JPH0673008A - Pyridine derivative having angiotensin ii antagonism - Google Patents

Abstract

PURPOSE:To obtain a new pyridine derivative useful as a antihypertensive agent and a therapeutic agent for heart failure effective in treatment and preven tion of hypertension and heart failure and its pharmacologically permissible salt. CONSTITUTION:A pyridine derivative of formula I {R<1> and R<4> are (substituted) 1-6C alkyl; R<2> is 1-6C alkyl or formula II [R<5> is H, alkyl or acyl; R<6> and R<7> are H, OH, alkyl, alkoxy, benzyl, alkoxycarbonyl, etc., or R<6> and R<7> form a ring together with N; (m) and (n) are 0-2]; R<3> is formula III, benzyl or biphenylmethyl} and its pharmacologically permissible salt, e.g. 2,6-dimethyl-3-[3-(N-tert.-butoxycarbonyl-Nisopropylamino-2-hydroxypro poxy]-4-[2'-(tetrazol-5-yl)biphenyl-4-yl]methoxypyridine. This compound of formula I is obtained by reacting, e.g. a compound of formula IV with a compound of formula V (R<10> is benzyl or biphenylmethyl; X is halogen, etc.).

Description

Detailed Description of the Invention

[Background of the Invention]

FIELD OF THE INVENTION The present invention relates to an antihypertensive agent and a therapeutic agent for heart failure, which are effective for the treatment and prevention of hypertension and heart failure, containing a pyridine derivative having an angiotensin II antagonistic effect and at least one of them as an active ingredient. Regarding

[0002]

BACKGROUND OF THE INVENTION Angiotensin II is a hormone induced by angiotensin I by angiotensin converting enzyme, and is a potent pressor substance in mammals such as rats, dogs and humans, and is considered to be one of the causative substances of hypertension. . Therefore, a drug that inhibits the action of angiotensin converting enzyme and a drug that has an antagonistic action on the receptor of angiotensin II are expected to be effective as a therapeutic drug for hypertension and congestive heart failure.

A large number of angiotensin converting enzyme inhibitors such as captopril and enalapril have already been developed and clinically used as antihypertensive agents and heart failure therapeutic agents. Furthermore, in recent years, research has also been advanced on angiotensin II receptor antagonists. Initially, peptidic angiotensin receptor antagonists similar to the structure of angiotensin II were reported (for example, circulase
Chon Research Magazine Vol. 29, 673 Page (1971), Jar
Null of Medicinal Chemistry, Volume 32, 466,89
8, 1366 page (1989)), and has not yet been used clinically. More recently, non-peptide angiotensin II receptor antagonists have been reported. For example, imidazopyridine derivatives (JP-A-62-240683 and EP4158).
66), substituted imidazole derivative (Japanese Patent Publication No. 63-64428, Japanese Patent Publication No. 63-23868, WO91 / 00281, WO91 / 00277, EP40).
3158 and EP403159), substituted pyrroles, pyrazoles,
Triazole derivatives (Japanese Patent Laid-Open No. 1-287071, EP411507,
EP412594 and EP409332). Further, a quinazolinone derivative (EP411766), a pyrimidone derivative (JP-A-3-44377 and EP419048), a benzimidazole derivative (JP-A-3-5456, JP-A-3-27362, JP-A-3-63264 and US Pat. No. 4,880,804). , An imidazole derivative fused to a 5- to 7-membered ring (EP400974, EP40
1030, EP407102), pyridine derivative (EP453210) and the like. For pyridine derivatives, 3 of the pyridine ring
It is only the report of the present inventors disclosed in WO91-19697 that a compound having an alkoxy group at the position is disclosed.

[Outline of the Invention]

DISCLOSURE OF THE INVENTION The present inventors searched for a novel pyridine derivative having a strong angiotensin II antagonistic action and high oral absorption. As a result, they found that certain pyridine derivatives have these properties and completed the present invention.

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

Another object of the present invention is to provide an antihypertensive agent and a therapeutic agent for heart failure, which comprises a novel pyridine derivative having angiotensin II antagonistic activity.

The pyridine derivative according to the present invention is a compound represented by the following general formula (I) and pharmaceutically acceptable salts thereof.

[0008]

[Chemical 2] (In the formula, R ¹ and R ⁴ may be the same or different and each represents an optionally substituted C _1-6 alkyl group, and R ² is an optionally substituted C _1-6 alkyl group, or a group ^{_{- (CH 2) m-CH}} (oR 5) - (CH 2) n-n
R ⁶ R ⁷ (wherein R ⁵ is a hydrogen atom or an optionally substituted C
It represents a _1-6 alkyl group or _{C 1 to 4} acyl group, ^{R 6}
And R ⁷ may be the same or different and each is a hydrogen atom, a hydroxyl group, an optionally substituted C _1-6 alkyl group, a C _3-7 cycloalkyl group, or an optionally substituted C _1-6 alkoxy. Group, optionally substituted C
_2-6 alkoxycarbonyl group, a benzyl group, a biphenyl methyl group (wherein the benzyl or biphenyl methyl group may be substituted with a carboxyl group or a tetrazolyl group), or a group -CHR ⁸ -COOR
⁹ (wherein R ⁸ is a hydrogen atom or an optionally substituted C
_1-6 alkyl group, a phenyl group, or a benzyl group which may be substituted with a hydroxyl group, and R ⁹ represents a hydrogen atom or a C _1-6 alkyl group), or R ⁶ and R ⁷ together with the nitrogen atom to which they are attached may optionally contain a nitrogen atom, an oxygen atom or a sulfur atom, and may be a 5- or 6-membered heterocycle which may be fused with another ring. ^May form a ring, m represents an integer of 0 to 2, n represents an integer of 0 to 2), and R ³ represents a group — (CH ₂ ) m—CH (OR ⁵ ) — ( CH
₂ ) n-NR ⁶ R ⁷ (wherein R ⁵ , R ⁶ and R ⁷ have the same meanings as described above), a benzyl group or a biphenylmethyl group (wherein the benzyl group or the biphenylmethyl group is a carboxyl group or It may be substituted with a tetrazolyl group). ) The compound represented by the general formula (I) does not have the agonistic action found in peptide-type receptor antagonists, and exhibits a selective antagonism to the angiotensin II receptor.

The compound represented by the general formula (I) has low toxicity, excellent oral absorption and long-lasting action, and its angiotensin II antagonistic activity is comparable to that of conventional non-peptide angiotensin II antagonistic activity. It is excellent in comparison. Therefore, a safe antihypertensive agent and a therapeutic agent for heart failure can be supplied to the human body.

DETAILED DESCRIPTION OF THE INVENTION Compound of Formula (I) In the present specification, the term “C _1-6 alkyl group” is used to mean a straight chain or branched chain alkyl group. And more preferably a C _1-4 alkyl group. Further, the “optionally substituted C _1-6 alkyl group” means that one or more hydrogen atoms of this alkyl group may be substituted by a substituent, and an example of the substituent is a fluorine atom. And halogen atoms such as chlorine atom, bromine atom and element atom. Preferred examples of the optionally substituted C _1-6 alkyl group are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobuyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and tri. Fluoromethyl, 2-fluoroethyl, difluoroethyl, 2,2,2-trifluoroethyl and the like can be mentioned.

The group represented by R ² and R ³ is-(CH ₂ ) m-
In CH (OR ⁵ )-(CH ₂ ) n-NR ⁶ R ⁷ ,
The C _1-4 acyl group represented by R ⁵ is preferably a C _1-4 alkylcarbonyl group, and examples thereof include an acetyl group and a propionyl group.

In the same group, preferred examples of the C _3-7 cycloalkyl group represented by R ⁶ and R ⁷ include cyclopropyl, cyclopentyl and cyclohexyl. The C _1-6 alkoxy group represented by R ⁶ and R ⁷ is preferably a C _1-4 alkoxy group. This alkoxy group may be substituted, and examples of the substituent include a halogen atom and a phenyl group. Preferred examples of the optionally substituted C _1-6 alkoxy group include methoxy, ethoxy, n-propoxy, isopropyloxy, n-butoxy, trifluoroethoxy and benzyloxy groups. Further, optionally substituted C _2-6 represented by R ⁶ and R ⁷
A preferred example of the alkoxycarbonyl group is tert-
Butoxycarbonyl, benzyloxycarbonyl, 2,2,
Examples thereof include 2-trichloroethoxycarbonyl and 9-fluorenylmethoxycarbonyl groups. Furthermore, R ⁶ and R ⁷ may be a benzyl group or a biphenylmethyl group, and the benzyl group and the biphenylmethyl group may have a carboxyl group or a tetrazolyl group as a substituent. Specific examples thereof include 4-carboxybenzyl, 4- (tetrazol-5-yl) benzyl, (2'-carboxybiphenyl-4-yl) methyl, [2 '-(tetrazol-5-yl) biphenyl-4-. Il] methyl and the like.

