KR0181215B1 - N-substituted hetero compound, and its preparation process - Google Patents

Abstract

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

Organic compounds and pharmaceuticals.

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

Compound (I) represented by the following general formula (I), wherein R ₁ is C ₁ to C ₆ alkyl or C ₂ to C ₆ alkene, R ₂ is hydroxy, ethoxy or methoxy, R ₃ is C Bonded tetrazole, carboxy or dialkylaminosulfate, X is methylene substituted with ethoxymethene, methoxymethene, ethoxyoxime or methoxyoxime; or unsubstituted or substituted with one or more methyl, ethyl or benzyl Unsaturated ethene; or ( to be);

4. Important uses of the invention

Treatment of central nervous system diseases and cardiovascular diseases.

Description

N-substituted hetero compound and preparation method thereof

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

Angiotensin II is a biologically active product of the Lenin-Angiotensin system and has potent blood pressure boosting activity and other physiological effects on the central nervous system and kidneys. Thus, compounds that inhibit the action of angiotensin II are useful for the treatment of symptoms of central nervous system, renal vascular symptoms such as hypertension and heart failure. Many angiotensin II inhibitors are known so far, but from a pharmacological point of view, there is still a need for the development of new angiotensin II inhibitors that can be substituted, as well as effective synthesis methods in terms of their production yield.

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 heterocompound derivatives of the general formula (I) having excellent angiotensin II antagonistic activity:

Wherein R ₁ is C ₁ to C ₆ alkyl or C ₂ to C ₆ alkene, R ₂ is hydroxy, ethoxy or methoxy, R ₃ is C-linked tetrazole, carboxy or dialkylaminosulfate , X is methylene substituted with ethoxymethene, methoxymethene, ethoxyoxime or methoxyoxime; Or unsaturated ethene unsubstituted or substituted with one or more methyl, ethyl or benzyl; or ( )to be.

Geometric isomers that may be present when X of the compounds of the invention are unsubstituted or substituted ethene.

In addition, the present invention reacts a compound of formula (II) with a compound of formula (III) and optionally inverts the groups of R ₂ in the compound of formula (I), removes a protecting group, Provided is a method of preparing a compound of formula (I) and a pharmaceutically acceptable salt thereof by reacting with a base to form a salt.

Wherein R ₁ , R ₂ , R ₃ and X are as defined above.

The reaction of the compound of formula (II) and the compound of formula (III) according to the present invention may be carried out by heat stirring in an inert solvent such as toluene or acetonitrile.

Interconversion of the R ₂ groups in the compounds of formula (I), which may be carried out in any process in the process of the invention, is for example hydrolyzed with sodium hydroxide, or as conventional methoxy or ethoxylation processes.

In the process of the invention, for example, an acid such as hydrochloric acid or formic acid (preferably 88% formic acid) can be used for the removal of the 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 formula (II) used as starting materials in the process for the preparation of compounds of formula (I) according to the invention are described in J. Med. Chem. 1993, 36, 2676-2688, alkylamine can be synthesized by adding the compound of formula (IV) and tetrahydrofuran (THF) according to the reaction scheme described below and stirring at room temperature:

Another starting material used in the process of the invention is the compound of formula (III), which is described in J. Med. Chem. 1993, 36, 2676-2688 can be synthesized according to the known method.

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 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 the general formula (I) of the present invention exhibits excellent contraction as a result of converting the contraction at an angiotensin II concentration 3 × 10 ⁻⁸ M at which the maximum contraction occurs to E _max and the contraction rate in% to E _mx in the tissue to which the drug is applied. Proven to have an inhibitory effect.

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

Example 1 (a)

N-propyl-N- [2 '-(1-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

10 g (17.8 mmol) of 2-triphenylmethyl-5- (4'-methylbiphenyl-2-yl) -2H-tetrazole and 58.6 ml of propylamine were added to 80 ml THF and stirred at room temperature for 2 hours. The reaction solution was distilled under reduced pressure, dissolved in 100 ml of chloroform and washed with dilute potassium hydroxide solution. After drying over potassium carbonate and concentrating again, crystallization with ethyl acetate and hexane gave 6.5 g of the title compound.

¹ H NMR (CDCl ₃ ; δ) 0.84 (3H, t), 1.56 (2H, m), 3.6 (2H, t), 3.76 (2H, s), 6.8 to 7.6 (23H, m).

Example 1 (b)

N-propyl-N- (2-ethoxycarbonyl-ethano-1-yl) -N- [2 '-(1-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-yl Methyl] -amine

2 g (3.73 mol) of N-propyl-N- [2 '-(1-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine obtained from Example 1 (a) above ) And 2.4 g (14.9 mmol) of diethylmalonate were added to 50 ml of toluene and heated and stirred for 2 hours. The reaction solution was distilled under reduced pressure, and then separated by column chromatography (ethyl acetate: hexane of 1: 3) to obtain 2.32 g of the target compound.

