JPH0317054A - Stable crystalline salt and thromboxane acceptor antagonist containing same salt - Google Patents

Abstract

NEW MATERIAL:Calcium (+)-(5Z)-7-[3-endo-[(phenylsulfonyl)amino]- bicyclo[2,2,1]hept-2-exo-yl]heptenoate. ((+)-S-145 for short). USE:A thromboxane acceptor antagonist useful for preventing and treating inflam mation, hypertension, thrombosis, cerebral apoplexy, myocardial infarction, angina pectoris, cerebral intarct and asthma. PREPARATION:(+) S-145 is crystallized as calcium salt from a polar solvent (e.g. water or ethanol) to give calcium salt of (+)-S-145. Since the calcium salt of (+)-S-145 is high melting pure crystal and has proper solubility in various solvents including water, it is readily pharmaceutically manufactured. Calcium of (+)-S-145 is extracted with acidic water and removed to give (+)-S-145, a free acid.

Description

[Detailed Description of the Invention] A compound expressed by the formula: (+) - (
5z)-7-[monendo[(phenylsulfonyl)amino]bicyclo[2,1]hept-2-exo-yl]
Heptenoic acid (hereinafter referred to as <+>-S-145) is known. The present invention provides a stable crystalline calcium salt of (+)-S-1 4 5. Compound 4 of the present invention suppresses the effects of thromboxane A, and is used to treat inflammation, hypertension, thrombosis, stroke, myocardial stiffness,
It is effective in the prevention and treatment of angina pectoris, cerebral palsy, and asthma. (Hereafter in the margin) ``Ue raw(5Z)-7-[:3-endo-[<phenylsulfonyl)amino]bicyclo[2,1]hept-2-echinyl]heptenoic acid (hereinafter referred to as S-145) , its racemic form and optically active form are disclosed in JP-A-63-13
No. 9161, it is disclosed that these have a strong trompoxane receptor antagonistic effect. The racemic compound (Kushi-S-145) is easily crystallized and has a relatively high melting point (approximately 90°C), making it easy to purify and suitable as a pharmaceutical. It is also known that (+)-S-1 4 5 has a strong biological activity, but (-)-S-1 4 5 has a slightly weaker biological activity. (+)-S- in the publication
The synthesis method, purification method, and physical properties of 1 4 5 are shown, and the purification is performed by column chromatography. This is due to the fact that the optically active form (+)-S-1 4 5 has a low melting point of about 60°C and is difficult to recrystallize. Even if (+)-S-1 4 5 is formed into a salt with sodium or arginine, it is difficult to crystallize and is difficult to isolate. Even if (+)-S-1 4 5 is isolated, it undergoes decomposition accompanied by changes in appearance, such as wetting to liquefaction during storage at 40 to 50°C. Therefore, (+
Even if it turns out that the biological activity of )-S-1 4 5 is higher than that of the racemate, it is difficult to obtain stable crystals with (+)-S-1 4 5 as it is, and the crystallinity is also poor. The only industrial purification method was to use column chromatography, and it was thought that there were problems in handling the final substance. The disclosed invention comprises a. (+)-s-14 5 as a crystalline derivative suitable as a pharmaceutical; b. to do so in an industrially inexpensive manner; and c. (+)-S-14
It is intended to easily purify 5. In view of the above points, the present inventors (+)-S-1 4 5
It has been completely unexpectedly discovered that pure crystals with a high melting point can be obtained in a high yield by crystallizing the calcium salt from a polar solvent, thereby completing the present invention. (+)-S-1 4
5 can also be made with an alkali metal salt such as sodium or a salt with an organic base such as diethylamine, but these are not preferred because they are difficult to crystallize and have a low melting point. The recrystallization solvent that can be used in the present invention is preferably a polar solvent,
Examples include water, ethanol, methanol, n-propanol, inpropanol, and acetonitrile, which may be used alone or as a mixture. If desired, ethyl acetate, ether, methylene chloride, benzene, toluene, n-hexane, etc. may be mixed as appropriate. The method of recrystallizing the calcium salt of (+)-S-145 provided by the present invention is based on the method for recrystallizing the calcium salt of (-)-3, which exists as an impurity.
It is also effective when removing -145 etc. The calcium salt of (+)-S-1 4 5 purified in this way may be used as it is as a pharmaceutical raw material, or the calcium salt may be further extracted and removed with acidic water to obtain the free acid (+)-S-
It is also possible to set it to 1 4 5. The calcium salt of (+)-S-145 provided by the present invention has high biological activity and moderate solubility in various solvents including water, so it can be easily formulated into various carriers. It can also be made into injections, oral preparations, suppositories, etc. The dosage varies depending on the target therapeutic effect, administration method, age, body weight, etc., so it cannot be determined unconditionally, but the daily dosage is usually 1kJ of body weight! per parenteral dosage of about 0.001 mg to about 5a+g, more preferably about o.
