JP3116347B2 - Pharmaceutical composition - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition.

[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]

SUMMARY OF THE INVENTION The present invention provides a pharmaceutical composition comprising a novel sulfonamide derivative having an excellent endothelin antagonistic activity as an active ingredient.

[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
_{A group represented by 2} -or -CH _2- , Y is a group represented by 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 -NH
A group represented by-, R is a substituted or unsubstituted aromatic heterocyclic group or aryl group, R ¹ is a hydrogen atom, a substituted or unsubstituted mono- or di-lower alkylamino group,
Substituted or unsubstituted lower alkyl group, substituted or unsubstituted lower alkenyl group, substituted or unsubstituted lower alkynyl group, substituted or unsubstituted lower alkylthio group, substituted or unsubstituted lower alkoxy group, substituted or unsubstituted heterocyclic group or aryl Represents a group. ) Or a pharmacologically acceptable salt thereof as an active ingredient.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION In the sulfonamide derivative [I], which is an active ingredient of the present invention, the hydrocarbon group may be a monocyclic, bicyclic or tricyclic carbon which may be partially or wholly saturated. The following 15 or less are mentioned. 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 specific examples thereof include the following, in addition to a fluorenyl group, a phenanthryl group, an anthryl group, an acenaphthylenyl group, and a biphenylenyl group.

[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:
Lower alkyl group; lower alkoxy group; lower alkenyl group; lower alkynyl group; lower alkylthio group; cycloalkyl group; trifluoromethyl group; carboxyl group; cyano group; tetrazolyl group, for example, a halogen atom; Formyl group; carbamoyl group; mono- or di-lower alkylaminocarbonyl group; lower alkoxycarbonyl group; lower alkoxycarbonyl-lower alkoxy group; lower alkoxycarbonyl-lower alkyl group; lower alkoxycarbonyl-lower alkenyl group; Alkoxy-substituted lower alkyl group; amino-substituted lower alkyl group; hydroxy-lower alkyl group; carboxyl-substituted lower alkyl group; carboxyl-substituted lower alkenyl group; carboxyl-substituted lower alkoxy group; Mopyrimidinyloxy lower alkyl group; lower alkylenedioxy group; aryl lower alkoxy group; mono- or di-lower alkylamino group; lower alkylsulfinyl group; lower alkylsulfonyl group; pyridyl group; nitro group; imidazole group; A thiazole group; a triazole group; a furyl group; a phenyl group which may be substituted with 1 to 5 groups selected from a halogen atom, 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 alkyl group; or an arylaminocarbonyl group.

The substituent on the phenyl group in ring A and / or ring B is particularly preferably a lower alkyl group, a lower alkoxy group or a lower alkylenedioxy group.

The ring A and / or ring B may be 1) a monocyclic group, which may have 1 to 3 substituents which are 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 the 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 carbamoyl group; an N-lower alkylcarbamoyloxy group;
N-lower alkoxyiminomethyl group; lower alkyl group; hydroxy lower alkyl group; cycloalkyl group; lower alkoxy-lower alkyl group; lower alkoxycarbonyl-lower alkenyl group; trifluoromethyl group; Group-substituted lower alkyl group; lower alkylthio group; mono- or di-lower alkylamino group; lower alkanoylamino group; lower alkoxy group; lower alkoxy group optionally substituted with a carboxyl group which may be protected; aryloxy group; Lower alkoxy-lower alkenyl group; lower alkanoyl group; arylcarbonyl group; lower alkenyloxy group; hydroxy lower alkynyl group; lower alkynyl group which may be protected by trimethylsilyl group; Ano-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; an aromatic heterocyclic group-substituted hydroxyl group optionally substituted with 1 to 3 groups selected from a halogen atom and a lower alkyl group; Examples include an aromatic heterocyclic group which may be substituted with an alkyl group.

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

[0028] In addition, mono in R ¹ - or di -
Examples of the substituent on the lower alkylamino group 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. As the substituent on the lower alkenyl group, a lower alkyl group, an amino group,
Examples include 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 hydroxy lower alkoxy group, and a carboxyl group. Further, as a substituent on the heterocyclic group, a lower alkyl group, an amino group,
Examples include 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 the hydroxyl group and / or the carboxyl group, a conventional protecting group which can be used as a protecting group for the hydroxyl group and / or the carboxyl group can be used. , A methoxymethyl group, a tetrahydropyranyl group, and the like, and examples of the protective group for the carboxyl group include a methyl group, an ethyl group, a tert-butyl group, and a benzyl group.

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], which is the active ingredient of the present invention, are as follows: 1) Ring A is a substituted monocyclic hydrocarbon group, and Ring B is substituted or unsubstituted. A 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 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, and ring B is a substituted or unsubstituted carbon. Hydrogen group,
6) ring A is a substituted heterocyclic group, ring B is a substituted or unsubstituted heterocyclic group, 7) ring A is a substituted or unsubstituted heterocyclic group, ring B is a substituted monocyclic or bi- to tricyclic Hydrocarbon group, 8)
Compounds in which ring A is a substituted or unsubstituted heterocyclic group and ring B is a substituted heterocyclic ring, wherein 1) ring A is a substituted monocyclic hydrocarbon group, and ring B is a substituted or unsubstituted bicyclic A 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, and ring B is a substituted monocyclic hydrocarbon group. Compounds that are cyclic or bi- to tricyclic 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 sulfonamide derivatives [I], which are the active ingredients of the present invention, those compounds which are preferable in terms of efficacy are phenyl groups in which ring A is substituted with a lower alkyl group or a lower alkylenedioxy group in the general formula [I]. Wherein ring B is a thienyl group or a benzothienyl group which may be substituted with a naphthyl group, a pyridyl group, a furyl group, a lower alkyl group, or a ring A which is substituted with a di-lower alkylamino group. Good naphthyl, indenyl,
An anthryl group, a thienyl group optionally substituted with a pyridyl group or a lower alkyl group, a benzofuryl group or a benzothienyl group, wherein ring B is a phenyl group 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 optionally substituted with a lower alkyl group, wherein Q is a single bond or a group represented by the formula -O-, and Y is a group represented by the formula-
A group represented by O-, Alk is a lower alkylene group, Z is a group represented by the formula -O-, R is a halogen atom, a pyrimidinyl group substituted with a thienyl group or a lower alkylthio group, R ¹ is a hydrogen atom, It is a compound which is a hydroxy lower alkylamino group, a lower alkyl group, a carboxyl group-substituted lower alkylthio group, a hydroxy lower alkoxy group, a pyrimidinyl group, a hydroxypiperidinyl group, a lower alkyl group-substituted piperazinyl group or a morpholino group.

