JPH0959160A - Medicinal composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicinal composition having excellent endothelin antagonismic action and useful for preventing and treating hypertension, etc. SOLUTION: This medicinal composition contains a benzenesulfonamide derivative of the formula (rings A and B are each benzene ring; Q is a single bond hand, O, etc.; Y is O, S or NH; Alk is a lower alkylene, etc.; (z) is a single bond hand, O or NH; R is an aromatic heterocyclic ring or an aryl; R' is H, an aromatic heterocyclic ring, an aliphatic heterocyclic ring, an aryl, etc.) or its salt as an active ingredient. The daily dose of the compound of the formula is 0.001-100mg/kg. The composition is useful for preventing and treating diseases related to endothelin activity, e.g. hypertension, myocardial infarction, Raynaud's disease, diabetes mellitus, asthma, gastric ulcer, Crohn's disease, shock, carcinogenesis, thrombosis, cardiac insufficiency, glaucoma, migraine, etc. The compound of the formula includes 4-tert-butyl-N-[5-(4- methylphenyl)-6- 2-(5-(3-thienyl)pyrimidin-2-yloxy)ethoxy}pyrimidin-4- yl]benzenesulfonamide.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition.

[0002]

BACKGROUND OF THE INVENTION Endothelin is a polypeptide consisting of 21 amino acids and is produced by endothelial cells of humans, pigs, etc., and is known to have a strong vasoconstrictor action, bronchoconstrictor action and cell proliferation action. . 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, cyclosporin-induced nephrotoxicity, myocardial infarction, angina, arrhythmia, glaucoma, migraine, cerebral vasospasm, cerebral infarction, etc. 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 and JP-A-5-222003 disclose N-{[5] as a benzenesulfonamide derivative having an endothelin antagonistic action.
-Substituted phenyl (or substituted phenoxy)]-6-hydroxyalkoxypyrimidin-4-yl} -substituted benzenesulfonamides.

[0004]

DISCLOSURE OF THE INVENTION The present invention provides a pharmaceutical composition containing a novel benzenesulfonamide derivative having an excellent endothelin antagonistic activity as an active ingredient.

[0005]

The present invention has the general formula [I]

[0006]

Embedded image

(However, ring A and ring B are the same or different and are substituted or unsubstituted phenyl groups, and Q is a single bond or a formula-
O -, - S -, - SO -, - SO 2 - or -CH ₂ -
, Y is a group represented by the formula —O—, —S— or —NH—, Alk is a lower alkylene group or a lower alkenylene group, Z is a single bond or is represented by the formula —O— or —NH—. Group, R is a substituted or unsubstituted aromatic heterocyclic group or aryl group, R ¹ is a hydrogen atom, a trifluoromethyl group, a 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, aromatic heterocyclic group, substituted or non-substituted It represents a substituted aliphatic heterocyclic group or an aryl group. However, when Z is a single bond, R is not an aryl group. And a benzenesulfonamide derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION In the benzenesulfonamide derivative [I], which is an active ingredient of the present invention, the aromatic heterocyclic group has 1 to 4 different substituents selected from nitrogen atom, oxygen atom and sulfur atom. A monocyclic or bicyclic aromatic heterocyclic group containing an atom is preferable, for example, a pyrrolyl group, an imidazolyl group, a furyl group, a thienyl group, a thiazolyl group, an isoxazolyl group, an oxazolyl group, an oxazolinyl group, a pyrazolyl group, a quinazolinyl group Group, thienopyrimidinyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group, triazinyl group, tetrazolyl group, quinolyl group, isoquinolyl group, quinoxalinyl group,
Examples thereof include a benzothiazolyl group, a benzoxazolyl group and a benzimidazolyl group.

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

The aliphatic heterocyclic group is preferably a monocyclic or bicyclic aliphatic heterocyclic group containing 1 to 4 different ring atoms selected from nitrogen atom, oxygen atom and sulfur atom. Examples thereof include a piperazinyl group, a pyrrolidinyl group, a piperidyl group, a homopiperidyl group, a thiomorpholinyl group and a morpholinyl group.

The substituents on ring A and / or ring B include
For example, halogen atom; 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; 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; di-lower alkoxy group-substituted lower alkyl group; hydroxy group-substituted lower alkyl group; carboxyl group-substituted lower alkyl group; carboxyl group-substituted lower alkenyl group; carboxyl group-substituted lower alkoxy group; bromopyrimidinyloxy lower alkyl group; lower Examples thereof include an alkylenedioxy group; an aryl lower alkoxy group; or an arylaminocarbonyl group.

Ring A and / or ring B may be the same or different and each may have 1 to 3 substituents.

Examples of the substituent on the aromatic heterocyclic group or aryl group in R include a halogen atom; an optionally protected hydroxy group; a nitro group; a cyano group; an amino group; a formyl group; a carboxyl group. Carbamoyl group; N-mono- or di-lower alkylcarbamoyl group; N-lower alkylcarbamoyloxy group; N-
Hydroxyiminomethyl group; N-lower alkoxyiminomethyl group; lower alkyl group; hydroxylower alkyl group; cycloalkyl group; lower alkoxy-lower alkyl group; lower alkoxycarbonyl-lower alkenyl group; trifluoromethyl group; hydroxy group and aryl Group-substituted lower alkyl group; lower alkylthio group; mono- or di-lower alkylamino group; lower alkanoylamino group; lower alkoxy group; lower alkoxy group substituted with an optionally protected carboxyl group; aryloxy group; lower Alkoxycarbonyl group; lower alkoxy-lower alkenyl group; lower alkanoyl group; arylcarbonyl group; lower alkenyloxy group; hydroxy lower alkynyl group; lower alkynyl group optionally protected by trimethylsilyl group; 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 group Group; phenyl lower alkenyl group; phenyl lower alkoxy group; arylcarbonylamino group; aromatic heterocyclic group substituted hydroxyl group optionally substituted with 1 to 3 groups selected from halogen atom and lower alkyl group; or lower Examples thereof include an aromatic heterocyclic group which may be substituted with an alkyl group.

As the protecting group for the hydroxyl group and / or the carboxyl group, a conventional protecting group that can be a protecting group for the hydroxyl group and / or the carboxyl group can be used. For example, as the protecting group for the hydroxyl group, a benzyl group can be used. , A methoxymethyl group, a tetrahydropyranyl group, and the like, and a carboxyl group protecting group includes a methyl group, an ethyl group, a tert-butyl group, a benzyl group, and the like.

The aromatic heterocyclic group and / or aryl group may be the same or different and each may have 1 to 4 substituents.

Further, examples of the substituent on the lower alkyl group for R ¹ include a halogen atom, a carboxyl group, a lower alkoxycarbonyl group, an aromatic heterocyclic group, an aryl group and the like. Examples of the substituent of the lower alkenyl group and / or lower alkynyl group include a carboxyl group and the like. Examples of the substituent on the lower alkylthio group and / or the lower alkoxy group include a hydroxy group and a hydroxy lower alkoxy group. Further, examples of the substituent on the aliphatic heterocyclic group include a lower alkyl group.

The substituents on the lower alkyl group, lower alkenyl group, lower alkynyl group, lower alkylthio group, lower alkoxy group and / or aliphatic heterocyclic group are the same or different, and 1 to 4 of the above-mentioned substituent groups are used. You may have.

Among the benzenesulfonamide derivatives [I] which are the active ingredients of the present invention, the compounds which are preferable in terms of medicinal effect are:
Ring A and Ring B are the same or different; halogen atom; 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 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; di-lower alkoxy Group-substituted lower alkyl group; hydroxy lower alkyl group; carboxyl group-substituted lower alkyl group; carboxyl group-substituted lower alkenyl group; carboxyl group-substituted lower alkoxy group; bromopyrimidinyloxy lower alkyl group; lower Rukirenedioxy group; aryl lower alkoxy group; and phenyl group which may be substituted with 1 to 3 groups selected from arylaminocarbonyl group, R is a halogen atom; hydroxy group which may be protected; nitro group Cyano group; amino group; formyl group;
Carboxyl group; Carbamoyl group; N-mono- or di-lower alkylcarbamoyl group; N-lower alkylcarbamoyloxy group; N-hydroxyiminomethyl 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; hydroxy group and aryl group substituted lower alkyl group; lower alkylthio group; mono- or di-lower alkyl Amino group; lower alkanoylamino group; lower alkoxy group; lower alkoxy group substituted with an optionally protected carboxyl group; aryloxy group; lower alkoxycarbonyl group; lower alkoxy-lower alkenyl group; lower alkanoyl group; arylcarbonyl Group; lower alkenyloxy group; hydroxy lower alkynyl group; lower alkynyl group optionally protected by trimethylsilyl group; cyano lower alkoxy group; cycloalkyl-lower alkoxy group; lower alkyl sulfi Group; lower alkylsulfonyl group; aryl group; phenyl lower alkyl group; aromatic heterocyclic group substituted lower alkyl group; aromatic heterocyclic group substituted lower alkoxy group; phenyl lower alkenyl group; phenyl lower alkoxy group; arylcarbonyl Amino group; Aromatic heterocyclic group optionally substituted with 1 to 3 groups selected from halogen atom and lower alkyl Substituted oxy group; and aromatic heterocyclic group optionally substituted with lower alkyl group Optionally substituted with 1 to 4 groups selected from
Aromatic heterocyclic group or aryl group, R ¹ is (1) hydrogen atom, (2) trifluoromethyl group, (3) mono- or di-lower alkylamino group, (4) halogen atom, carboxyl group, lower A lower alkyl group optionally substituted with 1 to 4 groups selected from an alkoxycarbonyl group, an aromatic heterocyclic group and an aryl group, (5) a lower alkenyl group, (6) substituted with a carboxyl group, Good lower alkynyl group, (7) lower alkylthio group, (8)
A lower alkoxy group which may be substituted with a hydroxy group or a hydroxy lower alkoxy group, (9) an aromatic heterocyclic group, (10) an aliphatic heterocyclic group which may be substituted with a lower alkyl group, or (11 ) A compound which is an aryl group.

Of these, the aromatic heterocyclic group is a nitrogen atom,
A monocyclic or bicyclic aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen atom and sulfur atom, wherein the aliphatic heterocyclic group is selected from nitrogen atom, oxygen atom and sulfur atom. A compound which is a monocyclic or bicyclic aliphatic heterocyclic group containing 1 to 4 heteroatoms represented by
Aromatic heterocyclic group is 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, A pyrazinyl group,
A triazinyl group, a tetrazolyl group, a quinolyl group, an isoquinolyl group, a quinoxalinyl group, a benzothiazolyl group, a benzoxazolyl group or a benzimidazolyl group,
An aliphatic heterocyclic group is a piperazinyl group, a pyrrolidinyl group,
A piperidyl group, a homopiperidyl group, a thiomorpholinyl group or a morpholinyl group, and the aryl group and the aryl moiety in the arylcarbonylamino group, arylaminocarbonyl group, aryloxy group and arylcarbonyl group is a phenyl group, a lower alkoxyphenyl group or a naphthyl group. The compound is more preferable in terms of efficacy.

Among the benzenesulfonamide derivatives [I] which are the active ingredients of the present invention, a compound more preferable in view of efficacy is a ring A having a lower alkyl group; a lower alkoxy group; a lower alkoxycarbonyl-lower alkyl group; a hydroxy lower alkyl. Group; and a phenyl group substituted with a group selected from lower alkoxycarbonyl-lower alkoxy group, ring B is a trifluoromethyl group; formyl group; lower alkyl group; lower alkoxy group; lower alkylenedioxy group; hydroxy lower alkyl And a phenyl group which may be substituted with a group selected from a lower alkoxycarbonyl group, Q is a single bond or a group represented by formula -O- or -S-, and Y is a group represented by formula -O-. , Alk is a lower alkylene group, Z is a group represented by the formula —O—, R is an amino group, a nitro group, and a halo. A phenyl group optionally substituted with a group selected from a hydrogen atom and a hydroxy lower alkyl group; a pyridyl group optionally substituted with a group selected from an amino group, a nitro group, a trifluoromethyl group and a lower alkanoylamino group; Halogen atom, formyl group, N-
Hydroxyiminomethyl group, N-lower alkoxyiminomethyl group, thienyl group, furyl group, pyridyl group, lower alkyl group, hydroxy lower alkyl group, lower alkylthio group, lower alkanoyl group, lower alkynyl group, lower alkenyloxy group, lower alkoxy Substituted with a group selected from a group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a cyano lower alkoxy group, a thiazolyl group, a lower alkyl group-substituted thienyl group, a lower alkyl group-substituted pyrrolyl group, a phenyl group and a lower alkoxyphenyl group. Or a benzothiazolyl group, R ¹ is a hydrogen atom, a lower alkyl group, a morpholinyl group, a pyridyl group or a pyrimidinyl group.

Among the benzenesulfonamide derivatives [I] which are the active ingredients of the present invention, the phenyl in which ring A is substituted with a group selected from a lower alkyl group and a hydroxyl lower alkyl group is more preferable in view of its efficacy. Group, a phenyl group in which ring B is substituted with a group selected from a halogen atom, a lower alkyl group and a lower alkoxy group, and R is a group selected from a halogen atom, a hydroxy lower alkyl group, a thienyl group, a furyl group and a lower alkylthio group. Is a pyrimidinyl group substituted with, and R ¹ is a hydrogen atom or a pyrimidinyl group.

Among the benzenesulfonamide derivatives [I] which are the active ingredients of the present invention, 4-tert-butyl-N- [5- (4-methylphenyl) -6- {2- (5- (3-thienyl) pyrimidin-2-yloxy) ethoxy} pyrimidin-4-yl] benzenesulfonamide, 4-tert-butyl-
N- [5- (4-methylphenyl) -6- {2- (5-
Methylthiopyrimidin-2-yloxy) ethoxy} pyrimidin-4-yl] benzenesulfonamide, 4-t
ert-butyl-N- [5- (4-methylphenyl)-
6- {2- (5- (2-furyl) pyrimidin-2-yloxy) ethoxy} pyrimidin-4-yl] benzenesulfonamide, 4-tert-butyl-N- [5- (4
-Methylphenyl) -6- {2- (5- (2-thienylpyrimidin-2-yloxy) ethoxy} pyrimidine-
4-yl] benzenesulfonamide, 4-tert-butyl-N- [5- (4-methylphenyl) -6- {2-
(5-bromopyrimidin-2-yloxy) ethoxy}
Pyrimidin-4-yl] benzenesulfonamide, 4-
tert-butyl-N- [5- (4-methylphenyl)
-6- {2- (5-Bromopyrimidin-2-yloxy) ethoxy} -2- (2-pyrimidyl) pyrimidine-
4-yl] benzenesulfonamide, 4-tert-butyl-N- [5- (4-methylphenyl) -6- {2-
(5-chloropyrimidin-2-yloxy) ethoxy}
Pyrimidin-4-yl] benzenesulfonamide, 4-
tert-Butyl-N- [5- (4-methoxyphenyl) -6- {2- (5-methylthiopyrimidin-2-yloxy) ethoxy} pyrimidin-4-yl] benzenesulfonamide, 4-tert-butyl-N -[5-
(2-Methoxyphenoxy) -6- {2- (5- (2-
Thienyl) pyrimidin-2-yloxy) ethoxy} pyrimidin-4-yl] benzenesulfonamide, 4-t
ert-butyl-N- [5- (4-methylphenyl)-
6- {2- (5- (3-furyl) pyrimidin-2-yloxy) ethoxy} pyrimidin-4-yl] benzenesulfonamide, 4-tert-butyl-N- [5- (4
-Chlorophenyl) -6- {2- (5-methylthiopyrimidin-2-yloxy) ethoxy} pyrimidine-4-
Il] benzenesulfonamide, 4-tert-butyl-N- [5- (2-methoxyphenylthio) -6- {2
-(5-bromopyrimidin-2-yloxy) ethoxy} -2- (2-pyrimidyl) pyrimidin-4-yl]
Benzenesulfonamide 4-tert-butyl-N-
[5- (4-methylphenyl) -6- {2- (5-hydroxymethylpyrimidin-2-yloxy) ethoxy}}
Pyrimidin-4-yl] benzenesulfonamide or 4
-(2-Hydroxy-1,1-dimethylethyl) -N-
[5- (4-methylphenyl) -6- {2- (5-bromopyrimidin-2-yloxy) ethoxy} pyrimidin-4-yl] benzenesulfonamide.

