JPH09110691A - Pharmaceutical composition - Google Patents

Abstract

(57) [Abstract] [PROBLEMS] Good absorption in the digestive tract, rapid activation of the active form, and strong angiotensin II antagonism.
The present invention provides a more useful pharmaceutical composition as an antihypertensive drug. SOLUTION: General formula [In the formula, R ¹ is a lower alkyl group, R ² is a lower alkanoyl group, and R ³ and R ⁴ represent a lower alkyl group, or are alkylene groups having 3 to 6 carbon atoms which are bonded to each other at the terminals. A pharmaceutical composition comprising an imidazopyridine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition.

[0002]

BACKGROUND OF THE INVENTION Angiotensin II is a physiologically active peptide consisting of 8 amino acids in which angiotensin I is mainly limited in the pulmonary circulation by angiotensin converting enzyme. It contracts vascular smooth muscle and secretes aldosterone in the adrenal cortex. Increases blood pressure by promoting it. Therefore, it is known that an angiotensin II antagonist can be used as a therapeutic agent for hypertension.

As an antihypertensive drug based on the above-mentioned mechanism of action, for example, JP-A-5-279361 discloses 2-lower alkyl-5-lower alkanoyl-3- (substituted biphenylyl) methyl-4,5,6,7-tetrahydro. Imidazo [4,5
-C] Pyridine-4-carboxylic acid and other imidazopyridine derivatives or pharmacologically acceptable salts thereof are described.

However, the above-mentioned known compounds have poor absorption in the gastrointestinal tract when the drug is orally administered, or even if the absorption in the gastrointestinal tract is high, the absorbed compound is unlikely to be an active substance in plasma. Because it was a thing,
Excellent angiotensin II, which is well absorbed in the digestive tract and, immediately after absorption, becomes active form in plasma
A drug that exerts an antagonistic effect has been desired.

[0005]

DISCLOSURE OF THE INVENTION The present invention provides a pharmaceutical composition containing a novel imidazopyridine derivative as an active ingredient, which is well absorbed in the digestive tract, rapidly becomes an active substance, and has a strong angiotensin II antagonistic action. It is a thing.

[0006]

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

[0007]

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[In the formula, R ¹ represents a lower alkyl group;
² represents a lower alkanoyl group, R ³ and R ⁴ represent a lower alkyl group, or they are bonded to each other at their terminals and have 3 carbon atoms.
Forming an alkylene group of ~ 6] or an imidazopyridine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION Among the imidazopyridine derivatives [I] which are the active ingredients of the present invention, 2-n-propyl-5-acetyl-3--3- is particularly preferable as a compound having a medicinal effect.
[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine-4-carboxylic acid. (3
-Pentyl) oxycarbonyloxymethyl ester and 2-n-propyl-5-acetyl-3- [2 '-(1
H-tetrazol-5-yl) biphenyl-4-yl]
Methyl-4,5,6,7-tetrahydroimidazo [4,4
5-c] pyridine-4-carboxylic acid / cyclohexyloxycarbonyloxymethyl ester and the like can be mentioned.

The imidazopyridine derivative [I], which is the active ingredient of the present invention, can be used in medicinal use either in a free form or in the form of a pharmacologically acceptable salt thereof. As the pharmacologically acceptable salt, for example, hydrochloride can be preferably used because of its excellent crystallinity.

The imidazopyridine derivative [I], which is the active ingredient of the present invention, may have optical isomers based on an asymmetric carbon atom, but the active ingredient of the present invention includes both of these optical isomers and mixtures thereof. It includes.

The imidazopyridine derivative [I] which is the active ingredient of the present invention is suitable for oral administration,
Of course, it can also be administered parenterally (for example, intravenously, intramuscularly, subcutaneously).

The dosage form for oral administration may be solid preparations such as tablets, granules, capsules and powders,
It may be a liquid preparation such as a solution, suspension or emulsion, and can be used as a pharmaceutical preparation together with a pharmaceutical carrier suitable for oral administration. Examples of such pharmaceutical carriers include binders (syrup, gum arabic, gelatin, sorbit,
Tragant, polyvinylpyrrolidone, etc.), excipients (lactose, sugar, cornstarch, potassium phosphate, sorbit, glycine, etc.), lubricants (magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrants (biration starch) Etc.) or a wetting agent (sodium lauryl sulfate, etc.) or any other conventional one can be used.

