JP2585497B2 - Angiotensin 2 antagonistic pyridine derivative - Google Patents

Description

Description: BACKGROUND OF THE INVENTION (Industrial Application Field) The present invention relates to a pyridine derivative having an antagonistic action on angiotensin II, and an antihypertensive containing at least one of them as an active ingredient, which is effective for treating or preventing hypertension. The present invention relates to a drug, a therapeutic agent for heart failure, an anxiolytic and a memory enhancer.

(Prior art) Angiotensin II is a hormone derived from angiotensin I by an angiotensin converting enzyme,
It is a potent vasopressor in mammals such as rats, dogs and humans, and is considered as one of the causative agents of hypertension. Therefore, an angiotensin converting enzyme inhibitor or an angiotensin II receptor antagonist can be expected to be effective as a therapeutic agent for hypertension or congestive heart failure. In addition, an anxiolytic effect and a memory promoting effect based on the receptor antagonism of angiotensin II in the brain have been reported (Neuroreport 1).
Vol. 15, p. 1990), and can be expected to be effective as an anxiolytic and memory enhancer. Examples of angiotensin converting enzyme inhibitors include captopril and enalapril, which are already in clinical use. Drugs that antagonize the angiotensin II receptor have not yet been used clinically, but Circulation Research, Vol. 29, p. 673 (1
971), Journal of Medicinal Chemistry 32, 466, 898, p. 1366 (1989) reports a peptidic angiotensin II receptor antagonist similar to the structure of angiotensin II. In addition, JP-A-62-2406
83 and EP415886, imidazopyridine derivatives, JP-B-63-64428, JP-A-63-23868, WO / 91-00281, W0 / 91
-0027, EP403158 and EP403159 have substituted imidazole derivatives, JP-A-1-287707, EP411507, EP412594 and EP408332 have substituted pyrrole, pyrazole and triazole derivatives, EP411766 has quinazolinone derivatives, and JP-A-3-44377 and EP419048. Is a pyrimidone derivative,
JP-A-3-5464, JP-A-3-27362, JP-A-3-63264 and US Pat. No. 4,880,804 disclose a benzimidazole derivative, EP4
00974, EP401030 and EP407102 disclose imidazole derivatives fused to 5- to 7-membered rings as non-peptide angiotensin II receptor antagonists. However, the pyridine derivative is not yet known.

SUMMARY OF THE INVENTION The present inventors have now found that certain pyridine derivatives have strong angiotensin II antagonism and exhibit blood pressure lowering, anti-heart failure, anti-anxiety and memory promoting effects in animal models. In addition, this pyridine derivative does not have the agonistic action found in peptide receptor antagonists, and is excellent in oral absorption and sustained action. Furthermore, its angiotensin II antagonism is superior to conventional non-peptide angiotensin II antagonists.

Therefore, an object of the present invention is to provide a novel pyridine derivative having an antagonistic effect on angiotensin II.

The present invention also provides a pharmaceutical composition, particularly a pharmaceutical composition used as an antihypertensive, a therapeutic agent for heart failure, an anxiolytic, or a memory promoting agent, comprising a novel pyridine derivative having an angiotensin II antagonistic action. It is intended to be.

Another object of the present invention is to provide a method for treating hypertension and heart failure, and a method for suppressing anxiety and promoting memory.

The pyridine derivative according to the present invention has the following general formula (I)
And a pharmacologically acceptable salt thereof.

Where A is [Where R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom; a halogen atom; a hydrogen group; a nitro group; a cyano group; a phenyl group; a lower alkyl group; a halo-lower alkyl group; An alkenyl group; a C _1-8 alkoxy group wherein the alkoxy group comprises a halogen atom, a C _3-7 cycloalkyl group, one nitrogen atom and optionally one oxygen atom and is substituted by a lower alkyl group. A 5- or 6-membered heterocyclic ring or a carbamoyl group which may be substituted with a lower alkyl group); a lower alkenyloxy group; a C _3-7 cycloalkyloxy group; a halogen atom, a lower alkyl group A benzyloxy group optionally substituted with a halo-lower alkyl or lower alkoxy group; a group — (CH ₂ ) mOR ⁵ (where m represents an integer of 1 to 3, and R ⁵ is water Elementary atom,
C _{3 to 7} cycloalkyl, lower alkyl, lower alkenyl, benzene group, group ^{_{- (CH 2) nNR 6 R}} 7 ( wherein, n represents 1
And R ⁶ or R ⁷ independently represents a hydrogen atom or a lower alkyl group, or R ⁶ and R ⁷ together with the nitrogen atom to which they are attached are a 5- or 6-membered heterocyclic saturated ring may be formed this heterocyclic saturated ring may be substituted by one comprise may have also a lower alkyl group optionally hydrogen atom) or a group ^{_{- ((CH 2) pCOR 8}} ( wherein And p represents an integer of 0 to 4, and R ⁸ is a hydroxyl group, a lower alkyl group, a lower alkoxy group, a phenyl group or NR ⁹ R
¹⁰ (wherein R ⁹ and R ¹⁰ independently represent a hydrogen atom or a lower alkyl group); a group —CO—R ¹¹ (where R ¹¹ represents a hydrogen atom or a lower alkyl group); a group -CONR ¹² R ¹³ (wherein, either R ¹² and R ¹³ are independently a hydrogen atom, a lower alkyl group or phenyl, or the R ¹² and R
¹³ may form it is bound to which may contain 5 or possibly an oxygen atom together with the nitrogen atom 6-membered heterocyclic saturated ring with); radical -COO-R ¹⁴ (wherein Wherein R ¹⁴ is a hydrogen atom, a lower alkyl group or a group-
(CH ₂ ) q-R ¹⁵ (q represents an integer of 1-4, and R ¹⁵
Represents a 5- or 6-membered saturated ring containing one or two nitrogen atoms and optionally one oxygen atom and optionally substituted by lower alkyl or phenyl lower alkyl))); Or a group -NR ¹⁶ R ^17, wherein R ¹⁶ and R ¹⁷ independently represent a hydrogen atom, a lower alkyl group or a lower acyl group; or R ¹ , R ² , R ³ and R ⁴ Any two are together
(CH ₂₎ r- (wherein r is an integer of 3 or 4)
May be represented.

B represents a group COOR ¹⁸ (where R ¹⁸ represents a hydrogen atom, a lower alkyl group or a group —CH ₂ OCOC (CH ₃ ) ₃ ), or a tetrazolyl group.

X is -O -, - NR ¹⁹ - (wherein R ¹⁹ represents a hydrogen atom, a lower alkyl group or lower acyl group), or, -S
(O) t- (where t represents an integer of 0 to 2). The pharmaceutical composition according to the present invention comprises at least one compound represented by the above general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient, and further comprises at least one pharmacologically acceptable salt. And a carrier.

Further, the method for treating hypertension and heart failure and the method for suppressing anxiety and promoting memory according to the present invention comprise administering an effective amount of at least one compound represented by the general formula (I) to a mammal. is there. DETAILED DESCRIPTION OF THE INVENTION Compounds As used herein, the term "lower alkyl" or "lower alkoxy" as a group or part of a group refers to a group wherein the group is straight or branched having 1 to 6, preferably 1 carbon atoms. ~ 4 alkyl groups. Further, the term "lower alkenyl" means a group having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, in which the group is linear or branched and contains at least one carbon-carbon double bond. . Further, a halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The term "haloalkyl" as a group or part of a group means that one or more hydrogen atoms therein has been replaced with a halogen atom.

The halo-lower alkyl group represented by R ¹ , R ² , R ³ and R ⁴ is
Preferably 2-fluoroethyl, difluoromethyl, 2,
2,2-trifluoroethyl.

The C _1-8 alkoxy group represented by R ¹ , R ² , R ³ and R ⁴ is preferably a C _1-6 alkoxy group, wherein the alkoxy group is a halogen atom, a C _3-7 cycloalkyl group (for example, cyclopropyl, A cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl group, etc., a 5- or 6-membered saturated saturated ring containing one nitrogen atom and optionally one oxygen atom and optionally substituted by a lower alkyl group (e.g. -Pyrrolidinyl, 1-piperidinyl, 2,2,6,
6-tetramethylpyridin-1-yl, 4-methylpiperidin-1-yl, 4-diphenylmethylpiperazine-
1-yl, morpholin-1-yl, etc.), or a carbamoyl group optionally substituted with a lower alkyl group. When the alkoxy group is substituted with the C _3-7 cycloalkyl group, a 5- or 6-membered heterocyclic ring containing one nitrogen atom or a carbamoyl group, the carbon number of the alkyl group portion of the alkoxy group is preferably 1-3, more preferably 1 or 2.

The lower alkenyloxy group represented by R ¹ , R ² , R ³ and R ⁴ is preferably vinyloxy, allyloxy, butenyloxy, cyclohexenyloxy.

The benzyl group represented by R ¹ , R ² , R ³ and R ⁴ may be substituted, and preferable examples thereof include o, m and p-methoxybenzyloxy, o, m and p-nitrobenzyloxy, o, m and p-methylbenzyloxy, o, m and p-chlorobenzyloxy, o, m and p-fluorobenzyloxy, o, m and p-trifluoromethylbenzyloxy, o, m and p-hydroxybenzyloxy, o, m and p-aminobenzyloxy, o, m and p
-Acetylaminobenzyloxy group and the like.

Group - (CH ₂₎ If R ⁵ in mOR ⁵ represents a C _{3 to 7} cycloalkyl-lower alkyl, m is preferably 1,
Preferred examples thereof include (cyclopropyl) methyloxy, (cyclobutyl) methyloxy, and (cyclopentyl) methyloxy.

The group - in _{^{(CH 2) nNR 6 R 7}} , n is preferably 1
To 3, more preferably 1 and 2. This NR ⁶ R
⁷ is preferably an amino, methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, diisopropylamino group. Also, this R ⁶ and R ⁷
May form, together with the nitrogen atom to which it is bonded, a 5- or 6-membered saturated ring which may optionally contain an oxygen atom, and the same specific examples as described above are preferred. , group - in (CH ₂₎ pCOR ^8, p is preferably 0
~ 2, more preferably 0 or 1.

In the group -CONR ¹² R ^13, R ¹² and R ¹³ are be formed it is combined with which may contain 5 or possibly an oxygen atom together with the nitrogen atom 6-membered heterocyclic saturated ring Often, the same specific examples as described above are preferred.

Group R ¹⁴ represents - in ^{_{(CH 2) q-R 15}} , q is preferably 1-3, more preferably 2. Also this R
Examples of the 5- or 6-membered saturated ring containing one or two nitrogen atoms and optionally one oxygen atom represented by ¹⁵ include pyrrolidinyl, piperidinyl, pyrazolidinyl, piperazinyl, morpholinyl group and the like.

Preferred compounds of the compounds according to the invention are (Where R ²⁰ and R ²¹ are independently a lower alkyl group, a phenyl group or a group — (CH ₂ ) mOR ⁵ (where m and R ⁵ have the same meanings as in the above formula (I)) Represents).

Another preferred group of compounds according to the invention is (Here, R ²² and R ²³ independently represent a methyl group or an ethyl group, and R ¹ has the same meaning as in the above formula (I)).

Other preferred compounds of the compounds according to the invention are (Where R ²² and R ²³ have the same meaning as described above;
²⁴ represents a C _1-8 alkoxy group, which is a halogen atom, a C _3-7 cycloalkyl group,
And optionally a 5- or 6-membered heterocyclic ring containing one oxygen atom and optionally substituted with a lower alkyl group or optionally substituted with a carbamoyl group optionally substituted with a lower alkyl group. ).

