JP3013778B2 - Benzenesulfonamide derivatives and their production - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel benzenesulfonamide derivative having an endothelin antagonism and a method for producing the same.

[0002]

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

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

[0004]

SUMMARY OF THE INVENTION The present invention provides a novel benzenesulfonamide derivative having high water solubility and excellent endothelin antagonism. The present invention also provides a method for producing such a novel benzenesulfonamide derivative.

[0005]

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

[0006]

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(Wherein, ring A and ring B are substituted or unsubstituted phenyl groups, Q is a single bond or a group represented by the formula -O-, R is a substituted or unsubstituted aromatic heterocyclic group, R ¹ is A benzenesulfonamide derivative represented by a substituted or unsubstituted amino group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted lower alkylthio group or a substituted or unsubstituted heterocyclic group. Or a pharmacologically acceptable salt thereof is provided.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION R ¹ in the object [I] of the present invention
Examples of the heterocyclic group in 1 include monocyclic, bicyclic or tricyclic aliphatic or aromatic heterocyclic groups which may be partially saturated.

The aromatic heterocyclic group is a 5- to 10-membered monocyclic or bicyclic aromatic heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Preferred are, 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,
Pyrazolyl group, quinazolinyl group, thienopyrimidinyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group, triazinyl group, tetrazolyl group, quinolyl group, isoquinolyl group, quinoxalinyl group, benzothienyl group, benzothiazolyl group, benzoxazolyl group or Examples include a benzimidazolyl group and a ring in which a part thereof is saturated.

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

The aromatic heterocyclic group represented by R is a 5- to 10-membered monocyclic or bicyclic aromatic heterocyclic ring containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. What is a formula group is preferred, for example, 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,
Examples include a benzothienyl group, a benzothiazolyl group, a benzoxazolyl group, and a benzimidazolyl group.

The substituent on ring A and / or ring B includes:
For example, a lower alkyl group or a lower alkoxy group is exemplified.

Ring A and / or ring B may have the same or different and have 1 to 3 substituents as described above.

Examples of the substituent on the aromatic heterocyclic group for R include a halogen atom, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy group, a phenyl group, a furyl group, a thienyl group and a pyridyl group. Can be

The aromatic heterocyclic groups for R may be the same or different and each may have 1 to 4 of the above substituents.

The substituent on the amino group in R ¹ may be a mono- or di-hydroxy lower alkyl group, a lower alkyl group, a lower alkoxy group, an amino lower alkyl group, a mono- or di-lower alkylamino-lower alkyl group. Group, lower alkoxy-lower alkyl group or carboxy lower alkyl group, and the like.Examples of the substituent on the lower alkyl group include a carboxyl group or a hydroxyl group.The substituent on the lower alkoxy group includes a hydroxyl group. A carboxyl group, a hydroxy lower alkyl group, a carboxy lower alkyl group, an amino lower alkyl group or a mono- or di-lower alkylamino group, and the like. As the substituents on the lower alkylthio group, a hydroxyl group, a carboxyl group, a lower Alkoxycarbonyl group, amino group Mono - or di - include lower alkylamino groups such as the substituents on the heterocyclic group, a hydroxyl group, a carboxyl group, an amino group or a mono- - or di - like lower alkylamino group.

An amino group, a lower alkyl group for R ¹ ,
The lower alkoxy group, the lower alkylthio group and / or the heterocyclic group may be the same or different, and may have 1 to 4 substituents described above.

Among the desired compounds [I] of the present invention, compounds which are preferable from the viewpoint of pharmacological properties are those represented by the general formula [I] wherein Ring A and Ring B are selected from lower alkyl groups and lower alkoxy groups.
Phenyl group optionally substituted with R groups, R is a halogen atom, a lower alkyl group, a hydroxy lower alkyl group,
A lower alkoxy group, a phenyl group, a furyl group, a thienyl group and an aromatic heterocyclic group optionally substituted with 1 to 4 substituents selected from the group consisting of a pyridyl group,
A said heterocyclic radical is nitrogen atom, an oxygen atom and 1 to 4 5 to 10 membered monocyclic or bicyclic aromatic heterocyclic group containing hetero atom selected from sulfur atom, R ¹ Is a mono- or di-hydroxy lower alkyl group, a lower alkyl group, a lower alkoxy group, an amino lower alkyl group, a mono- or di-lower alkylamino-lower alkyl group,
An amino group optionally substituted with one or two groups selected from a lower alkoxy-lower alkyl group and a carboxy lower alkyl group; a lower alkyl group optionally substituted with a carboxyl group or a hydroxyl group;
A lower alkoxy group which may be substituted with a group selected from a carboxyl group, a hydroxy lower alkyl group, a carboxy lower alkyl group, an amino lower alkyl group and a mono- or di-lower alkylamino group;
A lower alkylthio group which may be substituted with a group selected from a carboxyl group, a lower alkoxycarbonyl group, an amino group and a mono- or di-lower alkylamino group;
Hydroxyl, carboxyl, amino and mono-
Or 1-4 selected from di-lower alkylamino groups
Is a heterocyclic group which may be substituted with a single group, wherein the heterocyclic group is a monocyclic, bicyclic or tricyclic aliphatic or an aromatic heterocyclic group which may be partially saturated. The compound is a group.

Among the desired compounds [I] of the present invention, compounds having a more preferable effect than the above are those represented by the general formula [I] wherein the ring A is 1 to 3
A phenyl group substituted with two lower alkyl groups, ring B
Is a phenyl group substituted with 1 to 3 lower alkyl groups or 1 to 3 lower alkoxy groups, R is a halogen atom, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy group, a phenyl group, a furyl group, A pyrimidinyl group substituted with 1 to 4 groups selected from a thienyl group and a pyridyl group, R ¹ is a mono- or di-hydroxy lower alkyl group, a lower alkyl group, a lower alkoxy group,
An amino lower alkyl group, a mono- or di-lower alkylamino-lower alkyl group, a lower alkoxy-lower alkyl group and a carboxy lower alkyl group
An amino group optionally substituted with two groups; a lower alkyl group optionally substituted with a carboxyl group or a hydroxyl group; a hydroxyl group, a carboxyl group, a hydroxy lower alkyl group, a carboxy lower alkyl group, an amino lower alkyl group And a lower alkoxy group optionally substituted with a group selected from mono- or di-lower alkylamino groups; hydroxyl group, carboxyl group, lower alkoxycarbonyl group, amino group and mono- or di-
A lower alkylthio group which may be substituted with a group selected from a lower alkylamino group; which is substituted with 1 to 4 groups selected from a hydroxyl group, a carboxyl group, an amino group and a mono- or di-lower alkylamino group. A piperidyl group; or a tetrazolyl group.