On the other hand, the dosage form for parenteral administration is preferably an injection or drip injection using, for example, distilled water for injection, physiological saline, an aqueous glucose solution or the like.

Although the dose varies depending on the age, weight, condition of the patient or the degree of disease, the daily dose is usually 0.01 to 10 mg / kg in the case of oral administration,
Particularly, 0.03 to 5 mg / kg, in the case of parenteral administration, 0.002 to 1 mg / kg, particularly 0.01 to 5 mg / kg.
It is preferably 0.3 mg / kg.

The imidazopyridine derivative [I], which is the active ingredient of the present invention, has the general formula [II]

[0017]

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[Wherein Y represents a hydrogen atom or a protecting group, and other symbols have the same meanings as described above], a salt thereof or a reactive derivative at the carboxyl group thereof and the general formula [III].

[0019]

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[In the formula, X represents a reactive residue, and other symbols have the same meanings as described above. ] When Y is a protecting group, it can be produced by removing the protecting group from the product after the reaction with the compound represented by

The reaction of the compound [II], a salt thereof or a reactive derivative of the carboxyl group thereof with the compound [III] can be carried out according to a conventional method.

For example, the reaction of the free compound [II] or a salt thereof with the compound [III] is carried out in a suitable solvent (for example, di-lower alkylformamide) under cooling to heating.
It can be carried out in the presence of a deoxidizing agent (for example, an alkali metal carbonate such as potassium carbonate).

When the compound produced by the above reaction has a protecting group, the protecting group can be easily removed by a conventional method. Examples of the protecting group include a trityl group and the like.

When the compound [I] thus obtained is a racemate, the racemic compound [I] can be easily optically resolved according to a conventional method.

In the present specification, the lower alkyl group represents one having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and the lower alkanoyl group represents 2 to 6 carbon atoms, preferably 2 carbon atoms. ~ 4 is represented.

The alkyl group having 1 to 4 carbon atoms includes methyl, ethyl, n-propyl, isopropyl and n.
-Butyl, isobutyl, sec-butyl, tert-butyl group, etc., and the alkanoyl group having 2 to 4 carbon atoms includes acetyl, propionyl, butyryl, isobutyryl group, etc., and alkylene group having 3 to 6 carbon atoms. Examples thereof include a trimethylene group, a tetramethylene group, a pentamethylene group and a hexamethylene group.

Experimental Example 1 (Angiotensin II pressor suppressive action in anesthetized dogs)
Normotensive dogs (weight 12.0 to 16.8 kg; 1 group 2)
1% Nikkol after anesthesia with pentobarbital
A sample 0.3 mg / kg dissolved or suspended in the solution was intraduodenally administered. Angiotensin II was administered intravenously 15 minutes, 30 minutes and 60 minutes after the administration of the sample,
The antihypertensive effect of the specimen on angiotensin II pressor was evaluated by the pressor inhibition rate (%) calculated according to the following equation.

[0028]

(Equation 1)

The results are shown in Table 1 below, when the pressurization suppression rate (%) was the maximum.

[0030]

[Table 1]

Production Example 1 (1) 2-n-propyl-5-acetyl-3- [2'-
(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine-4-carboxylic acid / methyl ester / 1/2 fumarate 300 g was suspended in a mixed solution of 2 liters of chloroform and 1 liter of water, and 50 g of sodium hydrogen carbonate was added to neutralize the mixture, and 2-n-propyl-5-
Acetyl-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-4,5,6,7-
270 g of tetrahydroimidazo [4,5-c] pyridine-4-carboxylic acid / methyl ester are obtained.

