JP3116256B2 - (Thio) urea derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel (thio) urea derivative. More specifically, it has angiotensin II antagonism, 1) Formula (I)

[0002]

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(Wherein all symbols have the same meanings as described below), (thio) urea derivatives, their non-toxic salts and acid addition salts, 2) their production methods, and 3) their use. It relates to a drug contained as an active ingredient.

[0004]

BACKGROUND OF THE INVENTION The renin-angiotensin system is an important mechanism for the regulation and maintenance of blood pressure, body fluid or electrolyte metabolism, and is deeply involved in the development and progression of various hypertension diseases, congestive heart failure, edema disease and the like. Angiotensin II, the protagonist of this system, has strong vasoconstrictor action,
It has an aldosterone secretion stimulating action or a catecholamine secretion stimulating action, and directly or indirectly increases blood pressure. Therefore, suppression of this system requires angiotensin II
It is most important to suppress the production of or its action. Currently, angiotensin II converting enzyme (ACE) inhibitors that suppress the production of angiotensin II are widely used as inhibitors of the renin-angiotensin system. Although excellent inhibitory effects have been recognized, they also inhibit kininase II, which degrades kinins, and thus have the problem of having an effect of increasing the amount of bradykinin and prostaglandin.

[0005] In addition, as another method for suppressing the angiotensin II, angiotensin II receptor
There is an antagonist with II. According to this antagonism, since the action of angiotensin II is specifically suppressed, there is no side effect unlike an ACE inhibitor, and the antihypertensive effect is considered to be enhanced. Angiotensin II-like peptides were first studied as inhibitors for this. However, it has not been widely applied clinically because it has problems such as short action time, ineffectiveness by oral administration, and also having an agonistic effect. At present, studies on non-peptide angiotensin II antagonists are being actively conducted in order to find a specific antagonist which can be orally administered.

[0006]

[Prior art and comparison with it] Angiotensin II
Many compounds having an N-containing heterocycle as a basic skeleton are known as antagonists. For example, JP-A-63-23868, imidazole derivatives such as JP-A-3-115278, U.S. Pat.
Examples thereof include triazole derivatives such as 552, benzimidazole derivatives such as JP-A-3-5464 and JP-A-3-27362, and imidazopyridine derivatives such as JP-A-62-240683 and JP-A-3-95181. European Patent Publication No. 44
3983 or EP 490820 discloses (sulfone) amide or carbamate derivatives. Of these, for example, U.S. Pat.
General formula (A)

[0007]

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Wherein R ^A represents a hydrogen atom, a halogen or an alkyl group, etc., R ^2A represents a propyl, butyl, propenyl or butenyl group, etc., and R ^3A represents R ^4A NHC.
^{H (R 6A) CO-, R} 5A OOC-CH (R 6A) -NHC
O- or ^{R 5A OOC-CH ((CH} 2) n COO
R ^5A ) -NHCO- group and the like, wherein R ^4A is benzyloxycarbonyl (CBZ), t-butoxycarbonyl (B
Represents OC) or COPh group, R ^5A represents hydrogen, methyl, ethyl or t- butyl group other, R ^6A represents hydrogen, methyl, ethyl or propyl group other. ) Is disclosed. In the compound represented by the general formula (A), R ^3A is R ^5A OOC-CH
When a group represented by the formula (R ^6A ) —NHCO— is represented by the general formula (B):

[0009]

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(Wherein all symbols have the same meanings as described above), which represents a compound containing a urea group. One of the nitrogen atoms of the urea group in the compound of the present invention represented by the general formula (I) is a tertiary amine to which a functional group (R ¹ ) is bonded, and the other nitrogen atom is also a functional group (

[0011]

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And R ³ ) is an attached secondary or tertiary amine. In contrast, two nitrogen atoms of the urea group in the compound represented by the general formula (B) are both second
Amine. In addition, the compound of the present invention represented by the general formula (I) has a Z group (tetrazolyl group)
And the substituted biphenylmethyl group is bonded. On the other hand, in the compound represented by the general formula (B), a phenyl group substituted by a triazolyl group is bonded to a nitrogen atom of the urea group. The tetrazolyl group and the triazolyl group have completely different chemical structures and properties. European Patent Publication No. 490820 discloses a compound represented by the general formula (C):

[0013]

