-methyl-2-pyridyl group, 2-methyl-4-pyridyl group, 3-methyl- 4-pyridyl group, 5-methyl-4-pyridyl group, 6-methyl-4-pyridyl group, 2-methoxy-3-pyridyl group, 4-methoxy-3-pyridyl group, 5-methoxy-3-pyridyl group, 6-methoxy-3-pyridyl group, 3-methoxy-2-pyridyl group, 4-methoxy-2-pyridyl group, 5-methoxy-2-pyridyl group, 6-methoxy-2-pyridyl group, 2-methoxy-4 -Pyridyl group, 3-methoxy -4-pyridyl group, 5-methoxy-4-pyridyl group, 6-methoxy-4-pyridyl group, 2-ethoxy-3-pyridyl group, 4-ethoxy-3-pyridyl group, 3-ethoxy-2-pyridyl group 4-ethoxy-2-pyridyl group, 3-ethoxy-4-pyridyl group, 2-hydroxy-3-pyridyl group, 4-hydroxy-3-pyridyl group, 3-hydroxy-2-pyridyl group, 3-hydroxy- 4-pyridyl group, 2-chloro-3-pyridyl group, 4-chloro-3-pyridyl group, 3-chloro-2-pyridyl group, 4-chloro-2-pyridyl group, 3-chloro-4-pyridyl group, 5-methyl-2-pyrazyl group, 6-methyl-2-pyrazyl group, 5-methoxy-2-pyrazyl group, 6-methoxy-2-pyrazyl group, 5-ethoxy-2-pyrazyl group, 6-ethoxy-2 -Pirazi Groups, such as 5-chloro-2-pyrazinyl group, 6-chloro-2-pyrazinyl group and the like. Preferred Ar 2 , Ar Three As phenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 4-methylphenyl group, 4-methoxyphenyl group, 4-cyanophenyl group, 3-pyridyl group, 4-pyridyl group, Particularly preferred are phenyl group, 4-fluorophenyl group, 4-methylphenyl group, 4-methoxyphenyl group, 4-cyanophenyl group, 3-pyridyl group and 4-pyridyl group.
[0011]
Ar 2 And Ar Three When a third ring is formed by a group bonded to both of the following formulas in formula (I):
[Chemical 3]
As a structure represented by the following formula:
[0012]
[Formula 4]
The structure represented by these can be mentioned and these are also preferable.
[0013]
X represents a methine group (CH) or a nitrogen atom, Y represents a single bond or an oxygen atom when X is a methine group, represents a single bond when X is a nitrogen atom, and Z represents a methine group Y represents a hydrogen atom or a hydroxyl group when X is a single bond, and when X is a methine group and Y is an oxygen atom and X is a nitrogen atom (Y is a single bond), it represents a hydrogen atom. The following formula:
[0014]
[Chemical formula 5]
As a preferable structure represented by the following formula:
[0015]
[Chemical 6]
Among these, among these, the following formula:
[0016]
[Chemical 7]
The structure represented by is particularly preferable.
m represents 2 to 6, preferably 3 to 5, particularly preferably 3 to 4.
Specific preferred uracil derivatives of the present invention are shown in Tables 1 and 2.
[0017]
[Table 1]
[0018]
[Table 2]
[0019]
The uracil derivative represented by the general formula (I) can be synthesized according to the following formula.
[Chemical 8]
(In the formula, Hal represents a halogen atom, R 1 , R 2 , Ar 1 , Ar 2 , Ar Three , X, Y, Z and m are as defined above. )
[0020]
That is, it can be synthesized by reacting 1-aryl-6-halo-2,4 (1H, 3H) -pyrimidinedione represented by the formula (II) with an amine represented by the formula (III). 1-aryl-6-halo-2,4 (1H, 3H) -pyrimidinedione represented by the formula (II) can be synthesized, for example, by the method described in JP-A-8-109171. The amine represented by the formula (III) can be synthesized, for example, by the method described in JP-A-11-310581.
[0021]
Since the uracil derivative represented by the general formula (I) has a basic tertiary amino group, it can form salts with various acids. Examples of the pharmaceutically acceptable salt include hydrochloride, sulfate, acetate, succinate and the like. Moreover, when the uracil derivative has an acidic substituent, it can form a salt with various bases. Examples of the pharmaceutically acceptable salt in this case include sodium salt, potassium salt, calcium salt, ammonium salt and the like. These salts can be obtained by a conventional method such as recrystallization after mixing a uracil derivative and an acid or base.
[0022]
The therapeutic agents for allergic diseases of the present invention (antihistamines, antiallergic agents, and allergic conjunctivitis, allergic rhinitis, chronic urticaria, atopic dermatitis, asthma or chronic bronchitis preventive and therapeutic agent) are tablets, capsules In addition to oral preparations such as powders, it can be used in various dosage forms such as injections and external preparations. For example, the uracil derivative or pharmaceutically acceptable salt of the present invention can be mixed with an ointment base such as petrolatum to form an ointment. The uracil derivative of the present invention or a pharmaceutically acceptable salt and excipients such as lactose and starch, lubricants such as magnesium stearate and talc, and other conventional additives may be mixed to form tablets. it can.
[0023]
The dose of the therapeutic agent for allergic diseases of the present invention is appropriately determined according to the patient's sex, age, weight, type of disease, symptoms, etc., for example, atopic dermatitis, contact dermatitis, psoriasis, etc. In this skin disease, an ointment containing 0.01 to 10% of the active ingredient can be applied to the affected area once to several times a day. In general, oral preparations such as tablets, capsules and powders can be administered in the range of 0.01 to 100 mg / kg per day or in a single dose or divided into several doses.
[0024]
【Example】
EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.
Reference Example 1 3- (4-Diphenylmethyl-1-piperazinyl) propylamine
1- (Diphenylmethyl) piperazine 5.0 g (20 mmol) was dissolved in 150 ml of acetonitrile, 5.6 g (21 mmol) of 3-bromopropylphthalimide and 2.9 ml (21 mmol) of triethylamine were added, and the mixture was stirred at 80 ° C. for 2 hours. Acetonitrile was distilled off, the residue was partitioned between dichloromethane and 5% aqueous sodium hydrogen carbonate solution, and the organic layer was washed with 5% aqueous citric acid solution and 10% aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. Dichloromethane was concentrated, the residue was dissolved in 200 ml of ethanol, 3.74 ml (59 mmol) of 80% hydrazine was added, and the mixture was heated to reflux for 2 hours. Ethanol was distilled off, the residue was partitioned between 1N aqueous sodium hydroxide solution and dichloromethane, and the organic layer was washed with 10% aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. Dichloromethane was distilled off to obtain the title compound (5.5 g (18 mmol), 2-step yield 90%).
[0025]
Reference Example 2 3- (4-Bis (4-fluorophenyl) methyl-1-piperazinyl) propylamine
The title compound was obtained in the same manner as in Reference Example 1 using 1-bis (4-fluorophenyl) methylpiperazine instead of 1- (diphenylmethyl) piperazine.
[0026]
Reference Example 3 3- (4-((4-Methylphenyl) phenylmethyl) -1-piperazinyl) propylamine
The title compound was obtained in the same manner as in Reference Example 1 using 1-((4-methylphenyl) phenylmethyl) piperazine instead of 1- (diphenylmethyl) piperazine.
