JPH0967370A - New n-pyrimidinylthiophenesulfonamide derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound competitively inhibiting the combination of endothelin with a receptor and useful for the treatments of various diseases mainly including cardiovascular diseases, such as essential hypertension, pulmonary hypertension and bronchial asthma.

SOLUTION: This N-pyrimidinyl-thiophenesufonamide derivative of the formula [A is a lower alkylene; R¹ is a lower alkyl; either one of R², R³ is H, a lower alkyl, and the other is a lower alkyl, amino, a mono or di lower alkylamino, etc.; R⁴ is a lower alkyl, a lower alkoxy, a halogen, trifluoromethyl, etc.; (n) is an integer of 0-4] or its pharmaceutically acceptable salt. For example, dimethyl N-[[[5-(2-methoxyphenoxy)-6-[5-2-propyl)-2thienylsulfonylamino]-2-(2- pyrimidinyl)-4-pyrimidinyl]acetyl]-(L)-aspartate. The compound of the formula is obtained by reacting the corresponding carboxylic acid with an amino compound.

COPYRIGHT: (C)1997,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel N-pyrimidinyl thiophene sulfonamide derivative or a pharmaceutically acceptable salt thereof having a high affinity for a drug, particularly an endothelin receptor, and an active ingredient thereof. And an anti-endothelin drug.

[0002]

Endothelin is an endogenous physiologically active peptide consisting of 21 amino acids, and three types of isopeptides, ET-1, ET-2, and ET-3, which are slightly different in amino acid sequence, are known.

Endothelin expresses its physiological action by binding to the endothelin receptor on the target cell membrane. At least two subtypes of endothelin receptors have so far been found to exist,
They are designated ET _A and ET _B receptors. They are,
There is a difference in affinity with endothelin, ET _A receptor binds to ET-1 and ET-2 more strongly than ET-3, and ET _B receptor binds to 3 kinds of endothelin with similar strength. .

Endothelin and the endothelin receptor are
It is produced or expressed in various cells of various organs, and various physiological actions resulting from them are known. For example, in blood vessels, ET-1 produced and secreted in vascular endothelial cells binds to ET _A receptors on vascular smooth muscle cells present in the vicinity, and strongly and persistently contracts blood vessels. On the other hand, vascular endothelial cells themselves express ET _B receptor, and when ET-1 binds to this, nitric oxide (N
O) is produced and released. Since nitric oxide has the effect of relaxing vascular smooth muscle, blood vessels relax. In fact, experimentally, when ET-1 was intravenously administered to rats, a continuous increase in pressure was observed after a transient decrease in pressure. As can be seen from the above physiological actions in blood vessels, endothelin, particularly ET-
1 has one aspect as a very potent and persistent vasoconstrictor physiologically active peptide, and therefore its involvement with diseases, especially cardiovascular diseases, has been discussed from the beginning.

Nowadays, not only cardiovascular diseases but also many other diseases, endothelin, especially ET-1 hypersecretion (specifically E in local or tissue, circulating blood)
It is pointed out that the increase in T-1 concentration) may be involved. For example, essential hypertension, pulmonary hypertension, erythropoietin-induced hypertension, cyclosporin A-induced hypertension, bronchial asthma, acute renal failure, chronic renal failure, glomerulonephritis, acute myocardial infarction, unstable angina, chronic heart failure, mainly arachnoid. Cerebral vasospasm after bleeding, urinary incontinence, benign prostatic hypertrophy, arteriosclerosis, Raynaud's syndrome, diabetic peripheral circulation disorder, diabetic nephropathy, preeclampsia, preterm birth, peptic ulcer, liver failure, rheumatism, after PTCA Has been reported to be associated with diseases such as restenosis (GMRUBANYI, MAPOLOKOFF, Pharmaco
logicalRevies , Vol.46, No.3,325 (1994), latest medicine 49
Vol. 3, No. 335 (1994)).

Therefore, an agent that inhibits the binding between ET-1 and the endothelin receptor by binding to the endothelin receptor, that is, an endothelin antagonist, can be an effective preventive agent or therapeutic agent for the above diseases. . As such an endothelin antagonist, a series of sulfonamide derivatives are disclosed in JP-A-5-155864 and JP-A-5-155864.
222003, JP-A-6-212810, JP-A-7-
It has already been disclosed in 17972. In particular, Japanese Patent Application Laid-Open
The compound described in Example 67 of 222003 (generic name bosentan) has been reported to be effective and orally absorbable in a model animal for disease state. However, the receptor affinity of these compounds is insufficient, and it has been earnestly desired to create an endothelin antagonist having a stronger receptor affinity.

[0007]

Under the circumstances described above, the inventors of the present invention have advanced the screening for compounds having a strong affinity for the endothelin receptor, and as a result, novel N -Pyrimidinyl thiophene sulfonamide derivatives are used for endothelin receptors, especially E
They have found that they have a high affinity for the T _A receptor and have completed the present invention.

[0008]

The present invention relates to an N-pyrimidinyl thiophene sulfonamide derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[0009]

Embedded image

(However, the symbols in the formulas have the following meanings: A: lower alkylene group; R ¹ : lower alkyl group.

R ² and R ³ are either a hydrogen atom or a lower alkyl group, and the other is a lower alkyl group, an amino group, a mono- or di-lower alkylamino group, or a 5- or 6-membered hetero atom containing a nitrogen atom. Ring group. However, the 5
Alternatively, the 6-membered heterocyclic group may be substituted with a lower alkyl group, and the other lower alkyl group is a hydroxyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a nitrogen-containing 5- or 6-membered heterocyclic group, an amino group. , A mono- or di-lower alkylamino group, or a carboxyl group may be substituted. Further, the 5- or 6-membered heterocyclic group which is a substituent of the other lower alkyl group may be substituted with a lower alkyl group.

[0012]

Embedded image You may form the group shown by.

Here, R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same or different and each is a hydrogen atom, a lower alkyl group, an amino group or a hydroxyl group, but R ⁶ and R ⁷ are integrated. A lower alkylene group may be formed.

R ^{4 is a} lower alkyl group, a lower alkoxy group, a halogen atom, a trifluoromethyl group, a lower alkylthio group, a lower alkylsulfinyl group or a lower alkylsulfonyl group. n: an integer of 0 to 4. )

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the general formula (I) is further described as follows. In the present specification, the term "lower" means a straight or branched hydrocarbon chain having 1 to 6 carbon atoms. Therefore, as the "lower alkyl group", specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, Neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1- Ethylbutyl group, 2-ethylbutyl group,
Examples thereof include a 1,1,2-trimethylpropyl group, a 1,2,2-trimethylpropyl group, a 1-ethyl-1-methylpropyl group, and a 1-ethyl-2-methylpropyl group.

