KR100216427B1 - Proline derivatives method for preparation and pharmaceutical composition comprising such compounds as angiotensin ii antagonist - Google Patents

Abstract

The present invention relates to a novel proline derivative compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition as an angiotensin II antagonist containing the same:

Wherein R 1 is a group selected from C _1-6 alkyl, C _2-6 alkenyl and C _3-7 cycloalkyl; W is alkoxy, hydroxy or hydrogen; X is a group selected from -CH ₂ CH ₂ -,-CH ₂ COCH ₂ -and -CH _2- ; Y is a group selected from -COOR ₃ , CONR ₄ R ₅ , CH ₂ OR ₃ and C-bonded tetrazole; Z is oxygen or hydrogen atom; R 3, R 4 and R 5 are each independently a group selected from H, C _1-6 alkyl and C _3-7 cycloalkyl.

Description

Proline derivatives, preparation method thereof and angiotensin II antagonist composition containing the same

It is an object of the present invention to provide a new medicament that exhibits potent antagonism against angiotensin II.

Angiotensin II is a biologically active product of the Lenin-Angio-Tensin system, which exhibits potent blood pressure boosting activity, and other compounds that inhibit the action of angiotensin II due to its physiological effects on the central nervous system and kidneys, It is well known to be useful for the treatment of cardiovascular symptoms such as hypertension and heart failure. Many angiotensin II antagonists are known so far, but there is still a need to develop new antagonists to replace them, as well as to efficiently synthesize such substances.

In the present invention, as well as novel compounds exhibiting strong antagonistic action against angiotensin II, as well as efficient methods for preparing the compounds, to develop a drug effective in the treatment of central nervous system symptoms and cardiovascular symptoms.

The present invention relates to novel proline derivative compounds represented by the following general formula (I) and salts thereof, in particular pharmaceutically acceptable organic inorganic salts.

Wherein R 1 is a group selected from C _1-6 alkyl, C _2-6 alkenyl and C _3-7 cycloalkyl; W is alkoxy, hydroxy or hydrogen; X is a group selected from -CH ₂ CH ₂ -,-CH ₂ COCH ₂ -and -CH _2- ; Y is a group selected from -COOR ₃ , CONR ₄ R ₅ , CH ₂ OR ₃ and C-bonded tetrazole; Z is oxygen or hydrogen atom; R 3, R 4 and R 5 are each independently a group selected from H, C _1-6 alkyl and C _3-7 cycloalkyl.

In addition, the present invention provides a compound of the following general formula (III) by Nalkylation of a compound of the following general formula (II), acylating this product to obtain a compound of the following general formula (IV), N alkylation to obtain a compound of the general formula (V), followed by deprotection and / or hydrolysis, wherein the compound of the general formula (I) is prepared.

Wherein R 1, X, Z, Y and W are as defined above.

Illustratively illustrating the manufacturing method of the present invention by the reaction scheme as follows.

According to the above scheme, Compound (II) was obtained by applying appropriate alkylamine at room temperature for 24 hours or more in tetrahydrolan (THF) solvent. Compound (III) was obtained by applying alkanoyl halide with appropriate substituent in the temperature range of -50 ° C to 4 ° C in the presence of diisopropylethylamine in methylene chloride solvent. In order to obtain compound (V), compound (IV) was treated in a solvent such as acetonitrile at an appropriate temperature in the temperature range from diisopropylethylamine, tanzanana potassium and appropriate secondary cycloamine to normal heating to reflux. At this time, if necessary for the progress of the reaction, an appropriate amount of sodium iodide was added. Compounds of formula (I), compound (V), are obtained by stirring at room temperature for any time using 88% formic acid in dichloromethane solvent, or the compounds obtained by the above-mentioned methods are again added with methane in solvent It could be obtained by treating sodium hydroxide with concentration.

The present invention also relates to a pharmaceutical composition as an angiotensin II antagonist, characterized in that it contains a therapeutically effective amount of the compound of formula (I) according to the invention and a pharmaceutically acceptable carrier.