Of these, particularly preferred is 4- (2
-Hydroxy-1,1-dimethylethyl) -N- [5-
(4-Methylphenyl) -6- {2- (5-bromopyrimidin-2-yloxy) ethoxy} pyrimidine-4-
Il] benzenesulfonamide.

Other compounds which are preferable in view of efficacy are ring A
Is a phenyl group substituted with a lower alkyl group, ring B is a phenyl group substituted with a lower alkyl group or a lower alkoxy group, Q is a single bond or a group represented by the formula —O—,
Y is a group represented by the formula -O-, Alk is a lower alkylene group, Z is a group represented by the formula -O-, R is a halogen atom, a formyl group, a cyano group, a hydroxy group, a lower alkylthio group, a lower alkanoyl group, Lower alkynyl group, lower alkenyloxy group, lower alkoxy group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkylamino-lower alkanoyloxy group, cyano lower alkoxy group, hydroxy lower alkyl group, lower alkoxy-
Substituted with a group selected from lower alkenyl group, lower alkyl group substituted pyrrolyl group, thiazolyl group, thienyl group, lower alkyl group substituted thienyl group, furyl group, pyridyl group, di-lower alkyl group substituted oxazolinyl group and phenyl group. And a compound in which R ¹ is a hydrogen atom, a morpholinyl group, a pyridyl group or a pyrimidinyl group.

Of these, more preferred are those in which R is a halogen atom, lower alkylthio group, lower alkanoyl group, lower alkoxy group, hydroxy lower alkyl group, lower alkoxy-lower alkenyl group, thienyl group, furyl group, pyridyl group and A pyrimidinyl group substituted with a group selected from a phenyl group, and a compound in which R ¹ is a hydrogen atom, a morpholinyl group or a pyrimidinyl group.

The benzenesulfonamide derivative [I], which is the active ingredient of the present invention, may have optical isomers based on an asymmetric carbon atom or an asymmetric sulfur atom. Any of these optical isomers and mixtures thereof can be used. It also includes.

The benzenesulfonamide derivative [I], which is the active ingredient of the present invention, can be used in medicinal use either in the free form or in the form of a pharmacologically acceptable salt. Such pharmacologically acceptable salts include acid addition salts with inorganic acids or organic acids, salts with inorganic bases, organic bases or amino acids, for example, hydrochlorides, sulfates, hydrobromides, methane. Sulfonates, acetates, fumarates, maleates, oxalates, alkali metals (sodium,
Examples thereof include potassium salts), alkaline earth metal (magnesium, calcium, etc.) salts, triethylamine salts, salts with lysine, and the like.

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

The benzenesulfonamide derivative [I] or a pharmaceutically acceptable salt thereof, which is the active ingredient of the present invention, is
It can be administered orally or parenterally, and can be used as an appropriate pharmaceutical preparation such as tablets, granules, capsules, powders, injections and inhalants by a conventional method.

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 suspension, which is suitable for oral administration. It can be used as a pharmaceutical preparation 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, the dosage form for parenteral administration is preferably an injection or drip injection using, for example, distilled water for injection, physiological saline, an aqueous glucose solution or the like.

The dose of the benzenesulfonamide derivative [I] or a pharmacologically acceptable salt thereof varies depending on the administration method, age of the patient, body weight, condition or degree of disease, but is usually administered daily. The amount is about 0.001-10
It is preferably about 0 mg / kg.

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

That is, the benzenesulfonamide derivative [I] or a pharmaceutically acceptable salt thereof, which is the active ingredient of the present invention, has high stability and an excellent endothelin antagonism.

The benzenesulfonamide derivative [I] or a pharmaceutically acceptable salt thereof, which is the active ingredient of the present invention, has low toxicity, for example, 4-tert-butyl-N-.
[5- (4-Methylphenyl) -6- {2- (5-bromopyrimidin-2-yloxy) ethoxy} pyrimidin-4-yl] benzenesulfonamide sodium salt was administered to rats at 100 mg / kg for 25 consecutive days. No oral mortality was observed even after oral administration.

Therefore, the pharmaceutical composition of the present invention provides a disease associated with endothelin activity such as 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 drug for infarction, angina, arrhythmia, glaucoma, migraine, cerebral vasospasm, cerebral infarction and the like.

The benzenesulfonamide derivative [I], which is the active ingredient of the present invention, comprises the following [Method A], [Method B] and [C].
Method D] or [Method D].

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

[0039]

Embedded image

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

[0041]

Embedded image

(Wherein the symbols have the same meanings as described above) and can be produced by reacting with a compound or salt thereof.

[Method B] Further, the compound [I] has the general formula [IV]

[0044]

Embedded image

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

[0046]

[Chemical 6]

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

[Method C] In the benzenesulfonamide derivative [I] which is the active ingredient of the present invention, a general formula [Ia] in which Z is a group represented by the formula —O— or —NH—

[0049]

[Chemical 7]

(However, Z ¹ is of the formula —O— or —NH—
And the other symbols have the same meanings as described above. The compound represented by the general formula [VI]

[0051]

Embedded image

(Where the symbols have the same meaning as described above) or a salt thereof, and a compound of the general formula [VI
I]

[0053]

Embedded image

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

[Method D] Further, in the benzenesulfonamide derivative [I] which is the active ingredient of the present invention, a compound of the general formula [Ib] in which Q is a single bond.

[0056]

Embedded image

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

[0058]

Embedded image

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

[0060]

[Chemical 12]

(Wherein W represents a lower alkyl group, and ring B
Has the same meaning as described above. ) Can be produced by reacting the compound of formula (1).

The salts of the compounds [III], [IV], [VI] or [VIII] include, for example, salts with inorganic acids such as hydrochlorides and sulfates 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 or the like can be preferably used.

[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. As the deoxidizing agent, alkali metal hydrides, alkali metal carbonates, alkali metal alkoxides, alkyl alkali metals, alkali metals, alkali metal hydroxides and the like can be preferably used. Further, as the solvent, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, hexamethylphosphoramide, 1,3-dimethyl-2-imidazolidinone, dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether and the like can be appropriately used. This reaction is carried out at room temperature to 150 ° C., especially room temperature to 1
Properly proceeds at 00 ° 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 preferably used. This reaction is carried out at 0 to 150
Suitably progresses at ℃, especially room temperature to 100 ℃. Also,
This reaction proceeds more suitably when a catalytic amount of a phase transfer catalyst such as tetrabutylammonium hydrogensulfate, trimethylbenzylammonium chloride or 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 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, hexamethylphosphoramide, dioxane, tetrahydrofuran, toluene and the like can be appropriately used. The reaction is carried out at room temperature to
It proceeds preferably at 150 ° C, especially at room temperature to 100 ° C.

[Method D]: The reaction of compound [VIII] or a salt thereof with compound [IX] can be carried out in the presence of a catalyst in a suitable solvent. 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 is based on the Journal of Organic Chemistry (J. Org. C
hem. ) According to the method described in Vol. 58, p. 1963 (1993), copper (I) chloride, copper (I) bromide, copper (I) iodide, etc. are added more preferably, and copper (I) salts are more suitably processed. To do. Examples of the solvent include dioxane, ethylene glycol dimethyl ether, dimethylacetamide, dimethylformamide, hexamethylphosphoramide, benzene, tetrahydrofuran, toluene, dioxane,
1,3-Dimethyl-2-imidazolidinone, dimethoxyethane, water or a mixed solvent thereof can be appropriately used. This reaction suitably proceeds at 50 to 100 ° C.
The benzenesulfonamide derivative [I], which is the active ingredient of the present invention, can also be produced by interconverting the target product obtained as described above into another target product.
Such an interconversion reaction between the target substances may be appropriately selected depending on the kind of the substituent that the compound has, and can be carried out, for example, as in the following methods (a) to (w).

Method (a): Compound [I] in which R is a substituted aromatic heterocyclic group or aryl group can be prepared by converting the 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 substituted with a lower alkanoyl group (eg, acetyl group or the like) or an aryl group has the corresponding R is lower alkoxy-lower alkenyl. It can be produced by acid-treating a compound which is an aromatic heterocyclic group or an aryl group substituted with a group (for example, a 1-ethoxyvinyl group etc.). As the acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, trifluoroacetic acid or the like can be preferably used.
This reaction suitably proceeds at 0 ° C to room temperature.

Method (c): Compound [I] in which R is an aromatic heterocyclic group substituted with a hydroxy group-substituted lower alkyl group or an aryl group has a corresponding R substituted with a lower alkanoyl group or a formyl group. It can be produced by treating a compound which is an aromatic heterocyclic group or an aryl group with a reducing agent. As the reducing agent, sodium borohydride or the like can be preferably used. This reaction is 0 ℃
~ Properly proceeds at room temperature.

Method (d): Compound [I] in which R is an aromatic heterocyclic group substituted with a lower alkyl group or an aryl 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. Halogenation can be carried out by reacting with thionyl chloride or the like. The reduction can be carried out by treating with palladium-carbon or the like. Further, this reduction reaction is preferably carried out in a hydrogen atmosphere in the presence of a deoxidizing agent, and as the deoxidizing agent, triethylamine, pyridine or the like can be preferably 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 the corresponding 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): In addition, the compound [I] in which R is an unsubstituted aromatic heterocyclic group or aryl group has 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 carried out in a hydrogen atmosphere in the presence of a catalyst such as Raney nickel. This reaction suitably proceeds at room temperature to 50 ° C.

Method (g): Compound [I] in which R is a formyl group, a hydroxy group-substituted lower alkyl group, or an aromatic heterocyclic group substituted with a hydroxy group and an aryl group-substituted lower alkyl group or an aryl group is , A compound in which the corresponding R is a halogen atom-substituted aromatic heterocyclic group or aryl group is lithiated and then reacted with the corresponding carbonyl compound (eg, dimethylformamide, acetone, benzaldehyde, etc.). can do. Lithiation can be suitably carried out by reacting with n-butyllithium or the like. This reaction is -10
It suitably proceeds at 0 ° C to 25 ° C.

Method (h): The compound [I] in which R is an aromatic heterocyclic group substituted with an amino group or an aryl group is a compound of formula (I) in which the corresponding R is substituted with a nitro group. It can be produced by reducing a compound which 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. Palladium-carbon, platinum oxide or the like can be suitably used as the transition metal catalyst, and tin, stannous chloride, zinc, iron or the like can be suitably used as the reducing agent. The reaction is carried out at -2
It suitably proceeds at 0 ° C to 80 ° C.

Method (i): Compound [I] in which R is an aromatic heterocyclic group or aryl group substituted with a lower alkanoylamino group or an arylcarbonylamino group has the corresponding R 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, it is preferable to carry out this reaction in the presence of a condensing agent such as N, N′-dicyclohexylcarbodiimide or N-dimethylaminopropyl-N′-ethylcarbodiimide. When this reaction is carried out using a reactive derivative, it is preferably carried out in the presence of a deoxidizing agent such as an organic base (triethylamine, pyridine, etc.). The reaction is
It suitably proceeds at -20 ° C to 100 ° C.

Method (j): Compound [I] in which R is an aromatic heterocyclic group substituted with a mono- or di-lower alkylamino group or an aryl group has the corresponding R substituted with an amino group. It can be produced by alkylating a compound which is an aromatic heterocyclic group or an aryl group. Alkylation is carried out by (1) reacting a lower alkyl halide (lower alkyl chloride, etc.) or lower alkyl sulfonate (methane sulfonate, toluene sulfonate, etc.) in the presence of a deoxidizing agent, or (2) in the presence of a reducing agent, It can be carried out by reducing the reaction product with a lower alkyl aldehyde. As the deoxidizing agent, alkali metal hydroxide, alkali metal hydrogen carbonate, alkali metal carbonate and the like can be preferably used. As the reducing agent, sodium borohydride, sodium triacetoxyborohydride,
Formic acid and the like can be preferably used. This reaction is 0-1
Properly proceeds at 00 ° C.

Method (k): Compound [I] in which R is an aromatic heterocyclic group substituted with a tetrazolyl group or an aryl 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
Suitably proceeds at 0 ° C.

Method (l): Compound [I] in which R is an aromatic heterocyclic group or aryl group substituted with an optionally protected carboxyl group-substituted lower alkoxy group is a compound [I] in which R is a hydroxy group. It 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. This reaction suitably proceeds in the presence of a deoxidizing agent such as alkali metal hydrogen carbonate or alkali metal carbonate. This reaction suitably proceeds at 0 to 100 ° C. As the carboxyl protecting group, a conventional carboxyl protecting group can be used. Moreover, the said protecting group can be removed by a conventional method.

Method (m): Compound [I] in which R is an aromatic heterocyclic group substituted with a lower alkoxy-lower alkyl group or an aryl group has the corresponding R substituted with a lower alkyl group substituted with a hydroxy group. It can be produced by halogenating a compound which is an aromatic heterocyclic group or an aryl group and then alkoxylating the compound. As the halogenating agent, a halogenating agent such as thionyl chloride can be preferably 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. This alkoxylation reaction is preferably carried out in the presence of a deoxidizing agent, and as the deoxidizing agent,
Organic bases (triethylamine, pyridine, etc.) and the like can be preferably used. This reaction suitably proceeds at -20 ° C to 100 ° C.

Method (n): Compound [I] in which R is an aromatic heterocyclic group or aryl group substituted with a lower alkylsulfinyl group and / or a lower alkylsulfonyl group is
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 and the like can be preferably used. This reaction suitably proceeds at 0 to 50 ° C.

Method (o): Compound [I] in which R is an aromatic heterocyclic group substituted with a lower alkylthio group or an aryl group is an aromatic heterocycle in which the corresponding R is substituted with a lower alkylsulfinyl group. It can be produced by first reacting a compound which is a formula group or an aryl group in the presence of an acid anhydride, then hydrolyzing it to a thiol, and further reacting it 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 substituted with a cyano group or an aryl group can be prepared by reacting the corresponding R with a halogen atom. It can be produced by reacting an aryl group compound with zinc cyanide in the presence of a catalyst. As the catalyst, any of the catalysts described in the above method [D] can be suitably used. This reaction suitably proceeds at 60 to 100 ° C.

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

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

Method (s): The compound [I] in which R is an aromatic heterocyclic group substituted with a phenyl lower alkyl group or an aryl group is an aromatic heterocyclic group in which the corresponding R is substituted with a phenylalkenyl group. It can be produced by reducing a compound which is a formula group or an 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] wherein ring A and / or ring B is a benzene ring substituted with a formyl group can be prepared by reacting corresponding ring A and / or ring B with a lower alkyl substituted with a di-lower alkoxy group. The compound having a benzene ring substituted with a group can be produced by hydrolyzing in the presence of an acid. As the acid, p-toluenesulfonic acid or the like can be preferably used. This reaction suitably proceeds at 0 to 50 ° C.

Method (u): The compound [I] in which ring A and / or ring B is a benzene ring substituted with a lower alkoxycarbonyl-lower alkenyl group has a corresponding ring A and / or ring B being a formyl group. It can be produced by reacting a compound which is a substituted benzene ring with a triphenyl phosphorus complex of a group to be substituted. This reaction suitably proceeds at room temperature to 60 ° C.

Method (v): The compound [I] in which ring A and / or ring B is a benzene ring substituted with a lower alkenyl group substituted with a carboxyl group can be prepared by reacting ring A and / or ring B with a lower alkoxycarbonyl group. It can be produced by hydrolyzing a compound having a benzene ring substituted with a lower alkenyl group in the presence of an alkali metal hydroxide or the like. Sodium hydroxide or the like can be preferably used as the alkali metal hydroxide. This reaction suitably proceeds at 0 ° C to room temperature.