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(Wherein R ^1C represents an unsubstituted or substituted aliphatic hydrocarbon group or the like, and R ^2C represents 1H-tetrazole-5-
Yl, carboxy, esterified or amidated carboxy, etc., R ^3C represents carboxy, 1H-tetrazol-5-yl, etc., X is linear alkylene,-
X ₁ -Ph-X ₂ -wherein X ₁ and X ₂ are a bond or alkylene; Ph represents unsubstituted or substituted phenylene; and p and q are both 1 Or p represents 0 and q represents 0 or 1. )
Are disclosed. In the compound represented by the general formula (C), p and q represent 1, and X represents -X ₁ -P
When hX ₂ is represented, the formula

[0015]

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Wherein p is 0, q is 1 and X is -X ₁ -P
When hX ₂ is represented, the formula

[0017]

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And a compound having an amide skeleton represented by In the specification, as Example 18, the formula

[0019]

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The compound represented by the formula:

[0021]

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The compounds represented by the following are specifically disclosed. The compound of the present invention represented by the general formula (I) is a compound having a urea group or a thiourea group. On the other hand, the compound represented by the general formula (C) is a compound having a carbamate group or an amide group. A urea group or a thiourea group and a carbamate group or an amide group have completely different chemical structures and properties. Therefore, the compound represented by the general formula (I) is a novel compound having a novel structure. It is completely unpredictable that the compound of the present invention having this novel structure has an angiotensin II antagonism.

[0023]

The present invention has been studied to find a compound having a novel structure and an angiotensin II antagonism, and has found that the compound of the present invention represented by the general formula (I) achieves the object. Heading, the present invention has been completed.

[0024]

DISCLOSURE OF THE INVENTION The present invention relates to 1) a compound represented by the general formula (I)

[0025]

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(Wherein T represents an oxygen atom or a sulfur atom, R ¹ represents a C1-8 alkyl group, R ² each independently represents 1) a hydrogen atom 2) a C1-4 alkyl Group, 3) C1-4 alkoxy groups, 4) C1-4 alkylthio groups, 5) hydroxyl group, 6) hydroxy (C1-4) alkyl group, 7) halogen atom, 8) trihalomethyl group, 9) Trihalomethyloxy group, 10) nitro group, 11) phenyl group, 12) benzyloxy group, 13) C1-4 alkylsulfinyl group, 14) C1-4 alkylsulfonyl group, or 15) -DR (wherein, D is, 1) ^four single bond, 2) C1 -4 amino alkylene or 3) represents a C1 -4 alkylene group, R ⁴
Is 1) COOR ⁵ (wherein, R ⁵ is a hydrogen atom,
4 alkyl groups or -CH ₂ CONR ⁶ R ⁷ group (wherein, R ⁶ and R ⁷ represent. A hydrogen atom or a C1~4 alkyl group). ), 2)

[0027]

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(Wherein, R ⁵ has the same meaning as described above) 3)

[0029]

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(Wherein, R ⁵ has the same meaning as described above) 4)

[0031]

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Or 5) CONR ⁸ R ⁹ group (wherein R ⁸ represents a hydrogen atom or a C1-4 alkyl group, R ⁹ represents a hydrogen atom,
1-4 alkyl or -CH ₂ COOR ¹⁰ group (group in R ¹⁰ represents. A hydrogen atom or a C1~4 alkyl group). )

[0033]

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Are 1) a benzene ring, 2) a 4- to 7-membered monocyclic unsaturated heterocyclic ring containing one sulfur atom, or 3) a 4- to 7-membered monocyclic unsaturated heterocyclic ring containing one nitrogen atom. represents an unsaturated heterocycle, R ³ is 1) hydrogen atom, 2) C1 -4 alkyl group, 3) C2-6 alkenyl group or 4) -COOR ¹¹ group, (wherein, R ¹¹ is Hydrogen atom or C
Represents 1 to 4 alkyl groups. ) Or -CONR ¹²
R ¹³ groups (wherein R ¹² and R ¹³ each independently represent a hydrogen atom or a C1-4 alkyl group, or together with an adjacent nitrogen atom, form one or two nitrogen atoms Or a 4- to 7-membered monocyclic saturated heterocycle containing one nitrogen atom and one oxygen atom.) Represents a C1-4 alkyl group substituted by 1;

Z represents a 1H-tetrazol-5-yl group, and m represents an integer of 1 to 3. However, if m represents 3, in the three R ² together represents -D-R ⁴ group, three R ⁴ is -COOR ⁵ group (group in the radical, R
⁵ has the same meaning as described above. ),

[0036]

Embedded image (In the group, R ⁵ has the same meaning as described above.)

[0037]

Embedded image (Wherein, R ⁵ has the same meaning as described above) and -C
It does not represent a group selected from ONR ⁸ CH ₂ COOR ¹⁰ groups (wherein R ⁸ and R ¹⁰ have the same meaning as described above). ), Their non-toxic salts or their acid addition salts, 2) their production methods, and 3) drugs containing them as active ingredients.