The present invention will be described in more detail with reference to the following Examples and Examples. However, these examples should not be understood as limiting the scope of the present invention.

Reference Example 1

Preparation of Butyl- {4- (2- (1H-1, 2, 3, 4-tetrazol-5-yl) phenyl] benzyl} amine (Journal of Medicinal Cemistry (1993), 36, 18, 1683)

165 ml of tetrahydrofuran was added to 18 g of 2-triphenylmethyl-5- (4'-bromomethyl-2-yl) -2H-tetrazole, and 120 ml of butylamine was added thereto. After stirring for 48 hours at room temperature, the mixture was distilled under reduced pressure, and the remaining residue was dissolved in chloroform and washed with 1 normal potassium hydroxide. The organic worms were dried over potassium carbonate, filtered and the filtrate was distilled under reduced pressure, and the silver was purified through column chromatography (hexane, ethyl acetate 2: 1), to obtain 12.7 g of the target compound.

¹ H-NMR (CDCL ₃ ): 8.0-6.8 (23H, m), 3.79 (2H, s), 2.89 (2H, t), 1.6-1.2 (4H, m), 0.93 (3H, t)

Reference Example 2

Preparation of N-1-butyl-N-1- {4- [2- (1H-1, 2, 3, 4-tetrazol-5-phenyl] benzyl} -2-chloroacetamide

1 g of butyl- {4- [2- (1H-1, 2, 3, 4-tetrazol-5-yl) phenyl] benzyl] amine was added to 40 ml of methylene chloride, 0.38 ml of diisopropyl ethanol was added, followed by ice. After the temperature was adjusted to 4 ° C., 0.15 ml of chloroacetyl chloride was slowly added dropwise. After stirring for 1 hour while maintaining the temperature 75ml of water to give a layer separation to take an organic layer. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting brown oil was purified through column chromatography (hexane, ethyl acetate 2: 1), to obtain 0.8 g of the target compound.

¹ H-NMR (CMSO ₆ ): 0.87 (3H, t), 1.24 (2H, m), 1.95 (2H, m), 2.46 (1H, m), 3.15 (1H, m), 3.42-3.76 (7H, m), 4.32 (1H, m), 4.47-4.85 (2H, m), 5.28 (1H, dd), 7.00-7.53 (8H, m)

Example 2

(2S, 4R) -1-butyl- {4- [2- (1H-1, 2, 3, 4-tetrazol-5-yl) phenyl] benzyl} carbamoylmethyl-4-hydroxyazolane-2- Preparation of Carboxylate

80 mg of the compound obtained in Example 1 was mixed with 5 ml of methanol and 5 ml of 1N sodium hydroxide and stirred at room temperature for 5 hours. Methanol was removed under reduced pressure and then adjusted to pH = 3 using formic acid. 10 ml of ethyl acetate was used twice to extract organic material, and the organic layer was concentrated to obtain 30 mg of the target compound.

¹ H-NMR (DMSO ₃ -d ₆ + D ₂ O): 0.85 (3H, t), 1.24 (2H, m), 1.45 (2H, m), 2.25 (2H, m), 2.90 (1H, m) , 3.20 (2H, m), 3.52 (2H, m), 3.75 (2H, m), 4.40-4.65 (5H, m), 7.06-7.21 (4H, m), 7.54-7.70 (4H, m)

Reference Example 3

Preparation of (2S) -1-butyl- {4- [2- (1H-1, 2, 3, 4-tetrazol-5-yl) phenyl] benzyl} carbamoylmethyl-5-oxoazolane-2-carboxylic acid

N-1-butyl-N-1- {4- [2- (1H-1, 2, 3, 4-tetrazol-5-yl) phenyl] benzyl} -2-chloroacetamide obtained in Reference Example 2 300 mg was mixed with 62 mg of (s)-(-) (2) -pyrrolidinone-5-carboxylic acid, 124 mg of diisopropylethylamine and 5 ml of acetonitrile and heated to reflux for 7 hours. The reaction mixture was concentrated under reduced pressure, dissolved in 100 ml of ethyl acetate, and washed twice with 100 ml of water. The organics were dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, and the remaining residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1-> methylene chloride: methanol = 95: 5) to obtain 220 mg of a purified compound. .