Method (w): Compound [I] in which Q is a group represented by the formula -SO- or -SO _2- has the corresponding Q represented by the formula -S-.
Can be produced by reacting a compound which is a group represented by the formula in the presence of an oxidizing agent. As the oxidizing agent, 3-chloroperbenzoic acid or the like can be preferably used. This reaction is 0
It proceeds favorably at ５０50 ° C.

The solvent used in the reactions (a) to (w) is not particularly limited as long as it is an inert solvent for the reaction, and examples thereof include dioxane, ethylene glycol dimethyl ether, dimethylacetamide, dimethylformamide, hexamethyl. Phosphoramide, benzene, tetrahydrofuran, toluene, dioxane, ethyl acetate, lower alcohol, methylene chloride, chloroform, 1,3-dimethyl-2-imidazolidinone, diethyl ether, dimethoxyethane, dimethyl sulfoxide, water or a mixed solvent thereof. It can be used as appropriate.

The raw material compounds [II] and [VI] of the benzenesulfonamide derivative which is the active ingredient of the present invention
Are described in, for example, JP-A-5-155864 or JP-A-5-5-2.
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]

[0093]

Embedded image

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

[0095]

Embedded image

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

[0097]

Embedded image

(Wherein ring B has the same meaning as described above), the product is represented by the general formula in the presence of a base (sodium ethylate, etc.).

[0099]

Embedded image

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

[0101]

Embedded image

(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]

[0103]

Embedded image

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

[0105]

Embedded image

(Wherein X ⁵ represents a reactive residue, and other symbols have the same meanings as described above), and the compound is represented by the general formula [XV]

[0107]

Embedded image

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

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

[0110]

[Chemical 21]

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

[0112]

Embedded image

(However, ring B has the same meaning as described above), and this is prepared in the presence of a base (sodium methylate, etc.) for the amidine compound [XIII].
And reacting with the general formula [XVIII]

[0114]

Embedded image

(Where the symbols have the same meanings as described above), and then a step of converting the hydroxyl group of the compound [XII] wherein Q is a single bond to a reactive residue. Similarly, the general formula [XIX]

[0116]

Embedded image

(Where the symbols have the same meaning as described above), and then the compound [XI
V] and compound [XV] to give compound [II].

Further, the compound [VI] is obtained by converting the corresponding compound [II] into the general formula [XX].

[0119]

Embedded image

(Wherein Y, Alk and Z ¹ have the same meanings as described above) and the compound can be produced by reacting them in the presence of a deoxidizing agent (sodium hydride, etc.).

The starting compound [IV] is the compound (II) compound [XIV] or compound [XIX] and compound [II].
I] in the presence of a deoxidizing agent (eg, sodium hydride) to give a compound of the general formula [XXI]

[0122]

[Chemical formula 26]

(Where the symbols have the same meanings as described above), and this compound is reacted with sodium azide to give a compound of the general formula [XXII]

[0124]

Embedded image

(Where the symbols have the same meanings as described above), and then the compound is produced by catalytic hydrogen reduction, or (ii) compound [XIV] or compound [XIX], Ammonia is reacted to give a compound of the general formula [XXIII]

[0126]

Embedded image

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

In the starting compound [IV], Z is of the formula —O—
Alternatively, a group represented by -NH- is represented by the general formula [IV-
a]

[0129]

[Chemical 29]

(Where the symbols have the same meanings as described above), the compound (i) compound [XIV] or compound [XIX] and compound [XX] are treated with a deoxidizing agent (eg sodium hydride). ) In the presence of the general formula [XXIV]

[0131]

Embedded image

(Where the symbols have the same meanings as described above), and this is reacted with sodium azide to give a compound of the general formula [XXV]

[0133]

[Chemical 31]

(Wherein the symbols have the same meanings as described above), the compound of the formula [XXVI] is obtained by catalytic hydrogen reduction.

[0135]

Embedded image

(Where the symbols have the same meanings as described above), and the compound [VII] is reacted with the compound [VII] in the presence of a deoxidizing agent (eg sodium hydride). , Or (ii) compound [XXII
I] is reacted with compound [XX] to give compound [XXV].
After obtaining I), it can be produced by reacting this with compound [VII] in the presence of a deoxidizing agent (eg, sodium hydride or the like).

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

[0138]

[Chemical 33]

(Wherein R ¹ has the same meaning as described above) and the compound [XV] are reacted in the presence of a deoxidizing agent (eg sodium hydride) to give a compound of the general formula [XXVIII].

[0140]

Embedded image

(Where the symbols have the same meanings as described above), and the compound [II] is prepared in the presence of a deoxidizing agent (eg sodium hydride).
I] and reacting with the general formula [XXIX]

[0142]

Embedded image

(Provided that 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) compound [XXVII ] And the compound [III]
In the presence of a deoxidizing agent (eg sodium hydride) to give a compound of the general formula [XXX]

[0144]

Embedded image

(Where the symbols have the same meanings as described above), and this compound is reacted with sodium azide to give a compound of the general formula [XXXI]

[0146]

Embedded image

(Where the symbols have the same meanings as described above), and then catalytic hydrogen reduction is carried out to obtain a compound of the general formula [XXXII].

[0148]

Embedded image

(Where the symbols have the same meaning as described above), and the compound [V] is reacted with the compound [V] in the presence of a deoxidizing agent (sodium hydride, etc.). It can be produced by forming [XXIX] and further forming a reactive residue with a halogenating agent or the like.

In the starting compound [VIII], Z is represented by the formula-
General formula [VI, which is a group represented by O- or -NH-
II-a]

[0151]

Embedded image

(Where the symbols have the same meanings as described above), the compounds represented by (i) compound [XXVII
I] in the presence of a deoxidizing agent (eg, sodium hydride, etc.)
Reacting with the compound [XX] to obtain a compound of the general formula [XXXIII]

[0153]

[Chemical 40]

(Where the symbols have the same meaning as described above), and then treated with a halogenating agent (for example, N-bromosuccinimide etc.) to form a reactive residue, and the compound of the general formula [ XXXIV]

[0155]

Embedded image

(Wherein the symbols have the same meanings as described above), and then the compound [VII] is reacted in the presence of a deoxidizing agent (for example, sodium hydride). Alternatively, (ii) compound [XXVII] and compound [XX] are reacted in the presence of a deoxidizing agent (eg, sodium hydride) to give a compound of general formula [XXX
V]

[0157]

Embedded image

(Where the symbols have the same meanings as described above), and this compound is reacted with sodium azide to give a compound of the general formula [XXXVI].

[0159]

Embedded image

(Where the symbols have the same meanings as described above), and then the compound is subjected to catalytic hydrogen reduction to give a compound of the general formula [XXXVII].

[0161]

Embedded image

(Where the symbols have the same meanings as described above), and the compound [V] is reacted with the compound of the general formula [XXXVIII].

[0163]

Embedded image

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

In the present specification, 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 group or a lower alkylsulfonyl group is a carbon atom. The number 1-6, especially 1-4 are mentioned. Further, lower alkenyl group, lower alkanoyl group, lower alkanoylamino group, lower alkoxycarbonyl group, lower alkynyl group, lower alkenyloxy group, lower alkenylene group, N-lower alkylcarbamoyloxy group, N-lower alkoxyiminomethyl group or N
The lower alkylaminocarbonyl group has 2 to 7 carbon atoms, especially 2 to 5 carbon atoms. Further, the cycloalkyl group has 3 to 8 carbon atoms, especially 3 to 6 carbon atoms. Examples of the halogen atom include chlorine, bromine, fluorine and iodine.

Experimental Example 1 [Endothelin Binding Inhibitory Action in Porcine Aortic Membrane Specimen] The porcine aorta from which endothelial cells had been detached was 10 times as much as 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 ×
Centrifuge at g for 15 minutes, and further cool the obtained supernatant under cooling,
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.

Membrane preparation 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 Tables 1 to 5 below as the concentration (IC ₅₀ ) required to suppress 50% of the specific binding from the concentration inhibition curve.

[0168]

[Table 1]

[0169]

[Table 2]

[0170]

[Table 3]

[0171]

[Table 4]

[0172]

[Table 5]

Experimental Example 2 [Inhibition of endothelin contraction in rat aorta preparation] After extracting the thoracic aorta from SD rats, ice-cooled nutrient solution of pH 7.4 (composition: 137 mM sodium chloride, 2.7 mM potassium chloride, 1 1 mM magnesium chloride, 11.9 mM sodium hydrogen carbonate, 5.5 mM
Blood) and adipose tissue adhered in glucose),
Endothelial cells were peeled off to obtain a ring-shaped specimen having a length of about 4 mm. Specimen is kept at 37 ± 0.5 ℃, 95% O ₂ , 5%
A preload weight of about 1.5 g was added and suspended in an organ bath containing 10 ml of a nutrient solution in which a mixed gas of CO ₂ was aerated, and the change in tension was measured. First, stabilize the specimen in the nutrient solution for 90 minutes or more and then 3x10 ^-8
M endothelin-1 (manufactured by Peptide Lab.) Was added, and the obtained shrinkage was defined as 100%, and the shrinkage inhibition rate (%) was evaluated. The sample was dissolved in a 30% DMSO-0.1% bovine serum albumin solution and added 20 minutes before the addition of endothelin-1. The results are shown in Table 6 below.

[0174]

[Table 6]

Experimental Example 3 [Inhibitory action of big endothelin-1 pressor in ganglion-blocked rat] In the experiment, a body weight of 300-39 fasted overnight was used.
SD male rats (9-10 weeks old; 4 to 5 animals) of 0 g were used. Oral administration of 5 ml of 0.25% CMC solution of 1.0 mg / kg of sample or 5 ml of solvent was followed by inactin-1
Anesthesia was carried out by intraperitoneally administering 00 mg / kg. After the rat was fixed on the holding platform in the dorsal position, a midline incision was made in the neck, a cannula was inserted into the trachea, and artificial respiration (1 ml / 100 g / strok) was performed.
es, 70 stroke / min, Shinano, SN-48
0-7) was applied. For blood pressure, a blood pressure cannula inserted in the right femoral artery was used as a pressure transducer (Nihon Kohden, TP-
400T) and pressure / strain gauge (Nihon Kohden, AP-62)
1G). In addition, a polyethylene tube with a 27G injection needle was inserted into the left femoral vein for drug administration, and the femoral vein was mecamylamine (manufactured by Sigma) (3 m).
g / kg) and atropine (manufactured by Wako Pure Chemical Industries, Ltd.) (0.4 m
(g / kg) was administered intravenously to block ganglia. Big End Serine-1 (Peptide Lab) (1
(nmole / kg) was intravenously administered 1 hour after the administration of the sample, and the pressor suppression rate (%) of the sample with respect to pressorization of big endothelin-1 was examined. It is as shown in Table 7 below.

[0176]

[Table 7]

Production Example 1 60 mg of sodium hydride (62.7% dispersion type) was gradually added to 0.5 ml of a solution of 130 mg of 2-pyridinemethanol in 0.5 ml of dimethylacetate, followed by 4 steps.
100 mg of -tert-butyl-N- {6-chloro-5- (3-methoxyphenoxy) pyrimidin-4-yl} benzenesulfonamide are added. After the reaction at 100 ° C. for 30 minutes, the mixture is cooled and adjusted to pH 8 with a saturated aqueous ammonium chloride solution. Extract with ethyl acetate, wash the extract,
After drying, the residue is dried under reduced pressure, and the residue is crystallized from ethyl acetate to give 4-tert-butyl-N- {5- (3-methoxyphenoxy) -6- (2-pyridinylmethoxy) pyrimidin-4-yl}. 110 mg of benzenesulfonamide are obtained as crystals. m. p. : 206-207.5 ° C.

Production Examples 2 to 18 The corresponding starting compound was treated in the same manner as in Production Example 1 to give the following 8th to 8th compounds.
10 The compounds listed in Table are obtained.

[0179]

[Table 8]

[0180]

[Table 9]

[0181]

[Table 10]

Production Example 19 (1) 4-tert-butyl-N- {6-chloro-5-
After treating (3-methoxyphenoxy) pyrimidin-4-yl} benzenesulfonamide and 2-aminoethanol in the same manner as in Production Example 1, N- {6- (2-aminoethoxy) was used as the precipitated crystal as a hydrochloride. -5- (3-Methoxyphenoxy) pyrimidin-4-yl} -4-te
rt-Butylbenzenesulfonamide hydrochloride [Compound A] is obtained. On the other hand, the mother liquor was purified by silica gel column chromatography (eluting solvent: chloroform: methanol: acetic acid = 10: 1: 0.3) and then recrystallized from chloroform-diisopropyl ether to give 4-tert-butyl-
N- {6- (2-hydroxyethylamino) -5- (3
-Methoxyphenoxy) pyrimidin-4-yl} benzenesulfonamide [Compound B] is obtained. [Compound A]; m. p. : 201.5-202 ° C [Compound B]; m.p. p. : 161-163 ° C.

(2) A mixed solution of 150 mg of the above compound A, 61 mg of 2-chloropyrimidine, 122 mg of potassium carbonate and 1.5 ml of dimethylacetamide is heated and stirred at 100 ° C. for 3 days. The reaction solution is diluted with an aqueous ammonium chloride solution and extracted with ethyl acetate. The extract is washed and dried. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (elution solvent; chloroform: methanol = 1).
00: 1) and then recrystallized from ethyl acetate-n-hexane to give 4-tert-butyl-N- [5- (3-methoxyphenoxy) -6- {2- (2-pyrimidinylamino) ethoxy}. 135 mg of pyrimidin-4-yl] benzenesulfonamide hydrate are obtained as crystals.

M. p. : 101-102 ° C (decomposition).

Production Example 20 A solution of 116 mg of the compound B obtained in Production Example 19- (1) in 2 ml of dimethylacetamide was added with sodium hydride (60%).
33 mg (dispersed) and then 40 mg of 2-chloropyrimidine. The reaction mixture is stirred at room temperature overnight, treated with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. After washing and drying the ethyl acetate layer, the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: chloroform: methanol = 20: 1), and crystallized from chloroform-diisopropyl ether to give 4-tert-butyl-N- [5- (3-methoxyphenoxy) -6-. 125 mg of {2- (pyrimidin-2-yloxy) ethylamino} pyrimidin-4-yl] benzenesulfonamide are obtained as crystals. m. p. 147.5-149 ° C.

Preparation Example 21 4-tert-butyl-N- {6- (2-hydroxyethoxy) -5- (3-methoxyphenoxy) pyrimidin-4-yl} benzenesulfonamide (250 mg) in dimethylacetamide (5 ml) at room temperature. Add 64 mg of sodium hydride (60% dispersion type) and stir for 20 minutes. To the reaction solution is added 5-bromo-2-chloropyrimidine (133 mg), and the mixture is stirred at room temperature for 18 hours. The reaction solution is poured into ice water, neutralized with a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. After washing and drying the ethyl acetate layer, the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; chloroform: methanol = 40:
Purified in 1) to obtain crude crystals, recrystallized from ethyl acetate-diisopropyl ether to give N- [6- {2- (5-bromopyrimidin-2-yloxy) ethoxy} -5- (3-
Methoxyphenoxy) pyrimidin-4-yl] -4-t
280 mg of ert-butylbenzenesulfonamide are obtained as crystals. m. p. : 168-168.5 ° C.

Production Examples 22 to 75 The corresponding starting material compounds were treated in the same manner as in Production Example 21 to give the following first
The compounds described in Tables 1 to 18 are obtained.