Further, a group represented by R ⁶ and R ⁷ is —CHR ⁸
In -COOR ⁹ , a preferable example of the benzyl group which may be substituted with the hydroxyl group represented by R ⁸ is a 4-hydroxybenzyl group.

Further, R ⁶ and R ⁷ may form a 5- or 6-membered heterocyclic ring together with the nitrogen atom to which they are bonded. The heterocycle may further contain a nitrogen atom, an oxygen atom or a sulfur atom to form a 5- or 6-membered ring, and the heterocycle may be condensed with another ring. Specific examples of these heterocycles include morpholino, piperazinyl, piperidinyl, pyridyl, pyrrolidino, imidazolyl, oxazolidino, thiazolidinyl, isoxazolidino, indolino and quinolinyl groups.

R ³ is the above-mentioned group-(CH ₂ ) m-CH
It represents (OR ⁵ )-(CH ₂ ) n-NR ⁶ R ⁷ or represents a benzyl group or a biphenylmethyl group. Here, this benzyl group or biphenylmethyl group may have a carboxyl group or a tetrazolyl group as a substituent. Specific examples thereof include 4-carboxybenzyl, 4- (tetrazol-5-yl) benzyl, (2 '
-Carboxybiphenyl-4-yl) methyl, [2'-
(Tetrazol-5-yl) biphenyl-4-yl] methyl and the like.

A preferred group of compounds of the present invention is R ¹
And R ⁴ is a methyl group, and R ² is a group — (CH ₂ ) m.
_{^{-CH (OR 5) - (CH}} 2) a ^n-NR 6 ^{R 7,}
Examples include compounds in which R ³ is a biphenylmethyl group substituted with a carboxyl group or a tetrazolyl group.

A particularly preferred compound is 2,6-dimethyl-3- (3-isopropylamino-2-hydroxypropoxy) -4- [2 '-(tetrazol-5-yl) biphenyl-4-yl] methoxypyridine. , 2, 6
-Dimethyl-3- [3- (morpholin-1-yl) -2
-Hydroxypropoxy] -4- [2 '-(tetrazol-5-yl) biphenyl-4-yl] methoxypyridine, and the like.

The compound of the present invention can exist as a stereoisomer derived from an asymmetric carbon atom in the molecule and a compatible isomer derived from a tetrazole ring, and any isomer is included in the present invention. Is.

The compound of the present invention can be a salt thereof. Such salts include medically acceptable non-toxic salts. Suitable salts include alkali metal or alkaline earth metal salts such as sodium salts, potassium salts or calcium salts, hydrofluoric acid salts, hydrochloride salts, hydrobromic acid salts, hydroiodic acid salts, and the like. Inorganic acid salts such as hydrohalides, nitrates, perchlorates, sulfates and phosphates, lower alkyl sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate, benzene Sulfonates, aryl sulfonates such as p-toluene sulfonate, fumarate,
Examples include organic acid salts such as succinate, citrate, tartrate, oxalate and maleate, and amino acid salts such as glutamate and aspartate.

Preparation of Compound of General Formula (I) The compound according to the present invention can be prepared by various methods (methods A to C) as shown below. According to the first method (method A) of the present invention, a compound of the general formula (I) (wherein R ³ is a benzyl or biphenylmethyl group substituted by a carboxyl group or a tetrazolyl group) is General formula (II):

[0021]

[Chemical 3] (Wherein R ¹ , R ² and R ⁴ have the same meanings as in the case of the general formula (I)), a compound represented by the formula (III
): R ¹⁰ X (III) (In the formula, R ¹⁰ represents a carboxyl group which may be protected, or a benzyl group which may be substituted with a tetrazolyl group or a nitrile group, or a biphenylmethyl group, X is a halogen atom, An alkylsulfonyloxy group or an arylsulfonyloxy group) and a benzyl derivative or a biphenylmethyl derivative represented by a solvent that does not participate in the reaction (for example, N, N-dimethylformamide, dioxane, tetrahydrofuran, methanol, ethanol, acetone, In an organic solvent such as dimethylsulfoxide or a mixed solvent of these solvents and water) in the presence of a base, the reaction is carried out at a reaction temperature of -30 to 150 ° C, preferably 10 to 100 ° C for 30 minutes to 24 hours, and necessary. Can be obtained by removing the protecting group.

Further, when R ¹⁰ is a benzyl group or a biphenylmethyl group substituted by a nitrile group, it is necessary to convert the nitrile group into a tetrazolyl ring as follows. That is, the compound obtained by the reaction is converted into an azide derivative (for example, sodium azide,
Potassium azide, trimethyltin azide, tributyltin azide, etc.) and a solvent that does not participate in the reaction.
The compound is reacted at a temperature of ˜200 ° C. for 30 minutes to 1 week, then protected and purified if necessary, and then the protecting group is removed to obtain the compound of general formula (I).

In the above reaction, when the benzyl or biphenylmethyl group of R ^{10 has} a carboxyl group or a tetrazolyl group as a substituent, the carboxyl group and the tetrazolyl group may be protected.
As a protective group for the carboxyl group, a methyl group, an ethyl group,
t-butyl group, benzyl group, p-methoxybenzyl group, diphenylmethyl group, p-nitrobenzyl group and the like,
Examples of the protective group for the tetrazolyl group include a trityl group, a 2-cyanoethyl group, a p-methoxybenzyl group and a methoxymethyl group.

Examples of the halogen atom represented by X include chlorine atom, bromine atom, iodine atom and the like. Examples of the alkylsulfonyloxy include methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy and the like, and further examples of the arylsulfonyloxy group include benzenesulfonyloxy and p-toluenesulfonyloxy.

Examples of the base used in the above reaction include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, hydrogen such as sodium hydride and potassium hydride. Examples thereof include metal amines, organic amines such as triethylamine and pyridine.

According to the second method (method B) according to the present invention, the compound of the general formula (I) (wherein R ³ is a group — (CH 2
₂ ) m-CH (OR ⁵ )-(CH ₂ ) n-NR ⁶ R ⁷ is a compound represented by the general formula (II) and the following general formula (IV):

[0027]

[Chemical 4] (In the formula, R ¹¹ , R ¹² , R ¹³ and R ¹⁴ represent a hydrogen atom or a C _1-4 alkyl group, and Y represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group) And the above method (A
Reaction) under the same conditions as described above, and the obtained epoxy ether derivative is further added with the following formula (V): HNR ¹⁵ R ¹⁶ (V) (wherein, R ¹⁵ and R ¹⁶ are the above-mentioned general formula (I)). represents the same meaning as ^{R 6} and ^{R 7,} provided that group -CHR ⁸ -
COOR ⁹ is a group —CHR ⁸ —COOR ¹⁷ (wherein R ¹⁷
Is a C _1-6 alkyl group or a carboxyl group-protecting group). ) With an amine or amino acid derivative represented by a solvent that does not participate in the reaction (for example, an organic solvent such as N, N-dimethylformamide, dioxane, tetrahydrofuran, methanol, ethanol, acetone, dimethylsulfoxide, or these solvents) Mixed solvent with water), in the presence of a base, at −30 to 150 ° C., preferably 10
It can be obtained by reacting at a reaction temperature of -100 ° C for 30 minutes to 24 hours, and removing a protecting group if necessary.

Here, as the halogen atom represented by Y,
Examples thereof include chlorine atom, bromine atom, iodine atom and the like. Examples of the alkylsulfonyloxy include methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy and the like, and further examples of the arylsulfonyloxy group include benzenesulfonyloxy and p-toluenesulfonyloxy.

Examples of the protective group for the carboxyl group represented by R ¹⁷ include benzyl group, p-methoxybenzyl group, diphenylmethyl group, p-nitrobenzyl group and the like.

According to the third method (method C) of the present invention, the compound of general formula (I) (wherein R ³ is a benzyl or biphenylmethyl group substituted by a carboxyl group or a tetrazolyl group) is The following general formula (V
I):

[0031]

[Chemical 5] (Wherein R ¹ , R ² and R ⁴ have the same meanings as in the case of the general formula (I), and Z represents a halogen atom or a nitro group), and a compound represented by the formula (VII): R ^And a reactive salt of a benzyl derivative or a biphenylmethyl derivative represented by ¹⁰ OH (VII) (wherein R ¹⁰ has the same meaning as in the case of the above formula (III)) and the above method (method A). It can be obtained by reacting under similar conditions and removing a protecting group if necessary. The reactive salt of the benzyl derivative or the biphenylmethyl derivative represented by the formula (VII) includes alkali metal salts such as sodium, potassium and lithium.