Among the sulfonamide derivatives [I], which are the active ingredients of the present invention, those compounds which are more preferable in terms of medicinal properties are those in which ring A is substituted with a lower alkyl group or a lower alkylenedioxy group in the general formula [I]. A phenyl group, ring B is a thienyl group or a benzothienyl group which may be substituted with a naphthyl group, a pyridyl group, a furyl group, a lower alkyl group, or ring A is substituted with a di-lower alkylamino group. Naphthyl group, 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; Wherein 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, and Z is a group represented by the formula -O-. A pyrimidinyl group in which R is substituted with a halogen atom, a thienyl group or a lower alkylthio group;
¹ is a hydrogen atom, a hydroxy lower alkylamino group, a lower alkyl group, a carboxyl group-substituted lower alkylthio group,
Compounds which are a hydroxy lower alkoxy group, a pyrimidinyl group, a hydroxypiperidinyl group, a lower alkyl group-substituted piperazinyl group or a morpholino group.

Among the sulfonamide derivatives [I], which are the active ingredients of the present invention, a more preferred compound from the standpoint of pharmacological effect is a phenyl group in which ring A is substituted with a lower alkyl group in the general formula [I]. B is a thienyl group optionally substituted with a lower alkyl group, a naphthyl group, a pyridyl group,
A ring is a furyl group or a benzothienyl group, or a ring A is a thienyl group optionally substituted with a di-lower alkylamino group or a naphthyl group or a pyridyl group, and ring B is a lower alkyl group or A phenyl group substituted by a lower alkoxy group, wherein Q is a single bond, R
Is a pyrimidinyl group substituted with a halogen atom or a lower alkylthio group, and R ¹ is a hydrogen atom, a pyrimidinyl group or a morpholino group.

Among the sulfonamide derivatives [I], which are the active ingredients of the present invention, compounds that are particularly preferred in terms of pharmacological effect are:
In the general formula (I), Ring A is a phenyl group substituted with a lower alkyl group, and Ring B is a thienyl group, a naphthyl group or a benzothienyl group optionally substituted with a lower alkyl group, 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 sulfonamide derivatives [I], which are the active ingredients of the present invention, other compounds that are preferable from the viewpoint of efficacy are phenyl groups in which ring A is substituted with a lower alkyl group in the general formula [I], Ring B is a thienyl group, 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 formula -O- group, Y group which is represented by the formula -O-, Alk is a lower alkylene group, Z is a group represented by formula -O-, a pyrimidinyl group R is substituted by a halogen atom or a thienyl group, R ¹ is a lower alkyl Group,
The compound is a morpholino group, a lower alkyl group-substituted piperazinyl group or a pyrimidinyl group.

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

The sulfonamide derivative [I], which is an active ingredient of the present invention, may have optical isomers based on asymmetric carbon atoms, and the present invention includes both of these optical isomers and mixtures thereof. It is a thing.

The sulfonamide derivative [I], which is the active ingredient of the present invention, can be used in a free form or in the form of a pharmacologically 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 hydrochloride, sulfate, hydrobromide, methane Sulfonate, acetate, fumarate, maleate, oxalate, alkali metal (sodium, potassium, etc.) salts, alkaline earth metal (magnesium, calcium, etc.) salts, triethylamine salts, salts with lysine, etc. can give.

The sulfonamide derivative [I] or a pharmaceutically acceptable salt thereof, which is an active ingredient of the present invention, includes an inner salt, an adduct, a complex, a hydrate or a solvate thereof. .

The sulfonamide derivative [I] or a pharmaceutically acceptable salt thereof, which is the active ingredient of the present invention, can be administered orally or parenterally. Granules, capsules, powders, injections,
It can be used as a suitable pharmaceutical preparation such as an inhalant.

The dosage form for oral administration may be a solid preparation such as tablets, granules, capsules and powders, or a liquid preparation such as a solution or a suspension. It can be used as a pharmaceutical formulation together with a pharmaceutical carrier. Such pharmaceutical carriers include, for example, binders (syrup, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar,
Corn starch, potassium phosphate, sorbite, glycine, etc.), lubricants (magnesium stearate, talc,
Any of conventional materials such as polyethylene glycol, silica and the like, disintegrant (potato starch and the like) or wetting agent (sodium lauryl sulfate and the like) can be used.

On the other hand, in the case of parenteral administration, the dosage form is preferably an injection or drip injection using, for example, distilled water for injection, physiological saline, aqueous glucose solution or the like.

The dosage of the sulfonamide derivative [I] or a pharmaceutically acceptable salt thereof as the active ingredient of the present invention is as follows:
Usually, it is preferably about 0.001 to 100 mg / kg per day, although it varies depending on the administration method, age of the patient, weight and condition.

The pharmaceutical composition of the present invention can be suitably used especially as an endothelin antagonist.