[0188]

[Table 11]

[0189]

[Table 12]

[0190]

[Table 13]

[0191]

[Table 14]

[0192]

[Table 15]

[0193]

[Table 16]

[0194]

[Table 17]

[0195]

[Table 18]

Production Example 76 6- [2- (5-Bromopyrimidin-2-yloxy)
Ethoxy] -5- (4-methylphenyl) pyrimidine-
A mixture of 150 mg of 4-amine, 184 mg of 4-tert-amylbenzenesulfonyl chloride, 300 mg of 96% potassium hydroxide (powder), 34 mg of tetrabutylammonium hydrogensulfate and 10 ml of toluene is stirred overnight at room temperature. Dilute with saturated aqueous ammonium chloride and extract with ethyl acetate. The ethyl acetate layer is washed and dried, and then the solvent is distilled off. The residue was subjected to silica gel column chromatography (elution solvent; chloroform: ethyl acetate = 5: 1).
And then recrystallized from hexane-ethyl acetate to give 4-t.
188 mg of ert-amyl-N- {6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -5- (4-methylphenyl) pyrimidin-4-yl} benzenesulfonamide are obtained. m. p. 153.5-154.5 ° C IR (nujol, cm ^-1 ): 3270, 1570, ¹
550 FABMS (m / z): 614,612 (MH ^<+> ).

Production Examples 77-82 The corresponding starting compound was treated in the same manner as in Production Example 76 to give the following first compound.
9 The compounds listed in Table are obtained.

[0198]

[Table 19]

Production Example 83 6- [2- (5-bromopyrimidin-2-yloxy)
Ethoxy] -5- (4-methylphenyl) pyrimidine-
A mixture of 150 mg 4-amine, 191 mg 4-bromobenzenesulfonyl chloride, 112 mg sodium iodide, 45 mg sodium hydride (60% dispersion) and 5 ml tetrahydrofuran is stirred overnight at room temperature. Further, 191 mg of 4-bromobenzenesulfonyl chloride and 45 mg of sodium hydride (60% dispersion type) are added, and the mixture is heated under reflux overnight. After cooling, the reaction is treated with saturated ammonium chloride and extracted with ethyl acetate. After washing and drying the ethyl acetate layer, the solvent is distilled off, and the residue is subjected to preparative thin-layer chromatography (developing solvent; chloroform: ethyl acetate = 1).
0: 1) to give 4-bromo-N- {6- [2-
(5-bromopyrimidin-2-yloxy) ethoxy]
-5- (4-methylphenyl) pyrimidin-4-yl}
85 mg of benzenesulfonamide are obtained. m. p. : 217-218 ° C IR (nujol, cm ^-1 ): 2800-2400, ¹
575, 1560 FABMS (m / z): 624, 622, 620 (MH
⁺ ).

Production Example 84 N- {5-bromo-6- [2- (5-methylthiopyrimidin-2-yloxy) ethoxy] pyrimidin-4-yl} -4-tert-butylbenzenesulfonamide 1
00 mg, 3,4-dimethoxyphenyltributyltin 220 mg, bis (triphenylphosphine) palladium (II) chloride 26 mg, copper (I) chloride 11 mg,
Crystals 2,3 of 2,6-di-tert-butylcresol
A mixture of the pieces and 5 ml of dioxane is heated at reflux for 1.5 hours. After cooling, the reaction solution is diluted with ethyl acetate and an aqueous potassium fluoride solution, and stirred at room temperature for 30 minutes. The insoluble material is removed by filtration, the filtrate is acidified with 10% hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed and dried, and the solvent was distilled off,
The residue was purified by preparative thin layer chromatography (developing solvent; chloroform: ethyl acetate = 3: 1) and then recrystallized from ethyl acetate-diisopropyl ether to give 4-tert.
-Butyl-N- {5- (3,4-dimethoxyphenyl)
82 mg of -6- [2- (5-methylthiopyrimidin-2-yloxy) ethoxy] pyrimidin-4-yl} benzenesulfonamide are obtained. m. p. : 170.5-171.5 ° C IR (nujol, cm ^-1 ): 3200, 1590, ¹
570, 1520, 1510.

Production Examples 85-95 The corresponding starting compounds were treated in the same manner as in Production Example 84, and the following second
0 and 21 The compounds listed in Table 1 are obtained.

[0202]

[Table 20]

[0203]

[Table 21]

Production Example 96 N- [6- {2- (5-bromopyrimidin-2-yloxy) ethoxy} -5- (3-methoxyphenoxy) pyrimidin-4-yl] -4-tert-butylbenzenesulfonamide 150 mg, tributylphenyl tin 1
A mixture of 31 mg, 8.5 mg of bis (triphenylphosphine) palladium (II) chloride and 4 ml of dioxane is heated under reflux for 12 hours. The reaction is diluted with ethyl acetate and treated with a 10% aqueous potassium fluoride solution. The insoluble material is removed by filtration, and the ethyl acetate layer is separated. After washing with water and drying, the solvent was distilled off, the residue was purified by silica gel column chromatography (eluting solvent: chloroform), and recrystallized from ethyl acetate-diisopropyl ether to give 4-tert-butyl-N- [5- (3 -Methoxyphenoxy) -6- {2
-(5-Phenylpyrimidin-2-yloxy) ethoxy} pyrimidin-4-yl] benzenesulfonamide 8
5 mg are obtained as crystals. m. p. : 160-161 ° C.

Production Example 97-118 N- [6- {2- (5-bromopyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl] -4-tert-butylbenzene The sulfonamide and the corresponding raw material compound are treated in the same manner as in Production Example 96 to obtain the compounds shown in Tables 22 to 24 below.

[0206]

[Table 22]

[0207]

[Table 23]

[0208]

[Table 24]

Production Example 119 N- [6- {2- (5-bromopyrimidin-2-yloxy) ethoxy} -5- (2-methoxyphenoxy) pyrimidin-4-yl] -4-tert-butylbenzenesulfonamide And corresponding starting material compound were treated in the same manner as in Production Example 96 to give 4-tert-butyl-N- [5- (2-
(Methoxyphenoxy) -6- {2- (5- (2-thienyl) pyrimidin-2-yloxy) ethoxy} pyrimidin-4-yl] benzenesulfonamide. m. p. : 185.5-186.5 ° C.

Production Example 120 4-tert-butyl-N- [5- (3-methoxyphenoxy) -6- {2- (2-methylthiopyrimidine-4]
-Yloxy) ethoxy {pyrimidin-4-yl] benzenesulfonamide 250 mg, Raney nickel (W-
2) A mixture of 2 g and 5 ml of ethanol is stirred overnight at room temperature and heated under reflux for 4 hours. The Raney nickel is filtered off and washed with ethanol and acetic acid. The filtrate is concentrated under reduced pressure, and the residue is extracted with ethyl acetate. Wash the ethyl acetate layer,
After drying, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (elution solvent; chloroform: methanol =
10: 1) and then recrystallized from ethyl acetate-n-hexane to give 4-tert-butyl-N- [5- (3-methoxyphenoxy) -6- {2- (pyrimidin-4-yloxy) ethoxy. } Pyrimidin-4-yl] benzenesulfonamide 76 mg is obtained as crystals. m. p. 149-150.5 ° C.

Production Example 121 4-tert-butyl-N- [6- {2- (6-chloropyridazin-3-yloxy) ethoxy} -5- (3-
Methoxyphenoxy) pyrimidin-4-yl] benzenesulfonamide 150 mg, 10% palladium-carbon 3
0 mg, triethylamine 52 mg, methanol 8 ml
And a mixture of 6 ml of tetrahydrofuran in a hydrogen atmosphere (1
Stir at room temperature under atmospheric pressure) for 5 hours. After removing the catalyst by filtration, the filtrate is dried under reduced pressure. The residue is treated with an aqueous citric acid solution, extracted with chloroform, washed, dried, and the solvent is distilled off. The residue was recrystallized from ethyl acetate-diisopropyl ether to give 4-tert-butyl-N- [5- (3-methoxyphenoxy) -6- {2- (pyridazin-3-yloxy).
111 mg of [ethoxy [pyrimidin-4-yl] benzenesulfonamide are obtained as crystals. m. p. 169.5-170 ° C.

Production Example 122 4-tert-butyl-N- [6- {2- (1-methyl-4,5-dibromoimidazol-2-yloxy) ethoxy} -5- (3-methoxyphenoxy) pyrimidine-4 -Yl] benzenesulfonamide was treated as in Preparation 121 to give 4-tert-butyl-N- [6- {2.
-(1-methylimidazol-2-yloxy) ethoxy} -5- (3-methoxyphenoxy) pyrimidine-4
-Yl] benzenesulfonamide is obtained. m. p. : 124-126 ° C.

Production Example 123 (1) To a solution of 1.31 g of 2-mercaptoethanol in 15 ml of dimethylacetamide was added 520 mg of sodium hydride (62.3% dispersion type) under an argon atmosphere.
After 5 minutes, 4-tert-butyl-N- {6-chloro-5
-(3-Methoxyphenoxy) pyrimidin-4-yl}
1.5 g of benzenesulfonamide are added and the mixture is reacted under argon atmosphere at 70 ° C. for 2 hours, 100 ° C. for 3 hours and further at 130 ° C. for 2 hours. The reaction solution is treated with 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 was purified by silica gel column chromatography (elution solvent; chloroform: methanol = 70: 1), and recrystallized from ethyl acetate-n-hexane to give 4-tert-butyl-N- {6- (2-
1.14 g of hydroxyethylthio) -5- (3-methoxyphenoxy) pyrimidin-4-yl} benzenesulfonamide are obtained as crystals. m. p. 149.5-150.5 ° C.

(2) 200 mg of this product, 61 mg of 2-chloropyrimidine, sodium hydride (62.3% dispersion type)
A mixture of 47 mg and dimethylacetamide 3 ml is stirred at room temperature overnight. After treatment with ammonium chloride solution,
Extract with ethyl acetate. After washing and drying the ethyl acetate layer,
The solvent is distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (elution solvent; chloroform: methanol =
After purification with 50: 1), it was recrystallized from ethyl acetate-n-hexane to give 4-tert-butyl-N- [5- (3-methoxyphenoxy) -6- {2- (pyrimidin-2-yloxy). 191 mg of ethylthio} pyrimidin-4-yl] benzenesulfonamide are obtained as crystals. m. p. 167.5-168 ° C.

Production Example 124 4-tert-butyl-N- [6- {2- (5- (1-
Ethoxyethenyl) pyrimidin-2-yloxy) ethoxy {-5- (3-methoxyphenoxy) pyrimidine-
4-yl] benzenesulfonamide 1.022 g, 10
A mixture of 1 ml of 1% hydrochloric acid and 20 ml of acetone is reacted at room temperature for 4 hours. The reaction solution is p
After H6, the solvent is distilled off. An aqueous ammonium chloride solution and ethyl acetate are added to the residue, and the ethyl acetate layer is separated. After washing and drying the ethyl acetate layer, the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; ethyl acetate: n-hexane = 1: 1 to ethyl acetate), and recrystallized from ethyl acetate-n-hexane to give N- [6- {2- (5- Acetylpyrimidin-2-yloxy) ethoxy} -5- (3-methoxyphenoxy)
849 mg of pyrimidin-4-yl] -4-tert-butylbenzenesulfonamide are obtained as crystals. m. p. : 142.5-144 ° C.

Production Example 125 N- [6- {2- (5-acetylpyrimidin-2-yloxy) ethoxy} -5- (3-methoxyphenoxy)
Pyrimidin-4-yl] -4-tert-butylbenzenesulfonamide 756 mg, tetrahydrofuran 10
To a mixed solution of 10 ml of isopropyl alcohol and 48 ml of sodium borohydride, 48 mg of sodium borohydride is added under stirring with ice cooling, and the mixture is stirred for 40 minutes under cooling with ice. After that, 14 mg of sodium borohydride is added to the reaction solution, and the mixture is further stirred for 30 minutes. After dilution with water, the mixture is extracted with ethyl acetate, and the ethyl acetate layer is washed, dried, and dried under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; chloroform: methanol = 40: 1 to 20: 1), and then ethyl acetate-n-
Recrystallization from hexane gave 4-tert-butyl-N- [6
-{2- (5- (1-hydroxyethyl) pyrimidine-
571 mg of 2-yloxy) ethoxy} -5- (3-methoxyphenoxy) pyrimidin-4-yl] benzenesulfonamide are obtained as crystals. m. p. : 133-135 ° C.

Production Example 126 The corresponding starting compound was treated in the same manner as in Production Example 125 to give N-.
[6- {2- (5-Methylthiopyrimidin-2-yloxy) ethoxy} -5- (4-hydroxymethylphenyl) pyrimidin-4-yl] -4-tert-butylbenzenesulfonamide is obtained. m. p. : 172-173 ° C.

Production Example 127 N- [6- {2- (4-acetylphenoxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl] -4-tert-butylbenzenesulfonamide was produced. 4-tert-butyl-
N- [6- {2- (4- (1-hydroxyethyl) phenoxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl] benzenesulfonamide is obtained. m. p. 176-178 ° C.

Production Example 128 4-tert-butyl-N- [6- {2- (5- (1-
(Hydroxyethyl) pyrimidin-2-yloxy) ethoxy {-5- (3-methoxyphenoxy) pyrimidine-
4-yl] benzenesulfonamide (150 mg) was added to a methylene chloride (3 ml) solution, and thionyl chloride (90 mg) was added.
React at room temperature for 0.5 hours. The reaction mixture is dried under reduced pressure, 10% palladium-carbon (30 mg), triethylamine (76 mg) and ethanol (3 ml) are added to the residue, and the mixture is stirred at room temperature under a hydrogen (1 atm) atmosphere for 2 hours. Filter off the catalyst,
The filtrate is evaporated to dryness under reduced pressure. After the residue is extracted with ethyl acetate, the ethyl acetate layer is washed and dried, and the solvent is distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (elution solvent;
After purification with chloroform: ethyl acetate = 10: 1), it was recrystallized from ethyl acetate-n-hexane to give 4-tert-butyl-N- [6- {2- (5-ethylpyrimidin-2-yloxy) ethoxy}. -5- (3-Methoxyphenoxy) pyrimidin-4-yl] benzenesulfonamide 1
37 mg are obtained as crystals. m. p. 158.5-159.5 ° C.

Production Example 129 N- [6- {2- (5-Bromopyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl] -4-tert-butylbenzenesulfonamide 0.75 ml of n-butyllithium (1.6Mn-hexane solution) is added to a solution of 300 mg of tetrahydrofuran in 10 ml at -78 ° C. After stirring at -78 ° C for 5 minutes, acetone 58 mg and tetrahydrofuran 1 ml
The solution is added and the mixture is allowed to warm to room temperature. After treatment with an aqueous ammonium chloride solution, the mixture is extracted with ethyl acetate. After washing and drying the ethyl acetate layer, the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; chloroform: ethyl acetate = 2: 1 to 1: 1).
After purification with, recrystallize with ethyl acetate-n-hexane to give 4-
tert-Butyl-N- [6- {2- (5- (1-hydroxy-1-methylethyl) pyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl] benzenesulfone 88 mg of amide are obtained as crystals. m. p. 149.5-150.5 ° C.

Production Example 130 N- [6- {2- (5-bromopyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl] -4-tert-butylbenzenesulfonamide And benzaldehyde were treated in the same manner as in Production Example 129 to give 4-tert-butyl-N- [6- {2-.
(5- (α-hydroxybenzyl) pyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl] benzenesulfonamide is obtained. m. p. 183-185 ° C.

Production Examples 131 to 133 N- [6- {2- (4-bromophenoxy) ethoxy}
-5- (4-methylphenyl) pyrimidin-4-yl]
-4-tert-butylbenzenesulfonamide 600
mg, (1-ethoxyvinyl) tributyltin 680 m
g, bis (triphenylphosphine) palladium (I
I) A mixture of 35.5 mg of chloride and 24 ml of dioxane is heated under reflux for 18 hours. After dilution with ethyl acetate, 10
% Potassium fluoride aqueous solution is added, and the precipitate is filtered off. The filtrate is extracted with ethyl acetate, and the ethyl acetate layer is washed, dried, and dried under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 5:
After purification by 1-3: 1 to 1: 1), the obtained compound was recrystallized from ethyl acetate-diisopropyl ether to give 4-tert-butyl-N- {5- (4-methylphenyl) -6-. (2-phenoxyethoxy) pyrimidine-4
-Yl} benzenesulfonamide [Compound A] 42m
g, N- [6- {2- (4-acetylphenoxy) ethoxy} -5- (4-methylphenyl) pyrimidine-4-
Yl] -4-tert-butylbenzenesulfonamide [Compound B] 242 mg and 4-tert-butyl-N
-[6- {2- (4-ethoxycarbonylphenoxy)
Ethoxy} -5- (4-methylphenyl) pyrimidine-
4-yl] benzenesulfonamide [Compound C] 58m
get g.