In addition to the compound of the general formula (I) obtained by the above method A, method B or method C, a group-(CH ₂ ) m-CH (OR ⁵ )-( CH
₂₎ As ^{R 5} in the ^n-NR 6 ^{R 7} can be introduced into the _{C 1 to 6} alkyl groups or _{C 1 to 4} acyl groups. The alkylation can be obtained by reacting a haloalkyl having a desired structure (eg, methyl iodide) with the compound of the general formula (I) in the presence of a base as described above. In addition, acylation is performed by reacting a carboxylic acid anhydride having a desired structure (for example, acetic anhydride) or a carboxylic acid halide (for example, acetyl chloride, propionyl chloride, etc.) in the presence of a base as described above. Can be obtained. In both cases of alkylation and acylation, the compound of general formula (I) can be obtained by removing the protecting group after the reaction, if necessary.

The pyridine or pyridone derivative represented by the above general formulas (II) and (VI) is a known method using a pyrone compound produced by the method described in French Patent FR1516463 and a method similar thereto. (See, for example, JP-A-60-178890), Journal of Organic Chemistry, Vol. 28, page 725 (1963), Vol. 44, page 870 (1979), Chemisches Berichte, vol. 54, page 1089. (1921), vol. 94, 48
It can be synthesized by the method described on page 6 (1961) or a method similar thereto.

Further, the above general formulas (III) and (VII)
The biphenylmethyl derivative represented by
89-06233, Japanese Patent Laid-Open No. 1-117876 and journals
Volume 56 of Organic Chemistry, page 2395 (19
1991))).

The compound of the general formula (I) synthesized by the above-mentioned production method is purified by a conventional purification method such as recrystallization, reprecipitation, solvent extraction, silica gel column chromatography, column chromatography with an adsorptive resin and the like. be able to. Use of compound / pharmaceutical composition The compound represented by the general formula (I) and a pharmaceutically acceptable salt thereof have angiotensin II antagonistic activity. Therefore, the compound according to the present invention and its pharmacologically acceptable salt are effective for the prevention and treatment of angiotensin II-related diseases. Specifically, the compound according to the present invention and its pharmacologically acceptable salt can be used as an antihypertensive drug and a therapeutic agent for heart failure.

The pharmaceutical composition containing the compound according to the present invention and a pharmacologically acceptable salt thereof as a main component is mainly orally or parenterally administered to humans and non-human animals (for example, intramuscular injection, mousse). Injection, subcutaneous administration, rectal administration,
Transdermal administration, etc.), preferably oral administration.

The pharmaceutical composition containing the compound of the present invention as an active ingredient is used in various dosage forms suitable for oral or parenteral administration. For example, depending on its application, tablets,
Preparation in the form of oral preparations such as capsules, granules, powders, pills, fine granules, and lozenges, and injections, rectal preparations, oily suppositories, water-soluble suppositories, etc. You can These various preparations include commonly used excipients, fillers, binders, wetting agents, disintegrating agents, surfactants,
It can be produced by a conventional method using a lubricant, a dispersant, a buffer, a preservative, a solubilizing agent, an antiseptic, a flavoring agent, a soothing agent, a stabilizer and the like. Examples of non-toxic additives that can be used include lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methyl cellulose, carboxymethyl cellulose or salts thereof, gum arabic, polyethylene glycol. , Syrup, petrolatum, glycerin, ethanol, propylene glycol, citric acid, sodium chloride, sodium sulfite, sodium phosphate and the like.

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

The dose is appropriately determined in consideration of the usage, the age of the patient, the sex, the degree of symptoms, etc., but is usually about 0.1 to 1000 mg, preferably 0.5 to 20 mg per day for an adult.
The amount is preferably about 0 mg, which can be administered once or several times a day.

[0040]

EXAMPLES The present invention will be described in more detail with reference to the following examples, test examples and formulation examples. These are merely examples and the present invention is not limited thereto. In addition, the NMR data of the following examples uses measurement data by 400 MHz NMR, and δ value (ppm) based on TMS.
showed that.

Reference Example 1 2,6-Dimethyl-3- (3-isopropylamino-2)
-Hydroxypropoxy ) -4 (1H) -pyridone a) 60% sodium hydride 1.056 g (26.4)
mM) dried N, N-dimethylformamide (DM
F) Suspended in 20 ml, and stirred at room temperature for 30 minutes under an argon gas atmosphere. To this suspension, under ice cooling, 3.08 g (22-hydroxy-3-hydroxy-2,6-dimethyl-4-pyrone)
(mM) and DMF (10 ml) were added at 10 to 15 ° C for about 20
Stir for minutes. Then, under cooling, 5.13 ml (66 mM) of epichlorohydrin was added dropwise to the reaction mixture at room temperature for 7 minutes.
The mixture was further stirred at 70 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, 70 ml of diluted saline was added to the residue, and ethyl acetate 2
It was extracted twice with 00 ml. The extract layer was washed with water, brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with hexane and then purified by silica gel column chromatography (chloroform: methanol = 25: 1 to 10: 1).
4.8 g (about 90% purity) of 2,6-dimethyl-3- (2,3-epoxy) propoxy-4-pyrone as a pale yellow oily substance was obtained. ¹ H NMR (CDC1 ₃ ) δ: 2.24 (3H,
s), 2.35 (3H, s), 3.30 (1H, m),
3.89 (2H, dd), 4.46 (2H, dd),
6.14 (1H, s). EIMS ( m / z ): 196 (M ⁺ ).

B) 4.8 g of the compound obtained in the above a)
(Equivalent to 22 mM) was dissolved in 20 ml of ethanol, 8.56 ml of isopropylamine was added, and the mixture was stirred at 60 ° C. for 4 hours. After evaporating the solvent under reduced pressure, crystallization was performed with hexane-ethyl acetate (4: 1 to 3: 1). The precipitated crystals were collected and dried to give 2.36 g (9.25 mM, 2,6-dimethyl-3- (3-isopropylamino-2-hydroxypropoxy) -4-pyrone as colorless crystals.
Yield 42.1%) was obtained. ¹ H NMR (CDC1 ₃ ) δ: 1.06 (6H,
d), 2.26 (3H, s), 2.34 (3H, s),
2.65 to 2.85 (3H, m), 3.85 (1H, d
d), 3.95 (1H, m), 4.04 (1H, d
d), 6.18 (1H, s). SIMS ( m / z ): 256 (M + 1) ⁺ .

C) Compound 1.02 obtained in b) above
12 g of concentrated aqueous ammonia was added to g (4 mM), and the mixture was stirred at 80 ° C. for 4 hours in a sealed tube. The reaction solution was concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 1: 1 to methanol) to give the title compound 8 as a pale yellow oil.
40 mg (3.3 mM, yield 82.7%) was obtained. ¹ H NMR (CDC1 ₃ ) δ: 1.09 (6H,
d), 2.27 (3H, s), 2.34 (3H, s),
2.75 (2H, m), 2.84 (1H, m), 3.8
2 (1H, dd), 3.99 (1H, m), 4.05
(1H, dd), 6.22 (1H, s). EIMS ( m / z ): 254 (M ⁺ ).

Reference Example 2 2,6-Dimethyl-3- [3- (Nt-butoxycal)
Bonyl-N-isopropylamino) -2-hydroxypropyl
Ropoxy] -4 (1H) -pyridone a) 840 mg (3.3 m) of the compound obtained in Reference Example 1
M) was dissolved in 12 ml of tetrahydrofuran, a solution of 550 μl (3.97 mM) of triethylamine and 792 mg (3.68 mM) of di-t-butyl dicarbonate in tetrahydrofuran (3 ml) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (chloroform:
1.05 g (2.98 m) of the title compound as a milky white powder by purification with methanol = 25: 1 to 5: 1).
M, yield 90.2%) was obtained. ¹ H NMR (CDC1 ₃ ) δ: 1.18 (3H,
d), 1.22 (3H, d), 1.45 (9H, s),
2.29 (3H, s), 2.36 (3H, s), 3.2
0 (1H, m), 3.34 (1H, br s), 3.8
0 (1H, m), 4.04 (3H, m), 6.19 (1
H, s). SIMS ( m / z ): 355 (M + 1) ⁺ .

The compound of Reference Example 2 is the same as that of Reference Example 1. b)
It can also be synthesized as described below from the pyrone obtained in.

B) Reference example 1. 730 mg of pyrone b)
(2.86 mM) was dissolved in 5 ml of tetrahydrofuran, and 530 μl of triethylamine (3.82 m) under ice cooling.
M) and 802 mg (3.675 mM) of di-t-butyldicarbonate dissolved in 2 ml of tetrahydrofuran were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution is concentrated under reduced pressure,
40 ml of ice water was added to the obtained residue, and 80 m of ethyl acetate was added.
Extract 3 times with 1. The ethyl acetate extract layer was washed with diluted saline and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained yellow oily substance was converted to diethyl ether 5
After washing with 0 ml, it was dried and purified by silica gel column chromatography (chloroform: ethyl acetate = 20: 1) to give a pale yellow oily 2.3-dimethyl-.
880 mg (2.60 mM, yield 90.8%) of 3- [3- (N-t-butoxycarbonyl-N-isopropylamino) -2-hydroxypropoxy] -4-pyrone was obtained. ¹ H NMR (CDC1 ₃ ) δ: 1.18 (3H,
d), 1.20 (3H, d), 1.46 (9H, s),
2.26 (3H, s), 2.33 (3H, s), 3.2
5 (1H, m), 3.38 (1H, br s), 3.8
1 (1H, dd), 3.98 (1H, m), 4.04
(1H, dd), 5.45 (1H, br s), 6.1
8 (1H, s). EIMS ( m / z ): 356 (M + 1) ⁺ .

