JP3013752B2 - Sulfonamide derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel sulfonamide derivative having an endothelin antagonistic action.

[0002]

2. Description of the Related Art Endothelin is a polypeptide consisting of 21 amino acids, is produced from endothelial cells of humans and pigs, and is known to have potent vasoconstriction, bronchoconstriction and cell proliferation. . Endothelin is clinically normal in patients with essential hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's disease, diabetes, atherosclerosis, asthma, and airway lavage fluid. It is reported that the number has clearly increased. Thus, endothelin is an endogenous bioactive substance that directly or indirectly continuously contracts vascular and non-vascular smooth muscle, and its overproduction and hypersecretion are caused by hypertension and pulmonary hypertension. , Renal hypertension, Raynaud's disease, bronchial asthma, gastric ulcer, inflammatory bowel disease (Crohn's disease), shock, carcinogenesis, restenosis after angioplasty, organ dysfunction after organ transplantation, diabetes, thrombosis, arteriosclerosis It is considered to be one of the causes of pathogenesis, heart failure, acute renal failure, glomerulonephritis, cyclosporine-induced nephrotoxicity, myocardial infarction, angina, arrhythmia, glaucoma, migraine, cerebral vasospasm, cerebral infarction Have been. Therefore, a substance that strongly antagonizes endothelin is considered to be useful for treating the above various pathological conditions.

On the other hand, JP-A-5-155864, JP-A-5-222003, JP-A-6-212810 and JP-A-7-17972 disclose N-Ｎ [as a benzenesulfonamide derivative having an endothelin antagonistic action. 5
-Substituted phenyl (or substituted phenoxy)]-6-hydroxyalkoxypyrimidin-4-yl} -substituted benzenesulfonamides.

[0004]

DISCLOSURE OF THE INVENTION The present invention provides a novel sulfonamide derivative having an excellent endothelin antagonism.

[0005]

The present invention provides a compound of the general formula [I]

[0006]

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(However, ring A represents a substituted or unsubstituted monocyclic or bicyclic to tricyclic hydrocarbon group or a substituted or unsubstituted heterocyclic group, and ring B is (1) ring A is substituted or In the case of an unsubstituted monocyclic hydrocarbon group, it is a substituted or unsubstituted bicyclic to tricyclic hydrocarbon group or a substituted or unsubstituted heterocyclic group, and (2) ring A is substituted or unsubstituted bi to tricyclic In the case of a hydrocarbon group or a substituted or unsubstituted heterocyclic group, it represents a substituted or unsubstituted monocyclic or bi- to tricyclic hydrocarbon group or a substituted or unsubstituted heterocyclic group,
Q is a single bond or a formula -O-, -S-, -SO-, -SO
₂ - or -CH ₂ - group represented by, Y has the formula -O-,
A group represented by -S- or -NH-, Alk is a lower alkylene group or a lower alkenylene group, Z is a group represented by the formula -O- or -N
A group represented by H-, R is a substituted or unsubstituted aromatic heterocyclic group or aryl group, R ¹ is a hydrogen atom, a trifluoromethyl group, a substituted or unsubstituted mono- - or di - lower alkylamino group, a substituted Or an unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group, a substituted or unsubstituted lower alkynyl group, a substituted or unsubstituted lower alkylthio group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted heterocyclic group or an aryl group Represents ) Or a pharmacologically acceptable salt thereof.

The hydrocarbon group in the object [I] of the present invention includes a monocyclic, bicyclic or tricyclic group having 15 or less carbon atoms which may be partially or wholly saturated.
The monocyclic hydrocarbon group is preferably one having 5 to 8 carbon atoms, and more specifically, a phenyl group and the following groups are exemplified.

[0009]

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The bicyclic hydrocarbon group has 9 to 9 carbon atoms.
Eleven are preferred, and more specifically, in addition to a naphthyl group, an indenyl group, and an azulenyl group, the following groups are exemplified.

[0011]

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The tricyclic hydrocarbon group has 12 carbon atoms.
To 15 are preferable, and more specifically, those shown below, in addition to a fluorenyl group, a phenanthrenyl group, an anthracenyl group, an acenaphthylenyl group and a biphenylenyl group, are exemplified.

[0013]

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The heterocyclic group in ring A and / or ring B is, for example, a monocyclic, bicyclic or tricyclic aliphatic or partially saturated aromatic heterocyclic group. Can be

The aromatic heterocyclic group is preferably a monocyclic or bicyclic aromatic heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. For example, a pyrrolyl group, an imidazolyl group, a furyl group, a thienyl group, a thiazolyl group, an isoxazolyl group,
Oxazolyl group, oxazolinyl group, pyrazolyl group, quinazolinyl group, thienopyrimidinyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group, triazinyl group, tetrazolyl group, quinolyl group, isoquinolyl group, quinoxalinyl group, benzothienyl group, benzothiazolyl group, Examples include a benzoxazolyl group or a benzimidazolyl group and a ring in which a part thereof is saturated.

The ring in which a part of the aromatic heterocyclic group is saturated includes, for example, those shown below.

[0017]

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The aliphatic heterocyclic group is preferably a monocyclic or bicyclic aliphatic heterocyclic group containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Examples thereof include a piperazinyl group, a pyrrolidinyl group, a piperidyl group, a homopiperidyl group, a thiomorpholino group, and a morpholino group.

The aromatic heterocyclic group represented by R is a monocyclic or bicyclic aromatic heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Are preferred, for example, pyrrolyl group, imidazolyl group, furyl group, thienyl group, thiazolyl group, isoxazolyl group, oxazolyl group, oxazolinyl group, pyrazolyl group, quinazolinyl group, thienopyrimidinyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group, Triazinyl group, tetrazolyl group, quinolyl group, isoquinolyl group, quinoxalinyl group, benzothienyl group,
Examples thereof include a benzothiazolyl group, a benzooxazolyl group and a benzimidazolyl group.

The heterocyclic group for R ¹ includes, for example, a monocyclic, bicyclic or tricyclic aliphatic or aromatic heterocyclic group.

The aromatic heterocyclic group is preferably a monocyclic or bicyclic aromatic heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. For example, a pyrrolyl group, an imidazolyl group, a furyl group, a thienyl group, a thiazolyl group, an isoxazolyl group,
Oxazolyl group, oxazolinyl group, pyrazolyl group, quinazolinyl group, thienopyrimidinyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group, triazinyl group, tetrazolyl group, quinolyl group, isoquinolyl group, quinoxalinyl group, benzothienyl group, benzothiazolyl group, Examples thereof include a benzoxazolyl group and a benzimidazolyl group.

The aliphatic heterocyclic group is preferably a monocyclic or bicyclic aliphatic heterocyclic group containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Examples thereof include a piperazinyl group, a pyrrolidinyl group, a piperidyl group, a homopiperidyl group, a thiomorpholino group, and a morpholino group.

The substituent on ring A and / or ring B includes:
For example, a halogen atom; a hydroxyl group which may be protected; a lower alkyl group; a lower alkoxy group; a lower alkenyl group;
Lower alkynyl group; lower alkylthio group; cycloalkyl group; trifluoromethyl group; carboxyl group; cyano group; tetrazolyl group; formyl group; carbamoyl group; mono- or di-lower alkylaminocarbonyl group; lower alkoxycarbonyl group; Carbonyl-lower alkoxy group; lower alkoxycarbonyl-lower alkyl group; lower alkoxycarbonyl-lower alkenyl group; di-lower alkoxy group-substituted lower alkyl group; amino-substituted lower alkyl group;
Carboxyl-substituted lower alkenyl; carboxyl-substituted lower alkoxy; bromopyrimidinyloxy-lower alkyl; lower alkylenedioxy; aryl-lower alkoxy; mono- or di-lower alkylamino; Alkylsulfinyl group, lower alkylsulfonyl group, pyridyl group, nitro group, imidazole group, oxazole group, thiazole group, triazole group, furyl group, halogen atom,
A phenyl group which may be substituted with 1 to 5 groups selected from a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkanoyloxy group and a lower alkoxycarbonyloxy group; an arylcarbonylamino group; a carboxyl group-substituted lower alkanoyloxy lower An alkyl group; or an arylaminocarbonyl group.

The ring A and / or ring B may be 1) a monocyclic group, which may have 1 to 3 substituents, which may be the same or different, and 2) a bicyclic to tricyclic group. In this case, they may have the same or different 1 to 4 substituents.

The substituent on the aromatic heterocyclic group or aryl group for R includes, for example, a halogen atom; a hydroxyl group which may be protected; a nitro group; a cyano group; an amino group; a formyl group; a carboxyl group; Group; N
A lower alkylcarbamoyloxy group; an N-hydroxyiminomethyl group; an N-lower alkoxyiminomethyl group;
A lower alkyl group; a hydroxyl-substituted lower alkyl group; a cycloalkyl group; a lower alkoxy-lower alkyl group; a lower alkoxycarbonyl-lower alkenyl group; a trifluoromethyl group; a hydroxyl and aryl group-substituted lower alkyl group; a lower alkylthio group; Di-lower alkylamino group; lower alkanoylamino group; lower alkoxy group; lower alkoxy group substituted with an optionally protected carboxyl group; aryloxy group; lower alkoxycarbonyl group; lower alkoxy-lower alkenyl group; lower alkanoyl. Group; arylcarbonyl group; lower alkenyloxy group; hydroxyl-substituted lower alkynyl group; lower alkynyl group optionally protected by trimethylsilyl group;
Cyano lower alkoxy group; cycloalkyl-lower alkoxy group; lower alkylsulfinyl group; lower alkylsulfonyl group; aryl group; phenyl lower alkyl group; aromatic heterocyclic group-substituted lower alkyl group; aromatic heterocyclic group-substituted lower alkoxy A phenyl-lower alkenyl group; a phenyl-lower alkoxy group; an arylcarbonylamino group;
Or an aromatic heterocyclic group substituted with an aromatic heterocyclic group which may be substituted with a group represented by the following formula: or an aromatic heterocyclic group optionally substituted with a lower alkyl group.

The aromatic heterocyclic group and / or the aryl group for R may be the same or different, and may have 1 to 4 substituents described above.

