KR100632698B1 - Processes for the preparation of S-(-)-amlodipine nicotinate crystalline dihydrate - Google Patents

Abstract

The present invention relates to a process for the preparation of S-(-)-amlodipine nicotinate crystalline dihydrate. S-(-)-amlodipine nicotinate crystalline dihydrate prepared by the production method of the present invention has a superior pharmacological effect compared to (R.S) -amlodipine nicotinate.

S-(-)-Amlodipine Nicotinate Crystalline Dihydrate

Description

Process for the preparation of S-(-)-amlodipine nicotinate crystalline dihydrate}

1 is an XRD chart of S-(-)-amlodipine nicotinate prepared in Example 2,

2 is peak list data of an XRD pattern of S-(-)-amlodipine nicotinate prepared in Example 2,

3 is a graph showing the effect of amlodipine nicotinate on systolic blood pressure in congenital hypertensive rats,

Figure 4 is a graph showing the effect of optically active S-(-)-amlodipine nicotinate in systolic blood pressure in congenital hypertensive rats,

FIG. 5 is a graph showing dose-response curves of amlodipine nicotinate and optically active S-(-)-amlodipine nicotinate for peak changes in systolic blood pressure in congenital hypertensive rats.

The present invention relates to a process for preparing the S-(-)-amlodipine nicotinate crystalline dihydrate.

Amlodipine 1a and its salts are long acting calcium channel blockers and are useful in the treatment of cardiovascular diseases such as angina, hypertension and congestive heart failure. The two enantiomers of amlodipine and their salts have different pharmacological profiles. S-(-)-isomers are more potent calcium channel blockers, and R-(+)-isomers are also active in the treatment or prevention of atherosclerosis.

J.E. Arrowsmith et al., J. Med. Chem. (1986) 29 1969 describes a method for separating two isomers of amlodipine by the separation of diastereomeric azide ester 1b, see European Patent No. A331315 [J.E. Arrowsmith describes a method for preparing salts using cinnaconidine for acid 1c followed by optical splitting to ultimately obtain enantiomerically pure amlodipine isomers. S. Goldman et al., J. Med. Chem. (1992) 35 334 describes a method for chromatographic separation of diastereomeric amide isomers 1d, and Korean Patent Registration No. 10-0188980 [Spago Peter Lionel, PCT / EP 1995/00847] by tartaric acid. A method for separating the optical isomers of amlodipine via salt formation is described.

Korean Patent Registration No. 10-0188980 [Spago Peter Lionel, PCT / EP 1995/00847] shows high yield and optical purity, but uses S-(-)-amlodipine with expensive D-(-)-tartaric acid. There are limitations in terms of economics by separation. Therefore, the researchers developed a method to separate S-(-)-amlodipine with cheaper L-(+)-tartaric acid, and then reacted with nicotinic acid to form a more stable S-(-) in terms of pharmaceutical efficacy. Amlodipine nicotinate salts were prepared to complete the present invention.

The present invention provides a method for preparing a novel optical isomer, S-(-)-amlodipine nicotinate crystalline dihydrate, wherein the S-(-)-amlodipine nicotinate crystalline dihydrate is (RS) -amlodipine. It has a superior pharmacological effect compared to nicotinate.

S-(-)-amlodipine and nicotinic acid are reacted to obtain S-(-)-amlodipine nicotinate which is pharmaceutically stable and excellent in efficacy.

Scheme 1

The present invention is illustrated by the following examples.

Optical purity was measured by Jasco DIP-1000.

Example 1 Preparation of (S)-(-)-Amlodipine Nicotinate Hydrate

Nicotinic acid (602 mg, 4.89) dissolved in (S)-(-)-amlodipine (2.0 g, 4.89 mmol) completely in 95% industrial methylated alcohol (10.0 mL), and then slurried in 95% industrial methylated alcohol (2.5 mL). mmole). The solution was slowly warmed to react at reflux for 5 hours, and then cooled to 5 ° C. or lower to form amlodipine nicotinide salt hydrate, which was filtered and washed with industrial isopropanol (5.0 mL).