More preferable compounds from the viewpoint of efficacy are a phenyl group in which ring A is substituted with a lower alkyl group, a phenyl group in which ring B is substituted with a lower alkyl group or a lower alkoxy group, and R is a compound represented by formula (I). A pyrimidinyl group substituted with a halogen atom or a lower alkoxy group, R
Wherein ¹ is an unsubstituted amino group or an amino substituted with one or two groups selected from a mono- or di-hydroxy lower alkyl group, a mono- or di-lower alkylamino-lower alkyl group and a lower alkoxy-lower alkyl group; The compound is a group.

Compounds which are even more preferable in terms of efficacy are phenyl groups in which ring A is substituted with a lower alkyl group, phenyl group in which ring B is substituted with a lower alkyl group or a lower alkoxy group, and R Is a pyrimidinyl group substituted with a halogen atom or a lower alkoxy group, R
^A compound in which ¹ is an amino group substituted with a hydroxy lower alkyl group.

As a particularly preferable compound in terms of pharmacological effect, N- {6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -2- (2-hydroxyethylamino) -5- (2-methoxyphenoxy) Pyrimidine-
4-yl} -4-tert-butylbenzenesulfonamide, N- {6- [2- (5-bromopyrimidine-2-
Yloxy) ethoxy] -2- (2-hydroxyethylthio) -5- (2-methoxyphenoxy) pyrimidine-
4-yl} -4-tert-butylbenzenesulfonamide, N- {6- [2- (5-bromopyrimidine-2-
Iloxy) ethoxy] -2- (4-hydroxypiperidino) -5- (2-methoxyphenoxy) pyrimidine-
4-yl} -4-tert-butylbenzenesulfonamide, N- {6- [2- (5-bromopyrimidine-2-
Iloxy) ethoxy] -2- (3-hydroxypiperidino) -5- (2-methoxyphenoxy) pyrimidine-
4-yl} -4-tert-butylbenzenesulfonamide, N- {6- [2- (5-bromopyrimidine-2-
Yloxy) ethoxy] -2-methylthio-5- (2-
Methoxyphenoxy) pyrimidin-4-yl {-4-t
tert-butylbenzenesulfonamide, N- @ 6-
[2- (5-bromopyrimidin-2-yloxy) ethoxy] -2- (2-methoxyethylamino) -5- (2
-Methoxyphenoxy) pyrimidin-4-yl {-4-
tert-butylbenzenesulfonamide, N- @ 6-
[2- (5-methoxypyrimidin-2-yloxy) ethoxy] -2- (2-methoxyethylamino) -5-
(2-methoxyphenoxy) pyrimidin-4-yl}-
4-tert-butylbenzenesulfonamide, N-
{6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -2- (2-hydroxyethoxy) -5
-(2-methoxyphenoxy) pyrimidin-4-yl}
-4-tert-butylbenzenesulfonamide and N
-{6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -2- (2-hydroxyethylamino)
-5- (4-methylphenyl) pyrimidin-4-yl}
-4-tert-butylbenzenesulfonamide.

Among the desired compounds [I] of the present invention, other preferred compounds are a phenyl group in which ring A is substituted with a lower alkyl group and ring B is a lower alkyl group or a lower alkoxy group in the general formula [I]. A phenyl group substituted with a group,
R is a pyrimidinyl group substituted with a halogen atom or a lower alkoxy group, R ¹ is a mono- or di-hydroxy lower alkyl group, a lower alkyl group, an amino lower alkyl group, a mono- or di-lower alkylamino-lower alkyl group An amino group optionally substituted with one or two groups selected from a lower alkoxy-lower alkyl group and a carboxy lower alkyl group; a lower alkyl group substituted with a carboxyl group or a hydroxyl group; a hydroxyl group, a carboxyl group And a lower alkoxy group which may be substituted with a group selected from a mono- or di-lower alkylamino group; a group selected from a hydroxyl group, a carboxyl group, a lower alkoxycarbonyl group and a mono- or di-lower alkylamino group. Optionally substituted lower alkylthio ; It is a compound which is or a tetrazolyl group; piperidyl group substituted by a hydroxyl group.

Among these, more preferred compounds are those wherein in formula (I), R ¹ is substituted by a group selected from a hydroxy lower alkyl group, a mono- or di-lower alkylamino-lower alkyl group and a lower alkoxy-lower alkyl group. An amino group optionally substituted with a hydroxy lower alkyl group and an amino group substituted with a lower alkyl group; a lower alkyl group substituted with a hydroxyl group; a lower alkoxy group optionally substituted with a hydroxyl group or a carboxyl group; A compound which is a lower alkylthio group which may be substituted with a group selected from a hydroxyl group, a carboxyl group and a lower alkoxycarbonyl group; a piperidyl group substituted with a hydroxyl group; or a tetrazolyl group.

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

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

[0027]

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(Where X ¹ represents a lower alkylsulfonyl group or a phenylsulfonyl group, and the other symbols have the same meanings as described above) or a salt thereof and a general formula [III]

[0029]

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

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

[0032]

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

[0034]

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(Wherein X ² represents a halogen atom, and other symbols have the same meanings as described above).

[Method C] The target compound [I] in which R ¹ is an amino group can be produced by reducing a compound in which the corresponding R ¹ is an azide group or a salt thereof.

[Method D] The target product [I] wherein R ¹ is a tetrazolyl group can be produced by reacting a compound or a salt thereof in which R ¹ is a cyano group with tributyltin azide.

The salts of the compounds described in the above-mentioned [Method A], [Method B], [Method C] and [Method D] include, for example, salts with inorganic acids such as hydrochloride, sulfate and the like, alkali metal salts and alkali metal salts. Salts with inorganic bases such as earth metal salts can be used.

[Method A]: The reaction of compound [II] or a salt thereof with compound [III] or a salt thereof is carried out in the presence or absence of a deoxidizing agent in a suitable solvent or without a solvent. Can be. Examples of the deoxidizing agent include an alkali metal hydride, an alkali metal carbonate, an alkali metal alkoxide, an alkyl alkali metal, an alkali metal, an alkaline earth metal, an alkali metal hydroxide, an alkaline earth metal hydroxide, an organic base (1,8- Diazabicyclo [5.4.0] undec-7
-En etc.) can be preferably used. As the solvent, toluene, dimethylacetamide, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dimethoxyethane, and the like can be used as appropriate. The present reaction suitably proceeds at 0 to 150 ° C, particularly at room temperature to 120 ° 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 deoxidizer,
Those described in the above [Method A] can be suitably used.
As the solvent, tetrahydrofuran, dimethylacetamide, dimethylformamide, dimethoxyethane, or the like, or a mixed solvent thereof can be used as appropriate. The present reaction suitably proceeds at 0 ° C to 100 ° C, particularly at room temperature to 50 ° C.