Another preferred group of compounds according to the invention is (Wherein, R ²² and R ²³ have the same meanings as defined above, R ⁵
Has the same meaning as in formula (I)).

Yet another preferred group of compounds according to the invention are (Where R ²² and R ²³ have the same meaning as described above;
¹¹ has the same meaning as in formula (I)).

Yet another preferred group of compounds according to the invention are (Where R ²² and R ²³ have the same meaning as described above;
¹⁴ has the same meaning as in formula (I)).

Yet another preferred group of compounds according to the invention are (Where R ²² and R ²³ have the same meaning as described above;
¹² and R ¹³ have the same meanings as in the above formula (I)).

Yet another preferred group of compounds according to the invention are (Where R ²² and R ²³ have the same meaning as described above;
¹⁶ and R ¹⁷ have the same meanings as in the above formula (I)).

Particularly preferred compounds are 2-ethyl-6-methyl-4- [2 '-(tetrazol-5-yl) biphenyl-4-yl] methoxypyridine; 2,6-diethyl-4- [2'-(tetrazol- 5-
Yl) biphenyl-4-yl] methoxypyridine; 2,6-diethyl-4- (2'-carboxybiphenyl-4-yl) methoxypyridine; 2-ethyl-3-methoxy-6-methyl-4- [2 '
-(Tetrazol-5-yl) biphenyl-4-yl]
3-methoxy-2,6-dimethyl-4- [2 '-(tetrazol-5-yl) biphenyl-4-yl] methoxypyridine; 3-ethoxy-2,6-dimethyl-4- [2' -(Tetrazol-5-yl) biphenyl-4-yl] methoxypyridine; 2,6-dimethyl-3-iso-propoxy-4- [2'-
(Tetrazol-5-yl) biphenyl-4-yl] methoxypyridine; 3-allyloxy-2,6-dimethyl-4- [2'-
(Tetrazol-5-yl) biphenyl-4-yl] methoxypyridine; 3-benzyloxy-2,6-dimethyl-4- [2'-
(Tetrazol-5-yl) biphenyl-4-yl] methoxypyridine; 3-ethoxy-2,6-dimethyl-4- (2'-carboxybiphenyl-4-yl) methoxypyridine; 3-ethoxymethyl-2,6 -Dimethyl-4- [2'-
(Tetrazol-5-yl) biphenyl-4-yl] methoxypyridine; 3-allyloxymethyl-2,6-dimethyl-4-
[2 '-(tetrazol-5-yl) biphenyl-4-
Yl] methoxypyridine; 3- (cyclopropyl) methyloxymethyl-2,6-
Dimethyl-4- [2 '-(tetrazol-5-yl) biphenyl-4-yl] methoxypyridine; 2,6-dimethyl-3- (N, N-dimethylcarbamoyloxy) methyl-4- [2'-( Tetrazol-5-yl) biphenyl-4-yl] methoxypyridine; 3-acetyl-2,6-dimethyl-4- [2 '-(tetrazol-5-yl) biphenyl-4-yl] methoxypyridine; 3-formyl -2,6-dimethyl-4- [2 '-(tetrazol-5-yl) biphenyl-4-yl] methoxypyridine; 3-ethoxycarbonyl-2,6-dimethyl-4-
[2 '-(tetrazol-5-yl) biphenyl-4-
Yl] methoxypyridine; 3-ethoxycarbonyl-2,6-dimethyl-4-
(2'-carboxybiphenyl-4-yl) methoxypyridine; 3-ethoxycarbonyl-2-ethyl-6-methyl-
4- [2 '-(tetrazol-5-yl) biphenyl-
4-yl] methoxypyridine; 3-ethoxycarbonyl-6-ethyl-2-methyl-
4- [2 '-(tetrazol-5-yl) biphenyl-
4-yl] methoxypyridine; 2-ethyl-3-methoxycarbonyl-6-methyl-4
-[2 '-(tetrazol-5-yl) biphenyl-4
-Yl] methoxypyridine; 2,6-dimethyl-3-iso-propoxycarbonyl-4
-[2 '-(tetrazol-5-yl) biphenyl-4
2,6-dimethyl-3- (N, N-dimethyl) carbamoyl-4- [2 '-(tetrazol-5-yl) biphenyl-4-yl] methoxypyridine; and 2,6- Dimethyl-3- (piperidin-1-yl) carbonyl-4- [2 '-(tetrazol-5-yl) biphenyl-4-yl] methoxypyridine and pharmaceutically acceptable salts thereof.

The compound according to the present invention can exist as a stereoisomer derived from a sulfur atom in the molecule and a tautomer derived from a tetrazole ring, and both isomers are included in the present invention.

The compounds according to the invention can be in the form of their salts.
Such salts include non-toxic pharmaceutically acceptable salts, preferably alkali metal or alkaline earth metal salts such as sodium, potassium or calcium salts, hydrofluoric acid, hydrochloric acid Inorganic acid salts such as salts, hydrobromides, hydrohalides such as hydroiodide, nitrates, perchlorates, sulfates, phosphates, metasulfonates, trifluoromethanesulfonates , Lower alkyl sulfonates such as ethane sulfonate, benzene sulfonates, aryl sulfonates such as p-toluene sulfonate, fumarate, succinate, citrate, tartrate, oxalate Organic acid salts such as acid salts, maleates and the like, and amino acid salts such as glutamates and aspartates.

Production of Compounds The compounds according to the present invention can be produced by various production methods as described below.

According to the first method (A) according to the present invention, a compound of the general formula (I) (where t = 0 when X represents a group -S (O) t-) has the following general formula: (II): (Wherein, R ¹ , R ² , R ³ and R ⁴ have the same meaning as in the above formula (I), and X represents —O—, —NH— or —S—) and a compound represented by the following formula: The following formula (III): (In the formula, Y represents a halogen atom or an alkyl or arylsulfonyloxy group, B has the same meaning as in the above formula (I), and when B represents a tetrazole group, the tetrazolyl group is protected. May be used in a solvent that does not participate in the reaction (for example, an organic solvent such as N, N-dimethylformamide, dioxane, tetrahydrofuran, methanol, ethanol, acetone, or dimethyl sulfoxide) or a mixture of these solvents and water. -30 to 150 in a mixed solvent in the presence of a base
The reaction can be carried out at a reaction temperature of 10 ° C., preferably 10 to 100 ° C., for 30 minutes to 24 hours, usually 1 to 6 hours, and if necessary, the protective group can be removed.

Examples of the substituent of Y in the compound of the formula (III) include a halogen atom such as a chlorine atom, a bromine atom and an iodine atom, an alkylsulfonyloxy group such as methanesulfonyloxy, ethanesulfonyloxy and trifluoromethanesulfonyloxy, and benzenesulfonyloxy And arylsulfonyloxy groups such as p-toluenesulfonyloxy. Examples of the base used in the condensation reaction include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, and potassium carbonate; Examples thereof include metal hydrides such as sodium and potassium hydride, and organic amines such as triethylamine and pyridine.

Examples of the protective group for the tetrazolyl group in B include a trityl group and a 2-cyanoethyl group.

According to a second method (B) according to the invention, the compound of general formula (I) (where t = 0 when X represents a group -S (O) t-) has the following general formula: (IV): (Wherein, R ¹ , R ² , R ³ and R ⁴ have the same meanings as in the above formula (I), and Z represents a halogen atom or a nitro group); ): (Wherein X represents -O-, -NH- or -S-;
Has the same meaning as in the above formula (I), and when B represents a tetrazolyl group, the tetrazolyl group may be protected.) Or a reactive salt thereof with the method (A) The reaction can be carried out under the same conditions as described above, and the protective group can be removed if necessary.

Examples of the reactive salt of the compound of the formula (V) include alkali metal salts such as sodium, potassium and lithium.

According to a third method (C) according to the invention, a compound of general formula (I), wherein B represents a tetrazolyl group, is obtained by converting another compound of general formula (I) according to the following reaction: Can be manufactured by

(In the formula, A has the same meaning as in the above formula (I),
^18a represents a hydrogen atom or lower alkyl, preferably C _1-4 alkyl, and B ¹ represents a tetrazolyl group. Step (i) is a reaction of a compound of the formula (Ia) with ammonia to form a compound of the general formula (VI) This is a step of synthesizing an amidated product.
When R ^18a is a hydrogen atom, prior to the reaction, formula (Ia)
It is preferable that the compound of the formula (1) is an acid halide or an active ester. Acid chlorides and acid bromides are used as acid halides. These compounds are prepared by converting a compound of the formula (Ia) into an acid halide such as thionyl chloride, thionyl bromide, phosphorus pentachloride, phosphorus oxychloride, and oxalyl chloride; It can be obtained by reacting at a temperature of -20 to 150 ° C in the presence or absence of a solvent that does not participate in the reaction. Esters such as N-hydroxysuccinimide and N-hydroxybenztriazole are used as the active ester.

The reaction of the compound of formula (Ia) with ammonia is from 0 to 150
It can be completed in a solvent such as water, methanol, ethanol, tetrahydrofuran, dioxane and the like at a temperature of ° C. in 30 minutes to 24 hours.

Step (ii) is a step of nitrifying the compound of formula (VI) by a dehydration reaction of the amide. The reaction is carried out using thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, thionyl bromide or the like as a dehydrating agent in the presence or absence of a solvent which does not participate in the reaction at a temperature of -20 to 150 ° C for 30 minutes to 24 hours. Can be completed in time.

Step (iii) is a step of reacting the nitrile with the azide derivative to form a tetrazole ring. The tetrazole ring can be formed by reacting a compound of formula (VII) with an azide derivative such as sodium azide, potassium azide, trimethyltin azide or tributyltin azide in the presence or absence of a solvent that does not participate in the reaction. At a temperature of ~ 200 ° C, 3
It proceeds by reacting for 0 minutes to 2 weeks. The tetrazole compound thus obtained is optionally a trityl group, a p-methoxybenzyl group, a methoxymethyl group,
Protected with 2-cyanoethyl group, etc.
Can be obtained a compound of the general formula (I) in which

Further, the compound of the formula (VII) can also be produced by reacting the compound of the above (II) with 2′-cyano-4-bromomethylbiphenyl. This reaction can be allowed to proceed under the same conditions as in the above method (A).

According to yet another method (D), among the compounds of general formula (I), the following general formula (Ib): (Wherein R ²² and R ²³ independently represent a methyl group or an ethyl group, and R ⁵ and B have the same meanings as in the above formula (I)). can do.

(Wherein, R ²² and R ²³ have the same meanings as described above, R ⁵ and B have the same meanings as in the above formula (I), and when B represents a tetrazole group, the tetrazolyl group is protected. R ²⁵ represents a lower alkyl group, and Y has the same meaning as in formula (III).) Step (i) reduces the compound of formula (VIII) to form a compound of formula (IX)
Is a step of synthesizing the compound of As the reducing reagent, lithium aluminum hydride, sodium borohydride, and homologs thereof can be used, and an appropriate Lewis acid (for example, aluminum chloride or cesium chloride) may be used in some cases. The reaction is carried out in a solvent not involved in the reduction (for example, tetrahydrofuran, ether, dioxane, methanol, ethanol, dichloromethane, etc.) at 0 ° to
It can be completed in 30 minutes to 48 hours at a temperature of 100 ° C.

Step (ii) is a condensation reaction of a compound represented by compound Y-R ⁵ of formula (IX), the protecting group is removed if necessary, is in the process of synthesizing the compounds of general formula (Ib) .
The reaction can be carried out under the same conditions as in the above method (A).

According to the process (E) according to the invention, among the compounds of the general formula (I), the following general formula (Ic): (Wherein, R ²² and R ²³ have the same meanings as described above, and B has the same meaning as in the case of the above general formula (I)). To remove the protecting group.