Further, examples of the substituent on the mono- or di-lower alkylamino group for R ¹ include a hydroxyl group and a carboxyl group. Examples of the substituent on the lower alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, a lower alkoxycarbonyl group, an aromatic heterocyclic group and an aryl group. Examples of the substituent on the lower alkenyl group include a lower alkyl group, an amino group, a hydroxyl group and a carboxyl group. Examples of the substituent on the lower alkynyl group include a carboxyl group. Examples of the substituent on the lower alkylthio group include a carboxyl group. Examples of the substituent on the lower alkoxy group include a hydroxyl group, a hydroxyl-substituted lower alkoxy group, a carboxyl group, and the like. Further, examples of the substituent on the heterocyclic group include a lower alkyl group, an amino group, a hydroxyl group and a carboxyl group.

The mono- or di-lower alkylamino group, lower alkyl group, lower alkenyl group, lower alkynyl group, lower alkylthio group, lower alkoxy group and / or heterocyclic group represented by R ¹ may be the same or different from those described above. It may have 1 to 4 substituents.

As the protecting group for a hydroxyl group and / or a carboxyl group, a conventional protecting group which can be a protecting group for a hydroxyl group and / or a carboxyl group can be used. Examples of the protecting group for a hydroxyl group include a benzyl group and a methoxymethyl group. And a tetrahydropyranyl group, and the protecting group for the carboxyl group includes methyl, ethyl, tert
-Butyl group, benzyl group and the like.

Examples of the aryl group and the aryl moiety in the arylcarbonylamino group, the arylaminocarbonyl group, the aryloxy group and the arylcarbonyl group include a phenyl group, a lower alkoxyphenyl group and a naphthyl group.

Specific examples of the combination of ring A and ring B in the sulfonamide derivative [I] of the present invention include: 1) ring A is a substituted monocyclic hydrocarbon group, and ring B is a substituted or unsubstituted bicyclic hydrocarbon. Hydrogen group, 2) ring A is a substituted monocyclic hydrocarbon group,
Ring B is a substituted or unsubstituted heterocyclic group, 3) ring A is a substituted or unsubstituted bicyclic hydrocarbon group, ring B is a substituted hydrocarbon group, 4) ring A is a substituted or unsubstituted bicyclic hydrocarbon Group,
Ring B is a substituted heterocyclic group, 5) Ring A is a substituted heterocyclic group, Ring B is a substituted or unsubstituted hydrocarbon group, 6) Ring A is a substituted heterocyclic group, Ring B is a substituted or unsubstituted heterocyclic group Cyclic group, 7)
Ring A is a substituted or unsubstituted heterocyclic group, ring B is a substituted monocyclic or bi- to tricyclic hydrocarbon group, 8) ring A is a substituted or unsubstituted heterocyclic group, and ring B is a substituted heterocyclic ring Certain compounds are mentioned, wherein 1) ring A is a substituted monocyclic hydrocarbon group,
Ring B is a substituted or unsubstituted bicyclic hydrocarbon group, 2) ring A
Is a substituted monocyclic hydrocarbon group, ring B is a substituted or unsubstituted heterocyclic group, 3) ring A is a substituted or unsubstituted bicyclic hydrocarbon group, ring B is a substituted monocyclic or bi- to tricyclic Compounds that are hydrocarbon groups are preferred, and those in which ring A is a substituted monocyclic hydrocarbon group and ring B is an unsubstituted heterocyclic group are particularly preferred.

Among the desired compounds [I] of the present invention, a compound which is preferable in terms of efficacy is a phenyl group in which the ring A is substituted with a lower alkyl group or a lower alkylenedioxy group in the general formula [I], and the ring B Is a naphthyl group, a pyridyl group,
A furyl group, a thienyl group or a benzothienyl group which may be substituted with a lower alkyl group, or a naphthyl group, an indenyl group, an anthryl group, a pyridyl group wherein Ring A may be substituted with a di-lower alkylamino group Or a phenyl group, a naphthyl group, a pyridyl group, or a furyl group, which is a thienyl group, a benzofuryl group, or a benzothienyl group which may be substituted with a lower alkyl group, wherein ring B is substituted with a lower alkyl group or a lower alkoxy group. A thienyl group or a benzothienyl group which may be substituted with a lower alkyl group, Q is a single bond or a group represented by the formula -O-, Y is a group represented by the formula -O-, Alk is a lower alkylene A group, Z is a group represented by the formula -O-, and R is a pyrimidini in which R is substituted with a halogen atom, a thienyl group or a lower alkylthio group. Group, R ¹ is a hydrogen atom, a hydroxyl group-substituted lower alkylamino group, a lower alkyl group, a carboxyl group-substituted lower alkylthio group, a hydroxyl group-substituted lower alkoxy group, a pyrimidinyl group, hydroxy-substituted piperidinyl group, a lower alkyl group substituted piperazinyl group or a morpholino group A certain compound.

A compound more preferable in terms of efficacy is a phenyl group in which ring A is substituted with a lower alkyl group or a lower alkylenedioxy group in the general formula [I], and ring B is a naphthyl group, a pyridyl group, a furyl group. A thienyl group or a benzothienyl group which may be substituted with a lower alkyl group, or a naphthyl group in which ring A may be substituted with a di-lower alkylamino group, an indenyl group,
A phenyl group or a lower alkyl group which is a thienyl group, a benzofuryl group or a benzothienyl group which may be substituted with an anthryl group, a pyridyl group or a lower alkyl group, and wherein ring B is substituted with a lower alkyl group or a lower alkoxy group; Is a compound which is a thienyl group substituted with

More preferable compounds from the pharmacological effect are a phenyl group in which ring A is substituted with a lower alkyl group and a thienyl group which may be substituted with a lower alkyl group in the general formula [I], and naphthyl. A ring, a pyridyl group, a furyl group or a benzothienyl group, or a thienyl group in which ring A may be substituted with a naphthyl group or a pyridyl group which may be substituted with a di-lower alkylamino group; Is a phenyl group substituted with a lower alkyl group or a lower alkoxy group, Q is a single bond, R is a pyrimidinyl group substituted with a halogen atom or a lower alkylthio group, R ¹ is a hydrogen atom, a pyrimidinyl group or morpholino. The compound is a group.

Particularly preferred compounds from the pharmacological effect are a phenyl group in which ring A is substituted with a lower alkyl group and a thienyl group which may be substituted with a lower alkyl group in the general formula [I], naphthyl, Or a compound wherein Ring A is a naphthyl group and Ring B is a phenyl group substituted with a lower alkyl group.

Among the desired compounds [I] of the present invention, another preferred compound is a phenyl group in which ring A is substituted with a lower alkyl group and ring B is a thienyl group in formula [I]. Or ring A is a naphthyl group or a thienyl group, ring B is a phenyl group substituted with a lower alkoxy group, and Q is a single bond or a group represented by the formula -O-,
Y is a group represented by the formula -O-, Alk is a lower alkylene group, Z is a group represented by the formula -O-, R is a pyrimidinyl group substituted with a halogen atom or a thienyl group, R ¹
Is a lower alkyl group, a morpholino group, a lower alkyl group-substituted piperazinyl group or a pyrimidinyl group.

Among them, more preferred compounds are those in the general formula [I] wherein R is a pyrimidinyl group substituted by a halogen atom and R ¹ is a pyrimidinyl group.

According to the present invention, the target compound [I] can be produced by the following [Method A], [Method B], [Method C] or [Method D].

[Method A] The target compound [I] of the present invention has the general formula [II]

[0040]

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(Where X ¹ represents a reactive residue, and other symbols have the same meanings as described above) and a compound of the general formula [III]

[0042]

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(Wherein, the symbols have the same meanings as described above) or a salt thereof.

[Method B] Compound [I] is a compound of the general formula [IV]

[0045]

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(Wherein the symbols have the same meanings as described above) or a salt thereof and a compound of the general formula [V]

[0047]

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(Wherein, X ² represents a reactive residue, and ring A has the same meaning as described above).

[Method C] The compound [I] is a compound of the general formula [VI]

[0050]

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(Wherein the symbols have the same meanings as described above) or a salt thereof, and a compound represented by the general formula [VI
I]

[0052]

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(Where X ³ represents a reactive residue, and other symbols have the same meanings as described above).

[Method D] The compound of the general formula [I-a] wherein Q is a single bond in the object [I] of the present invention.

[0055]

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(Wherein the symbols have the same meanings as described above) are represented by the general formula [VIII]

[0057]

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(Where X ⁴ represents a reactive residue, and other symbols have the same meanings as described above) or a salt thereof and a compound of the general formula [IX]

[0059]

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(Where W represents a lower alkyl group;
Has the same meaning as described above. ) Can be produced by reacting the compound of formula (1).

The salts of the compounds [II], [IV], [VI] and [VIII] include, for example, salts with inorganic acids such as hydrochlorides, sulfates and the like and inorganic salts such as alkali metal salts and alkaline earth metal salts. Salts with bases can be used.

As the reactive residue of X ¹ , X ² , X ³ or X ⁴ , a halogen atom, a lower alkylsulfonyloxy group or an arylsulfonyloxy group can be preferably used. preferable.

[Method A]: Compound [II] and Compound [II
The reaction with I] or a salt thereof can be carried out in the presence of a deoxidizing agent in a suitable solvent or without solvent. Examples of the deoxidizing agent include an alkali metal hydride, an alkali metal carbonate, an alkali metal amide, an alkali metal alkoxide, an alkyl alkali metal, an alkali metal, an alkaline earth metal, an alkali metal hydroxide, an alkali earth metal hydroxide, an organic base ( 1,
8-diazabicyclo [5.4.0] undec-7-ene and the like can be preferably used. As the solvent, dimethylsulfoxide, dimethylacetamide, dimethylformamide, hexamethylphosphoramide, sulfolane, 1,3-dimethyl-2-imidazolidinone, dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether and the like can be appropriately used. This reaction is carried out at room temperature to 150 ° C., particularly at room temperature to 100 ° C.
Proceeds favorably at C.

[Method B]: The reaction of compound [IV] or a salt thereof with compound [V] can be carried out in the presence of a deoxidizing agent in a suitable solvent or without a solvent. As the deoxidizing agent and the solvent, any of the deoxidizing agent and the solvent described in the above [Method A] can be suitably used. This reaction is carried out at 0 to 150
C., especially at room temperature to 100 C. Also,
This reaction proceeds more suitably when a catalytic amount of a phase transfer catalyst such as tetrabutylammonium hydrogen sulfate, trimethylbenzylammonium chloride, 18-crown-6 is added.

