JPH0528711B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to the general formula (wherein R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, and n represents an integer of 1 to 3) and salts thereof. (Industrial Application Field) The compound of the general formula () of the present invention has an inhibitory effect on the synthesis of thromboxane A ₂ (hereinafter abbreviated as TXA ₂ ), and is effective against diseases involving TXA ₂ , such as angina pectoris,
It is useful for the prevention and treatment of ischemic heart diseases such as myocardial infarction, cerebrovascular disorders, and thrombosis. (Prior Art) TXA ₂ is a physiologically active substance that is biosynthesized from arachidonic acid in vivo. To explain in more detail, arachidonic acid is converted into prostaglandin G ₂ (hereinafter referred to as PGG ₂ ) and prostaglandin H ₂ (hereinafter referred to as PGH ₂ ) by cyclooxygenase. This PGG ₂ ,
PGH ₂ is converted into prostacyclin (hereinafter PGI ₂ ) and prostaglandin E ₂ (hereinafter referred to as PGI 2 ) by various enzymes.
PGE ₂ ), prostaglandin F _2a ) and TXA ₂
etc. are produced. Regarding the physiological activities of TXA ₂ , it is known that it has a strong platelet aggregation promoting effect and vasoconstricting effect, and it is known that in some patients with angina pectoris, TXA ₂ production is increased during angina attacks. There is. (M. Tada et al.
Circulation, Vol. 64, No. 6, p. 1107, 1981) Drugs that suppress TXA ₂ production include cyclooxygenase inhibitors such as aspirin or indomethacin, and dazoxyben (4-[2-(1-imidazolyl)ethoxy]benzoic acid hydrochloride) salt) etc.
TXA ₂ synthase inhibitors are known. The former cyclooxygenase inhibitor suppresses the production of TXA ₂ and at the same time suppresses the production of other prostaglandins such as PGI ₂ and PGE ₂ . PGI ₂ is
It has physiological activities that are contradictory to TXA ₂ , namely strong platelet aggregation inhibitory and vasodilatory effects.
Suppression of PGI ₂ production is not favorable for ischemic heart diseases such as angina pectoris and myocardial infarction. On the other hand, the latter TXA ₂ synthetase inhibitor suppresses TXA ₂ production, but rather increases the production of PGI ₂ , PGE _2, etc., so the latter is more preferable than the former. However, known TXA ₂ synthase inhibitors also exhibit cyclooxygenase inhibitory effects at high concentrations. Therefore, a compound having a highly selective TXA ₂ synthesis inhibitory effect is desired. The present inventors completed the present invention as a result of intensive studies aimed at overcoming these drawbacks of conventional TXA ₂ synthesis inhibitors. (Structure of the Invention) The present invention relates to a compound of general formula () and a salt thereof. Examples of salts include acid addition salts with inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as fumaric acid, maleic acid, tartaric acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid;
When R ² is a hydrogen atom, examples thereof include alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts and magnesium salts of carboxylic acids. Next, a method for producing the compound of general formula () of the present invention will be described. (In the formula, R ²¹ and R ³ each represent a lower alkyl group, and R ¹ and n are the same as above.) That is, a compound represented by the formula () is converted into a compound represented by the formula ()
By reacting a compound represented by the formula or a compound represented by the formula () in a solvent such as tetrahydrofuran, dioxane or dichloromethane in the presence or absence of an inorganic salt such as sodium hydride, sodium alkoxide or potassium tert-butoxide, the formula Compounds of formula (a) in which R ² is a lower alkyl group can be produced. By hydrolyzing the generated compound of formula (a) using an acid such as hydrochloric acid or sulfuric acid or an alkali such as sodium hydroxide or potassium hydroxide, the formula ()