220 mg of the organic material obtained by the above method was mixed with 5 ml of methylene chloride and 5 ml of 88% formic acid and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the lead residue was purified by silica gel column chromatography (methylene chloride: methanol = 95: 5 -methanol) to obtain 50 mg of the target compound.

¹ H-NMR (DMSO-d ₆ ): 8.2-7.0 (8H, m), 5.0-4.2 (5H, m), 3.2-3.0 (2H, m), 2.5-2.0 (4H, m), 1.6-0.8 (7H, m)

Example 4

Preparation of (2S) -1-butyl- {4- [2- (1H-1, 2, 3, 4-tetrazol-5-yl) phenyl] benzyl} carbamoylmethyl-5-oxoazolane-2-carboxylic acid

N-1-butyl-N-1- {4- [2- (1H-1, 2, 3, 4-tetrazol-5-yl) phenyl] benzyl} -2-chloroacetamide obtained in Reference Example 2 467 mg was mixed with 95 mg of L-prolineamide, 96 mg of diisopropylethylamine, and 5 ml of acetonitrile and heated to reflux for 7.5 hours. The reaction mixture was concentrated under reduced pressure, dissolved in 100 ml of ethyl acetate, and washed twice with 100 ml of water. The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, and the remaining residue was purified by silica gel column chromatography (methylene chloride: methanol = 95: 5) to obtain 400 mg of a purified compound.

400 mg of the organic material obtained by the above method was mixed with 10 ml of methylene chloride and 10 ml of 88% formic acid and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the lead residue was purified by silica gel column chromatography (methylene chloride: methanol = 4: 1) to obtain 50 mg of the target compound.

¹ H-NMR (DMSO-d ⁶ ): 4.8-4.2 (2H, m), 3.8-2.8 (10H, m), 2.2-1.8 (1H, m), 1.80-0.7 (9H, m)

Example 5

Preparation of methyl (2S) -1-butyl- {4- [2- (1H-1, 2, 3, 4-tetrazol-5-yl) phenyl] benzyl} carbamoylmethylazolane-2-carboxylate

N-1-butyl-N-1- {4- [2- (1H-1, 2, 3, 4-tetrazol-5-yl) phenyl] benzyl} -2-chloroacetamide obtained in Reference Example 2 300 mg of L-proline methyl ester was mixed with 95.4 mg of hydrochloride, 186.2 mg of diisopropylethylamine, and 5 ml of acetonitrile and heated to reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, dissolved in 100 ml of ethyl acetate, and washed twice with 80 ml of water. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the remaining residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 330 mg of a purified compound.

300 mg of the organic material obtained by the above method was mixed with 10 ml of methylene chloride and 10 ml of 88% formic acid and stirred at room temperature for a time. The reaction mixture was concentrated under reduced pressure, and the lead residue was purified by silica gel column chromatography (methylene chloride: methanol = 95: 5 -methanol) to obtain 80 mg of the target compound.

¹ H-NMR (DMSO-d ₆ ): 8.5-6.8 (8H, m), 4.8-4.2 (2H, m), 3.8-2.8 (12H, m), 2.2-2.0 (1H, m), 2.0-0.7 (10H, m)

Example 6

Methyl (2S) -1- (3-butyl- {4- [2- (1H-1, 2, 3, 4-tetrazol-5-yl) phenyl] benzyl} carbamoyl-2-oxopropyl) azolane- Preparation of 2-carboxylate

400 mg of butyl- {4- [2- (1H-1, 2, 3,4-tetrazol-5-yl) phenyl] benzyl} amine obtained in Reference Example 2 were mixed with 400 mg of diisopropylethylamine and 10 ml of methylene chloride. Cool to -50 ° C. 1.3 ml of 4-chloro-3-oxobutanoyllite was added dropwise while maintaining the temperature. After stirring the mixed solution for 30 minutes, the solvent was removed under reduced pressure, and 10 ml of acetonitrile and 120 mg of L-proline methyl ester hydrochloride were mixed together and heated to reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, and the lead residue was 140 mg of a purified compound through silica gel column chromatography (hexane: ethyl acetate = 1: 1).