Therefore, the pharmaceutical composition of the present invention is useful for treating diseases related to endothelin activity, for example, hypertension, pulmonary hypertension, renal hypertension, Raynaud's disease, bronchial asthma, gastric ulcer, inflammatory bowel disease (clone) Disease), shock, carcinogenesis, restenosis after angioplasty, organ dysfunction after organ transplantation, diabetes, thrombosis, arteriosclerosis, heart failure, acute renal failure, glomerulonephritis, cyclosporine-induced nephrotoxicity, myocardium It is useful as a preventive or therapeutic agent for infarction, angina, arrhythmia, glaucoma, migraine, cerebral vasospasm and cerebral infarction.

The sulfonamide derivative [I] as an active ingredient of the present invention can be produced by the following [Method A], [Method B], [Method C] or [Method D].

[Method A] The sulfonamide derivative [I] which is an active ingredient of the present invention of the present invention has the general formula [II]

[0050]

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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]

[0052]

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

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

[0055]

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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]

[0057]

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

[Method C] In addition, compound [I] is represented by the general formula [VI]

[0060]

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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]

[0062]

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

[Method D] Further, among the sulfonamide derivatives [I], which are the active ingredients of the present invention, general formula [Ia] wherein Q is a single bond

[0065]

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

[0067]

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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]

[0069]

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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).

Examples of the salt of the compound [II], [IV], [VI] or [VIII] include salts with inorganic acids such as hydrochloride and sulfate 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 suitably used, and a halogen atom is particularly 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. The reaction is carried out at room temperature to 150 ° C., especially at room temperature to 120 ° 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 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 the Journal of Organic Chemistry (J. Org.
m. In accordance with the method described in Vol. 58, p. 1963 (1993), copper (I) chloride, copper (I) bromide, copper (I) iodide
When copper (I) salt such as is added, the process proceeds more suitably. 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, diethyl ether, dimethoxyethane, water or a mixed solvent thereof can be used as appropriate. This reaction suitably proceeds at 50 to 100 ° C.

The sulfonamide derivative [I] as the active ingredient of the present invention can also be produced by interconverting the compound obtained as described above into another compound. Such an interconversion reaction between compounds may be appropriately selected depending on the type of the substituents possessed by the compound, and may be carried out, for example, as in the following methods (a) to (w).

Method (a): The compound [I] in which R is an aromatic heterocyclic group having a substituent or an aryl group has a corresponding R
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 compound [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 alkenyl. It can be produced by subjecting a compound that is an aromatic heterocyclic group or an aryl group substituted with a 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 compound [I] in which R is an aromatic heterocyclic group or an aryl group substituted with a hydroxy lower alkyl group is an aromatic compound wherein the corresponding R is substituted with a lower alkanoyl group or a formyl group. It can be produced by treating a compound which is a group heterocyclic group or an aryl group 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): 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-
It can be carried out by treating with a palladium-based catalyst such as carbon, palladium-barium sulfate, palladium-aluminum oxide, and palladium black. Further, the present reduction reaction is preferably carried out in a hydrogen atmosphere in the presence of a deoxidizing agent. As the deoxidizing agent, triethylamine, pyridine, potassium carbonate, sodium hydrogencarbonate, sodium acetate and the like can be suitably used. . This reaction suitably proceeds at room temperature to 60 ° C.

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

Method (f): The compound [I] in which R is an unsubstituted aromatic heterocyclic group or aryl group is prepared by reacting the corresponding R
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 performed in a hydrogen atmosphere in the presence of a catalyst such as Raney nickel and palladium-carbon. The reaction is carried out at room temperature to 5
Proceeds favorably at 0 ° C.

Method (g): The compound [I] wherein R is a formyl group, a hydroxy 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 R is an aromatic heterocyclic group or an aryl group substituted with a halogen atom by lithiation and then reacting with a corresponding carbonyl compound (eg, dimethylformamide, acetone, benzaldehyde, etc.) Can be. 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
It proceeds favorably at a temperature of from 25 ° C to 25 ° C.

Method (h): Compound (I) in which R is an aromatic heterocyclic group or an aryl group substituted with an amino group can be obtained by reacting a corresponding aromatic heterocyclic group or a group in which R is substituted with a nitro group. It can be produced by reducing a compound that is an aryl group. 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): In the compound [I] wherein R is an aromatic heterocyclic group or an aryl group substituted with a lower alkanoylamino group or an arylcarbonylamino group, the corresponding R is substituted with an amino group. It can be produced by acylating a compound which 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): In the compound [I] wherein R is an aromatic heterocyclic group or an aryl group substituted with a mono- or di-lower alkylamino group, the corresponding R is substituted with an amino group. It can be produced by alkylating a compound that is an aromatic heterocyclic group or an aryl group. Alkylation is performed by (1) lower alkyl halide (lower alkyl chloride, lower alkyl bromide, etc.) or lower alkyl lower alkane sulfonate (lower alkyl methane sulfonate), lower alkyl aryl sulfonate (toluene sulfonate, etc.) in the presence of a deoxidizing agent. The reaction can be carried out, or (2) reducing the reaction product with a lower alkyl aldehyde in the presence of a reducing agent. As the deoxidizing agent, alkali metal hydroxide, alkali metal bicarbonate, alkali metal carbonate, organic base (triethylamine,
Pyridine and the like can be suitably used. As the 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 compound [I] in which R is an aromatic heterocyclic group or an aryl group substituted with a carboxyl group-substituted lower alkoxy group which may be protected is a compound wherein 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). The reaction is carried out at 0 to 100
Proceeds favorably at C. As the carboxyl protecting group, a conventional carboxyl protecting group can be used. The protecting group can be removed by a conventional method.