Manganese dioxide, nickel peroxide,
Chromic acid, chromic acid-pyridine complex, dimethylsulfoxide and additives (for example, dicyclohexylcarbodiimide, acetic anhydride, trifluoroacetic anhydride, oxalyl chloride, etc.) can be used. The reaction can be completed in a solvent that does not participate in the oxidation (eg, dichloromethane, dioxane, acetone, ethyl ether, pyridine, water, etc.) at a temperature of −70 to 100 ° C. for 30 minutes to 24 hours.

Further according to the process (F) according to the invention, the general formula (I)
Of the compounds of the following general formula (Id): (Wherein, R ²² and R ²³ represent the same meaning as described above,
R ¹⁶ , R ¹⁷ and B have the same meanings as in the above formula (I)) can be produced according to the following reaction.

(Wherein, R ²² and R ²³ represent the same meaning as described above,
R ¹⁶ , R ¹⁷ and B have the same meanings as in the above formula (I), and when B represents a tetrazolyl group, the tetrazolyl group may be protected.) Step (i) comprises the steps of formula (X) In this step, the nitro group of the compound is reduced to produce an amino compound. Examples of the reducing agent include a metal (for example, iron, zinc, tin, etc.) and an acid (for example, acetic acid or hydrochloric acid), catalytic reduction (for a catalyst, palladium, platinum, Raney nickel, etc.), borohydride Sodium and the like. Water, methanol, ethanol, dioxane and the like can be used as the solvent.

The reaction can be completed in a solvent that does not participate in the reduction at a temperature of 0 to 150 ° C. for 30 minutes to 24 hours.

Step (ii) is a step of alkylating or acylating the compound of the formula (XI), removing a protecting group if necessary, and synthesizing the compound of the general formula (I).

The alkylation reaction is carried out in a solvent that does not participate in the reaction, in the presence or absence of a base, at a temperature of −20 to 100 ° C., at 30 ° C.
It can be completed in minutes to 24 hours. Examples of the alkylating agent include alkyl halides (eg, methyl iodide, ethyl iodide, ethyl bromide, propyl iodide, butyl iodide, etc.) and alkyl sulfonates (methyl methanesulfonate, methyl p-toluene sulfonate, etc.). And the like). Further, alkylation with sodium borohydride or sodium cyanoborohydride and an aldehyde (for example, formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, etc.) can also be used. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate and potassium carbonate, and hydrogenation such as sodium hydride and potassium hydride. Metals, organic bases such as pyridine, triethylamine and diisopropylethylamine can be mentioned.

The acylation reaction is performed in a solvent that does not participate in the reaction.
It can be completed in the presence or absence of a base at a temperature of −20 to 100 ° C. in 30 minutes to 24 hours. As the acylating agent, acid chlorides such as acetyl chloride and propionyl chloride and acid anhydrides such as acetic anhydride and propionic anhydride can be used. As the base, for example, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, alkali metal carbonates such as potassium carbonate, sodium hydride,
Metal hydrides such as potassium hydride and organic bases such as pyridine, triethylamine and diisopropylethylamine can be used.

In the general formula (I), the sulfoxide compound and the sulfone compound in which X represents -S (O) t- and t is 1 or 2 are the same as those in the general formula (I) in which X is -S-.
Can be produced by oxidizing the compound of This oxidation reaction is carried out in a solvent (for example, benzene, chloroform, methylene chloride, methanol, ethanol,
Acetic acid, formic acid, water or a mixed solvent thereof)
In the case of 1, 1 to 2 equivalents, preferably 1 to 1.2 equivalents of the oxidizing agent is used, and in the case of t = 2, 2 to 3 equivalents, preferably 2 to 2.5 equivalents of the oxidizing agent are used. -40 ~ 60 ℃,
Preferably, the reaction can be completed at -20 to room temperature for 5 minutes to 6 hours. Preferred oxidizing agents include, for example, peracetic acid, hydrogen peroxide, trifluoroperacetic acid, metachloroperbenzoic acid, sodium metaperiodate, N-bromosuccinimide, tert-butyl hydroperoxide, manganese dioxide and the like.

The pyridine or pyridone derivatives represented by the general formulas (II) and (IV) can be prepared by a known method (for example,
Nos. 60-178890, 61-17589, JP-A-1-215881,
JP-A-61-148122) and Journal of Organic Chemistry, Vol. 26, p. 1673 (19
Vol. 28, p. 725 (1963), Vol. 44, p. 870 (1979), Vol. 51, p. 268 (1986), Hemisches Berichte, Vol. 54, p. 1089 (1921), Vol. 94, p. 48
6 pages (1961), Journal of Indian Chemical Society 101, 950 pages (1974),
Journal of the American Chemical Society 83: 193 (1961), Pharmaceutical Journal 91: 740 (1971), Bretane of the Chemical Society of Japan 42: 2389 (1969) Heterocycles 13: 239 (1979), Liebigs Ann.C
hem., page 1466 (1982).

The biphenyl derivatives represented by the general formulas (III) and (V) can be prepared by known methods (WO-89 / 06233, JP-A-1-117876, Journal of Organic Chemistry, vol. 56, p. 2395). , 1991).

The compound represented by the general formula (I) synthesized by the above synthesis method can be purified by a usual production method, for example, recrystallization, reprecipitation, solvent extraction, silica gel column chromatography, column chromatography using an adsorptive resin, and the like. I can do it.

Use of Compound / Pharmaceutical Composition The compound represented by the general formula (I) according to the present invention has an angiotensin II antagonistic action (angiotensin II
For details of the antagonism, see the experimental examples described later). Therefore, the compounds according to the present invention are useful for treating and preventing diseases in which angiotensin II is involved. In particular,
The compounds according to the invention can be used as antihypertensives, therapeutics for heart failure, anxiolytics and memory enhancers.

A pharmaceutical composition containing the compound according to the present invention as an active ingredient,
It can be administered to humans and non-human animals by any of oral and parenteral (eg, intravenous, intramuscular, subcutaneous, rectal, transdermal) administration routes.

Accordingly, the pharmaceutical composition containing the compound according to the present invention as an active ingredient is made into an appropriate dosage form according to the administration route, and specifically, mainly injections such as intravenous injection and intramuscular injection, capsules, tablets, and granules. And oral preparations such as powders, pills, fine granules and lozenges, rectal preparations, oily suppositories, aqueous suppositories and the like. These various formulations are commonly used excipients, extenders, binders, wetting agents, disintegrants,
It can be produced by a conventional method using a surfactant, a lubricant, a dispersant, a buffer, a preservative, a solubilizer, a preservative, a flavoring agent, a soothing agent, a stabilizer and the like. Examples of the non-toxic additives that can be used include, for example, lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or a salt thereof, Arabic com, polyethylene glycol , Syrup, petrolatum, glycerin, ethanol, propylene glycol, citric acid, sodium chloride, sodium sulfite,
Sodium phosphate and the like.

The content of the compound according to the present invention in the pharmaceutical composition varies depending on the dosage form, but is usually about 1 to 70% by weight, preferably about 5 to 50% by weight of the whole composition.

The dose is appropriately determined depending on the individual case, taking into account symptoms, age, sex, etc. This is administered once or several times a day. In addition, for anti-anxiety or memory promotion, it is usually about 0.1 μg to 100 mg, preferably 1 μg to 10 mg per day for an adult, which is administered once or several times a day.

The present invention will be described in more detail by the following examples, but the present invention is not limited to these examples.

The NMR data in the following examples are data measured by 400 MHz NMR, and are shown as δ values (ppm) based on TMS.

Example 1 2,6-diethyl-4- [2 '-(tetrazol-5-
Yl) biphenyl-4-yl] methoxypyridine (a) 115 mg of 60% sodium hydride was suspended in 2.4 ml of dry N, N-dimethylformamide, stirred at room temperature for 20 minutes, and then treated with 2,6-diethyl-4 ( 1H) -pyridone 363 mg and
2.4 ml of N, N-dimethylformamide was added, and the mixture was further stirred for 1 hour. Next, 4'-bromomethyl-
1.537 g of 2- (triphenylmethyltetrazol-5-yl) biphenyl was dried in N, N-dimethylformamide 7
The mixture was dissolved in ml, and added thereto. After completion of the reaction, the temperature was returned to room temperature, 40 ml of cold water was added to the reaction solution, and the mixture was extracted three times with 80 ml of ethyl acetate. The ethyl acetate extract was washed with a saturated aqueous solution of sodium hydrogen carbonate, water and brine in that order, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography, and chloroform:
From ethyl acetate = 25: 1 to 5: 1 elution, 1.22 g of white powdered 2,6-diethyl-4- [2 ′-(triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methoxypyridine ( (81% yield). ¹ H NMR (CDCl ₃ ) δ: 1.29 (6H, t), 2.78 (4H, q), 4.95
(2H, s), 6.57 (2H, s), 6.91 (6H, m), 7.17 (4H, m), 7.
22 to 7.34 (9H), 7.40 (1H, dd), 7.47 (1H, dt), 7.51 (1
H, dt), 7.95 (1H, dd); FDMS (m / z): 628 (M + 1) ⁺ . (B) Dissolve 1.0 g of the compound of (a) in 12 ml of a mixture of methanol: methylene chloride (2: 1), and add 4N HCl 0.64 under ice-cooling.
ml was added and the mixture was stirred at 10 to 15 ° C for 2.5 hours. After the reaction,
The pH of the reaction solution was adjusted to 13 with 5N NaOH, 10 ml of water was added, and the mixture was washed twice with 40 ml of diethyl ethyl ether. Next, the reaction solution was neutralized, and the organic solvent was distilled off under reduced pressure. 1N under ice cooling
The pH of the reaction solution was adjusted to 3 to 4 with HCl, and the mixture was stirred at the same temperature for about 30 minutes. The precipitated crystals were collected by filtration, washed with water and n-hexane, and dried to obtain 530 mg (yield: 86%) of the title compound as an anhydrous crystalline powder. ¹ H NMR (DMSO-d ₆ ) δ: 1.20 (6H, t), 2.65 (4H, q), 5.1
6 (2H, s), 6.79 (2H, s), 7.13 (2H, d), 7.39 (2H, d),
7.56 (2H, m), 7.68 (2H, m); FDMS (m / z): 386 (M + 1) ⁺ . Examples 2-37 Instead of 2,6-diethyl-4 (1H) -pyridone, various pyridones were replaced with 4'-bromomethyl-2- (triphenylmethyltetrazol-5-yl) as in Example 1.
After reacting with biphenyl, the compound was detritylated to obtain the compounds of Examples 2 to 37 shown in Table 1.