[Method C]: The reduction reaction of a compound wherein R ¹ is an azide group or a salt thereof can be carried out in the presence of a reducing agent in a suitable solvent or without a solvent. As a reducing agent,
Phosphines such as triphenylphosphine can be suitably used. As the solvent, tetrahydrofuran, dimethylformamide, water, or a mixed solvent thereof can be used as appropriate. The reaction is carried out at 0 ° C to 100 ° C.
C., especially at room temperature to 60 C.

The starting compound in which R ¹ is an azide group can be produced by reacting compound [II] with sodium azide in a conventional manner.

[Method D]: The reaction of a compound in which R ¹ is a cyano group or a salt thereof with tributyltin azide can be carried out in a suitable solvent or without a solvent. As the solvent, for example, toluene, xylene, tetrahydrofuran,
Dimethylacetamide, dimethylformamide, and the like, or a mixed solvent thereof can be used as appropriate. The reaction is
It proceeds favorably at room temperature to 150 ° C, especially at 50 to 120 ° C.

The starting compound in which R ¹ is a cyano group can be produced by reacting the compound [II] with potassium cyanide by a conventional method.

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

Method (a): The target compound [I] in which R ¹ is a carboxy lower alkylthio group is obtained by treating a compound in which R ¹ is a lower alkoxycarbonyl-lower alkylthio group with bistributyltin oxide and then hydrolyzing the compound. It can be manufactured by the following. The reaction is carried out at 60 to 12
Proceeds favorably at 0 ° C.

Method (b): The target product [I] in which R ¹ is a lower alkoxy group substituted with a hydroxyl group is a compound represented by the corresponding R
¹ hydroxyl group (e.g., tert- butyldiphenylsilyl group, etc.) that are protected can be produced by the presence of a deprotecting agent a compound which is substituted lower alkoxy group, is reacted. As the deprotecting agent, tetrabutylammonium fluoride, hydrogen fluoride-pyridine and the like can be suitably used. The reaction is
It proceeds favorably at 0 ° C. to room temperature.

Method (c): The target product [I] wherein R ¹ is a hydroxyl-substituted lower alkyl group is a lower alkyl group wherein the corresponding R ¹ is substituted by a protected hydroxyl group (for example, a methoxymethyloxy group). It can be produced by treating a compound which is an alkyl group with an acid.

As the acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, hydrochloric acid and the like can be suitably used. This reaction suitably proceeds at 0 ° C to room temperature.

The (d) The method: the target compound R ¹ is an amino group substituted with hydroxy-lower alkyl group (I), the corresponding hydroxy lower alkyl group R ¹ is a protected (e.g.,
The compound can be produced by treating a compound which is an amino group substituted with a tetrahydropyranyloxy group) with an acid. As the acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid and the like can be suitably used. This reaction suitably proceeds at 0 ° C to room temperature.

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

The starting compound [II] of the present invention can be produced, for example, according to the method described in JP-B-52-7054. That is, the compound [II] in which X ¹ is a methylsulfonyl group is first prepared by the general formula [VI]

[0053]

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(Wherein rings B and Q have the same meanings as described above) by converting an alkali metal alkoxide (such as sodium methoxide), an alkali metal hydroxide,
After reacting with thiourea in the presence of an alkali metal carbonate or the like, and then reacting with methyl iodide, the compound represented by the general formula [VII]

[0055]

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(Wherein, rings B and Q have the same meaning as described above). Next, the hydroxyl group of the product is treated with a halogenating agent (such as phosphorus oxychloride) to be converted into a reactive residue, and is converted into a general formula [VIII]

[0057]

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(Where X ³ represents a reactive residue, and other symbols have the same meanings as described above). The resulting compound [VIII] is converted to a compound of the general formula [IX]

[0059]

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

[0061]

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(Wherein the symbols have the same meanings as described above), and the obtained compound [X] is treated with ethylene glycol and a deoxidizing agent (sodium hydride, alkali metal alkoxide, alkali metal, etc.). Reacting in the presence of the compound of the general formula [XI]

[0063]

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(Wherein the symbols have the same meanings as described above), and the obtained compound [XI] is further combined with a compound [V] and a deoxidizing agent (sodium hydride,
(Alkali metal alkoxide, alkali metal, etc.)

[0065]

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(Wherein the symbols have the same meanings as described above), and the resulting compound [XI
I] with an oxidizing agent (such as m-chloroperbenzoic acid).

On the other hand, the starting compound [IV] in which R ¹ is a methylthio group is obtained, for example, by oxidizing the compound [XI] with an oxidizing agent (such as m-chloroperbenzoic acid) to give a compound of the general formula [XIII]

[0068]

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(Wherein the symbols have the same meanings as described above), and the resulting compound [XII
After protecting the hydroxyl group of I) with a protecting group such as a tetrahydropyranyl group, compound [III] and a deoxidizing agent (sodium hydride, sodium hydroxide, potassium hydroxide,
In the presence or absence of potassium carbonate, etc.)
It can be produced by removing the protecting group after the reaction.

The object [I] of the present invention may have optical isomers based on an asymmetric carbon atom, and the present invention includes both these optical isomers and mixtures thereof.

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

The target compound [I] of the present invention or a pharmaceutically acceptable salt thereof also includes an inner salt, an adduct, a complex, a hydrate or a solvate thereof.

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

The dose of the target compound [I] of the present invention or a pharmaceutically acceptable salt thereof varies depending on the administration method, age, weight and condition of the patient.
It is preferable to be about 01 to 100 mg / kg.

In the present invention, the lower alkyl group, lower alkoxy group, lower alkylthio group or lower alkylamino group has 1 to 6 carbon atoms, especially 1 to 4 carbon atoms. The lower alkoxycarbonyl group includes those having 2 to 7 carbon atoms, particularly 2 to 5 carbon atoms. Further, examples of the halogen atom include chlorine, bromine, fluorine and iodine.

[0076]

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

Example 1 N- {6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -5- (2-methoxyphenoxy)-
2-methylsulfonylpyrimidin-4-yl} -4-t
tert-butylbenzenesulfonamide 500 mg, ethanolamine 172 mg dimethylacetamide 4 m
The solution is heated and stirred at 110-120 ° C for 20 hours.
After cooling, an aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After washing with water and drying, the solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: chloroform: ethyl acetate = 3: 1) to give N- $ 6.
-[2- (5-bromopyrimidin-2-yloxy) ethoxy] -2- (2-hydroxyethylamino) -5-
(2-methoxyphenoxy) pyrimidin-4-yl}-
57 mg of 4-tert-butylbenzenesulfonamide
Is obtained as a powder (described in Table 1). IR (Nujol): 3400, 3190 cm
^-1 .