Method (m): The compound [I] wherein R is an aromatic heterocyclic group or an aryl group substituted with a lower alkoxy-lower alkyl group is an aromatic compound wherein the corresponding R is substituted with a hydroxy lower alkyl group. The compound can be produced by halogenating a compound that is a group heterocyclic group or an aryl group, and then alkoxylating the compound. 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): 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): Compound [I] wherein R is an aromatic heterocyclic group or an aryl group substituted with a lower alkylthio group is an aromatic heterocyclic group wherein the corresponding R is substituted with a lower alkylsulfinyl group. A compound that is a formula group or an aryl group is first reacted with an acid anhydride, then hydrolyzed to a compound in which the corresponding R is substituted with a thiol group, and then the corresponding R is further substituted with a thiol group. The compound can be produced by reacting a compound 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. it can. This reaction suitably proceeds at 0 to 50 ° C.

Method (p): The compound [I] in which R is an aromatic heterocyclic group or an aryl group substituted with a cyano group is an aromatic heterocyclic group or a compound in which the corresponding R is substituted with a halogen atom. The compound 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): In the compound [I] wherein R is an aromatic heterocyclic group or an aryl group substituted with a trimethylsilyl group-substituted lower alkynyl group or a hydroxy-lower alkynyl group, the corresponding R is substituted with a halogen atom. The compound which is an aromatic heterocyclic group or an aryl group thus obtained can be produced by lower alkynyl or hydroxy lower alkynyl substituted with a trimethylsilyl group. Trimethylsilyl-substituted lower alkynylation or hydroxy 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 compound [I] wherein R is an aromatic heterocyclic group or an aryl group substituted with a lower alkynyl group is an aromatic compound wherein the corresponding R is substituted with a trimethylsilyl group-substituted lower alkynyl group. The compound can be produced by reacting a compound that is a 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): Compound [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. The compound can be produced by reducing a compound represented by the formula group or the aryl group in a hydrogen atmosphere 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 is performed at room temperature to 60 ° C.
The process proceeds favorably.

Method (t): Compound (I) in which ring A and / or ring B is a hydrocarbon group or a heterocyclic group substituted with a formyl group, is obtained when the corresponding ring A and / or ring B is di- The compound can be produced by hydrolyzing a compound which is a hydrocarbon group or a heterocyclic group substituted with a lower alkoxy group-substituted lower alkyl group 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. This reaction is performed
Proceeds favorably at 50 ° C.

Method (u): Compound [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 prepared by reacting the corresponding ring A and / or 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, and a triphenyl phosphorus complex of the group to be substituted. This reaction suitably proceeds at room temperature to 60 ° C.

Method (v): Compound [I] in which ring A and / or ring B is a hydrocarbon group or heterocyclic group substituted with a carboxyl-substituted lower alkenyl group is prepared by reacting 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 lower alkoxycarbonyl-lower alkenyl group in the presence of an inorganic base. As the inorganic base, an alkali metal hydroxide such as sodium hydroxide or the like can be suitably used. This reaction is 0
Properly proceeds at a temperature of from ℃ to room temperature.

Method (w): Compound [I] in which Q is a group represented by the formula —SO— or —SO ₂ —
Can be produced by subjecting a compound which is a group represented by the formula to an oxidation reaction 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 or 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 does not inhibit the reaction, and examples thereof include dioxane, ethylene glycol dimethyl ether, dimethylacetamide, dimethylformamide, and hexamethylphosphonate. Lamide, benzene, tetrahydrofuran, toluene, ethyl acetate, lower alcohol, methylene chloride, chloroform, carbon tetrachloride, 1,3-dimethyl-2-imidazolidinone, diethyl ether, dimethoxyethane, dimethyl sulfoxide, water or a mixed solvent thereof Can be used as appropriate.

The starting compounds [II] and [VI] of the sulfonamide derivative [I] as the active ingredient of the present invention.
Are described in, for example, JP-A-5-155864 or
It can be produced according to the method described in No. 22003. That is, the compound [II] in which Q is a single bond is first represented by the general formula [X]

[0103]

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(Wherein ring B has the same meaning as described above) by treating with a halogenating agent (such as thionyl chloride) to give the corresponding acid halide, and then treating with alcohol to give the 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]

[0105]

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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

[0107]

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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).

[0109]

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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]

[0111]

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(Where 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]

[0113]

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(Wherein R ¹ has the same meaning as described above) to give 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 into a general formula [XIV]

[0115]

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

[0117]

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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 give a reactive residue. Convert to general formula [XV]

[0119]

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

[0121]

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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]

[0124]

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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] wherein Q is a group represented by the formula -O- is represented by the general formula [XVIII]

[0127]

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

[0129]

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

[0131]

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

[0133]

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Wherein the symbols have the same meanings as described above, or by reacting compound [XIX] with urea in the presence of a base (such as sodium methoxide).

[0135]

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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 give a reactive residue. Converted to the general formula [XXII]

[0137]

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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 obtained by converting the corresponding compound [II] into a compound of the general formula [XXIII].

[0140]

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(However, Y, Alk and Z have the same meanings as described above), and can be produced in the presence of 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]

[0143]

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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]

[0145]

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(Wherein the symbols have the same meanings as described above), and the compound is produced by catalytic reduction, or (ii) a compound [XIV] or a compound [XXI] and ammonia With the general formula [XX
VI]

[0147]

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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]

[0150]

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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]

[0152]

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

[0154]

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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) a compound [XXV
I] is reacted with compound [XXIII] to give compound [X
XIX] can be produced by reacting this with compound [VII] in the presence of a deoxidizing agent (eg, sodium hydride or the like).