[Compound A]: m. p. : 186.5-187.5 ° C [Compound B]: m.p. p. : 205-206.5 ° C [Compound C]: m.p. p. : 199.5-200.5 ° C
.

Production Example 134 4-tert-butyl-N- {5- (4-methylphenyl) -6- {2- (5-nitropyridin-2-yloxy) ethoxy} pyrimidin-4-yl} benzenesulfonamide 200 mg of 10% palladium-carbon is added to 20 ml of a solution of 975 mg of isopropanol-tetrahydrofuran (1: 1), and the mixture is stirred at room temperature for 1.5 hours under a hydrogen atmosphere (1 atm). After removing the catalyst by filtration, the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; chloroform: ethyl acetate = 2: 1),
Recrystallized from ethyl acetate-n-hexane to give N- [6- {2
-(5-Aminopyridin-2-yloxy) ethoxy}
-5- (4-methylphenyl) pyrimidin-4-yl}
-4-tert-butylbenzenesulfonamide 829
mg is obtained as crystals. m. p. : 165-167 ° C (decomposition).

Production Example 135 N- [6- {2- (5-aminopyridin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl} -4-tert-butylbenzenesulfonamide A solution of benzoyl chloride (43 mg) in methylene chloride (0.4 ml) was added to pyridine (2 mg) solution (150 mg), and the mixture was stirred at room temperature for 2 hours. After washing and drying the ethyl acetate layer, the solvent is distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to give N- (6- [2- {6- (4-te
rt-butylphenylsulfonylamino) -5- (4-
161 mg of methylphenyl) pyrimidin-4-yloxy} ethoxy] pyridin-3-yl) benzamide are obtained as crystals. m. p. : 173-174.5 ° C.

Production Example 136 N- [6- {2- (5-aminopyridin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl} -4-tert-butylbenzenesulfonamide And acetic anhydride were treated in the same manner as in Production Example 135 to give N- (6- [2- {6- (4-tert-butylphenylsulfonylamino) -5- (4-methylphenyl) pyrimidin-4-yloxy} ethoxy. ] Pyridine-3-
Il) to obtain acetamide. m. p. 175-176 ° C.

Production Example 137 N- [6- {2- (5-aminopyridin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl} -4-tert-butylbenzenesulfonamide And pivaloyl chloride were treated in the same manner as in Production Example 135 to give N- (6- [2- {6- (4-tert-butylphenylsulfonylamino) -5- (4-methylphenyl) pyrimidin-4-yloxy. } Ethoxy] pyridin-3-yl) pivalamide is obtained. m. p. : 140-141 ° C.

Production Example 138 4-tert-butyl-N- {6- [2- (4-benzyloxyphenoxy) ethoxy] -5- (4-methylphenyl) pyrimidin-4-yl} benzenesulfonamide 3.95 g 1.5% of 10% palladium-carbon and ethanol-tetrahydrofuran (80 ml-80 ml)
Under a hydrogen atmosphere (1 atm) at room temperature for 24 hours. After filtering off the catalyst, the filtrate is concentrated. The residue was crystallized from ethyl acetate-diisopropyl ether to give 4-tert-butyl-N- {6- [2- (4-hydroxyphenoxy) ethoxy] -5- (4-methylphenyl) pyrimidin-4-yl} benzene. 3.31 g of sulfonamide are obtained. m. p. : 161.5-163 ° C IR (nujol, cm ^-1 ): 3260, 1590, ¹
570 FABMS (m / z): 556 ((M + Na) ⁺ ), 5
34 (MH ^<+> ).

Preparative Example 139 The compound obtained in Preparative Example 62 was treated in the same manner as in Preparative Example 138 to give 4-tert-butyl-N- {6-
[2- (5-hydroxypyrimidin-2-yloxy)
Ethoxy] -5- (4-methylphenyl) pyrimidine-
This gives 4-yl @ benzenesulfonamide. m. p. 186.5-188 ° C.

Production Example 140 4-tert-butyl-N- {5- (4-methylphenyl) -6- [2- (4-nitrophenoxy) ethoxy]
Pyrimidin-4-yl @ benzenesulfonamide 383
mg, 10% palladium-carbon 50 mg and a mixture of ethanol-tetrahydrofuran (6 ml-3 ml) are subjected to a catalytic reduction under a hydrogen atmosphere (1 atm) at room temperature for 2 hours.
After filtering off the catalyst, the filtrate is concentrated. The residue was subjected to silica gel column chromatography (elution solvent: chloroform:
After purification with ethyl acetate = 10: 1, recrystallization with ethyl acetate-diisopropyl ether gave N- {6- [2-
(4-Aminophenoxy) ethoxy] -5- (4-methylphenyl) pyrimidin-4-yl} -4-tert-
358 mg of butylbenzenesulfonamide are obtained. m. p. : 190-191 ° C IR (nujol, cm ^-1 ): 3440, 3360, 3
260,1740,1630,1610 FABMS (m / z): 533 (MH ^<+> ).

Production Example 141 N- {6- [2- (4-aminophenoxy) ethoxy]
-5- (4-methylphenyl) pyrimidin-4-yl}
-4-tert-butylbenzenesulfonamide 100
38 mg of formic acid in 2 ml of tetrahydrofuran solution
And 0.05 ml of 35% aqueous formaldehyde solution are added, and the mixture is stirred at 50 ° C. for 3 hours. The reaction solution is poured into ice water, neutralized with a saturated aqueous solution of sodium hydrogen carbonate, 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), crystallized from ethyl acetate-diisopropyl ether, and 4-tert-butyl-N- {6- [2- (4-
67 mg of dimethylaminophenoxy) ethoxy] -5- (4-methylphenyl) pyrimidin-4-yl} benzenesulfonamide are obtained. m. p. : 142-145 ° C IR (nujol, cm ^-1 ): 3260, 1590, ¹
570 FABMS (m / z): 561 (MH ^<+> ).

Production Example 142 4-tert-butyl-N- {6- [2- (4-cyanophenoxy) ethoxy] -5- (4-methylphenyl)
Pyrimidin-4-yl @ benzenesulfonamide 1.3
1 g, tributyltin azide 1.60 g and toluene 1
3 ml of the mixture is heated to reflux for 24 hours under an argon atmosphere. After cooling, ethyl acetate and a 10% aqueous potassium fluoride solution are added to the reaction solution. The insoluble material is removed by filtration, and the ethyl acetate layer is dried under reduced pressure. A 10% aqueous sodium hydroxide solution and diethyl ether are added, and the mixture is stirred at room temperature for 20 minutes. The aqueous layer is washed with diethyl ether, acidified with 10% hydrochloric acid under ice cooling, and extracted with ethyl acetate. The ethyl acetate layer was washed and dried, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent; chloroform only to chloroform: methanol = 20: 1), crystallized with ethyl acetate, and 4-tert-. Butyl-N- {5- (4
1.26 g of -methylphenyl) 6- [2- (4- (5-tetrazolyl) phenoxy) ethoxy] pyrimidin-4-yl} benzenesulfonamide are obtained. m. p. : 165-166 ° C IR (nujol, cm ^-1 ): 3260, 1620, ¹
580 FABMS (m / z): 586 (MH ^<+> ).

Production Example 143 4-tert-butyl-N- {6- [2- (4-hydroxyphenoxy) ethoxy] -5- (4-methylphenyl) pyrimidin-4-yl} benzenesulfonamide 2
To a solution of 00 mg in 2 ml of dimethylformamide was added 32 mg of sodium hydride (60% dispersion type),
Stir for 0 minutes. Then, tert-butyl bromoacetic acid 7
A solution of 7 mg of dimethylformamide in 2 ml is added under ice cooling, and the mixture is stirred at the same temperature for 1 hour. The reaction solution is poured into ice water, treated with a saturated aqueous solution of 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; hexane: ethyl acetate = 3: 1) and then crystallized from ethyl acetate-diisopropyl ether to give 4- {2.
-[6- (4-Tert-butylbenzenesulfonylamino) -5- (4-methylphenyl) pyrimidine-4-
225 mg of iloxy] ethoxy} phenoxyacetic acid tert-butyl ester are obtained. m. p. 129.5-130.5 ° C IR (nujol, cm ^-1 ): 3280, 1765, ¹
590,1570 FABMS (m / z): 648 (MH ^<+> ).

Production Example 144 4- {2- [6- (4-tert-butylbenzenesulfonylamino) -5- (4-methylphenyl) pyrimidin-4-yloxy] ethoxy} phenoxyacetic acid ter
t-butyl ester 1.25 g dichloromethane 120
2.09 g of anisole and 20 ml of trifluoroacetic acid are added to the ml solution under ice cooling. After stirring at room temperature for 5 hours, the reaction solution is washed with water and extracted with a 10% aqueous sodium hydroxide solution. After washing the aqueous layer with chloroform, under ice cooling, 10
Acidify with% hydrochloric acid. It was extracted with ethyl acetate, the ethyl acetate layer was washed and dried, and then the solvent was distilled off.
Crystallization with diisopropyl ether gave 4- {2- [6
-(4-tert-butylbenzenesulfonylamino)
1.14 g of -5- (4-methylphenyl) pyrimidin-4-yloxy] ethoxy} phenoxyacetic acid are obtained. m. p. : 183-14.5 ° C IR (nujol, cm ^-1 ): 3260, 3240, ¹
760, 1740, 1710, 1580, 1565 FABMS (m / z): 592 (MH ^<+> ).

Production Example 145 4-tert-butyl-N- {6- [2- (4- (1-
Hydroxyethyl) phenoxy) ethoxy] -5- (4
-Methylphenyl) pyrimidin-4-yl｝ benzenesulfonamide (85 mg) in dichloromethane (3 ml),
Add 54 mg of thionyl chloride and stir for 1 hour. The reaction solution is evaporated to dryness under reduced pressure, the residue is dissolved in ethanol-tetrahydrofuran (6 ml-2 ml), 45 mg of triethylamine is added at room temperature, and the mixture is stirred for 3 hours. Evaporate the solvent,
The residue is dissolved in ethyl acetate, washed, dried and the solvent is distilled off. The residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 3: 1),
Recrystallize from ethyl acetate-diisopropyl ether to give 4
61 mg of -tert-butyl-N- {6- [2- (4- (1-ethoxyethyl) phenoxy) ethoxy] -5- (4-methylphenyl) pyrimidin-4-yl} benzenesulfonamide are obtained. m. p. 139-140 ° C IR (nujol, cm ^-1 ): 3270, 1610, ¹
590,1570 FABMS (m / z): 590 (MH ^<+> ).

Production Example 146 N- [6- {2- (5-Bromopyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl] -4-tert-butylbenzenesulfonamide To a solution of 700 mg of tetrahydrofuran in 15 ml, 1.46 ml of n-butyllithium (1.6Mn-hexane solution) was added dropwise at -78 ° C. 15 at -78 ° C
After stirring for minutes, 0.28 ml of dimethylformamide is added, and the mixture is reacted at the same temperature for 15 minutes. After treatment with an aqueous ammonium chloride solution, the mixture is acidified with 10% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed, dried and purified by silica gel column chromatography (eluting solvent: chloroform: ethyl acetate = 100: 1 to 30: 1), then recrystallized from diisopropyl ether to give 4-tert-butyl-N-.
198 mg of [6- {2- (5-formylpyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl] benzenesulfonamide are obtained as crystals. m. p. 191-193 [deg.] C. FABMS (m / z): 548 (MH ^<+> ).

Production Example 147 4-tert-butyl-N- [6- {2- (5-formylpyrimidin-2-yloxy) ethoxy} -5- (4
-Methylphenyl) pyrimidin-4-yl] benzenesulfonamide (143 mg) in tetrahydrofuran-isopropanol (4 ml-4 ml) solution was added with ice-cooling 13 mg of sodium borohydride and reacted for 2 hours.
Treat with aqueous ammonium chloride and extract with ethyl acetate. After washing and drying the ethyl acetate layer, the solvent is distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (elution solvent; chloroform: methanol = 200: 1 to 50:
After purification in 1), crystallize with diethyl ether to give 4
-Tert-butyl-N- [6- {2- (5-hydroxymethylpyrimidin-2-yloxy) ethoxy} -5
96 mg of-(4-methylphenyl) pyrimidin-4-yl] benzenesulfonamide are obtained. m. p. 172-173 [deg.] C. FABMS (m / z): 550 (MH ^<+> ).

Production Example 148 Sodium hydride (0.25 g) in tetrahydrofuran (5 m)
1 suspension was added with 4-tert-butyl-N- [6- (2-
(Hydroxyethoxy) -5- (4-methylphenyl)-
2-n-propylpyrimidin-4-yl] benzenesulfonamide (1.00 g) in dimethylacetamide (3 ml) and tetrahydrofuran (10 ml) was added dropwise at room temperature.
Add 0.56 g of -chloro-5-bromopyrimidine and stir at room temperature for 2.5 hours. The reaction mixture is acidified by adding ice-cooled diluted hydrochloric acid, extracted with ethyl acetate, washed, dried, and the solvent is distilled off. The obtained oily substance was purified by silica gel column chromatography (eluting solvent: chloroform), and further crystallized from n-hexane to give 4-tert-.
Butyl-N- [6- {2- (5-bromopyrimidine-2
1.21 g of -yloxy) ethoxy} -5- (4-methylphenyl) -2-n-propylpyrimidin-4-yl] benzenesulfonamide are obtained as crystals. m. p. : 184-186 ° C.

Production Examples 149 to 189 The corresponding starting material compounds are treated in the same manner as in Production Example 148 to obtain the compounds shown in Tables 25 to 33 below.

[0240]

[Table 25]

[0241]

[Table 26]

[0242]

[Table 27]

[0243]

[Table 28]

[0244]

[Table 29]

[0245]

[Table 30]

[0246]

[Table 31]

[0247]

[Table 32]

[0248]

[Table 33]

Production Example 190 4-tert-butyl-N- [6- {2- (5-bromopyrimidin-2-yloxy) ethoxy} -5- (4-
Methylphenyl) -2-n-propylpyrimidine-4-
A mixture of 300 mg of [yl] benzenesulfonamide, 670 mg of 2-thienyltributyltin, 16 mg of bis (triphenylphosphine) palladium (II) chloride and 5 ml of dioxane is heated under reflux for 80 minutes. After cooling, the reaction solution is diluted with ethyl acetate, a 10% aqueous potassium fluoride solution is added, and the mixture is stirred at room temperature for 1 hour. After washing and drying the reaction solution, the solvent is distilled off, and the residue is purified by silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 30: 1 to 10: 1). Further, it was crystallized with a mixed solution of methylene chloride-n-hexane to give 4-tert-
Butyl-N- [6- {2- (5- (2-thienyl) pyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) -2-n-propylpyrimidin-4-yl] benzenesulfonamide 209 mg are obtained as crystals. m. p. : 165 to 166 ° C.

Production Example 191 The product of Production Example 150 and 2-pyridyltributyltin were treated in the same manner as in Production Example 190 to give 4-tert-butyl-N- [6- {2- (5- (2-pyridyl ) -Pyrimidin-2-yloxy) ethoxy} -5- (2-methoxyphenoxy) -2- (2-pyrimidyl) pyrimidine-
4-yl] benzenesulfonamide is obtained. m. p. 149-157 ° C.