304 mg of the title compound was obtained by adding concentrated ammonia water to an ethanol solution of 415 mg (1.17 mM) of the above compound in the same manner as in c) of Reference Example 1 and reacting in a sealed tube at 80 ° C. for 5.5 hours. (0.859 mM, yield 73.4%) was obtained. The spectral data of this compound is shown in Reference Example 2. It was possible to confirm that the compounds were the same, in agreement with the data of the compounds obtained in a).

Reference Example 1. Instead of the isopropylamine of b), various amines (A) were used in Example 1. Reaction was carried out in the same manner as in b), and Reference Example 1. The pyridones of Reference Examples 3 to 8 were obtained by treating with ammonia in the same manner as in c).

Reference Example 3 2,6-dimethyl-3- (3-cyclohexylamino-
2-hydroxypropoxy) -4 (1H) - pyridone (A) cyclohexylamine _{^{1 H NMR (CDC1 3) δ}} : 1.05~1.30
(5H), 1.64 (1H, m), 1.74 (2H,
m), 1.93 (2H, m), 2.26 (3H, s),
2.32 (3H, s), 2.46 (1H, m), 2.7
9 (2H, br s), 3.72 (1H, m), 3.8
2 (1H, m), 4.01 (2H, m), 6.21 (1
H, s). EIMS ( m / z ): 294 (M ⁺ ).

Reference Example 4 2,6-Dimethyl-3- (3-diethylamino-2-hi)
Mud propoxy) -4 (1H) - pyridone (A) diethylamine _{^{1 H NMR (CDC1 3) δ}} : 1.08 (6H,
t), 2.31 (3H, s), 2.36 (3H, s),
2.70 (2H, q), 2.72 (4H, q), 3.8
6 (1H, dd), 4.02 (2H, s), 4.03
(1H, m), 6.22 (1H, s). EIMS ( m / z ): 268 (M ⁺ ).

Reference Example 5 2,6-Dimethyl-3- [3- (morpholin-4-i]
) -2-Hydroxypropoxy] -4 (1H) -pyri
Don (A) morpholine ¹ H NMR (DMSO- d ₆ ) δ: 2.21 (3
H, s), 2.25 (3H, s), 3.31 (5H, b)
r s), 3.63 (5H, br s), 3.70 (1
H, m), 3.93 (2H, m), 6.08 (1H,
s). EIMS ( m / z ): 282 (M ⁺ ).

Reference Example 6 2,6-Dimethyl-3- (3-t-butylamino-2-)
Hydroxypropoxy) -4 (1H) - pyridone (A) t-butylamine _{^{1 H NMR (CDC1 3) δ}} : 1.13 (9H,
s), 2.26 (3H, s), 2.34 (3H, s),
2.72 (2H, br s), 3.83 (1H, m),
3.94 (1H, br s), 4.05 (1H, m),
5.35 (1H, br s), 6.20 (1H, s). SIMS ( m / z ): 269 (M + 1) ⁺ .

Reference Example 7 2,6-Dimethyl-3- (3-methoxyamino-2-hi)
Droxypropoxy ) -4 (1H) -pyridone (A) O-methylhydroxylamine hydrochloride ¹ H NMR (CDC1 ₃ ) δ: 2.30 (3H,
s), 2.35 (3H, s), 2.96 (1H, d
d), 3.09 (1H, dd), 3.53 (3H,
s), 3.89 (1H, dd), 4.02 (1H, d
d), 4.09 (1H, m), 6.27 (1H, s). SIMS ( m / z ): 243 (M + 1) ⁺ .

Reference Example 8 2,6-Dimethyl-3- [3- (N-hydroxy-N-
Methylamino) -2-hydroxypropoxy] -4 (1
H) - pyridone (A) N-methylhydroxylamine hydrochloride _{^{1 H NMR (CDC1 3: CD}} 3 OD = 1: 3)
δ: 2.32 (3H, s), 2.38 (3H, s),
2.94 (2H, m), 3.38 (3H, s), 3.9
2 (1H, dd), 4.08 (1H, dd), 4.16
(1H, m), 6.31 (1H, s). SIMS ( m / z ): 243 (M + 1) ⁺ .

Example 1 2,6-Dimethyl-3- [3- (Nt-butoxycal)
Bonyl-N-isopropylamino-2-hydroxypro
Poxy] -4- [2 '-(tetrazol-5-yl) bi
Phenyl-4-yl] methoxypyridine a) 60% Sodium hydride 37 mg (0.92 m)
M) was suspended in 2 ml of dried N, N-dimethylformamide and stirred under an argon gas atmosphere at room temperature for 15 minutes. This suspension was cooled with ice to 2,6-dimethyl-3-
[3- (Nt-butoxycarbonyl-N-isopropylamino) -2-hydroxypropoxy] -4 ( 1H )
-Add 283 mg (0.8 mM) of pyridone and add 2 at room temperature.
Stir for 0 minutes.

Then, 535 mg (0.96 mM) of 4'-bromomethyl-2- (triphenylmethyltetrazol-5-yl) biphenyl dissolved in 3 ml of N, N-dimethylformamide was added to this reaction solution under water cooling, and the mixture was cooled to room temperature. Stirred overnight. 10 ml of cold water was added to the reaction solution, and the mixture was extracted twice with 80 ml of ethyl acetate. The ethyl acetate extract layer was washed twice with 50 ml of diluted saline and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the obtained residue was washed with hexane, and then purified by silica gel column chromatography (chloroform: ethyl acetate-4: 1 to chloroform: methinol = 50: 1) to give a pale yellow color. Oily 2,6-dimethyl-3- [3- (N-
t-butoxycarbonyl-N-isopropylamino)-
2-Hydroxypropoxy] -4- [2 '-(triphenylmethyltetrazol-5-yl) biphenyl-4-
Il] methoxypyridine 250 mg ( a-1 , 0.30
mM, yield 37.7%) and pale yellow oily 2,6-dimethyl-3- (3-isopropylamino-2-hydroxypropoxy) -4- [2 '-(triphenylmethyltetrazol-5-yl). Biphenyl-4-yl] methoxypyridine 310 mg ( a-2 , 0.425 mM, yield 5
3.1%) was obtained. a-1 : ¹ H NMR (CDC1 ₃ ) δ: 1.07 (3H,
d), 1.12 (3H, d), 1.45 (9H, s),
2.42 (3H, s), 2.48 (3H, s), 3.3
7 (2H, br s), 3.91 (2H, br s),
4.03 (2H, m), 4.99 (2H, s), 6.5
8 (1H, s), 6.92 (6H, m), 7.15-
7.35 (13H), 7.39 (1H, dd), 7.4
9 (2H, m), 7.94 (1H, dd). SIMS ( m / z ): 831 (M + 1) ⁺ . ^{a-2: 1 H NMR (} CDC1 3) δ: 1.07 (3H,
d), 1.09 (3H, d), 2.44 (3H, s),
2.46 (3H, s), 3.38 to 3.50 (2H,
m), 4.03 (3H, m), 4.58 (1H, m),
4.99 (2H, s), 6.62 (1H, s), 6.9
4 (6H, m), 7.18 to 7.35 (13H), 7.
41 (1H, dd), 7.50 (2H, m), 7.93
(1H, dd). SIMS ( m / z ): 731 (M + 1) ⁺ .

B) Compound a-1 11 obtained in the above a)
0 mg (0.1325 mM) 0.5 ml of methylene chloride
Dissolve in a mixture of 1.0 ml of methanol and 4 ml of methanol, and under ice cooling,
HCl (0.09 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, and the resulting residue was mixed with 2 m of water.
1 was added, the pH was adjusted to 11.4 with 1N NaOH, and the mixture was washed twice with 15 ml of diethyl ether. Further, the pH of the aqueous layer was adjusted to 4.2 with 1N HCl while cooling, and the mixture was stirred at the same temperature for about 30 minutes. The white crystals were collected by filtration, washed with cold water and dried to give 52 mg (0.088 mM, yield 6) of the title compound as a colorless crystalline powder.
6.7%) was obtained. ¹ H NMR (DMSO- d ₆ ) δ: 1.07 (6
H, br d), 1.32 (9H, br s), 2.3
5 (3H, s), 2.36 (3H, s), 3.36 (2
H, m), 3.75 (1H, m), 3.87 (3H,
m), 5.18 (2H, s), 6.93 (1H, s),
7.13 (2H, d), 7.39 (2H, d), 7.5
6 (2H, m), 7.67 (1H, d), 7.68 (1
H, dd). SIMS ( m / z ): 589 (M + 1) ⁺ .