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

[0157]

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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]

[0159]

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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).
I] and reacting with the general formula [XXXII]

[0161]

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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 With compound [III] in the presence of a deoxidizing agent (eg, sodium hydride) to obtain a compound of the general formula [XXXIII]

[0163]

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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 [XXXIV]

[0165]

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

[0167]

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(Wherein the symbols have the same meanings as described above), and then reacting with the compound [V] in the presence of a deoxidizing agent (such as sodium hydride) [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 the formula (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]

[0170]

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(Wherein the symbols have the same meanings as described above), and then treated with a halogenating agent (eg, N-bromosuccinimide, bromine, etc.) to form a reactive residue. General formula [XXXVII]

[0172]

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(Where the symbols have the same meanings as described above), and then the compound is reacted with the 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 of the general formula [XX
XVIII]

[0174]

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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]

[0176]

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

[0178]

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(Provided that the symbols have the same meanings as described above), which is then reacted with compound [V] to give compound [XXXVI], which is converted to a halogenating agent (for example, N-bromosuccinimide, bromine, etc.) to form a reactive residue.
XVII] and then reacting with compound [VII] in the presence of a deoxidizing agent (eg, sodium hydride).

In the sulfonamide derivative [I] which is the active ingredient of the present invention, a lower alkyl group, a lower alkoxy group, a lower alkylene group, a lower alkylenedioxy group, a lower alkylthio group, a lower alkylamino group, a lower alkylsulfinyl Examples of the group or lower alkylsulfonyl group include those having 1 to 6, particularly 1 to 4 carbon atoms. Further, a lower alkenyl group, a lower alkanoyl group, a lower alkanoylamino group, a lower alkoxycarbonyl group, a lower alkynyl group, a lower alkenyloxy group, a lower alkenylene group, an N-lower alkylcarbamoyloxy group, an N-lower alkoxyiminomethyl group or N The lower alkylaminocarbonyl group has 2 to 7 carbon atoms, especially 2 carbon atoms;
~ 5. 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.

Experimental Example 1 [Endothelin Binding Inhibition in Porcine Aortic Membrane Specimen] The porcine aorta from which endothelial cells had been detached was reduced to 10 times the volume of 20%
The mixture was homogenized in a 10 mM MOPS buffer containing sucrose (pH 7.4) using a Polytron homogenizer. The obtained homogenate is cooled to 1000 ×
g, and centrifuged for 15 minutes.
Centrifuged at 90000 × g for 45 minutes. 5 mM precipitate
Resuspended in HEPES / Tris buffer approximately 6 mg / m
A membrane specimen was prepared to be 1. The membrane specimen was stored frozen at -80 ° C and thawed and diluted before use.

The membrane specimen prepared by the above method (2 mg /
ml) 50 μl, 120 pM ¹²⁵ I-endothelin-1 (Amsham Japan Ltd., specific activity: 74TBq
/ Mmol) 50 μl of the sample and 50 μl of the sample were mixed, and 50
mM Tris / HCl buffer (pH 7.4: 0.1%
Bovine serum albumin, 0.1 mM phenylmethylsulfonyl fluoride, 1 μM pepstatin A, 2 μM leupeptin, 1 mM 1,10-phenanthroline and 1 mM
Incubated in 150 μl (containing EDTA) at 25 ° C. for 2 hours. Ice-cooled 5 mM HEPES / Tri
The reaction was stopped by adding s-buffer (pH 7.4: containing 0.1% bovine serum albumin), and a glass filter (GF / B, manufactured by Whatman) using a cell harvester (24R, manufactured by Brandale). ).
The radioactivity on the filter was measured using a gamma counter (ARC-
360, Aloka). The specific binding was calculated by subtracting the binding in the presence of 2 × 10 ⁻⁷ M endothelin-1 (manufactured by Peptide Laboratories) from the total binding. The results are shown in Table 1 below as the concentration (IC ₅₀ ) required to suppress 50% of specific binding from the concentration inhibition curve.

[0183]

[Table 1]

Hereinafter, the active ingredient of the present invention will be described in more detail with reference to Production Examples, but the present invention is not limited thereto.

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

[0186]

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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 (eluent; 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 ⁺ ).

Production Example 2 N- {6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -5- (4-methylphenyl) pyrimidin-4-yl} -2-naphthalenesulfonamide

[0189]

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4-amino-6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -5- (4-methylphenyl) pyrimidine 150 mg, 2-naphthalenesulfonyl chloride 170 mg, 96% potassium hydroxide (powder A) A mixture of 300 mg, 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 subjected to silica gel column chromatography (elution 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 ⁺ ).

Production Example 3-6 4-Amino-6- [2- (5-bromopyrimidine-2-
Yloxy) ethoxy] -5- (4-methylphenyl)
The pyrimidine and the corresponding starting compound are treated in the same manner as in Production Example 2 to obtain the compounds shown in Table 2 below.

[0192]

[Table 2]

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

[0194]

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100 mg of 4-amino-6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -5- (2-methoxyphenoxy) -2- (2-pyrimidinyl) -pyrimidine, sodium hydride (60 mg) %Distributed)
A mixture of 53.5 mg and 3 ml of tetrahydrofuran is stirred at room temperature for 20 minutes. Subsequently, 23.4 mg of 2-thiophenesulfonyl chloride is added, and the mixture is 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 is distilled off, and 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 ⁺ ).

Production Example 8 N- {6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -5- (2-methoxyphenoxy)
-2- (2-pyrimidinyl) pyrimidin-4-yl}-
2-naphthalenesulfonamide

[0197]

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Production Example of 4-amino-6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -5- (2-methoxyphenoxy) -2- (2-pyrimidinyl) -pyrimidine and the corresponding starting compound The same treatment as in 7 is performed to obtain the target compound. m. p. 163.0-165.0 ° C IR (nujol, cm ^-1 ): 1560 MS (m / z): 704 (MH ⁺ ).