Production Example 192 (1) N- [6-chloro-2- (2-pyrimidyl) -5
-(2-methoxyphenoxy) pyrimidin-4-yl}
-4-tert-butylbenzenesulfonamide 1.0
5 g and 2- (4-acetylphenoxy) ethanol 7
To 12 ml of a 28 mg dimethylacetamide solution is added 240 mg of sodium hydride under ice cooling, and the mixture is stirred at room temperature overnight. The reaction solution is acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed and dried, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (elution solvent;
After purification with chloroform: acetonitrile = 2: 1), it was recrystallized from a mixed solution of ethyl acetate-n-hexane to give N-.
[6- {2- (4-acetylphenoxy) ethoxy}-
482 mg of 2- (2-pyrimidyl) -5- (2-methoxyphenoxy) pyrimidin-4-yl} -4-tert-butylbenzenesulfonamide are obtained as crystals. m. p. 169-172 ° C.

(2) To a mixture of 197 mg of this product, 2 ml of isopropyl alcohol and 2 ml of tetrahydrofuran was added 26 mg of sodium borohydride under ice cooling, and the mixture was stirred at the same temperature for 2 hours. After the reaction, the solvent is distilled off, the residue is acidified with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed and dried, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent; chloroform: acetonitrile = 1: 1), and then ethyl acetate-
Recrystallization from a mixed solution of n-hexane and N- [6- {2- (4
-(1-hydroxyethyl) phenoxy) ethoxy}-
85 mg of 2- (2-pyrimidyl) -5- (2-methoxyphenoxy) pyrimidin-4-yl} -4-tert-butylbenzenesulfonamide are obtained as crystals. m. p. : 191-194 ° C.

Production Example 193 N- [6-chloro-2- (2-pyrimidyl) -5- (2
-Methoxyphenoxy) pyrimidin-4-yl {-4-
tert-butylbenzenesulfonamide and 2- (4-
Bromophenoxy) ethanol and Production Example 192-
The same treatment as in (1) was carried out to give N- [6- {2- (4-bromophenoxy) ethoxy} -2- (2-pyrimidyl) -5.
-(2-methoxyphenoxy) pyrimidin-4-yl}
-4-tert-Butylbenzenesulfonamide is obtained. m. p. : 251-256 ° C.

Production Example 194 4-tert-butyl-N- [6- {2- (5-methylthiopyrimidin-2-yloxy) ethoxy} -5-
To a solution of 1.0 g of (4-methylphenyl) pyrimidin-4-yl] benzenesulfonamide sodium salt in 10 ml of chloroform, 412 mg of 3-chloroperbenzoic acid was added at 0 ° C, and the mixture was added at the same temperature for 1 hour and then at room temperature overnight. Stir. The reaction solution is diluted with a saturated sodium hydrogen carbonate solution and extracted with chloroform. After washing and drying the extract, the solvent is distilled off and concentrated. The residue was subjected to silica gel column chromatography (elution solvent; chloroform: ethyl acetate = 2: 1).
~ 1: 1), the obtained compound was recrystallized from a mixed solution of ethyl acetate-n-hexane to give 4-tert-.
91 mg of butyl-N- [6- {2- (5-methylsulfonylpyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl] benzenesulfonamide [Compound A] as colorless crystals. , Further 4-tert-butyl-N- [6- {2- (5-methylsulfinylpyrimidin-2-yloxy) ethoxy}
-5- (4-methylphenyl) pyrimidin-4-yl]
601 mg of benzenesulfonamide [Compound B] is obtained as colorless crystals. [Compound A] m. p. : 170-172 ° C. [Compound B] m.p. p. : 206.5-208 ° C.

Production Example 195 (1) 4-tert-butyl-N- [6- {2- (5-
Methylsulfinylpyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-
Yl] benzenesulfonamide (471 mg), a mixture of trifluoroacetic anhydride (5 ml) and methylene chloride (5 ml),
Heat to reflux for 0 minutes and evaporate the solvent. After dissolving the residue in a mixed solution of methanol and triethylamine (1: 1), the solvent is distilled off. The residue was dissolved in chloroform, washed and dried, and the solvent was concentrated to give 4-tert-butyl-N- [6- {2-
529 mg of (5-mercaptopyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl] benzenesulfonamide are obtained as a pale yellow foam.

(2) 200 mg of this product, 10 potassium carbonate
A mixture of 0 mg, ethyl iodide 97 mg and dimethylformamide 4 ml is stirred at room temperature for 2 hours under an argon atmosphere. The reaction solution is diluted with 10% hydrochloric acid and then extracted with ethyl acetate. The extract is washed, dried and concentrated. The residue was subjected to column chromatography (elution solvent; chloroform:
After purification with ethyl acetate = 15: 1), the obtained compound was recrystallized from a mixed solution of ethyl acetate-n-hexane to give 4-ter.
90 mg of t-butyl-N- [6- {2- (5-ethylthiopyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl] benzenesulfonamide as colorless crystals. m. p. 177-178 ° C.

Production Example 196 The corresponding starting compound was treated in the same manner as in Production Example 195 (1) and (2) to give N- [6- {2- (5-isopropylthiopyrimidin-2-yloxy) ethoxy} -5-. (4-Methylphenyl) pyrimidin-4-yl} -4-tert
-To obtain butylbenzenesulfonamide. m. p. : 161.5-162.5 ° C.

Production Example 197 4-tert-butyl-N- [6- {2- (5-bromopyrimidin-2-yloxy) ethoxy} -5- (4-
Methylphenyl) pyrimidin-4-yl] benzenesulfonamide 1.0 g, zinc cyanide 784 mg, tetrakis (triphenylphosphine) palladium (0) 25
0 mg and 1,3-dimethyl-2-imidazolidinone 4
After stirring 0 ml of the mixture under an argon atmosphere at 80 ° C. for 6 hours, it is cooled to room temperature. The reaction solution is diluted with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. After washing and drying the extract, the solvent is distilled off and concentrated. The residue was subjected to silica gel column chromatography (elution solvent; chloroform:
After purification with ethyl acetate = 10: 1), the obtained compound was recrystallized from a tetrahydrofuran-ethyl acetate mixed solution to give 4-
590 mg of tert-butyl-N- [6- {2- (5-cyanopyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl] benzenesulfonamide are obtained as colorless crystals. m. p. : 196-197 ° C.

Production Example 198 4-tert-butyl-N- [6- {2- (5-bromopyrimidin-2-yloxy) ethoxy} -5- (4-
Methylphenyl) pyrimidin-4-yl] benzenesulfonamide 1.0 g, trimethylsilylacetylene 33
0 mg, bis (triphenylphosphine) palladium (II) chloride 58 mg, copper iodide 32 mg, triethylamine 420 mg and dimethylformamide 5 ml
After stirring the mixture of under an argon atmosphere at 50 ° C. for 3 hours,
Cool to room temperature. The reaction solution is diluted with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. After washing and drying the extract, the solvent is distilled off and concentrated. The residue was purified by silica gel column chromatography (elution solvent; chloroform: ethyl acetate = 40: 1), and the obtained compound was recrystallized from a mixed solution of ethyl acetate-n-hexane to give 4-tert-butyl-N- [6. -{2- (5-trimethylsilylethynylpyrimidin-2-yloxy) ethoxy} -5- (4
837 mg of -methylphenyl) pyrimidin-4-yl] benzenesulfonamide are obtained as colorless crystals. m. p. : 200-202 ° C.

Production Example 199 The corresponding starting compound was treated in the same manner as in Production Example 198 to give 4-t.
tert-butyl-N- [6- {2- (5- (3-hydroxy-3-methyl-1-butynyl) pyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl To obtain benzenesulfonamide. m. p. : 172.5-173.5 ° C.

Production Example 200 4-tert-butyl-N- [6- {2- (5-trimethylsilylethynylpyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidine-4-
A mixture of 667 mg of benzenesulfonamide, 299 mg of potassium carbonate and 13 ml of methanol was stirred at 0 ° C. for 2 hours and diluted with a saturated aqueous solution of ammonium chloride.
Extract with ethyl acetate. After washing and drying the extract, the solvent is distilled off and concentrated. The residue was subjected to silica gel column chromatography (elution solvent; chloroform: ethyl acetate = 30:
After purification in 1), the obtained compound was recrystallized from a mixed solution of methylene chloride and ethyl acetate to give 4-tert-butyl-N-.
502 mg of [6- {2- (5-ethynylpyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl] benzenesulfonamide are obtained as colorless crystals. m. p. : 207-210 ° C.

Production Example 201 4-tert-butyl-N- [6- {2- (5-methylthiopyrimidin-2-yloxy) ethoxy} -5-
(4-Diethoxymethylphenyl) pyrimidin-4-yl] benzenesulfonamide 558 mg, p-toluenesulfonic acid monohydrate 50 mg, tetrahydrofuran 1
After stirring a mixture of 8 mg and 6 ml of water at room temperature for 1 hour,
The tetrahydrofuran is distilled off. After the residue is diluted with ethyl acetate, the ethyl acetate layer is washed, dried, evaporated, and concentrated. The residue was purified by silica gel column chromatography (elution solvent; chloroform: ethyl acetate = 2: 1), and the obtained compound was recrystallized from a mixed solution of methylene chloride and ethyl acetate to give 4-tert-butyl-N- [6- {2-
(5-Methylthiopyrimiridin-2-yloxy) ethoxy} -5- (4-formylphenyl) pyrimidine-4
-Yl] benzenesulfonamide (345 mg) is obtained as colorless crystals. m. p. : 223-224 ° C.

Production Example 202 4-tert-butyl-N- [6- {2- (5-methylthiopyrimidin-2-yloxy) ethoxy} -5-
A mixture of (4-formylphenyl) pyrimidin-4-yl] benzenesulfonamide 269 mg, (carboethoxyethylidene) triphenylphosphorane 242 mg and chloroform 5 ml was stirred at room temperature for 4 hours, diluted with chloroform, washed, dried and then used as a solvent. Is distilled off and concentrated.
The residue was purified by silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 1: 1), and the obtained compound was recrystallized from a mixed solution of ethyl acetate-n-hexane (E) -3- [4 -{4- (4-Tert-butylphenylsulfonylamino) -6- {2- (5-methylthiopyrimidin-2-yloxy) ethoxy} pyrimidin-5-yl] phenylacrylic acid ethyl ester 2
61 mg are obtained as colorless crystals.

M. p. : 172-173 ° C.

Production Example 203 (E) -3- [4- {4- (4-tert-butylphenylsulfonylamino) -6- {2- (5-methylthiopyrimidin-2-yloxy) ethoxy} pyrimidine-
5-yl] phenylacrylic acid ethyl ester 182m
g of a 1N aqueous sodium hydroxide solution, 0.56 ml of tetrahydrofuran and 1 ml of water at room temperature for 30 minutes.
After stirring for an hour, dilute with chloroform and acidify with 10% hydrochloric acid. The mixture is extracted with chloroform, the extract is washed and dried, the solvent is distilled off and the mixture is concentrated. The residue was purified by column chromatography (elution solvent; chloroform: methanol = 10: 1), and the obtained compound was diluted with ethyl acetate.
Recrystallization from an n-hexane mixed solution gave (E) -3- [4-
31 mg of {4- (4-tert-butylphenylsulfonylamino) -6- {2- (5-methylthiopyrimidin-2-yloxy) ethoxy} pyrimidin-5-yl] phenylacrylic acid are obtained as colorless crystals. m. p. 196-204 ° C.

Production Example 204 The corresponding starting material compound was treated in the same manner as in Production Example 203 and 4-
{4- (4-tert-Butylphenylsulfonylamino) -6- {2- (5-methylthiopyrimidin-2-yloxy) ethoxy} pyrimidin-5-yl] benzoic acid is obtained. m. p. : 226-227 ° C.

Production Examples 205 and 206 4-tert-butyl-N- [6- {2- (5-bromopyrimimidin-2-yloxy) ethoxy} -5- (2
To a solution of 464 mg of -methoxyphenylthio) pyrimidin-4-yl] benzenesulfonamide in 9 ml of chloroform is added 217 mg of 3-chloroperbenzoic acid at 0 ° C, and the mixture is stirred at the same temperature for 2 hours. Dilute the reaction with saturated aqueous sodium bicarbonate and extract with chloroform. After washing and drying the extract, the solvent is distilled off and concentrated. The residue was purified by column chromatography (elution solvent; chloroform: ethyl acetate = 10: 1), and the compound obtained from the first eluted fraction was recrystallized from a methylene chloride-ethyl acetate mixed solution to give 4-tert-butyl-N. -[6-
{2- (5-Bromopyrimidin-2-yloxy) ethoxy} -5- (2-methoxyphenylsulfonyl) pyrimidin-4-yl] benzenesulfonamide 197m
g are obtained as colorless crystals. m. p. : 208-210 ° C.

The compound obtained from the fraction eluted next to the above fraction was recrystallized from a mixed solution of ethyl acetate-n-hexane to give 4-tert-butyl-N- [6- (2- (5-bromopyrimimidine- 2-yloxy) ethoxy} -5- (2
167 mg of -methoxyphenylsulfinyl) pyrimidin-4-yl] benzenesulfonamide are obtained as colorless crystals. m. p. : 163-164.5 ° C.

Production Example 207 Sodium hydride (60% dispersion type) 65 mg dimethylacetamide 0.5 ml-tetrahydrofuran 0.5 m
4- (2-hydroxy-1,1-
A suspension of 135 mg of dimethylethyl) -N- {6- (2-hydroxyethoxy} -5- (4-methylphenyl) pyrimidin-4-yl} benzenesulfonamide was added to a solution of 2 ml of dimethylacetamide-2 ml of tetrahydrofuran over 5 minutes. Then, 399 mg of 5-bromo-2-chloropyrimidine is added thereto, and the mixture is stirred at room temperature for 6 days. The reaction solution is acidified by adding ice-dilute hydrochloric acid and extracted with ethyl acetate. The residue was purified by silica gel column chromatography (elution solvent; chloroform: ethyl acetate = 100: 1), and the obtained compound was recrystallized from a methylene chloride-isopropyl ether mixed solution to give 4- {2- ( 5-Bromopyrimidin-2-yloxy) -1,1-dimethylethyl} -N- [6-
{2- (5-Bromopyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-
77 mg of [yl] benzenesulfonamide are obtained as colorless crystals. m. p. 156-158 ° C.

Production Example 208 4-tert-Butyl-N- [6- {2- (5-hydroxypyrimidin-2-yloxy) ethoxy} -5-
(4-methylphenyl) pyrimidin-4-yl @ benzenesulfonamide 200 mg of dimethylformamide 4
154 mg of calcium carbonate and 5-bromo-
Add 216 mg of 2-chloropyrimidine and stir at 50 ° C. for 2 hours. The reaction solution is acidified by adding ice-dilute hydrochloric acid, and extracted with ethyl acetate. After the extract is washed and dried, the solvent is distilled off. The residue was purified by silica gel column chromatography (elution solvent; chloroform: ethyl acetate = 50: 1), and the obtained compound was recrystallized from a mixed solution of methylene chloride-isopropyl ether to give 4-tert-butyl-N-.
[6- {2- (5- (5-bromopyrimidin-2-yloxy) pyrimidin-2-yloxy) ethoxy} -5
238 mg of-(4-methylphenyl) pyrimidin-4-yl} benzenesulfonamide are obtained as colorless needles. m. p. 183-184 ° C.

Production Examples 209-213 The corresponding starting material compounds were treated in the same manner as in Production Example 208 to obtain the compounds shown in Table 34 below.

[0272]

[Table 34]

Production Example 214 4-tert-butyl-N- [6- {2- (5- (α-
Styryl) pyrimidin-2-yloxy) ethoxy｝-
5- (4-methylphenyl) pyrimidin-4-yl {benzenesulfonamide 130 mg, 10% palladium-
A mixture of 42 mg of carbon, 1 ml of ethanol and 10 ml of triethylamine was added at room temperature under a hydrogen atmosphere (1 atm).
Stir for hours. After removing the catalyst by filtration, the filtrate is dried under reduced pressure. The residue was purified by column chromatography (eluting solvent; chloroform: ethyl acetate = 15: 1), and the obtained compound was recrystallized from a mixed solution of ethyl acetate-isopropyl ether to give 4-tert-butyl-N- [6- {. 2- (5- (α
111 mg of -phenethyl) pyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl] benzenesulfonamide are obtained as colorless needles. m. p. 158.5-160.5 ° C.