Example 2 2,6-Dimethyl-3- (3-isopropylamino-2)
-Hydroxypropoxy) -4- [2 '-(tetrazo
Lu-5-yl) biphenyl-4-yl] methoxypyridi
Down Example 1. 307 mg of compound a-2 obtained in a)
(0.42 mM) in 4N HCl Example 1. After detriphenylmethylation in the same manner as in b), it was washed with diethyl ether. Next, the pH of the aqueous layer was adjusted to 2.9 with 1N HCl, and purified by DIAION HP-20 (20 ml, eluted with 45% acetone water) to give 134 mg (0.275 mM, yield) of the title compound as colorless prism crystals. 65.
4%). ¹ H NMR (DMSO- d ₆ ) δ:
1.02 (3H, d), 1.07 (3H, d), 2.3
2 (3H, s), 2.36 (3H, s), 3.51 (2
H, t), 3.85 (1H, m), 3.98 (1H, d
d), 4.05 (1H, dd), 4.72 (1H,
m), 5.18 (2H, s), 6.95 (1H, s),
7.14 (2H, d), 7.41 (2H, d), 7.5
6 (1H, dd), 7.59 (1H, dd), 7.67
(1H, d), 7.68 (1H, dd). SIMS ( m / z ): 489 (M + 1) ⁺ .

2,6-Dimethyl-3- [3-of Example 1
In the same manner as in Example 1, using the pyridones of Reference Examples 2 to 5 instead of (Nt-butoxycarbonyl-N-isopropylamino) -2-hydroxypropoxy] -4 ( 1H ) -pyridone, 4 The compounds of Examples 3 to 6 and Example 8 were obtained by reacting with'-bromomethyl-2- (triphenylmethyltetrazol-5-yl) biphenyl and then deprotecting.

Example 3 2,6-Dimethyl-3- (3-t-butylamino-2-)
Hydroxypropoxy) -4- [2 '-(tetrazole
-5-yl) biphenyl-4-yl] methoxypyridine a) 2,6-dimethyl-3- (3-t-butylamino-2-hydroxypropoxy) -4 ( 1H ) -pyridone (270 mg, 1 mM) was used. Example 1. a) The same reaction and post-treatment give 2,6-
Dimethyl-3- (3-t-butylamino-2-hydroxypropoxy) -4- [2 '-(triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methoxypyridine 470 mg (0.632 mM, yield 63.2
%) Was obtained. ¹ H NMR (CDC1 ₃ ) δ: 1.12 (9H,
s), 2.42 (3H, s), 2.48 (3H, s),
2.73 (1H, dd), 2.87 (1H, dd),
3.96 (2H, s), 3.98 (1H, m), 5.0
0 (2H, s), 6.59 (1H, s), 6.93 (6
H, d), 7.15 to 7.35 (13H), 7.40.
(1H, dd), 7.48 (1H, m), 7.92 (1
H, dd). SIMS ( m / z ): 745 (M + 1) ⁺ .

B) 320 m of the compound obtained in the above a)
g (0.43 mM) to Example 1. After detritylation as in b) and washing with diethyl ether, the aqueous layer was washed with 1N HC
The pH was adjusted to 1.0 with l. This solution is Diaion H
By purification with P-20 (20 ml, 40% acetone water elution), 87 mg of the title compound was obtained as a colorless crystalline powder.
(0.173 mM, yield 40.3%) was obtained. ¹ H NMR (CDC1 ₃ ) δ: 1.36 (9H,
s), 2.41 (3H, s), 2.49 (3H, s),
2.93 (1H, dd), 3.05 (1H, dd),
3.72 (1H, dd), 3.81 (1H, dd),
4.09 (1H, br s), 4.90 (2H, s),
6.68 (1H, s), 7.16 (2H, d), 7.2
2 (2H, d), 7.44 (3H, m), 7.81 (1
H, dd). SIMS ( m / z ): 503 (M + 1) ⁺ .

Example 4 2,6-Dimethyl-3- (3-cyclohexylamino-
2-hydroxypropoxy) -4- [2 '-(tetrazo
Ol-5-yl) biphenyl-4-yl] methoxypyri
Zin a) Using 2,6-dimethyl-3- (3-cyclohexylamino-2-hydroxypropoxy) -4 (1 H ) -pyridone 254 mg (0.864 mM) Example 1. By reacting in the same manner as in a) and post-treating, the following three compounds were obtained. Purify by silica gel column chromatography, and extract from 2,6-dimethyl-3- [3- [N-cyclohexyl-N- [2 '-(triphenylmethyltetrazole-5
-Yl) biphenyl-4-yl] methylamino] -2-
Hydroxypropoxy] -4- [2 '-(triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methoxypyridine 158 mg ( a-1 , 0.126
(8 mM, yield 14.7%) from the elution part of chloroform: methanol = 25: 1 from 2,6-dimethyl-3-
[3-Cyclohexylamino-2- [2 '-(triphenylmethyltetrazol-5-yl) biphenyl-4-
Iyl] methoxypropoxy] -4- [2 '-(triphenylmethyltetrazol-5-yl) biphenyl-4-
74 mg ( a-2 , 0.059)
4 mM, yield 6.9%), and 2,6-dimethyl-3-from the elution part of chloroform: methanol = 5: 1.
(3-Cyclohexylamino-2-hydroxypropoxy) -4- [2 '-(triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methoxypyridine 362 mg ( a-3 , 0.47 mM, yield 54. 4%)
Got ^{a-1: 1 H NMR (} CDC1 3) δ: 1.0~1.9 (1
1H), 2.40 (3H, s), 2.46 (3H,
s), 2.63 (2H, m), 3.54 (2H, q),
3.82 (1H, m), 3.94 (2H, m), 4.9
9 (2H, s), 6.56 (1H, s), 6.91 (1
2H, m), 7.0-7.5 (32H), 7.88 (1
H, dd), 7.93 (1H, m). SIMS ( m / z ): 1247 (M + 1) ⁺ . ^{a-2: 1 H NMR (} CDC1 3) δ: 0.95~1.80
(11H), 2.40 (3H, s), 2.49 (3H,
s), 2.75 to 2.95 (2H, m), 3.87 (1
H, m), 4.08 (2H, d), 4.57 (2H,
q), 4.99 (2H, s), 6.60 (1H, s),
6.89 (12H, m), 7.0-7.5 (32H),
7.92 (2H, m). SIMS ( m / z ): 1247 (M + 1) ⁺ . ^{a-3: 1 H NMR (} CDC1 3) δ: 1.0~1.3 (4
H), 1.5 to 1.9 (6H), 2.25 (1H,
m), 2.42 (3H, s), 2.47 (3H, s),
2.71 (1H, dd), 2.86 (1H, dd),
3.60-3.75 (2H, m), 3.93 (3H,
m), 5.00 (2H, s), 6.59 (1H, s),
6.94 (6H, m), 7.05 to 7.55 (16H)
7.92 (1H, dd). SIMS ( m / z ): 771 (M + 1) ⁺ .

B) Compound a- 32 obtained in the above a)
70 mg (0.35 mM) was added to Example 1. 100 mg (0.189 mM, yield 54.0) of the title compound was obtained as a colorless crystalline powder by detritylation and post-treatment in the same manner as in b).
%) Was obtained. ¹ H NMR (CDC1 ₃ ) δ: 0.9 to 2.1 (1
0H), 2.40 (3H, s), 2.48 (3H,
s), 2.9 to 3.1 (3H), 3.77 (2H,
m), 4.13 (1H, m), 4.88 (2H, s),
6.66 (1H, s), 7.14 (2H, d), 7.2
3 (2H, d), 7.38 to 7.45 (3H, m),
7.79 (1H, d). SIMS ( m / z ): 529 (M + 1) ⁺ .

Example 5 2,6-Dimethyl-3- [3- [N-cyclohexyl-
N- [2 '-(tetrazol-5-yl) biphenyl-
4-yl] methylamino] -2-hydroxypropoxy
Si] -4- [2 ′-(tetrazol-5-yl) bife
Nyl-4-yl] methoxypyridine Compound a-1 obtained in Example 4 a) 135 mg
(0.108 mM) was used in Example 1. Deprotection reaction and post treatment were carried out in the same manner as in b) to obtain 70 mg (0.919 mM, yield 85.1%) of the title compound as a colorless crystalline powder. ¹ H NMR (DMSO- d ₆ : CDCl ₃ = 20:
1) δ: 1.0 to 1.9 (11H), 2.28 (3
H, s), 2.30 (3H, s), 2.80 (2H,
m), 3.7 to 4.0 (5H), 5.17 (2H,
s), 6.94 (2H, d), 6.95 (1H, s),
7.11 (2H, d), 7.21 (2H, d), 7.3
8 (2H, d), 7.40 to 7.70 (8H). SIMS ( m / z ): 763 (M + 1) ⁺ .