Examples 2 to 14 The corresponding starting compounds were treated in the same manner as in Example 1 to obtain the compounds shown in Tables 1 and 2 below.

[0079]

[Table 1]

[0080]

[Table 2]

Example 15 A mixture of 239 mg of the desired product obtained in Example 3, 570 mg of bistributyltin oxide and 4 ml of toluene was added to 9
React at 0 ° C. for 2 days. After cooling, the reaction solution is extracted with ethyl acetate. After washing with water and drying, the solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 1: 1), and further treated with n-hexane to give 3- {6- [2- (5-bromopyrimidine-2
-Yloxy) ethoxy] -4- (4-tert-butylbenzenesulfonamido) -5- (2-methoxyphenoxy) pyrimidin-2-ylthiodipropionic acid 12
5 mg are obtained as a powder (described in Table 3). IR (Nujol): 3390, 1730, 171
0, 1590, 1560, 1495 cm ^-1 .

[0082]

[Table 3]

Example 16 (1) 4-tert-butyl-N- {5- (2-methoxyphenoxy) -2-methylsulfonyl-6- [2-
A mixture of (tetrahydropyran-2-yloxy) ethoxy] pyrimidin-4-yl} benzenesulfonamide (the desired product of Reference Example 2- (2)) 200 mg, N, N-dimethylaminoethylamine 138.8 mg, and dimethylsulfoxide 1 ml was mixed. 15 hours at 100 ° C, then 120 ° C
And react for 5 hours. After treatment with ammonium chloride, 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 preparative silica gel thin layer chromatography (developing solvent; chloroform: methanol =
10: 1) to give 4-tert-butyl-N-
{2- (2- (dimethylamino) ethylamino) -5
(2-methoxyphenoxy) -6- [2- (tetrahydropyran-2-yloxy) ethoxy] pyrimidine-4
99.7 mg of -yl @ benzenesulfonamide are obtained as crystals. m. p. 82-86 ° C.

(2) 70.6 mg of this product in 1 m of methanol
12.6 mg of p-toluenesulfonic acid is added to the 1 solution and reacted at room temperature for 5 hours. 5.5 mg of sodium hydrogen carbonate is added, and the mixture is extracted with chloroform. After washing and drying, the solvent was distilled off under reduced pressure, and the residue was purified by preparative silica gel thin-layer chromatography (developing solvent; chloroform: methanol = 10: 1) to give 4-tert-butyl-
N- [6- (2-hydroxyethoxy) -2- (2-
46.3 mg of (dimethylamino) ethylamino) -5- (2-methoxyphenoxy) pyrimidin-4-yl] benzenesulfonamide are obtained as crystals. m. p. 102.5-106 ° C.

(3) Sodium hydride (60% dispersion type) was added to a solution of 37.3 mg of this product in 2 ml of tetrahydrofuran.
Add 4 mg, then add 52 mg of 5-bromo-2-chloropyrimidine and stir at room temperature for 1 hour. The reaction solution is neutralized with 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 purified by preparative silica gel thin-layer chromatography (developing solvent; chloroform: ethyl acetate = 1: 2) to give N- {6- [2- (5-bromopyrimidine-2).
-Yloxy) ethoxy] -2- (2- (dimethylamino) ethylamino) -5- (2-methoxyphenoxy)
24.6 mg of pyrimidin-4-yl} -4-tert-butylbenzenesulfonamide are obtained as crystals (fourth)
Described in the table).

Examples 17 to 24 The corresponding starting compounds were treated in the same manner as in Example 16 to obtain the compounds shown in Table 4 below.

[0087]

[Table 4]

Example 25 (1) To 2 ml of ethylene glycol was added 125.8 mg of sodium hydride (60% dispersion type).
4-tert-butyl-N- {6- [2- (tetrahydropyran-2-yloxy) ethoxy] -5- (2-methoxyphenoxy) -2-methylsulfonylpyrimidin-4-yl} benzenesulfonamide (Reference Example) 2-
500 mg of the desired product (2) is added, and the mixture is stirred at room temperature for 18 hours. An aqueous ammonium chloride solution is added to the reaction solution, and the mixture is extracted with ethyl acetate. After washing with water and drying, the solvent is distilled off,
The residue was purified by silica gel column chromatography (elution solvent: chloroform: ethyl acetate = 1: 1).
4-tert-butyl-N- {2- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -6- [2
-(Tetrahydropyran-2-yloxy) ethoxy]
Pyrimidin-4-yl @ benzenesulfonamide 44
0.5 mg is obtained as a colorless caramel. ESI-MS (m / z): 618 (MH ⁺ ) IR (Nujol): 3600-3050,157
0,1460,1340 cm ^-1 .

(2) 425 mg of this product, 208 mg of tert-butyldiphenylsilyl chloride, 3.42 mg of 4-dimethylaminopyridine and 83. triethylamine.
A solution of 6 mg of methylene chloride in 3 ml is stirred at room temperature for 18 hours. After diluting with chloroform, wash with water, dry and evaporate under reduced pressure. The residue is dissolved in 5 ml of methanol and 5 ml of tetrahydrofuran, 100 mg of p-toluenesulfonic acid is added, and the mixture is stirred at room temperature for 1 hour. After neutralization with sodium bicarbonate, the mixture is extracted with ethyl acetate. After washing with water and drying, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 2: 1 to 1:
After purifying in 1), 4-tert-butyl-N- [2-
548 mg of (2-tert-butyldiphenylsilyloxyethoxy) -6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) pyrimidin-4-yl] benzenesulfonamide are obtained as a colorless oil. ESI-MS (m / z): 772 (MH ⁺ ) IR (Neat): 3600-3100,158
0, 1460, 1430, 1350 cm ^-1 .

(3) Sodium hydride (60% dispersion type) in a solution of 240.7 mg of this product in 5 ml of tetrahydrofuran
Add 37.4 mg and stir at room temperature for 15 minutes. Next, 90.4 mg of 5-bromo-2-chloropyrimidine is added and the mixture is stirred at room temperature for 2 hours. An aqueous ammonium chloride solution is added to the reaction solution, and 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 purified by preparative silica gel thin-layer chromatography (elution solvent: n-
Purification with hexane: ethyl acetate = 3: 2) yields N- ｛6
-[2- (5-bromopyrimidin-2-yloxy) ethoxy] -2- (2-tert-butyldiphenylsilyloxyethoxy) -5- (2-methoxyphenoxy)
132.4 mg of pyrimidin-4-yl} -4-tert-butylbenzenesulfonamide are obtained as a colorless oil. ESI-MS (m / z): 929 (MH ^<+> ).