[0027]
Reference Example 4 3- (4-((4-Chlorophenyl) phenylmethyl) -1-piperazinyl) propylamine
The title compound was obtained in the same manner as in Reference Example 1 except that 1-((4-chlorophenyl) phenylmethyl) piperazine was used in place of 1- (diphenylmethyl) piperazine.
[0028]
Reference Example 5 3- (4-((4-Methoxyphenyl) phenylmethyl) -1-piperazinyl) propylamine
The title compound was obtained in the same manner as in Reference Example 1 except that 1-((4-methoxyphenyl) phenylmethyl) piperazine was used in place of 1- (diphenylmethyl) piperazine.
[0029]
Reference Example 6 3- (4-((4-Fluorophenyl) phenylmethyl) -1-piperazinyl) propylamine
The title compound was obtained in the same manner as in Reference Example 1 except that 1-((4-fluorophenyl) phenylmethyl) piperazine was used in place of 1- (diphenylmethyl) piperazine.
[0030]
Reference Example 7 3- (4- (hydroxydiphenylmethyl) -1-piperidinyl) propylamine
The title compound was obtained in the same manner as in Reference Example 1 using α, α-diphenyl-4-piperidinylmethanol instead of 1- (diphenylmethyl) piperazine.
[0031]
Reference Example 8 3- (4- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) -1-piperazinyl) propylamine
The title compound was obtained in the same manner as in Reference Example 1 using 1- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) piperazine instead of 1- (diphenylmethyl) piperazine.
[0032]
Reference Example 9 3- (4- (Diphenylmethoxy) -1-piperidinyl) propylamine
Dissolve benzhydrol 5.0 g (27 mmol) in 190 ml of toluene, add 2.7 g (27 mmol) of 4-hydroxypiperidine and 5.7 g (30 mmol) of p-toluenesulfonic acid monohydrate and heat at reflux for 3 hours. . After cooling, the reaction solution was washed successively with 5% aqueous sodium hydroxide solution and distilled water and dried over anhydrous sodium sulfate. A portion of the residue obtained by distilling off toluene, 1.2 g, was dissolved in 50 ml of acetonitrile, 1.3 g (5.0 mmol) of 3-bromopropylphthalimide and 697 μl (5.0 mmol) of triethylamine were added, and the mixture was stirred at 80 ° C. for 2 hours. . After acetonitrile was distilled off, the residue was partitioned between dichloromethane and 5% aqueous sodium hydrogen carbonate solution, and the organic layer was washed with 5% aqueous citric acid solution and 10% aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Dichloromethane was distilled off under reduced pressure and purified by silica gel chromatography (dichloromethane: methanol = 70: 1 to 50: 1) to obtain 3- (4- (diphenylmethoxy) -1-piperidinyl) propylphthalimide. It melt | dissolved in ethanol 50 ml, 80% hydrazine 1.76 ml (28 mmol) was added, and it heated at reflux for 2 hours. After distilling off ethanol, the residue was partitioned between 1N aqueous sodium hydroxide solution and dichloromethane, and the organic layer was washed with 10% aqueous sodium chloride solution and dried over sodium sulfate. Dichloromethane was distilled off under reduced pressure to obtain the title compound (1.7 g (5.2 mmol), yield of 3 steps: 19%).
[0033]
Example 1 6- [3- [4- (Diphenylmethyl) -1-piperazinyl] propylamino] -3-methyl-1-phenyluracil (Compound 17)
325 mg (1.1 mmol) of 3- (4- (diphenylmethyl) -1-piperazinyl) propylamine was dissolved in 5 ml of dimethyl sulfoxide, 237 mg (1.0 mmol) of 6-chloro-3-methyl-1-phenyluracil, Sodium carbonate 138 mg (1.3 mmol) was added, and the mixture was stirred at 100 ° C for 1.5 hours. After allowing to cool, distilled water was added and extracted with ethyl acetate, and the organic layer was washed twice with distilled water. After concentration, it was redissolved in 30 ml of ethyl acetate and extracted with 1N hydrochloric acid. The aqueous layer was adjusted to pH 11 with 5N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with 10% aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. Ethyl acetate was distilled off and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 80: 1-50: 1) to give the title compound (167 mg, 0.33 mmol, yield 33%).
1 H-NMR (CDCl Three , δppm): 7.15-7.56 (15H, m), 4.94 (1H, s), 4.34 (1H, br.t, J = 5.1 Hz), 4.17 (1H, s), 3.32 (3H, s), 3.07 ( 2H, dt, J = 5.1 Hz, J = 6.5 Hz), 2.23-2.28 (10H, m), 1.62 (2H, tt, J = 6.5 Hz)
Time-of-flight mass spectrometer (TOF-Mass): 510 (M + H)
[0034]
Example 2 6- [3- [4- (Diphenylmethyl) -1-piperazinyl] ethylamino] -3-methyl-1-phenyluracil (Compound 16)
The title compound was obtained in the same manner as in Example 1, except that 2- (4- (diphenylmethyl) -1-piperazinyl) ethylamine was used instead of 3- (4- (diphenylmethyl) -1-piperazinyl) propylamine. .
1 H-NMR (CDCl Three , δppm): 7.19-7.46 (15H, m), 5.00 (1H, br.t, J = 4.1 Hz), 4.85 (1H, s), 4.21 (1H, s), 3.33 (3H, s), 2.97 ( 2H, dt, J = 4.1 Hz, J = 5.9 Hz), 2.42 (2H, t, J = 5.9 Hz), 2.20-2.30 (10H, m)
Time-of-flight mass spectrometer (TOF-Mass): 496 (M + H)
[0035]
Example 3 6- [3- [4- (Diphenylmethyl) -1-piperazinyl] butylamino] -3-methyl-1-phenyluracil (Compound 18)
The title compound was obtained in the same manner as in Example 1, except that 4- (4- (diphenylmethyl) -1-piperazinyl) butylamine was used instead of 3- (4- (diphenylmethyl) -1-piperazinyl) propylamine. .
1 H-NMR (CDCl Three , δppm): 7.14-7.56 (15H, m), 4.19 (1H, s), 3.70 (1H, br.t, J = 4.9 Hz), 3.23 (3H, s), 3.00 (2H, dt, J = 4.9 Hz, J = 6.5 Hz), 2.37 (8H, m), 2.26 (2H, t, J = 6.5 Hz), 1.33-1.50 (4H, m)
Time-of-flight mass spectrometer (TOF-Mass): 524 (M + H)
[0036]
Example 4 6- [3- [4- (Diphenylmethoxy) -1-piperidinyl] propylamino] -3-methyl-1-phenyluracil (Compound 28)
The title compound was obtained in the same manner as in Example 1, except that 3- (4- (diphenylmethoxy) -1-piperidinyl) propylamine was used instead of 3- (4- (diphenylmethyl) -1-piperazinyl) propylamine. It was.