In formula (I), the C1-8 alkyl groups represented by R ¹ are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomers thereof. In the general formula (I), R
² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ ,
The C1~4 alkyl group represented by R ^11, R ¹² and R ^13, is methyl, ethyl, propyl, butyl and isomeric groups thereof.

In the general formula (I), the C2-6 alkenyl group represented by R ³ includes ethenyl, propenyl, butenyl, pentenyl, hexenyl and isomers thereof. In the formula (I), a C1~4 alkoxy groups represented by R ² is methoxy, ethoxy, propoxy, butoxy and isomeric groups thereof. In the general formula (I), C1 to represented by R ²
The four alkylthio groups are methylthio, ethylthio,
Propylthio, butylthio and isomers thereof.

In the general formula (I), the hydroxy (C1-4) alkyl group represented by R ² includes hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and isomers thereof. In the general formula (I), the halogen atom represented by R ² , the halogen atom in the trihalomethyl group or the halogen atom in the trihalomethyloxy group is a fluorine, chlorine, bromine and iodine atom.

In the general formula (I), the C1-4 alkylsulfinyl group represented by R ² is a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, a butylsulfinyl group or an isomer thereof. In the general formula (I), C1 represented by R ²
The “to 4 alkylsulfonyl groups” are a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, a butylsulfonyl group, and isomers thereof. In the general formula (I), the C1-4 alkylene group represented by D includes methylene, ethylene, trimethylene, tetramethylene and isomers thereof.

In the general formula (I), C represented by D
1-4 alkyleneoxy groups are methyleneoxy,
Ethyleneoxy, trimethyleneoxy, tetramethyleneoxy and isomers thereof. General formula (I)
Wherein R ¹² and R ¹³ are taken together with an adjacent nitrogen atom to represent a 4- to 7-membered monocyclic saturated heterocycle containing 1 or 2 nitrogen atoms or 1 nitrogen atom and 1 oxygen atom, Are, for example, pyrrolidine, piperidine, perhydroazepine, imidazolidine, pyrazolidine, perhydrodiazein (such as piperazine), perhydrodiazepine,
Oxazolidine, perhydrooxazine (such as morpholine), perhydrooxazepine and the like. In the general formula (I),

[0043]

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Examples of the 4- to 7-membered monocyclic unsaturated heterocyclic ring containing one sulfur atom represented by the following include thiophene, thiaine, tiepin and the like. In the general formula (I),

[0045]

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Examples of the 4- to 7-membered monocyclic unsaturated heterocycle containing one nitrogen atom represented by are pyrrole, pyridine, azepine and the like.

In the present invention, all isomers are included unless otherwise indicated. For example, alkyl groups, alkenyl groups, alkoxy groups, alkylthio groups, and alkylene groups include straight-chain and branched-chain ones, and the double bond in the alkenyl group is a mixture of E, Z, and EZ. including. It also includes isomer groups resulting from the presence of asymmetric carbon atoms, such as when a branched alkyl group is present.

[0048]

[Salts and Acid Addition Salts] The compounds of the present invention represented by the general formula (I) can be converted into corresponding salts and acid addition salts by known methods. The salts and acid addition salts are preferably non-toxic and water-soluble. Suitable salts include alkali metals (potassium,
Sodium), alkaline earth metals (calcium,
Magnesium, etc.), ammonium salts, pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopetylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine,
Tris (hydroxymethyl) amine, lysine, arginine, N-methyl-D-glucamine and the like.

The non-toxic acid addition salts include hydrochloride,
Inorganic salts such as hydrobromide, sulfate, phosphate, nitrate, or acetate, lactate, tartrate, oxalate,
Fumarate, maleate, citrate, benzoate,
Methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate,
Organic acid salts such as glucuronate and gluconate are exemplified. Preferred is the hydrochloride salt.

Specific compounds of the present invention include N-allyl-N- (2-carboxymethylphenyl) -N'-
Butyl-N '-[(2'-(1H-tetrazole-5-
Yl) -1,1'-biphenyl-4-yl) methyl] urea, N-carboxymethyl-N- (2-carboxymethylphenyl) -N'-butyl-N '-[2'-(1H
-Tetrazol-5-yl) -1,1'-biphenyl-
4-yl) methyl] urea, N-carbamoylmethyl-
N- (2-carboxymethylphenyl) -N'-butyl-N '-[(2'-(1H-tetrazol-5-yl)
-1,1'-biphenyl-4-yl) methyl] urea,