[Method C]: The reaction of compound [VI] or a salt thereof with compound [VII] can be carried out in the presence of a deoxidizing agent in a suitable solvent or without a solvent. As the deoxidizing agent, any of the deoxidizing agents described in the above [Method A] can be suitably used. As the solvent, dimethyl sulfoxide, dimethylacetamide, dimethylformamide,
1,3-dimethyl-2-imidazolidinone, ethylene glycol dimethyl ether, hexamethylphosphoramide, sulfolane, dioxane, tetrahydrofuran, toluene, or a mixed solvent thereof can be used as appropriate. The reaction is carried out at 0 ° C to 150 ° C, especially at room temperature to 100 ° C.
Proceeds favorably at C.

[Method D]: The reaction of compound [VIII] or a salt thereof with compound [IX] can be carried out in a suitable solvent in the presence of a catalyst. As the catalyst, a palladium-based catalyst such as bis (triphenylphosphine) palladium (II) chloride, palladium (II) acetate and tetrakis (triphenylphosphine) palladium (0) can be used as appropriate. This reaction was performed according to Journal of Organic Chemistry (J. Org. C).
hem. In accordance with the method described in Vol. 58, p. 1963 (1993), copper (I) salts such as copper (I) chloride, copper (I) bromide, and copper (I) iodide are added to proceed more suitably. I do. As the solvent, for example, dioxane, ethylene glycol dimethyl ether, dimethylacetamide, dimethylformamide, hexamethylphosphoramide, benzene, tetrahydrofuran, toluene, ethyl acetate, lower alcohol, methylene chloride, chloroform, carbon tetrachloride, 1,3-dimethyl- 2-imidazolidinone, acetic acid,
Diethyl ether, dimethoxyethane, water, or a mixed solvent thereof can be used as appropriate. The reaction is carried out at 50-
Properly proceeds at 100 ° C.

The target substance [I] of the present invention can also be produced by interconverting the target substance obtained as described above into another target substance. Such an interconversion reaction between the objective compounds may be appropriately selected depending on the type of the substituents of the compound. For example, the following (a) to (a)
It can be carried out as in the method (w).

Method (a): The target product [I] in which R is an aromatic heterocyclic group having a substituent or an aryl group is a compound represented by the formula:
Is a compound having an aromatic heterocyclic group or an aryl group substituted with a halogen atom, and a trialkyltin complex of the group to be substituted in the presence of a catalyst. As the catalyst, any of the catalysts described in the above [Method D] can be suitably used. This reaction suitably proceeds at room temperature to 100 ° C.

Method (b): The target product [I] in which R is an aromatic heterocyclic group or an aryl group substituted by a lower alkanoyl group (for example, acetyl group or the like) has a structure in which the corresponding R is lower alkoxy-lower. It can be produced by subjecting a compound that is an aromatic heterocyclic group or an aryl group substituted with an alkenyl group (for example, a 1-ethoxyvinyl group) to an acid treatment. As the acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, acetic acid and the like can be suitably used. This reaction suitably proceeds at 0 ° C to room temperature.

Method (c): The target product [I] in which R is an aromatic heterocyclic group or an aryl group substituted with a hydroxyl-substituted lower alkyl group has the corresponding R substituted with a lower alkanoyl group or a formyl group. The compound which is an aromatic heterocyclic group or an aryl group is treated with a reducing agent. As the reducing agent, sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride and the like can be suitably used. This reaction suitably proceeds at 0 ° C to room temperature.

Method (d): The target compound [I] wherein R is an aromatic heterocyclic group or an aryl group substituted with a lower alkyl group.
Can be produced by halogenating a compound in which the corresponding R is an aromatic heterocyclic group or an aryl group substituted by a hydroxy-substituted lower alkyl group, and then reducing the compound. The halogenation can be carried out by reacting with a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus tribromide and the like. Reduction is palladium-
Carbon, palladium-barium sulfate, palladium-aluminum oxide, palladium black or the like can be used to carry out the treatment.The present reduction reaction is preferably carried out in a hydrogen atmosphere in the presence of a deoxidizing agent. As the agent, triethylamine, pyridine, potassium carbonate, sodium hydrogen carbonate, sodium acetate and the like can be suitably used. This reaction suitably proceeds at room temperature to 60 ° C.

Method (e): The target product [I] in which R is an unsubstituted aromatic heterocyclic group or aryl group is an aromatic heterocyclic group or aryl group in which the corresponding R is substituted with a halogen atom. Can be produced by reduction. The reduction can be suitably carried out under the same conditions as described in the above method (d).

Method (f): The target product [I] in which R is an unsubstituted aromatic heterocyclic group or aryl group is a compound represented by the formula
Can be also produced by subjecting a compound, which is an aromatic heterocyclic group or an aryl group substituted with a lower alkylthio group, to a desulfurization reaction. The desulfurization reaction can be suitably carried out in the presence of a catalyst such as Raney nickel and palladium-carbon. This reaction suitably proceeds at room temperature to 50 ° C.

Method (g): The target product [I] wherein R is a formyl group, a hydroxyl-substituted lower alkyl group, or an aromatic heterocyclic group or an aryl group substituted with a hydroxyl group and an aryl group-substituted lower alkyl group, A compound in which the corresponding R is an aromatic heterocyclic group or an aryl group substituted with a halogen atom, is lithiated, and then produced by reacting with a corresponding carbonyl compound (eg, dimethylformamide, acetone, benzaldehyde, etc.). be able to. Lithiation can be suitably performed by reacting with a lithiation agent such as n-butyllithium, s-butyllithium, t-butyllithium and the like. The reaction is carried out at -100 ° C
Proceeds favorably at 25 ° C.

Method (h): The target product [I] in which R is an aromatic heterocyclic group or an aryl group substituted with an amino group is an aromatic heterocyclic group in which the corresponding R is substituted with a nitro group. Alternatively, it can be produced by reducing an aryl group compound. The reduction reaction can be carried out by reducing in a hydrogen atmosphere in the presence of a transition metal catalyst or by reacting with a reducing agent. As the transition metal catalyst, palladium-carbon, palladium-aluminum oxide, palladium black, colloidal palladium, platinum oxide, Raney nickel, etc., and as the reducing agent, lithium aluminum hydride, tin, stannous chloride, zinc, iron, etc. are preferable. Can be used. This reaction suitably proceeds at -20 ° C to 80 ° C.

Method (i): The target product [I] in which R is an aromatic heterocyclic group or an aryl group substituted with a lower alkanoylamino group or an arylcarbonylamino group, has the corresponding R substituted with an amino group. By acylating a compound that is an aromatic heterocyclic group or an aryl group. Examples of the acylating agent include a carboxylic acid or a reactive derivative thereof (acid chloride, acid bromide, acid anhydride, mixed acid anhydride and the like). When this reaction is carried out using a free carboxylic acid, the reaction is carried out in the presence of a condensing agent such as N, N'-dicyclohexylcarbodiimide, N-dimethylaminopropyl-N'-ethylcarbodiimide, diethylphosphoric acid cyanide, diphenylphosphoric acid azide. When the reaction is carried out using a reactive derivative of a carboxylic acid, an alkali metal hydroxide, an alkali metal hydrogencarbonate,
It is preferable to carry out the reaction in the presence of a deoxidizing agent such as an alkali metal carbonate and an organic base (such as triethylamine and pyridine).
This reaction suitably proceeds at -20 ° C to 100 ° C.

Method (j): The target product [I] in which R is an aromatic heterocyclic group or an aryl group substituted with a mono- or di-lower alkylamino group, has the corresponding R substituted with an amino group. The compound can be produced by alkylating a compound that is an aromatic heterocyclic group or an aryl group. The alkylation is carried out by (1) reacting a lower alkyl halide (lower alkyl chloride, lower alkyl bromide, etc.) or lower alkyl sulfonate (methane sulfonate, toluene sulfonate, etc.) in the presence of a deoxidizing agent, or (2) a reducing agent By reducing the reactant with the lower alkyl aldehyde in the presence of As the deoxidizing agent, an alkali metal hydroxide, an alkali metal hydrogencarbonate, an alkali metal carbonate, an organic base (such as triethylamine and pyridine) can be preferably used. As a reducing agent,
Sodium borohydride, sodium triacetoxyborohydride, formic acid and the like can be suitably used. This reaction suitably proceeds at 0 to 100 ° C.

Method (k): Compound (I) wherein R is an aromatic heterocyclic group or an aryl group substituted with a tetrazolyl group
Can be produced by reacting a compound in which the corresponding R is an aromatic heterocyclic group or an aryl group substituted with a cyano group with tributyltin azide. This reaction is 50 to 12
Proceeds favorably at 0 ° C.

Method (l): The target product [I] in which R is an aromatic heterocyclic group or an aryl group substituted with a carboxyl-substituted lower alkoxy group which may be protected, is a compound in which the corresponding R is a hydroxyl group. The compound can be produced by reacting a compound which is a substituted aromatic heterocyclic group or an aryl group with an optionally protected carboxyl group-substituted lower alkyl halide or an optionally protected carboxyl group-substituted lower alkyl sulfonate. This reaction suitably proceeds in the presence of a deoxidizing agent such as an alkali metal hydroxide, an alkali metal hydrogencarbonate, an alkali metal carbonate, and an organic base (such as triethylamine and pyridine). This reaction suitably proceeds at 0 to 100 ° C. As the carboxyl group-protecting group, a conventional carboxyl group-protecting group can be used, and can be removed by a conventional method according to the type.

Method (m): The target product [I] in which R is an aromatic heterocyclic group or an aryl group substituted with a lower alkoxy-lower alkyl group, has the corresponding R substituted with a hydroxyl-substituted lower alkyl group. Can be produced by halogenating a compound which is an aromatic heterocyclic group or an aryl group, followed by alkoxylation. As the halogenating agent, the halogenating agent described in the method (d) can be suitably used. This reaction suitably proceeds at -20 ° C to 100 ° C. The alkoxylation can be performed by reacting with a lower alcohol such as methanol, ethanol, or isopropanol. The present alkoxylation reaction is preferably carried out in the presence of a deoxidizing agent. As the deoxidizing agent, an alkali metal hydroxide, an alkali metal hydrogencarbonate, an alkali metal carbonate, an organic base (triethylamine, pyridine, etc.) and the like are suitably used. be able to. This reaction suitably proceeds at -20 ° C to 100 ° C.