Example 38 2,6-Dimethyl-3- (p-methoxybenzyloxy) -4- [2 '-(tetrazol-5-yl) biphenyl-4-yl] methoxypyridine (a) 2,6-dimethyl-3 Using-(p-methoxybenzyloxy) -4- (1H) -pyridone, the reaction was carried out in the same manner as in Example 1 to give 2,6-dimethyl-3- (p-methoxybenzyloxy)-as a pale yellow powder. 4- [2'-
(Triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methoxypyridine (yield about 100%)
I got ¹ H NMR (CDCl ₃ ) δ: 2.37 (3H, s), 2.44 (3H, s), 3.78
(3H, s), 4.90 (2H, s), 5.04 (2H, s), 6.63 (1H, s), 6.
83 (2H, d), 6.89 to 6.94 (6H), 7.16 to 7.32 (15H), 7.42
(1H, dd), 7.47 (1H, dt), 7.52 (1H, dt), 7.94 (1H, d
d); SIMS (m / z): 736 (M + 1) ⁺ . (B) 200 mg of the compound obtained in (a) was treated with dioxane 2
The mixture was dissolved in a mixed solvent of 2 ml of ethanol and 2 ml of ethanol, 2 ml of concentrated aqueous ammonia was added, and the mixture was heated at 100 ° C. for 8 hours in a sealed tube. After completion of the reaction, the reaction solution was concentrated, water was added thereto, the pH was adjusted to 13 with 1N NaOH, and the aqueous layer was washed with ether. Then the pH of the aqueous layer
Was adjusted to 4 with 1N HCl, and the resulting precipitate was collected by filtration and dried to give the title compound (114 mg, yield 85%) as a colorless powder. ¹ H NMR (DMSO-d ₆ ) δ: 2.24 (3H, s), 2.38 (3H, s), 3.7
5 (3H, s), 4.84 (2H, s), 5.23 (2H, s), 6.88 (2H, d),
6.99 (1H, s), 7.17 (2H, d), 7.25 (2H, d), 7.44 (2H,
d), 7.57 (1H, d), 7.58 (1H, t), 7.68 (1H, d), 7.69 (1
H, t); SIMS (m / z): 494 (M + 1) ⁺ . Example 39 3-Hydroxy-2,6-dimethyl-4- [2 '-(tetrazol-5-yl) biphenyl-4-yl] methoxypyridine 300 mg of the compound of Example 38 (a) was treated with 1.5 ml of dioxane and 3 ml of methanol. Was dissolved in a mixed solvent of 5N, and 0.8 ml of 5N HCl was added thereto, followed by stirring at 60 to 70 ° C for 2 hours. After completion of the reaction, the reaction solution was concentrated, water was added, and the mixture was washed with ether. Water layer is 1N NaO
The pH was adjusted to pH 3.4, and the resulting precipitate was collected by filtration and dried to give 118 mg (yield 78%) of the title compound as a colorless powder. _{^{1 H NMR (DMSO-d 6}} ) δ: 2.33 (3H, s), 2.37 (3H, s), 5.2
4 (2H, s), 7.01 (1H, s), 7.13 (2H, d), 7.43 (2H, d),
7.52 (1H, d), 7.55 (1H, t), 7.64 (1H, t), 7.65 (1H,
d); SIMS (m / z): 374 (M + 1) ⁺ . Example 40 3-ethoxycarbonyl-2,6-dimethyl-4- [2 '
-(Tetrazol-5-yl) biphenyl-4-yl]
Methoxypyridine (a) Convert sodium hydride to potassium carbonate and 2,6-
2,6-Dimethyl-3-ethoxycarbonyl was prepared in the same manner as in Example 1 except that diethyl-4 (1H) -pyridone was replaced with 3-ethoxycarbonyl-2,6-dimethyl-4 (1H) -pyridone. 4- [2 '-(Triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methoxypyridine was obtained. (94% _{^{yield) 1 H NMR (CDCl 3)}} δ: 1.30 (3H, t), 2.47 (3H, s), 2.51
(3H, s), 4.35 (2H, q), 5.02 (2H, s), 6.58 (1H, s), 6.
19 (6H, m), 7.15 (4H), 7.19 to 7.33 (9H), 7.39 (1H, d
d), 7.46 (1H, dt), 7.51 (1H, dt), 7.92 (1H, dd); FDMS
(M / z): 672 (M + 1) ⁺ . (B) The title compound was obtained as a colorless powder by subjecting the compound obtained in (a) to detritylation in the same manner as in Example 1 (b). (Yield 85%) ¹ H NMR (DMSO-d ₆ ) δ: 1.21 (3H, t), 2.43 (3H, s), 2.5
3 (3H, s), 4.30 (2H, q), 5.31 (2H, s), 7.14 (2H, d),
7.27 (1H, s), 7.35 (2H, d), 7.56 (1H, d), 7.59 (1H,
t), 7.68 (1H, d), 7.70 (1H, t); EIMS (m / z): 429 (M + 1)
⁺ . Examples 41 to 50 In the same manner as in Example 40, 3-ethoxycarbonyl-2,
The compounds of Examples 41 to 50 shown in Table 2 were obtained except that various pyridones were used instead of 6-dimethyl-4 (1H) -pyridone.

Example 51 3-Carboxy-2,6-dimethyl-4- [2 '-(tetrazol-5-yl) biphenyl-4-yl] methoxypyridine 150 mg of the compound of Example 40 was dissolved in 2 ml of 1N NaOH, and
The mixture was stirred at 70 ° C for 24 hours. After cooling, pH the reaction mixture with 1N HCl.
The resulting precipitate was collected by filtration, washed with water, and dried to give the title compound (84 mg, yield 60%) as a colorless powder. _{^{1 H NMR (DMSO-d 6}} ) δ: 2.35 (3H, s), 2.40 (3H, s), 5.2
1 (2H, s), 6.97 (1H, s), 7.13 (2H, d), 7.36 (2H, d),
7.56-7.61 (2H, m), 7.65-7.71 (2H, m); FDMS (m / z):
402 (M + 1) ⁺ . Example 52 3-carboxy-2-ethyl-6-methyl-4- [2 '
-(Tetrazol-5-yl) biphenyl-4-yl]
Methoxypyridine: The title compound was obtained by subjecting the compound of Example 45 (a) to alkaline hydrolysis in the same manner as in Example 51. (Yield 70%) ¹ H NMR (DMSO-d ₆ ) δ: 1.19 (3H, t), 2.10 (3H, s), 2.6
5 (2H, q), 5.20 (2H, s), 6.93 (1H, s), 7.14 (2H, d),
7.37 (2H, d), 7.56 (1H, d), 7.57 (1H, t), 7.67 (1H,
d), 7.68 (1H, t); SIMS (m / z): 416 (M ⁺ ). Example 53 2,6-Dimethyl-3- (N, N-dimethylcarbamoyl)-
4- [2 '-(tetrazol-5-yl) biphenyl-
4-yl] methoxypyridine (a) The compound (656 mg) of Example 48 (a) was dissolved in N, N-dimethylformamide (10 ml), 60% sodium hydride (48 mg) was added, and the mixture was stirred at room temperature for 30 minutes. Then, methyl iodide 0.1.
75 ml was added, and the mixture was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in 3 ml of N, N-dimethylformamide, and 60% sodium hydride 210%
The same reaction as described above was repeated using mg and 0.75 ml of methyl iodide, and treated in the same manner. The obtained residue was purified by silica gel column chromatography (60 g, chloroform: methinol = 50: 1) to give 2,6-dimethyl-3- (N, N-dimethylcarbamoyl) -4- [2 ′-(triphenyl) 286 mg (yield 43%) of methyltetrazol-5-yl) biphenyl-4-yl] methoxypyridine were obtained. ¹ H NMR (CDCl ₃ ) δ: 2.34 (3H, s), 2.36 (3H, s), 2.80
(3H, s), 3.09 (3H, s), 5.03 (2H, s), 6.57 (1H, s), 6.
89 to 6.96 (6H), 7.12 (2H, d), 7.16 (2H, d), 7.21 to 7.3
5 (9H), 7.39 (1H, dd), 7.47 (1H, dt), 7.51 (1H, dt),
7.91 (1H, dd); SIMS (m / z): 671 (M + 1) ⁺ . (B) The title compound was obtained as a colorless powder by subjecting the compound obtained in (a) to detritylation in the same manner as in Example 1 (b). (Yield 70%) ¹ H NMR (DMSO-d ₆ ) δ: 2.30 (3H, s), 2.48 (3H, s), 2.7
5 (3H, s), 2.98 (3H, s), 5.25 (2H, s), 7.11 (1H, d),
7.13 (2H, d), 7.33 (2H, d), 7.57 (1H, d), 7.58 (1H,
t), 7.68 (1H, d), 7.69 (1H, t); SIMS (m / z): 429 (M + 1)
⁺ . Example 54 3- (N-benzyl-N-methylcarbamoyl) -2,6
-Dimethyl-4- [2 '-(tetrazol-5-yl)
Biphenyl-4-yl] methoxypyridine benzyl bromide in place of methyl iodide
The title compound was obtained by reaction with the compound of Example 48 (a) and deprotection reaction in the same manner as in 53. (Yield 31%) ¹ H NMR (DMSO-d ₆ ) δ: 2.26 and 2.30 (total 3H, each
s), 2.41 and 2.44 (3H, s), 2.66 and 2.90 (3H, s), 4.
26,4.31,4.46 and 4.87 (2H, d), 5.15-5.22 (2H), 6.9
5 to 7.35 (10H), 7.54 to 7.61 (2H), 7.65 to 7.71 (2H); S
IMS (m / z): 505 (M + 1) ⁺ . Example 55 3-Hydroxymethyl-2,6-dimethyl-4- [2'-
(Tetrazol-5-yl) biphenyl-4-yl] methoxypyridine (a) Dissolve 2.64 g of the compound of Example 40 (a) in 30 ml of tetrahydrofuran and add 440 mg of lithium aluminum hydride little by little at room temperature to give 6 Heated to reflux for an hour. After completion of the reaction, 150 ml of ethyl acetate and 30 ml of cold water were added to the reaction solution under cooling.
Was added carefully, and the mixture was stirred for 15 minutes under ice-cooling and further for 30 minutes at room temperature. After filtering off insolubles using Celite, the ethyl acetate layer was washed with water, dehydrated with anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (50 g, chloroform: methanol = 25: 1) to give 3-hydroxymethyl-2, a pale yellow powder.
1.9 g (79% yield) of 6-dimethyl-4- [2 '-(triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methoxypyridine was obtained. ¹ H NMR (CDCl ₃ ) δ: 2.48 (3H, s), 2.59 (3H, s), 4.73
(2H, s), 5.00 (2H, s), 6.60 (1H, s), 6.92 (6H, m), 7.
20 to 7.38 (13H), 7.41 (1H, dd), 7.48 (1H, dt), 7.52
(1H, dt), 7.96 (1H, dd); FDMS (m / z): 630 (M + 1) ⁺ . (B) The compound obtained in the above (a) was deprotected with hydrochloric acid in a mixture of methanol and dioxane (1: 1) in the same manner as in Example 1 (b) to give the title compound as an anhydrous powder. I got (Yield 48%) ¹ H NMR (DMSO-d ₆ ) δ: 2.40 (3H, s), 2.48 (3H, s), 4.5
2 (2H, s), 5.17 (2H, s), 6.93 (1H, s), 7.14 (2H, d),
7.40 (2H, d), 7.55 (2H, m), 7.65 (2H, m); FDMS (m /
z): 388 (M + 1) ⁺ . Example 56 2-ethyl-3-hydroxymethyl-6-methyl-4-
[2 '-(tetrazol-5-yl) biphenyl-4-
Yl] methoxypyridine (a) Example 45 (a)
By reducing in the same manner as in (a), 2
-Ethyl-3-hydroxymethyl-6-methyl-4-
[2 '-(Triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methoxypyridine was obtained.
(Yield 73%) ¹ H NMR (CDCl ₃ ) δ: 1.27 (3H, t), 2.48 (3H, s), 2.88
(2H, q), 4.73 (2H, s), 5.01 (2H, s), 6.61 (1H, s), 6.
93 (6H, m), 7.17 (4H, s), 7.23 ~ 7.34 (9H), 7.41 (1H,
dd), 7.48 (1H, dt), 7.52 (1H, dt), 7.95 (1H, dd); FDM
S (m / z): 644 (M + 1) ⁺ . (B) The compound obtained in the above (a) was deprotected in the same manner as in Example 55 (b) to give the title compound as a colorless powder. (Yield 64%) ¹ H NMR (DMSO-d ₆ ) δ: 1.20 (3H, t), 2.42 (3H, s), 2.8
0 (2H, q), 4.54 (2H, s), 5.19 (2H, s), 6.93 (1H, s),
7.14 (2H, d), 7.42 (2H, d), 7.57 (2H, m), 7.66 (2H,
m); FDMS (m / z): 402 (M + 1) ⁺ . Example 57 3-methoxymethyl-2,6-dimethyl-4- [2'-
(Tetrazol-5-yl) biphenyl-4-yl] methoxypyridine (a) 120 mg of 60% sodium hydride was suspended in 3 ml of N, N-dimethylformamide and stirred at room temperature for 15 minutes.
472 mg of the compound obtained in (a) was dissolved in 3 ml of N, N-dimertiformamide and added, followed by stirring at room temperature for 30 minutes. Under cooling, 94 μl of methyl iodide was added to the reaction solution, and the mixture was stirred at room temperature overnight. After completion of the reaction, 10 ml of cold water was added to the reaction solution, and the mixture was extracted with 120 ml of ethyl acetate. Ethyl acetate extract layer was diluted with diluted saline 40m
After washing twice with l, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (10 g, chloroform: ethyl acetate = 10: 1 to 1:
By purifying in 1), 300 mg of light yellow powder of 3-methoxymethyl-2,6-dimethyl-4- [2 '-(triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methoxypyridine (yield: Rate of 62%). ¹ H NMR (CDCl ₃ ) δ: 2.47 (3H, s), 2.57 (3H, s), 3.32
(3H, s), 4.53 (2H, s), 4.99 (2H, s), 6.58 (1H, s), 6.
92 (6H, m), 7.15 to 7.35 (13H), 7.41 (1H, m), 7.49 (2
H, m), 7.94 (1H, dd); SIMS (m / z): 644 (M + 1) ⁺ . (B) The title compound was obtained as a colorless powder by subjecting the compound obtained in (a) to detritylation in the same manner as in Example 1 (b). (Yield 71%) ¹ H NMR (DMSO-d ₆ ) δ: 2.39 (3H, s), 2.43 (3H, s), 4.4
5 (2H, s), 5.19 (2H, s), 6.92 (1H, s), 7.14 (2H, d),
7.38 (2H, d), 7.57 (2H, t), 7.67 (2H, m); SIMS (m /
z): 402 (M + 1) ⁺ . Examples 58 to 67 The compounds of Examples 58 to 66 shown in Table 3 were obtained in the same manner as in Example 57 except that various alkylating agents or acylating agents were used in place of methyl iodide.