N- (2-carboxymethylphenyl)-
N-morpholinocarbonylmethyl-N'-butyl-N '
-[(2 '-(1H-tetrazol-yl) -1,1'
-Biphenyl-4-yl) methyl] urea, N- (2-
Carboxymethylphenyl) -N-pyrrolidinocarbonylmethyl-N'-butyl-N '-[(2'-(1H-tellurazol-5-yl) -1,1'-biphenyl-4-
Yl) methyl] urea, N- [3- (2-carboxy)
Thienyl] -N-methyl-N'-butyl-N'-
[(2 '-(1H-tetrazol-5-yl) -1,
1'-biphenyl-4-yl) methyl] urea, N-
[2- (5-carboxy) pyridyl] -N-methyl-
N'-butyl-N '-[(2'-(1H-tetrazol-5-yl) -1,1'-biphenyl-4-yl) methyl] urea;

N-carboxymethyl-N- [3- (2-
Carboxy) thienyl] -N'-butyl-N'-
[(2 '-(1H-tetrazol-5-yl) -1,
1'-biphenyl-4-yl) methyl] urea, N-carboxymethyl-N- [2- (5-carboxy) pyridyl] -N'-butyl-N '-[(2'-(1H-tetrazole-5 -Yl) -1,1'-biphenyl-4-yl) methyl] urea, N-carbamoylmethyl-N-
[3- (2-carboxy) thienyl] -N'-butyl-
N '-[(2'-(1H-tetrazol-5-yl)-
1,1′-biphenyl-4-yl) methyl] urea,

N-carbamoylmethyl-N- [2- (5
-Carboxy) pyridyl] -N'-butyl-N'-
[(2 '-(1H-tetrazol-5-yl) -1,
1'-biphenyl-4-yl) methyl] urea, N-
[2- (3-carbamoylpropyloxy) phenyl]
-N'-butyl-N '-[(2'-(1H-tetrazol-5-yl) -1,1'-biphenyl-4-yl) methyl] urea, N- [2- (1-hydroxymethyl- 1
-Oxomethyl) phenyl] -N'-butyl-N'-
[(2 '-(1H-tetrazol-5-yl) -1,
1'-biphenyl-4-yl) methyl] urea,

N- (2-carbamoylmethyloxycarbonylphenyl) -N'-butyl-N '-[(2'-
(1H-tetrazol-5-yl) -1,1'-biphenyl-4-yl) methyl] urea, N- (2-carboxymethylphenyl) -N'-butyl-N '-[(2'-
(1H-tetrazol-5-yl) -1,1'-biphenyl-4-yl) methyl] thiourea, N- (2-carboxyphenyl) -N-methyl-N'-butyl-N'-
[(2 '-(1H-tetrazol-5-yl) -1,
1'-biphenyl-4-yl) methyl] thiourea, N
-[3- (2-carboxy) thienyl] -N'-butyl-N '-[(2'-(1H-tetrazol-5-yl)
-1,1'-biphenyl-4-yl) methyl] thiourea, N- [2- (5-carboxy) pyridyl] -N'-
Butyl-N '-[(2'-(1H-tetrazole-5-
Yl) -1,1'-biphenyl-4-yl) methyl] thiourea, salts thereof, and the compounds of Examples described later.

[0055]

[Production method of the compound of the present invention] The compound of the present invention represented by the general formula (I)

[0056]

Embedded image (In the formula, R ^2a is a group represented by —D—R ⁴ represented by R ² ;
Group ^4a (in the group, R ^4a is 1) —COOR ⁵ group (in the group, R ⁵ has the same meaning as described above), 2)

[0057]

Embedded image (Wherein, R ⁵ has the same meaning as described above.), 3)

[0058]

Embedded image (Wherein, R ⁵ has the same meaning as described above.), 4)

[0059]

Embedded image (Wherein, R ⁵ has the same meaning as described above.), 5)

[0060]

Embedded image (In the group, R ⁵ has the same meaning as described above.), 6)

[0061]

Embedded image 7)

[0062]

Embedded image 8)

[0063]

Embedded image Or 9) —CONR ⁸ R ⁹ (wherein R ⁸ and R ⁹ have the same meaning as described above), and D has the same meaning as described above. ), Or the same meaning as R ² , or a trimethylsilyloxy group, a trimethylsilyloxy (C1-4) alkyl group, a t-butyldimethylsilyloxy group or a t-butyldimethylsilyloxy (C1-4) alkyl group And Za represents ^a 1- (2-cyanoethyl) tetrazol-5-yl group, and all other symbols have the same meanings as described above. ) Can be produced by subjecting it to a deprotection reaction.

