JPH0466234B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the following general formula (In the formula, R ¹ is a hydrogen atom or a lower alkyl group, n is an integer of 1 to 5, A is -CH ₂ -,

[expression] or

Indicates a group represented by [Formula]. ) and its salts. (Industrial Application Field) The compound of the general formula () of the present invention has thromboxane A ₂ (hereinafter referred to as TXA ₂ ) synthesis inhibiting action,
It is useful for the prevention and treatment of diseases involving TXA ₂ , such as angina pectoris, 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 to prostaglandin G ₂ (hereinafter referred to as PGG ₂ ) and further to prostaglandin H ₂ (hereinafter referred to as PGH ₂ ) by cyclooxygenase. Prostacyclin (hereinafter referred to as PGI ₂ ), prostaglandin E ₂ ( _hereinafter referred to as PGE ₂ ), prostaglandin F _2a (hereinafter referred to as PGF _2a ), TXA ₂ , etc. are produced from this PGG ₂ and PGH 2 by various enzymes. . Regarding the physiological activities of TXA ₂ , it is known that it has a strong platelet aggregation promoting effect and a vasoconstricting effect. It is known that TXA ₂ production is increased in some angina patients during angina attacks. (M. Tada et al., Circulation, Vol. 64, No. 6, 1107
Page, 1981). Drugs that suppress TXA ₂ production include cyclooxygenase inhibitors such as aspirin and indomethacin, and TXA ₂ synthase inhibitors such as dazoxiben (4-[2-(1-imidazolyl)ethoxy]benzoic acid hydrochloride). It has been known. 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 synthetase 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 intensive 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 ¹ 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. Next, a method for producing the compound of general formula () of the present invention will be explained. As a typical method for producing the compound of general formula (), a method for producing a compound in which pyridyl alkyl is substituted at the 2-position of 1,2,3,4-tetrahydronaphthalene is shown below. (In the formula, R ² is a lower alkyl group, m is 0 to 4
, and n is the same as above. ) That is, when the compound of formula () is heated and reacted in a mixture of the compound of formula (), acetic acid and pyridine, the compound of formula () is produced. By catalytically reducing this in an alcohol such as methanol, ethanol, or acetic acid using palladium charcoal or platinum as a catalyst, pyridyl alkyl is substituted at the 2-position of 1,2,3,4-tetrahydronaphthalene in formula (), and R ¹ is lower alkyl and A is

A compound of formula (') can be prepared. When the compound of formula (') is reacted with sodium borohydride in an alcohol such as ethanol, and the crude product obtained is treated with concentrated hydrochloric acid in alcohol, the compound of formula () is produced.
By catalytically reducing this in an alcohol such as ethanol, methanol, or acetic acid using palladium charcoal or platinum as a catalyst, pyridyl alkyl is substituted at the 2-position of 1,2,3,4-tetrahydronaphthalene in formula (), and R ¹ is A compound of formula ('') where A is -CH ₂ - in a lower alkyl group can be produced. The compound of formula (') or formula ('') thus obtained is treated with sodium hydroxide and hydroxide. By hydrolysis using an alkali such as potassium or an inorganic acid such as hydrochloric acid or sulfuric acid, pyridyl alkyl is substituted at the 2-position of 1,2,3,4-tetrahydronaphthalene in formula (), and R ¹ is a hydrogen atom. A is −CH ₂ − or

Compounds of the formula can be prepared. Furthermore, in formula (), pyridyl alkyl is substituted at the 2-position of 1,2,3,4-tetrahydronaphthalene, R ¹ is a hydrogen atom, and A is

By reacting a compound of [formula] with hydrazine, pyridyl alkyl in formula () is 1,2,3,
R ₁ substituted at the 2-position of 4-tetrahydronaphthalene
is a hydrogen atom and A is