The "lower alkylene group" formed by A or R ⁶ and R ⁷ integrally includes, for example, methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group. , Hexamethylene group, methylmethylene group, propylene group, dimethylmethylene group,
Examples thereof include a methylethylene group, a methyltrimethylene group, a 1,1-dimethyltetramethylene group, and a 1,2-dimethyltetramethylene group, and the lower alkylene group for A is a methylene group, an ethylene group, a trimethylene group, or a dimethylmethylene group. A group is preferred, and an ethylene group is preferred as the lower alkylene group formed by R ⁶ and R ⁷ integrally.

"Mono- or di-lower alkylamino group"
Means an amino group having a linear or branched alkyl group having 1 to 6 carbon atoms. As the "mono-lower alkylamino group", specifically, for example, a methylamino group,
Ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, sec-
Butylamino group, tert-butylamino group, pentylamino group, isopentylamino group, neopentylamino group, tert-pentylamino group, 1-methylbutylamino group, 2-methylbutylamino group, 1,2-dimethylpropyl Amino group, hexylamino group, isohexylamino group, 1-methylpentylamino group, 2-methylpentylamino group, 3-methylpentylamino group, 1,1-
Dimethylbutylamino group, 1,2-dimethylbutylamino group, 2,2-dimethylbutylamino group, 1,3-dimethylbutylamino group, 2,3-dimethylbutylamino group, 3,3-dimethylbutylamino group, 1-ethylbutylamino group, 2-ethylbutylamino group, 1,1,2-
Examples thereof include a trimethylpropylamino group, a 1,2,2-trimethylpropylamino group, a 1-ethyl-1-methylpropylamino group and a 1-ethyl-2-methylpropylamino group.

The "di-lower alkylamino group" is specifically, for example, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di (sec-
Butyl) amino group, di (tert-butyl) amino group,
Examples thereof include a dipentylamino group, a diisopentylamino group, a dineopentylamino group, and a di (tert-pentyl) amino group. In addition, methyl lower amino groups such as methylethylamino group, methylpropylamino group, methylisopropylamino group, methylbutylamino group and methylisobutylamino group, ethylpropylamino group, ethylisopropylamino group, ethylbutylamino group, ethyl Examples thereof include ethyl lower alkylamino groups such as isobutylamino group and ethyl sec-butylamino group.

Examples of the nitrogen-containing 5- or 6-membered heterocyclic group include a pyrrolidinyl group, a pyrazolidinyl group, a piperidyl group, a piperazinyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group and a morpholinyl group. These may be further substituted with a specific group of the above lower alkyl group.

Specific examples of the "lower alkoxy group" for R ² or R ³ and R ⁴ include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group,
Isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, 1
-Methylbutoxy group, 2-methylbutoxy group, 1,2-
Dimethylpropoxy group, hexyloxy group, isohexyloxy group, 1-methylpentoxyoxy group, 2-methylpentoxyoxy group, 3-methylpentoxyoxy group, 1,1-dimethylbutoxy group, 1,2-dimethyl Butoxy group, 2,2-dimethylbutoxy group, 1,3-dimethylbutoxy group, 2,3-dimethylbutoxy group, 3,3
-Dimethylbutoxy group, 1-ethylbutoxy group, 2-ethylbutoxy group, 1,1,2-trimethylpropoxy group, 1,2,2-trimethylpropoxy group, 1-ethyl-1-methylpropoxy group, 1-ethyl Examples thereof include a 2-methylpropoxy group, and a methoxy group is particularly preferable.

The "lower alkoxycarbonyl group (-COOR)" for R ² or R ³ includes the alkoxycarbonyl groups having the above lower alkoxy group.

Examples of the "halogen atom" of R ⁴ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0023] In addition, the R ⁴ "lower alkylthio group (-S
R) ”specifically includes, for example, methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group, sec-butylthio group, tert-butylthio group, pentylthio group, isopentylthio group, Neopentylthio group, tert-pentylthio group, 1-methylbutylthio group, 2-methylbutylthio group, 1,2-dimethylpropylthio group, hexylthio group, isohexylthio group, 1-methylpentylthio group, 2- Methylpentylthio group, 3-methylpentylthio group, 1,1-dimethylbutylthio group, 1,2-dimethylbutylthio group, 2,2-dimethylbutylthio group, 1,
3-dimethylbutylthio group, 2,3-dimethylbutylthio group, 3,3-dimethylbutylthio group, 1-ethylbutylthio group, 2-ethylbutylthio group, 1,1,2-trimethylpropylthio group, 1,2,2-trimethylpropylthio group, 1-ethyl-1-methylpropylthio group, 1
Examples include -ethyl-2-methylpropylthio group.

[0024] The term "lower alkylsulfinyl group of R ⁴ (-
SOR) "," lower alkylsulfonyl group (-SO
₂ R) ”is an alkylsulfinyl group having an alkyl group similar to the above lower alkylthio group,
An alkylsulfonyl group is mentioned.

The compound of the present invention may have an asymmetric carbon atom, and isomers based on the asymmetric carbon atom may exist.
The present invention includes mixtures and isolated forms of these optical isomers. Further, among the compounds of the present invention,

[0026]

Embedded image

And when at least one of R ⁵ , R ⁶ , R ⁷ and R ⁸ is a hydrogen atom, a tautomer exists. For example, when R ⁶ and R ⁸ are hydrogen atoms, there exist tautomers as shown in the following formula.

[0028]

[Chemical 6]

The present invention includes each of these tautomers, and mixtures in any proportion.

Further, the compound of the present invention may form a salt, specifically, hydrochloric acid, hydrobromic acid, hydroiodic acid,
Inorganic acids such as sulfuric acid and phosphoric acid, formic acid, acetic acid, propionic acid,
Acid addition salts with organic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid, sodium, potassium And basic salts with alkaline metals such as calcium and magnesium.

Further, the present invention also includes various solvates and polymorphic substances of the compound (I) of the present invention and salts thereof.

(Production Method) The compound of the present invention and its salt can be produced by applying various synthetic methods by utilizing the characteristics based on the basic skeleton or the kind of the substituent. At that time, depending on the kind of the functional group, when it is effective in manufacturing technology to replace the functional group with an appropriate protecting group at the stage of the raw material or the intermediate, that is, a group which can be easily converted into the functional group. There is. After that, the protecting group can be removed if necessary to obtain the desired compound. Examples of such a functional group include a hydroxyl group and an amino group, and examples of protective groups thereof include, for example, Green and Wuts, [Pro.
tective Groups in Organic
Synthesis ", 2nd edition can be mentioned, and these may be appropriately used depending on the reaction conditions.