Then, 270 g of this product was added to chloroform 1.
Dissolve in 5 liters, add 65 g of triethylamine and 158 g of trityl chloride, and stir at room temperature overnight. After the reaction solution was washed and dried, the solvent was distilled off and recrystallized from an ethanol-ether mixed solution to give 2-n-propyl-5-acetyl-3- [2 '-(1-trityl-1H-tetrazole-5. -Yl) biphenyl-4-yl] methyl-4,
325.8 g of 5,6,7-tetrahydroimidazo [4,5-c] pyridine-4-carboxylic acid / methyl ester is obtained.

M. P. 188-189 ° C (decomposition) FAB-MS (m / z): 742 (M + H), 243
(Base) NMR (CDCl ₃ ) δ: 0.85 and 0.96 (both t, J = 7.3, 3H in total), 1.73 and 2.
20 (both s, 3H in total).

(2) 318 g of this product was suspended in a mixed solution of 2 liters of ethanol and 200 ml of tetrahydrofuran, a solution of 20.0 g of sodium hydroxide in 20 ml of water was added, and the mixture was stirred overnight at room temperature. Then, the solvent is distilled off, 2 liters of chloroform is added, and after washing and drying, the solvent is distilled off. The residue was triturated with ether to give 2-n-propyl-
5-Acetyl-3- [2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl] methyl-4,5,6,7-tetrahydroimidazo [4,5-
c] 319 g of pyridine-4-carboxylic acid are obtained.

FAB-MS (m / z): 728 (M +
1), 243 (base) NMR (DMSO-d6) δ: 0.69 and 0.79
(Both t, J = 7.4, total 3H), 1.56 and 2.02 (both s, total 3H).

(3) This product (2.92 g) was dissolved in dimethylformamide (30 ml), potassium carbonate (0.83 g) was added, and the mixture was ice-cooled, and 3-pentyloxycarbonyloxymethyl chloride (0.87 g) in dimethylformamide (5 ml) was added dropwise. To do. After the dropping, the temperature is returned to room temperature and the mixture is stirred overnight. After adding ethyl acetate, washing and drying, the solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 1: 1) to give 2-n-propyl-5-. Acetyl-3- [2 '-(1-trityl-
1H-tetrazol-5-yl) biphenyl-4-yl] methyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine-4-carboxylic acid-3-pentyloxycarbonyloxymethyl ester 2. 95 g are obtained as caramel.

FAB-MS (m / z): 872 (M +
H), 243 (base) NMR (CDCl ₃ ) δ: 4.60 (1H, quin
t), 5.18 (2H, ABq), 5.61 (2H, A
Bq).

(4) To 2.92 g of this product was added 20 ml of 85% formic acid under ice cooling, and the mixture was returned to room temperature and stirred for 1 hour. The reaction solution is diluted with ice water, insoluble materials are filtered off and washed. Then, the mixture is neutralized with saturated sodium hydrogen carbonate under ice cooling, extracted with chloroform, washed and dried, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (elution solvent; chloroform: methanol = 50: 1) to give 2-n-
Propyl-5-acetyl-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-
4,5,6,7-tetrahydroimidazo [4,5-c]
2.09 g of pyridine-4-carboxylic acid-3-pentyloxycarbonyloxymethyl ester is obtained as a caramel. Further, 0.50 g of this product is dissolved in ethanol, 27% hydrogen chloride-ethanol solution is added, and the solvent is distilled off under reduced pressure. The residue was recrystallized from an ethanol-ether mixed solution to give 2-n-propyl-5-acetyl-3-
[2 '-(1H-Tetrazol-5-yl) biphenyl-4-yl] methyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine-4-carboxylic acid-3-
0.31 g of pentyloxycarbonyloxymethyl ester hydrochloride is obtained.

M. P. : 198-200 ° C (decomposition) FAB-MS (m / z): 630 (M + H), 207.
(Base) NMR (DMSO-d6) δ: 4.54 (1H, qui)
nt).

Production Examples 2-3 (1) 2-n-propyl-5-obtained in Production Example 1- (2)
Acetyl-3- [2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl] methyl-
4,5,6,7-tetrahydroimidazo [4,5-c]
By treating pyridine-4-carboxylic acid and the corresponding compound [III] in the same manner as in Production Example 1- (3), the following second
The compounds shown in the table are obtained.

