JPH0564628B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention is based on the following general formula: (In the formula, R represents a hydrogen atom or a lower alkyl group, n
represents an integer from 1 to 3) and salts thereof.

(Industrial Application Field) The compound of formula () of the present invention has a strong thromboxane A ₂ (hereinafter referred to as TXA ₂ ) synthesis inhibitory effect, and is effective against diseases involving TXA ₂ , such as angina pectoris and myocardial It is useful as a prophylactic or therapeutic agent for ischemic heart diseases such as infarction, cerebrovascular disorders, thrombosis, and the like.

(Prior Art) TXA ₂ is a physiologically active substance that is biosynthesized from arachidonic acid in vivo. More specifically, 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
Prostacyclin (hereinafter referred to as PGI ₂ ) and prostaglandin are produced from PGG ₂ and PGH ₂ by various enzymes.
E ₂ (hereinafter referred to as PGE ₂ ), prostaglandin F _2a (hereinafter referred to as PGF _2a ), TXA ₂ and the like are produced. TXA ₂
Its physiological activities are known to have strong platelet aggregation promoting effects and vasoconstricting effects. It is known that TXA ₂ production is increased in some angina patients during attacks. (M. Tada et al., Circulation, Vol. 64, No. 6,
1107, 1981) Drugs that suppress TXA ₂ production include cyclooxygenase inhibitors such as aspirin and indomethacin, and dazoxiben (4-[2-(1-
TXA _{2 synthesis inhibitors are known, typified by TXA 2} synthesis inhibitors such as (imidazolyl)ethoxy]benzoic hydrochloride) and the like.

The former cyclooxygenase inhibitor suppresses the production of TXA ₂ and at the same time inhibits the production of other prostaglandins such as PGI ₂ and PGE ₂ . PGI ₂
Since PGI 2 has physiological activities that are contradictory to those of TXA ₂ , namely, a strong platelet aggregation inhibitory effect and vasodilating effect, inhibition of PGI ₂ production is preferable for ischemic diseases such as angina pectoris and myocardial infarction. No, no. On the other hand, TXA ₂ synthase inhibitors suppress the production of TXA ₂ , but inhibit the production of other prostaglandins, i.e.
The latter can be said to be more preferable for ischemic diseases since it rather increases the production amount of PGI ₂ , PGE ₂ and the like.

However, dazoxiben, a known TXA ₂ synthase inhibitor, also exhibits cyclooxygenase inhibitory effects at higher concentrations. Therefore, a compound having a more selective TXA ₂ synthesis inhibitory effect is desired.

The present inventors have completed the present invention as a result of extensive studies aimed at overcoming these drawbacks of conventional compounds having an inhibitory effect on TXA ₂ synthesis.

That is, 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, sulfuric acid, and nitric acid, and organic acids such as fumaric acid, tartaric acid, maleic acid, succinic acid, oxalic acid, benzenesulfonic acid, toluenesulfonic acid, and methanesulfonic acid;
When R 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 carboxyl groups.

The compound of the present invention can be produced according to the reaction formula shown below.

(In the formula, R ₁ represents a lower alkyl group, n represents an integer of 1 to 3, and X represents a toluenesulfonyloxy group, a methanesulfonyloxy group, or a halogen atom). A compound of formula () in which R is a lower alkyl group can be prepared by reacting with imidazole in a solvent in the presence of sodium hydride or sodium alkoxide. By hydrolyzing the obtained compound using an acid such as dilute hydrochloric acid or dilute sulfuric acid or an alkali such as sodium hydroxide or potassium hydroxide, a compound of formula () in which R is a hydrogen atom is produced. can do.

(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, thromboxane B ₂ (hereinafter referred to as TXB ₂ ) is a stable metabolite of TXA ₂ produced by adding arachidonic acid to platelet-rich plasma (PRP) obtained from rat blood.
The production amount of TXA 2 was measured by specific radioimmunoassay (RIA method), and the 50% inhibitory molar concentration (IC ₅₀ value) for TXA ₂ synthesis was determined in comparison with the non-administered group. . Furthermore, 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-administered group. The ratio between this and the amount of inhibition of TXB 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.