Typical methods for producing the compound of the present invention will be illustrated below. (First manufacturing method)

[0034]

[Chemical 7]

(Wherein A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ , R ⁸ and n have the meanings given above. X represents a leaving group such as a hydroxyl group, a halogen atom, a lower alkoxy group or an aralkyloxy group, which can be easily substituted by a nucleophile. The compound (I) of the present invention can be obtained by reacting a carboxylic acid represented by the general formula (II) or a reactive derivative thereof with an amino compound represented by the general formula (III) by a conventional method.

For example, the carboxylic acid represented by the general formula (II) is reacted with the amino compound represented by the general formula (III), preferably in the presence of a condensing agent, in an inert solvent at 0 ° C. or under heating under reflux. Can be obtained by The reaction is carried out, for example, by dicyclohexylcarbodiimide (D
CC), diisopropylcarbodiimide (DIPC),
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), benzotriazole-1-yltris (dimethylamino) phosphonium hexafluorophosphide salt (BOP), diphenylphosphoryl azide (DPPA), 1,1 ′ -Carbonylbis-1H-imidazole (CDI), oxalyl dichloride ((CO
Cl) ₂ ) or the like in the presence of a condensing agent, for example N-hydroxysuccinimide (HONSu),
1-hydroxybenzotriazole (HOBt), 3-
Hydroxy-4-oxo-3,4-dihydro-1,2,2
Additives such as 3-benzotriazine (HOObt) are added, and aromatic solvents such as benzene, toluene and xylene, tetrahydrofuran, 1,4-
In an ether solvent such as dioxane, a halogenated hydrocarbon solvent such as dichloromethane, chloroform and 1,2-dichloroethane, an amide solvent such as dimethylformamide and dimethylacetamide, a basic solvent such as pyridine, or a mixed solvent thereof. It is preferable to carry out.

Alternatively, the compound (I) of the present invention has the general formula (I
I) a reactive derivative of a carboxylic acid and a general formula (I
It can also be obtained by reacting the amino compound of II) with an inert solvent.

Examples of the reactive derivative of carboxylic acid include acid halides, acid anhydrides (including mixed acid anhydrides) and ester derivatives. Specifically, the acid halides include acid chlorides or bromides. As the mixed acid anhydride, ethyloxycarbonyl chloride, an alkyloxy chloride type such as isobutyloxycarbonyl chloride, and diethyl acetyl chloride, a mixed acid anhydride with an α-polyalkyl-substituted carboxylic acid chloride type compound such as trimethylacetyl chloride, As the ester derivative, p-
Mention may be made of active esters such as nitrophenyl ester, N-hydroxysuccinimide ester, pentafluorophenyl ester and common esters such as methyl ester and ethyl ester. Such a reactive derivative of a carboxylic acid is prepared according to a general method which is usually carried out.
It can be easily obtained from the corresponding carboxylic acid.

When reacting with an acid halide or acid anhydride (including mixed acid anhydride), the reaction can be carried out in the presence of a base or an excess of an amino compound in a solvent under cooling to room temperature. As the base, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
Inorganic bases such as sodium hydrogencarbonate, and organic bases such as triethylamine and pyridine, benzene, toluene, aromatic hydrocarbon solvents such as xylene, tetrahydrofuran, ether solvents such as 1,4-dioxane, dichloromethane, Chloroform, 1,2
-Halogenated hydrocarbon solvents such as dichloroethane, amide solvents such as dimethylformamide and dimethylacetamide, basic solvents such as pyridine, and mixed solvents thereof.

The reaction with the ester derivative is carried out in the presence of an equimolar or excess amino compound (III) without solvent or in a solvent while cooling or heating. In the case of an active ester, for example, tetrahydrofuran, 1,2-dimethoxyethane, an ether solvent such as dioxane, an ester solvent such as ethyl acetate, dimethylformamide or a mixed solvent thereof, in the case of another ester, For example, methanol, ethanol,
The reaction is preferably carried out in an alcohol solvent such as isopropanol, an ether solvent such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane, dimethylformamide, dimethylsulfoxide or a mixed solvent thereof. In some cases, after the solvent is distilled off, heating at about 130 ° C. for a short time is also possible.

(Second manufacturing method)

[0042]

Embedded image

(Wherein A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ , R ⁸ and n have the above-mentioned meanings, and Y means a leaving group. The compound (I) of the present invention can be obtained by reacting the mercapto-substituted pyrimidine compound (IV) represented by the general formula (IV) with the compound (V) having a suitable leaving group Y. Examples of the suitable leaving group Y include a halogen atom and the like.

The reaction is carried out in an inert solvent such as methanol, ethanol, tetrahydrofuran, acetone, methyl ethyl ketone, dimethylformamide, dimethylsulfoxide, etc., if necessary, with an inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate or the like. It can be carried out in the presence of an organic base such as triethylamine or pyridine at 0 ° C. or under heating under reflux.

(Third manufacturing method)

[0046]

Embedded image (In the formula, A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸
And n have the above-mentioned meanings, and Hal means a halogen atom. The compound (I) of the present invention can also be obtained by reacting the halogen-substituted pyrimidine compound (VI) with the compound (VII) having a mercapto group.

The reaction is carried out by adding an equivalent or excess amount of the compound (VII) having a mercapto group to the halogen-substituted pyrimidine compound (VI) such as methanol, ethanol, isopropanol, diethyl ether, tetrahydrofuran, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide and the like. It is carried out by reacting in a solvent in the presence of a base such as sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate at 0 ° C. or under reflux with heating. Compound (VII)
Can also be previously reacted as a salt with the base in the absence of a base.

Starting compound (II) in the above production method,
(IV) and (VI) are manufactured as follows, for example.

[0049]

Embedded image (In the formula, A, R ¹ , R ⁴ , X, Hal, Y and n have the above-mentioned meanings. M means an alkali metal such as sodium or potassium.)

The starting compound (VI) in the third process is
It is obtained by reacting a dihalogenated pyrimidine (VIII) with a salt of 2-thiosulfonamide (IX). Dihalogenated pyrimidines (VIII) are disclosed in
It is manufactured by the method described in No. 222003 or a method similar thereto. In addition, a salt of 2-thiosulfonamide (I
X) is prepared by reacting the free sulfonamide with a suitable inorganic base.