Compounds of the formula can be prepared. (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. 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. The present invention will be explained below using Examples and Test Examples. Example 1 6-(3-pyridylmethyl)-5-oxo-5,
Ethyl 6,7,8-tetrahydro-2-naphthalenecarboxylate (1) 6-(3-pyridylmethylidene)-5-oxo-5,6,7,8-tetrahydro-2-naphthalenecarboxylate ethyl 5-oxo -5.0g of ethyl 5,6,7,8-tetrahydro-2-naphthalenecarboxylate
- Mix 2.5 g of pyridine aldehyde, 10 ml of acetic acid and 10 ml of piperidine and stir at 100° C. for 4 hours. Concentrate under reduced pressure, dissolve the residue in ethyl acetate, and extract with 10% hydrochloric acid. The hydrochloric acid layer is separated, neutralized with sodium hydrogen carbonate, and extracted with chloroform. The extract was washed with water, dried, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 5.6 g of pale yellow crystals. Melting point 112-114℃. (2) 6-(3-pyridylmethyl)-5-oxo-
Ethyl 5,6,7,8-tetrahydro-2-naphthalenecarboxylate 6.3g of the compound prepared above was added to 50ml of ethanol.
and 10% palladium on charcoal in 50 ml of ethyl acetate
catalytic reduction using g. After hydrogen absorption is completed,
The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4.8 g of the title compound as an oil. ¹ H-NMR spectrum (CDCl ₃ ) δ: 1.40 (3H, t, -CO ₂ CH ₂ C H ₃ ) 1.8 to 2.2 (2H, m, hydrogen at the 7th position of naphthalene) 2.6 to 3.6 (5H, m, naphthalene 6, 8th position hydrogen,
methylene hydrogen) 4.36 (2H, q, -CO ₂ CH ₂ CH ₃ ) 7.1-8.5 (7H, m, aromatic ring hydrogen) Example 2 6-(3-pyridylmethyl)-5-oxo-5,
6,7,8-tetrahydro-2-naphthalenecarboxylic acid hydrochloride 6-(3-pyridylmethyl)- prepared in Example 1
5-oxo-5,6,7,8-tetrahydro-2
- Mix 4.5 g of ethyl naphthalenecarboxylate with 8.5 g of sodium hydroxide and 100 ml of water, and heat and stir at 100°C for 3 hours. After cooling, the mixture is neutralized with acetic acid, and the precipitated crystals are collected by filtration and washed with water. Suspend in ethanol, add hydrogen chloride-ethanol solution, dry under reduced pressure, and recrystallize from methanol to obtain colorless crystals of the title compound.
get g. Melting point 239-250℃. Elemental analysis value C ₁₇ H ₁₅ NO ₃・HCl Calculated value C 64.25, H 5.08, N 4.41 Experimental value C 64.40, H 4.97, N 4.03 Example 3 6-(3-pyridylmethyl)-5-hydrazono-
5,6,7,8-tetrahydro-2-naphthalenecarboxylic acid hydrochloride 6-(3-pyridylmethyl)- produced in Example 2
5-oxo-5,6,7,8-tetrahydro-2
- 1.6 g of naphthalene carboxylic acid hydrochloride are mixed with 2 g of 80% hydrazine hydrate, 1.9 g of potassium hydroxide and 20 ml of ethylene glycol and heated at 120° C. for 4 hours. After cooling, the reaction solution is poured into water, and acetic acid is added to neutralize it. The precipitated powder is collected by filtration, mixed with a hydrogen chloride-ethanol solution, and concentrated under reduced pressure. The residue was recrystallized from a mixture of methanol and ether to obtain 0.9 g of the title compound as a powder. Melting point 275℃
(Disassembly). Elemental analysis value C ₁₇ H ₁₇ N ₃ O ₂・2HCl Calculated value C 55.44, H 5.20, N 11.41 Experimental value C 55.89, H 5.52, N 11.61 Example 4 6-(3-pyridylmethyl)-5,6, 7,8-
Ethyl tetrahydro-2-naphthalenecarboxylate (1) Ethyl 6-(3-pyridylmethyl)-7,8-dihydro-2-naphthalenecarboxylate 6-(3-pyridylmethyl) prepared in Example 1
Dissolve 3 g of ethyl -5-oxo-5,6,7,8-tetrahydro-2-naphthalenecarboxylate in 50 ml of ethanol, and dissolve sodium borohydride.
Add 0.9 g little by little and heat under reflux at room temperature for 1 hour. Concentrate under reduced pressure, add water to the residue, and extract with chloroform. The extract is washed with water, dried, and concentrated under reduced pressure to obtain an oil. Add this oil to 80% ethanol
ml, add 20 ml of concentrated hydrochloric acid, and heat under reflux for 5 hours. After neutralization with sodium hydrogen carbonate, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain 1.8 g of the title compound as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.36 (3H, t, -CO ₂ CH ₂ C H ₃ ) 2.0 to 2.4 (2H, m, hydrogen at the 7th position of naphthalene) 2.6 to 2.9 (2H, m, hydrogen at the 8th position of naphthalene) ) 3.5 (2H, m,