oos mg to about IIIg, orally about 0
．． 01 mg to about 50 a+g, more preferably about 0.01 mg to about 50 a+g.
05 rngN is approximately 10 mg, which can be administered in 1 to 5 divided doses. (The following is a margin) The present invention will be explained in more detail by showing Examples and Experimental Examples below, but these are not intended to limit the present invention in any way. Example 1 (+)-S-1 45 (2.45 g: 6
．． 5mM) in 15ml of water, add 6.5ml of IN sodium hydroxide at 15°C, and dissolve with stirring. A trace amount of insoluble matter was filtered, the filtrate was lyophilized, and (+)-S-1
Obtain 2.60 g of the sodium salt of 45. (Quantitative) Dissolve this in 10 m of water, and dissolve calcium chloride (721 mg).
; 6.5mM) at 15-20°C to obtain a white precipitate. This reaction solution was heated to room temperature (20-25°C).
It crystallizes when stirred for 5 to 10 hours. If this is collected by filtration, thoroughly washed with water, and then air-dried, 2.58 g of crystalline calcium salt (96.1 g as a 1.0 M combined water) is obtained.
%). Colorless crystalline powder. This one is about 120℃~
Melts at 168℃. Thermal analysis: Decomposes from about 350℃.
[Elemental analysis Cx*H*aNO*S'1/2CIL4. As OHmO, i1j%Ji[:C. 57.94+H.
6.82+N. 3.38i Ca. 4.83H
．． 0. 4.35+ 'JJ3Ji: C. 57.80;H. 6.6
8;N. 3.61 Ca. 5.06Hm0. 4
．． 50. (Moisture determination is by Karl Fischer method.) IR
(Nujol): 3275. 1548. 116
0, 1094. 758,719. 689, 59
1. 557 cab-''HNflR (CDC1
#) ε: 0.93 to 2.55・(m, 1
7H). 3.02 (en. IH). 5.24
(m. 2H), 6.48 (++r. LH). 7
．． 35-7.60 (-, 31). 7.8
5-8.00 (m. 2H)-[αkoe +1
9. Dl. 6 (26.5'C, MeOH.
c=1.010). This crystalline powder was poured over phosphorus pentoxide,
When dried under reduced pressure at 50℃ for 8 hours, a colorless powder (2.4
8 g) is obtained. This one is 120-168℃
Melt at . (Left below) [Motoharu analysis C **Hs*N O 4S -1/2C a-0.2
As H*O, Ei Tsuji] { : C, 60.02;
}I. 6.66i N. a. so; Ca. 5.0
L H*0. 1.02. '3! ．． /11 value:C. 6
0.20; }I. a. si; N, 3.74iC
a. 4.66. Hs0. 1.02. IR (Nu
jol): 3275. 1548, 1158,
1094. 755, 719, 689, 591.
557 cab-1'HNMR (CDC1*)#
: 0.93-2.55 (m, 17H).
3.02 (m. 18). 5.22 (n, 2
}{). 6.50 (m. IH). 7.35-7
．． 60 (m, 3H). 7.85=8.03 <m
．． 2H). [:(2]D”20.6±0.6
(25°C, MaOH. c: 1.017). Furthermore, (+
)-S-1 4 5 in IN sodium hydroxide and then directly adding an aqueous calcium chloride solution to the resulting aqueous solution of the sodium salt without freeze-drying, exactly the same result can be obtained. (Left below) Reference example 1 (sodium salt) <+)-s-i 4 5 (1.0 0 g
: 2.8 4 8mM) in methanol 4
．． Sodium methoxide (0.1 9M methanol solution: 13.9 ml (
2. 648mM)) and stir. The reaction solution was concentrated under reduced pressure to obtain 1.08 g (100%) of a colorless foamy substance.
) is obtained. I tried to crystallize this from a small amount of water or 99.5% ethanol, but only a solution was obtained and no crystals were formed. As mentioned above, in sodium and arginine (+}-S-
1 4 5 could not be crystallized. Reference Example 2 (Free Acid) (+)-S-145 (4.30 g) was dissolved in 20 ml of toluene, and 5.0 g of n-hexane was added. 5 ml was added and left at -20°C for 20 hours to form colorless plate crystals.
Obtain 19 g (crystallinity 97.4%). mp. 82.5℃. [αko. +27,7*0.7” (25℃, CHs
OH, c=1.007>. (Space below) Experimental Example 1 Stability tests were conducted on the compounds obtained in (+)-S-1 4 5 and Examples/Reference Examples using the method shown below. The results are shown in the table. (Test method) Weigh approximately 5 mg of the test compound onto a platinum board (3 samples per compound). Place this in a desiccator containing phosphorus pentoxide and dry under reduced pressure overnight. After measuring the weight of each sample after drying, immediately fill each sample into a colorless tablet bottle, seal it tightly, and leave the two samples in a constant temperature bath (50°C). One sample should be stored at -20°C as a control. (Residual titer measurement) The residual titer of the test compound was measured by HPLC. The HPLC conditions are shown below. Danye 1S standard column: YMC pack column A-302 (S-5
120A ODS) 4.6 am I. D. X 15
cm (YMC) Mobile phase: Acetonitrile/methanol/water/acetic acid = 300/200/300/1 (
v/v). Flow rate: 1. O ml/min detection: 224 nm (column temperature: room temperature) Table

Claims (4)

[Claims] (1) (+)-(5Z)-7-[3-endo-[(phenylsulfonyl)amino]bicyclo[2,2,1]hept-2-exo-yl]heptenoic acid calcium salt. (2) The calcium salt according to claim (1) is recrystallized from a polar solvent and then converted into a free acid (+
)-(5Z)-7-[3-endo-[(phenylsulfonyl)amino]bicyclo[2,2,1]hept-2-exo-yl]heptenoic acid. (3) The purification method according to claim (2), wherein the polar solvent is water, isopropanol, or a mixture thereof. (4) Pharmacological efficacy of (+)-(5Z)-7-[3-endo-[(phenylsulfonyl)amino]bicyclo[2,2,1]hept-2-exo-yl]heptenoic acid calcium salt A thromboxane receptor antagonist containing an amount.