The starting compound (IV) in the second production method is
It is produced by converting the halogen atom on the pyrimidine ring of compound (VI) into a thiol group by sulfiding.

Of the starting compound (II) in the first production method, the one in which X is a lower alkoxy group is produced by reacting compound (IV) with ester (X) in the presence of an organic base. By hydrolyzing this, X
Can have a hydroxyl group.

The reaction product obtained by each of the above production methods is
It is isolated and purified as various solvates such as free compounds, salts or hydrates thereof. The salt can be produced by subjecting it to an ordinary salt-forming reaction. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, and various types of chromatography.

[0054]

INDUSTRIAL APPLICABILITY The compound of the present invention has an affinity for the endothelin receptor, and in particular, shows a high affinity for the ET _A receptor which is a subtype of the endothelin receptor. Therefore, the compound of the present invention competitively inhibits the binding of endothelin to the receptor and can be used for the treatment of various diseases such as cardiovascular diseases. Examples of such diseases include essential hypertension, pulmonary hypertension, erythropoietin-induced hypertension, cyclosporin A-induced hypertension, bronchial asthma, acute renal failure, chronic renal failure, glomerulonephritis, acute myocardial infarction, unstable angina. Disease, chronic heart failure, cerebrovascular spasm mainly after subarachnoid hemorrhage, urinary incontinence, benign prostatic hypertrophy, arteriosclerosis, Raynaud's syndrome, diabetic peripheral circulatory disorder, diabetic nephropathy, preeclampsia, preterm birth, peptic ulcer, Examples thereof include liver failure, rheumatism, restenosis after PTCA and the like.

The pharmacological actions of the compounds of the present invention will be described below by posting experimental examples.

[0056] Binding of (Experimental Method) Endothelin (ET-1) and human ET _A receptor suppressed
Human ET _A by RT-PCR method from mRNA of the braking test human lung
Obtaining the cDNA of the receptor, the expression vector pEF-B
A plasmid was prepared by introducing it into the OS. It was created plasmid added with DEAE-dextran in culture (cell line derived from African green monkey kidney cells) COS-1 cells were transfected with CDNA human ET _A in COS-1 cells. Furthermore, normal DMEM (10%
After culturing in FBS (containing FBS) for 3 days, COS-1 cells were collected and hypotonic buffer solution (Tris-HCl, 10 mM; E).
The cells were suspended in DTA, 5 mM; pH 7.4) and disrupted with a polytron. The cell-disrupted suspension was subjected to ultracentrifugation (100,000 G, 30 min., 4 ° C.), and the sediment (cell membrane fraction) was subjected to Tris buffer (Tris-HCl, 50).
After resuspending in mM; MgCl ₂ , 10 mM; pH 7.4), the suspension was -80 ° C (protein amount, about 1 mg / m 2).
It was frozen and stored in 1).

In the receptor binding experiment, the frozen cell membrane preparation was thawed and the test buffer solution (Tris-HCI, 50 m) was used.
M; MgCl ₂ , 10 mM; bovine serum albumin, 0.
It was resuspended in 01%; pH 7.4). 200 μl of membrane suspension containing 1.25 μg of membrane protein, 25 μl of test buffer containing different concentrations of test compound and [
25 μl of ¹²⁵ I] ET-1 (specific activity 2,200 Ci / mM, final concentration 25 μM) was incubated together at 25 ° C. for 3 hours, and then filtered through a glass fiber filter using a Brandel cell harvester. The radioactivity on the glass fiber filter was measured by a gamma counter (counting efficiency 81%). In addition, non-specific binding is 0.1μ
Determined by using the test buffer containing M ET-1. The [ ¹²⁵ I] ET-1 binding inhibitory activity of the test compound was the concentration (I) required to inhibit 50% of the specific binding.
_C50 ).

ET-1 in rat aortic ring preparation
Inhibition test of induced contraction A ring specimen having a length of 2 mm was prepared from a thoracic aorta of a male Wistar rat having a body weight of 300 to 350 g. The endothelium was removed by gently rubbing the lumen of the ring with absorbent cotton. Each ring sample was suspended at a static tension of 1 g in a Magnus tank filled with 10 ml of Krebs-Henseleit solution aerated with 95% CO ₂ and 5% O ₂ . The tension generated on the ring specimen was recorded isometrically. After a 10 minute incubation with the test compound, ET-1 was cumulatively added to the Magnus bath. The ET-1 antagonistic activity of the test compound is doubled to the right of the ET-1 concentration action curve from the width of the rightward movement (dose ratio) of the ET-1 concentration action curve by various concentrations of the test compound. It was calculated as the concentration (pA ₂ ) of the test compound required for

[0059] The results of these tests, the compounds of the invention potently inhibit the binding of ET-1 to human ET _A receptor, was also strongly inhibited the ET-1 induced contraction in rat aorta ring specimen.

The pharmaceutical composition containing, as an active ingredient, one or more of the compounds represented by the general formula (I) or a salt thereof, may include a carrier, an excipient and other additives usually used for formulation. Is prepared using.

A drug containing the compound (I) of the present invention or a salt thereof as an active ingredient can be prepared by a method commonly used using a carrier for a drug, an excipient, etc. which are commonly used in the art. You can Administration may be in any form of oral administration such as tablets, pills, capsules, granules, powders, solutions, etc., or parenteral administration such as injections such as intravenous injection and intramuscular injection, suppositories, transdermal administration, etc. Good.

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, the one or more active substances are at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminometasilicate. Mixed with magnesium acid. The composition may contain, in a conventional manner, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a stabilizer such as lactose, glutamic acid or asparagine. A solubilizing agent such as an acid may be contained. If necessary, tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a film of gastric or enteric substance.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and generally used inert diluents. For example, it contains purified water and ethanol. In addition to an inert diluent, this composition includes auxiliary agents such as wetting agents and suspending agents,
It may contain a sweetening agent, a flavoring agent, and an aromatic agent. Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of the water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing (eg, lactose) and solubilizing agents (eg, glutamic acid, aspartic acid). These are sterilized by, for example, filtration through a bacteria-retaining filter, addition of a bactericide, or irradiation. They can also be used by preparing a sterile solid composition and dissolving it in sterile water or a sterile solvent for injection before use.

The dose is appropriately determined depending on the individual case in consideration of symptoms, age of the subject, sex, etc.
In the case of oral administration to adults, the daily dose is 0.
The dose is 001 to 20 mg, preferably 0.01 to 5 mg, and the dose is administered once or in 2 to 4 divided doses.

[0065]

The present invention will be described below in more detail with reference to examples. The method for producing the starting compounds used in the examples will be described as reference examples.