Production Example 9 N- {6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -5- (2-methoxyphenoxy)
-2-morpholinopyrimidin-4-yl} -2-thiophenesulfonamide

[0200]

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4-Amino-6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -5- (2-methoxyphenoxy) -2-morpholinopyrimidine 200
mg, sodium hydride (60% dispersion type) 46.2 mg
And 6 ml of tetrahydrofuran are stirred at room temperature for 20 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 is distilled off, and the residue is recrystallized from ether-hexane to obtain 46 mg of the target compound. m. p. : 186-188 ° C.

Production Example 10 N- {6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -5- (2-methoxyphenoxy)
-2-morpholinopyrimidin-4-yl} -2-naphthalenesulfonamide

[0203]

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4-Amino-6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -5- (2-methoxyphenoxy) -2-morpholinopyrimidine and the corresponding starting compound were treated in the same manner as in Preparation 9. To obtain the target compound. m. p. : 178.0-181.5 ° C IR (nujol, cm ^-1 ): 1560, 1460, ¹
380, 1320 MS (m / z): 709 (MH ^<+> ).

Production Example 11 4-tert-butyl-N- {5- (2-benzothienyl) -6- [2- (5-methylthiopyrimidin-2-yloxy) ethoxy] pyrimidin-4-yl} benzenesulfonamide

[0206]

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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 (elution 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 ⁺ ).

Production Example 12-16 N- {5-bromo-6- [2- (5-methylthiopyrimidin-2-yloxy) ethoxy] pyrimidin-4-yl} -4-tert-butylbenzenesulfonamide and corresponding raw materials The compound was treated in the same manner as in Production Example 11 to obtain the compounds described in Table 3 below.

[0209]

[Table 3]

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

[0211]

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N- {6- (2-hydroxyethoxy)-
5- (2-methoxyphenoxy) -2-methylpyrimidin-4-yl} -2-naphthalenesulfonamide and 5
-Bromo-2-chloropyrimidine is treated in the same manner as in Production Example 1 to obtain a target compound. m. p. : 162.5-164.5 ° C.

The compounds which are the active ingredients of the present invention have been described in detail above. Representative compounds contained in the active ingredients of the present invention include those described in the above-mentioned Production Examples and Tables 4 to 5 below. Table 5 can be cited.

[0214]

[Table 4]

[0215]

[Table 5]

Reference Example 1 (1) To a mixture 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) A mixture of 21.85 g of 2- {6-chloro-5- (4-methylphenyl) pyrimidin-4-yloxy} ethanol, 10.7 g of sodium azide and 260 ml of dimethylformamide at 75 to 80 ° C. Heat and stir 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-
19.6 g of methylphenyl) pyrimidin-4-yloxydiethanol are obtained. m. p. : 83.5-85 [deg.] C MS (m / z): 271 (M ^<+> ).

(3) 19.6 g of 2- {6-azido-5- (4-methylphenyl) pyrimidin-4-yloxy} ethanol 10% palladium-carbon (50% water-containing)
A mixture of 4.0 g and 240 ml of ethanol is subjected to catalytic reduction under a hydrogen atmosphere (1 atm) at room temperature for 1 hour. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give 2- {6-amino-5- (4-methylphenyl) pyrimidin-4-yloxy} ethanol 1
5.9 g 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 purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate 10: 1 to ethyl acetate only),
4-amino-6-chloro-5- (4-methylphenyl)
1.89 g of pyrimidine are obtained. m. p. : 168-171 ° C.

(2) 4-amino-6-chloro-5- (4
-Methylphenyl) pyrimidine 500 mg, ethylene glycol 10 ml, sodium hydride (60% dispersion type)
0.46 g of the mixture was added at 70 ° C. for 2 hours,
Let react for 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 was crystallized from hexane-ethyl acetate to give 2- {6-amino-5- (4-methylphenyl) pyrimidin-4-yloxy} ethanol 4
22 mg are obtained. 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 (elution solvent: chloroform: methanol 100: 1 to 80:
After purification in 1), recrystallization from tetrahydrofuran-diethyl ether gave 11.27 g of 4-amino-6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -5- (4-methylphenyl) pyrimidine. Get. 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. : 22
5-226.5 ° 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 1.66 g of 4-tert-butyl-N- (6-chloropyrimidin-4-yl) benzenesulfonamide was further added. And stirred at 60 ° C. for 20 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 to give 4-tert-butyl-N- [6- (2-
1.58 g of 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-
116 mg of N-bromosuccinimide is added to a solution of 210 mg of (2-hydroxyethoxy) pyrimidin-4-yl) benzenesulfonamide in 4 ml of dimethylformamide, and the mixture is stirred 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 (elution solvent: chloroform:
After purification with methanol = 40: 1), recrystallization from hexane-ethyl acetate gave N- [5-bromo-6- (2-hydroxyethoxy) pyrimidin-4-yl] -4-tert.
169 mg of -butylbenzenesulfonamide are obtained. 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-ter
To a solution of 3.10 g of t-butylbenzenesulfonamide in 30 ml of dimethylacetamide was added sodium hydride (60 ml).
% Dispersion type) and stirred at room temperature for 30 minutes.
Then, 2-chloro-5-methylthiopyrimidine 1.5
Add 1 g and 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 (elution solvent; chloroform: ethyl acetate = 10: 1), recrystallized from hexane-ethyl acetate, and N- {5-bromo-6- [2- (5-methylthiopyrimidine). -2-yloxy) ethoxy] pyrimidin-4-yl} -4-t
3.34 g of 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 purified by silica gel column chromatography (eluent; chloroform: ethyl acetate 5: 1 to 2: 1) to give 5.67 g of 2- (6-chloropyrimidin-4-yloxy) ethanol as an oil. IR (nujol, cm ^-1 ): 3300, 1575, ¹
545 MS (m / z): 175 (MH ^<+> ).