1 H-NMR (CDCl Three , δppm): 7.23-7.55 (15H, m), 5.47 (1H, s), 4.93 (1H, s), 4.74 (1H, br.t, J = 4.3 Hz), 3.32 (4H, m), 3.09 ( 2H, dt, J = 4.3 Hz, J = 6.5 Hz), 2.51 (2H, m), 2.25 (2H, t, J = 6.5 Hz), 1.92 (2H, m), 1.57-1.63 (4H, m) 1.41 (2H, m)
Time-of-flight mass spectrometer (TOF-Mass): 525 (M + H)
[0037]
Example 5 3-Ethoxycarbonylmethyl-6- [3- [4- (diphenylmethyl) -1-piperazinyl] propylamino] -1-phenyluracil (Compound 106)
The title compound was obtained in the same manner as in Example 1, except that 6-chloro-3-ethoxycarbonylmethyl-1-phenyluracil was used instead of 6-chloro-3-methyl-1-phenyluracil.
1 H-NMR (CDCl Three , δppm): 7.19-7.53 (14H, m), 5.30 (1H, s), 4.87 (1H, m), 4.67 (2H, s), 4.20 (2H, q, J = 7.0 Hz), 3.33 (2H, m), 2.27-2.87 (10H, m), 1.59 (2H, m), 1.26 (2H, t, J = 7.0 Hz),
Time-of-flight mass spectrometer (TOF-Mass): 582 (M + H)
[0038]
Example 6 6- [3- [4- (Diphenylmethyl) -1-piperazinyl] propylamino] -3-methyl-1- (1-naphthyl) uracil (Compound 728)
The title compound was obtained in the same manner as in Example 1, except that 6-chloro-3-methyl-1- (1-naphthyl) uracil was used instead of 6-chloro-3-methyl-1-phenyluracil.
1 H-NMR (CDCl Three , δppm): 7.99 (2H, m), 7.52-7.63 (10H, m), 7.37 (1H, d, J = 7.6 Hz), 7.17-7.38 (4H, m), 5.03 (1H, s), 4.42 ( 1H, br.t, J = 4.9 Hz), 4.09 (1H, s), 3.36 (3H, s), 3.04 (2H, m), 2.01-2.08 (10H, m), 1.53 (2H, m)
Time-of-flight mass spectrometer (TOF-Mass): 560 (M + H)
[0039]
Example 7 6- [3- [4- (Diphenylmethoxy) -1-piperazinyl] propylamino] -3-methyl-1- (1-naphthyl) uracil (Compound 734)
3- (4- (diphenylmethyl) -1-piperazinyl) propylamine using 6-chloro-3-methyl-1- (1-naphthyl) uracil instead of 6-chloro-3-methyl-1-phenyluracil The title compound was obtained in the same manner as in Example 1, except that 3- (4- (diphenylmethoxy) -1-piperidinyl) propylamine was used in place of.
1 H-NMR (CDCl Three , δppm): 7.93 (1H, d, J = 8.1 Hz), 7.84 (1H, m), 7.47-7.63 (5H, m), 7.32 (10H, m), 5.42 (1H, s), 5.02 (1H, s), 4.77 (1H, brt, J = 4.9 Hz), 3.36 (3H, s), 3.21 (1H, m), 3.05 (2H, m), 2.32 (2H, m), 2.07 (4H, m), 1.49-1.73 (6H, m)
Time-of-flight mass spectrometer (TOF-Mass): 575 (M + H)
[0040]
Example 8 6- [3- [4- (Diphenylmethyl) -1-piperazinyl] propylamino] -1- (4-fluorophenyl) -3-methyluracil (Compound 758)
The title compound was obtained in the same manner as in Example 1, except that 6-chloro-1- (4-fluorophenyl) -3-methyluracil was used instead of 6-chloro-3-methyl-1-phenyluracil.
1 H-NMR (CDCl Three , δppm): 7.15-7.42 (14H, m), 4.93 (1H, s), 4.74 (1H, br.s), 4.16 (1H, s), 3.31 (3H, s), 3.19 (2H, m), 2.18-2.31 (10H, m), 1.67 (2H, m)
Time-of-flight mass spectrometer (TOF-Mass): 529 (M + H)
[0041]
Example 9 1- (4-Chlorophenyl) -6- [3- [4- (diphenylmethyl) -1-piperazinyl] propylamino] -3-methyluracil (Compound 788)
The title compound was obtained in the same manner as in Example 1, except that 6-chloro-1- (4-chlorophenyl) -3-methyluracil was used instead of 6-chloro-3-methyl-1-phenyluracil.
1 H-NMR (CDCl Three , δppm): 7.14-7.54 (14H, m), 4.93 (1H, s), 4.80 (1H, br.t, J = 4.9 Hz), 4.21 (1H, s), 3.31 (3H, s), 3.08 ( 2H, dt, J = 4.9 Hz, J = 6.1 Hz), 2.15-2.32 (10H, m), 1.65 (2H, tt, J = 6.1 Hz)
Time-of-flight mass spectrometer (TOF-Mass): 545 (M + H)
[0042]
Example 10 1- (4-Bromophenyl) -6- [3- [4- (diphenylmethyl) -1-piperazinyl] propylamino] -3-methyluracil (Compound 818)
The title compound was obtained in the same manner as in Example 1, except that 1- (4-bromophenyl) -6-chloro-3-methyluracil was used instead of 6-chloro-3-methyl-1-phenyluracil.
1 H-NMR (CDCl Three , δppm): 7.14-7.71 (14H, m), 4.93 (1H, s), 4.78 (1H, br.t, J = 4.9 Hz), 4.24 (1H, s), 3.31 (3H, s), 3.08 ( 2H, dt, J = 4.9 Hz, J = 6.3 Hz), 2.15-2.32 (10H, m), 1.62 (2H, tt, J = 6.3 Hz)
Time-of-flight mass spectrometer (TOF-Mass): 589 (M + H)
[0043]
Example 11 6- [3- [4- (Diphenylmethyl) -1-piperazinyl] propylamino] -3-methyl-1- (4-methylphenyl) uracil (Compound 848)
The title compound was obtained in the same manner as in Example 1, except that 6-chloro-3-methyl-1- (4-methylphenyl) uracil was used instead of 6-chloro-3-methyl-1-phenyluracil.
1 H-NMR (CDCl Three , δppm): 7.13-7.40 (14H, m), 4.92 (1H, s), 4.38 (1H, br.t, J = 4.7 Hz), 4.15 (1H, s), 3.16 (3H, s), 3.07 ( 2H, dt, J = 4.7 Hz, J = 6.5 Hz), 2.42 (3H, s), 2.24-2.37 (10H, m), 1.62 (2H, tt, J = 6.5 Hz)
Time-of-flight mass spectrometer (TOF-Mass): 524 (M + H)
[0044]
Example 12 1- (2,3-Dimethylphenyl) -6- [3- [4- (diphenylmethyl) -1-piperazinyl] propylamino] -3-methyluracil (Compound 878)
The title compound was obtained in the same manner as in Example 1, except that 6-chloro-1- (2,3-dimethylphenyl) -3-methyluracil was used instead of 6-chloro-3-methyl-1-phenyluracil. .