¹ H NMR (CDCl ₃ ; δ) 0.86 (3H, t), 1.24 (3H, t), 1.60 (2H, m), 3.14 to 3.30 (2H, m), 3.52 (2H, d), 4.12 (2H, m), 4.62 (2H, d), 6.42-7.48 (23H, m).

Example 1 (c)

N-propyl-N- (2-ethoxycarbonyl-ethano-1-yl) -N- [2 '-(1-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-yl Methyl] -amine

N-propyl-N- (2-ethoxycarbonyl-ethano-1-yl) -N- [2 '-(1-triphenylmethyl-2H-tetrazol-5 obtained from Example 1 (b) above 1 g (1.53 mmol) of -yl) biphenyl-4-ylmethyl] -amine was added to 14 ml of 88% formic acid and 10 ml of dichloromethane, followed by stirring at room temperature for 3 hours. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove formic acid, and 50% formic acid was added to the residue to solidify triphenylmethanol. The solution removed by filtration of triphenylmethanol was further distilled under reduced pressure, and water was added thereto. The aqueous solution was extracted with chloroform and dried over sodium sulfate to obtain 520 g of the title compound.

¹ H NMR (CDCl ₃ ; δ) 0.96 (3H, t), 1.28 (3H, t), 1.64 (2H, m), 3.28 (2H, t), 3.38 (2H, d), 4.12 (2H, m) , 4.48 (2H, d), 6.82-7.92 (8H, m).

Example 2

Ethyl (1-ethoxy-2-ethoxycarbonyl) prop-1-fe-3-noate

To 5 g (31.2 mmol) of diethylmalonate, 10.3 ml of triethoxymethane and 2.9 ml of acetylacetate were added and stirred for 12 hours. After the reaction was concentrated under reduced pressure and separated by column chromatography to obtain 3.5g of the title compound.

¹ H NMR (CDCl ₃ ; δ) 1.08 (6H, t), 3.96 (3H, s), 4.06 (2H, q), 4.18 (2H, q).

Example 3

N-propyl-N- (2-carboxy-ethano-1-yl) -N- [2 '-(2H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

N-propyl-N- (2-ethoxycarbonyl-ethano-1-yl) -N- [2 '-(2H-tetrazol-5-yl) biphenyl- obtained from Example 1 (c) above. 260 mg (0.638 mmol) of 4-ylmethyl] -amine were added to 2 ml of 2.5 hydroxide sodium hydroxide and 6 ml of ethanol, followed by heat stirring for 2 hours. The reaction solution was distilled under reduced pressure to remove the reaction solvent, and the filtrate was adjusted to pH 2 to 3 with 50% formic acid and extracted with ethyl acetate to obtain 80 mg of the title compound.

1 H NMR (CDCl ₃ ; δ) 0.62 (3H, m), 0.98 (2H, m), 3.00 (2H, m), 3.5 (2H, s), 4.24 (2H, s), 6.8 to 7.8 (8H, m ).

Example 4

N-ethyl-N- (2-carboxy-ethano-1-yl) -N- [2 '-(2H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

N-ethyl-N- (2-ethoxycarbonyl-ethano-1-yl, using a method similar to Examples 1 (a), (b), and 1 (c) except that ethylamine is used 400 mg of) -N- [2 '-(2H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine were obtained, and 150 mg of the dual compound was taken and the title compound was prepared using a method similar to that of Example 3. 70 mg were obtained.

¹ H NMR (CDCl ₃ ; δ) 0.92 (3H, t), 2.68 (2H, m), 3.54 (2H, s), 4.18 (2H, s), 6.8 to 7.6 (8H, m).

Example 5

N-butyl-N- (2-carboxy-ethano-1-yl) -N- [2 '-(2H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine

N-butyl-N- (2-ethoxycarbonyl-ethano-1- using a method similar to Examples 1 (a), 1 (b), and 1 (c) except that butylamine is used 450 mg of 1) -N- [2 '-(2H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine were obtained, and 200 mg of the dual compound was taken and titled using a method similar to that of Example 3. 90 mg of compound was obtained.

¹ H NMR (DMSO-d ₆ ; δ) 0.87 (3H, m), 1.01 (2H, t), 1.48 (2H, m), 3.21 (2H, m), 3.49 (2H, m), 4.62 (2H, d), 7.01 to 7.25 (4H, m), 7.6 to 7.81 (4H, m).

Example 6

N-propyl-N- (3-ethoxy-2-ethoxycarbonyl-pro-2-phen-1-noyl) -N- [2 '-(2H-tetrazol-5-yl) biphenyl-4 Monomethyl] -amine

A method analogous to Examples 1 (a), 1 (b), and 1 (c) using ethyl 1-ethoxy-2-ethoxycarbonyl-pro-1-fe-3-noate and propylamine 84 mg of the title compound was obtained.