[Formula] ) 4.32 (2H, q, -CO ₂ C H ₂ CH ₃ ) 6.21 (1H, m, hydrogen at 5th position of naphthalene) 6.9-8.45 (7H, m, aromatic ring hydrogen) (2) 6-(3- pyridylmethyl)-5,6,7,8
-ethyl tetrahydro-2-naphthalenecarboxylate 1.8g of the compound prepared above was added to 100ml of ethanol.
and catalytic reduction using 1 g of 10% palladium on charcoal. After hydrogen absorption is completed, the catalyst is removed by filtration,
The filtrate was concentrated under reduced pressure to obtain 1.8 g of the title compound as an oil. ¹ H-NMR spectrum (CDCl ₃ ) δ: 1.36 (3H, t, -CO ₂ CH ₂ C H ₃ ) 1.8-2.3 (2H, m, hydrogen at 7-position of naphthalene) 2.4-3.3 (7H, m-naphthalene 5, 6 , 8-position hydrogen, methylene hydrogen) 4.32 (2H, q, -CO ₂ C H ₂ CH ₃ ) 7.0-8.5 (7H, m, aromatic ring hydrogen) Example 5 6-(3-pyridylmethyl)-5,6 ,7,8-
Tetrahydro-2-naphthalenecarboxylic acid hydrochloride 6-(3-pyridylmethyl) prepared in Example 4
1.8 g of ethyl -5,6,7,8-tetrahydro-2-naphthalenecarboxylate was mixed with 50 ml of 6N hydrochloric acid, heated under reflux for 4 hours, and then dried under reduced pressure. The resulting residue was recrystallized from methanol to obtain 1.04 g of colorless crystals of the title compound. Melting point 222-226℃. ¹ H-NMR spectrum (dimethyl sulfoxide- _d6 ) δ: 1.8-2.2 (2H, m, hydrogen at the 7th position of naphthalene) 2.4-3.3 (7H, m, hydrogen at the 5th, 6th, and 8th positions of naphthalene, methylene hydrogen) 7.1-8.9 (7H, m, aromatic ring hydrogen) Elemental analysis value C ₁₇ H ₁₇ NO ₂・HCl Calculated value C 67.21, H 5.97, N 4.61 Experimental value C 67.17, H 6.02, N 4.55 Test example In vitro platelet TXA ₂ production inhibition Preparation of test PRP (platelet-rich plasma) Citrate-added blood (1 volume of 3.13% sodium citrate was added to 9 volumes of blood) from male Wistar Kondo rats weighing 280 to 320 g through cardiac puncture under pentobarbital anesthesia. ) 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 g.
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,
10μ of this mixture was added to 90μ of a 100μM flurpiprofen 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, TXA ₂
PGE ₂ , PGF _2a due to deficiency or inhibition of synthetic enzymes
and increased production of 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
B ₂ Production Amount The larger this value is, the stronger the TXA ₂ synthesis inhibitory effect is and the weaker the cyclooxygenase inhibitory effect. The activity of the compounds of the present invention obtained in the test examples is shown in the table below.

【table】

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ is a hydrogen atom or a lower alkyl group, n is an integer of 1 to 5, A is -CH ₂ -,
Indicates a group represented by [Formula] or [Formula]. ) and its salts.