1 H-NMR (CDCl Three , δppm): 7.14-7.40 (13H, m), 4.95 (1H, s), 4.34 (1H, br.t, J = 4.9 Hz), 4.17 (1H, s), 3.33 (3H, s), 3.07 ( 2H, m), 2.34 (3H, s), 2.22-2.27 (10H, m), 2.02 (3H, s), 1.62 (2H, m),
Time-of-flight mass spectrometer (TOF-Mass): 538 (M + H)
[0045]
Example 13 1- (2,3-Dimethylphenyl) -6- [3- [4- (diphenylmethoxy) -1-piperidinyl] propylamino] -3-methyluracil (Compound 884)
Using 6-chloro-1- (2,3-dimethylphenyl) -3-methyluracil instead of 6-chloro-3-methyl-1-phenyluracil, 3- (4- (diphenylmethyl) -1-piperazinyl The title compound was obtained in the same manner as in Example 1, except that 3- (4- (diphenylmethoxy) -1-piperidinyl) propylamine was used in place of propylamine.
1 H-NMR (CDCl Three , δppm): 7.22-7.33 (13H, m), 5.47 (1H, s), 4.94 (1H, s), 4.59 (1H, brt, J = 4.9 Hz), 3.33 (4H, m), 3.08 (2H, dt, J = 4.9 Hz, J = 6.2 Hz), 2.51 (2H, m), 2.30 (3H, s), 2.23 (2H, t, J = 6.2 Hz), 2.02 (3H, s) 1.93 (2H, m ), 1.57-1.66 (4H, m), 1.47 (2H, m)
Time-of-flight mass spectrometer (TOF-Mass): 553 (M + H)
[0046]
Example 14 6- [3- [4- (Diphenylmethyl) -1-piperazinyl] propylamino] -1- (2-methoxyphenyl) -3-methyluracil (Compound 908)
The title compound was obtained in the same manner as in Example 1, except that 6-chloro-1- (2-methoxy) -3-methyluracil was used instead of 6-chloro-3-methyl-1-phenyluracil.
1 H-NMR (CDCl Three , δppm): 7.03-7.51 (14H, m), 4.93 (1H, s), 4.32 (1H, br.t, J = 4.9 Hz), 4.18 (1H, s), 3.80 (3H, s), 3.32 ( 3H, s), 3.07 (2H, m), 2.34 (3H, s), 2.22-2.28 (10H, m), 1.62 (2H, m),
Time-of-flight mass spectrometer (TOF-Mass): 540 (M + H)
[0047]
Example 15 6- [3- [4- (Diphenylmethoxy) -1-piperidinyl] propylamino] -1- (2-methoxyphenyl) -3-methyluracil (Compound 914)
Using 6-chloro-1- (2-methoxyphenyl) -3-methyluracil instead of 6-chloro-3-methyl-1-phenyluracil, 3- (4- (diphenylmethyl) -1-piperazinyl) propyl The title compound was obtained in the same manner as in Example 1, except that 3- (4- (diphenylmethoxy) -1-piperidinyl) propylamine was used instead of amine.
1 H-NMR (CDCl Three , δppm): 7.19-7.45 (13H, m), 7.06 (2H, m), 5.74 (1H, s), 4.92 (1H, s), 4.65 (1H, br.t, J = 4.9 Hz), 3.80 ( 3H, s), 3.32-3.41 (4H, m), 3.09 (2H, s), 2.53 (2H, m), 2.24 (2H, t, J = 6.2 Hz), 1.98 (2H, m), 1.60-1.72 (4H, m), 1.49 (2H, m)
Time-of-flight mass spectrometer (TOF-Mass): 555 (M + H)
[0048]
Example 16 6- [3- [4- (Diphenylmethyl) -1-piperazinyl] propylamino] -1- (4-methoxyphenyl) -3-methyluracil (Compound 938)
The title compound was obtained in the same manner as in Example 1, except that 6-chloro-1- (4-methoxyphenyl) -3-methyluracil was used instead of 6-chloro-3-methyl-1-phenyluracil.
1 H-NMR (CDCl Three , δppm): 7.40 (4H, d, J = 7.4 Hz), 7.14-7.29 (11H, m), 4.91 (1H, s), 4.60 (1H, br.s), 4.16 (1H, s), 3.85 ( 1H, s), 3.32 (3H, s), 3.07 (2H, m), 2.20-2.30 (10H, m), 1.64 (2H, m)
Time-of-flight mass spectrometer (TOF-Mass): 541 (M + H)
[0049]
Example 17 6- [3- [4- (Diphenylmethyl) -1-piperazinyl] propylamino] -3-methyl-1- (4-trifluoromethylphenyl) uracil (Compound 968)
The title compound was obtained in the same manner as in Example 1, except that 6-chloro-3-methyl-1- (4-trifluoromethyl) uracil was used instead of 6-chloro-3-methyl-1-phenyluracil.
1 H-NMR (CDCl Three , δppm): 7.83 (2H, d, J = 8.4 Hz), 7.44 (2H, d, J = 8.4 Hz), 7.14-7.39 (12H, m), 4.96 (1H, s), 4.62 (1H, br. s), 4.16 (1H, s), 3.32 (3H, s), 3.11 (2H, m), 2.34 (10H, m), 1.59 (2H, m),
Time-of-flight mass spectrometer (TOF-Mass): 579 (M + H)
[0050]
Example 18 1- (4-Ethoxycarbonylmethylphenyl) -3-ethyl-6- [3- [4- (diphenylmethyl) -1-piperazinyl] propylamino] uracil (Compound 1005)
The title compound was obtained in the same manner as in Example 1, except that 6-chloro-1- (4-ethoxycarbonylmethylphenyl) -3-ethyluracil was used instead of 6-chloro-3-methyl-1-phenyluracil. .
1 H-NMR (CDCl Three , δppm): 7.14-7.44 (14H, m), 4.92 (1H, s), 4.24 (1H, br.t, J = 4.9 Hz), 4.10-4.18 (3H, m), 3.97 (2H, q, J = 7.0 Hz), 3.66 (2H, s), 3.06 (2H, dt, J = 6.5 Hz, J = 4.9 Hz), 2.23-2.31 (10H, m), 1.65 (2H, m), 1.20-1.30 (6H , m),
Time-of-flight mass spectrometer (TOF-Mass): 611 (M + H)
[0051]
Example 19 6- [3- [4- (Diphenylmethyl) -1-piperazinyl] propylamino] -1- (3-ethoxycarbonylphenyl) -3-methyluracil (Compound 1058)
The title compound was obtained in the same manner as in Example 1, except that 6-chloro-1- (3-ethoxycarbonylphenyl) -3-methyluracil was used instead of 6-chloro-3-methyl-1-phenyluracil.
1 H-NMR (CDCl Three , δppm): 7.78 (1H, d, J = 7.8 Hz), 7.98 (1H, s), 7.14-7.63 (12H, m), 4.96 (1H, s), 4.56 (1H, br.t, J = 4.9 Hz), 4.37 (2H, q, J = 7.6 Hz), 4.11 (1H, s), 3.32 (3H, s), 3.09 (2H, dt, J = 4.9 Hz, J = 6.5 Hz), 2.11-2.30 ( 10H, m), 1.66 (2H, tt, J = 6.5 Hz), 1.35 (3H, t, J = 7.6 Hz),
Time-of-flight mass spectrometer (TOF-Mass): 583 (M + H)
[0052]
Example 20 6- [3- [4- (Diphenylmethyl) -1-piperazinyl] propylamino] -1- (4-ethoxycarbonylphenyl) -3-methyluracil (Compound 1088)
The title compound was obtained in the same manner as in Example 1, except that 6-chloro-1- (4-ethoxycarbonylphenyl) -3-methyluracil was used instead of 6-chloro-3-methyl-1-phenyluracil.