190 mg of the organic material obtained by the above method was mixed with 10 ml of methylene chloride and 10 ml of 88% formic acid and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the lead residue was purified by silica gel column chromatography (methylene chloride: methanol = 95: 5) to obtain 60 mg of the target compound.

¹ H-NMR (DMSO-d ₃ ): 8.0-7.0 (8H, m), 4.6-4.3 (2H, m), 3.7-3.0 (1H, m), 1.9-1.6 (4H, m), 1.6-1.0 (4H, m), 1.0-0.8 (3H, m)

Example 7

(2S) -1- (3-butyl- {4- [2- (1H-1, 2, 3, 4-tetrazol-5-yl) phenyl] benzyl} carbamoyl-5-oxopropyl) -5- Preparation of oxoazolane-2-carboxylic acid

400 mg of butyl- {4- [2- (1H-1, 2, 3,4-tetrazol-5-yl) phenyl] benzyl} amine obtained in Reference Example 1 were mixed with 400 mg of diisopropylethylamine and 10 ml of methylene chloride. Cool to -50 ° C. 1.3 ml of 4-chloro-3-oxobutanoyl chloride was added dropwise while maintaining the temperature. After stirring the mixed solution for 30 minutes, the solvent was removed under reduced pressure, and then 10 ml of acetonitrile and 94 ml of (s)-(-)-2-phyllolidinone-5-carboxylic acid were mixed together and heated to reflux for 6 hours. After the reaction mixture was concentrated under reduced pressure, the remaining residue was purified by silica gel column chromatography (methylene chloride: methanol = 95: 5) to obtain 140 mg of a purified compound.

140 mg of the organic material obtained by the above method was mixed with 110 ml of methylene chloride and 10 ml of 88% formic acid and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the lead residue was purified by silica gel column chromatography (methylene chloride: methanol = 95: 5) to obtain 60 mg of the target compound.

¹ H-NMR (DMSO-d ₃ ): 8.0-6.8 (8H, m), 4.5-4.3 (2H, m), 4.0-3.0 (9H, m), 2.1-1.8 (2H, m), 1.6-1.0 (4H, m), 1.0-0.8 (3H, m)

Example 8

Methyl (2S) -1- (3-butyl- {4- [2- (1H-1, 2, 3, 4-tetrazol-5-yl) phenyl] benzyl} carbamoylethylazolane-2-carboxylate Manufacture

1000 mg of butyl-N-1- {4- [2- (1H-1, 2, 3,4-tetrazol-5-yl) amine obtained in Reference Example 1, 0.48 mg of diisopropylethylamine, and 50 ml of methylene chloride Mix and cool to -10 ° C. 0.2 ml of 3-bromopropanoylchloride was added dropwise while maintaining the temperature. After stirring the mixed solution for 30 minutes, 50 ml of water was added, the organic layer was taken out, dried over magnesium sulfate, filtered and concentrated under reduced pressure, 400 mg of the remaining residue was collected, 30 ml of acetonitrile, 96 mg of L-proline methyl ester hydrochloride, and 160 mg of potassium carbonate. 20 mg of sodium iodide were mixed together and heated to reflux for 12 hours. The reaction mixture was concentrated under reduced pressure, dissolved in 70 ml of ethyl acetate, and washed with 70 ml of water. The organic layer was concentrated under reduced pressure, and the remaining residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to obtain 60 mg of the purified compound.

110 mg of the organic material obtained by the above method was mixed with 7 ml of methylene chloride and 7 ml of 88% formic acid, and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2-> methylene chloride: methanol = 10: 1) to obtain 60 mg of the target compound.