A compound of formula (b) in which R ² is a hydrogen atom can be produced. Further, a compound in which R ¹ and R ² both represent a hydrogen atom in formula () can also be produced by heating the compound of formula () with malonic acid in pyridine. (Effects of the Invention) The compound of formula () of the present invention has a strong TXA ₂ synthesis inhibitory effect. Regarding the strength of its activity, we specifically determined the production amount of thromboxane B ₂ (hereinafter referred to as TXB ₂ ), a stable metabolite of TXA ₂ , produced by adding arachidonic acid to platelet-rich plasma (PRP) obtained from rat blood. It was measured by radioimmunoassay (RIA method), and the 50% inhibition molar concentration (IC ₅₀ value) for TXA ₂ synthesis was determined in comparison with the non-administered group. In addition, selectivity for inhibition of TXA ₂ synthesis was determined by the method described below. Inhibiting cyclooxygenase reduces the amount of PGE ₂ produced, but inhibiting TXA ₂ synthase increases the amount of PGE ₂ produced, so when measuring the amount of TXB ₂ produced earlier, it is necessary to measure the amount of PGE ₂ produced. , determine the amount of increase in PGE ₂ production compared to that of the non-administration group. The ratio between this and the amount of inhibition of TXA ₂ production was determined, and this was used as an index of selectivity for inhibition of TXA ₂ synthesis. The larger this index is, the higher the selectivity of suppressing TXA ₂ synthesis. The compound of the present invention had a stronger and more selective TXA ₂ synthesis inhibitory effect than dazoxiben, a known TXA ₂ synthase inhibitor. (Examples) The present invention will be explained below with reference to Examples and Test Examples. The compound of general formula () which is a raw material of the present invention is a new compound, and an example of its synthesis method is shown in Reference Example. Reference example 1 4-(5-thiazolylmethyl)benzaldehyde (1) Ethyl 4-(2-chloro-2-formylethyl)benzoate Suspend 11.9 g of ethyl p-aminobenzoate in a mixture of 18 ml of water and 18 ml of concentrated hydrochloric acid, and suspend on ice. Cool down. -5~0
A solution of 6 g of sodium nitrite and 27 ml of water was added dropwise at 0°C, and the mixture was further stirred at 0°C for 20 minutes. Add sodium bicarbonate to neutralize. Add this solution to 11.7 ml of acrolein, 4.49 g of cupric chloride, and calcium oxide.
Add to an ice-cold solution consisting of 1.8 g and 90 ml of acetone. After further stirring for 2 hours under ice cooling, acetone was distilled off under reduced pressure and extracted with benzene. The organic layer was separated, washed with water, dried, and concentrated under reduced pressure to obtain 15.1 g of the title compound as an oil. (2) Ethyl 4-[(2-aminothiazol-5-yl)methyl]benzoate 15.1 g of the compound prepared in (1) was mixed with 240 ml of ethanol together with 4.78 g of thiourea and heated under reflux for 25 hours.
Concentrate under reduced pressure, neutralize the residue with sodium hydrogen carbonate, and extract with chloroform. Wash the extract with water,
After drying, the mixture was concentrated under reduced pressure, and the residue was crystallized from a mixture of benzene and n-hexane to obtain 18.8 g of colorless prism crystals of the title compound. Melting point 108-110℃. (3) Ethyl 4-[(2-chlorothiazol-5-yl)methyl]benzoate (18.8 g of the compound prepared from (2) was dissolved in 80 ml of acetonitrile.
11.6 g of cupric chloride, 10.4 g of tertiary butyl nitrite and 200 g of acetonitrile
ml solution at 55-60°C. After dropping, stir at 60°C for 20 minutes. Cool the reaction solution and incubate for 15
Add 150ml of % hydrochloric acid and extract with chloroform.
After drying the extract, it was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 12.1 g of the title compound as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.39 (3H, t, -CO ₂ CH ₂ C H ₃ ) 4.13 (2H, s, -CH ₂ -) 4.37 (2H, q, -CO ₂ C H ₂ CH ₃ ) 7.26 (1H, s, thiazole 4-position hydrogen) 7.31 (2H, d, benzene ring hydrogen) 8.01 (2H, d, benzene ring hydrogen) (4) Made from ethyl 4-(5-thiazolylmethyl)benzoate (3) Dissolve 11.8g of the compound in 200ml of acetic acid,
Add 5.49 g of subpowder and reflux for 2 hours. Insoluble matters are removed by filtration, and the filtrate is concentrated under reduced pressure. The residue was dissolved in chloroform, washed with water, dried, and concentrated under reduced pressure to obtain 8.49 g of the title compound as an oil. (5) 4-(5-thiazolylmethyl)benzyl alcohol 8.49 g of the compound prepared in (4) was added to tetrahydrofuran.