1 H-NMR (CDCl Three , δppm): 8.24 (2H, d, J = 8.4 Hz), 7.16-7.42 (12H, m), 4.95 (1H, s), 4.64 (1H, br.t, J = 4.9 Hz), 4.44 (2H, q, J = 7.3 Hz), 4.10 (1H, s), 3.32 (3H, s), 3.07 (2H, m), 2.26-2.51 (10H, m), 1.66 (2H, m), 1.35 (3H, t , J = 7.3 Hz)
Time-of-flight mass spectrometer (TOF-Mass): 583 (M + H)
[0053]
Example 21 6- [3- [4- (Diphenylmethoxy) -1-piperidinyl] propylamino] -1- (4-ethoxycarbonylphenyl) -3-methyluracil (Compound 1094)
Using 6-chloro-1- (4-ethoxycarbonylphenyl) -3-methyluracil instead of 6-chloro-3-methyl-1-phenyluracil, 3- (4- (diphenylmethyl) -1-piperazinyl) The title compound was obtained in the same manner as in Example 1, except that 3- (4- (diphenylmethoxy) -1-piperidinyl) propylamine was used instead of propylamine.
1 H-NMR (CDCl Three , δppm): 8.20 (2H, d, J = 8.4 Hz), 7.23-7.32 (14H, m), 5.44 (1H, s), 4.96 (1H, s), 4.63 (1H, br.t, J = 4.6 Hz), 4.30 (2H, q, J = 7.0Hz), 3.32 (4H, m), 3.08 (2H, dt, J = 4.6 Hz, J = 5.9 Hz), 2.46 (2H, m), 2.25 (2H, t, J = 5.9 Hz), 1.99 (2H, m), 1.51-1.62 (8H, m), 1.33 (3H, t, J = 7.0 Hz)
Time-of-flight mass spectrometer (TOF-Mass): 597 (M + H)
[0054]
Example 22 1- (3-Cyanophenyl) -6- [3- [4- (diphenylmethyl) -1-piperazinyl] propylamino] -3-methyluracil (Compound 1298)
The title compound was obtained in the same manner as in Example 1, except that 6-chloro-1- (3-cyanophenyl) -3-methyluracil was used instead of 6-chloro-3-methyl-1-phenyluracil.
1 H-NMR (CDCl Three , δppm): 7.78 (1H, d, J = 7.8 Hz), 7.71 (2H, d, J = 7.8 Hz), 7.56 (1H, m), 7.15-7.42 (10H, m), 4.97 (1H, s) , 4.68 (1H, br.t, J = 4.9 Hz), 4.19 (1H, s), 3.47 (3H, s), 3.12 (2H, dt, J = 4.9 Hz, J = 5.9 Hz), (2H, m ), 2.12-2.34 (10H, m), 1.66 (2H, tt, J = 5.9 Hz)
Time-of-flight mass spectrometer (TOF-Mass): 537 (M + H)
[0055]
Example 23 1- (4-Cyanophenyl) -6- [3- [4- (diphenylmethyl) -1-piperazinyl] propylamino] -3-methyluracil (Compound 1328)
The title compound was obtained in the same manner as in Example 1, except that 6-chloro-1- (4-cyanophenyl) -3-methyluracil was used instead of 6-chloro-3-methyl-1-phenyluracil.
1 H-NMR (CDCl Three , δppm): 7.85 (2H, d, J = 8.4 Hz), 7.17-7.47 (12H, m), 4.96 (1H, s), 4.83 (1H, br.t, J = 4.6 Hz), 4.20 (1H, s), 3.30 (3H, s), 3.10 (2H, dt, J = 4.6 Hz, J = 6.1 Hz), 2.11-2.31 (10H, m), 1.65 (2H, tt, J = 6.1 Hz)
Time-of-flight mass spectrometer (TOF-Mass): 535 (M + H)
[0056]
Example 24 1- (4-Cyanophenyl) -6- [3- [4- (hydroxydiphenylmethyl) -1-piperidinyl] propylamino] -3-methyluracil (Compound 1333)
Using 6-chloro-1- (4-cyanophenyl) -3-methyluracil instead of 6-chloro-3-methyl-1-phenyluracil, 3- (4- (diphenylmethyl) -1-piperazinyl) propyl The title compound was obtained in the same manner as in Example 1, except that 3- (4- (hydroxydiphenylmethyl) -1-piperidinyl) propylamine was used in place of the amine.
1 H-NMR (CDCl Three , δppm): 8.03 (2H, d, J = 8.6 Hz), 7.57 (2H, d, J = 8.6 Hz), 7.09-7.51 (10H, m), 5.71 (1H, m), 5.23 (1H, s) , 4.82 (1H, m), 3.08 (3H, s), 2.97 (2H, m), 2.77 (2H, m) 2.16 (2H, m), 1.80 (2H, m), 1.35-1.53 (4H, m) , 1.19 (2H, m)
Time-of-flight mass spectrometer (TOF-Mass): 550 (M + H)
[0057]
Example 25 1- (4-Cyanophenyl) -6- [3- [4- (diphenylmethoxy) -1-piperidinyl] propylamino] -3-methyluracil (Compound 1334)
Using 6-chloro-1- (4-cyanophenyl) -3-methyluracil instead of 6-chloro-3-methyl-1-phenyluracil, 3- (4- (diphenylmethyl) -1-piperazinyl) propyl The title compound was obtained in the same manner as in Example 1, except that 3- (4- (diphenylmethoxy) -1-piperidinyl) propylamine was used instead of amine.
1 H-NMR (CDCl Three , δppm): 7.78 (2H, d, J = 8.1 Hz), 7.44 (2H, d, J = 8.1 Hz), 7.22-7.37 (10H, m), 5.47 (1H, s), 4.97 (1H, s) , 4.93 (1H, br.t, J = 4.6 Hz), 3.30-3.45 (4H, m), 3.08 (2H, dt, J = 4.6 Hz, J = 5.8 Hz), 2.51 (2H, m), 2.29 ( 2H, t, J = 5.8 Hz), 1.92 (2H, m), 1.61-1.65 (4H, m), 1.32 (2H, m)
Time-of-flight mass spectrometer (TOF-Mass): 550 (M + H)
[0058]
Example 26 1- (4-Cyanophenyl) -6- [3- [4-[(4-fluorophenyl) phenylmethyl] -1-piperazinyl] propylamino] -3-methyluracil (Compound 1341)
Using 6-chloro-1- (4-cyanophenyl) -3-methyluracil instead of 6-chloro-3-methyl-1-phenyluracil, 3- (4- (diphenylmethyl) -1-piperazinyl) propyl The title compound was obtained in the same manner as in Example 1, except that 3- (4-((4-fluorophenyl) phenylmethyl) -1-piperazinyl) propylamine was used in place of the amine.