The resulting salt was warmed in 95% methanol: isopropanol (1: 9) or water: isopropanol (5:95) solution (10.0 mL), dissolved completely, and stirred slowly at room temperature, cooled to 0 ° C., and the resulting crystals were filtered. Washed with isopropanol (5.0 mL) and dried at 80 ° C. for 5 hours under reduced pressure.

2.2-2.26 g of dihydrate salts were obtained having the following analytical values.

Yield: 79.3-81.4%

Melting Point: 178-180 ℃

¹ H-NMR (CDCl ₃ ): 9.19 (s, 1H), 8.63 (d, 1H), 8.24 (d, 1H), 7.75 (s, 1H)

                6.97-7.34 (m. 5H), 5.33 (s, 1H), 4.74 (gq, 2H), 4.01 (m, 2H)

                3.76 (bs, 2H), 3.55 (s, 3H), 3.17 (bs, 2H), 2.28 (s, 3H)

                1.15 (t, 3 H)

[α] _D ²⁵ = -24.4 (c = 1, MeOH)

1 is an XRD chart of S-(-)-amlodipine nicotinate prepared in Example 2. FIG.

2 is peak list data of an XRD pattern of S-(-)-amlodipine nicotinate prepared in Example 2. FIG.

* XRD model name; Rigaku Rotaflex 12Kw XRD-2000

LOD (dry weight loss test): Take 200 mg of the salt precisely, and dried for 5 hours under reduced pressure of 120 ° C or less than 5 mmHg, and confirmed that it was a dihydrate by weight difference.

Example 2

The (S)-(-)-amlodipine nicotinate salt hydrate obtained in Example 1 was dried at 115-125 ° C. for 5 hours under reduced pressure to obtain amlodipine nicotinate salt anhydride.

Melting Point: 179-181 ℃

Calculated (%): C; 58.70 H; 5.68 N; 7.90

Found (%): C; 58.65 H; 5.60 N; 7.91

Experimental Example 1.

Drug Test Results of Amlodipine Nicotinate and Optically Active S-(-)-Amlodipine Nicotinate

Introduction

This experiment was performed to measure / compare the cardiovascular pharmacological effects on two test substance amlodipine nicotinate and the optically active S-(-)-amlodipine nicotinate obtained in Example 1. As an experimental item, an in vivo activity assay for measuring antihypertensive activity in congenital hypertensive rats was used.

2. Experimental method

(1) reagent

Amlodipine nicotinate (M.W. 531.0) and optically active S-(-)-amlodipine nicotinate (M.W. 531.0) were dissolved in distilled water and administered. All drugs and reagents used in the experiment were prepared just before use.

(2) experimental animals

Congenital hypertensive rats (SHR, male, 13-14 weeks of age) were purchased from Charles River, Japan, and are clean animals with constant temperature (22.5 ± 1 ° C), humidity (55 ± 5%) and contrast automatically adjusted at 12 hour intervals. After stabilization in the nursery was used for the experiment.

(3) Antihypertensive Action in Congenital Hypertensive Rats (SHR)

SHR was used only for systolic blood pressure of 170 mmHg or more and 6-8 animals per group. Blood pressure was measured by Multichannel 8000 (TSE, Germany) using the tail-cuff method, which is a method for measuring blood pressure from the tail of an experimental animal. In order to measure blood pressure smoothly, the experimental animals were warmed for about 10 minutes in a constant temperature box at 37 ℃. Test substance 1, 3 and 10 mg / kg doses were dissolved in distilled water (0.5 ml / 100g rat) and administered orally. Blood pressure measurements were taken before drug administration 2, 4, 6, 8, 10, 24 hours after drug administration.

(4) statistics

All experimental results were mean ± S.E.M. Statistical analysis of the experimental results was performed by unpaired t-test and one-way analysis of variance (ANOVA) using Sigma Stat program of Jandel Co., USA, and the secondary test was Dunnett multiple comparisons test. .