(Example) The present invention will be explained below using reference examples, examples, and test examples. The raw material compounds of the present invention are each new compounds, and typical manufacturing methods thereof are shown in the following Reference Examples.

Reference Example 1 Ethyl (4-bromo-1-indanilidene) acetate 10 g of zinc and mercurous chloride (catalytic amount) in benzene
Suspend in 50 ml and heat to 100℃, 4-bromo-1
- A solution consisting of 10.6 g of indanone, 14 ml of ethyl bromoacetate and 100 ml of tetrahydrofuran was added.
After heating under reflux for 2 hours, the reaction solution was added to 200 ml of 6N sulfuric acid, and the organic layer was separated and concentrated to dryness. silica gel
The mixture was applied to a 100 g column and eluted with chloroform to obtain a pale yellow oil. This was added to 50 ml of formic acid, and after heating for 2 hours, the reaction solution was concentrated to dryness. After neutralizing with potassium carbonate, the mixture was extracted with chloroform. Apply to silica gel column and elute with chloroform to remove oil.
I got 10.5g.

NMR (deuterated chloroform) δ: 6.23 (1H, t, CH) 6.46 (1H, bs, CH) According to NMR, the above oil is ethyl (4-bromo-
1-indanilidene) acetate and ethyl (4-
It was a 1:2 mixture of bromo-1-indene) acetate.

Reference example 2 2-(4-bromo-1-indanyl)
Ethanol 1.4 g of lithium aluminum hydride was suspended in 50 ml of tetrahydrofuran, and the oil obtained in Reference Example 1 was dissolved in 20 ml of tetrahydrofuran and added dropwise thereto. Stirred at room temperature for 2 hours. After adding water, insoluble matter was filtered off and the solvent was distilled off under reduced pressure. The residue was applied to a silica gel column and eluted with chloroform to obtain 6.1 g of an oil.

NMR (deuterated chloroform) δ: 2.80 (2H, m, CH ₂ ) 2.29 (2H, d, indane-3 position CH ₂ ) 3.87 (2H, t, CH ₂ O) 6.32 (1H, bs, CH) 6.8-7.4 (3H, m, aromatic ring H) According to NMR, the above oil contains 2 in addition to the title compound.
-(4-bromo-1-indenyl)ethanol was present.

Reference example 3 Ethyl 1-(2-hydroxyethyl)
Indane-4-carboxylate Three drops of concentrated hydrochloric acid were added to a mixture of 6.0 g of the oil obtained in Reference Example 2 and 2.1 g of 2,3-dihydropyran, and the mixture was stirred at room temperature for 20 hours. Potassium carbonate aqueous solution 50
ml was added and extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain an oil. It was applied to a silica gel column and eluted with chloroform to obtain 7.1 g of an oily substance.

NMR (deuterochloroform) δ: 4.62 (1H, bs, tetrahydropyran-2 position) 6.55 (1H, bs, C=CH) 2.1 g of magnesium and 10 ml of tetrahydrofuran
A mixture of 7.0 g of the above oil and 4.7 g of ethyl bromide dissolved in 30 ml of tetrahydrofuran was added dropwise to the heated mixture. After heating under reflux for 3 hours, the mixture was added to dry ice and stirred for 1 hour. 20 ml of concentrated hydrochloric acid and water were added, and the mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate solution was extracted with an aqueous potassium carbonate solution, acidified with concentrated hydrochloric acid, and then extracted again with 100 ml of ethyl acetate. The solvent was distilled off, the residue was dissolved in 40 ml of ethanol, 5 ml of concentrated sulfuric acid was added, and the mixture was heated under reflux for 15 hours. Ethanol was distilled off under reduced pressure, and the mixture was extracted with 100 ml of chloroform. After washing with an aqueous potassium carbonate solution, the solvent was distilled off. The obtained oil was applied to a silica gel column and eluted with chloroform to obtain 600 mg of the title compound as an oil.