1 H-NMR (CDCl Three , δppm): 7.86 (2H, d, J = 8.6 Hz), 6.93-7.48 (11H, m), 4.96 (1H, s), 4.83 (1H, brt, J = 4.9 Hz), 4.19 (1H, s) , 3.31 (3H, s), 3.10 (2H, dt, J = 4.9 Hz, J = 6.2 Hz), 2.07-2.33 (10H, m), 1.65 (2H, tt, J = 6.2 Hz)
Time-of-flight mass spectrometer (TOF-Mass): 553 (M + H)
[0059]
Example 27 6- [3- [4-[(4-Chlorophenyl) phenylmethyl] -1-piperazinyl] propylamino] -1- (4-cyanophenyl) -3-methyluracil (Compound 1343)
Using 6-chloro-1- (4-cyanophenyl) -3-methyluracil instead of 6-chloro-3-methyl-1-phenyluracil, 3- (4- (diphenylmethyl) -1-piperazinyl) propyl The title compound was obtained in the same manner as in Example 1, except that 3- (4-((4-chlorophenyl) phenylmethyl) -1-piperazinyl) propylamine was used instead of amine.
1 H-NMR (CDCl Three , δppm): 7.86 (2H, d, J = 8.6 Hz), 7.46 (2H, d, J = 8.6 Hz), 7.16-7.41 (9H, m), 4.97 (1H, s), 4.81 (1H, br. t, J = 5.1 Hz), 4.18 (1H, s), 3.31 (3H, s), 3.09 (2H, dt, J = 5.1 Hz, J = 6.2 Hz), 2.08-2.33 (10H, m), 1.65 ( (2H, tt, J = 6.2 Hz)
Time-of-flight mass spectrometer (TOF-Mass): 570 (M + H)
[0060]
Example 28 1- (4-Cyanophenyl) -3-methyl-6- [3- [4-[(4-methylphenyl) phenylmethyl] -1-piperazinyl] propylamino] uracil (Compound 1345)
Using 6-chloro-1- (4-cyanophenyl) -3-methyluracil instead of 6-chloro-3-methyl-1-phenyluracil, 3- (4- (diphenylmethyl) -1-piperazinyl) propyl The title compound was obtained in the same manner as in Example 1, except that 3- (4-((4-methylphenyl) phenylmethyl) -1-piperazinyl) propylamine was used in place of the amine.
1 H-NMR (CDCl Three , δppm): 7.85 (2H, d, J = 8.6 Hz), 7.07-7.47 (11H, m), 4.96 (1H, s), 4.86 (1H, brt, J = 4.9 Hz), 4.16 (1H, s) , 3.30 (3H, s) 3.09 (2H, dt, J = 4.9 Hz, J = 6.2 Hz), 2.09-2.33 (13H, m), 1.65 (2H, tt, J = 6.2 Hz)
Time-of-flight mass spectrometer (TOF-Mass): 549 (M + H)
[0061]
Example 29 1- (4-Cyanophenyl) -6- [3- [4-[(4-methoxyphenyl) phenylmethyl] -1-piperazinyl] propylamino] -3-methyluracil (Compound 1347)
Using 6-chloro-1- (4-cyanophenyl) -3-methyluracil instead of 6-chloro-3-methyl-1-phenyluracil, 3- (4- (diphenylmethyl) -1-piperazinyl) propyl The title compound was obtained in the same manner as in Example 1, except that 3- (4-((4-methoxyphenyl) phenylmethyl) -1-piperazinyl) propylamine was used in place of the amine.
1 H-NMR (CDCl Three , δppm): 7.85 (2H, d, J = 8.6 Hz), 7.25-7.47 (9H, m), 6.82 (2H, d, J = 8.6 Hz), 4.96 (1H, s), 4.86 (1H, br. t, J = 4.9 Hz), 4.15 (1H, s), 3.76 (3H, s), 3.31 (3H, s), 3.09 (2H, dt, J = 4.9 Hz, J = 5.9 Hz), 2.08-2.33 ( 10H, m), 1.65 (2H, tt, J = 5.9 Hz)
Time-of-flight mass spectrometer (TOF-Mass): 565 (M + H)
[0062]
Example 30 1- (4-Cyanophenyl) -6- [3- [4- [bis (4-fluorophenyl) methyl] -1-piperazinyl] propylamino] -3-methyluracil (Compound 1349)
Using 6-chloro-1- (4-cyanophenyl) -3-methyluracil instead of 6-chloro-3-methyl-1-phenyluracil, 3- (4- (diphenylmethyl) -1-piperazinyl) propyl The title compound was obtained in the same manner as in Example 1, except that 3- (4- (bis (4-fluorophenyl) methyl) -1-piperazinyl) propylamine was used instead of amine.
1 H-NMR (CDCl Three , δppm): 7.86 (2H, d, J = 8.6 Hz), 7.45 (2H, d, J = 8.6 Hz), 7.38 (4H, m), 6.97 (4H, m), 4.97 (1H, s), 4.81 (1H, brt, J = 4.9 Hz), 4.19 (1H, s), 3.31 (3H, s), 3.08 (2H, dt, J = 4.9 Hz, J = 5.7 Hz), 2.06-2.33 (10H, m) , 1.65 (2H, tt, J = 5.7 Hz)
Time-of-flight mass spectrometer (TOF-Mass): 571 (M + H)
[0063]
Example 31 6- [3- [4- (Diphenylmethyl) -1-piperazinyl] propylamino] -1- (4-nitrophenyl) -3-methyluracil (Compound 1358)
The title compound was obtained in the same manner as in Example 1, except that 6-chloro-3-methyl-1- (4-nitrophenyl) uracil was used instead of 6-chloro-3-methyl-1-phenyluracil.
1 H-NMR (CDCl Three , δppm): 8.44 (2H, d, J = 8.6 Hz), 7.53 (2H, d, J = 8.6 Hz), 7.16-7.40 (10H, m), 5.07 (1H, br.t, J = 4.3 Hz) , 4.97 (1H, s), 3.93 (1H, s), 3.13 (3H, s), 3.11 (2H, dt, J = 4.3 Hz, J = 5.9 Hz), 2.32 (2H, t, J = 5.9 Hz) , 2.03 (4H, m), 1.99 (4H, m), 1.66 (2H, tt, J = 5.9 Hz)
Time-of-flight mass spectrometer (TOF-Mass): 555 (M + H)
[0064]
Example 32 1- (4-Cyanophenyl) -6- [3- [4- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) -1-piperazinyl] propylamino ] -3-Methyluracil (Compound 1606)
Using 6-chloro-1- (4-cyanophenyl) -3-methyluracil instead of 6-chloro-3-methyl-1-phenyluracil, 3- (4- (diphenylmethyl) -1-piperazinyl) propyl The title compound was obtained in the same manner as in Example 1, except that 3- (4- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) -1-piperazinyl) propylamine was used instead of amine. Got.