In the process for producing the compound of the present invention, the deprotection reaction is known. For example, (1) When it is only necessary to convert a ^Za group to a Z group, an inert organic solvent (eg, tetrahydrofuran (THF) ), Diethyl ether, dimethoxyethane, dioxane, etc.) in an organic base (for example,
1,8-diazabicyclo [5.4.0] -7-undecene (DBU), 1,5-diazabicyclo [3.4.0]
-5-nonene or 1,4-diazabicyclo [2.2.
2] -octane) at 0 to 40 ° C. (2) and converting the Z ^a group in Z group, R ^2a and R
If it is only necessary to convert the carboxylic acid ester in the ^three groups into a carboxylic acid, an inert organic solvent miscible with water (eg, methanol, ethanol, dioxane, etc.)
The reaction is carried out at 0 to 50 ° C. using an aqueous solution of an alkali (eg, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, etc.).

(3) converting the ^Za group to a Z group;
Trimethylsilyloxy group in R ^2a group, only when necessary to convert the group containing hydroxy or it groups containing t- butyldimethylsilyl group or their inert organic solvent (e.g., THF, In diethyl ether, dimethoxyethane, dioxane, etc.) using a fluoride salt, preferably a quaternary ammonium salt (for example, tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride (TBAF), etc.). The reaction is carried out at で 40 ° C.

[0066] (4) converting the Z ^a group in Z group, R ^2a
Converting a trimethylsilyloxy group, a t-butyldimethylsilyloxy group, or a group containing them, into a hydroxy group or a group containing the same;
If it is necessary to convert the carboxylic acid ester in the ^2a and R ³ groups to a carboxylic acid, then in (3) an inert organic solvent (eg, methanol, ethanol, dioxane, etc.) which is miscible with water, The reaction is carried out at 0 to 50 ° C. using an aqueous solution of an alkali (for example, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, etc.). The compound represented by the general formula (II) can be produced by the following reaction scheme.

[0067]

Embedded image In the reaction scheme, R ^2b is a group represented by —D—R ^4a represented by R ^2a —
A ^{DR 4b} group (in the group, R ^4b is a group represented by R ^4a ,

[0068]

Embedded image (Wherein, R ⁵ represents. As defined above) represents the same meaning as R ^4a except that do not represent, D is as defined above. ), But has the same meaning as R ^2a . R ^2c has -D-R ^4a group represented by R ^2a, (in radical, R ^4c is, 1) -D-R ^4c groups in -COOR ^5c group (radical, R
^5c represents a C1-4 alkyl group, a benzyl group or -C
H ₂ CONR ⁶ R ⁷ (wherein R ⁶ and R ⁷ have the same meaning as described above). ), 2)

[0069]

Embedded image (Wherein, R ^5c represents the same meaning as described above.), 3)

[0070]

Embedded image (Wherein, R ^5c has the same meaning as described above.), 4)

[0071]

Embedded image 5)

[0072]

Embedded image Group, or 6) CONR ⁸ R ^9c group (in the group, R ⁸ has the same meaning as described above, and R ^9c is a hydrogen atom, a C1-4 alkyl group or a —CH ₂ COOR ^10c group (in the group, R ^10c Is C1
Represents up to 4 alkyl groups or benzyl groups. ). ), And D has the same meaning as described above. ), And a hydroxyl group or hydroxy (C1-C1) represented by R ^2a
4) It has the same meaning as R ^2a except that it does not represent an alkyl group. R ^3a is a COOR ^11a group represented by one COR-4 alkyl group substituted with one COOR ¹¹ group represented by R ³ (wherein R ^11a represents a C1-4 alkyl group or a benzyl group). Has the same meaning as R ³ except that the alkyl group is substituted with 1 to 4 alkyl groups. Y represents a halogen atom. All other symbols have the same meaning as described above.

In each reaction in the present specification, the reaction product is purified by a conventional purification means, for example, distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography,
Alternatively, it can be purified by a method such as column chromatography or washing and recrystallization. Purification may be performed for each reaction or may be performed after completion of several reactions. The starting materials represented by the general formulas (V), (VI) and (VIII) and the respective reagents in the present invention are known per se or can be produced by a known method. For example, among the compounds represented by the general formula (VI) used as a starting material,

[0074]

Embedded image Are commercially available.