Example 67 3-acetoxymethyl-2,6-dimethyl-4- [2'-
(Tetrazol-5-yl) biphenyl-4-yl] methoxypyridine (a) Dissolve 850 mg of the compound obtained in Example 55 (a) in 2 ml of pyridine, add 1 ml of acetic anhydride under ice-cooling, and add Stirred overnight. After completion of the reaction, add 20 ml of ice water, and add ethyl acetate.
Extracted with 300 ml. The ethyl acetate extract layer was washed with a saturated saline solution, a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution in that order, then simplified with anhydrous magnesium sulfate, and concentrated under reduced pressure.
The obtained residue was washed with 50 ml of diethyl ether and dried to give 3-acetoxymethyl-2,6-colorless powder.
There was obtained 715 mg (79% yield) of dimethyl-4- [2 '-(triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methoxypyridine. ¹ H NMR (CDCl ₃ ) δ: 2.02 (3H, s), 2.47 (3H, s), 2.54
(3H, s), 5.02 (2H, s), 5.23 (2H, s), 6.59 (1H, s), 6.
91 (6H, d), 7.16 (4H, s), 7.21 ~ 7.34 (9H), 7.40 (1H,
dd), 7.49 (2H, m), 7.94 (1H.m); FDMS (m / z): 672 (M +
1) ⁺ . (B) Example 1 was prepared using 210 mg of the compound obtained in (a) above.
Deprotection is performed in the same manner as in (b).
Was adjusted to pH 6.8 to 7.0 with 1N NaOH, followed by washing with 30 ml of diethyl ether. The resulting precipitate was collected by filtration, washed with cold water and diethyl ether, and dried to give the title compound as a colorless crystalline powder (80 ml, yield 60%). ¹ H NMR (DMSO-d ₆ ) δ: 1.99 (3H, s), 2.40 (3H, s), 2.4
4 (3H, s), 5.13 (2H, s), 5.21 (2H, s), 6.92 (1H, s),
7.13 (2H, d), 7.38 (2H, d), 7.57 (2H, dt), 7.67 (2H,
m); SIMS (m / z): 430 (M + 1) ⁺ . Example 68 3-Formyl-2,6-dimethyl-4- [2 '-(tetrazol-5-yl) biphenyl-4-yl] methoxypyridine (a) 944 mg of the compound obtained in Example 55 (a) was obtained. It was dissolved in 12 ml of methylene chloride, 565 mg of pyridinium chlorochromate was added under cooling, and the mixture was stirred at room temperature for 3 hours. After the completion of the reaction, the mixture was cooled, 50 ml of ethyl acetate was added to the reaction solution, insolubles were removed by filtration, and the insolubles were washed several times with 50 ml of ethyl acetate. The combined ethyl acetate layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and diluted saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (30 g, chloroform: ethyl acetate = 50: 1) to give 3-formyl-2,6-dimethyl-4- [2 '-(triphenyl) as a pale yellow powder. Methyltetrazol-5-yl) biphenyl-4-yl] methoxypyridine 410 mg (44% yield) was obtained. ¹ H NMR (CDCl ₃ ) δ: 2.53 (3H, s), 2.76 (3H, s), 5.08
(2H, s), 6,72 (1H, s), 6.91 (6H, m), 7,15 to 7.25 (10
H), 7.32 (3H, m), 7.40 (1H, dd), 7.50 (2H, m), 7.98
(1H, dd); SIMS (m / z): 628 (M + 1) ⁺ . (B) 400 mg of the compound obtained in the above (a) was used in Example 1.
By performing the deprotection reaction in the same manner as in (b), 175 mg (yield 71%) of the title compound was obtained as a colorless powder. _{^{1 H NMR (DMSO-d 6}} ) δ: 2.47 (3H, s), 2.61 (3H, s), 5.3
1 (2H, s), 7.15 (2H, d), 7.16 (1H, s), 7.45 (2H, d),
7.59 (2H, dt), 7.69 (2H, m), 10.51 (1H, s); EIMS (m /
z): 383 (M-2) ⁺ . Example 69 3-Amino-2,6-dimethyl-4- [2 '-(tetrazol-5-yl) biphenyl-4-yl] methoxypyridine 400 mg of the compound obtained in Example 29 was dissolved in 12 ml of methanol and 1 ml of acetic acid. The suspension was suspended in a mixed solvent, and 400 mg of iron powder was added. Next, 0.4 ml of 5N HCl was added, and the mixture was heated and stirred at 80 ° C. for 5 hours.
The insolubles were removed by filtration using Celite, and the filtrate was concentrated under reduced pressure. Water was added to the concentrated reaction solution, the pH was adjusted to 14 with 1N NaOH, and the insoluble material was removed by filtration using Celite. The obtained filtrate was adsorbed on 50 ml of HP-20 adsorption resin, washed with water, and then the target compound was eluted with a 30% acetone aqueous solution. The eluted portion was concentrated to dryness under reduced pressure, and the resulting precipitate was dried to give 367 mg (yield 95%) of the title compound. ¹ H NMR (CD ₃ OD) δ: 2.44 (3H, s), 2.49 (3H, s), 5.31
(2H, s), 7.07 (1H, s), 7.16 (2H, d), 7.30 (2H, d), 7.
40 to 7.45 (2H), 7.50 (1H, t), 7.58 (1H, d); SIMS (m /
z): 373 (M + 1) ⁺ . Example 70 3-Acetylamino-2,6-dimethyl-4- [2'-
(Tetrazol-5-yl) biphenyl-4-yl] methoxypyridine 100 mg of the compound obtained in Example 69 was added to 1 ml of acetic anhydride in 2 ml of pyridine, and the mixture was stirred at 60 ° C for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (8 g, chloroform: methanol = 2: 1) to give 95 mg of the title compound as a colorless powder (86% yield). ) Got. ¹ H NMR (CD ₃ OD) δ: 2.13 (3H, s), 2.39 (3H, s), 2.50
(3H, s), 5.20 (2H, s), 6.99 (1H, s), 7.15 (2H, d), 7.
31 (2H, d), 7.47 (1H, t), 7.49 (1H, t), 7.55 (1H, t),
7.59 (1H, d); SIMS (m / z): 415 (M + 1) ⁺ . Example 71 2-methyl-4- [2 '-(tetrazol-5-yl)
Biphenyl-4-yl] methoxypyridine (a) 240 mg of 60% sodium hydride was suspended in 4 ml of N, N-dimethylformamide, stirred at room temperature for 20 minutes, and 545 mg of 2-methyl-4 (1H) -pyridone was added to N, N. It was dissolved in 6 ml of N-dimethylformamide and added, followed by stirring at room temperature for 30 minutes. Next, 3.07 g of 4'-bromomethyl-2- (triphenylmethyltetrazol-5-yl) biphenyl was added to the reaction mixture.
Dissolved in 12 ml of N, N-dimethylformamide,
The mixture was heated and stirred at 4 ° C. for 4 hours. After completion of the reaction, the temperature was returned to room temperature, 50 ml of cold water was added to the reaction solution, and the mixture was extracted twice with 150 ml of ethyl acetate. The ethyl acetate extract was washed with a saturated aqueous solution of sodium hydrogen carbonate, water and brine in that order, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (100 g) to obtain two components. Among them, chloroform-ethyl acetate = 25: 1 eluted part showed pale yellow oil 2-
1.0 g (34% yield) of methyl-4- [2 '-(triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methoxypyridine was obtained. ¹ NMR (CDCl ₃ ) δ: 2.51 (3H, s), 4.96 (2H, s), 6.66 (1
H, dd), 6.72 (1H, d), 6.91 (6H, bt.d), 7.22 ~ 7.34 (13
H), 7.40 (1H, dd), 7.49 (2H, m), 7.96 (1H, dd), 8.30
(1H, d); FDMS (m / z): 586 (M + 1) ⁺ . (B) In the purification by the silica gel column chromatography of the above (a), chloroform: methanol = 2
From the elution part of 0: 1 to 5: 1, 2-methyl-1-
1.52 g (52% yield) of [2 '-(triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl-4 (1H) -pyridone was obtained. ¹ NMR (CDCl ₃ ) δ: 2.09 (3H, s), 4.86 (2H, s), 6.32 (2
H, m), 6.78 (2H, br.d), 6.90 (6H, m), 7.15 (2H, m), 7.
23-7.28 (11H), 7.35 (2H, m), 7.50 (2H, m), 7.99 (1
H, dd); FDMS (m / z): 586 (M + 1) ⁺ . (C) 880 mg of the compound obtained in the above (a) was dissolved in a mixed solvent of 1 ml of methylene chloride and 8 ml of methanol, and the solution was dissolved in 4N under ice-cooling.
HCl (0.6 ml) was added, and the mixture was stirred at 10 to 15 ° C. for 1 hour. After completion of the reaction, a post-treatment was carried out in the same manner as in Example 1 (b), whereby
266 mg (52% yield) of the title compound were obtained as a colorless powder. _{^{1 NMR (DMSO-d 6)}} δ: 2.42 (3H, s), 5.16 (2H, s), 6.87
(1H, dd), 6.94 (1H, d), 7.13 (2H, d), 7.39 (2H, d),
7.56 (2H, m), 7.67 (2H, m), 8.26 (1H, d); EIMS (m /
z): 343 (M ⁺ ). Example 72 2-methyl-1- [2 '-(tetrazol-5-yl)
Biphenyl-4-yl] methyl-4 (1H) -pyridone 1.11 g of the compound obtained in Example 71 (b) was obtained by treating Example 1.
By deprotection reaction in the same manner as in (c), 371 mg (57% yield) of the title compound was obtained as a colorless powder. ¹ NMR (DMSO-d ₆ ) δ: 2.17 (3H, s), 5,20 (2H, s), 6.12
(1H, s), 6.14 (1H, d), 7.05 (2H, d), 7.12 (2H, d), 7.
51 ~ 7.59 (2H, m), 7.67 (2H, m), 7.83 (1H, d); FDMS (m
/ z): 344 (M + 1) ⁺ . Example 71 using 3-methoxy-2-methyl-4 (1H) -pyridone instead of 2-methyl-4 (1H) -pyridone
By reacting in the same manner as in Example 73 and Example
Two compounds of 74 were obtained.