Production Example 215 4-tert-butyl-N- {2-trifluoromethyl-6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) pyrimidin-4-yl} benzenesulfonamide and 2- Chloro-5-bromopyrimidine was treated as in Preparation 148 to give 4-tert-butyl-N-.
[6- {2- (5-Bromopyrimidin-2-yloxy) ethoxy} -5- (2-methoxyphenoxy) -2
-Trifluoromethylpyrimidin-4-yl] benzenesulfonamide is obtained. m. p. : 51-56 ° C.

Production Example 216 4-tert-butyl-N- {2-trifluoromethyl-6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) pyrimidin-4-yl} benzenesulfonamide and 2- Chloro-5- (2-thienyl) pyrimidine was treated as in Preparation 148 to give 4-tert-butyl-N- [6- {2- (5- (2-thienyl) pyrimidin-2-yloxy) ethoxy}. -5- (2-methoxyphenoxy) -2-trifluoromethylpyrimidine-
4-yl] benzenesulfonamide is obtained. m. p. : 65-72 ° C.

Production Example 217 4-tert-butyl-N- {2-trifluoromethyl-6- (2-hydroxyethoxy) -5- (4-methylphenyl) pyrimidin-4-yl} benzenesulfonamide and 2- Production Example 1 of chloro-5-bromopyrimidine
Treated in the same manner as 48, 4-tert-butyl-N- [6
-{2- (5-Bromopyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) -2-trifluoromethylpyrimidin-4-yl] benzenesulfonamide is obtained. m. p. : 182-183 ° C.

Production Example 218 4-tert-butyl-N- {2-trifluoromethyl-6- (2-hydroxyethoxy) -5- (4-methylphenyl) pyrimidin-4-yl} benzenesulfonamide and 2- Chloro-5- (2-thienyl) pyrimidine was treated as in Preparation 148 to give 4-tert-butyl-N- [6- {2- (5- (2-thienyl) pyrimidin-2-yloxy) ethoxy}. -5- (4-Methylphenyl) -2-trifluoromethylpyrimidin-4-yl] benzenesulfonamide is obtained. m. p. : 163-166 ° C.

Production Example 219 N- {5-bromo-6- (2-hydroxyethoxy) pyrimidin-4-yl} -4-tert-butylbenzenesulfonamide and phenyltributyltin were produced in Production Example 8
4-tert-butyl-N- {6-
(2-Hydroxyethoxy) -5-phenylpyrimidin-4-yl} benzenesulfonamide is obtained. Further obtained 4-tert-butyl-N- {5-phenyl-6
-(2-Hydroxyethoxy) pyrimidin-4-yl}
Benzenesulfonamide and 5-bromo-2-chloropyrimidine were treated as in Preparation 21 to give 4-tert-.
Butyl-N- [6- {2- (5-bromopyrimidine-2
-Yloxy) ethoxy} -5-phenylpyrimidine-
4-yl] benzenesulfonamide is obtained. m. p. : 163-165 ° C.

Production Example 220 4-tert-butyl-N- {6- (2- (5-formylpyrimidin-2-yloxy) ethoxy) -5- (4
135 mg of sodium acetate and 137 mg of methoxyamine hydrochloride are added to a mixed solution of -methylphenyl) pyrimidin-4-yl} benzenesulfonamide in ethanol (7 ml) -tetrahydrofuran (5 ml), and the mixture is stirred at room temperature for 5 hours. The reaction solution is diluted with water and then extracted with ethyl acetate. After washing and drying the ethyl acetate layer, the solvent is distilled off under reduced pressure. The residue is chloroform-isopropyl ether-n-
Recrystallization from hexane gave 4-tert-butyl-N- [6
-{2- (5- (methoxyiminomethyl) pyrimidine-
2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl] benzenesulfonamide 2
89 mg are obtained as colorless crystals. m. p. : 163-169 ° C.

Production Example 221 4-tert-butyl-N- {6- (2- (5-formylpyrimidin-2-yloxy) ethoxy) -5- (4
-Methylphenyl) pyrimidin-4-yl} benzenesulfonamide and hydroxylamine hydrochloride were treated in the same manner as in Preparation Example 220 to give 4-tert-butyl-N-.
[6- {2- (5- (hydroxyiminomethyl) pyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl] benzenesulfonamide is obtained. m. p. : 218-224 ° C.

Production Example 222 4-tert-butyl-N- [6- {2- (5-hydroxypyrimidin-2-yloxy) ethoxy} -5-
(4-Methylphenyl) pyrimidin-4-yl] benzenesulfonamide and N, N-dimethylcarbamoyl chloride were treated as in Preparation 208 to give 4-tert-.
Butyl-N- [6- {2- (5- (N, N-dimethylcarbamoyloxy) pyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidine-4-
Ill] benzenesulfonamide is obtained. m. p. : 161-162 ° C.

Production Example 223 4-tert-butyl-N- [6- {2- (5-hydroxypyrimidin-2-yloxy) ethoxy} -5-
(4-Methylphenyl) pyrimidin-4-yl] benzenesulfonamide and 1-chloroisoquinoline were treated as in Preparation 208 to give 4-tert-butyl-N-.
[6- {2- (5- (1-isoquinolyloxy) pyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl] benzenesulfonamide is obtained. m. p. 179-182 ° C.

Reference Example 1 To 7 ml of 1,3-propanediol was added 312 mg of sodium hydride (60% dispersion type), and further 4-ter.
707 mg of t-butyl-N- {6-chloro-5- (3-methoxyphenoxy) pyrimidin-4-yl} benzenesulfonamide are added. The reaction solution is reacted at 90 ° C for 2 hours and further at 130 ° C for 1 hour. After that, the reaction solution was
Acidify with hydrochloric acid, extract with ethyl acetate, wash the ethyl acetate layer, dry, and dry under reduced pressure. Purify the residue by silica gel column chromatography (eluting solvent; chloroform: ethyl acetate = 10: 1), then add acetic acid. Crystallized from ethyl-diisopropyl ether to give 4-tert-butyl-N-
{6- (3-hydroxypropyloxy) -5- (3-
315 mg of methoxyphenoxy) pyrimidin-4-yl} benzenesulfonamide are obtained as crystals. m. p. : 113-114 ° C.

Reference Examples 2 to 12 The corresponding compounds are treated in the same manner as in Reference Example 1 to obtain the compounds shown in Tables 35 and 36 below.

[0285]

[Table 35]

[0286]

[Table 36]

Reference Example 13 (1) To a mixed solution of 400 ml of tetrahydrofuran and 60 ml of ethylene glycol was added 3.38 g of sodium hydride (60% dispersion type) under stirring with ice cooling, and then 4,6-
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 75-80 ° 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-yloxy} ethanol are obtained. m. p. : 83.5-85 [deg.] C MS (m / z): 271 (M ^<+> ).

(3) 2- {6-Azido-5- (4-methylphenyl) pyrimidin-4-yloxy} ethanol 19.6 g, 10% palladium-carbon (50% water content)
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 14 (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 and at 90 ° C. for 5 hours.
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 15 2- {6-amino-5- (4-methylphenyl) pyrimidin-4-yloxy} ethanol 7.54 g in a tetrahydrofuran 150 ml solution was added with 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 16 (1) 1.33 g of 4,6-dichloropyrimidine and 4-
To a solution of 1.96 g of tert-butylbenzenesulfonamide in 20 ml of dimethyl sulfoxide is added 714 mg of sodium hydride (60% dispersion type). After stirring at room temperature for 2 hours, the reaction solution is diluted with 10% hydrochloric acid and water, and extracted with ethyl acetate. The ethyl acetate layer was washed and dried, and the solvent was distilled off. The residue was recrystallized from ethyl acetate to obtain 2.02 g of 4-tert-butyl-N- (6-chloropyrimidin-4-yl) benzenesulfonamide. . m. p. : 225-26.5 ° C IR (nujol, cm ^-1 ): 3035, 1630, ¹
595, 1575 MS (m / z): 325 (M ^<+> ).

(2) To 20 ml of ethylene glycol was added 1.03 g of sodium hydride (60% dispersion type), and further 1.66 g of 4-tert-butyl-N- (6-chloropyrimidin-4-yl) benzenesulfonamide. And stirred at 60 ° C. for 20 hours. After cooling, acidify with 10% hydrochloric acid and extract with ethyl acetate. The ethyl acetate layer is washed and dried, and then 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 FABMS (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. The ethyl acetate layer is washed and dried, and then 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 FABMS (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. The ethyl acetate layer is washed and dried, and then the solvent is distilled off. The residue was purified by silica gel column chromatography (eluting 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 FABMS (m / z): 556,554 (MH ^<+> ).

Reference Example 17 (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 FABMS (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 FABMS (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 FABMS (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) 2- (6-Amino-5-bromopyrimidin-4-yloxy) ethanol 611 mg in 20 ml of dimethylformamide was added with sodium hydride (6
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. The ethyl acetate layer is washed and dried, and then 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
1 mg is obtained. m. p. : 126-129 ° C IR (nujol, cm ^-1 ): 3450, 3270, ¹
635, 1585, 1570, 1540 MS (m / z): 359, 357 (MH ^<+> ).

(6) 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)
Was added, 198 mg of 4-tert-butylbenzenesulfonyl chloride was added, and the mixture was 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 5 (4).

Reference Example 18 (1) Diethyl (4-methylphenyl) malonate 9.4
To a solution of 5 g and 5.00 g of butylamidine hydrochloride in 25 ml of methanol, 19.67 g of 28% sodium methoxide is added under ice cooling, and the mixture is stirred overnight at room temperature. After the reaction, the solution is concentrated by half, diluted with water, and acidified with 10% hydrochloric acid. The precipitated crystals are filtered, washed and dried to obtain 5.17 g of 5- (4-methylphenyl) -4,6-dihydroxy-2-n-propylpyrimidine as a crystalline powder. m. p. > 300 ° C.

(2) A mixture of 5.14 g of this product, 5 ml of N, N-diethylaniline and 20 ml of phosphorus oxychloride was heated under reflux for 2 hours, after the reaction, phosphorus oxychloride was distilled off, and the mixture was slowly added to 300 ml of water. . The mixture is stirred at room temperature for 20 minutes and extracted with ether. After washing and drying, the mixture is treated with activated carbon and the solvent is distilled off to obtain 5.91 g of 5- (4-methylphenyl) -4,6-dichloro-2-n-propylpyrimidine as crystals. m. p. 91-93 ° C.

(3) To a suspension of 2.10 g of this product in 25 ml of dimethyl sulfoxide, 1.91 g of 4-tert-butylbenzenesulfonamide and 4.13 g of potassium carbonate.
And stir at 80 ° C. for 9 hours. After cooling, the reaction mixture is added to ice-cooled hydrochloric acid and extracted with ethyl acetate. After washing and drying, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluting solvent: chloroform: ethyl acetate = 50: 1), and further crystallized with n-hexane to give 4-tert-butyl-N- [. 6-chloro-5- (4
-Methylphenyl) -2-n-propylpyrimidine-4
-Yl] benzenesulfonamide 3.0. g are obtained as a powder. m. p. 138-139 ° C.

(4) To a solution of 2.94 g of this product in 50 ml of ethylene glycol, 0.74 g of sodium was added little by little at room temperature, and the mixture was stirred at 135 ° C. for 18 hours. After cooling, the reaction mixture is diluted with dilute hydrochloric acid under cooling and extracted with ethyl acetate. After washing and drying the extract, the solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent; chloroform: ethyl acetate = 50: 1) to give 4-tert.
-Butyl-N- [6- (2-hydroxyethoxy) -5
2.21 g of-(4-methylphenyl) -2-n-propylpyrimidin-4-yl] benzenesulfonamide are obtained as a crystalline powder. m. p. 133-134 ° C.

Reference Example 19 Diethyl (4-methylphenyl) malonate and isobutylamidine hydrochloride were treated in the same manner as in Reference Example 18 to give 4-
tert-Butyl-N- [6- (2-hydroxyethoxy) -5- (4-methylphenyl) -2-i-propylpyrimidin-4-yl] benzenesulfonamide is obtained. m. p. 143-144 ° C.

Reference Example 20 (1) To a solution of 1.69 g of thiophene in 20 ml of anhydrous tetrahydrofuran was added 1.6 M at 0 ° C. under an argon atmosphere.
11.4 ml of n-butyllithium-n-hexane solution is added dropwise over 30 minutes. To this mixture, a solution of 5- (4-methylphenyl) -4,6-dichloropyrimidine (4.0 g) in anhydrous tetrahydrofuran (5 ml) was slowly added dropwise at -60 ° C, the temperature was raised to 0 ° C, and the mixture was stirred for 1.5 hours. . After the reaction, 1.5 g of acetic acid and 0.25 g of water were added, and further, a solution of 5.70 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 5 ml of tetrahydrofuran was added, and the mixture was stirred at 0 ° C. for 1 hour. I do. This is treated with carbon powder, extracted with a mixture of ethyl acetate and an aqueous solution of citric acid, washed and dried, and the solvent is distilled off. The residue was purified by silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 50: 1) to give 5- (4-methylphenyl) -4,6-dichloro-2- (2-thienyl) pyrimidine 2. 64 g are obtained as a powder. m. p. 119.5-120 ° C.

(2) Using 2.64 g of this product as a reference example 18-
Treated in the same manner as (3), 4-tert-butyl-N-
[6-chloro-5- (4-methylphenyl) -2- (2
3.38 g of -thienyl) pyrimidin-4-yl] benzenesulfonamide are obtained as a powder. m. p. > 300 ° C.

(3) 3.38 g of this product was used in Reference Example 18-
Treated in the same manner as (4), 4-tert-butyl-N-
2.11 g of [6- (2-hydroxyethoxy) -5- (4-methylphenyl) -2- (2-thienyl) pyrimidin-4-yl] benzenesulfonamide are obtained as a powder. m. p. > 300 ° C.

Reference Example 21 An ether solution of 5- (4-methylphenyl) -4,6-dichloropyrimidine is cooled to -30 ° C, and 1.8M phenyllithium-cyclohexane solution is added dropwise. The reaction mixture was treated in the same manner as in Reference Example 20- (1) to give 5- (4-
Methylphenyl) -4,6-dichloro-2-phenylpyrimidine is obtained as a crystalline powder. m. p. 165-165 ° C.

(2) This product was treated in the same manner as in Reference Example 18- (3) to give 4-tert-butyl-N- [6-chloro-5.
-(4-Methylphenyl) -2-phenylpyrimidine-
4-yl] benzenesulfonamide is obtained as a powder. m. p. 249-250 ° C.

(3) This product was treated in the same manner as in Reference Example 18- (4) to give 4-tert-butyl-N- [6- (2-hydroxyethoxy) -5- (4-methylphenyl) -2. −
Phenylpyrimidin-4-yl] benzenesulfonamide is obtained as crystals. m. p. 197.5-198.5 ° C.

Reference Example 22 2-Chloro-5-bromopyrimidine and 2-furyltributyltin were treated in the same manner as in Production Example 190 to give 2-chloro-5- (2-furyl) pyrimidine. m. p. 134.5-136 ° C.

Reference Example 23 2-Chloro-5-bromopyrimidine and 2-thienyltributyltin were treated in the same manner as in Production Example 190 to give 2-chloro-5- (2-thienyl) pyrimidine. m. p. 124.5-125.5 ° C.

Reference Example 24 2-Chloro-5-bromopyrimidine and 3-thienyltributyltin were treated in the same manner as in Production Example 190 to give 2-chloro-5- (3-thienyl) pyrimidine. m. p. 154-157 ° C.