The solution dissolved in 60 ml was added dropwise to a suspension consisting of 1.3 g of lithium aluminum hydride and 30 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 5 hours. 2 ml of water, 2 ml of a 15% aqueous sodium hydroxide solution and 6 ml of water were sequentially added dropwise to the reaction mixture under ice cooling, and insoluble materials were filtered off.
The filtrate is concentrated under reduced pressure and extracted with chloroform.
The extract was washed with water, dried, and concentrated under reduced pressure to obtain 6.3 g of the title compound as an oil. (6) 4-(5-thiazolylmethyl)benzaldehyde Dissolve 5.04 g of the compound prepared in (5) in a mixture of 25 ml of dimethyl sulfoxide and 25 ml of benzene, and add 2 ml of pyridine and 15.2 g of dicyclohexylcarbodiimide.
Add 0.95 ml of trifluoroacetic acid and stir at room temperature for 71 hours. 500 ml of ether is added to the reaction solution, and then a solution of 6.63 g of oxalic acid dissolved in 30 ml of methanol is added dropwise. After stirring for 30 minutes at room temperature, water was added and insoluble materials were filtered off. The organic layer of the filtrate is washed with saturated aqueous sodium bicarbonate solution. After drying, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1.75 g of the title compound as an oil. ¹ H-NMR (CDCl ₃ ) δ: 4.27 (2H, s, -CH ₂ -) 7.39 (2H, d, benzene ring hydrogen) 7.67 (1H, s, hydrogen at 4-position of thiazole) 7.87 (2H, d, benzene ring Hydrogen) 8.70 (1H, s, hydrogen at 2-position of thiazole) 9.98 (1H, s, -CHO) Example 1 (E)-3-[4-(5-thiazolylmethyl)phenyl]propenoic acid 4 produced in Reference Example 1 -(5-thiazolylmethyl)
0.2 g of benzaldehyde and 104 mg of malonic acid are mixed with 0.3 ml of pyridine and heated at 100° C. for 4 hours. After cooling, dilute ammonia water is added and insoluble matter is filtered off. The filtrate is made acidic with concentrated hydrochloric acid, and the crystals are collected by filtration and recrystallized from aqueous ethanol to obtain 130 mg of the title compound as a colorless powder. Melting point 183-185℃. ¹ H-NMR (CDCl ₃ ) δ: 4.21 (2H, s, -CH ₂ -) 6.43 (1H, d, J = 16 Hz) 7.25 (2H, d, J = 8 Hz, benzene ring hydrogen) 7.52 (2H, d , J = 8Hz, benzene ring hydrogen) 7.67 (1H, s, hydrogen at 4th position of thiazole) 7.76 (1H, d, J = 16Hz) 8.72 (1H, s, hydrogen at 2nd position of thiazole) Elemental analysis C ₁₃ H ₁₁ NO ₂ S Calculated value C 63.65, H 4.52, N 5.71 Analytical value C 63.61, H 4.47, N 5.76 Example 2 Ethyl (E)-2-methyl-3-[4-(5-thiazolylmethyl)phenyl]propenoate Reference example 1 4-(5-thiazolylmethyl) prepared by
1.0 g of benzaldehyde and 1.51 g of ethyl 2-(triphenylphosphoranylidene)propionate were dissolved in 25 ml of dichloromethane and stirred at room temperature for 2 hours. Concentrate under reduced pressure, and purify the residue using silica gel column chromatography to obtain 0.79 g of the title compound as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, t, -CO ₂ CH ₂ C H ₃ ) 2.11 (3H, d, J=1.3Hz, -CH ₃ ) 4.20 (2H, s, -CH ₂ - ) 4.27 (2H, q, -CO ₂ C H ₂ CH ₃ ) 7.22 (2H, d, benzene ring hydrogen) 7.37 (2H, d, benzene ring hydrogen) 7.67 (2H, s, thiazole 4-position hydrogen, -CH
=) 8.68 (1H, s, hydrogen at 2-position of thiazole) Example 3 (E)-2-methyl-3-[4-(5-thiazolylmethyl)phenyl]propenoic acid (E)-2- produced in Example 2 Methyl-3[4-(5
-Thiazolylmethyl)phenyl]ethyl propenoate (790 mg) was added to a mixture of 1.9 ml of 6N aqueous sodium hydroxide solution and 2 ml of ethanol and heated under reflux for 30 minutes. Concentrate under reduced pressure, add water, and filter off insoluble matter. The filtrate was adjusted to pH 7 with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration.