Method (n): The target compound [I] in which R is an aromatic heterocyclic group or an aryl group substituted with a lower alkylsulfinyl group and / or a lower alkylsulfonyl group,
The compound can be produced by reacting a compound in which the corresponding R is an aromatic heterocyclic group or an aryl group substituted with a lower alkylthio group in the presence of an oxidizing agent. As the oxidizing agent, 3
-Chloroperbenzoic acid, peracetic acid, hydrogen peroxide, pertrifluoroacetic acid, sodium periodate, sodium hypochlorite, potassium permanganate and the like can be suitably used. This reaction suitably proceeds at 0 to 50 ° C.

Method (o): The target product [I] in which R is an aromatic heterocyclic group or an aryl group substituted with a lower alkylthio group is an aromatic heterocyclic group in which the corresponding R is substituted with a lower alkylsulfinyl group. A compound which is a cyclic group or an aryl group can be produced by first reacting in the presence of an acid anhydride, then hydrolyzing to a thiol, and further reacting with a lower alkyl halide in the presence of a base. As the acid anhydride, trifluoroacetic anhydride, acetic anhydride and the like can be preferably used, and as the base, potassium carbonate, sodium carbonate, lower alkoxysodium (for example, MeONa, EtONa) and the like are preferably used. Can be. This reaction suitably proceeds at 0 to 50 ° C.

Method (p): The target product [I] in which R is an aromatic heterocyclic group or an aryl group substituted with a cyano group is an aromatic heterocyclic group in which the corresponding R is substituted with a halogen atom. Alternatively, it can be produced by reacting an aryl group compound with zinc cyanide in the presence of a catalyst. As the catalyst, any of the catalysts described in the above method [D] can be suitably used. This reaction suitably proceeds at 60 to 100 ° C.

Method (q): The target product [I] in which R is an aromatic heterocyclic group or an aryl group substituted with a trimethylsilyl group-substituted lower alkynyl group or a hydroxyl-substituted lower alkynyl group has a structure in which the corresponding R is a halogen atom Can be produced by subjecting a compound, which is an aromatic heterocyclic group or an aryl group, to a trimethylsilyl group-substituted lower alkynylation or a hydroxy group-substituted lower alkynylation. Trimethylsilyl-substituted lower alkynylation or hydroxyl-substituted lower alkynylation can be produced by reacting in the presence of a catalyst and an organic base. As the catalyst, any of the catalysts described in the above method [D], and as the organic base, any of the organic bases described in the above method [j] can be suitably used. This reaction proceeds more suitably when a copper (I) salt is added, as in the above method [D]. This reaction suitably proceeds at room temperature to 100 ° C.

Method (r): The target product [I] in which R is an aromatic heterocyclic group or an aryl group substituted with a lower alkynyl group is an aromatic compound in which the corresponding R is substituted with a lower alkynyl group substituted with a trimethylsilyl group. It can be produced by reacting a compound which is a group heterocyclic group or an aryl group in the presence of an acid or an inorganic base. As the acid, hydrochloric acid, sulfuric acid, hydrobromic acid and the like can be suitably used, and as the base, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide and the like can be suitably used. This reaction suitably proceeds at 0 ° C to room temperature.

Method (s): The target product [I] in which R is an aromatic heterocyclic group or an aryl group substituted with a phenyl lower alkyl group is an aromatic heterocyclic group in which the corresponding R is substituted with a phenylalkenyl group. A compound that is a cyclic group or an aryl group,
It can be produced by reacting in the presence of a catalyst. As the catalyst, any of the catalysts described in the above method [d] can be suitably used. This reaction suitably proceeds at room temperature to 60 ° C.

Method (t): The target product [I] in which ring A and / or ring B is a hydrocarbon group or heterocyclic group substituted with a formyl group, is obtained when the corresponding ring A and / or ring B -A lower alkoxy group-substituted compound which is a hydrocarbon or heterocyclic group substituted with a lower alkyl group, can be produced by reacting in the presence of an acid. As the acid, an organic acid such as p-toluenesulfonic acid and oxalic acid, or a mineral acid such as hydrochloric acid, sulfuric acid and hydrogen bromide can be suitably used. The reaction is 0-5
Proceeds favorably at 0 ° C.

Method (u): The target product [I] in which ring A and / or ring B is a hydrocarbon group or a heterocyclic group substituted with a lower alkoxycarbonyl-lower alkenyl group is obtained by treating the corresponding ring A and / or Alternatively, it can be produced by reacting a compound in which ring B is a hydrocarbon group or a heterocyclic group substituted with a formyl group with a triphenylphosphorus complex of the group to be substituted. This reaction suitably proceeds at room temperature to 60 ° C.

Method (v): The target product [I] in which ring A and / or ring B is a hydrocarbon group or a heterocyclic group substituted by a carboxy-substituted lower alkenyl group is prepared by treating the corresponding ring A and / or The compound can be produced by reacting a compound in which ring B is a hydrocarbon group or a heterocyclic group substituted with a lower alkoxycarbonyl-lower alkenyl group in the presence of an inorganic base.
As the inorganic base, an inorganic base such as sodium hydroxide can be suitably used. This reaction suitably proceeds at 0 ° C to room temperature.

Method (w): The target compound [I] in which Q is a group represented by the formula —SO— or —SO ₂ — is a compound represented by the formula:
Can be produced by reacting a compound which is a group represented by the formula in the presence of an oxidizing agent. As the oxidizing agent, 3-chloroperbenzoic acid, peracetic acid, hydrogen peroxide, pertrifluoroacetic acid, sodium periodate, sodium hypochlorite, potassium permanganate and the like can be suitably used. This reaction suitably proceeds at 0 to 50 ° C.

The solvent used in the reactions described in the above (a) to (w) is not particularly limited as long as it is a solvent inert to the reaction. For example, dioxane, ethylene glycol dimethyl ether, dimethylacetamide, dimethylformamide, hexamethyl Phosphoramide, benzene, tetrahydrofuran, toluene, ethyl acetate, lower alcohol, methylene chloride, chloroform, carbon tetrachloride, 1,3-dimethyl-2-imidazolidinone, acetic acid, diethyl ether, dimethoxyethane, dimethyl sulfoxide, water or their Can be used as appropriate.

The starting compounds [II] and [VI] of the present invention can be produced, for example, according to the method described in JP-A-5-155864 or JP-A-5-222003. That is, the compound [II] wherein Q is a single bond
First, the general formula [X]

[0093]

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(However, ring B has the same meaning as described above) is treated with a halogenating agent (such as thionyl chloride) to give a corresponding acid halide, and then treated with an alcohol to give a corresponding ester. And then reacted with diethyl carbonate in the presence of a base (sodium hydride, potassium t-butoxide, etc.) to give a compound of the general formula [XI]

[0095]

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(Wherein, ring B has the same meaning as described above). The product is then treated with ammonia for amidation to give the general formula

[0097]

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(Wherein ring B has the same meaning as described above), and the product is reacted with a compound of the general formula (II) in the presence of a base (such as sodium ethylate).

[0099]

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(Wherein R ¹ has the same meaning as described above), and reacted with a compound of the general formula [XI
I]

[0101]

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(Wherein the symbols have the same meanings as described above), or the compound [X
I] in the presence of a base (such as sodium methoxide) in the general formula [XIII]

[0103]

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(Wherein R ¹ has the same meaning as described above) to give a compound [XII]. Further, the hydroxyl group of the product is treated with a halogenating agent (such as phosphorus oxychloride) to be converted into a reactive residue, and is converted to a general formula [XIV]

[0105]

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(Where X ⁵ represents a reactive residue and the other symbols have the same meanings as described above), or the compound [XI] is used as a base (eg, sodium methoxide). Reacting with an amidine compound urea in the presence of

[0107]

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(Wherein ring B has the same meaning as described above), and the hydroxyl group of the product is converted to a reactive residue by treating it with a halogenating agent (such as phosphorus oxychloride). Let the general formula [XV]

[0109]

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(Wherein the symbols have the same meanings as described above). Furthermore, the general formula [XV
I]

[0111]

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(Wherein W ¹ represents a lower alkyl group, and other symbols have the same meanings as described above) to give compound [XIV].

The compound represented by the general formula [XVII]

[0114]

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(Wherein ring A has the same meaning as described above) and a deoxidizing agent (sodium hydride,
Sodium hydroxide, potassium hydroxide, potassium carbonate, etc.)
Can be produced by reacting in the presence of

On the other hand, the compound [II] in which Q is a group represented by the formula -O- has the general formula [XVIII]

[0117]

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(Wherein ring B has the same meaning as described above) and diethyl bromomalonate in the presence of a deoxidizing agent (such as potassium carbonate) to give a compound of the general formula [XIX]

[0119]

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(Wherein, ring B has the same meaning as described above), and this compound is used in the presence of an amidine compound [XIII] in the presence of a base (eg, sodium methylate).
And reacting with the general formula [XX]

[0121]

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(Wherein the symbols have the same meanings as described above), a step of converting the hydroxyl group of the compound [XII] in which Q is a single bond into a reactive residue, Similarly, the general formula [XXI]

[0123]

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(Wherein the symbols have the same meanings as described above), or the compound [XIX] is reacted with urea which is an amidine compound in the presence of a base (such as sodium methoxide). General formula

[0125]

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(Wherein ring B has the same meaning as described above), and the hydroxyl group of the product is treated with a halogenating agent (such as phosphorus oxychloride) to convert it to a reactive residue. And the general formula [XXII]

[0127]

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(Wherein ring B has the same meaning as described above). Further, the compound [XV
I] to give compound [XXI]. Subsequently, the compound [II] can be produced by treating in the same manner as in the reaction of the compound [XIV] with the compound [XVII].

Further, the compound [VI] is prepared by converting the corresponding compound [II] into a compound of the general formula [XXIII].

[0130]

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(However, Y, Alk and Z have the same meanings as described above), and can be produced by reacting the compound with a deoxidizing agent (such as sodium hydride).