1 H-NMR (CDCl Three , δppm): 7.86 (2H, d, J = 8.6Hz), 7.39 (2H, d, J = 8.6 Hz), 7.07-7.26 (8H, m), 5.91 (1H, m), 4.84 (1H, s) , 4.12 (1H, m), 3.79-3.88 (2H, m), 3.24-3.30 (7H, m), 2.65-2.87 (10H, m) 1.97 (2H, m)
Time-of-flight mass spectrometer (TOF-Mass): 560 (M + H)
[0065]
Example 33 1- (3-Carboxyphenyl) -6- [3- [4- (diphenylmethyl) -1-piperazinyl] propylamino] -3-methyluracil (Compound 1118)
Compound 1058 400 mg (0.69 mmol) dissolved in ethanol 50 ml, 1N? Add 1.4 ml of aqueous sodium hydroxide solution and stir at 50 ° C. for 30 minutes. After concentrating the solvent, distilled water was added and the resulting solid was neutralized with 1N hydrochloric acid and collected by filtration to obtain the title compound (316 mg (0.57 mmol), yield 82%).
1 H-NMR (DMSO-d 6 , δppm): 8.06 (1H, d, J = 7.3 Hz), 7.80 (1H, s), 7.56-7.67 (2H, m), 7.14-7.42 (10H, m), 5.62 (1H, br.t, J = 5.7 Hz), 4.83 (1H, s), 4.22 (1H, s), 3.09 (3H, s), 2.96-3.09 (2H, m), 2.19-2.32 (10H, m), 1.54 (2H, m) ,
Time-of-flight mass spectrometer (TOF-Mass): 554 (M + H)
[0066]
Example 34 1- (4-Carboxymethylphenyl) -3-ethyl-6- [3- [4- (diphenylmethyl) -1-piperazinyl] propylamino] uracil (Compound 1035)
The title compound was obtained in the same manner as in Example 33 using compound 1005 in place of compound 1058.
1 H-NMR (DMSO-d 6 , δppm): 7.14-7.42 (14H, m), 5.42 (1H, m), 4.78 (1H, s), 4.23 (1H, s), 3.75 (2H, m), 3.60 (2H, s), 2.99 ( 2H, m), 2.16-2.30 (10H, m), 2.03 (2H, m), 1.05 (6H, m), 1.05 (3H, t, J = 7.3 Hz)
Time-of-flight mass spectrometer (TOF-Mass): 582 (M + H)
[0067]
Example 35 1- (4-Carboxyphenyl) -6- [3- [4- (diphenylmethyl) -1-piperazinyl] propylamino] -3-methyluracil (Compound 1148)
The title compound was obtained in the same manner as in Example 33 using compound 1088 instead of compound 1058.
1 H-NMR (DMSO-d 6 , δppm): 8.07 (2H, d, J = 8.4 Hz), 7.14-7.45 (12H, m), 5.66 (1H,, J = 5.3 Hz m), 4.84 (1H, s), 4.22 (1H, s) , 3.09 (3H, s), 3.01 (2H, m), 2.25-2.50 (10H, m), 1.55 (2H, m)
Time-of-flight mass spectrometer (TOF-Mass): 554 (M + H)
[0068]
Example 36 1- (4-Carboxyphenyl) -6- [3- [4- (diphenylmethoxy) -1-piperidinyl] propylamino] -3-methyluracil (Compound 1154)
The title compound was obtained in the same manner as in Example 33 using compound 1094 instead of compound 1058.
1 H-NMR (DMSO-d 6 , δppm): 8.11 (2H, d, J = 8.4 Hz), 7.21-7.39 (12H, m), 5.71 (1H, m), 5.65 (1H, s), 4.88 (1H, s), 3.12 (3H, s), 1.91-3.08 (15H, m)
Time-of-flight mass spectrometer (TOF-Mass): 569 (M + H)
[0069]
Example 37 6- [3- [4- (Diphenylmethyl) -1-piperazinyl] propylamino] -3-methyl-1- [3- (1H-tetrazol-5-yl) phenyl] uracil (Compound 1238)
Compound 1298 450 mg (0.84 mmol) was dissolved in N, N-dimethylformamide 34 ml, sodium azide 437 mg and ammonium chloride 359 mg were added, and the mixture was stirred at 90 ° C. for 8 hours. After allowing to cool, the solvent was concentrated, distilled water was added, and the mixture was neutralized with 1N hydrochloric acid. The mixture was stirred at room temperature for 30 minutes, and the resulting solid was collected by filtration. After adding dichloromethane 25 ml and hexane 22 ml to the solid and stirring for 30 minutes, the solid was collected by filtration to obtain the title compound (410 mg (0.71 mmol), yield 85%).
1 H-NMR (DMSO-d 6 , δppm): 8.12 (1H, d, J = 7.8 Hz), 7.56 (1H, br.s), 7.61 (2H, t, J = 7.8 Hz), 7.18-7.45 (12H, m), 5.78 (1H, br.t, J = 5.7 Hz), 4.89 (1H, s), 4.41 (1H, s), 3.46 (3H, s), 3.01-3.12 (8H, m), 2.79 (2H, m), 2.50 (2H , m), 1.73 (2H, m)
Time-of-flight mass spectrometer (TOF-Mass): 537 (M + H)
[0070]
Example 38 6- [3- [4- (Diphenylmethoxy) -1-piperazinyl] propylamino] -3-methyl-1- [4- (1H-tetrazol-5-yl) phenyl] uracil (Compound 1274)
The title compound was obtained in the same manner as in Example 37 using compound 1334 instead of compound 1298.
1 H-NMR (DMSO-d 6 , δppm): 8.11 (2H, d, J = 8.4 Hz), 7.26-7.33 (14H, m), 5.71 (1H, br.t, J = 5.9 Hz m), 5.65 (1H, m), 4.88 (1H , s), 3.38 (1H, m), 3.12 (3H, s), 3.06 (4H, m), 2.74 (4H, m), 1.91 (2H, m), 1.73 (2H, m)
Time-of-flight mass spectrometer (TOF-Mass): 593 (M + 1)
[0071]
Example 39 6- [3- [4- (Diphenylmethyl) -1-piperazinyl] propylamino] -3-methyl-1- [4- (1H-tetrazol-5-yl) phenyl] uracil (Compound 1268 )
The title compound was obtained in the same manner as in Example 37 using compound 1328 instead of compound 1298.
1 H-NMR (DMSO-d 6 , δppm): 8.14 (2H, d, J = 8.4 Hz), 7.16-7.41 (12H, m), 5.75 (2H, s), 4.87 (1H, s), 4.32 (1H, s), 3.11 (3H, s), 2.50-3.06 (12H, m), 1.69 (2H, m)
Time-of-flight mass spectrometer (TOF-Mass): 579 (M + H)
[0072]
Example 40 1- (3-Carboxamidophenyl) -6- [3- [4- (diphenylmethyl) -1-piperazinyl] propylamino] -3-methyluracil (Compound 1178)
Compound 1118 300 mg (0.71 mmol) is suspended in 20 ml of N, N-dimethylformamide, 88 mg of 1-hydroxybenzotriazole and 125 mg of N-ethyl-N′-3-dimethylaminopropylcarbodiimide are added, and at room temperature for 2 hours. Stir. Under ice-cooling, 254 μl of 29% aqueous ammonia solution was added and stirred for 1 hour. The solvent was concentrated, extracted with dichloromethane and 5% aqueous sodium hydrogen carbonate solution, and the organic layer was washed with 10% aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solid obtained by distilling off the solvent was resuspended in 15 ml of dichloromethane and stirred for 30 minutes, and the solid was collected by filtration to obtain the title compound (153 mg, 0.28 mmol, yield 51%).