Example 6 2,6-Dimethyl-3- [3- (morpholin-4-i
2-hydroxypropoxy] -4- [2 '-(the
Trazol-5-yl) biphenyl-4-yl] methoxy
Cypyridine a) 2,6-dimethyl-3- [3- (morpholine-4
-Yl) -2-hydroxypropoxy] -4 ( 1H )-
Example 1 was performed using 282 mg (1 mM) of pyridone.
By reacting in the same manner as in a) and purifying, 2,6-dimethyl-3- [3- (morpholin-4-yl) -2-hydroxypropoxy] -4- [2 '-(tri- Phenylmethyltetrazol-5-yl) biphenyl-4-yl] methoxypyridine 560 mg (0.739
mM, yield 73.9%) was obtained. ¹ H NMR (CDCl ₃ ) δ: 2.43 (3H,
s), 2.49 (3H, s), 2.3 to 2.6 (6H,
m), 3.67 (4H, m), 3.90 to 4.05 (3
H, m), 5.00 (2H, s), 6.60 (1H,
s), 6.92 (6H), 7.15 to 7.35 (13
H), 7.40 (1H, dd), 7.50 (2H,
m), 7.93 (1H, dd). SIMS ( m / z ): 759 (M + 1) ⁺ .

B) Compound 380m obtained in the above a)
g (0.5 mM) in Example 1. deprotect as in b),
After the post-treatment, the aqueous layer was adjusted to pH 13 with 1N KOH.
This solution was added to Diaion HP-20 (25 ml, 15-
220 mg (0.397 mM, yield 79.4%) of the title compound by purification with 30% acetone water elution)
Was obtained as a potassium salt. ¹ H NMR (DMSO- d ₆ ) δ: 2.35 (6
H, s), 2.43 (6H, m), 3.53 (4H,
t), 3.82 (1H, dd), 3.83 (1H, d
d), 3.93 (1H, m), 5.12 (2H, s),
6.89 (1H, s), 7.15 (2H, d), 7.3
3 (2H, d), 7.42 (3H, m), 7.62 (1
H, dd). SIMS ( m / z ): 517 (M + 1) ⁺ .

Example 7 2,6-Dimethyl-3- [2-acetoxy-3- (mol
Folin-4-yl) propoxy] -4- [2 '-(tet
Razol-5-yl) biphenyl-4-yl] methoxy
Pyridine a) Example 6. 140 mg of the compound obtained in a)
(0.185 mM) was dissolved in 0.2 ml of pyridine, 0.1 ml of acetic anhydride was added under ice cooling, and the mixture was stirred at room temperature overnight. 5 ml of cold water was added to the reaction solution, and the mixture was extracted twice with 40 ml of ethyl acetate. The ethyl acetate extract layer was washed with water and diluted brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with hexane and dried to give 2,6-dimethyl-3- [3-acetoxy-3- (morpholin-4-yl) propoxy] -4-.
[2 '-(triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methoxypyridine 144m
g (0.18 mM, yield 97.5%) was obtained. ¹ H NMR (CDCl ₃ ) δ: 2.09 (3H,
s), 2.44 (3H, s), 2.45 (4H, m),
2.47 (3H, s), 2.61 (2H, d), 3.6
0 (4H, t), 4.03 to 4.16 (2H, m),
4.99 (2H, s), 5.25 (1H, m), 6.6
0 (1H, s), 6.93 (6H), 7.15 to 7.3
5 (13H), 7.40 (1H, dd), 7.50 (2
H, m), 7.94 (1H, dd). FDMS ( m / z ): 800 (M ⁺ ).

B) Compound 135m obtained in the above a)
g (0.169 mM) to Example 1. After deprotection and post-treatment in the same manner as in b), Diaion HP-20 (30-4
Purification by elution with 5% acetone) gave 55 mg (0.099 mM, yield 58.6%) of the title compound. ¹ H NMR (DMSO- d ₆ ) δ: 1.19 · 1.
95 (total 3H, each s), 2.28 to 2.38
(8H), 2.63 (2H, br s), 3.48
3.75 (total 4H), 3.75 to 4.10 (3H,
m), 5.15.15.16 (total 2H, each s),
6.93 (1H, br s), 7.13 (2H, br)
d), 7.49 (2H, brd), 7.5 to 7.7 (4
H). SIMS ( m / z ): 559 (M + 1) ⁺ .

Example 8 2,6-Dimethyl-3- (3-diethylamino-2-hi)
Droxypropoxy) -4- [2 '-(tetrazole-
5-yl) biphenyl-4-yl] methoxypyridine a) 2,6-dimethyl-3- (3-diethylamino-
2-hydroxypropoxy) -4 (1 H ) -pyridone 2
70 mg (1 mM) were used in Example 1. By reacting and purifying in the same manner as in a), 2,6-dimethyl-3- (3-diethylamino-2-hydroxypropoxy) -4- [2 '-(triphenylmethyltetrazole-5- Yl) biphenyl-4-yl] methoxypyridine 550 mg (0.739 mM, yield 73.9%)
Got ¹ H NMR (CDCl ₃ ) δ: 1.02 (6H,
t), 2.43 (3H, s), 2.49 (3H, s),
2.45 to 2.70 (6H, m), 3.95 (3H,
m), 4.99 (2H, s), 6.59 (1H, s),
6.93 (6H), 7.15 to 7.35 (13H),
7.39 (1H, dd), 7.49 (2H, m), 7.
93 (1H, dd). SIMS ( m / z ): 745 (M + 1) ⁺ .

B) Compound 335m obtained in the above a)
g (0.45 mM) to Example 1. After deprotection and post-treatment in the same manner as in b), the pH of the aqueous layer was adjusted to 1 and purified by DIAION HP-20 (15% acetone water elution) to give 120 mg (0.223 mM of the title compound). ，
Yield 49.6%) was obtained as the hydrochloride salt. ¹ H NMR (DMSO- d ₆ ) δ: 1.21 (6
H, t), 2.58 (3H, s), 2.60 (3H,
s), 3.16 (6H, m), 4.00 (2H, m),
4.27 (1H, br d), 5.38 (2H, s),
5.97 (1H, br s), 7.19 (2H, d),
7.46 (1H, s), 7.47 (2H, d), 7.5
8 (2H, m), 7.68 (2H, m). SIMS (m / z): 503 (M + 1) ⁺ .

Example 9 2,6-Dimethyl-3- (3-isopropylamino-2)
-Hydroxypropoxy) -4- (2'-carboxybi
Phenyl-4-yl) methoxypyridine a) Example 1. 2,6-dimethyl-3 as in a)
-[3- (Nt-butoxycarbonyl-N-isopropylamino) -2-hydroxypropoxy] -4 (1
H ) -pyridone 354 mg (1 mM) in the presence of sodium hydride, instead of 4′-bromomethyl-2- (triphenylmethyltetrazol-5-yl) biphenyl, methyl 4′-bromomethylbiphenyl-2-carboxylate 336 mg ( 1.1 mM) and post-treated to give 2,6-dimethyl-3- [3- (N
-T-butoxycarbonyl-N-isopropylamino)
-2-Hydroxypropoxy] -4- (2'-methoxycarbonylbiphenyl-4-yl) methoxypyridine 5
40 mg was obtained. ¹ H NMR (CDCl ₃ ) δ: 1.08 to 1.18
(6H, m), 1.48 (9H, s), 2.45 (3
H, s), 2.47 (3H, s), 3.35 (2H, b)
rd), 3.64 (3H, s), 3.92 (2H, b)
rs), 4.03 (2H, m), 5.16 (2H,
s), 6.65 (1H, s), 7.32 to 7.46 (2
H, m), 7.34 (2H, d), 7.45 (2H,
d), 7.53 (1H, dd), 7.85 (1H, d
d). EIMS ( m / z ): 578 (M ⁺ ).

B) 500 m of the compound obtained in the above a)
g (0.865 mM) was dissolved in 2.5 ml of methanol, and 0.33 ml of formic acid and 5N HCl 1.7 under ice cooling.
3 ml was added, and the mixture was stirred at room temperature for 9 hours. PH of reaction solution
Was adjusted to 3-4 with 5N NaOH, and the organic solvent was evaporated under reduced pressure. 5 ml of water was added to the obtained residue to dissolve it,
After washing with 60 ml of diethyl ether, the aqueous layer was concentrated to dryness under reduced pressure. 50 ml of ethanol was added to the residue to remove insoluble matter, and the ethanol extract layer was concentrated to dryness to give a pale yellow oily 2,6-dimethyl-3- (3-isopropylamino-2-hydroxypropoxy)-. 4-
440 mg (crude product) of (2′-methoxycarbonylbiphenyl-4-yl) methoxypyridine was obtained. ¹ H NMR (CDCl ₃ ) δ: 1.25 (3H,
d), 1.29 (3H, d), 2.49 (3H, s),
2.51 (3H, s), 2.90 (1H, dd), 3.
17 (2H, m), 3.74 (3H, s), 3.92
(1H, dd), 4.03 (2H, dd), 4.40
(1H, m), 5.13 (2H, s), 6.71 (1
H, s), 7.34 to 7.50 (2H, m), 7.36
(2H, d), 7.45 (2H, d), 7.56 (1
H, ddd), 7.87 (1H, dd). SIMS ( m / z ): 479 (M + 1) ⁺ .