Recrystallization from aqueous ethanol gives 340 mg of crystals of the title compound. Melting point 182-184℃. ¹ H-NMR (CDCl ₃ ) δ: 2.14 (3H, d, -CH ₃ ) 4.21 (2H, s, -CH ₂ -) 7.26 (2H, d, J = 8 Hz, benzene ring hydrogen) 7.41 (2H, d , J=8Hz, benzene ring hydrogen) 7.69 (1H, s) 7.79 (1H, s) 8.73 (1H, s, hydrogen at 2-position of thiazole) Elemental analysis C ₁₄ H ₁₃ NO ₂ S Calculated value C 64.84, H 5.05, N 5.40 Analytical values C 64.81, H 5.21, N 5.31 Test example In vitro platelet TXA ₂ production inhibition test Preparation of PRP (platelet rich plasma) Male Wistar Kondo rats weighing 280 to 320 g were subjected to cardiac puncture under pentobarbital anesthesia. Collect citrated blood (1 volume of 3.13% sodium citrate added to 9 volumes of blood) at room temperature, 230 × g
Centrifuged for 7 minutes. The obtained supernatant (PRP)
Dilute with PPP (platelet poor plasma) to reduce the platelet count to 5.
The concentration was adjusted to ×10 ⁸ cells/ml, and the following test was used.
As PPP, the residue after PRP separation is 1500 x 10
The mixture was centrifuged for a minute and the supernatant was used. TXA ₂ and PGE ₂ production reaction and its measurement Add 90μ of the above PRP to 10μ of the sample solution, shake for 1 minute, and then take 90μ of this mixture.
Combined with 10μ of 5mM sodium arachidonic acid solution and shaken at room temperature. After shaking for 5 minutes,
10 μl of this mixed solution was added to 90 μl of a 100 μM flurbiprofen solution to stop the reaction. The reaction solution was centrifuged at 1000 x g for 5 minutes, and the supernatant obtained was
TXB ₂ (stable decomposition product of TXA ₂ ) and PGE ₂ concentration
It was measured according to the radioimmunoassay method of Morris et al. (Prostaglandins 21 , 771, 1981). Each specimen and reagent was dissolved in saline or methanol to form a concentrated solution, diluted with saline to an appropriate concentration, and used. The TXA ₂ synthesis inhibition rate was calculated using the following formula, and the TXA ₂
The synthesis inhibitory activity was expressed as the concentration of the sample exhibiting a 50% inhibition rate (IC ₅₀ ). Inhibition rate = 100 - (TXB ₂ concentration at the time of sample addition / TXB ₂ concentration in control x 100) In platelets, inhibition of cyclooxygenase suppresses the production of not only TXB ₂ but also PGE ₂ and PGF _2a (Hamberg et al., Proc. Nat.
Acad.Sci.USA, 71 , 3824, 1974); conversely, deficiency or inhibition of TXA ₂ synthetase leads to the production of PGE ₂ , PGF _2a and
Increased production of PGD ₂ (Defreyn et al., Brot,
J. Haematol. 49 , 29, 1981). Therefore, the selectivity index for inhibition of TXA ₂ synthesis was calculated using the following formula, and the relationship between the effects on both TXA ₂ synthase and cyclooxygenase was shown. Selectivity index of TXA ₂ synthesis inhibition = PGE ₂ production amount when sample is added - PGE ₂ production amount of control / TXB ₂ production amount of control - when sample is added
TXB ₂ production amount The larger this number is, the stronger the TXA ₂ synthesis inhibitory effect is and the weaker the cyclooxygenase inhibitory effect. The effects of the compounds of the present invention obtained in the test examples are shown in the table below. 【table】

Claims (1)

[Claims] 1. General formula Thiazole derivatives and salts thereof represented by (wherein R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, and n represents an integer of 1 to 3)