Example 73 3-Methoxy-2-methyl-4- [2 '-(tetrazol-5-yl) biphenyl-4-yl] methoxypyridine colorless powder ¹ NMR (DMSO-d ₆ ) δ: 2.16 (3H, s) , 3.70 (3H, s), 5.23
(2H, s), 6.19 (1H, d), 7.03 (2H, d), 7.11 (1H, d), 7.
52 ~ 7.59 (2H, m), 7.66 (2H, m), 7.77 (1H, d); FDMS (m
/ z): 374 (M + 1) ⁺ . Example 74 3-Methoxy-2-methyl-1- [2 '-(tetrazol-5-yl) biphenyl-4-yl] methyl-4 (1
H) -Pyridone colorless crystalline substance ¹ NMR (DMSO-d ₆ ) δ: 2.38 (3H, s), 3.75 (3H, s), 5.21
(2H, s), 7.04 (1H, d), 7.14 (2H, d), 7.42 (2H, d), 7.
55 ~ 7.60 (2H, m), 7.65 ~ 7.70 (2H, m), 8.07 (1H, d); F
DMS (m / z): 374 (M + 1) ⁺ . Example using 5-methoxy-2-methyl-4 (1H) -pyridone in place of 2-methyl-4 (1H) -pyridone
By reacting in the same manner as in 71, two compounds of Example 75 and Example 76 were obtained.

Example 75 5-Methoxy-2-methyl-4- [2 '-(tetrazol-5-yl) biphenyl-4-yl] methoxypyridine colorless powder ¹ NMR (DMSO-d ₆ ) δ: 2.33 (3H, s) , 3.82 (3H, s), 5.10
(2H, s), 6.78 (1H, s), 7.01 (2H, d), 7.15 (2H, d), 7.
37 (1H, d), 7.46 (1H, t), 7.52 (1H, t), 7.73 (1H, s),
7.81 (1H, d); FDMS (m / z): 374 (M + 1) ⁺ . Example 76 5-Methoxy-2-methyl-1- [2 '-(tetrazol-5-yl) biphenyl-4-yl] methyl-4 (1
H) -Pyridone colorless crystalline substance ¹ NMR (DMSO-d ₆ ) δ: 2.13 (3H, s), 3.58 (3H, s), 5.20
(2H, s), 6.10 (1H, s), 7.03 (2H, d), 7.09 (2H, d), 7.
51 ~ 7.70 (4H, m), 8.32 (1H, s); FDMS (m / z): 374 (M + 1)
⁺ . Example 77 2,6-Dimethyl-4- [2 '-(tetrazol-5-yl) biphenyl-4-yl] methoxypyridine (a) 369 mg of 2,6-dimethyl-4 (1H) -pyridone was added to N, N
-Dissolved in 5 ml of dimethylformamide, added 144 mg of 60% sodium hydride and stirred at room temperature for 15 minutes. Then
900 mg of 4-bromomethyl-2'-cyanobiphenyl was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, ethyl acetate was added to the reaction solution, washed with water, and dried over anhydrous magnesium sulfate. The organic solvent layer was concentrated under reduced pressure, ethyl acetate was added, and the precipitated crystals were collected by filtration and dried to obtain 296 mg.
And the filtrate is purified by silica gel column chromatography (80 g, chloroform: ethyl acetate = 3: 1 to 2: 3) to obtain 329 mg of 2,6-dimethyl-4- (2'-cyanobiphenyl-4-yl). ) Methoxypyridine (total 625m
g, yield 66%). ¹ NMR (CDCl ₃ ) δ: 2.50 (6H, s), 5.15 (2H, s), 6.61 (2
H, s), 7.47 (1H, dt), 7.53 (1H, dd), 7.54 (2H, d), 7.6
0 (2H, d), 7.66 (1H, dt), 7.78 (1H, dd); EIMS (m / z):
314 (M ⁺ ). (B) 575 mg of the compound obtained in the above (a) was added to 10 m of toluene.
Then, 475 mg of sodium azide and 2 ml of tri (n-butyl) tin chloride were added, and the mixture was heated and stirred at 120 ° C. for 3 days. Then, under cooling, 0.22 ml of 10N NaOH and 622 mg of trityl chloride were added to the reaction solution, followed by stirring at 60 ° C. for 10 hours. Ethyl acetate was added to the reaction solution, the organic solvent layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Since the raw material was recognized in the obtained residue, dioxane 10 ml and 10N NaOH 0.5
Then, the mixture was stirred at room temperature for 30 minutes, and 1 g of trityl chloride was added to further react. After completion of the reaction, ethyl acetate and water were added, and insolubles were removed by filtration using Celite. The aqueous layer of the filtrate was extracted with ethyl acetate, and the ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (70
g, chloroform: ethyl acetate = 3: 1) to give 2,6-dimethyl-4- [2 '-(triphenylmethyltetrazol-5-yl) biphenyl-4-yl].
759 mg (69% yield) of methoxypyridine was obtained. ¹ NMR (CDCl ₃ ) δ: 2.47 (6H, s), 4.94 (2H, s), 6.54 (2
H, s), 6.91 (2H, d), 6.91 (4H, m), 7.22 ~ 7.34 (12H),
7.40 (1H, dd), 7.49 (1H, m), 7.95 (1H, dd), 8.02 (2H,
br.s); FDMS (m / z): 600 (M + 1) ⁺ . This NMR data indicates the precursor of the compound of Example 2 (a compound in which a tetrazole group was protected with a triphenylmethyl group).
Was consistent with the NMR data.

(C) The title compound was obtained by subjecting the compound obtained in (b) to a deprotection reaction in the same manner as in Example 1 (b). (Yield: 78%) The spectrum data of this compound was consistent with the data of the compound of Example 2, and it could be confirmed that the compound was the same.

Example 78 2,6-Dimethyl-4- (2'-carboxybiphenyl-
4-yl) methoxypyridine (a) A suspension of 96 mg of 60% sodium hydride in 2 ml of dry N, N-dimethylformamide was stirred at room temperature for 20 minutes, and then 246 mg of 2,6-dimethyl-4 (1H) -pyridone was stirred. And add
Stirred for an additional 30 minutes. Next, 732 mg of methyl 4'-bromomethylbiphenyl-2-carboxylate was dissolved in 4 ml of dry N, N-dimethylformamide and added to the reaction solution, and the mixture was heated at room temperature for 4 hours and further heated to 60 ° C. for 30 minutes. Stirred. After the completion of the reaction, return to room temperature, add 40 ml of cold water to the reaction solution,
Extracted twice with 100 ml of ethyl acetate. The ethyl acetate extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (chloroform: ethyl acetate = 25: 1).
~ 10: 1) to give 2,6-
540 mg (78% yield) of dimethyl-4- (2'-methoxycarbonylbiphenyl-4-yl) methoxypyridine were obtained. ¹ NMR (CDCl ₃ ) δ: 2.48 (6H, s), 3.65 (3H, s), 5.12 (2
H, s), 6.60 (2H, s), 7.34 ~ 7.46 (6H, m), 7.54 (1H, d
t), 7.85 (1H, d); EIMS (m / z): 347 (M ⁺ ). (B) 350 mg of the compound obtained in the above (a) was added to ethanol 1
0 ml, add 1.0 ml of 5N NaOH, warm to 60 ° C,
Stirred for hours. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, and the obtained residue was dissolved by adding 5 ml of cooling water. After washing the aqueous solution with 20 ml of ethyl acetate, the pH is adjusted with 5N HCl under ice-cooling.
Was adjusted to 3, and the deposited precipitate was collected by filtration. After washing with water, 40 ℃
Dry overnight under reduced pressure to give the title compound as a colorless crystalline compound (290 mg)
(87% yield). ¹ NMR (DMSO-d ₆ ) δ: 2.64 (6H, s), 5.42 (2H, s), 7.40
(2H, d), 7.40 (1H, d), 7.41 (2H, s), 7.48 (1H, dt),
7.53 (2H, d), 7.59 (1H, dt), 7.76 (1H, d); FDMS (m /
z): 334 (M + 1) ⁺ . Examples 79-90 After reaction with methyl 4'-bromomethylbiphenyl-2-carboxylate as in Example 78 using various pyridones instead of 2,6-dimethyl-4 (1H) -pyridone By deesterification, Examples 79 to 79 shown in Table 4 were obtained.
90 compounds were obtained.

Example 91 2,3-Dimethyl-4- (2'-carboxybiphenyl-
4-yl) methoxypyridine (a) A suspension of 96 mg of 60% sodium hydride in 2 ml of dry N, N-dimethylformamide was stirred at room temperature for 20 minutes, and then 246 mg of 2,3-dimethyl-4 (1H) -pyridone was added. And add
Stirred for an additional 30 minutes. Next, 732 mg of methyl 4'-bromomethylbiphenyl-2-carboxylate was dissolved in 4 ml of dry N, N-dimethylformamide and added to the reaction solution, and the mixture was heated at room temperature for 4 hours and further heated to 60 ° C. for 30 minutes. Stirred. After the completion of the reaction, return to room temperature, add 40 ml of cold water to the reaction solution,
Extracted twice with 100 ml of ethyl acetate. The ethyl acetate extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain two components. Of these, 170 mg of pale yellow oily 2,3-dimethyl-4- (2'-methoxycarbonylbiphenyl-4-yl) methoxypyridine was eluted with chloroform: ethyl acetate = 25: 1 and chloroform: methanol = 50: 1. (Yield 25
%). ¹ NMR (CDCl ₃ ) δ: 2.22 (3H, s), 2.51 (3H, s), 3.64 (3
H, s), 5.16 (2H, s), 6.71 (1H, d), 7.32 ~ 7.50 (6H,
m), 7.54 (1H, dt), 7.85 (1H, dd), 8.23 (1H, d); EIMS
(M / z): 347 (M ⁺ ). (B) In the purification by the silica gel column chromatography in the above (a), 2,3-dimethyl-4-white powder was obtained from the elution part of chloroform: methanol = 5: 1.
380 mg (55% yield) of (2'-methoxycarbonylbiphenyl-4-yl) methyl-4 (1H) -pyridone were obtained. ¹ NMR (CDCl ₃ ) δ: 2.21 (3H, s), 2.26 (3H, s), 3.68 (3
H, s), 5.10 (2H, s), 6.40 (1H, d), 7.06 (2H, d), 7.30
~ 7.37 (4H, m), 7.43 (1H, dt), 7.54 (1H, dt), 7,87 (1
H, dd); EIMS (m / z): 347 (M ⁺ ). (C) 153 mg of the compound obtained in the above (a) was added to ethanol 4
Dissolved in 5 ml, added 0.44 ml of 5N NaOH, and heated to 60 ° C.
Stirred for ~ 4 hours. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, and 4 ml of water was added to the obtained residue to dissolve it. After washing the aqueous solution with 10 ml of ethyl acetate, the pH was adjusted to 3 to 4 with 5N HCl under ice cooling, and the precipitated precipitate was collected by filtration. After washing with water, 40
Dry at reduced pressure overnight at 140 ° C to give 140 mg of the colorless crystalline title compound.
(96% yield). ¹ NMR (DMSO-d ₆ ) δ: 2.22 (3H, s), 2.64 (3H, s), 5.51
(2H, s), 7.40 (2H, d), 7.40 (1H, d), 7.48 (1H, t), 7.
54 (2H, d), 7.58 (1H, d), 7.59 (1H, t), 7.75 (1H, d),
8.60 (1H, d), 12.80 (1H, br.s); FDMS (m / z): 334 (M + 1)
⁺ . Example 92 2,3-Dimethyl-1- (2'-carboxysibiphenyl-4-yl) methyl-4 (1H) -pyridone The compound (350 mg) obtained in Example 91 (b) was treated in Example 91
Deprotection was carried out in the same manner as in (c) to give 290 mg (87% yield) of the title compound as colorless and crystalline. ¹ NMR (DMSO-d ₆ ) δ: 1.91 (3H, s), 2.19 (3H, s), 5.27
(2H, s), 6.10 (1H, d), 7.11 (2H, d), 7.35 (2H, d), 7.
36 (1H, d), 7.44 (1H, t), 7.55 (1H, t), 7.70 (1H, d),
7.81 (1H, d); EIMS (m / z): 333 (M ⁺ ). By reacting in the same manner as in Example 90 using 2,3-cyclopenteno-4 (1H) -pyridone instead of 2,3-dimethyl-4 (1H) -pyridone, Examples 93 and 94 were obtained.
Was obtained.