3. Experimental Results

Experimental results of measuring the antihypertensive effect of the test substance amlodipine nicotinate and optically active S-(-)-amlodipine nicotinate in congenital hypertensive rats are shown in FIGS. 3 to 5 and Tables 1 to 2. Amlodipine nicotinate (FIG. 3, Table 1) and optically active S-(-)-amlodipine nicotinate (FIG. 4, Table 1) were all dose-dependently lowering blood pressure, and the hypotension pattern was found in all dose groups. Similarly appeared. Significant antihypertensive effects began to appear after 2 hours of test substance administration, with maximum effects between 2 and 6 hours of administration. These antihypertensive effects lasted for more than 10 hours, especially at high doses of 10 mg / kg, which persisted even after 24 hours of administration. Only the maximum antihypertensive effect for each dose is shown separately in FIG. 5, wherein the maximum antihypertensive effect of amlodipine nicotinate and optically active S-(-)-amlodipine nicotinate at the 1 mg / kg dose was- 10.20 ± 2.71, -12.4 ± 1.73% (p <0.05 vs. amlodipine nicotinate), at 3 mg / kg doses -26.8 ± 3.22 and -28.3 ± 3.31%, respectively, at high doses of 10 mg / kg- 40.9 ± 2.08, -43.6 ± 1.65%, which was significant at the 1 mg / kg dose. On the other hand, ED ₂₀ levels (20% suppression of blood pressure, 95% confidence interval) showed that amlodipine nicotinate and optically active S-(-)-amlodipine nicotinate were 2.19 ± 0.57 and 1.91 ± 0.49 mg / kg, respectively. Appeared (Table 2).

 Maximum antihypertensive effect at each dose Sample Name Dose 1mg / kg Drop in blood pressure 3mg / kg Drop in blood pressure 10mg / kg Drop in blood pressure Amlodipine Nicotinate -10.20 ± 2.71 1.00 -26.8 ± 3.22 1.00 -40.9 ± 2.08 1.00  Optically Active S-(-)-Amlodipine Nicotinate  -12.4 ± 1.73  1.22  -28.3 ± 3.31  1.06  -43.6 ± 1.65  1.07

ED ₂₀ values Sample name Dose (mg) About effective strength Amlodipine Nicotinate 2.19 ± 0.57 1.00 Optically Active S-(-)-Amlodipine Nicotinate 1.91 ± 0.49 1.15

4. Conclusion

Antihypertensive activity of congenital hypertensive rats against amlodipine nicotinate and optically active S-(-)-amlodipine nicotinate was measured. At 1 mg / kg concentration of optically active S-(-)-amlodipine nicotinate (p <0.05 vs. amlodipine nicotinate), 1.22 times better efficacy was found than amlodipine nicotinate. On the other hand, comparing the ED ₂₀ values for antihypertensive action, the optically active S-(-)-amlodipine nicotinate was 1.15 times stronger than A-Amlodipine nicotinate.

The preparation method of the present invention provides S-(-)-amlodipine nicotinate crystalline dihydrate, and S-(-)-amlodipine nicotinate crystalline dihydrate is compared to (RS) -amlodipine nicotinate. It has an excellent pharmacological effect.

Claims (2)

A method of preparing S-(-)-amlodipine nicotinate crystalline dihydrate having the following XRD pattern by reacting S-(-)-amlodipine with nicotinic acid in a water-containing industrial methylated spirit. 2-Theta Intensity ratio count% 8.87024 49.5 12.40769 50.5 13.25102 100.0 14.65376 25.7 17.44421 26.1 19.73034 28.1 20.34481 27.2 21.99343 46.5 22.48365 51.7 24.65381 34.1 26.70359 38.0 28.63978 19.6 The method according to claim 1, wherein the S-(-)-amlodipine is reacted with nicotinic acid in a water-containing industrial methylated alcohol and then recrystallized with a 95% methanol-isopropanol or water-isopropanol mixed solvent to obtain an S-(-) having the following XRD pattern. A process for preparing amlodipine nicotinate crystalline dihydrate. 2-Theta Intensity ratio count% 8.87024 49.5 12.40769 50.5 13.25102 100.0 14.65376 25.7 17.44421 26.1 19.73034 28.1 20.34481 27.2 21.99343 46.5 22.48365 51.7 24.65381 34.1 26.70359 38.0 28.63978 19.6

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