[0075]

[Pharmacological activity] The compound of the present invention represented by the general formula (I)
As described above, it has angiotensin II antagonism.
For example, in a laboratory experiment, the following results were obtained. [Experimental method] Angiotensin II antagonism using isolated rabbit aorta Japanese white rabbits (2-4 kg in weight) were exsanguinated and killed.
The thoracic aorta was removed. The aorta is a spiral specimen (width 1 to
2 mm, length 20-25 mm) and suspended in 10 ml of tissue solution filled with Krebs-Henseleit solution (37 ° C., 95% O ₂ -5% CO ₂ ). 1g for aortic specimen
The experiment was started after applying the load and stabilizing for about 90 minutes. The antagonist activity against angiotensin II was examined by adding angiotensin II from 10 ⁻¹⁰ to 10 ⁻⁶ M cumulatively 15 minutes after the test drug was added. Aortic or isometric changes in the aorta were recorded on a recorder using a transducer and via an amplifier. Responses are expressed as percent of maximal response by Angiotensin II and
The pA ₂ value was calculated according to the method. Table 1 shows the results.

[0076]

[Table 1]

[0077]

[Toxicity] The toxicity of the compound of the present invention is very low,
It can be determined that it is safe enough for use as a medicine.

[0078]

[Application to pharmaceuticals] The compound of the present invention represented by the general formula (I) has an angiotensin II antagonistic action,
It is useful for prevention and / or treatment of various hypertension, congestive heart failure, edema disease and the like. In order to use the compound of the present invention represented by the general formula (I), a non-toxic acid addition salt thereof, or a hydrate thereof for the above-mentioned purpose, it is usually used systemically or locally in an oral or parenteral form. Is administered. The dose varies depending on the age, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually 1 m per adult per dose.
g to 1000 mg orally once to several times a day, or per adult per parenterally from 1 mg to 100 mg once to several times a day (preferably, Intravenous administration) or continuous intravenous administration for 1 hour to 24 hours per day. Of course, as described above, since the dose varies depending on various conditions, a smaller amount than the above dose may be sufficient,
In some cases, it may be necessary to go beyond the range.

When the compound of the present invention is administered, it is used as a solid composition, a liquid composition and other compositions for oral administration, an injection, an external preparation, a suppository and the like for parenteral administration. Solid compositions for oral administration include tablets,
Pills, capsules, powders, granules and the like are included. Capsules include hard capsules and soft capsules. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents (water,
Ethanol etc.). Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Other compositions for parenteral administration include external preparations such as topical solutions, ointments, liniments and suppositories for rectal administration, which contain one or more active substances and are formulated in a conventional manner. And pessaries.

[0080]

Reference Examples and Examples Hereinafter, the present invention will be described in detail with reference to Reference Examples and Examples, but the present invention is not limited thereto. The solvent in parentheses shown at the point of separation by chromatography indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio. Unless otherwise specified, NMR was measured in a heavy methanol solution.

Reference Example 1 N- (2-ethoxycarbonylphenyl) -N'-butyl-N '-[[2'-[1- (2-cyanoethyl) tetrazol-5-yl] -1,1'-biphenyl -4-yl] methyl] urea

[0082]

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N-butyl-N-[[2 '-[1- (2-
Cyanoethyl) tetrazol-5-yl] -1,1′-
Biphenyl-4-yl] methyl] amine hydrochloride (20
0 mg) in a THF suspension (2 ml), triethylamine (77 μl) and ethyl 2-isocyanatobenzoate (1).
(05 mg). The mixture was stirred at room temperature for 1 hour.
The reaction solution was poured into IN hydrochloric acid under ice cooling, and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 2:
Purified in 1) to give the title compound (27) having the following physical data.
5 mg). TLC (n-hexane: ethyl acetate = 1: 1): Rf
0.47.

Reference Example 2 N- (2-t-butyldimethylsilyloxymethylphenyl) -N'-butyl-N '-[[2'-[1- (2-
Cyanoethyl) tetrazol-5-yl] -1,1′-
Biphenyl-4-yl] methyl] urea

[0085]

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Trichloromethyl chloroformate (0.12 ml)
Was added to a solution of 2-t-butyldimethylsilyloxymethylaniline (226 mg) and triethylamine (0.28 ml) in ethyl acetate (0.5 ml).
ml) was added. The mixture was heated at reflux for 10 hours. The reaction solution was concentrated and dried. The residue contains N-butyl-N-
[[2 ′-[1- (2-cyanoethyl) tetrazole-
5-yl] -1,1'-biphenyl-4-yl] methylamine hydrochloride (330 mg) and triethylamine (0.
23 ml) of a pyridine solution (4 ml) was added. The mixture was stirred at room temperature for 1 hour. Ethyl acetate / water was added to the reaction solution, and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (n
-Hexane: ethyl acetate = 2: 1 → 1: 1),
The title compound (390 mg) having the following physical data was obtained. TLC (n-hexane: ethyl acetate = 2: 1): Rf
0.2.