(4) To a solution of 82.9 mg of this product in 3 ml of tetrahydrofuran was added 0.09 ml of a 1.0 M tetrabutylammonium fluoride-tetrahydrofuran solution, and the mixture was stirred at room temperature for 1 hour. The solvent is distilled off and extracted with ethyl acetate. After washing and drying the ethyl acetate layer, the solvent is distilled off under reduced pressure. The residue was treated with n-hexane to give N-
{6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -2- (2-hydroxyethoxy) -5
-(2-methoxyphenoxy) pyrimidin-4-yl}
-4-tert-butylbenzenesulfonamide 49m
g are obtained as crystals (described in Table 5).

Example 26 (1) Methoxymethyloxymethyltributyltin 65
1.63M in 6ml of 5mg solution of tetrahydrofuran
1.09 ml of n-butyllithium-n-hexane solution is added dropwise at -78 ° C. After stirring at the same temperature for 4 minutes, 4-te
rt-butyl-N- [6- (2-hydroxyethoxy)
−5- (2-Methoxyphenoxy) -2-methylsulfonylpyrimidin-4-yl] benzenesulfonamide (the desired product of Reference Example 2- (1)) (2 mg) in tetrahydrofuran (2 ml) is added, and the mixture is stirred for 40 minutes. An aqueous ammonium chloride solution is added to the reaction solution, and 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: methanol = 100: 1 to 50:
Purified in 1), and 4-tert-butyl-N- [6- (2
-Hydroxyethoxy) -2-methoxymethyloxymethyl-5- (2-methoxyphenoxy) pyrimidine-4
-Yl] benzenesulfonamide (111 mg) as a colorless caramel. ESI-MS (m / z): 546 (MH ⁺ ) IR (Nujol): 3550-3400, 320
0, 1580, 1500, 1480, 1430 cm ^-1
.

(2) To a mixture of 80 mg of this product in 2 ml of tetrahydrofuran and 0.4 ml of dimethylacetamide was added 18 mg of sodium hydride (60% dispersion type), and then 42 mg of 5-bromo-2-chloropyrimidine.
Stir for 1 hour at room temperature. An aqueous ammonium chloride solution is added to the reaction solution, and 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 purified by preparative silica gel thin-layer chromatography (developing solvent; chloroform: ethyl acetate = 3: 1) to give N- {6- [2
-(5-Bromopyrimidin-2-yloxy) ethoxy] -2-methoxymethyloxymethyl-5- (2-methoxyphenoxy) pyrimidin-4-yl} -4-te
91 mg of rt-butylbenzenesulfonamide are obtained as a foam. ESI-MS (m / z): 70
6,704 (MH ^<+> ).

(3) 2 ml of methylene chloride of 85 mg of this product
Add 11 ml of trifluoroacetic acid to the solution and stir at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was purified by preparative silica gel thin-layer chromatography (developing solvent; chloroform: methanol = 30: 1), and further recrystallized from ethyl acetate-n-hexane to give N- {6- 26 mg of [2- (5-bromopyrimidin-2-yloxy) ethoxy] -2-hydroxymethyl-5- (2-methoxyphenoxy) pyrimidin-4-yl} -4-tert-butylbenzenesulfonamide are obtained as crystals ( Described in Table 5).

Example 27 (1) N- [6- {2- (5-bromopyrimidine-2-)
Yloxy) ethoxy {-5- (2-methoxyphenoxy) -2-methylsulfonylpyrimidin-4-yl]-
300 mg of 4-tert-butylbenzenesulfonamide (the target compound of Reference Example 1- (6)), sodium azide 9
2 mg and a mixture of 2 ml of dimethylformamide at 80 ° C
For 1 hour. After cooling, water is added and extracted with ethyl acetate. After washing with water and drying, the solvent was distilled off, and the residue was purified by preparative silica gel thin-layer chromatography (developing solvent; chloroform: ethyl acetate = 2: 1) to give N-
[2-azido-6-2- (5-bromopyrimidine-2
This gives 323.3 mg of -yloxy) ethoxy {-5- (2-methoxyphenoxy) pyrimidin-4-yl] -4-tert-butylbenzenesulfonamide as a foam. ESI-MS (m / z): 673 (MH ⁺ ) IR (Nujol): 3400-2800, 214
0,1680,1600-1560,1500,146
0 cm ^-1 .

(2) 293.3 mg of this product, 127.1 mg of triphenylphosphine and 2 m of tetrahydrofuran
was stirred at room temperature for 15 minutes. Extract with chloroform, wash with water and dry. The solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (elution solvent: chloroform: ethyl acetate = 2: 1) to obtain 317.5 mg of an adduct of triphenylphosphine. 275mg of this product
Was added to a solution of 2 ml of tetrahydrofuran and stirred at room temperature for 12 hours. After neutralization with aqueous sodium bicarbonate, 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 purified by preparative silica gel thin-layer chromatography (developing solvent; ethyl acetate: n-hexane = 3: 2) to give N- [2-amino-6- {2- (5-bromopyrimidine-2-). 121.6 mg of iloxy) ethoxy {-5- (2-methoxyphenoxy) pyrimidin-4-yl] -4-tert-butylbenzenesulfonamide are obtained as crystals (fifth).
Described in the table).

[0097]

[Table 5]

Example 28 (1) N- [6- (2-benzyloxyethoxy) -5
-(4-Methylphenyl) -2-methylsulfonylpyrimidin-4-yl] -4-tert-butylbenzenesulfonamide (the target compound of Reference Example 3- (6)) 300 mg
And a mixture of 4 ml of 2-aminoethanol are heated and stirred at 120 ° C. for 3 hours. After cooling, an aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After washing with water and drying, the solvent is distilled off, and the residue is subjected to silica gel column chromatography (elution solvent: chloroform: methanol = 1).
0: 1) and further crystallized from isopropyl ether-n-hexane to give N- [6- (2-benzyloxyethoxy) -2- (2-hydroxyethylamino)-
5- (4-methylphenyl) pyrimidin-4-yl]-
4-tert-butylbenzenesulfonamide 260m
g are obtained as crystals. m. p. 124-126 ° C.

(2) To a solution of 245 mg of this product and 0.1 ml of dihydropyran in 4 ml of methylene chloride was added 4 mg of 10-camphorsulfonic acid, followed by stirring at room temperature for 6 hours.
The reaction solution is treated with dilute aqueous sodium bicarbonate and extracted 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;
Purification with ethyl acetate: n-hexane = 1: 10 to 1: 3) yielded N- {6- (2-benzyloxyethoxy) -2.
-[2- (tetrahydropyran-2-yloxy) ethylamino] -5- (4-methylphenyl) pyrimidine-
234 mg of 4-yl} -4-tert-butylbenzenesulfonamide are obtained as caramel. ESI-MS (m / z): 675 (MH ⁺ ) IR (Nujol): 1460, 1380, 10
80 cm ^-1 .