¹ H-NMR (DMSO-d ₃ ): 0.98 (3H, t, J = 7.3 Hz), 1.3 (2H, m), 1.6 (2H, m), 1.98 (3H, m), 2.30 (1H, m) , 2.50 (2H, m), 2.75 (1H, m), 3.05 (1H, m), 3.30 (3H, m), 3.52-3.62 (2H, m), 3.75 (3H, m), 4.53 (2H, m) ), 7.08-8.00 (8H, m)

Example 9

Methyl (2S, 4R) -1- (3-butyl- {4- [2- (1H-1, 2, 3, 4-tetrazol-5-yl) phenyl] benzyl} carbamoylethyl-4-hydroxy Preparation of Azolan-2-carboxylate

600 mg of the residue obtained in Reference Example 8 was taken, and 30 ml of acetonitrile, 200 mg of 4-hydroxyproline methyl ester, 380 mg of potassium carbonate, and 30 mg of sodium iodide were mixed together and heated to reflux for 7 hours. The reaction mixture was concentrated under reduced pressure, dissolved in 70 ml of ethyl acetate, and then washed with 70 ml of water. The organic layer was concentrated under reduced pressure, and the remaining residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2-> hexane: ethyl acetate = 1: 2) to obtain 180 mg of a purified compound.

110 mg of the organic material obtained by the above method was mixed with 7 ml of methylene chloride and 7 ml of 88% formic acid, and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the remaining residue was purified by silica gel column chromatography (hexane: Acetate = 1: 2-> methylene chloride: Methanol = 10: 1) to obtain 80 mg of the target compound.

¹ H-NMR (DMSO-d ₃ ): 0.96 (3H, m), 1.37 (2H, m), 1.59 (2H, m), 3.27-2.36 (2H, m), 2.62-2.72 (2H, m), 3.10-3.54 (4H, m), 3.76, 3.81 (3H, 2s), 4.51 (3H, m), 6.99-7.90 (8H, m)

Example 10

(2S, 4R) -1- (3-butyl- {4- [2- (1H-1, 2, 3, 4-tetrazol-5-yl) phenyl] benzyl} carbamoylethyl-4-hydroxyazolane Preparation of 2-carboxylate

60 mg of the compound obtained in Example 9 was mixed with 5 ml of methanol and 5 ml of 1N sodium hydroxide and stirred at room temperature for 2 hours. Methanol was removed under reduced pressure and then adjusted to pH = 3 using formic acid. 10 ml of ethyl acetate was used twice to extract the organic material, and 40 mg of the target compound was obtained by concentrating the organic insects.

¹ H-NMR (DMSO-d ₆ ): 0.83 (3H, m), 1.20 (2H, sextet), 1.46 (2H, m), 2.70 (1H, m), 2.85 (1H, m), 3.00 (1H, dd), 3.16 (1H, m), 3.24 (1H, m), 4.30 (1H, m), 4.45-4.50 (2H, 2s), 7.04 (4H, m), 7.35-7.49 (4H, m)

Example 11

(2S) -1- (3-butyl- {4- [2- (1H-1, 2, 3, 4-tetrazol-5-yl) phenyl] benzyl} carbamoylethyl) isolan-2-carboxyl Manufacture of acid

30 mg of the compound obtained in Example 8 was mixed with 5 ml of methanol and 5 ml of 1N sodium hydroxide and stirred at room temperature for 1 day. Methanol was removed under reduced pressure and then adjusted to pH = 3 using formic acid. 10 ml of ethyl acetate was used twice to extract the organic material, and 20 mg of the target compound was obtained by concentrating the organic insects.