Reference Example 1 Nt-butyl-2-thiophenesulfonamide in 750 ml of tetrahydrofuran solution was -70 to -50 ° C.
And 1.64M n-butyllithium-hexane solution 1
20 ml was added. The solution was stirred at -70 to -60 ° C for 1 hour and then dissolved in 100 ml of tetrahydrofuran.
22.5 ml of iodopropane were added. The solution was slowly warmed to room temperature and stirred overnight at room temperature, then ice-1N
-Pour into HCl and extract twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 3.33 g of N 2.
-T-Butyl-5- (2-propyl) thiophenesulfonamide was obtained.

Nuclear magnetic resonance spectrum (CDCl ₃ , TM
S internal standard) δ: (ppm) 1.29 (9H, s), 1.34 (6
H, d), 3.16 (1H, m), 4.94 (1H, b
rs), 6.73 (1H, d), 7.42 (1H,
d).

Reference Example 2 2 drops of anisole and 20 ml of trifluoroacetic acid were added to 1.42 g of Nt-butyl-5- (2-propyl) -2-thiophenesulfonamide. The solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure. Ethyl acetate ether was added to the residue, and the mixture was washed with saturated sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 612 mg of 5- (2-propyl) -2-thiophenesulfonamide.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ: (ppm) 1.27 (6H, d), 3.19 (1
H, m), 6.89 (1H, d), 7.36 (1H,
d), 7.54 (2H, brs).

Reference Example 3 2.90 g of sodium hydride and dimethylformamide 3
To 0 ml of the mixture was added 6.77 g of 5- (2-propyl) -2-thiophenesulfonamide in 30 ml of dimethylformamide. After stirring this mixture at room temperature for 15 minutes, to this mixture was added a mixture of 11.5 g of 4,6-dichloro-5- (2-methoxyphenoxy) -2- (2-pyrimidinyl) pyrimidine and 50 ml of dimethylformamide. The mixture was stirred for 2 hours, poured into ice-1N-hydrochloric acid aqueous solution, and the precipitated crystals were collected by filtration. The obtained crude crystals were recrystallized from ethanol to give 9.56 g of N- [6-
Chloro-5- (2-methoxyphenoxy) -2- (2-
Pyrimidinyl) -4-pyrimidinyl] -5- (2-propyl) -2-thiophene sulfonamide was obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ: (ppm) 1.24 (6H, d), 3.17 (1
H, m), 3.73 (3H, s), 6.78 (1H,
d), 6.85 (1H, t), 6.95 (1H, d),
7.06-7.13 (2H, m). 7.73 (1H,
t), 8.34 (1H, m), 9.11 (2H, d).

Reference Example 4 In the same manner as in Reference Example 3, 4,6-dichloro-5- (2-
From methoxyphenoxy) -2- (2-pyrimidinyl) pyrimidine to N- [6-chloro-5- (2-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -5- (2-methylpropyl ) -2-Thiophenesulfonamide was obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: (ppm) 0.86 (6H, d), 1.80 (1
H, m), 2.67 (2H, d), 3.73 (3H,
s), 6.76 (1H, d), 6.85 (1H, d),
6.90 (1H, d), 7.06-7.13 (2H,
m), 7.72 (1H, t), 8.30 (1H, m),
9.10 (2H, d).

Reference Example 5 N- [6-chloro-5- (2-methoxyphenoxy)-
2- (2-pyrimidinyl) -4-pyrimidinyl] -5-
(2-propyl) -2-thiophene sulfonamide 5.
A solution of 00 g and 6.19 g of sodium hydrosulfide hydrate in 50 ml of dimethylformamide was stirred overnight under an argon stream. This solution was poured into ice-1N-hydrochloric acid aqueous solution, and the precipitated crystals were collected by filtration. The crystals are dried and 4.73 g N 2
-[6-mercapto-5- (2-methoxyphenoxy)
-2- (2-Pyrimidinyl) -4-pyrimidinyl] -5
-(2-Propyl) -2-thiophenesulfonamide was obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ: (ppm) 1.23 (6H, d), 3.16 (1
H, m), 3.32 (1H, m), 3.18 (3H,
s), 6.56 (1H, d), 6.74 (1H, t),
6.78-6.97 (2H, m), 7.03 (1H,
d), 7.80 (1H, t), 8.23 (1H, m),
9.14 (2H, d).

Reference Example 6 In the same manner as in Reference Example 5, N- [6-chloro-5- (2-
Methoxyphenoxy) -2- (2-pyrimidinyl) -4
-Pyrimidinyl] -5- (2-methylpropyl) -2-
N- [6-mercapto-5- (2-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -5- (2-methylpropyl) -2-thiophenesulfonamide was obtained from thiophene sulfonamide. It was Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: (ppm) 0.85 (6H, d), 1.79 (1
H, m), 2.67 (2H, d), 3.81 (3H,
s), 6.58 (1H, d), 6.74 (1H, d),
6.89 (1H, d), 6.97 (1H, m), 7.0
5 (1H, m), 7.81 (1H, t), 8.25 (1
H, d), 9.14 (2H, d).

Reference Example 7 N- [6-mercapto-5- (2-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl]
To a solution of 5.12 g of -5- (2-propyl) -2-thiophenesulfonamide and 1.47 g of potassium carbonate in N, N-dimethylformamide was added 20 ml of a solution of ethyl 2-bromoacetate in N, N-dimethylformamide at room temperature. Dropped. After stirring at the same temperature for 2 hours, ice and 1N hydrochloric acid aqueous solution were added to the reaction mixture to make it acidic. This was extracted three times with ethyl acetate, then the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (methylene chloride-methanol), and 3.53 g of ethyl 2-
[[5- (2-Methoxyphenoxy) -6- [5- (2
-Propyl) -2-thienylsulfonylamino] -2-
(2-Pyrimidinyl) -4-pyrimidinyl] thio] acetate was obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ: (ppm) 1.10 (3H, m), 1.29 (6
H, d), 3.12 (1H, m), 3.89 (3H,
s), 4.05 (4H, m), 6.62 (1H, m),
6.82-6.91 (2H, m), 7.00-7.15
(2H, m), 7.71 (1H, m), 8.32 (1
H, m), 9.14 (2H, m), 11.90 (1H,
brs).