Reference Example 3 N- (2-hydroxymethylphenyl) -N'-butyl-N '-[[2'-[1- (2-cyanoethyl) tetrazol-5-yl] -1,1'-biphenyl -4-yl] methyl] urea

[0088]

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Compound prepared in Reference Example 2 (344 mg)
Acetic acid (3 ml) / water (1 m) was added to a THF solution (1 ml).
l) was added. The mixture was stirred at room temperature for 12 hours. The reaction was concentrated and azeotroped with toluene. The residue was dissolved in ethyl acetate, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate =
1: 1) to give the title compound (270 mg) having the following physical data. TLC (n-hexane: ethyl acetate = 1: 1): Rf0.
2.

Reference Example 4 N- [2- (1-ethoxycarbonyl-1-oxomethyl) phenyl] -N'-butyl-N '-[[2'-[1
-(2-cyanoethyl) tetrazol-5-yl]-
1,1'-biphenyl-4-yl] methyl] urea

[0091]

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In an argon atmosphere, N- [2- (1 -Ethoxycarbonyl-1-hydroxymethyl) phenyl] -N'-butyl-N '-[[2'
A mixed solution of-[1- (2-cyanoethyl) tetrazol-5-yl] -1,1'-biphenyl-4-yl] methyl] urea (299 mg) in diethyl ether (9 ml) / methylene chloride (2 ml) was added. Was. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 2) to give the title compound (133 mg) having the following physical data. TLC (n-hexane: ethyl acetate = 1: 1): Rf
0.55.

Example 1 N- (2-ethoxycarbonylphenyl) -N'-butyl-N '-[[2'-(1H-tetrazol-5-yl) -1,1'-biphenyl-4-yl] Methyl] urea

[0094]

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Compound prepared in Reference Example 1 (275 mg)
DBU (0.2 ml) was added to a THF solution (0.5 ml). The mixture was stirred at room temperature for 5 hours. The reaction solution was cooled on ice,
Poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous sodium sulfate and concentrated to give the title compound having the following physical properties (250 m
g) was obtained. TLC (methylene chloride: methanol = 10: 1): Rf
0.50.

Example 2 N- (2-carboxyphenyl) -N'-butyl-N '
-[[2 '-(1H-tetrazol-5-yl) -1,
1'-biphenyl-4-yl] methyl] urea

[0097]

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Compound prepared in Reference Example 1 (149 mg)
To a 1,4-dioxane solution (2 ml) was added a 1N aqueous sodium hydroxide solution (1.08 ml). The mixture was stirred at room temperature for 30 minutes. 1N Hydrochloric acid was added to the reaction solution, and extracted with ethyl acetate. The extract was washed with water and saturated saline,
After drying over anhydrous sodium sulfate and concentration, the title compound (127 mg) having the following physical data was obtained. TLC (chloroform: methanol: acetic acid = 30: 1:
1): Rf 0.42.

Example 3 N- (2-ethoxycarbonylphenyl) -N'-butyl-N '-[[2'-(1H-tetrazol-5-yl) -1,1'-biphenyl-4-yl] Methyl] urea sodium salt

[0100]

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Compound prepared in Example 1 (109 mg)
Of 1,2-dioxane / water (2: 1) (3 ml)
And a 1N aqueous sodium hydroxide solution (0.22 ml) under ice-cooling
Was added. The mixture was freeze-dried to give the title compound (260 mg) having the following physical data. TLC (methylene chloride: methanol = 10: 1): Rf
0.50. NMR: δ 8.43 (1H, d), 8.01 (1H, dd), 7.58-7.33 (5
H, m), [7.15 (d), 7.08 (d) and 7.00 (t) total 5H], 4.
60 (2H, s), 4.35 (2H, q), 3.40-3.25 (2H, m), 1.75 -1.
55 (2H, m), [1.50-1.28 (m) and 1.38 (t) total 3H], 0.
95 (3H, t).

Examples 3 (1) to 3 (59) Using the corresponding compounds, Reference Example 1 → Example 1 → Example 3, Reference Example → Example 2 → Example 3, Reference Example 2 → Execution Example 1 → Example 3, Reference Example 2 → Reference Example 3 → Reference Example 4 → Example 2 → Example 3, Reference Example 2 → Reference Example 3 → Example 2 → Example 3, or Reference Example 2 → Example 2 → By the same operation as in Example 3, the compounds shown in the following Table 2 were obtained.