(3) A mixture of 220 mg of the product, 150 mg of palladium-carbon, 4 ml of methanol and 2 ml of tetrahydrofuran is subjected to catalytic reduction in a hydrogen atmosphere for 1.5 hours. The catalyst is removed by filtration and the filtrate is distilled off under reduced pressure. The residue was recrystallized from n-hexane to give 4-tert-butyl-N- {6}.
-(2-hydroxyethoxy) -2- [2- (tetrahydropyran-2-yloxy) ethylamino] -5
167 mg of (4-methylphenyl) pyrimidin-4-yl} benzenesulfonamide are obtained. m. p. 113-116 ° C.

(4) 63 mg of sodium hydride (60% dispersion type) is added to a mixture of 154 mg of this product, 5 ml of tetrahydrofuran and 3 ml of dimethylacetamide, and the mixture is stirred for 5 minutes. Then, 5-bromo-2-chloropyrimidine 1
Add 42 mg and stir at room temperature for 19 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 was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 40: 1) and further purified by n
Crystallized from -hexane to give N- {6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -2-
[2- (Tetrahydropyran-2-yloxy) ethylamino] -5- (4-methylphenyl) pyrimidine-4
141 mg of -yl｝ -4-tertbutylbenzenesulfonamide are obtained. m. p. 65-69 ° C.

(5) 124 mg of this product in 5 ml of methanol
Then, 2 ml of a 10% hydrochloric acid aqueous solution is added to a 1 ml solution of tetrahydrofuran and reacted at room temperature for 2 hours. After neutralization with sodium bicarbonate, the mixture is extracted with ethyl acetate. Washing the extract,
After drying, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: chloroform: ethyl acetate = 10: 1 to 2: 1).
Crystallization from isopropyl ether gave N- [6- {2
-(5-bromopyrimidin-2-yloxy) ethoxy} -2- (2-hydroxyethylamino) -5- (4
-Methylphenyl) pyrimidin-4-yl] -4-te
91 mg of rt-butylbenzenesulfonamide are obtained as crystals (described in Table 6).

Example 29 (1) 4-tert-butyl-N- {5- (2-methoxyphenoxy) -6- [2- (tetrahydropyran-2)
-Yloxy) ethoxy] -2-methylsulfonylpyrimidin-4-yl} benzenesulfonamide (Reference Example 2
-The desired product of (2)) 500 mg, potassium cyanide 15
A mixture of 3 mg and 5 ml of dimethylformamide was mixed with 120
Stir for 3 hours at 0 ° C. After cooling, an aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off, and 4-tert-butyl-N- {2-cyano-6- [2- (tetrahydropyran-2-yloxy) ethoxy] -5- (2-methoxy 425 mg of phenoxy) pyrimidin-2-yl @ benzenesulfonamide are obtained as crystals.

(2) 392 mg of this product in 5 ml of methanol
13 mg of p-toluenesulfonic acid is added to the solution and reacted at room temperature for 2 hours. The reaction solution is treated with water and extracted with ethyl acetate. After washing and drying the ethyl acetate layer, the solvent was distilled off under reduced pressure to give 4-tert-butyl-N- {2-cyano-6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) pyrimidine-4. 294 mg of -yl @ benzenesulfonamide are obtained as a foam.

(3) 54 mg of sodium hydride (60% dispersion type) was added to a mixture of 266 mg of this product, 3 ml of tetrahydrofuran and 0.5 ml of dimethylacetamide, followed by 10 minutes.
Stir for minutes. Next, 131 mg of 5-bromo-2-chloropyrimidine is added, and the mixture is stirred at room temperature for 1 hour. After treatment with aqueous ammonium chloride, 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 purified by silica gel column chromatography (elution solvent; chloroform: ethyl acetate = 10: 1), and further treated with ethyl acetate-n-hexane to give N-
206 mg of {6- [2- (5-bromopyrimidin-2-yloxy) ethoxy] -2-cyano-5- (2-methoxyphenoxy) pyrimidin-4-yl} -4-tert-butylbenzenesulfonamide as powder obtain.

(4) A mixture of 188 mg of this product, 182 mg of tributyltin azide and 3 ml of toluene is heated under reflux for 23 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 40: 1 to 10: 1) to give N- {6-
[2- (5-bromopyrimidin-2-yloxy) ethoxy] -5- (2-methoxyphenoxy) -2- (5-
Tetrazolyl) pyrimidin-4-yl {-4-tert
68 mg of -butylbenzenesulfonamide are obtained as a powder (listed in Table 6). IR (Nujol): 3350, 3190, 157
0.1460 cm ^-1 .

[0107]

[Table 6]

Reference Example 1 (1) Diethyl (2-methoxyphenoxy) malonate 1
0.0 g and 4.04 g of thiourea in 100 m of methanol
To this solution, 17.07 g of a 28% sodium methoxide-methanol solution was added dropwise over 30 minutes while stirring under ice-cooling, followed by stirring at room temperature overnight. After the reaction, the solvent was distilled off under reduced pressure, 200 ml of water was added to the residue, and 3.30 ml of methyl iodide was further added.
Add. After reacting at room temperature for 3 hours, the reaction solution is made acidic by adding a 10% aqueous hydrochloric acid solution. The precipitated crystals are collected by filtration, washed with water and dried, and 4,6-dihydroxy-5- (2-methoxyphenoxy) -2-methylthiopyrimidine 8.90.
g. m. p. 206-210 ° C.

(2) A mixture of 3.00 g of the product, 5 ml of diethylaniline and 15 ml of phosphorus oxychloride was heated under reflux for 2 hours. After the reaction, phosphorus oxychloride is distilled off under reduced pressure, poured into ice water, and extracted with ethyl acetate. After washing and drying the extract, the solvent is distilled off, and the residue is crystallized from n-hexane to obtain 2.67 g of 4,6-dichloro-5- (2-methoxyphenoxy) -2-methylthiopyrimidine. m. p. 148-149.5 ° C.

(3) To a solution of 1.0 g of this product in 10 ml of dimethyl sulfoxide was added 705 mg of 4-tert-butylbenzenesulfonamide and 1.31 g of potassium carbonate, and the mixture was stirred at 70 ° C. for 2 hours. After cooling, the reaction mixture is treated with ice water, made acidic with 10% aqueous hydrochloric acid, and extracted with ethyl acetate. The extract was washed and dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: chloroform: ethyl acetate = 20: 1), and further recrystallized from ethyl acetate-n-hexane. 4-tert-
1.14 g of butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2-methylthiopyrimidin-4-yl] benzenesulfonamide are obtained as crystals. m. p. 123-124 ° C.