(2) 2- (6-chloropyrimidine-4-
To a solution of 5.61 g of yloxy) ethanol in 60 ml of dimethylformamide is added 4.18 g of sodium azide, and the mixture is 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 is subjected to silica gel column chromatography (elution solvent; hexane: ethyl acetate = 1:
Purification in 1) gives 1.68 g of 2- (6-azidopyrimidin-4-yloxy) ethanol. m. p. : 49-50 ° C IR (nujol, cm ^-1 ): 3280, 2070, ¹
600, 1550 MS (m / z): 181 (MH ^<+> ).

(3) 2- (6-azidopyrimidine-4-
A mixture of 1.64 g of yloxy) ethanol, 0.25 g of 10% palladium-carbon 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 is recrystallized from ethanol-diethyl ether to obtain 1.11 g of 2- (6-aminopyrimidin-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-aminopyrimidine-4-
(Iloxy) 400 mg of ethanol 4 ml of methanol
A solution of 437 mg of bromine in 2 ml of methanol is added dropwise to the suspension. 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 washing and drying the organic layer, the solvent is distilled off to obtain 632 mg of 2- (6-amino-5-bromopyrimidin-4-yloxy) ethanol. IR (nujol, cm ^-1 ): 3480, 3420, 3
390, 3290, 1640, 1580 MS (m / z): 235,233 (M ^<+> ).

(5) Sodium hydride (6) was added to a solution of 611 mg of 2- (6-amino-5-bromopyrimidin-4-yloxy) ethanol in 20 ml of dimethylformamide.
125 mg (0% dispersion). After stirring for 20 minutes, 2-
461 mg of chloro-5-methylthiopyrimidine was added,
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 purified by silica gel column chromatography (elution solvent; chloroform: methanol = 20: 1),
Crystallization with ethyl acetate-diisopropyl ether gave 4
-Amino-5-bromo-6- [2- (5-methylthiopyrimidin-2-yloxy) ethoxy] pyrimidine 50
Obtain 1 mg. m. p. : 126-129 ° C IR (nujol, cm ^-1 ): 3450, 3270, ¹
635, 1585, 1570, 1540 MS (m / z): 359, 357 (MH ^<+> ).

(6) 4-amino-5-bromo-6- [2
-(5-methylthiopyrimidin-2-yloxy) ethoxy] pyrimidine (102 mg) in tetrahydrofuran (2 m)
34 mg of sodium hydride (60% dispersion type)
Is added, 198 mg of 4-tert-butylbenzenesulfonyl chloride is added, and the mixture is stirred 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- (5-methylthiopyrimidin-2-yloxy) ethoxy] pyrimidin-4-yl} -4-t
135 mg of 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 2-pyrimidinylamidine hydrochloride in 150 ml of methanol was added 36.58 g of 28% sodium methoxide in methanol 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. 244-246 ° C IR (nujol, cm ^-1 ): 1635,1600 MS (m / z): 272 (M ⁺ ).

(2) A mixture of 5.00 g of this product, 15 ml of N, 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 is distilled off, and the residue is purified by silica gel column chromatography (elution solvent: chloroform: ethyl acetate = 5: 1), and then 5- (2-thienyl) -4,6-dichloro-2. -(2-pyrimidinyl)
2.77 g of pyrimidine are obtained as crystals. m. p. 159-160 ° C IR (nujol, cm ^-1 ): 1560 MS (m / z): 308 (M ⁺ ).

(3) 2.30 g of 4-tert-butylbenzenesulfonamide and 6.19 g of potassium carbonate were added to a suspension of 2.77 g of this product in 30 ml of dimethyl sulfoxide.
And stirred at 80 ° C. for 8 hours. After cooling, the reaction mixture is acidified with ice-cold 10% hydrochloric acid. Ethyl acetate extraction,
After washing and drying, the solvent is distilled off, and the residue is subjected to silica gel column chromatography (elution solvent: hexane: ethyl acetate =
1: 1), and further crystallized from n-hexane-ethyl acetate to give 4-tert-butyl-N- [6-chloro-
5- (2-thienyl) -2- (2-pyrimidinyl) pyrimidin-4-yl] benzenesulfonamide 1.67 g
As a powder. m. p. 129.5 to 131.5 ° C IR (nujol, cm ^-1 ): 1640, 1560 MS (m / z): 486 (M ⁺ ).

(4) To 20 ml of ethylene glycol, 688 mg of sodium hydride (60% dispersion type) is added, and 1672 mg of this product is added. The reaction solution is stirred at room temperature for 20 minutes and then reacted at 140 ° C. for 3.5 hours. After cooling, the reaction solution was acidified with 10% hydrochloric acid and extracted with ethyl acetate.
The ethyl acetate layer was washed, dried, evaporated to dryness under reduced pressure, crystallized from n-hexane-ethyl acetate to give 4-tert-butyl-N
-{6- (2-hydroxyethyloxy) -5- (2-
Thienyl) -2- (2-pyrimidinyl) pyrimidine-4
1790 mg of -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) 5- (2-methoxyphenoxy) -4,6-dichloro-2- (2-pyrimidinyl) pyrimidine and ethylene glycol were treated in the same manner as in Reference Example 1- (1). , 2
-{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) Refer to Example 1- (2) using 5.37 g of this product.
To give 1.29 g of 2- {6-azido-5- (2-methoxyphenoxy) -2- (2-pyrimidinyl) pyrimidin-4-yloxy} ethanol 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 used in Reference Example 1- (3)
To give 788 mg of 2- {6-amino-5- (2-methoxyphenoxy) -2- (2-pyrimidinyl) pyrimidin-4-yloxy} ethanol as a powder. m. p. 183.5-185 ° C IR (nujol, cm ^-1 ): 3590, 3450, ¹
620 MS (m / z): 355 (M ^<+> ).