Example 93 2,3-cyclopenteno-4- (2'-carboxybiphenyl-4-yl) methoxypyridine pale yellow crystalline substance ¹ NMR (CDCl ₃ ) δ: 2.10 (2H, m), 2.90 (2H, t) , 2.98 (2
H, t), 5.20 (2H, s), 6.67 (1H, d), 7.31-7.44 (6H,
m), 7.48 (1H, dt), 7.88 (1H, d), 8.08 (1H, d); FDMS
(M / z): 346 (M + 1) ⁺ . Example 94 2,3 Shikumepenteno-1- (2'-carboxybiphenyl-4-yl) methyl -4 (IH) - pyridone colorless crystalline substance _{^{1 NMR (DMSO-d 6)}} δ: 1.93 (2H, m) , 2.61 (2H, t), 2.87
(2H, t), 5.17 (2H, s), 6.07 (1H, d), 7.20 (2H, d), 7.
32 to 7.37 (3H, m), 7.44 (1H, t), 7.55 (1H, t), 7.72 (1
H, d), 7.75 (1H, d); FDMS (m / z): 346 (M + 1) ⁺ . The same procedures as in Example 90 were carried out except that 3-benzyloxy-2-methyl-4 (1H) -pyridone was used instead of 2,3-dimethyl-4 (1H) -pyridone, whereby Example 95 and Example 90 were carried out. Two compounds of Example 96 were obtained.

Example 95 3-benzyloxy-2-methyl-4- (2'-carboxybiphenyl-4-yl) methoxypyridine colorless crystalline substance ¹ NMR (DMSO-d ₆ ) δ: 2.78 (3H, s), 5.11 ( 2H, s), 5,56
(2H, s), 7.38 (8H, m), 7.48 (1H, t), 7.59 (3H, t), 7.
71 (1H, q), 7.76 (1H, d), 8.52 (1H, d); FDMS (m / z): 4
25 (M ⁺ ). Example 96 3-benzyloxy-2-methyl-1- (2'-carboxybiphenyl-4-yl) methyl -4 (IH) - pyridone colorless crystalline material _{^{1 NMR (DMSO-d 6)}} δ: 2.02 (3H, s), 5.07 (2H, s), 5,23
(2H, s), 6.25 (1H, d), 6.99 (1H, d), 7.34 (8H, m), 7.
46 (1H, t), 7.58 (1H, t), 7.73 (1H, d), 7.79 (1H, d);
FDMS (m / z): 426 (M + 1) ⁺ . Instead of 2,3-dimethyl-4 (1H) -pyridone, 2-hydroxymethyl-5- (p-methoxybenzyloxy)
By reacting in the same manner as in Example 90 using -4 (1H) -pyridone, two compounds of Example 97 and Example 98 were obtained.

Example 97 2-Hydroxymethyl-5- (p-methoxybenzyloxy) -4- (2'-carboxybiphenyl-4-yl) methoxypyridine colorless powder ¹ NMR (CDCl ₃ : CD ₃ OD = 10: 1) δ : 3.81 (3H, s), 4.62 (2
H, s), 5.13 (2H, s), 5.32 (2H, s), 6.90 (2H, d), 7.12
(1H, s), 7.36 (2H, d), 7.39 (1H, d), 7.34-7.47 (8H,
m), 7.54 (1H, dt), 7,88 (1H, dd), 8.04 (1H, s); EIMS
(M / z): 471 (M ⁺ ). Example 98 2-Hydroxymethyl-5- (p-methoxybenzyloxy) -1- (2'-carboxybiphenyl-4-yl) methyl-4 (1H) -pyridone colorless powder ¹ NMR (CDCl ₃ : CD ₃ OD) = 10: 1) δ: 3.85 (3H, s), 4.40 (2
H, s), 5.06 (2H, s), 5.19 (2H, s), 6.55 (1H, s), 6.85
(2H, d), 6.94 (2H, d), 7.15 (1H, s), 7.28 (2H, s), 7.
31 (2H, d), 7.33 (1H, d), 7.44 (1H, dd), 7.55 (1H, d
d), 7.91 (1H, d); FDMS (m / z): 472 (M + 1) ⁺ . Example 99 5-hydroxy-2-hydroxymethyl-4- (2'-
Carboxybiphenyl-4-yl) methoxypyridine 95 mg of the compound obtained in Example 97 was suspended in 0.3 ml of anisole, 0.5 ml of trifluoroacetic acid was added under ice cooling, and the mixture was stirred at the same temperature for about 1 hour. After completion of the reaction, the reaction solution was poured into 20 ml of cooled isopropyl ether, and the deposited precipitate was collected by filtration. The obtained precipitate was dried under reduced pressure at 40 ° C. overnight to convert the title compound as a colorless powder to a trifluoroacetate salt.
85 mg (91.4% yield) were obtained. _{^{1 NMR (DMSO-d 6)}} δ: 4.66 (2H, s), 5.38 (2H, s), 7.40
(2H, d), 7.41 (1H, s), 7.47 (1H, dd), 7.56 (2H, d),
7.51 to 7.61 (2H, m), 7.76 (1H, d) 8.02 (1H, s); SIMS
(M / z): 352 (M + 1) ⁺ . Example 100 5-Hydroxy-2-hydroxymethyl-1- (2'-
Carboxybiphenyl-4-yl) methyl-4 (1H)-
Pyridone The title compound was obtained as a colorless powder by removing the p-methoxybenzyl group from the compound obtained in Example 98 with trifluoroacetic acid in the same manner as in Example 99. ¹ NMR (DMSO-d ₆ ) δ: 4.48 (2H, s), 5.41 (2H, s), 6.81
(1H, s), 7.19 (2H, d), 7.36 (2H, d), 7.37 (1H, d), 7.
46 (1H, dd), 7.57 (1H, dd), 7.74 (1H, d), 7.88 (1H,
s); FDMS (m / z): 352 (M + 1) ⁺ . Example 101 3-ethoxycarbonyl-2,6-dimethyl-4- (2 '
-Carboxybiphenyl-4-yl) methoxypyridine (a) 349 mg of 60% sodium hydride was suspended in 20 ml of dry N, N-dimethylformamidine, and cooled under ice-cooling to give 3-ethoxycarbonyl-2,6-dimethyl-4. (1H) -pyridone 154mg
Was dissolved in 5 ml of N, N-dimethylformamide, and the mixture was stirred at room temperature for 20 minutes. Then, 3.01 g of tert-butyl 4'-bromomethylbiphenyl-2-carboxylate was added to the reaction mixture.
Of N, N-dimethylformamide (5 ml) was added, and the mixture was further stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, 50 ml of water was added, and the mixture was extracted three times with 70 ml of ethyl acetate. The ethyl acetate extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 2) to give 3-ethoxycarbonyl-2,6-dimethyl-4- (2′tert-
2.18 g of butoxycarbonylbiphenyl-4-yl) methoxypyridine were obtained (yield: 60%). ¹ NMR (CDCl ₃ ) δ: 1.22 (9H, s), 1.35 (3H, t), 2.49 (6
H, s), 4.38 (2H, q), 5.20 (2H, s), 6.64 (1H, s), 7.28
~ 7.53 (7H, m), 7.77 ~ 7.82 (1H, m); SIMS (m / z): 462
(M + 1) ⁺ . (B) 461 mg of the compound obtained in (a) was added to a mixed solution of 3 ml of formic acid and 2 ml of 1N HCl, and the mixture was stirred at room temperature for 12 hours. After evaporating the solvent, 20 ml of a 6% aqueous sodium hydrogen carbonate solution was added under ice cooling, and the mixture was washed with ethyl acetate. The aqueous layer was made acidic with 1N HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is ethyl acetate-n-
Recrystallization from hexane gave the title compound 26
8 mg (yield 66%) were obtained as colorless needle crystals. ¹ NMR (CDCl ₃ : CD ₃ OD = 9: 1) δ: 1.28 (3H, t), 2.74 (3
H, s), 2.75 (3H, s), 4.37 (2H, q), 5.34 (2H, s), 6.87
(1H, s), 7.23 ~ 7.41 (6H, m), 7.45 ~ 7.50 (1H, m), 7.8
5-7.88 (1H, m); EIMS (m / z): 405 (M ⁺ ). Formulation Example 1. Tablets Compound of Example 1 2.5 g Lactose 12 g 6% HPC Lactose 8 g Potato starch 2 g Magnesium stearate 0.5 g A total of 25 g or more is thoroughly mixed and tableted to produce 1000 tablets.

Formulation Example 2. Capsules 2.5 g of the compound of Example 1 Lactose 18 g Potato starch 4 g Magnesium stearate 0.5 g A total of 25 g or more is thoroughly mixed and filled into hard capsules to prepare 1,000 capsules.

Formulation Example 3. Injection Compound of Example 2 0.5 g Glucose 7 g Distilled water for injection qs 1000 ml The compound of Example 2 and glucose were dissolved in distilled water for injection to make the total volume 1000 ml, and this was filtered through a glass filter. Then, 1 ml is dispensed into ampoules to make 1000 ampoule preparations.

Pharmacological Test (1) The angiotensin II antagonistic effect and antihypertensive effect of the compound of the general formula (I) were examined by the following in vitro and in vivo experiments.

Angiotensin II antagonist activity in in vitro were compared strength to antagonize the contractile response to angiotensin II in the rabbit thoracic aorta was excised (pA ₂ value) as an index. The in vivo activity was examined based on the inhibitory effect on exogenous angiotensin II hypertension in unanesthetized rats and the effect of reducing blood pressure in renal or spontaneously hypertensive rats.