(4) 441 mg of sodium hydride (60% dispersion type) was added to 11 ml of ethylene glycol, and after foaming was completed, 1.09 g of the product was added. 1 hour at 80 ° C,
Furthermore, it heats at 100 degreeC for 3 hours. After cooling, the reaction mixture is diluted with diluted hydrochloric acid under cooling, and extracted with ethyl acetate. After the extract was washed and dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent; ethyl acetate: n-hexane = 1: 2).
Recrystallized from -hexane to give 4-tert-butyl-N
866 mg of-[6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -2-methylthiopyrimidin-4-yl] benzenesulfonamide are obtained. m. p. 139-140.5 ° C.

(5) To a mixed solution of 15.0 g of this product in 150 ml of tetrahydrofuran and 15 ml of dimethylacetamide is added 3.46 g of sodium hydride (60% dispersion type) little by little, and the mixture is stirred for 10 minutes. Then, 5-bromo-2
-Add 8.36 g of chloropyrimidine and stir at room temperature for 1 hour. The reaction solution is poured into ice water, ammonium chloride is added, and 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 ethyl acetate-
Recrystallization from n-hexane gave N- {6- [2- (5-
Bromopyrimidin-2-yloxy) ethoxy] -5-
16.42 g of (2-methoxyphenoxy) -2-methylthiopyrimidin-4-yl} -4-tert-butylbenzenesulfonamide are obtained. m. p. 117-121 ° C.

(6) Chloroform 1 of 16.24 g of this product
To the 60 ml suspension, 10.67 g of m-chloroperbenzoic acid (85.4% purity) is added under ice-cooling, and the mixture is reacted at 0 ° C. for 1 hour and further at room temperature for 2 hours. An aqueous solution of sodium hydrogen sulfite is added to the reaction solution, and the chloroform layer is separated. After washing with water and drying, the solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: chloroform: ethyl acetate = 20: 1-3: 1) to give N- [6- {2-}
(5-bromopyrimidin-2-yloxy) ethoxy}
13.45 g of -5- (2-methoxyphenoxy) -2-methylsulfonylpyrimidin-4-yl] -4-tert-butylbenzenesulfonamide are obtained as a caramel. FAB-MS (m / z): 710, 708 (M
H ⁺ ) IR (Nujol): 3170 cm ^-1 .

Reference Example 2 (1) 4-tert-butyl-N- [6- (2-hydroxyethoxy) -5 obtained in Reference Example 1- (4)
(2-Methoxyphenoxy) -2-methylthiopyrimidin-4-yl] benzenesulfonamide (12.46 g) was treated with m-chloroperbenzoic acid as in Reference Example 1- (6).
Oxidation at 66 g gives 4-tert-butyl-N- [6-
(2-Hydroxyethoxy) -5- (2-methoxyphenoxy) -2-methylsulfonylpyrimidin-4-yl] benzenesulfonamide (11.10 g) is obtained as a colorless caramel. FAB-MS (m / z): 552 (MH ^<+> ).

(2) To a solution of 1.00 g of this product and 350.8 mg of dihydropyran in 20 ml of methylene chloride was added 21 mg of 10-camphorsulfonic acid, followed by stirring at room temperature for 2 hours. The reaction solution is treated with dilute aqueous sodium hydrogen carbonate and extracted with chloroform. The chloroform layer is washed with water, dried and evaporated under reduced pressure. The residue was recrystallized from methylene chloride-ethyl acetate,
Crystallize 790 mg of 4-tert-butyl-N- {6- [2- (tetrahydropyran-2-yloxy) ethoxy] -5- (2-methoxyphenoxy) -2-methylsulfonylpyrimidin-4-yl} benzenesulfonamide. Get as. m. p. 222-27.5 [deg.] C.

Reference Example 3 (1) A 28% sodium methoxide-methanol solution 3 was added to a solution of 13.69 g of thiourea in 150 ml of methanol.
4.70 g was added at 60 ° C., and further, 32.62 g of diethyl (4-methylphenyl) malonate was added at the same temperature, and the reaction solution was heated to reflux for 8 hours. After cooling, add water to the reaction solution,
Acidify (pH = 1) with hydrochloric acid under ice cooling. The precipitated crystals are collected by filtration, and the residue is washed and dried to obtain 12.53 g of 4,6-dihydroxy-2-mercapto-5- (4-methylphenyl) pyrimidine as crystals. m. p. 290-292 ° C (decomposition).

(2) 12.5 g of this product, potassium carbonate 7.
3.32 ml of methyl iodide is added dropwise to 37 g of a mixture of 65 ml of dimethyl sulfoxide at room temperature over 10 minutes.
Thereafter, the reaction is carried out at room temperature for 2 hours. Add water to the reaction solution,
Acidify with hydrochloric acid under ice-cooling. The precipitated crystals are collected by filtration,
The residue was washed and dried to give 4,6-dihydroxy-5
(4-methylphenyl) -2-methylthiopyrimidine 1
0.56 g is obtained as crystals. m. p. 226 [deg.] C-(decomposition).

(3) 10.56 g of this product was used in Reference Example 1-
The same treatment as in (2) was carried out to give 4,6-dichloro-5- (4
-Methylphenyl) -2-methylthiopyrimidine 6.4
5 g are obtained as crystals. m. p. 74.0-78.0 ° C.

(4) 6.45 g of this product and 4-tert-
Butylbenzenesulfonamide was treated in the same manner as in Reference Example 1- (3) to give 4-tert-butyl-N- [6-chloro-5- (4-methylphenyl) -2-methylthiopyrimidin-4-yl]. 7.31 g of benzenesulfonamide
Is obtained as crystals. m. p. 178-182 ° C.

(5) Sodium hydride (60% dispersion type)
To a suspension of 1.21 g of tetrahydrofuran in 60 ml of 2-
2.58 ml of benzyloxyethanol is added dropwise over 10 minutes, and then stirred for 10 minutes at room temperature. 15.2 g of this product is added to the reaction solution, and the mixture is heated and stirred at 50 ° C. for 4 hours. After cooling, the reaction solution is poured into ice-cold aqueous hydrochloric acid and extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 30: 1 to 10: 1).
Crystallization from n-hexane gave N- [6- (2-benzyloxyethoxy) -5- (4-methylphenyl) -2.
-Methylthiopyrimidin-4-yl] -4-tert-
2.12 g of butylbenzenesulfonamide are obtained. m. p. 115-116 ° C.

(6) Reference Example 1- (6)
Oxidized with 1.84 g of m-chloroperbenzoic acid in the same manner as
N- [6- (2-benzyloxyethoxy) -5- (4
-Methylphenyl) -2-methylsulfonylpyrimidin-4-yl] -4-tert-butylbenzenesulfonamide is obtained as crystals, 2.15 g. m. p. 129-130 ° C.