Reference Example 8 In the same manner as in Reference Example 7, N- [6-mercapto-5-
From (2-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl] -5- (2-methylpropyl) -2-thiophenesulfonamide, ethyl
[[5- (2-Methoxyphenoxy) -6- [5- (2
-Methylpropyl) -2-thienylsulfonylamino]
2- (2-Pyrimidinyl) -4-pyrimidinyl] thio] acetate was obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ: (ppm) 0.86 (6H, d), 1.09 (3
H, m), 1.79 (1H, m), 2.66 (2H,
d), 3.82 (3H, s), 3.96-4.24 (4
H, m), 6.60 (1H, m), 6.70-6.94.
(2H, m), 6.96-7.15 (2H, m), 7.
70 (1H, m), 8.32 (1H, m), 9.08
(2H, m), 11.90 (1H, brs).

Reference Example 9 Ethyl [[5- (2-methoxyphenoxy) -6-
[5- (2-Propyl) -2-thienylsulfonylamino] -2- (2-pyrimidinyl) -4-pyrimidinyl]
To a solution of 200 mg of thio] acetate in 2 ml of methanol was added 0.997 ml of a 1N aqueous sodium hydroxide solution, and the mixture was stirred overnight. The pH of this solution was adjusted to 2 with 1N aqueous hydrochloric acid, and the precipitated crystals were collected by filtration to give 150 mg of [[5-
(2-Methoxyphenoxy) -6- [5- (2-propyl) -2-thienylsulfonylamino] -2- (2-pyrimidinyl) -4-pyrimidinyl] thio] acetic acid was obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ: (ppm) 1.23 (6H, d), 3.15 (1
H, m), 3.82 (3H, s), 4.07 (2H,
s), 6.60 (1H, m), 6.65-6.95 (2
H, m), 7.04-7.18 (2H, m), 7.72.
(1H, m), 8.32 (1H, m), 9.10 (2
H, m), 11.85 (1H, brs), 12.75
(1H, brs).

Reference Example 10 In the same manner as in Reference Example 9, ethyl [[5- (2-methoxyphenoxy) -6- [5- (2-methylpropyl)-] was used.
2-thienylsulfonylamino] -2- (2-pyrimidinyl) -4-pyrimidinyl] thio] acetate,
[[5- (2-Methoxyphenoxy) -6- [5- (2
-Methylpropyl) -2-thienylsulfonylamino]
-2- (2-Pyrimidinyl) -4-pyrimidinyl] thio] acetic acid was obtained. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: (ppm) 0.85 (6H, d), 1.79 (1
H, m), 2.66 (2H, d), 3.82 (3H,
s), 4.08 (2H, brs), 6.60 (1H,
m), 6.70-6.95 (2H, m), 7.00-
7.20 (2H, m), 7.72 (1H, m), 8.3
5 (1H, m), 9.10 (2H, m), 11.85
(1H, brs), 12.78 (1H, brs).

Example 1 [[5- (2-methoxyphenoxy) -6- [5- (2
-Propyl) -2-thienylsulfonylamino] -2-
In a chloroform solution of 200 mg of (2-pyrimidinyl) -4-pyrimidinyl] thio] acetic acid, 127 mg of water-soluble carbodiimide hydrochloride, 131 mg of (L) -aspartic acid dimethyl ester, and 10 triethylamine.
1 mg was added, and the mixture was stirred at room temperature for 3 hours. This was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, collected by filtration, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform-methanol) to give 120
mg of dimethyl N-[[[5- (2-methoxyphenoxy) -6- [5- (2-propyl) -2-thienylsulfonylamino] -2- (2-pyrimidinyl) -4-pyrimidinyl] thio] acetyl ]-(L) -Aspartate was obtained.

Infrared absorption spectrum ν max (KB
r) cm ⁻¹ : 3280, 1746, 1680, 161
0, 1386, 1352, 1172, 1114. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: (ppm) 1.22 (6H, d), 2.72-
2.77 (2H, m), 3.14 (1H, m), 3.3
7-3.41 (5H, m), 3.46 (3H, s),
3.73-3.90 (5H, m), 6.59 (1H,
m), 6.80 (1H, m), 6.90 (1H, m),
7.05 (1H, m), 7.11 (1H, m), 7.7
5 (1H, m), 8.45 (1H, m), 9.09 (2
H, m), 11.90 (1H, brs).

Example 2 In the same manner as in Example 1, [[5- (2-methoxyphenoxy) -6- [5- (2-propyl) -2-thienylsulfonylamino] -2- (2-pyrimidinyl)) From 4--4-pyrimidinyl] thio] acetic acid, N-[(1-ethyl-2
-Pyrrolidinyl) methyl] -2-[[5- (2-methoxyphenoxy) -6- [5- (2-propyl) -2-thienylsulfonylamino] -2- (2-pyrimidinyl)] thio] acetamide It was Infrared absorption spectrum ν max (KBr) cm ⁻¹ :
3480, 3080, 1672, 1594, 1548,
1502, 1430, 1386, 1344, 1322
1176, 1124. Nuclear magnetic resonance spectrum (DMSO, TMS internal standard) δ: (ppm) 0.93-1.12 (3H, m),
1.20 (6H, d), 1.65 to 1.95 (4H,
m), 2.82-3.08 (3H, m), 3.07 (1
H, m), 3.30-3.64 (5H, m), 3.68.
(2H, s), 3.86 (3H, s), 6.34 (1
H, d), 6.66 (1H, d), 6.73 (1H,
t), 6.94 (1H, t), 7.06 (1H, d),
7.67 (1H, t), 8.05 (1H, d), 9.0
6 (2H, d), 9.54 (1H, brs).

Example 3 In the same manner as in Example 1, [[5- (2-methoxyphenoxy) -6- [5- (2-methylpropyl) -2-thienylsulfonylamino] -2- (2-pyrimidinyl). ) −
From 4-pyrimidinyl] thio] acetic acid, 2-[[5- (2
-Methoxyphenoxy) -6- [5- (2-methylpropyl) -2-thienylsulfonylamino] -2- (2-
Pyrimidinyl) -4-pyrimidinyl] thio] -N- [2
-(1-Piperidinyl) ethyl] acetamide was obtained. Infrared absorption spectrum ν max (KBr) cm ⁻¹ :
3464, 3288, 1658, 1594, 1548,
1502, 1430, 1386, 1348, 1254,
1206, 1176, 1126, 1086, 1046
1006. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: (ppm) 0.83 (6H, d), 1.20-
1.40 (6H, m), 1.73 (1H, m), 2.1
5-2.35 (4H, m), 2.54 (2H, d),
3.12-3.26 (5H, m), 3.59 (2H,
s), 3.86 (3H, s), 6.35 (1H, d),
6.60 (1H, d), 6.68 (1H, t), 6.9
3 (1H, t), 7.05 (1H, d), 7.65 (1
H, t), 7.88 (1H, d), 9.03 (2H,
d).