NMR (deuterochloroform) δ: 1.36 (3H, t, CH ₃ ) 1.4-2.5 (4H, m, CH ₂ ×2) 3.2 (3H, m, indane-1, 3-position CH, CH ₂ ) 3.74 (2H, t, OCH ₂ ) 4.33 (2H, q, OCH ₂ ) 7.0-7.42 (2H, m, indane-6, 7-position H) 7.82 (1H, dd, indane-5-position H) Example 1 1-[2- (1-Imidazolyl)ethyl]indan-4-carboxylic acid hydrochloride Ethyl obtained in Reference Example 3 1-(2-hydroxyethyl)indan-4-carboxylate 600 mg
was dissolved in 30 ml of pyridine, and 730 mg of p-toluenesulfonyl chloride was added under ice cooling. below 10℃
After standing for 16 hours, it was poured into a mixture of ice water and concentrated hydrochloric acid, and extracted with chloroform. After distilling off the solvent, an oil was obtained. 200 mg of imidazole was dissolved in 20 ml of tetrahydrofuran, 120 mg of 50% sodium hydroxide was added, and after 10 minutes, the above oil was added dropwise.
After being left at room temperature for 16 hours, the residue was distilled off under reduced pressure and extracted with chloroform. It was applied to a silica gel column and eluted with chloroform-ethanol (20:1) to obtain an oily substance of ethyl 1-[2-(1-imidazolyl)ethyl]indan-4-carboxylate.

The above oil was added to a mixture of 120 mg of sodium hydroxide, 20 ml of water and 5 ml of methanol and heated at 50°C for 3 hours. The mixture was acidified with concentrated hydrochloric acid and purified and separated using high performance liquid chromatography to obtain 120 mg of the title compound.
Melting point 172-174℃.

IR (KBr) cm ^-1 : 1710, 1205 NMR (heavy water) δ: 1.5 to 3.5 (7H, m, CH ₂ × 2, CH) 4.37 (2H, t, CH ₂ -N) 7.2 to 7.9 (5H, m , aromatic ring H) 8.79 (1H, s, imidazole-2H) Elemental analysis C ₁₅ H ₁₆ N ₂ O ₂・1/2H ₂ O Theoretical value C 59.70, H 6.01, N 9.28 Actual value C 59.65, H 5.89, N 8.73 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 and citrated blood was added (for 9 volumes of blood). 1 volume of 3.13% sodium citrate) was collected 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.
It was adjusted to ×10 ⁸ cells/ml and used in the following tests.
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 test bag 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,
10μ of this mixed solution was added to 90μ of a 100μ 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 /
Control TXB ₂ concentration 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, TXA ₂
Deficiency or inhibition of synthetic enzymes increases the production of PGE ₂ , PGF _2a and PGD ₂ (Defreyn et al.
Brot. J. Haematol. 49 , 29, 1981) is known. 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 -
Control PGE ₂ production amount / Control TXB ₂ production amount - TX when adding sample
Amount of B ₂ produced The larger this value is, the better the selectivity for the TXA ₂ synthesis inhibitory effect is.

The compound of Example 1 of the present invention had a TXA ₂ synthesis inhibitory activity, that is, IC ₅₀ of 0.86×10 ⁻⁶ M, and a selectivity index of 1.00, indicating a strong and highly selective activity. On the other hand, the IC ₅₀ of dazoxiben, a known TXA ₂ synthesis inhibitor, is 11 × 10 ^-6 , and the selectivity index is
0.86, and the compound of the present invention was superior to dazoxiben in both the TXA ₂ synthesis inhibitory effect and the selectivity index.

Claims (1)

[Claims] 1. General formula (In the formula, R represents a hydrogen atom or a lower alkyl group, n
represents an integer of 1 to 3) and its salts