C) Compound 430m obtained in b) above
g was dissolved in 4.3 ml of ethanol, and 5N NaOH was added.
0.86 ml was added, and the mixture was stirred at 60 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, 5 ml of water was added, and 30 ml of ethyl acetate was added.
It was washed twice with. After the solvent was distilled off under reduced pressure, the pH of the aqueous layer was adjusted to 7.2 with 1N HCl, and DIAION HP-2
0 (40% acetone in water) to give 6 from the title compound (260 mg, 0.56 mM, a).
4.8%). ¹ H NMR (CDCl ₃ ) δ: 1.09 (3H,
d), 1.16 (3H, d), 2.44 (3H, s),
2.47 (1H, d), 2.49 (3H, s), 2.7
6 (1H, d), 3.07 (1H, m), 3.63 (1
H, dd), 3.82 (1H, dd), 4.16 (1
H, m), 4.95 (2H, q), 6.70 (1H,
s), 7.29 to 7.55 (3H, m), 7.40 (2
H, d), 7.50 (2H, d), 7.56 (1H, d
d). SIMS ( m / z ): 465 (M + 1) ⁺

Example 10 2,6-Dimethyl-3- (3-isopropylamino-2)
-Hydroxypropoxy) -4- (4-carboxy) be
Benzyloxypyridine a) As in Example 9, 2,6-dimethyl-3- [3
354 mg (1 mM) of-(Nt-butoxycarbonyl-N-isopropylamino-2-hydroxypropoxy] -4 ( 1H ) -pyridone was added in the presence of sodium hydride.
274 mg of methyl 4-bromomethylbenzoate instead of methyl 4'-bromomethylbiphenyl-2-carboxylate
The colorless oily substance 2,6-dimethyl-3- [3- (Nt-butoxycarbonyl-N-isopropylamino) -2-hydroxypropoxy] -4 was obtained by reacting with (1.1 mM) and post-treatment. 500 mg of-(4-methoxycarbonyl) benzyloxypyridine (0.996 m
M, yield 99.6%). ¹ H NMR (CDCl
₃ ) δ: 1.08 (3H, d), 1.14 (3H,
d), 1.46 (9H, s), 2.43 (3H, s),
2.47 (3H, s), 3.37 (1H, br s),
3.91 (2H, m), 3.93 (3H, s), 4.0
5 (3H, m), 5.16 (2H, s), 6.58 (1
H, s), 7.49 (2H, d), 8.07 (2H,
d). SIMS ( m / z ): 503 (M + 1) ⁺ .

B) Compound 477m obtained in the above a)
g (0.95 mM) in methanol in Example 9.
In the same manner as in b), the reaction product is subjected to elimination (de-Boc) reaction of the t-butoxycarbonyl group with formic acid-hydrochloric acid to give 2,6-dimethyl-3- (3-isopropylamino-2) as a crude product.
380 mg of -hydroxypropoxy) -4- (4-methoxycarbonyl) benzyloxypyridine was obtained. ¹ H NMR (CDCl ₃ ) δ: 1.30 (3H,
d), 1.32 (3H, d), 2.49 (3H, s),
2.49 (3H, s), 3.04 (1H, dd), 3.
18 (2H, m), 3.94 (3H, s), 3.99
(2H, m), 4.39 (1H, m), 5.20 (2
H, s), 6.35 (1H, br s), 6.65 (1
H, s), 7.49 (2H, d), 8.08 (2H,
d). SIMS (m / z): 403 (M + 1) ⁺ . c) The compound 380 mg obtained in b) above is hydrolyzed in ethanol in the same manner as in c) of Example 9 to give 246 mg of the title compound as a white crystalline powder.
(0.634 mM, yield 66.7%) was obtained. ¹ H NMR (DMSO- d ₆ ): 1.17 (3
H, d), 1.19 (3H, d), 2.36 (6H,
s), 2.85 (1H, dd), 3.07 (2H,
m), 3.84 (1H, dd), 3.96 (1H, d
d), 4.15 (1H, m), 5.18 (2H, s),
6.91 (1H, s), 7.48 (2H, d), 8.0
1 (2H, d). SIMS (m / z): 389 (M + 1) ⁺ .

Example 11 3-Methoxy-2,6-dimethyl-4- (3-isopro)
Pyramino-2-hydroxypropoxy) methoxypyri
Gin a) 60% sodium hydride 192 mg (4.8 m
M) was suspended in 3 ml of dried N, N-dimethylformamide and stirred at room temperature for 30 minutes under an argon gas atmosphere. 2,6-dimethyl-3-methoxy-4 was added to this suspension.
612 mg (4 mM) of (1 H ) -pyridone was added, and the mixture was stirred at room temperature for 20 minutes. Then, 373 μl of epichlorohydrin (4.8 mM) was added dropwise to this reaction solution under water cooling,
Stir overnight at room temperature. Furthermore, the same amount of epichlorohydrin was added dropwise, and the mixture was stirred at 60 ° C. for 7 hours. Ethyl acetate was added to the reaction solution, the insoluble material was filtered off, and the mixture was concentrated under reduced pressure. 30 ml of water was added to the obtained residue, and 100 ml of ethyl acetate was added to 2
Extracted twice. The ethyl acetate extract layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (chloroform: ethyl acetate = 20: 1 to 1: 1).
5: 1) to give 3-methoxy-2,6-dimethyl-4- (2,3-epoxy) as a pale yellow oil.
Propoxypyridine 600 mg (2.87 mM, yield 7
1.8%) was obtained. ¹ H NMR (CDCl ₃ ) δ: 2.44 (3H,
s), 2.45 (3H, s), 2.78 (1H, d
d), 2.93 (1H, dd), 3.40 (1H,
m), 3.80 (3H, s), 4.00 (1H, d
d), 4.31 (1H, dd), 6.57 (1H,
s). EIMS ( m / z ): 209 (M ⁺ ).

B) Compound 125m obtained in the above a)
g (0.6 mM) was dissolved in 4 ml of ethanol, 260 μl (3 mM) of isopropylamine was added, and the mixture was stirred at room temperature for 6 hours and further at 60 ° C. for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (chloroform: methanol = 5: 1 to 2:
137 mg of the title compound by purifying in 1).
(0.51 mM, yield 85.0%) was obtained. ¹ H NMR (CDCl ₃ ) δ: 1.09 (6H,
d), 2.44 (3H, s), 2.44 (3H, s),
2.72 to 2.95 (3H, m), 3.78 (3H,
s), 4.03 (3H), 6.57 (1H, s). FDMS ( m / z ): 269 (M + 1) ⁺ .

Example 12 3-Methoxy-2,6-dimethyl-4- [3- [1-
(4-hydroxybenzyl) -1-methoxycarbonyl
Methyl] amino-2-hydroxypropoxy] pyridine Example 11. 226 mg (1.0) of the compound obtained in a)
8 mM) was dissolved in 8 ml of methanol, 625 mg (2.7 mM) of ( L ) -tylosin hydrochloride and 145 mg (2.58 mM) of potassium hydroxide were added, and the mixture was heated at 60 ° C. for 3 hours.
Further, the mixture was stirred at room temperature overnight. The precipitated insoluble matter is filtered off,
The reaction solution was concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 25: 1 to 10: 1) to give 400 mg of the title compound (0.99 mM, yield 91.7%).
Got ¹ H NMR (CDCl ₃ ) δ: 2.43 (6H, b
rs), 2.81 (1H, dd), 3.03 (1H,
dd), 3.46 (1H, m), 3.70 (3H,
s), 3.73 (3H, s), 3.74 (2H, d),
3.97 (3H, m), 6.53, 6.54 (total
1H, each s), 6.68 (1H, d), 6.69
(1H, d), 7.00 (1H, d), 7.01 (1
H, d). SIMS ( m / z ): 405 (M + 1) ⁺ .