[0103]

[Table 2]

[0104]

[Table 3]

[0105]

[Table 4]

[0106]

[Table 5]

[0107]

[Table 6]

[0108]

[Table 7]

[0109]

[Table 8]

[0110]

[Table 9]

[0111]

[Table 10]

[0112]

[Table 11]

[0113]

[Table 12]

[0114]

[Table 13]

[0115]

[Table 14]

[0116]

[Table 15]

[0117]

[Table 16]

[0118]

[Table 17]

[0119]

[Table 18]

[0120]

[Table 19]

[0121]

[Table 20]

[0122]

[Table 21]

[0123]

[Table 22]

[0124]

[Table 23]

[0125]

[Table 24]

[0126]

[Table 25]

[0127]

[Table 26]

[0128]

[Table 27]

[0129]

[Table 28]

[0130]

[Table 29]

[0131]

[Table 30]

[0132]

[Table 31]

[0133]

[Formulation example]

Formulation Example 1 The following components were mixed by a conventional method and then tableted to obtain 100 tablets each containing 50 mg of the active ingredient. N- (2-ethoxycarbonylphenyl) -N'-butyl-N '-[[2'-(1H-tetrazol-5-yl) -1,1'-biphenyl-4-yl] methyl] urea sodium Salt: 5.0 g ・ Carboxymethylcellulose calcium (disintegrant): 0.2 g ・ Magnesium stearate (lubricant): 0.1 g ・ Microcrystalline cellulose: 4.7 g

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-6-72985 (JP, A) JP-A-4-300589 (JP, A) JP-A-63-23868 (JP, A) US Pat. , A) (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 257/04 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula (I) (Wherein T represents an oxygen atom or a sulfur atom, R ¹ represents a C1-8 alkyl group, R ² each independently represents 1) a hydrogen atom, 2) a C1-4 alkyl group, 3) C1-4 alkoxy groups, 4) C1-4 alkylthio groups, 5) hydroxyl group, 6) hydroxy (C1-4) alkyl group, 7) halogen atom 8) trihalomethyl group, 9) trihalomethyloxy group, 10) a nitro group, 11) phenyl group, 12) benzyloxy, 13) C1 -4 alkyl sulfinyl group, 14) C1 -4 alkyl sulfonyl group or 15) -D-R ⁴ group, ( during group, D is, 1) a single bond, 2) C1 -4 amino alkylene or 3) represents a C1 -4 alkylene group,, R ⁴ is 1) -COOR ⁵ (group, R ⁵ Is a hydrogen atom,
C1~4 alkyl group or -CH ₂ CONR ⁶ R ⁷
Wherein R ⁶ and R ⁷ represent a hydrogen atom or a C1-4 alkyl group. ), 2) (In the group, R ⁵ has the same meaning as described above.), 3) (In the group, R ⁵ has the same meaning as described above.), 4) Or 5) —CONR ⁸ R ⁹ group (wherein R ⁸ represents a hydrogen atom or a C1-4 alkyl group, R ⁹ represents a hydrogen atom,
1-4 alkyl or -CH ₂ COOR ¹⁰ group (wherein, R ¹⁰ represents. A hydrogen atom or a C1~4 alkyl group). ), And A represents 1) a benzene ring, 2) a 4- to 7-membered monocyclic unsaturated hetero ring containing one sulfur atom, or 3) a 4- to 7-membered monocyclic unsaturated ring containing one nitrogen atom. Represents a heterocyclic ring, wherein R ³ is 1) a hydrogen atom, 2) a C1 to 4 alkyl group, 3) a C2 to 6 alkenyl group, or 4) a —COOR ¹¹ group (wherein R ¹¹ is a hydrogen atom Or C
Represents 1 to 4 alkyl groups. ) Or -CONR ¹²
R ¹³ group (wherein, R ¹² and R ¹³ each independently represent a hydrogen atom or a C1~4 alkyl group, or together with the adjacent nitrogen atom, 1 or 2 nitrogen atoms Or a 4- to 7-membered monocyclic saturated heterocyclic ring containing one nitrogen atom and one oxygen atom.) Represents a C1-4 alkyl group substituted by 1 and Z is 1H-
Represents a tetrazol-5-yl group, and m represents an integer of 1 to 3. However, when m represents 3, three R
² both represent a -DR ⁴ group, and three R
⁴ is a —COOR ⁵ group (wherein R ⁵ has the same meaning as described above); (In the group, R ⁵ has the same meaning as described above.) (Wherein, R ⁵ has the same meaning as described above) and -C
It does not represent a group selected from ONR ⁸ CH ₂ COOR ¹⁰ groups (wherein R ⁸ and R ¹⁰ have the same meaning as described above). Or a non-toxic salt thereof or an acid addition salt thereof.