1 H-NMR (DMSO-d 6 , δppm): 7.14-8.06 (16H, m), 5.76 (1H, s), 5.63 (1H, br.t, J = 5.4 Hz), 4.84 (1H, s), 4.21 (1H, s), 3.09 ( 3H, s), 3.09 (3H, s), 3.00 (2H, m), 2.17-2.30 (10H, m), 1.53 (2H, m)
Time-of-flight mass spectrometer (TOF-Mass): 553 (M + H)
[0073]
Example 41 1- (4-Carboxamidophenyl) -6- [3- [4- (diphenylmethyl) -1-piperazinyl] propylamino] -3-methyluracil (Compound 1208)
The title compound was obtained in the same manner as in Example 40 using compound 1148 instead of compound 1118.
1 H-NMR (DMSO-d 6 , δppm): 8.14 (1H, s), 8.03 (2H, d, J = 8.9 Hz), 7.56 (1H, s) 7.13-7.43 (12H, m), 5.64 (1H, br.t, J = 5.4 Hz ), 4.83 (1H, s), 4.22 (1H, s), 3.09 (3H, s), 3.00 (2H, m), 2.20-2.30 (10H, m), 1.53 (2H, m),
Time-of-flight mass spectrometer (TOF-Mass): 553 (M + H)
[0074]
(Evaluation example 1) OVA-induced mouse biphasic dermatitis inhibitory action
In order to verify the anti-inflammatory action of the novel uracil derivative having the antihistamine action of the present invention, an OVA-induced mouse biphasic dermatitis model showing both immediate type with strong histamine involvement and late type with strong inflammatory cell infiltration Evaluated. ICR male mice ovalbumin (OVA) 1 μg Al (OH) Three Sensitization was induced by intraperitoneal administration with 1 mg. On the 14th day of sensitization, 10 μg of OVA was administered directly into the auricle to induce an allergic reaction. The test drug was suspended in 0.5% CMC-Na aqueous solution and orally administered (30 mg / kg) 1 hour before induction. The thickness of the auricle was measured 1 hour and 24 hours after the induction, and the effect of the test compound on the suppression of dermatitis was evaluated using the difference from the thickness of the auricle before the induction as an index. As comparative examples, oxatomide (Oxatomide) and ketotifen fumarate were used, both suspended in 0.5% CMC-Na aqueous solution and administered orally 1 hour before the induction. The increase in auricular thickness 1 hour after induction was due to edema due to a chemical transmitter such as histamine, which was defined as an immediate phase. After 24 hours it was due to inflammatory cells such as eosinophils and this was defined as the late phase.
[0075]
As a result, as shown in Table 3, it can be seen that the compound of the present invention suppresses both the immediate phase and the delayed phase. In contrast, ketotifen, a known antihistamine, strongly suppressed the immediate phase but was ineffective against the late phase.
[0076]
[Table 3]
[0077]
(Evaluation example 2)
In order to verify that the novel uracil derivative of the present invention has an antihistamine action, it was evaluated by the Magnus method using a guinea pig ileum. The ileum extracted from the guinea pig was washed in Tyrode solution and stored in Tyrode solution at 32 ° C. with aeration. The ileum was excised with a length of about 2 cm, and one end was fixed to a fixing rod and the other end was fixed to a pressure transducer in a Magnus tube filled with Tyrode solution, so that the contraction of the ileum could be recorded. IC of each test drug against ileal contraction induced when 100 μL of 1.0 μM Histamine aqueous solution was added to Magnus tube filled with Tyrode solution 50 Asked. The test drug was added in a volume of 5 μL in Tyrode solution 2 minutes before Histamine was added. Diphenhydramine and oxatomide were used as comparative examples.
[0078]
As shown in Table 4, the compounds of the present invention were shown to have antihistaminic activity comparable to known antihistamines.
[0079]
[Table 4]
[0080]
(Formulation Example 1) Water-soluble ointment
A water-soluble ointment having the following composition was prepared by a conventional method.
[0081]
(Formulation example 2) Tablets for internal use
A tablet for internal use having the following composition was prepared by a conventional method.
[0082]
【The invention's effect】
The uracil derivative of the present invention has both an antihistaminic action and an anti-inflammatory action, and is useful as an antihistamine and / or an antiallergic agent. In particular, it has a remarkable anti-inflammatory action against allergic inflammation. The uracil derivative of the present invention suppresses itching caused by histamine and also effectively suppresses allergic inflammation. Therefore, prevention / It is useful as a therapeutic agent, and is a novel compound that is more satisfactory in terms of efficacy and safety than conventional antiallergic agents, antihistamines, anti-inflammatory agents and the like.

Claims (9)

  1. Formula (I):
    (In the formula, R 1 represents a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms or a substituted or unsubstituted aralkyl group having 7 to 10 carbon atoms, and R 2 represents a hydrogen atom or a carbon number of 1 to 4 represents an alkyl group, Ar 1 represents a substituted or unsubstituted aromatic group or a substituted or unsubstituted aromatic heterocyclic group, and Ar 2 and Ar 3 represent a substituted or unsubstituted phenyl group or a substituted or unsubstituted group, respectively. A substituted monocyclic aromatic heterocyclic group, a third ring may be formed by a group bonded to both Ar 2 and Ar 3 ; X represents a methine group (CH) or a nitrogen atom; Represents a single bond or an oxygen atom when X is a methine group, represents a single bond when X is a nitrogen atom, and Z represents a hydrogen atom or a hydroxyl group when X is a methine group and Y is a single bond. When X is a methine group and Y is an oxygen atom and X is a nitrogen atom (Y is a single bond), it represents a hydrogen atom, and m represents 2 to 6.)
    Or a pharmaceutically acceptable salt thereof.
  2. The uracil derivative or a pharmaceutically acceptable salt thereof according to claim 1 , wherein Ar 1 in formula (I) is a substituted or unsubstituted aromatic group.
  3. The uracil derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein in the general formula (I), Ar 2 and Ar 3 are each a substituted or unsubstituted phenyl group.
  4. In general formula (I), Ar 2 and Ar 3 are each (1) a phenyl group which may be substituted with a halogen atom or an alkyl group having 1 to 4 carbon atoms, or (2) a nitrogen atom or a sulfur atom in addition to the carbon atom. And a uracil derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a 5- to 8-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen atoms.
  5.   In general formula (I), X is a methine group, The uracil derivative or its pharmaceutically acceptable salt of any one of Claims 1-4.
  6.   In general formula (I), X is a nitrogen atom, The uracil derivative or its pharmaceutically acceptable salt of any one of Claims 1-4.
  7.   The antihistamine which contains the uracil derivative of any one of Claims 1-6, or its pharmaceutically acceptable salt as an active ingredient.
  8.   The antiallergic agent which contains the uracil derivative of any one of Claims 1-6, or its pharmaceutically acceptable salt as an active ingredient.
  9.   Allergic conjunctivitis, allergic rhinitis, chronic urticaria, atopic dermatitis, asthma or chronically containing uracil derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 as an active ingredient Prophylactic / therapeutic agent for bronchitis.
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