The starting compound [IV] of the present invention is
(I) reacting compound [XIV] or compound [XXI] with compound [III] in the presence of a deoxidizing agent (eg, sodium hydride or the like) to obtain a compound of the general formula [XXIV]

[0133]

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(Wherein the symbols have the same meaning as described above), which is reacted with sodium azide to give a compound of the general formula [XXV]

[0135]

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(Wherein the symbols have the same meanings as described above), and then the compound is produced by catalytic hydrogen reduction, or (ii) a compound [XIV] or a compound [XXI], By reacting ammonia, the general formula [X
XVI]

[0137]

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(Wherein the symbols have the same meanings as described above), and the compound is reacted with a compound [III] in the presence of a deoxidizing agent (eg, sodium hydride).
Can be produced by reacting

The starting compound [IV] can be obtained by compounding (i) the compound [XIV] or the compound [XXI] with the compound [XXI]
II] in the presence of a deoxidizing agent (eg, sodium hydride) to give a compound of the general formula [XXVII]

[0140]

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(Wherein the symbols have the same meanings as described above), which is reacted with sodium azide to give a compound of the general formula [XXVIII]

[0142]

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(Wherein the symbols have the same meanings as described above), and then catalytic hydrogen reduction to obtain a compound of the general formula [XXIX]

[0144]

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(Wherein the symbols have the same meanings as described above), and the compound is reacted with the compound [VII] in the presence of a deoxidizing agent (eg, sodium hydride). Or (ii) compound [XXVI]
With the compound [XXIII] to give the compound [XXI
X] can be produced by reacting it with compound [VII] in the presence of a deoxidizing agent (eg, sodium hydride or the like).

Furthermore, the starting compound [VIII] of the present invention
Is represented by (i) a general formula [XXX]

[0147]

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(Wherein R ¹ has the same meaning as described above) and the compound [XVII] in the presence of a deoxidizing agent (eg, sodium hydride) to give a compound of the general formula [XXXI]

[0149]

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(Wherein the symbols have the same meanings as described above), and this compound is reacted with a compound [II] in the presence of a deoxidizing agent (eg, sodium hydride or the like).
I] and reacting with the general formula [XXXII]

[0151]

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(Wherein the symbols have the same meanings as described above), and then a reactive residue is formed with a halogenating agent or the like, or (ii) the compound [XXX And compound [III] in the presence of a deoxidizing agent (eg, sodium hydride, etc.)
General formula [XXXIII]

[0153]

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(Wherein the symbols have the same meanings as described above), which is reacted with sodium azide to give a compound of the general formula [XXXIV]

[0155]

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(Wherein the symbols have the same meanings as described above), and then catalytic hydrogen reduction to obtain a compound of the general formula [XXXV]

[0157]

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(Wherein the symbols have the same meanings as described above), which is then reacted with the compound [V] in the presence of a deoxidizing agent (such as sodium hydride) to give the compound [XXXII], and can be produced by further forming a reactive residue with a halogenating agent or the like.

The starting compound [VIII] is represented by (i)
The compound [XXXVI] is reacted with the compound [XXIII] in the presence of a deoxidizing agent (eg, sodium hydride or the like) to give a compound of the general formula [XXXVI]

[0160]

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(Wherein the symbols have the same meanings as described above), and then treated with a halogenating agent (for example, N-bromosuccinimide or the like) to form a reactive residue. XXXVII]

[0162]

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(Where the symbols have the same meanings as described above), and then the compound is reacted with a compound [VII] in the presence of a deoxidizing agent (eg, sodium hydride). Or (ii) reacting the compound [XXX] with the compound [XXIII] in the presence of a deoxidizing agent (eg, sodium hydride or the like) to obtain a compound represented by the general formula [XX]
XVIII]

[0164]

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(Wherein the symbols have the same meanings as described above), which is reacted with sodium azide to give a compound of the general formula [XXXIX]

[0166]

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(Wherein the symbols have the same meanings as described above), and then catalytic hydrogen reduction to obtain a compound of the general formula [XXXX]

[0168]

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(Wherein the symbols have the same meanings as described above), which is then reacted with the compound [V] to give a compound of the general formula [XXXXXX]

[0170]

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(Wherein the symbols have the same meanings as described above), and the compound [XX] is treated with a halogenating agent (eg, bromine) to form a reactive residue.
XVII] and then reacting with compound [VII] in the presence of a deoxidizing agent (eg, sodium hydride).

The target compound [I] of the present invention may include optical isomers based on asymmetric carbon atoms, and the present invention includes both of these optical isomers and mixtures thereof.

The target compound [I] of the present invention can be used in a free form or in the form of a pharmaceutically acceptable salt for pharmaceutical use. Such pharmacologically acceptable salts include acid addition salts with inorganic or organic acids, salts with inorganic bases, organic bases or amino acids, such as hydrochlorides,
Sulfate, hydrobromide, methanesulfonate, acetate,
Fumarate, maleate, oxalate, alkali metal (sodium, potassium, etc.) salts, alkaline earth metal (magnesium, calcium, etc.) salts, triethylamine salts,
And a salt with lysine.

The target compound [I] of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally. For example, tablets, granules,
It can be used as an appropriate pharmaceutical preparation such as a capsule, a powder, an injection, and an inhalant.

The dose of the desired compound [I] of the present invention or a pharmaceutically acceptable salt thereof varies depending on the administration method, age, weight and condition of the patient, but is usually about 0.1 per day.
It is preferably about 100 mg / kg.

In the present invention, a lower alkyl group,
The lower alkoxy group, lower alkylene group, lower alkylenedioxy group, lower alkylthio group, lower alkylamino group, lower alkylsulfinyl group or lower alkylsulfonyl group have 1 to 6 carbon atoms, especially 1 to 4 carbon atoms. A lower alkenyl group, a lower alkanoyl group, a lower alkanoylamino group, a lower alkoxycarbonyl group, a lower alkynyl group, a lower alkenyloxy group,
The lower alkenylene group, N-lower alkylcarbamoyloxy group, N-lower alkoxyiminomethyl group or N-lower alkylaminocarbonyl group has 2 to 7 carbon atoms, especially 2 to 5 carbon atoms. Further, the cycloalkyl group has 3 to 8 carbon atoms, especially 3 to 6 carbon atoms. Examples of the halogen atom include chlorine, bromine, fluorine and iodine.

[0177]

The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the invention.

Example 1 N- [6- {2- (5-bromopyrimidin-2-yloxy) ethoxy} -5- (2-thienyl) -2- (2-
Pyrimidinyl) -pyrimidin-4-yl] -4-ter
t-butylbenzenesulfonamide

[0179]

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4-tert-butyl-N- {6- (2-
(Hydroxyethoxy) -5- (2-thienyl) -2-
1790 mg of (2-pyrimidinyl) -pyrimidin-4-yl @ benzenesulfonamide in tetrahydrofuran 2
Sodium hydride in a 0 ml solution at room temperature (60% dispersion type)
413 mg was added, and 4 ml of dimethylacetamide was further added, followed by stirring for 20 minutes. 952 mg of 5-bromo-2-chloropyrimidine is added to the reaction solution, and the mixture is stirred at room temperature for 46 hours. The reaction was acidified with 10% hydrochloric acid and extracted with ethyl acetate. After washing and drying the ethyl acetate layer, the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform: methanol = 4: 1) to obtain 617 mg of the target compound as crystals.

M. p. : 222.5-223.5 ° C IR (nujol, cm ^-1 ): 1640, 1610 MS (m / z): 670 (MH ⁺ ) Example 2 N- {6- [2- (5-bromopyrimidine-) 2-yloxy) ethoxy] -5- (4-methylphenyl) pyrimidin-4-yl {naphthalenesulfonamide

[0182]

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6- [2- (5-bromopyrimidine-2-
Yloxy) ethoxy] -5- (4-methylphenyl)
A mixture of 150 mg of pyrimidine-4-amine, 170 mg of 2-naphthalenesulfonyl chloride, 300 mg of 96% potassium hydroxide (powder), 34 mg of tetrabutylammonium hydrogen sulfate and 10 ml of toluene is stirred at room temperature overnight. Dilute with saturated aqueous ammonium chloride and extract with ethyl acetate. After washing and drying the ethyl acetate layer, the solvent is distilled off. The residue is purified by silica gel column chromatography (solvent; chloroform: ethyl acetate = 8: 1) and recrystallized from hexane-tetrahydrofuran to obtain 187 mg of the target compound.

M. p. : 204.0-204.5 ° C IR (nujol, cm ^-1 ): 1570 MS (m / z): 594 (MH ⁺ ) Example 3-6 6- [2- (5-bromopyrimidin-2-yloxy) )
Ethoxy] -5- (4-methylphenyl) pyrimidine-
The 4-amine and the corresponding starting compound are treated in the same manner as in Example 2 to obtain the compounds shown in Table 1 below.

[0185]

[Table 1]

Example 7 N- {6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -5- (2-methoxyphenoxy)
-2- (2-pyrimidinyl) -pyrimidin-4-yl}
-2-thiophene sulfonamide

[0187]

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6- [2- (5-bromopyrimidine-2-
Yloxy) ethoxy] -5- (2-methoxyphenoxy) -2- (2-pyrimidinyl) -pyrimidine-4-
Amine 100mg, sodium hydride (60% dispersion type)
A mixture of 53.5 mg and 3 ml of tetrahydrofuran is stirred at room temperature for 20 minutes. Subsequently, 23.4 mg of thiophenesulfonyl chloride is added and stirred for 22 hours. Treat the reaction with saturated ammonium chloride and extract with ethyl acetate. After washing and drying the ethyl acetate layer, the solvent was distilled off.
The residue is purified by preparative thin-layer chromatography (developing solvent; chloroform: methanol = 10: 1) to obtain 49.1 mg of the target compound.

M. p. :> 300 ° C IR (nujol, cm ^-1 ): 1560 MS (m / z): 658 (MH ⁺ ) Example 8 N- {6- [2- (5-bromopyrimidin-2-yloxy) ethoxy]- 5- (2-methoxyphenoxy)
-2- (2-pyrimidinyl) -pyrimidin-4-yl}
-2-Naphthalenesulfonamide

[0190]

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6- [2- (5-bromopyrimidine-2-
Yloxy) ethoxy] -5- (2-methoxyphenoxy) -2- (2-pyrimidinyl) -pyrimidine-4-
The target compound is obtained by treating the amine and the corresponding starting compound in the same manner as in Example 7.

