KR0184340B1 - N-substituted heterocyclic compounds and process for the preparation thereof - Google Patents

Abstract

1. The technical field to which the invention described in the claims belongs.

Organic Chemicals and Pharmacy

2. The technical field to be solved by the invention

Development of Improved Angiotensin II Antagonists

3. Summary of how to solve the technical problem

And a compound represented by the general formula (I) (wherein, R ¹ is hydrogen, halogen, C _2-5 alkoxy or unsubstituted, the C _2-5 alkyl substituted with halogen, amine, alcohol, nitrile or carbonyl, R ² is carboxy; nitrile; aminocarboxy: aminosulfate unsubstituted or substituted with C _1-5 alkyl, or C _1-5 alkoxy: or C-linked tetrazole:

4. Important uses of the invention

Treatment of central nervous system diseases and cardiovascular diseases

Description

N-substituted heterocyclic compound and preparation method thereof

The present invention relates to a novel N-substituted heterocyclic compound having an antagonistic action on angiotensin II, a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition containing the same.

Angiotensin II is a biologically active product of the Lenin-Angiotensin system, exhibits potent blood pressure boosting activity and other physiological effects on the central nervous system and kidneys. Therefore, compounds that inhibit the action of angiotensin II are useful for the treatment of symptoms of central nervous system, cardiovascular symptoms such as hypertension and heart failure. Although many angiotensin II inhibitors are known so far, the development of new angiotensin II inhibitors that can replace them from a pharmacological point of view is still required, and an effective synthesis method in terms of their production yield is still required.

Accordingly, an object of the present invention is to develop a novel angiotensin II inhibitor with improved pharmacological efficacy in accordance with the above-mentioned reality.

The present invention provides novel N-substituted heterocyclic derivatives of the general formula (I) having excellent angiotensin II antagonistic activity:

Wherein, R ¹ is hydrogen, halogen, C _2-5 alkoxy or unsubstituted, the C _2-5 alkyl substituted with halogen, amine, alcohol, nitrile or carbonyl, R ² is carboxy; Nitrile; Aminocarboxy: aminosulfate unsubstituted or substituted with C _1-5 alkyl, or C _1-5 alkoxy: or C-linked tetrazole.

The present invention further provides a compound of formula (I) or a medicament thereof by reacting a compound of formula (II) with a compound of formula (II) and optionally reacting with an acid or a base to form a pharmaceutically acceptable salt thereof. Provided are methods for preparing the academically acceptable salts.

Wherein R ¹ and R ² are as described above.

The reaction of the compound of general formula (II) with the compound of general formula (III) is generally carried out at room temperature, but if necessary, at any temperature below 140 ° C., any acid such as sodium carbonate, potassium carbonate, sodium hydroxide, sodium hydrate or triethylamine. It may be carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, tetrahydrofuran in the presence of a binder. Optionally, if necessary, the protecting group may be removed, and purification by pH, crystallization by solvent, or chromatography using silica gel may be performed.

In the process of the present invention, for example, an acid such as hydrochloric acid or formic acid may be used to remove a protecting group.

Compounds of the present invention also include salts with acids or bases, and acids or bases that may be used in the present invention include all organic or inorganic acids or bases that are well known in the art of organic chemistry.

Compounds of the general formula (II) used as starting materials in the preparation method of the compound of the general formula (I) according to the present invention are known 5- (4-methoxyphenylmethyl) -oxy-2-hydroxymethyl-4H- It can be obtained by dissolving pyran-4-one in acetone, adding Jones reagent, adding isopropyl alcohol, stirring, and then dissolving the product in dimethylformamide to add ethylenediamine and heat stirring.

Compounds of general formula (III), which are other starting materials used in the process of the present invention, can be obtained by synthesis according to the known methods described in US Pat. No. 4,870,186.

The present invention also encompasses pharmaceutical compositions used to treat diseases caused by the action of angiotensin II by mixing a compound of formula (I) with a pharmaceutically acceptable carrier.

The pharmaceutical compositions of the present invention may be administered orally or parenterally, for example in the form of tablets or capsules for oral administration, such as binders (eg starches) and wetting agents (eg sodium lauryl sulfate). It may contain conventional excipients. Parenteral can be injected or injected intramuscularly, intranasally, intraperitoneally, or the like.

The compound of general formula (I) of the present invention was excellent in terms of the contraction at the angiotensin II concentration of 3 × 10 ⁻⁸ M at which the maximum contraction occurred, E _max and the contraction in the tissue to which the drug was applied, in terms of% of E _max . It has been shown to exhibit a contraction inhibitory effect.

The following examples are merely intended to illustrate the invention and are not intended to limit the invention.