(4) 778 mg of this product was treated in the same manner as in Reference Example 3 to give 4-amino-6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -5- (2-methoxyphenoxy)- 2- (2-pyrimidinyl) pyrimidine 7
33 mg 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) A mixture of 1.00 g of the product, 1.28 ml of N, N-diethylaniline and 5 ml of phosphorus oxychloride was heated under reflux for 3 hours, phosphorus oxychloride was distilled off, and the mixture was 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 purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 30: 1), and then 5- (2-methoxyphenoxy) -2,4,6-. 351 mg of trichloropyrimidine are obtained as crystals. m. p. 150.5-152 ° C IR (nujol, cm ^-1 ): 1600 MS (m / z): 304 (M ⁺ ).

(3) N-methylmorpholine 113.5 m
g in toluene 5ml solution at 100 ℃ 300mg
Of toluene in 5 ml and stirred at 90 ° C. for 2 hours. After cooling, water was added, and the mixture was extracted with ethyl acetate, washed and dried. The solvent was distilled off, and the residue was crystallized from n-hexane to give 344 mg of 2-morpholino-4,6-dichloro-5- (2-methoxyphenoxy) pyrimidine. Obtained as a powder. m. p. 179.5-180 ° C IR (nujol, cm ^-1 ): 1600, 1540 MS (m / z): 355 (M ⁺ ).

(4) Tetrahydrofuran 20 ml, 2-
To a mixture of 3.66 g of benzyloxyethanol was added 917 mg of sodium hydride (60% dispersion type) at room temperature, and the mixture was stirred for 20 minutes. Then, 30 ml of a mixture of tetrahydrofuran-dimethyl sulfoxide containing 7.78 g of this product was added dropwise.
After stirring at room temperature for 1 hour, the mixture was stirred at 50 ° C. for 2 hours. The residue is dissolved in ethyl acetate, washed, dried, and dried under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 40: 1), and then purified by 6- (2-benzyloxyethoxy) -4-chloro-5- (2-methoxyphenoxy) -2-morpholino. 6.61 g of pyrimidine are obtained. m. p. : 133-134.5 ° C IR (nujol, cm ^-1 ): 1600, 1540-1
520 MS (m / z): 472 (M ^<+> ).

(5) Reference Example 1- (2)
To give 4-azido-6- (2-benzyloxyethoxy) -5- (2-methoxyphenoxy) -2-
5.83 g of morpholinopyrimidine are obtained as a powder. m. p. 146-147.5 ° C IR (nujol, cm ^-1 ): 2150, 1600 MS (m / z): 479 (M ⁺ ).

(6) Reference Example 1- (3)
To give 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 4-amino-6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -5- (2-methoxyphenoxy)- 290 mg of 2-morpholinopyrimidine are obtained as caramel. IR (nujol, cm ^-1 ): 3460-3100, ¹
600 MS (m / z): 519 (M ^<+> ).

[0247]

The sulfonamide derivative [I] or a pharmaceutically acceptable salt thereof, which is an active ingredient of the present invention, has excellent endothelin antagonism, so that diseases associated with 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, heart failure, acute renal failure, glomerulonephritis, cyclosporine-induced nephrotoxicity, myocardial infarction, angina,
It is useful as a preventive or therapeutic agent for arrhythmia, glaucoma, migraine, cerebral vasospasm and cerebral infarction. Further, the sulfonamide derivative [I], which is an active ingredient of the present invention, has low toxicity and high safety as a pharmaceutical compound.

──────────────────────────────────────────────────続 き Continued on front page (51) Int.Cl. ⁷ Identification symbol FI // C07D 239/46 C07D 239/46 239/47 239/47 Z 401/14 401/14 405/14 405/14 409/14 409/14 (72) Inventor Rinako Kono 4-180-1, Sakuragicho, Omiya City, Saitama 401, Towa Citycorp Omiya Sakuragicho 401 (56) References JP-A-8-311043 (JP, A) JP-A-8- 99961 (JP, A) JP-A-7-17972 (JP, A) JP-A-5-155864 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/505 A61K 31 / 506 C07D 239/46 C07D 239/47 C07D 401/14 C07D 405/14 C07D 409/14 CA (STN) REGISTRY (STN)

Claims (5)

(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 substituted or unsubstituted mono- or di-lower alkylamino group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group, a substituted or unsubstituted lower alkynyl group,
Represents 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 as an active ingredient. 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 thienyl group or a benzothienyl group which may be substituted with a naphthyl group, a pyridyl group, a furyl group, a lower alkyl group, or a ring A which may be 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 pyrimidinyl group in which R is substituted with a halogen atom, a thienyl group or a lower alkylthio group;
¹ is a hydrogen atom, a hydroxy lower alkylamino group, a lower alkyl group, a carboxyl group-substituted lower alkylthio group,
The pharmaceutical composition according to claim 1, which is a hydroxy lower alkoxy group, a pyrimidinyl group, a hydroxypiperidinyl group, a lower alkyl group-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 thienyl group or a benzothienyl group which may be substituted with a naphthyl group, a pyridyl group, a furyl group, a lower alkyl group, or a ring A which may be 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 pharmaceutical composition according to claim 2, which is a thienyl group substituted with a lower alkyl group. 4. The method according to claim 1, which is an endothelin antagonist.
Or the pharmaceutical composition according to 3. 5. Hypertension, pulmonary hypertension, renal hypertension, Raynaud's disease, bronchial asthma, gastric ulcer, inflammatory bowel disease (Crohn's disease), shock, carcinogenesis, restenosis after angioplasty, after organ transplantation Organ dysfunction, diabetes, thrombosis, arteriosclerosis, heart failure, acute renal failure, glomerulonephritis, cyclosporine-induced nephrotoxicity, myocardial infarction, angina, arrhythmia, glaucoma, migraine, cerebral vasospasm 5. The pharmaceutical composition according to claim 1, which is a prophylactic and / or therapeutic agent for cerebral infarction.