[0122]

The object compound [I] of the present invention or a pharmaceutically acceptable salt thereof is highly water-soluble and has excellent endothelin antagonism, so that diseases related to endothelin activity, for example, hypertension Disease, 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 Prevention of thrombosis, arteriosclerosis, heart failure, acute renal failure, glomerulonephritis, cyclosporin-induced nephrotoxicity, myocardial infarction, angina, arrhythmia, glaucoma, migraine, cerebral vasospasm and cerebral infarction Or it is useful as a therapeutic agent. Further, the object of the present invention has low toxicity and high safety when used as a pharmaceutical compound.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI A61P 1/04 A61P 1/04 9/00 9/00 9/12 9/12 43/00 111 43/00 111 (72) Invention Person Rinako Kono 4-180-1, Sakuragicho, Omiya City, Saitama Prefecture 401, Towa Citycorp Omiya Sakuragicho (56) References JP-A-8-99961 (JP, A) JP-A-8-208625 (JP, A) JP-A-5-155864 (JP, A) JP-A-5-222003 (JP, A) JP-A-6-211810 (JP, A) JP-A-7-17972 (JP, A) (58) Int.Cl. ⁷ , DB name) C07D 239/69 C07D 401/14 C07D 403/14 CA (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] 1. A compound of the general formula [I] (However, ring A and ring B are substituted or unsubstituted phenyl groups, Q is a single bond or a group represented by the formula -O-, R is a substituted or unsubstituted aromatic heterocyclic group, R ¹ is substituted or unsubstituted Substituted amino group, substituted or unsubstituted lower alkyl group,
Represents a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted lower alkylthio group, or a substituted or unsubstituted heterocyclic group. Or a pharmacologically acceptable salt thereof. 2. A phenyl group in which ring A and ring B may be substituted with 1 to 3 groups selected from a lower alkyl group and a lower alkoxy group, R represents a halogen atom, a lower alkyl group, and a hydroxy lower alkyl group. A lower alkoxy group, a phenyl group, a furyl group, a thienyl group and an aromatic heterocyclic group optionally substituted with 1 to 4 substituents selected from the group consisting of a pyridyl group, The group is a 5-10 membered monocyclic or bicyclic aromatic heterocyclic group containing 1-4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, wherein R ¹ is mono- or Di-hydroxy lower alkyl group, lower alkyl group, lower alkoxy group, amino lower alkyl group, mono- or di-lower alkylamino-lower alkyl group, lower alkoxy-lower alkyl group and An amino group optionally substituted with one or two groups selected from xy lower alkyl groups; a lower alkyl group optionally substituted with a carboxyl group or a hydroxyl group; a hydroxyl group, a carboxyl group, a hydroxy lower alkyl group, A lower alkoxy group which may be substituted with a group selected from a carboxy lower alkyl group, an amino lower alkyl group and a mono- or di-lower alkylamino group; a hydroxyl group, a carboxyl group, a lower alkoxycarbonyl group, an amino group and a mono- Or a lower alkylthio group which may be substituted with a group selected from di-lower alkylamino groups; and 1 to 4 groups selected from a hydroxyl group, a carboxyl group, an amino group and a mono- or di-lower alkylamino group. A heterocyclic group which may be substituted, Cyclic group is a single ring,
The compound according to claim 1, which is a bicyclic or tricyclic aliphatic or an aromatic heterocyclic group which may be partially saturated. 3. A phenyl group in which ring A is substituted with 1 to 3 lower alkyl groups, and a phenyl ring B is substituted with 1 to 3 lower alkyl groups or 1 to 3 lower alkoxy groups. Group, R is a halogen atom, a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy group, a phenyl group,
1 to 1 selected from a furyl group, a thienyl group and a pyridyl group
A pyrimidinyl group substituted with 4 groups, wherein R ¹ is a mono- or di-hydroxy lower alkyl group, a lower alkyl group, a lower alkoxy group, an amino lower alkyl group, a mono- or di-lower alkylamino-lower alkyl group ,
An amino group optionally substituted with one or two groups selected from a lower alkoxy-lower alkyl group and a carboxy lower alkyl group; a lower alkyl group optionally substituted with a carboxyl group or a hydroxyl group;
A lower alkoxy group which may be substituted with a group selected from a carboxyl group, a hydroxy lower alkyl group, a carboxy lower alkyl group, an amino lower alkyl group and a mono- or di-lower alkylamino group;
A lower alkylthio group which may be substituted with a group selected from a carboxyl group, a lower alkoxycarbonyl group, an amino group and a mono- or di-lower alkylamino group;
Hydroxyl, carboxyl, amino and mono-
Or 1-4 selected from di-lower alkylamino groups
3. The compound according to claim 2, which is a piperidyl group optionally substituted with a plurality of groups; or a tetrazolyl group. 4. R is 1 to 3 halogen atoms or 1 to 3
Pyrimidinyl group substituted with two lower alkoxy groups, R ¹ is selected from an unsubstituted amino group or a mono- or di-hydroxy lower alkyl group, a mono- or di-lower alkylamino-lower alkyl group and a lower alkoxy-lower alkyl group. 4. The compound according to claim 3, which is an amino group substituted with one or two groups. 5. A compound of the general formula [II] (However, ring A and ring B are substituted or unsubstituted phenyl groups, Q is a single bond or a group represented by the formula -O-, R is a substituted or unsubstituted aromatic heterocyclic group, and X ¹ is lower alkylsulfonyl Or a salt thereof, or a phenylsulfonyl group) and a salt thereof with the general formula [III]. (However, R ¹ represents a substituted or unsubstituted amino group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted lower alkylthio group, or a substituted or unsubstituted heterocyclic group.) Reacting with a compound of the formula (I) or a salt thereof and, if necessary, converting the product into a pharmaceutically acceptable salt thereof. Wherein the symbols have the same meanings as described above, or a pharmaceutically acceptable salt thereof. 6. A compound of the general formula [IV] (However, ring A and ring B are substituted or unsubstituted phenyl groups, Q is a single bond or a group represented by formula -O-, R ¹ is a substituted or unsubstituted amino group, a substituted or unsubstituted lower alkyl group, Or a substituted or unsubstituted lower alkylthio group or a substituted or unsubstituted heterocyclic group) or a salt thereof and a general formula [V]. (Where R is a substituted or unsubstituted aromatic heterocyclic group, X
² represents a halogen atom. Wherein the product is converted to a pharmaceutically acceptable salt thereof, if necessary. Wherein the symbols have the same meanings as described above, or a pharmaceutically acceptable salt thereof.