[0041]

[Table 2]

(2) By treating the above product in the same manner as in Production Example 1- (4), the compounds shown in Table 3 below are obtained.

[0043]

[Table 3]

Reference Example 1 Methyl chloroformate 25.0 g, sulfuryl chloride 35.
7 g and α, α'-azobisisobutyronitrile 100
The mg mixture is heated to reflux for 8 hours. Hexane 1 after cooling
Dilute with 50 ml and cool to 3-pentanol 24.0
Add g.

Pyridine (42.0 g) was added dropwise over 20 minutes under ice-cooling, and the mixture was stirred overnight at room temperature. After the reaction, 200 ml of hexane is added, washed with water, dried and filtered, and then the solvent is distilled off.

The residue was distilled under reduced pressure to obtain 26.3 g of 3-pentyloxycarbonyloxymethyl chloride.

Bp 102-105 ° C. (34 mmH
g) Reference Examples 2 to 3 Methyl chloroformate, sulfuryl chloride and the starting compound are treated in the same manner as in Reference Example 1 to obtain the compounds shown in Table 4 below.

[0048]

[Table 4]

[0049]

INDUSTRIAL APPLICABILITY The imidazopyridine derivative [I] and the pharmaceutically acceptable salt thereof, which are the active ingredients of the present invention, have a superior angiotensin II antagonism and / or natural hypertension as compared with conventionally known imidazopyridine derivatives. Since it has an antihypertensive effect in the developing rat (SHR), the pharmaceutical composition of the present invention provides hypertension, nephritis, diabetic nephritis, primary aldosteronism, arteriosclerosis, dementia, cerebral circulation failure, chronic heart failure or angina. It can be used as a pharmaceutical composition for the treatment and / or prevention of diseases.

Further, the imidazopyridine derivative [I] and its pharmacologically acceptable salt, which are the active ingredients of the present invention, are well absorbed in the digestive tract and rapidly become active bodies to give high blood concentrations. It can be safely and appropriately used especially as an oral preparation.

The imidazopyridine derivative [I] and its pharmaceutically acceptable salts, which are the active ingredients of the present invention, are:
Low toxicity and high safety. For example, 2-
n-Propyl-5-acetyl-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-4,5,6,7-tetrahydroimidazo [4,5-
c] pyridine-4-carboxylic acid-3-pentyloxycarbonyloxymethyl ester-hydrochloride 1800 mg
In the case of oral administration of 1 kg / kg, no death was observed even after 14 days.

Continuation of front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical indication location A61K 31/435 AEQ A61K 31/435 AEQ C07D 471/04 107 C07D 471/04 107E

Claims (6)

[Claims] 1. A compound of the general formula [I] [In the formula, R ¹ represents a lower alkyl group, R ² represents a lower alkanoyl group, R ³ and R ⁴ represent a lower alkyl group, or an alkylene group having 3 to 6 carbon atoms which is bonded to each other at the terminals. A pharmaceutical composition comprising an imidazopyridine derivative or a pharmaceutically acceptable salt thereof as an active ingredient. 2. 2-n-propyl-5-acetyl-3-
[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine-4-carboxylic acid. (3
-Pentyl) oxycarbonyloxymethyl ester or a pharmaceutical composition comprising a pharmacologically acceptable salt thereof as an active ingredient. 3. 2-n-propyl-5-acetyl-3-
[2 ′-(1H-Tetrazol-5-yl) biphenyl-4-yl] methyl-4,5,6,7-tetrahydroimidazo [4,5-c] pyridine-4-carboxylic acid cyclohexyloxycarbonyloxymethyl A pharmaceutical composition comprising an ester or a pharmaceutically acceptable salt thereof as an active ingredient. 4. The pharmaceutical composition according to claim 1, 2 or 3, wherein the pharmaceutically acceptable salt is hydrochloride. 5. The pharmaceutical composition according to claim 1, which is an angiotensin II antagonist. 6. Hypertension, nephritis, diabetic nephritis, primary aldosteronism, arteriosclerosis, dementia, cerebral circulation failure,
The pharmaceutical composition according to claim 1, which is a therapeutic and / or preventive agent for chronic heart failure or angina.