Example 4 In the same manner as in Example 1, [[5- (2-methoxyphenoxy) -6- [5- (2-methylpropyl) -2-thiophenylsulfonylamino] -2- (2- From pyrimidinyl) -4-pyrimidinyl] thio] acetic acid, 2-[[5
-(2-Methoxyphenoxy) -6- [5- (2-methylpropyl) -2-thiophenylsulfonylamino]-
2- (2-pyrimidinyl) -4-pyrimidinyl] thio]
-N- (4-morpholinyl) acetamide was obtained. Infrared absorption spectrum ν max (KBr) cm ⁻¹ :
3480, 3240, 1682, 1608, 1572,
1558, 1504, 1434, 1386, 1354
1256, 1212, 1174, 1112, 1072. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard, 80 ° C. NOSPIN measurement) δ: (ppm) 0.86 (6H, d), 1.79 (1
H, m), 2.56-2.80 (6H, m), 3.40.
-3.65 (6H, m), 3.82 (3H, s), 4.
27 (1H, m), 6.60 (1H, m), 6.76
(2H, m), 6.95-7.15 (2H, m), 7.
67 (1H, m), 7.90 (1H, m), 9.05
(2H, m), 9.22 (1H, brs).

Example 5 Ethyl 2-[[5- (2-methoxyphenoxy) -6
240 mg of [[5- (2-propyl) -2-thienylsulfonylamino] -2- (2-pyrimidinyl) -4-pyrimidinyl] thio] acetate and 2-amino-1,3
After stirring 2.00 g of propanediol at 70 ° C. for 3 hours, 50 ml of chloroform was added. The organic layer was washed with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product is subjected to silica gel column chromatography (chloroform, methanol,
Water) and 114 mg of N- (1,3-dihydroxy-2-propyl) -2-[[5- (2-methoxyphenoxy) -6- [5- (2-propyl) -2-thienylsulfonyl]. Amino] -2- (2-pyrimidinyl) -4-
Pyrimidinyl] thio] acetamide was obtained.

Infrared absorption spectrum ν max (KB
r) cm ⁻¹ : 3416, 2976, 1652, 160
8, 1550, 1502, 1430, 1404, 138
4,1346, 1320, 1254, 1206, 117
4,1116,1082,1046,1006. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: (ppm) 1.22 (6H, d), 3.07 (2
H, m), 3.35 (4H, d), 3.69 (1H,
d), 3.75 (2H, s), 3.84 (3H, s),
4.23 (2H, brs), 6.54 (1H, m),
6.70 (1H, m), 6.75 (1H, t), 6.9
6 (1H, m), 7.05 (1H, d), 7.62 (1
H, m), 7.75 (1H, brs), 7.96 (1
H, m), 9.01 (2H, d).

Example 6 In the same manner as in Example 5, ethyl [[5- (2-methoxyphenoxy) -6- [5- (2-propyl) -2-thiophenylsulfonylamino] -2- (2- Pyrimidinyl) -4-pyrimidinyl] thio] acetate to N-
[3- (4-morpholinyl) propyl] -2-[[5-
(2-Methoxyphenoxy) -6- [5- (2-propyl) -2-thiophenylsulfonylamino] -2- (2
-Pyrimidinyl) -4-pyrimidinyl] thio] acetamide was obtained. Infrared absorption spectrum ν max (KBr) cm ⁻¹ :
3424, 1662, 1608, 1505, 1352
1320, 1174, 1114, 1082. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: (ppm) 1.21 (6H, d), 1.76 (2)
H, m), 2.45-3.15 (4H, m), 3.06
(1H, m), 3.18-3.35 (4H, m), 3.
60-3.75 (7H, m), 3.84 (3H, s),
6.42 (1H, m), 6.64-6.84 (2H,
m), 6.96 (1H, m), 7.07 (1H, m),
7.69 (1H, m), 8.14 (1H, m), 9.0
9 (2H, d), 9.19 (1H, brs).

Example 7 In the same manner as in Example 5, ethyl 2-[[5- (2-methoxyphenoxy) -6- [5- (2-propyl) -2 was used.
-Thienylsulfonylamino] -2- (2-pyrimidinyl) -4-pyrimidinyl] thio] acetate to N-
(2,3-dihydroxypropyl) -2-[[5- (2
-Methoxyphenoxy) -6- [5- (2-propyl)
2-Thienylsulfonylamino] -2- (2-pyrimidinyl) -4-pyrimidinyl] thio] acetamide was obtained. Infrared absorption spectrum ν max (KBr) cm ⁻¹ :
3428, 1652, 1610, 1550, 1502
1432, 1386, 1348, 1322, 1254,
1206, 1174, 1116, 1084, 1046
1008. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: (ppm) 1.21 (6H, d), 2.95-
3.50 (7H, m), 3.70 (2H, s), 3.8
3 (3H, s), 4.41 (1H, m), 4.65 (1
H, m), 6.44 (1H, m), 6.75 (2H,
m), 6.97 (1H, m), 7.07 (1H, m),
7.68 (1H, m), 7.95 (1H, m), 8.8
9 (1H, m), 9.08 (2H, m).

Example 8 200 mg of [[5- (2-methoxyphenoxy) -6]
A solution of 59 mg of [[5- (2-propyl) -2-thienylsulfonylamino] -2- (2-pyrimidinyl) -4-pyrimidinyl] thio] acetic acid and 1,1′-carphonylbis-1H-imidazole in dimethylformamide was added to 60 parts.
After heating at 0 ° C for 40 minutes, a solution of methylguanidine (synthesized from 218 mg of methylguanidine and 99 mg of sodium methylate) in dimethylformamide was added. After stirring overnight at room temperature, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol-water) to obtain an oily substance. Crystallize this with ethanol,
The crystals were collected by filtration and washed with ethanol to give 98 mg of N 2.
-[[[6- (5-isopropyl-2-thienylsulfonylamino) -5- (2-methoxyphenoxy) -2-
(2-Pyrimidinyl) -4-pyrimidinyl] thio] acetyl] -N′-methylguanidine was obtained.

Infrared absorption spectrum ν max (KB
r) cm ⁻¹ : 3448, 1700, 1594, 154
8,1502,1430,1388,1254,112
8,1048. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: (ppm) 1.20 (6H, d), 2.85 (3
H, m), 3.06 (1H, m), 3.85-3.87.
(5H, m), 6.41 (1H, d), 6.68 (1
H, m), 6.74 (1H, t), 6.95 (1H,
t), 7.06 (1H, d), 7.66 (1H, t),
7.95 (1H, m), 8.53 (2H, m), 8.8
8 (1H, m), 8.98 (2H, d), 12.21
(1H, brs).