M. p. 163.0-165.0 ° C IR (nujol, cm ^-1 ): 1560 MS (m / z): 704 (MH ⁺ ) Example 9 N- {6- [2- (5-bromopyrimidine-2-) Yloxy) ethoxy] -5- (2-methoxyphenoxy)
-2-morpholinopyrimidin-4-yl} -2-thiophenesulfonamide

[0193]

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6- [2- (5-bromopyrimidine-2-
Yloxy) ethoxy] -5- (2-methoxyphenoxy) -2-morpholino-pyrimidin-4-amine 20
0mg, sodium hydride (60% dispersion type) 46.2m
g and 6 ml of tetrahydrofuran at room temperature for 20 minutes.
Stir for minutes. Subsequently, 211 mg of 2-thiophenesulfonyl chloride are added, and the mixture is stirred for 20 hours. Treat the reaction with saturated ammonium chloride and extract with ethyl acetate.
After washing and drying the ethyl acetate layer, the solvent was distilled off, and the residue was recrystallized from ether-hexane to give the target compound (46 mg).
Get.

M. p. : 186-188 ° C Example 10 N- {6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -5- (2-methoxyphenoxy)
-2-morpholinopyrimidin-4-yl} -2-naphthalenesulfonamide

[0196]

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6- [2- (5-bromopyrimidine-2-
Iloxy) ethoxy] -5- (2-methoxyphenoxy) -2-morpholino-pyrimidin-4-amine and the corresponding starting compound are treated as in Example 9 to give the target compound.

M. p. : 178.0-181.5 ° C IR (nujol, cm ^-1 ): 1560, 1460, ¹
380,1320 MS (m / z): 709 (MH ^<+> ) Example 11 4-tert-butyl-N- {5- (2-benzothienyl) -6- [2- (5-methylthiopyrimidin-2-yloxy) ) Ethoxy] pyrimidin-4-yl} benzenesulfonamide

[0199]

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N- {5-bromo-6- [2- (5-methylthiopyrimidin-2-yloxy) ethoxy] pyrimidin-4-yl} -4-tert-butylbenzenesulfonamide 200 mg, 2-benzothienyltributyltin 460 mg , Bis (triphenylphosphine) palladium (II) chloride 51 mg, triphenylphosphine 28 mg, copper (I) bromide 21 mg, 2,6-di-t
A mixture of 2,3 pieces of tert-butylcresol crystals and 6 ml of dioxane is heated to reflux for 2 hours. After cooling, the reaction solution is diluted with ethyl acetate and an aqueous potassium fluoride solution, and stirred at room temperature for 60 minutes. The insoluble material is removed by filtration and extracted with ethyl acetate. After washing and drying the ethyl acetate layer, the solvent is distilled off. The residue is purified by silica gel column chromatography (solvent; methylene chloride: acetone = 30: 1) and recrystallized from ethyl acetate to obtain 182 mg of the target compound.

M. p. 198.5-199.5 ° C IR (nujol, cm ^-1 ): 1610, 1570 MS (m / z): 608 (MH ⁺ ) Example 12-16 N- {5-bromo-6- [2- (5-Methylthiopyrimidin-2-yloxy) ethoxy] pyrimidin-4-yl} -4-tert-butylbenzenesulfonamide and the corresponding starting compounds are treated in the same manner as in Example 11 to obtain the compounds shown in Table 2 below.

[0202]

[Table 2]

Example 17 N- {6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -5- (2-methoxyphenoxy)-
2-methylpyrimidin-4-yl dinaphthalenesulfonamide

[0204]

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N- {6- (2-hydroxyethoxy)-
The target compound is obtained by treating 5- (2-methoxyphenoxy) -2-methylpyrimidin-4-yl} naphthalenesulfonamide and the corresponding starting compound in the same manner as in Example 1.

M. p. : 162.5-164.5 ° C The compounds of the present invention have been described in detail above. Representative compounds contained in the present invention include those described in the above Examples and Tables 3 to 4 below. Tables can be mentioned.

[0207]

[Table 3]

[0208]

[Table 4]

Reference Example 1 (1) To a mixed solution of 400 ml of tetrahydrofuran and 60 ml of ethylene glycol was added 3.38 g of sodium hydride (60% dispersion type) under ice-cooling and stirring.
Dichloro-5- (4-methylphenyl) pyrimidine 2
Add 0.0 g. After stirring for 30 minutes under ice cooling and further for 2 hours at room temperature, the mixture is made weakly acidic with acetic acid and concentrated under reduced pressure.
The residue is dissolved in ethyl acetate, washed, dried, and dried under reduced pressure. The residue was crystallized from hexane to give 2- {6-chloro-
21.85 g of 5- (4-methylphenyl) pyrimidin-4-yloxydiethanol are obtained.

M. p. : 62-64 ° C (2) 2- {6-chloro-5- (4-methylphenyl)
Pyrimidin-4-yloxydiethanol 21.85
g, 10.7 g of sodium azide and 260 ml of dimethylformamide are heated and stirred at 75 to 80 ° C. overnight. After cooling, treat with water and extract with ethyl acetate. After washing and drying the ethyl acetate layer, the solvent was distilled off and the residue was crystallized from hexane to give 2- {6-azido-5- (4-methylphenyl) pyrimidin-4-yloxy} ethanol.
6 g are obtained.

M. p. : 83.5-85 ° C MS (m / z): 271 (M ⁺ ) (3) 2- {6-azido-5- (4-methylphenyl)
Pyrimidin-4-yloxy} ethanol 19.6 g,
A mixture of 4.0 g of 10% palladium-carbon (containing 50% water) and 240 ml of ethanol is subjected to catalytic reduction under a hydrogen atmosphere (1 atm) at room temperature for 1 hour. Filter off the catalyst,
The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give 2- {6-amino-5- (4-methylphenyl).
15.9 g of pyrimidin-4-yloxy} ethanol are obtained.

M. p. : 104-105 ° C Reference Example 2 (1) 4,6-dichloro-5- (4-methylphenyl)
27% in a solution of 4.14 g of pyrimidine in 20 ml of ether
Add 30 ml of ammonia-methanol solution, and in a sealed tube,
Incubate at room temperature for 3 days. The solvent was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane:
(Ethyl acetate 10: 1 to ethyl acetate only).
Chloro-5- (4-methylphenyl) pyrimidine-4-
1.89 g of the amine are obtained.

M. p. 168-171 ° C (2) 6-chloro-5- (4-methylphenyl) pyrimidin-4-amine 500 mg, ethylene glycol 10
A mixture of 0.46 g of sodium hydride (60% dispersion type) is reacted at 70 ° C. for 2 hours and further at 90 ° C. for 5 hours. Treat the mixture with saturated aqueous ammonium chloride and extract with ethyl acetate. After washing and drying the ethyl acetate layer, the solvent is distilled off. The residue is crystallized from hexane-ethyl acetate to give 422 mg of 2- {6-amino-5- (4-methylphenyl) pyrimidin-4-yloxy} ethanol.

M. p. : 91.5-93.5 ° C Reference Example 3 To a solution of 7.54 g of 2- {6-amino-5- (4-methylphenyl) pyrimidin-4-yloxy} ethanol in 150 ml of tetrahydrofuran was added sodium hydride (60%).
% Dispersion type), and then add 7.73 g of 5-bromo-2-chloropyrimidine and stir at room temperature overnight. A saturated aqueous ammonium chloride solution is added to the reaction solution, and the solvent is distilled off under reduced pressure. The precipitated crystals are collected by filtration, washed and dried. The crude crystals are subjected to silica gel column chromatography (solvent; chloroform: methanol 100: 1 to 80: 1).
And then recrystallized with tetrahydrofuran-diethyl ether to obtain 11.27 g of 6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -5- (4-methylphenyl) pyrimidin-4-amine. .

M. p. : 178.5-179.5 ° C IR (nujol, cm ^-1 ): 3400, 3300, 3
130, 1640, 1580 MS (m / z): 401, 403 (M ⁺ ) Reference Example 4 (1) 1.33 g of 4,6-dichloropyrimidine and 4-
To a solution of 1.96 g of tert-butylbenzenesulfonamide in 20 ml of dimethyl sulfoxide is added 714 mg of sodium hydride (60% dispersion type). After stirring at room temperature for 2 hours, the reaction solution is diluted with 10% hydrochloric acid and water, and extracted with ethyl acetate. The ethyl acetate layer was washed and dried, and the solvent was distilled off. The residue was recrystallized from ethyl acetate to obtain 2.02 g of 4-tert-butyl-N- (6-chloropyrimidin-4-yl) benzenesulfonamide. .

M. p. : 225-26.5 ° C IR (nujol, cm ^-1 ): 3035, 1630, ¹
595, 1575 MS (m / z): 325 (M ⁺ ) (2) 1.03 g of sodium hydride (60% dispersion type) was added to 20 ml of ethylene glycol, and further 4-ter was added.
t-butyl-N- (6-chloropyrimidin-4-yl)
Add 1.66 g of benzenesulfonamide, and add
Stir for 0 hours. After cooling, acidify with 10% hydrochloric acid and extract with ethyl acetate. After washing and drying the ethyl acetate layer, the solvent is distilled off. The residue was crystallized from ethyl acetate,
1.58 g of 4-tert-butyl-N- [6- (2-hydroxyethoxy) pyrimidin-4-yl) benzenesulfonamide are obtained.

M. p. : 169-170.5 ° C IR (nujol, cm ^-1 ): 3440, 1600, ¹
570 MS (m / z): 352 (MH ⁺ ) (3) 4-tert-butyl-N- [6- (2-hydroxyethoxy) pyrimidin-4-yl) benzenesulfonamide (210 mg) was added to a solution of 210 mg of dimethylformamide in 4 ml of dimethylformamide. Add 116 mg of -bromosuccinimide and stir at room temperature for 1 hour. After being treated with an aqueous solution of sodium hydrogen sulfite, the mixture is extracted with ethyl acetate. After washing and drying the ethyl acetate layer, the solvent is distilled off. The residue was subjected to silica gel column chromatography (solvent; chloroform: methanol = 4).
0: 1), and recrystallized from hexane-ethyl acetate to give 169 mg of N- [5-bromo-6- (2-hydroxyethoxy) pyrimidin-4-yl] -4-tert-butylbenzenesulfonamide. obtain.