Reference Example 25 4.97 ml of tribromoboron was added dropwise to a solution of 1.9 g of 2-chloro-5-methoxypyrimidine in 30 ml of methylene chloride in a bath of dry ice-acetone over 15 minutes.
After completion of dropping, the mixture was stirred at room temperature for 22 hours. 30 ml of methanol was added dropwise to the reaction mixture under a dry ice-acetone bath, the reaction mixture was concentrated under reduced pressure, adjusted to pH 5 with an aqueous sodium hydroxide solution, and extracted with ethyl acetate. After the extract was washed and dried, the solvent was distilled off under reduced pressure to obtain crystals obtained by n-
Washing with hexane gives 1.47 g of 2-chloro-5-hydroxypyrimidine as colorless crystals. m. p. 194-195 ° C.

Reference Example 26 (1) 3-hydroxymethylthiophene (1.50 g) and thionyl chloride (2 ml) were added to methylene chloride under ice-cooling to give 3
Stir for 0 minutes. Water is added to the reaction solution, and extracted with chloroform. After washing and drying the extract, the solvent was distilled off under reduced pressure,
1.61 g of 3-chloromethylthiophene is obtained.

(2) 610 mg of this product, 2-chloro-5-
Hydroxypyrimidine 200 mg, potassium carbonate 635
mg and 3 ml of dimethylformamide at 50 ° C.
Stir for 1 hour. Water is added to the reaction solution, and extracted with ethyl acetate. After washing and drying the extract, the solvent is concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 20: 1 to 20:
After purification in 3), the solvent was distilled off to give 2-chloro-5- (3
345 mg of -thienylmethoxy) pyrimidine are obtained as colorless needles. m. p. 73-76 ° C.

Reference Examples 27-32 The corresponding compounds were treated in the same manner as in Reference Example 26 to give the compounds shown in Table 37 below.

[0321]

[Table 37]

Reference Example 33 (1) Diethyl (4-methylphenyl) malonate 10.
A solution of sodium methoxide in methanol (28%) (14.35 g) was added dropwise to a solution of 08 g and trifluoroacetamidine (5.0 g) in methanol (70 ml) over 10 minutes under ice cooling, followed by stirring at room temperature for 24 hours. About 4 reactions
The mixture is concentrated to one part, the residue is diluted with water, acidified with 10% hydrochloric acid, and collected by filtration. The residue was washed with water and n-hexane to remove 4,6-dihydroxy-2-trifluoromethyl-5-.
1.76 g of (4-methylphenyl) pyrimidine are obtained as pale yellow crystals. m. p. 270-275 ° C.

(2) 2.36 g of this product, phosphorus oxychloride 1
Reflux 0 ml and 2 ml diethylaniline for 7 hours.
After cooling, phosphorus oxychloride was distilled off under reduced pressure, the obtained brown oily substance was slowly poured into ice-cold water, and the mixture was stirred at room temperature for 30 minutes. The reaction solution is extracted with diethyl ether, the diethyl ether layer is washed, dried, and concentrated under reduced pressure to obtain 2.65 g of 4,6-dichloro-2-trifluoromethyl-5- (4-methylphenyl) pyrimidine. .

(3) A mixture of 2.65 g of this product, 1.93 g of 4-tert-butylbenzenesulfonamide, 3.58 g of potassium carbonate and 12 ml of dimethyl sulfoxide is stirred at room temperature for 1 hour and further at 60 ° C. for 30 minutes. After cooling, pour ice-cooled dilute hydrochloric acid and extract with ethyl acetate.
The extract was washed and dried, and the residue was purified by silica gel column chromatography (eluting solvent: chloroform), then n
Washed with hexane to give 4-tert-butyl-N-
1.46 g of {6-chloro-5- (4-methylphenyl) -2-trifluoromethylpyrimidin-4-yl} benzensulfonamide is obtained as colorless crystals. m. p. 198-203 ° C.

(4) Sodium hydride (60% dispersion type)
413 mg to ethylene glycol 18 ml at room temperature for 15
Add over 1 minute and add 1.0 g of this product at room temperature.
The mixture is stirred at 110 ° C. for 2 hours and at 120 ° C. for 4 hours. After cooling, ice-cooled dilute hydrochloric acid is poured into the reaction solution, and the mixture is extracted with ethyl acetate. The extract was washed and dried, and the residue was purified by silica gel column chromatography (eluting solvent: chloroform-chloroform: ethyl acetate = 200: 1-chloroform: ethyl acetate = 50: 1), concentrated under reduced pressure, and then 4- 1.01 g of tert-butyl-N- [6- {2-hydroxyethoxy-5- (4-methylphenyl) -2-trifluoromethylpyrimidin-4-yl} benzensulfonamide is obtained as colorless crystals. m. p. 181-183 ° C.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 403/12 233 C07D 403/12 233 235 235 237 237 239 239 403/14 207 403/14 207 233 233 405/12 239 405/12 239 405/14 213 405/14 213 239 239 409 409/12 239 409/12 239 409/14 213 409/14 213 239 239 413/14 239 413/14 239 417/12 239 417 / 12 239 417/14 239 417/14 239 (72) Inventor Rinako Kono 4-180 Sakuragi-cho, Omiya-shi, Saitama 1 Fujiwa City Coop Omiya-Sakuragi-cho 401

Claims (10)

[Claims] 1. A compound of the general formula [I] (However, ring A and ring B are the same or different and are substituted or unsubstituted phenyl groups, Q is a single bond or a formula —O—, —S
A group represented by —, —SO—, —SO ₂ — or —CH ₂ —, Y represents a group represented by the formula —O—, —S— or —NH—,
Alk is a lower alkylene group or a lower alkenylene group, Z
Is a single bond or a group represented by the formula —O— or —NH—, R is a substituted or unsubstituted aromatic heterocyclic group or aryl group, R ¹ is a hydrogen atom, trifluoromethyl group, mono- or di- A lower alkylamino group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group, a substituted or unsubstituted lower alkynyl group,
It represents a substituted or unsubstituted lower alkylthio group, a substituted or unsubstituted lower alkoxy group, an aromatic heterocyclic group, a substituted or unsubstituted aliphatic heterocyclic group or an aryl group. However, when Z is a single bond, R is not an aryl group. Or a pharmaceutically acceptable salt thereof as an active ingredient. 2. A halogen atom wherein ring A and ring B are the same or different; a lower alkyl group; a lower alkoxy group; a lower alkenyl group; a lower alkynyl group; a lower alkylthio group; a cycloalkyl group; a trifluoromethyl group; a carboxyl group; Cyano group; tetrazolyl group; 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; di-lower alkoxy group substituted lower alkyl group; hydroxy lower alkyl group; carboxyl group-substituted lower alkyl group; carboxyl group-substituted lower alkenyl group;
A lower alkoxy group substituted with a carboxyl group; a bromopyrimidinyloxy lower alkyl group; a lower alkylenedioxy group; an aryl lower alkoxy group; and a phenyl group which may be substituted with 1 to 3 groups selected from arylaminocarbonyl groups, R Is a halogen atom; an optionally protected hydroxy group; a nitro group; a cyano group; an amino group;
Formyl group; carboxyl group; carbamoyl group; N-mono- or di-lower alkylcarbamoyl group; N-lower alkylcarbamoyloxy group; N-hydroxyiminomethyl 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; hydroxy group and aryl group-substituted lower alkyl group;
Lower alkylthio group; mono- or di-lower alkylamino group; lower alkanoylamino group; lower alkoxy group; lower alkoxy group substituted with an optionally protected carboxyl group; aryloxy group; lower alkoxycarbonyl group; lower alkoxy -Lower alkenyl group; lower alkanoyl group; arylcarbonyl group; lower alkenyloxy group; hydroxy lower alkynyl group; lower alkynyl group optionally protected by trimethylsilyl group;
Cyano lower alkoxy group; cycloalkyl-lower alkoxy group; lower alkylsulfinyl group; lower alkylsulfonyl group; aryl group; phenyl lower alkyl group; aromatic heterocyclic group substituted lower alkyl group; aromatic heterocyclic group substituted lower alkoxy Group; phenyl lower alkenyl group; phenyl lower alkoxy group; arylcarbonylamino group; 1 to 3 selected from halogen atom and lower alkyl
An aromatic heterocyclic group-substituted oxy group which may be substituted with a group; and an aromatic heterocyclic group which is optionally substituted with a lower alkyl group, substituted with 1 to 4 groups selected from An aromatic heterocyclic group or an aryl group, R ¹ is (1) a hydrogen atom, (2) a trifluoromethyl group, (3)
1- selected from a mono- or di-lower alkylamino group, (4) halogen atom, carboxyl group, lower alkoxycarbonyl group, aromatic heterocyclic group and aryl group
A lower alkyl group which may be substituted with 4 groups,
(5) Lower alkenyl group, (6) Lower alkynyl group optionally substituted with carboxyl group, (7) Lower alkylthio group, (8) Lower alkoxy group optionally substituted with hydroxy group or hydroxy lower alkoxy group ,
The pharmaceutical composition according to claim 1, which is (9) an aromatic heterocyclic group, (10) an aliphatic heterocyclic group optionally substituted with a lower alkyl group, or (11) an aryl group. 3. The aromatic heterocyclic group is a monocyclic or bicyclic aromatic heterocyclic group containing 1 to 4 different ring atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and an aliphatic heterocyclic group. The pharmaceutical composition according to claim 2, wherein the heterocyclic group is a monocyclic or bicyclic aliphatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom. 4. The aromatic heterocyclic group is a 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, benzothiazolyl group, benzoxazolyl group or benzimidazolyl group , An aliphatic heterocyclic group is a piperazinyl group, a pyrrolidinyl group, a piperidyl group, a homopiperidyl group, a thiomorpholinyl group or a morpholinyl group, and an aryl group and an arylcarbonylamino group, an arylaminocarbonyl group, an aryloxy group and an arylcarbonyl group The pharmaceutical composition according to claim 2, wherein the aryl moiety is a phenyl group, a lower alkoxyphenyl group or a naphthyl group. 5. A phenyl group or ring in which ring A is substituted with a group selected from a lower alkyl group; a lower alkoxy group; a lower alkoxycarbonyl-lower alkyl group; a hydroxyl lower alkyl group; and a lower alkoxycarbonyl-lower alkoxy group. B is a trifluoromethyl group; formyl group; lower alkyl group; lower alkoxy group; lower alkylenedioxy group; hydroxy lower alkyl group; and phenyl group which may be substituted with a group selected from lower alkoxycarbonyl group, and Q is Single bond or group represented by formula -O- or -S-, Y is a group represented by formula -O-, Al
k is a lower alkylene group, Z is a group represented by the formula -O-, R
Is a phenyl group optionally substituted with a group selected from an amino group, a nitro group, a halogen atom and a hydroxy lower alkyl group; substituted with a group selected from an amino group, a nitro group, a trifluoromethyl group and a lower alkanoylamino group Optionally pyridyl group; halogen atom, formyl group, N-hydroxyiminomethyl group, N-lower alkoxyiminomethyl group, thienyl group, furyl group, pyridyl group, lower alkyl group, hydroxy lower alkyl group, lower alkylthio group, Lower alkanoyl group, lower alkynyl group, lower alkenyloxy group, lower alkoxy group, lower alkylsulfinyl group, lower alkylsulfonyl group,
A cyano lower alkoxy group, a thiazolyl group, a lower alkyl group-substituted thienyl group, a lower alkyl group-substituted pyrrolyl group, a phenyl group and a pyrimidinyl group which may be substituted with a group selected from a lower alkoxyphenyl group; or a benzothiazolyl group, R ¹ is The pharmaceutical composition according to claim 4, which is a hydrogen atom, a lower alkyl group, a morpholinyl group, a pyridyl group or a pyrimidinyl group. 6. A phenyl group in which ring A is substituted with a group selected from a lower alkyl group and a hydroxyl lower alkyl group, and a ring B is substituted with a group selected from a halogen atom, a lower alkyl group and a lower alkoxy group. The phenyl group, R is a pyrimidinyl group substituted with a group selected from a halogen atom, a hydroxy lower alkyl group, a thienyl group, a furyl group and a lower alkylthio group, and R ¹ is a hydrogen atom or a pyrimidinyl group. Composition. 7. The compound of 4-tert-butyl-N- [5- (4
-Methylphenyl) -6- {2- (5- (3-thienyl) pyrimidin-2-yloxy) ethoxy} pyrimidin-4-yl] benzenesulfonamide, 4-tert-butyl-N- [5- (4- Methylphenyl) -6- {2- (5-methylthiopyrimidin-2-yloxy) ethoxy} pyrimidin-4-yl] benzenesulfonamide, 4-tert-butyl-N- [5- (4-methylphenyl) -6 -｛2- (5- (2-furyl) pyrimidine-2
-Yloxy) ethoxy {pyrimidin-4-yl] benzenesulfonamide, 4-tert-butyl-N- [5- (4-methylphenyl) -6- {2- (5- (2-thienylpyrimidine-2)
-Yloxy) ethoxy {pyrimidin-4-yl] benzenesulfonamide, 4-tert-butyl-N- [5- (4-methylphenyl) -6- {2- (5-bromopyrimidin-2-yloxy) ethoxy} Pyrimidin-4-yl] benzenesulfonamide, 4-tert-butyl-N- [5- (4-methylphenyl) -6- {2- (5-bromopyrimidin-2-yloxy) ethoxy} -2- (2 -Pyrimidyl) pyrimidin-4-yl] benzenesulfonamide, 4-tert-butyl-N- [5- (4-methylphenyl) -6- {2- (5-chloropyrimidin-2-yloxy) ethoxy} pyrimidine- 4-yl] benzenesulfonamide, 4-tert-butyl-N- [5- (4-methoxyphenyl) -6- {2- (5-methylthio) Pyrimidine-2-
Iloxy) ethoxy} pyrimidin-4-yl] benzenesulfonamide, 4-tert-butyl-N- [5- (2-methoxyphenoxy) -6- {2- (5- (2-thienyl) pyrimidin-2-yloxy] ) Ethoxy} pyrimidin-4-yl] benzenesulfonamide, 4-tert-butyl-N- [5- (4-methylphenyl) -6- {2- (5- (3-furyl) pyrimidine-2.
-Yloxy) ethoxy} pyrimidin-4-yl] benzenesulfonamide, 4-tert-butyl-N- [5- (4-chlorophenyl) -6- {2- (5-methylthiopyrimidin-2-yloxy) ethoxy} pyrimidine -4-yl] benzenesulfonamide, 4-tert-butyl-N- [5- (2-methoxyphenylthio) -6- {2- (5-bromopyrimidine-2-
Iloxy) ethoxy} -2- (2-pyrimidyl) pyrimidin-4-yl] benzenesulfonamide, 4-tert-butyl-N- [5- (4-methylphenyl) -6- {2- (5-hydroxymethyl) Pyrimidine-
2-yloxy) ethoxy} pyrimidin-4-yl] benzenesulfonamide or 4- (2-hydroxy-
1,1-dimethylethyl) -N- [5- (4-methylphenyl) -6- {2- (5-bromopyrimidin-2-yloxy) ethoxy} pyrimidin-4-yl] benzenesulfonamide, or their A pharmaceutical composition comprising a pharmacologically acceptable salt as an active ingredient. 8. 4- (2-Hydroxy-1,1-dimethylethyl) -N- [5- (4-methylphenyl) -6-
A pharmaceutical composition comprising {2- (5-bromopyrimidin-2-yloxy) ethoxy} pyrimidin-4-yl] benzenesulfonamide or a pharmacologically acceptable salt thereof as an active ingredient. 9. The method according to claim 1, which is an endothelin antagonist.
The pharmaceutical composition according to 2, 3, 4, 5, 6, 7 or 8. 10. 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 failure, diabetes, thrombosis, arteriosclerosis, heart failure, acute renal failure, glomerulonephritis, cyclosporine-induced nephrotoxicity, myocardial infarction, angina, arrhythmia, glaucoma, migraine, cerebral vasospasm The pharmaceutical composition according to claim 1, 2, 3, 4, 5, 6, 7, 8 or 9, which is a preventive and / or therapeutic agent for stroke.