¹ H-NMR (DMSO-d ₆ ): 0.89 (2H, m), 1.24 (2H, m, 1.4-1.5 (2H, m), 1.60 (1H, m), 1.80-1.90 (2H, m), 2.05 (1H, m), 2.70 (1H, m), 2.81 (2H, m), 3.10-3.30 (5H, m), 3.45 (1H, m), 4.49 (2H, m), 7.03-7.54 (8H, m )

Example 10

(2S, 4R) -1- (3-butyl- {4- [2- (1H-1, 2, 3, 4-tetrazol-5-yl) phenyl] benzyl} carbamoylethyl-4-hydroxyazolane Preparation of 2-carboxylate

60 mg of the compound obtained in Example 9 was mixed with 5 ml of methanol and 5 ml of 1N sodium hydroxide and stirred at room temperature for 2 hours. Methanol was removed under reduced pressure and then adjusted to pH = 3 using formic acid. 10 ml of ethyl acetate was used twice to extract the organic material, and 40 mg of the target compound was obtained by concentrating the organic insects.

The following is a method of investigating contraction inhibition induced by agonists.

The rabbit's larynx of the rabbit was struck and stunned, and then the carotid artery was cut to lose blood. The incision was quickly removed from the closed aorta to remove adipose tissue and cut into 3-4 mm lengths to obtain a helical strip. 118 mmol / l NaCl immediately after removal of the endocerium, angiotensin II-shrinkage-reducing factor endothelium with a tip of tweezers; NaHCO ₃ 25 mmol / 1; Glucose 10 mmol / 1; KCl 4.7 mmol / 1; CaCl ₂ 2.5 mmol / 1; 1.2 mmol / 1; KH ₂ PO ₄ 1.2 mmol / 1; 15 ml of isotonic transducers in a trachea containing 0.001 mmol / l EDTA and containing a Krebs-bicarbonate nutrient solution passed through 95% O ₂ /5% CO ₂ incubated at 37 ° C. isotonic tranducer). Maintain equilibrium for 1 hour with a fresh load of 5-6 times with 1.0g of initial load.

An excipient (DMSO 1%, control) or test substance was added to search for drug effects, and angiotensin II was gradually added from 3 × 10 ⁻¹⁰ M after 10 minutes to obtain a concentration-response curve. After rinsing well with fresh buffer solution and maintaining equilibrium for 1 hour, KCl (122.8 mM) was added to induce contraction. Based on this, the contraction by angiotensin II at each concentration was expressed as% of KCl. The percentage of contraction by 3 × 10 ⁻⁸ M of angiotensin II, the concentration causing maximum contraction by angiotensin (II), was defined as Emax and the percentage of angiotensin II-shrinkage of the other tissues to which the drug was applied is expressed in terms of relative to Emax. Angiotensin II antagonism of the test substance was searched by obtaining the EC ₅₀ of angiotensin II from the final concentration-response curve thus obtained.

Claims (3)

A compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, Wherein R 1 is a group selected from C _1-6 alkyl, C _2-6 alkenyl and C _3-7 cycloalkyl; W is alkoxy, hydroxy or hydrogen; X is a group selected from -CH ₂ CH ₂ -,-CH ₂ COCH ₂ -and -CH _2- ; Y is a group selected from -COOR ₃ , CONR ₄ R ₅ , CH ₂ OR ₃ and C-bonded tetrazole; Z is oxygen or hydrogen atom; R 3, R 4 and R 5 are each independently a group selected from H, C _1-6 alkyl and C _3-7 cycloalkyl. Nalkylation of the compound of formula (II) to afford a compound of formula (III), acylating this product to give a compound of formula (IV), and Nalkylation of this product to the following general formula Obtaining a compound of formula (V) and detritylation to prepare a compound of formula (I) Wherein R 1 is a group selected from C _1-6 alkyl, C _2-6 alkenyl and C _3-7 cycloalkyl; W is alkoxy, hydroxy or hydrogen; X is a group selected from -CH ₂ CH ₂ -,-CH ₂ COCH ₂ -and -CH _2- ; Y is a group selected from -COOR ₃ , CONR ₄ R ₅ , CH ₂ OR ₃ and C-bonded tetrazole; Z is oxygen or hydrogen atom; R 3, R 4 and R 5 are each independently a group selected from H, C _1-6 alkyl and C _3-7 cycloalkyl. A pharmaceutical composition as an angiotensin II inhibitor comprising a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.