M. p. 146-147.5 ° C IR (nujol, cm ^-1 ): 3360, 3200, ¹
620,1575 MS (m / z): 432,430 (MH ⁺ ) (4) N- [5-bromo-6- (2-hydroxyethoxy) pyrimidin-4-yl] -4-tert-butylbenzenesulfonamide 3. Sodium hydride (60% dispersion type) 7 in 30 ml solution of dimethylacetamide of 3.10 g
Add 20 mg and stir at room temperature for 30 minutes. Then, 2-
1.51 g of chloro-5-methylthiopyrimidine was added,
Stir at room temperature overnight. The reaction is treated with 10% hydrochloric acid and saturated aqueous ammonium chloride and extracted with ethyl acetate.
After washing and drying the ethyl acetate layer, the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent; chloroform: ethyl acetate = 10: 1) and recrystallized from hexane-ethyl acetate to give N- {5-bromo-6- [2-
3.34 g of (5-methylthiopyrimidin-2-yloxy) ethoxy] pyrimidin-4-yl} -4-tert-butylbenzenesulfonamide are obtained.

M. p. : 120-121 ° C IR (nujol, cm ^-1 ): 1585, 1575, ¹
550 MS (m / z): 556,554 (MH ⁺ ) Reference Example 5 (1) 5.0 g of 4,6-dichloropyrimidine, 100 ml of ethylene glycol and 100 m of tetrahydrofuran
Under ice cooling, 1.34 g of sodium hydride (60% dispersion type) is added to 1 of the mixture. After stirring at the same temperature for 2 hours, the solvent is distilled off. The residue is extracted with ethyl acetate, and the extract is dried and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (solvent; chloroform: ethyl acetate 5: 1).
~ 2: 1) to give 2- (6-chloropyrimidine-
5.67 g of 4-yloxy) ethanol are obtained as an oil.

IR (nujol, cm ^-1 ): 3300,
1575, 1545 MS (m / z): 175 (MH ^<+> ) (2) 2- (6-chloropyrimidin-4-yloxy)
5.61 g of ethanol, 60 ml of dimethylformamide
4.18 g of sodium azide are added to the solution and stirred at 70 ° C. for 20 hours. After cooling, the reaction is treated with water and extracted with ethyl acetate. After drying the ethyl acetate layer, the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 1: 1) to give 2-
1.68 g of (6-azidopyrimidin-4-yloxy) ethanol are obtained.

M. p. : 49-50 ° C IR (nujol, cm ^-1 ): 3280, 2070, ¹
600, 1550 MS (m / z): 181 (MH ^<+> ) (3) 2- (6-azidopyrimidin-4-yloxy)
1.64 g of ethanol, 10% palladium-carbon 0.2
A mixture of 5 g and 20 ml of ethanol is subjected to catalytic reduction under a hydrogen atmosphere (1 atm) at room temperature for 1 hour. The catalyst is removed by filtration and the filtrate is concentrated. The residue was recrystallized from ethanol-diethyl ether to give 2- (6-aminopyrimidine-
This gives 1.11 g of 4-yloxy) ethanol.

M. p. : 133-137 ° C IR (nujol, cm ^-1 ): 3360, 3200, ¹
660, 1610, 1550 MS (m / z): 156 (MH ^<+> ) (4) 2- (6-Aminopyrimidin-4-yloxy)
A solution of 437 mg of bromine in 2 ml of methanol is added dropwise to a suspension of 400 mg of ethanol in 4 ml of methanol. After evaporating the solvent, the residue is dissolved in ethyl acetate. After treatment with a saturated aqueous sodium hydrogen carbonate solution, the mixture is extracted with ethyl acetate-tetrahydrofuran. After the organic layer was washed and dried, the solvent was distilled off to give 2- (6-amino-5-bromopyrimidine-4).
632 mg of -yloxy) ethanol are obtained.

IR (nujol, cm ^-1 ): 3480,
3420, 3390, 3290, 1640, 1580 MS (m / z): 235,233 (M ⁺ ) (5) 2- (6-amino-5-bromopyrimidine-4-
Sodium hydride (60% dispersion type) in a solution of 611 mg of yloxy) ethanol in 20 ml of dimethylformamide
Add 125 mg. After stirring for 20 minutes, 2-chloro-5-
Add 461 mg of methylthiopyrimidine and stir at room temperature for 3 hours. Add ice water and extract with ethyl acetate. After washing and drying the ethyl acetate layer, the solvent is distilled off. The residue was subjected to silica gel column chromatography (solvent; chloroform:
After purification with methanol = 20: 1), the residue was crystallized from ethyl acetate-diisopropyl ether to give 5-bromo-6- [2
-(5-Methylthiopyrimidin-2-yloxy) ethoxy] pyrimidin-4-amine (501 mg) is obtained.

M. p. : 126-129 ° C IR (nujol, cm ^-1 ): 3450, 3270, ¹
635, 1585, 1570, 1540 MS (m / z): 359,357 (MH ^<+> ) (6) 5-bromo-6- [2- (5-methylthiopyrimidin-2-yloxy) ethoxy] pyrimidin-4-amine After adding 34 mg of sodium hydride (60% dispersion type) to a 2 ml solution of 102 mg of tetrahydrofuran,
4-tert-butylbenzenesulfonyl chloride 19
Add 8 mg and stir at room temperature for 20 minutes. One drop of pyridine and water are added, the mixture is stirred at room temperature for 30 minutes, and then neutralized with a saturated aqueous ammonium chloride solution. After extraction with ethyl acetate, washing and drying of the ethyl acetate layer, the solvent was distilled off, and the residue was purified by preparative thin-layer chromatography (developing solvent; chloroform: methanol = 15: 1), followed by hexane-ethyl acetate. To give N- {5-bromo-6- [2-
135 mg of (5-methylthiopyrimidin-2-yloxy) ethoxy] pyrimidin-4-yl} -4-tert-butylbenzenesulfonamide are obtained. The physical properties are the same as in Reference Example 4 (4).

Reference Example 6 (1) To a solution of 18.0 g of diethyl (2-thienyl) malonate and 10.02 g of 5-pyrimidinylamidine hydrochloride in 150 ml of methanol, 36.58 g of 28% sodium methoxide and 36.58 g of methanol were added under ice-cooling. Add 30 ml solution and stir at room temperature for 16 hours. After the reaction, the solution is concentrated,
Acidify with 10% hydrochloric acid. After stirring for 30 minutes, the precipitated crystals were filtered, washed, and dried to give 5- (2-thienyl) -4,6-dihydroxy-2- (2-pyrimidinyl) pyrimidine.
15 g are obtained as a crystalline powder.

M. p. 244 to 246 ° C IR (nujol, cm ^-1 ): 1635,1600 MS (m / z): 272 (M ⁺ ) (2) 5.00 g of this product, 15 ml of N-diethylaniline
And 50 ml of phosphorus oxychloride was stirred at 80 ° C. for 2 hours and then at 90 ° C. for 3.5 hours. After the reaction, phosphorus oxychloride is distilled off and slowly poured into 300 ml of water. The mixture is stirred at room temperature and extracted with ethyl acetate. After washing and drying, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (solvent; chloroform: ethyl acetate = 5:
After purification in 1), 2.77 g of 5- (2-thienyl) -4,6-dichloro-2- (2-pyrimidinyl) pyrimidine is obtained as crystals.

M. p. 159-160 ° C IR (nujol, cm ^-1 ): 1560 MS (m / z): 308 (M ⁺ ) (3) 2.77 g of this product in 30 ml of dimethyl sulfoxide
2.30 g of 4-tert-butylbenzenesulfonamide and 6.19 g of potassium carbonate were added to the suspension,
Stir at C for 8 hours. After cooling, the reaction mixture was cooled on ice 1
Acidify with 0% hydrochloric acid. After extraction with ethyl acetate, washing and drying, the solvent was distilled off, and the residue was subjected to flash silica gel column chromatography (solvent; hexane: ethyl acetate = 1: 1).
After purification in 1), it was further crystallized from n-hexane-ethyl acetate to give 4-tert-butyl-N- [6-chloro-5-
1.67 g of (2-thienyl) -2- (2-pyrimidinyl) pyrimidin-4-yl] benzenesulfonamide are obtained as a powder.

M. p. 129.5 to 131.5 ° C IR (nujol, cm ^-1 ): 1640, 1560 MS (m / z): 486 (M ⁺ ) (4) 688 mg of sodium hydride (60% dispersion type) in 20 ml of ethylene glycol. Add this product 1672m
Add g. After stirring the reaction solution at room temperature for 20 minutes, 140
Incubate at 3.5 ° C for 3.5 hours. After cooling, the reaction solution was acidified with 10% hydrochloric acid, extracted with ethyl acetate, and the ethyl acetate layer was washed, dried, dried under reduced pressure, crystallized from n-hexane-ethyl acetate and 4-tert-butyl-ethyl acetate. N- ｛6- (3
-Hydroxyethyloxy) -5- (2-thienyl)-
1790 mg of 2- (2-pyrimidinyl) pyrimidin-4-yl @ benzenesulfonamide are obtained as crystals.

M. p. : 236-237 ° C IR (nujol, cm ^-1 ): 3450-3380, ¹
620 MS (m / z): 512 (M ⁺ ) Reference Example 7 (1) Reference Example 1 using 5- (2-methoxyphenoxy) -4,6-dichloro-2- (2-pyrimidinyl) pyrimidine and ethylene glycol. -Processing in the same manner as (1),
-{6-chloro-5- (2-methoxyphenoxy) -2
-(2-pyrimidinyl) pyrimidin-4-yloxy}
Ethanol 5.37 is obtained as a powder.

M. p. : 133-137 ° C IR (nujol, cm ^-1 ): 3600-3300, ¹
650 MS (m / z): 374 (M ⁺ ) (2) 5.37 g of this product was treated in the same manner as in Reference Example 1- (2) to give 2- {6-azido-5- (2-methoxyphenoxy). 1.29 g of 2- (2-pyrimidinyl) pyrimidin-4-yloxy} ethanol are obtained as a powder.