Example 13 3-Methoxy-2,6-dimethyl-4- [3- [1-
(4-Hydroxybenzyl) -1-carboxymethyl]
Amino-2-hydroxypropoxy] pyridine 400 mg (0.99 m of the compound obtained in Example 12
M) was dissolved in 8 ml of methanol and 1N NaOH1.
5 ml was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in 5 ml of 50% aqueous methanol. The pH of this reaction solution was adjusted to 10.4 with 1N HCl.
To remove insoluble matter, and then Sephadex LH-
20 (450 ml, eluted with 50% methanol water) to give 189 mg of the sodium salt of the title compound.
(0.458 mM, yield 46.3%) was obtained. ¹ H NMR (D ₂ O) δ: 2.42 (3H, s),
2.45 (3H, s), 2.7 to 3.7 (5H), 3.
77 / 3.80 (total 3H, each s), 3.85
4.25 (3H), 6.78 to 6.92 (3H, m),
7.18 (2H, m). SIMS ( m / z ): 413 (M + 1) ⁺ .

Formulation Example 1 Thoroughly mix the above amounts and tabletize to produce 1000 tablets.

Formulation Example 2 Thoroughly mix the above amounts and fill hard capsules to produce 1000 capsules.

Formulation Example 3 The compound of Example 2 and glucose were dissolved in distilled water for injection,
The total amount is 1000 ml, and this is filtered through a glass filter, and then 1 ml is dispensed into fan pulls to prepare 1000 ampoule formulations.

Pharmacological Test Example 1 The angiotensin II antagonism of the compound represented by the general formula (I) of the present invention was examined by the following in vitro and in vivo experiments.

The angiotensin II antagonistic activity in vitro was determined by using the strength (pA ₂ value) of antagonizing the contraction response to angiotensin II in the isolated rabbit thoracic aorta as an index. The activity in vivo was examined by the inhibitory effect on exogenous angiotensin II pressor in unanesthetized rat. 1-1. Angiotensin II yield in isolated vascular smooth muscle.
Shrinkage-suppressing effect From a male rabbit weighing 2.5 to 3.0 kg, a thoracic aortic helix sample was prepared in accordance with a conventional method, and this sample was aerated 37
It was suspended in a Magnus tube filled with a nutrient solution kept at ℃. The pA ₂ value is H. O. Schild's Method (British Journal of Pharmacology and Chemotherapeutics, Volume 2, 189-20
6 pages, 1947). That is, 10 ^-6
In the range of M to ^{10 -10} M, a dose-response curve of angiotensin II was obtained using a sample treated with the test compound at 3 to 5 doses and a sample without drug treatment, and from the shift of the dose-effect curve of the test compound, log (dose ratio-1) is calculated,
The pA ₂ value was determined from the Schild plot. As a result, for example, the compound of Example 2 and the compound of Example 6 exhibited pA ₂ values of 8.33 and 8.49, respectively. 1-2. Inhibitory activity against exogenous angiotensin II pressor
Spraque-Dawley of use body weight 250~300g
(SD strain) Male rats were cannulated into the femoral artery and femoral vein under anesthesia, and used for the experiment 24 hours or more after the operation. Angiotensin II (0.1 μg) administered via an intravenous catheter under unanesthetized and unrestrained conditions
/ Kg) induced pressor pressure was measured before and after drug administration. As for blood pressure, an arterial catheter was connected to a pressure transducer, and the mean blood pressure was measured invasively. The test compound was uniformly suspended or dissolved in a 0.5% carboxymethylcellulose aqueous solution and orally administered.

As a result, for example, at 3 mg / kg of the compound of Example 2 or Example 6, a significant angiotensin II pressor suppressive action was observed.

Pharmacological Test Example 2 Toxicity Test by Single Dosing The compound of Example 2 was orally administered by gavage to 5-week-old male ddy mice (average body weight: 20 g). as a result,
The LD ₅₀ value of the compound of Example 2 was 1000 mg / kg or more, and at 1000 mg / kg, it showed low toxicity without showing any special symptoms.

[Procedure amendment]

[Submission date] January 8, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] 0003

[Correction method] Change

[Correction content]

A large number of angiotensin converting enzyme inhibitors such as captopril and enalapril have already been developed and clinically used as antihypertensive agents and heart failure therapeutic agents. Furthermore, in recent years, studies have also been conducted on angiotensin II receptor antagonists. Initially, a peptide angiotensin receptor antagonist similar to the structure of angiotensin II was reported (for example, Circulation Research, Vol. 29, p. 673 (1971).
, Journal of Medicinal Chemistry 32, 466, 898, 1366 (1989)
Etc.)), and has not been used clinically. More recently, non-peptide angiotensin II receptor antagonists have been reported. For example, imidazopyridine derivatives (JP-A-62-240683 and EP41586).
6), a substituted imidazole attractant (Japanese Examined Patent Publication Sho 63-6442)
No. 8, JP-A-63-23868, WO91 / 0028
1, WO 91/00277, EP403158 and E
P403159), substituted pyrrole, pyrazole, triazole attractant (JP-A-1-2877071, EP411).
507, EP 41 594 and EP 409332). Furthermore, a quinazolinone derivative (EP4117
66), pyrimidone derivatives (JP-A-3-44377 and EP419048), benzimidazole derivatives (JP-A-3-5464, JP-A-3-27362, JP-A-3-63264 and US Pat. No. 4,880,804).
), An imidazole derivative fused to a 5- to 7-membered ring (EP
400974, EP401030, EP40710
2) and pyridine derivatives (EP453210). As for the pyridine attractant, WO 9 discloses a compound having an alkoxy group at the 3-position of the pyridine ring.
It is only the report of the present inventors disclosed in 1-19697.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display location C07D 401/14 257 8829-4C // (C07D 401/12 213: 00 6701-4C 257: 00) 7433-4C (C07D 401/14 213: 00 6701-4C 257: 00) 7433-4C (72) Inventor Shoro Shimizu 760 Shioka, Chohoku-ku, Yokohama-shi, Kanagawa Meiji Seika Co., Ltd. (72) ) Inventor Jun Jun 760 Meiji Seika Co., Ltd., Meiji Seika Co., Ltd. 760 Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Prefecture (72) Inventor Kazuyuki Fujishima 760 Shimo-oka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Seika Co., Ltd. (72) Inventor Kenichi Kono 760 Meiji Seika Co., Ltd., Meiji Seika Co., Ltd. 760 Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Prefecture (72) Inventor Konno Fusio, 760 Meiji-cho, Kohoku-ku, Yokohama-shi, Kanagawa Prefecture Meiji Candy Co., Ltd. medicine comprehensive within the Institute (72) inventor crane Takashi Oka mechanic Kohoku-ku, Yokohama Morooka-cho, 760 Meiji-made crackers, Ltd. chemicals Research Institute in

Claims (4)

[Claims] 1. A pyridine derivative represented by the following general formula (I) and pharmaceutically acceptable salts thereof. [Chemical 1] (In the formula, R ¹ and R ⁴ may be the same or different and each represents an optionally substituted C _1-6 alkyl group, and R ² is an optionally substituted C _1-6 alkyl group, or a group ^{_{- (CH 2) m-CH}} (oR 5) - (CH 2) n-n
R ⁶ R ⁷ (wherein, ^{R 5} is a hydrogen atom, a substituted _{C 1 to 6} optionally alkyl or _{C 1 to 4} acyl group, ^{R 6} and ^{R 7} may be the same or different, Hydrogen atom, hydroxyl group, and optionally substituted C _{1-6, respectively.}
Alkyl group, C _3-7 cycloalkyl group, optionally substituted C _1-6 alkoxy group, optionally substituted C _2-6 alkoxycarbonyl group, benzyl group, biphenylmethyl group (here, this benzyl A group or a biphenylmethyl group may be substituted with a carboxyl group or a tetrazolyl group), or a group —CHR ⁸ —COO
R ⁹ (wherein R ⁸ represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, a phenyl group, or a benzyl group optionally substituted with a hydroxyl group, and R ⁹ represents a hydrogen atom) Or represents a C _1-6 alkyl group), or R ⁶ and R ⁷ together with the nitrogen atom to which they are attached, optionally containing a nitrogen atom, an oxygen atom or a sulfur atom, May further form a 5- or 6-membered heterocyclic ring which may be condensed with another ring, m represents an integer of 0 to 2, and n represents an integer of 0 to 2) , R ³ is a group-(CH ₂ ) m-CH (OR ⁵ )-(CH ₂ ).
n-NR ⁶ R ⁷ (wherein R ⁵ , R ⁶ and R ⁷ have the same meanings as described above), benzyl group or biphenylmethyl group (wherein the benzyl group or biphenylmethyl group is a carboxyl group or a tetrazolyl group) May be substituted with). ) 2. R ¹ and R ⁴ represent a methyl group, and R ² is a group — (CH ₂ ) m—CH (OR ⁵ ) — (CH ₂ ) n—N.
The pyridine derivative according to claim 1, which represents R ⁶ R ⁷ , and R ³ is a biphenylmethyl group substituted with a carboxyl group or a tetrazolyl group, and a pharmaceutically acceptable salt thereof. 3. An antihypertensive agent comprising the pyridine derivative according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient. 4. A therapeutic agent for heart failure comprising the pyridine derivative according to claim 1 or 2 or a pharmacologically acceptable salt thereof as an active ingredient.