Example 1 (a)

[5- (4-methoxyphenylmethyl) -oxy-2-carboxylic-4H-pyran-4-one]

5 g (19 mmol) of 5- (4-methoxyphenylmethyl) -oxy-2-hydroxymethyl-4H-pyran-4-one was dissolved in 100 ml of acetone. The mixture was cooled to 5 ° C. and 15.4 mL of Johnson's reagent at a concentration of 1.4 M was slowly added. After stirring overnight at room temperature, 25 ml of isopropyl alcohol was added and the mixture was stirred for about 1 hour and filtered. The filtrate was concentrated, the container solvent was removed, and a solid precipitated. The solid was filtered to obtain 2.95 g of an off-white title compound.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.4 (s, 1H), 7.5 to 7.3 (m, 2H), 7.1 to 6.8 (m, 3H), 5.0 to 4.8 (s, 2H), 3.77 (s , 3H)

Example 1 (b)

[6- (4-methoxyphenylmethyl) -oxy-piperazino [1,2-a] pyridine-2,5-dione]

5 g (18.1 mmol) of 5- (4-methoxyphenylmethyl) -oxy-2-carboxylic-4H-pyran-4-one obtained in Example 1 (a) was dissolved in 100 ml of dimethylformamide. The mixture was cooled to 5 ° C., 6.05 mL (90.5 mmol) of ethylenediamine was added thereto, and the resultant was heated and stirred at a temperature of less than 140 ° C. for about 7 hours. The reaction product was concentrated, extracted with ethyl acetate and water, and concentrated. Then, 2.6 g of the titled compound was obtained by column chromatography (5: 1 acetonitrile: water).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.74 (s, 1H), 7.73 (s, 1H), 7.5 to 7.4 (m, 2H), 7.0 to 6.8 (m, 2H), 4.9 (s, 2H ), 4.1 to 4.0 (m, 2H), 3.5 to 3.3 (m, 2H)

Example 2

[1- (2'-Tetrazolylbiphenylmethyl) -6-hydroxy-piperazino [1,2-a] pyridine-2,5-dione]

3.5 g (11.6 mmol) of 6- (4-methoxyphenylmethyl) -oxy-pyrerazino [1,2-a] pyridine-2,5-dione and 2-triphenyl obtained from Example 1 (b) 9.6 g (17.2 mmol) of methyl-5- (4'-bromomethylbiphenyl-2-yl) -2H-tetrazole and 3.1 g (22.4 mmol) of potassium carbonate were mixed in 35 ml of dimethylformamide. After warming, the mixture was stirred for 5 hours at a temperature of less than about 100 ℃, concentrated and extracted with ethyl acetate and water. The organic layer was concentrated to obtain an oily intermediate using column chromatography (3: 1 ethyl acetate: water). The oily intermediate was dissolved in 50 ml of methanol, and 3 to 4 drops of concentrated hydrochloric acid were added and stirred for about 2 hours. The reaction solution was concentrated, separated using column chromatography (chloroform: methanol of 5: 1), and concentrated to obtain 700 mg of the target compound as a solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.74 (s, 1H), 7.8 to 6.8 (m, 9H), 4.9 (s, 2H), 4.2 to 4.0 (m, 2H), 3.5 to 3.3 (m , 3H)

[Pharmacological efficacy test]

After striking the rabbit's larynx and stunning it, the carotid artery was cut and blood was lost. The chest portion was cut and the descending aorta was quickly removed to remove adipose tissue and cut into 3-4 mm lengths to obtain a helical strip. Sodium chloride 118 mmol / L, sodium bicarbonate 25 mmol / L, glucose 10 mmol / L, potassium chloride 4.7 mmol / L, calcium chloride 2.5 mmol / L, magnesium sulfide heptahydrate 1.2 5 mmol / L, potassium potassium phosphate 1.2 mmol / L and EDTA 0.001 mmol / L, containing 5% Krebs-bicarbonate solution, passed through 95% oxygen, 5% carbon dioxide Hang on isotonic tranducer in ml of organ tissue. The equilibrium is maintained for 1 hour while the sacred buffer is continuously changed 5 to 6 times with 1.0 g of resting tension.

To examine the drug effect, an excipient (dimethylsulfoxide 1%, control) or test substance was added, and after 10 minutes, angiotensin II was gradually added from 3 × 10 ⁻¹⁰ molarity to obtain a concentration-response curve. After washing with plenty of fresh buffer solution and maintaining equilibrium for 1 hour, potassium chloride (122.8 mM) was added to cause contraction. Based on this, the contraction by angiotensin II at each concentration was expressed as% by potassium chloride. The percentage contraction by angiotensin II at a concentration of 3 × 10 ⁻⁸ molar concentration, E _max , which causes the maximum contraction by angiotensin II, was defined as E _max , and the contraction by angiotensin II in other tissues to which drug was applied was expressed in terms of relative to E _max . . The angiotensin II antagonism of the test substance was determined by obtaining the EC ₅₀ of angiotensin II from the final concentration-response curve thus obtained and the results are reported in Table 1 below.

From the above results, it can be seen that the compound of the present invention has excellent antagonistic activity against angiotensin II.

Claims (2)

Compound of Formula (I) or a pharmaceutically acceptable salt thereof: Wherein R ² is a C-linked tetrazole. A process for preparing a compound of formula (I) or a salt thereof by reacting a compound of formula (II) with a compound of formula (III): Wherein R ² is a C-linked tetrazole.