M. p. : 133-134.5 ° C IR (nujol, cm ^-1 ): 3430-3350,2
180, 2170, 1580 MS (m / z): 381 (M ⁺ ) (3) 1.29 g of this product was treated in the same manner as in Reference Example 1- (3) to give 2- {6-amino-5- (2 788 mg of -methoxyphenoxy) -2- (2-pyrimidinyl) pyrimidin-4-yloxy} ethanol are obtained as a powder.

M. p. 183.5-185 ° C IR (nujol, cm ^-1 ): 3590, 3450, ¹
620 MS (m / z): 355 (M ⁺ ) (4) This compound was treated with 778 mg in the same manner as in Reference Example 3 to give 6-
[2- (5-bromopyrimidin-2-yloxy) ethoxy] -5- (2-methoxyphenoxy) -2- (2-
733 mg of (pyrimidinyl) pyrimidin-4-amine are obtained as a powder.

M. p. : 124.5-128.5 ° C IR (nujol, cm ^-1 ): 3480, 3280, ¹
630 MS (m / z): 512 (M ⁺ ) Reference Example 8 (1) Diethyl (2-methoxyphenoxy) malonate 1
To a solution of 0.0 g and 3.83 g of 28% sodium methoxide in 100 ml of methanol is added 2.23 g of urea under heating, and the mixture is refluxed at 80 ° C. for 16 hours. After the reaction, the solution is concentrated and acidified with 10% hydrochloric acid. The precipitated crystals are filtered, washed and dried to give 5- (2-methoxyphenoxy) -2,4,6-
7.10 g of trihydroxypyrimidine are obtained as a crystalline powder.

M. p. 202-204 ° C IR (nujol, cm ^-1 ): 3500, 3180-2
800,1710 MS (m / z): 251 (M ⁺ ) (2) 1.00 g of this product, 1.28 N-diethylaniline
After heating a mixture of 5 ml of phosphorus oxychloride and 5 ml of phosphorus oxychloride under reflux for 3 hours, phosphorus oxychloride is distilled off and the mixture is slowly poured into water. The mixture is stirred at room temperature and extracted with ether. After washing and drying, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (solvent: hexane: ethyl acetate = 3).
After purification by 0: 1), 5- (2-methoxyphenoxy)-
351 mg of 2,4,6-trichloropyrimidine are obtained as crystals.

M. p. 150.5-152 ° C IR (nujol, cm ^-1 ): 1600 MS (m / z): 304 (M ⁺ ) (3) 300 mg of this product at 100 ° C in a solution of 113.5 mg of N-methylmorpholine in 5 ml of toluene. Toluene 5
ml solution and stirred at 90 ° C. for 2 hours. After cooling, water was added, and the mixture was extracted with ethyl acetate, washed and dried, and the solvent was distilled off. The residue was crystallized from n-hexane to give 2-N-morpholino-
344 mg of 4,6-dichloro-5- (2-methoxyphenoxy) pyrimidine are obtained as a powder.

M. p. 179.5-180 ° C IR (nujol, cm ^-1 ): 1600, 1540 MS (m / z): 355 (M ⁺ ) (4) A mixture of 20 ml of tetrahydrofuran and 3.66 g of 2-benzyloxyethanol was added at room temperature. After adding 917 mg of sodium hydride (60% dispersion type) and stirring for 20 minutes, 30 ml of a mixture of tetrahydrofuran-dimethylsulfoxide containing 7.78 g of this product was added dropwise, and the mixture was stirred at room temperature for 1 hour and then at 50 ° C. for 2 hours. Stirred. The residue is dissolved in ethyl acetate, washed, dried, and dried under reduced pressure. The residue was purified by silica gel column chromatography (solvent; chloroform: ethyl acetate = 40: 1), and then purified by 6- (2-benzyloxyethoxy) -4-chloro-5- (2-methoxyphenoxy) -2-morpholinopyrimidine. 6.61 g
Get.

M. p. : 133-134.5 ° C IR (nujol, cm ^-1 ): 1600, 1540-1
520 MS (m / z): 472 (M ⁺ ) (5) This product was treated with 8.26 g in the same manner as in Reference Example 1- (2) to give 4-azido-6- (2-benzyloxyethoxy).
5.83 g of -5- (2-methoxyphenoxy) -2-morpholinopyrimidine are obtained as a powder.

M. p. 146-147.5 ° C IR (nujol, cm ^-1 ): 2150, 1600 MS (m / z): 479 (M ⁺ ) (6) 5.83 g of this product was treated in the same manner as in Reference Example 1- (3). Work-up gives 3.40 g of 2- {6-amino-5- (2-methoxyphenoxy) -2-morpholinopyrimidin-4-yloxy} ethanol as a powder.

M. p. 136-138.5 ° C IR (nujol, cm ^-1 ): 3600-3200,1
630,1600 MS (m / z): 363 (M ⁺ ) (7) 200 mg of this product was treated in the same manner as in Reference Example 3 to give 6-
290 mg of [2- (5-bromopyrimidin-2-yloxy) ethoxy] -5- (2-methoxyphenoxy) -2-morpholinopyrimidin-4-amine are obtained as a caramel.

IR (nujol, cm ^-1 ): 3460-
3100,1600 MS (m / z): 519 (M ⁺ )

[0241]

The object compound [I] of the present invention or a pharmacologically acceptable salt thereof has excellent endothelin antagonism, so that diseases related to endothelin activity, for example, hypertension, pulmonary hypertension , Renal hypertension, Raynaud's disease, bronchial asthma, gastric ulcer, inflammatory bowel disease (Crohn's disease), shock, carcinogenesis, restenosis after angioplasty, organ dysfunction after organ transplantation, diabetes, thrombosis, arteriosclerosis Disease, heart failure, acute renal failure, glomerulonephritis, cyclosporine-induced nephrotoxicity, myocardial infarction, angina, arrhythmia, glaucoma, migraine,
It is useful as an agent for preventing or treating cerebral vasospasm and cerebral infarction. Further, the object of the present invention has low toxicity and high safety when used as a pharmaceutical compound.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/506 A61K 31/506 A61P 1/04 A61P 1/04 9/00 9/00 9/12 9/12 43/00 111 43/00 111 (72) Inventor Rinako Kono 4-180-1, Sakuragicho, Omiya City, Saitama Prefecture 401, Towa Citycorp Omiya Sakuragicho 401 (56) References JP-A-8-99961 (JP, A) JP-A-8 -208625 (JP, A) JP-A-5-155864 (JP, A) JP-A-5-222003 (JP, A) JP-A-6-211810 (JP, A) JP-A-7-17972 (JP, A) (58) Fields surveyed (Int. Cl. ⁷ , DB name) C07D 239/69 C07D 401/14 C07D 405/14 C07D 409/14 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. A compound of the general formula [I] (However, ring A represents a substituted or unsubstituted monocyclic or bi- to tricyclic hydrocarbon group or a substituted or unsubstituted heterocyclic group, and ring B is (1) ring A is a substituted or unsubstituted monocyclic group. In the case of a cyclic hydrocarbon group, it is a substituted or unsubstituted bi- to tricyclic hydrocarbon group or a substituted or unsubstituted heterocyclic group,
(2) When ring A is a substituted or unsubstituted bi- to tricyclic hydrocarbon group or a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted monocyclic or bi- to tricyclic hydrocarbon group or substituted or unsubstituted indicates that a non-substituted heterocyclic group, Q is a single bond or the formula -O -, - S -, - SO -, - SO 2 - or -CH ₂ - group represented by, Y has the formula -O -, -S- or -NH-, Alk is a lower alkylene group or a lower alkenylene group, Z is a group of the formula -O- or -NH-, R is a substituted or unsubstituted aromatic heterocyclic ring A formula group or an aryl group, R ¹ is a hydrogen atom, a trifluoromethyl group, a substituted or unsubstituted mono- or di-lower alkylamino group, a substituted or unsubstituted lower alkyl group,
Represents a substituted or unsubstituted lower alkenyl group, a substituted or unsubstituted lower alkynyl group, a substituted or unsubstituted lower alkylthio group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted heterocyclic group, or an aryl group. Or a pharmacologically acceptable salt thereof. 2. Ring A is a phenyl group substituted with a lower alkyl group or a lower alkylenedioxy group,
Ring B is a naphthyl group, a pyridyl group, a furyl group, a thienyl group or a benzothienyl group optionally substituted with a lower alkyl group, or a ring A is a naphthyl group optionally substituted with a di-lower alkylamino group A phenyl group in which a thienyl group, a benzofuryl group or a benzothienyl group which may be substituted with an indenyl group, an anthryl group, a pyridyl group or a lower alkyl group, and wherein ring B is substituted with a lower alkyl group or a lower alkoxy group; , A naphthyl group, a pyridyl group, a furyl group, a thienyl group or a benzothienyl group which may be substituted with a lower alkyl group,
Q is a single bond or a group represented by the formula -O-, Y is a group represented by the formula -O-
Wherein Alk is a lower alkylene group and Z is a group of the formula -O
A group represented by-, R is a halogen atom, a pyrimidinyl group substituted with a thienyl group or a lower alkylthio group, R ¹ is a hydrogen atom, a hydroxyl-substituted lower alkylamino group, a lower alkyl group, a carboxyl group-substituted lower alkylthio group, The compound according to claim 1, which is a hydroxyl-substituted lower alkoxy group, a pyrimidinyl group, a hydroxyl-substituted piperidinyl group, a lower alkyl-substituted piperazinyl group or a morpholino group. 3. A ring A is a phenyl group substituted with a lower alkyl group or a lower alkylenedioxy group,
Ring B is a naphthyl group, a pyridyl group, a furyl group, a thienyl group or a benzothienyl group optionally substituted with a lower alkyl group, or a ring A is a naphthyl group optionally substituted with a di-lower alkylamino group A phenyl group in which a thienyl group, a benzofuryl group or a benzothienyl group which may be substituted with an indenyl group, an anthryl group, a pyridyl group or a lower alkyl group, and wherein ring B is substituted with a lower alkyl group or a lower alkoxy group; 3. The compound according to claim 2, which is a thienyl group substituted with a lower alkyl group.