¹ H NMR (DMSO-d ₆ ; δ) 0.82 (3H, t), 1.26 (6H, q), 1.54 (2H, m), 3.48 (2H, m), 3.85 (2H, s), 4.18 (4H, q), 6.42 (1 H, t), 6.5 to 7.5 (8 H, m).

Example 7

(E) -N-propyl-N- (3-carboxy-2-phen-1-noyl) -N- [2 '-(2H-tetrazol-5-yl) biphenyl-4ylmethyl] -amine

0.24 g (19 mmol) of fumaric acid, 0.28 g (19 mmol) of 1-hydroxybenzotriazole hydrate, and 0.42 g (19 mmol) of dicyclohexyl diimide were placed in 50 ml of acetonitrile and stirred at room temperature for 2 hours. 1 g (18 mmol) of N-propyl-N- [2 '-(1-triphenyl-2H-tetrazol-5-yl) biphenyl-4ylmethyl] -amine was added to the reaction solution, and the mixture was sufficiently stirred for 12 hours. After distillation under reduced pressure, the solvent was removed. The residue was dissolved in 40 ml of ethyl acetate, washed with distilled water and dilute brine, respectively, concentrated and separated by column chromatography (9: 1 dichloromethane: ethanol). (E) -N-propyl-N- [3-carboxy-pro 160 mg of -2-fe-1noyl) -N- [2 '-(1-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine were obtained. This product was added to a methanol solution of 15 normal concentration in concentrated hydrochloric acid and deprotected for 2 hours to obtain 50 mg of the title compound.

Example 8

(Z) -N-propyl-N- (3-carboxy-pro-2-phen-1-noyl) -N- [2 '-(2H-tetrazol-5-yl) biphenyl-4-ylmethyl] -Amine

Toluene 1 g (18 mmol) of N-propyl-N- [2 '-(1-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine and 0.27 g (27 mmol) maleic acid It was placed in 50 ml and heated to reflux for 12 hours. After completion of the reaction, the product was distilled under reduced pressure and separated by column chromatography (5: 1 chloroform: methanol) to obtain (Z) -N-propyl-N- (3-carboxy-pro-2-phen-1-noyl) -N- 190 mg of [2 '-(1-triphenyl-2H-tetrazol-5-yl) biphenyl-4-ylmethyl] -amine was obtained. This product was taken up in a methanol solution of 15 normal concentration in concentrated hydrochloric acid and deprotected for 2 hours to obtain 60 mg of the title compound.

¹ H NMR (DMSO-d6; δ) 0.61 (3H, m), 1.21 (2H, m), 3.92 (2H, m), 4.25 (2H, d), 5.68 (1H, t), 6.43 (1H, dd ), 6.8 to 7.4 (8 h, m).

[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 7-hydrate 1.2 It was hung on an isotonic tranducer in 5 ml of organ tissue containing mmol / L, 1.2 mmol / L potassium phosphate and EDTA Krebs-bicarbonate solution. Maintain equilibrium talc for 1 hour with 1.0 g of resting tension and 5 to 6 replacements of sacred buffer.

To examine the drug effect, an excipient (dimethylsulfoxide 1%, control) or test substance was added and angiotensin II was gradually added from 3 × 10 ⁻¹⁰ molarity after 10 minutes to obtain a concentration-response curve. After rinsing well with fresh buffer solution and maintaining equilibrium for 1 hour, potassium chloride (122.8 mM) was added to induce contraction. The contraction by angiotensin II at each concentration was expressed as% of contraction by potassium chloride. The percentage of contraction by angiotensin II at a concentration of 3 × 10 ⁻⁸ molar concentration, which is the maximum causing contraction by angiotensin II, was determined as Emax, and the contraction by angiotensin II in other tissues to which the drug was applied was expressed in terms of relative to Emax. 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)

A compound of formula (I) or a pharmaceutically acceptable salt thereof: Wherein R ₁ is C ₁ to C ₆ alkyl or C ₂ to C ₆ alkene, R ₂ is hydroxy, ethoxy or methoxy, R ₃ is C-linked tetrazole, carboxy or dialkylaminosulfate , X is methylene substituted with ethoxymethene, methoxymethene, ethoxyoxime or methoxyoxime; Or unsaturated ethene unsubstituted or substituted with one or more methyl, ethyl or benzyl; or ( )to be. 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 ₁ is C ₁ to C ₆ alkyl or C ₂ to C ₆ alkene, R ₂ is hydroxy, ethoxy or methoxy, R ₃ is C-linked tetrazole, carboxy or dialkylaminosulfate , X is methylene substituted with ethoxymethene, methoxymethene, ethoxyoxime or methoxyoxime; Or unsaturated ethene unsubstituted or substituted with one or more methyl, ethyl or benzyl; or ( )to be.