Example 9 [[5- (2-Methoxyphenoxy) -6- [5- (2-propyl) -2-thienylsulfonylamino] -2- (2-pyrimidinyl) was prepared in the same manner as in Example 1. -4-Pyrimidinyl] thio] acetic acid to N, N-dimethyl-
[[[[6- (5-isopropyl-2-thiophenesulfonamide) -5- (2-methoxyphenoxy) -2-
(2-Pyrimidinyl) -4-pyrimidinyl] thio] methyl] carbonyl] hydrazine was obtained. Mp 116-119 ° C. Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard, 80 ℃) δ: (ppm ) 1.23 (6H, d, J = 6.4H
z), 2.48 (6H, s), 3.11 (1H, m),
3.82 (3H, s), 6.59 (1H, m), 6.7
8 (2H, m), 7.00-7.09 (2H, m),
7.68 (1H, m), 7.92 (1H, brm),
9.07 (2H, m).

Example 10 In the same manner as in Example 8, [[5- (2-methoxyphenoxy) -6- [5- (2-methylpropyl) -2-thienylsulfonylamino] -2- (2-pyrimidinyl). ) −
From 4-pyrimidinyl] thio] acetic acid, N-[[[[6-
[5- (2-Methylpropyl) -2-thienylsulfonylamino] -5- (2-methoxyphenoxy) -2-
(2-Pyrimidinyl) -4-pyrimidinyl] thio] acetyl] -N′-methylguanidine was obtained. Infrared absorption spectrum ν max (KBr) cm ⁻¹ :
3416, 2972, 1722, 1698, 1632,
1594, 1548, 1502, 1430, 1388,
1254, 1176, 1128, 1086, 1046. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: (ppm) 0.85 (6H, d), 1.75 (1
H, m), 2.56 (2H, d), 2.73 (3H,
m), 3.85-3.87 (5H, m), 6.40 (1
H, d), 6.63 (1H, m), 6.74 (1H,
t), 6.93 (1H, t), 7.06 (1H, d),
7.65 (1H, t), 8.00 (1H, m), 8.5
3 (2H, m), 8.89 (1H, m), 8.99 (2
H, d), 12.23 (1H, brs).

Example 11 Ethyl 2-[[5- (2-methoxyphenoxy) -6
-[5- (2-Propyl) -2-thienylsulfonylamino] -2- (2-pyrimidinyl) -4-pyrimidinyl] thio] acetate 447 mg and aminoethanol 1
The ml mixture was stirred at 70 ° C. for 3 hours. The reaction solution was poured into ice, adjusted to pH 2 with 5N hydrochloric acid aqueous solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform-methanol). Using the obtained sulfonamide compound and an ethanol solution of potassium hydroxide, potassium N- [6-[(2-hydroxyethyl)]
Carbonylmethylthio] -5- (2-methoxyphenoxy) -2- (2-pyrimidinyl) -4-pyrimidinyl]
160 mg of -5- (2-propyl) -2-thiophene sulfonamidate was obtained.

Infrared absorption spectrum ν max (KB
r) cm ⁻¹ : 3348, 3288, 1660, 159
4,1544,1502,1430,1384,134
4,1254,1206,1176,1126,108
4,1048. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: (ppm) 1.19 (6H, d), 3.04 (1
H, m), 3.04-3.08 (2H, m), 3.16.
-3.20 (3H, m), 3.61 (2H, s), 3.
85 (3H, s), 4.62 (1H, m), 6.38
(1H, d), 6.65 (1H, d), 6.73 (1
H, t), 6.93 (1H, t), 7.05 (1H,
d), 7.64 (1H, t), 7.89 (1H, d),
9.00 (1H, m), 9.03 (2H, d).

The chemical structural formulas of the compounds obtained in Examples 1 to 11 are listed in Tables 1 to 3 below.

[0099]

[Table 1]

[0100]

[Table 2]

[0101]

[Table 3]

The compounds listed in Tables 4 to 6 were prepared in the same manner as in the above-mentioned Examples or the production methods, or
They can be easily manufactured by applying some modifications that are obvious to those skilled in the art.

[0103]

[Table 4]

[0104]

[Table 5]

[0105]

[Table 6]

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication location C07D 409/14 239 C07D 409/14 239 (72) Inventor Junichi Kazami 4-3 Shirayama, Toride City, Ibaraki Prefecture −18 Fuji Heights 104 (72) Inventor Kiyoshi Yahiro 68 68 Shibasaki, Tsukuba, Ibaraki 117 (72) Inventor Katsumi Sudo 3-15 15 Namiki, Tsukuba, Ibaraki Hai Kamur Namiki 203

Claims (3)

[Claims] 1. An N-pyrimidinyl thiophene sulfonamide derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. Embedded image (However, the symbols in the formulas have the following meanings. A: Lower alkylene group. R ¹ : Lower alkyl group. R ² , R ³ : either one is hydrogen atom or lower alkyl group, and the other is lower alkyl. Group, amino group, mono- or di-lower alkylamino group, or 5- or 6-membered heterocyclic group containing a nitrogen atom, provided that 5 or 6
The member heterocyclic group may be substituted with a lower alkyl group, and the other lower alkyl group contains a hydroxyl group, a lower alkoxy group, a lower alkoxycarbonyl group, and a nitrogen-containing group.
Alternatively, it may be substituted with a 6-membered heterocyclic group, an amino group, a mono- or di-lower alkylamino group, or a carboxyl group. Further, the 5- or 6-membered heterocyclic group which is a substituent of the other lower alkyl group may be substituted with a lower alkyl group. Embedded image You may form the group shown by. Where R ⁵ , R ⁶ and R
^{Although 7} and R ⁸ are the same or different and each is a hydrogen atom, a lower alkyl group, an amino group or a hydroxyl group, R ⁶ and R ⁷ may be combined to form a lower alkylene group. R ^4: lower alkyl group, a lower alkoxy group, a halogen atom, a trifluoromethyl group, a lower alkylthio group, lower alkylsulfinyl group, or a lower alkylsulfonyl group. n: an integer of 0 to 4. ) 2. A drug, comprising the N-pyrimidinyl thiophene sulfonamide derivative according to claim 1 or a pharmaceutically acceptable salt thereof. 3. An anti-endothelin acting drug comprising the N-pyrimidinyl thiophene sulfonamide derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.