1-1. Angiotensin II antagonism in votro A thoracic aortic spiral specimen was prepared from a male rabbit weighing 2.5 to 3.0 kg according to a conventional method, and the specimen was aerated and kept in a Magnus tube filled with a nutrient solution kept at 37 ° C. Hanged up. pA ₂ value, a method of HOSchild (British Journal
Of Pharmacology and Chemotherapeutics, Vol. 2, pp. 189-206, 1947). That is, a dose-response curve by angiotensin II was obtained using a sample treated with a test compound at 3 to 5 doses and a sample without drug treatment in the range of 10 ⁻⁶ M to ^{10 −10} M, and From the curve shift, log (dose ratio-
1) is calculated to determine the pA ₂ value from Schild plot.

 The results are as shown in Table 1.

1-2. Inhibitory effect on exogenous angiotensin II pressurization Male Spraque-Dawley (SD) male rats weighing 250-300 g were cannulated into the femoral artery and femoral vein under anesthesia, and experiments were performed at least 24 hours after surgery. It was used for. Under anesthesia and unrestrained conditions, the blood pressure induced by angiotensin II (0.1 μg / kg) administered via an intravenous catheter was measured before and after drug administration. The blood pressure was measured by connecting an intravenous catheter to a pressure transducer and measuring the mean blood pressure in an open manner.
Oral administration was performed by uniformly suspending or dissolving in a 5% carboxymethylcellulose aqueous solution.

As a result, for example, Examples 21, 44, 53, 57, 68 and
At 3 mg / kg of 81 compounds, significant angiotensin
II An antihypertensive effect was observed.

In addition, the compounds of Examples 1, 3, 11, 12, 16, 45, 46, and 83 exhibited a significantly sustained inhibitory effect at a dose of 1 mg / kg or less. The strength of the inhibitory action of up to 6 hours after administration were compared in the index volume (ED ₅₀ value) of the compound required to inhibit boosted by angiotensin II 50%. The results are as shown in Table 6.

1-3. Blood pressure lowering effect in renal hypertensive rat (RHR) Renal hypertensive rat, which is a hyperrenin hypertension model,
It was prepared according to the method of JLCangiano et al. (Journal of Pharmacology and Experimental Therapeutics, 208, 310-313, 1979). That is, Spraque-Dawley (SD
System) Male rats were anesthetized and the left renal artery was ligated with a thread. Rats whose systolic blood pressure became 150 mmHg or more one week after the operation were used for the experiment. The test compound was uniformly suspended in a 0.5% carboxymethylcellulose aqueous solution and orally administered.
As in the case of 2, the mean blood pressure was measured invasively. The heart rate was measured from the pulse wave of blood pressure via a heart rate meter.

As a result, the compound of Example 11 and Example 45 was 3 mg / kg.
At a dose of up to 20-26%, a sustained and significant blood pressure lowering effect was observed.

1-4. Hypotensive action in spontaneously hypertensive rats (SHR) Test compound is orally administered to 28-week-old male spontaneously hypertensive rats (Charles River) in the same manner as in the above 1-3. Thereafter, the average blood pressure and heart rate were measured.

As a result, at the dose of 10 mg / kg of the compounds of Examples 11 and 45, a decrease in blood pressure of up to about 20% was observed, showing a sustained and significant blood pressure lowering effect.

(2) Anxiolytic effect The method of B. Costall et al. (Pharmacology, Biochemistry and Behavior, 32, 777-785,
1989) and the Plasmaze method by S. Pellow et al. (Journal of Neuroscience Methods, Vol. 14, pp. 149-167, 1985) to investigate anxiolytic effects. Done.

2-1. Light-dark box method The test compound is added to ddY male mice (4-5 weeks old) at 0.1-
Oral administration was performed at a dose of 1000 μg / kg. One hour later, the animals were placed in the light room of the light-dark box, and 10 seconds later, the door to the dark room was opened. Under soundproofing, the behavior of the animal in the light-dark box for 4 minutes was observed, and the latency of entry into the dark room, the number of transfers between the light and dark rooms, and the time spent in the light room were measured as indices. Was compared with the behavior of The test compound was uniformly suspended in a 0.5% carboxymethylcellulose aqueous solution and orally administered.

As a result, at 0.1 μg / kg of the compound of Example 11,
An increase in the latency of entry into the dark room and an increase in the time spent in the bright room were observed.

2-2. Plus-Maze Method A test compound was uniformly suspended in a 0.5% carboxymethylcellulose aqueous solution and orally administered to male Fisher344 rats (5 to 6 weeks old) at a dose of 1 to 100 μg / kg. Of the four arms of the elevated plusmaze (a device in which four arms are crossed at a height of 50 cm above the floor and connected in a cross), two opposed closed arms with side walls (closed arm) ), Two without side walls are called open arms. One hour after administration, animals are closed
The animals were placed in an arm, and then the behavior of the animals was observed for 5 minutes. As an index of the behavior, the latency from the first arm entered to the other arm and the time spent in each arm were measured, and other behaviors were also recorded. Using diazepam as a control drug, a comparative study was conducted between the drug administration group and the solvent administration group (the 0.5% carboxymethyl cellulose aqueous solution administration group).

As a result, the administration latency of diazepam 3 mg / kg, an anxiolytic drug, significantly reduced the migration latency,
The time spent outside the arm has increased. Similarly, at 1 μg / kg of the compound of Example 45, a significant increase in the number of transfers and a tendency to increase the stay time were observed.

(3) Memory-promoting action In order to examine the effect of drugs on memory and learning functions, the method of C. Giurgea et al. (Progressive of Neuropsychopharmacology, Vol. 1, pp. 235-247, 19)
77-year-old, step-through light-dark box (PA-M5 type,
Amara model due to electric shock in Ohara Medical Industry Co., Ltd.) was used.

The test compound was uniformly suspended in a 0.5% carboxymethylcellulose aqueous solution, and 1 hour before the acquisition trial and 1 hour before the regeneration trial, 1 mg / ml of ddY male mouse (4 to 5 weeks old)
Oral doses of ng / kg to 1 mg / kg were administered. First, the animal was placed in the light room, and after 30 seconds, the door at the boundary with the dark room was opened, and the animal was moved to the dark room, and at the same time, the floor of the dark room was energized (40 V) to acquire an avoidance response (trial acquisition). The animals that escaped to the light room were then removed and amnesic was induced by applying an electric shock (40 mA, 0.5 sec) via an ear clip. Then, a reproduction trial was performed 24 hours after that. That is, put the animal in the light room again, open the door after 30 seconds,
The time required for the animal to move to the dark room was measured up to 600 seconds, and compared with the movement time of the shock-amnestic animal in the vehicle-administered group.

As a result, the compound of Example 11 showed a significant prolongation of the transit time at 10 μg / kg, that is, an amnesic ameliorating effect, on the passive avoidance learning response of amnesic shock shock mice.

(4) Toxicity test Some of the compounds of the general formula [I] according to the present invention were orally administered to 5-week-old male ddY mice (average body weight: about 20 g).

 The results are as shown in Table 7.

None of the compounds showed any special symptoms at 1000 mg / kg. Also, Example 45 was administered to 6-week-old male SD rats.
As a result of repeated oral administration of 100 mg / kg of the compound for 2 weeks, no signs of toxicity were observed.

 ──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Hiromi Watanabe 760 Meijiokacho, Kohoku-ku, Yokohama, Kanagawa Prefecture Inside the Pharmaceutical Research Institute (72) Inventor Jun Nakura 760 Meijiokacho, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Seika Stock (72) Inventor Naomi Nagata 760 Meijiokacho, Kohoku-ku, Yokohama, Kanagawa Prefecture Meiji Confectionery Co., Ltd. (72) Inventor Yasuyuki Ichimaru 760 Shiokaokacho, Kohoku-ku, Yokohama, Kanagawa Prefecture Meiji Seika Co., Ltd. Inside the Research Institute (72) Inventor Fumio Konno 760 Meijiokacho, Kohoku-ku, Yokohama-shi, Kanagawa Prefecture Inside the Pharmaceutical Research Institute (72) Inventor Tomoya Machinami 760 Meijiokacho, Kohoku-ku, Yokohama-shi, Kanagawa Prefecture Meiji Seika Co., Ltd. Inside the Research Institute (72) Inventor Takashi Tsuruoka 760 Meijiokacho, Kohoku-ku, Yokohama, Kanagawa (56) References JP-A-54-12379 (JP, A) JP-A-58-146566 (JP, A) JP-A-57-136680 (JP, A) JP-A-57-135944 (JP, A)

Claims (5)

(57) [Claims] A compound represented by the following general formula (I) and a pharmacologically acceptable salt thereof. [Wherein, R ²² and R ²³ represents a methyl group or an ethyl group independently, one of R ²⁴ is C1~8 alkoxy group (the alkyl group is a halogen atom, C _{3 to 7} cycloalkyl group, a nitrogen atom And optionally a 5 or 6 membered saturated heterocyclic ring comprising one oxygen atom and optionally substituted by a lower alkyl group,
Alternatively, it may be substituted with a carbamoyl group which may be substituted with a lower alkyl group. A lower alkenyloxy group; a C _3-7 cycloalkyloxy group; or a benzyloxy group (this benzyloxy group may be substituted with a halogen atom, a lower alkyl group, a halo-lower alkyl group, or a lower alkoxyoxy group) B represents a group COOR ¹⁸ (where R ¹⁸ represents a hydrogen atom, a lower alkyl group, or a group —CH ₂ OCOC (CH ₃ ) ₃ ), or a tetrazolyl group. ) (2) 2-ethyl-methoxy-6-methyl-4-
[2 '-(tetrazol-5-yl) biphenyl-4-
3-methoxy-2,6-dimethyl-4- [2 '-(tetrazol-5-yl) biphenyl-4-yl] methoxypyridine; 3-ethoxy-2,6-dimethyl-4- [ 2 '-(tetrazol-5-yl) biphenyl-4-yl] methoxypyridine; 2,6-dimethyl-3-iso-propoxy-4- [2'-
(Tetrazol-5-yl) biphenyl-4-yl] methoxypyridine; 3-allyloxy-2,6-dimethyl-4- [2 '-(tetrazol-5-yl) biphenyl-4-yl] methoxypyridine; 3- Benzyloxy-2,6-dimethyl-4- [2'-
(Tetrazol-5-yl) biphenyl-4-yl] methoxypyridine; 3-ethoxy-2,6-dimethyl-4- [2 '-(carboxybiphenyl-4-yl) methoxypyridine; and pharmacologically acceptable The compound of claim 1, wherein the compound is selected from the group consisting of: 3. An anti-hypertensive agent comprising the compound according to claim 1 as an active ingredient. 4. A process for producing a compound according to claim 1 or 2, comprising the following general formula (II): (Wherein R ²² , R ²³ and R ²⁴ have the same meanings as in claim 1), and a compound represented by the following formula (III): (In the formula, Y represents a halogen atom, an alkylsulfonyloxy group, or an arylsulfonyloxy group, B has the same meaning as in claim 1, and when B is a tetrazolyl group, the group may be protected.) A method comprising reacting a compound represented by the formula (I) with a tetrazolyl group represented by B, wherein the protective group is removed. 5. A process for producing a compound according to claim 1 or 2, wherein B in the general formula (I) is a tetrazolyl group, comprising the following general formula (Ia): (Wherein, R ²² , R ²³ , and R ²⁴ have the same meanings as in claim 1, A has the same meaning as in claim 1, and R ^18a represents a hydrogen atom or a lower alkyl group). Reacting the resulting compound with ammonia to obtain an amide derivative, dehydrating the amide derivative to obtain a nitrile derivative, and reacting the nitrile derivative with an azide compound.