JPS60246380A - Tetrahydronaphthalene derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [one of R<1> and R<2> is lower alkoxycarbonyl or carboxy and the other is group of formula II (n is 1-6)] and its salt. EXAMPLE:6-( Thiazol-5-ylmethyl )-5,6,7,8-tetrahydro-2-naphthalenecarboxylic acid sodium salt. USE:Remedy and preventive for ischemic diseases such as stenocardia, myocardial infraction, etc., cerebrovascular disorder, and thrombosis. It inhibits the synthesis of thromboxane A2, and its activity and selectivity are superior to those of known dazoxiben. PREPARATION:The compound of formula I wherein one of R<1> and R<2> is lower alkoxycarbonyl and the other is group of formula II can be prepared e.g. by reacting the compound of formula III (one of R<3> and R<4> is lower alkoxycarbonyl and the other is group of formula IV) with a nitrous acid ester such as tert-butyl nitrite in a solvent such as dimethyl sulfoxide.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula [wherein one of R1 and R2 represents a lower alkoxycarbonyl group or a carboxyl group, and the other represents the following general formula (wherein the middle represents an integer from 1 to 6)] Represents the group shown] and salts thereof.

<Industrial application field> The compound of general formula (1) is thrombogysan A2 (hereinafter referred to as T
XA2) Diseases 1 that have a synthesis inhibitory effect and are thought to be associated with TX2, such as angina pectoris.

It is useful for the treatment and prevention of ischemic heart diseases such as myocardial infarction, cerebrovascular disorders, and thrombosis.

<Prior Art> TXA2 is a physiologically active substance biosynthesized from arachidonic acid, and its physiological effects include platelet aggregation inhibition and vasoconstriction. It is known that in some patients with angina pectoris, T X A2 increases during one attack. (M
, Ta6a et al., circuit 64, 6
No., p. 1107 (1981)) Compounds that inhibit cyclooxygenase, such as aspirin and indomethacin, and daxixiben (4-(2-(1-imidazolyl)ethoxy)benzoic acid) suppress the production of T X A2. Compounds having a TXA2 synthetase inhibitory effect, such as hydrochloride), are known.

However, some of the former compounds with cyclooxygenase inhibitory activity are prostacyclin (hereinafter referred to as PG).
It also suppresses the production of I2). -1' if Ix has actions that are opposite to those of TxA2, that is, platelet aggregation inhibiting action and vasodilatory action, and a decrease in Pct2 is desirable for patients with angina pectoris and myocardial infarction. It's not a thing.

Dacixiben (Dr.
ugs of the Future: 'A volume 11
No. 693 (1981)) is currently undergoing clinical trials.

Although its activity is strong, clear clinical trial results have not been obtained. Dashixiben also exhibits a cyclooxygenase inhibitory effect when the concentration is increased.

Therefore, there is a need for a compound that has a highly selective thromboxane synthetase inhibitory effect.

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 T X A2 synthesis.

That is, the present invention relates to a compound of general formula (1) and a salt thereof.

Examples of salts include inorganic acids such as hydrochloric acid and sulfuric acid, tartaric acid, maleic acid, fumaric acid, and methanesulfonic acid.

Acid addition salts with organic acids such as benzenesulfonic acid and paratoluenesulfonic acid, and when either R1 or Tsubo is a carboxyl group, alkali metal salts such as sodium salts and potassium salts, calcium salts, and magnesium salts thereof. Examples include alkaline earth metal salts such as

The method for producing the compound of general formula (1) of the present invention can be expressed as follows.

(I) (T') (In the formula, one represents a lower alkoxycarbonyl group, and the other represents a group represented by the formula (in the formula, R is the same as above).

One of R31 and Fc′+ represents a lower alkoxycarbonyl group, the other represents a group of formula (II), and R32
and R42, one represents a carboxyl group and the other represents a group of formula (1). ) Namely, by reacting the compound of formula (1) with a nitrite ester such as tert-butyl nitrite in the presence of a solvent such as dimethyl sulfoxide, dimethylformamide, dimethylacetamide, etc., R of the compound of formula (I) can be obtained. ] and R
A compound of formula (1') in which one of 2 is lower alkoxycarbonyl and the other is a group of formula (I[) can be produced. The compound of formula 1 (0) can also be prepared as follows: A compound of formula 1 (0) can be prepared by adding a second halide such as cupric chloride to the compound of formula 1 (0) in the presence of a solvent such as tetrahydrofuran, dioxane, acetonitrile, etc. by reacting with copper and a nitrite ester such as tert-butyl nitrite, or
A metal salt of nitrous acid such as sodium nitrite is reacted in an inorganic acid and then treated with a cuprous halide such as cuprous chloride. , and a metal such as iron, the desired compound of formula (1') can be produced.

The resulting compound of formula (0) was treated with sodium hydroxide.

By treating with an alkali such as potassium hydroxide or an acid such as hydrochloric acid or sulfuric acid, one of R1 and R2 in the compound of formula (1) is a carboxyl group.

Compounds of formula (I') can be prepared, the other being a group of formula (U).

A method for producing a compound in which male is a lower alkoxycarbonyl group and R3 is a group of formula (g) among the raw material compounds of formula <1) can be expressed as follows.

(y) (parent (in the formula, t represents a lower alkyl group), that is, 2 formula (7)
Compound 2) is diazotized by reacting with hydrochloric acid and sodium nitrite and then treated with acrolein and cuprous chloride to form compound 2). By treating this compound with thiourea in alcohol, the desired starting compound of formula (l') can be produced.

Further, a method for producing a compound in which P is a lower alkoxycarbonyl group and V is a group of the formula (M) in the raw material compound of formula (1) can be expressed as follows.

r (I['') (in the formula, t and deaf are the same as above), that is, the formula 7 (4
) is treated with a complex of bromine and dioxane in dichloromethane to produce the compound of formula 1 (4). This compound can be treated with thiourea in alcohol in the same manner as the compound of formula (1) above to produce the desired raw material compound of formula (1').

<Actions and Effects of the Invention> The thromboxane synthesis inhibiting effect of the TEF-hydronaphthalene derivative of the present invention is T Thromboxane B2, a stable metabolite of
(hereinafter referred to as TXB2) production amount was determined by specific radioimmunoassay (
50% of T X A2 synthesis compared to Funtrol as measured by radioimmunoassay (RIA method)
The inhibition molarity (I Cso ) was determined.

In addition, the selectivity of TXA2 synthesis inhibition was measured by the method described below. Drugs such as aspirin and indomethacin that have a cyclooxygenase inhibitory effect not only suppress TXA2 production but also inhibit other prostaglandins, ie, PGI2. Prostaglandin cysts (hereinafter referred to as P
GE2), prostaglandin F2a (hereinafter referred to as P
Although it also suppresses the production of GF2+1), the compound that has a TXA2 synthesis inhibitory effect is PGI2. PGFa, PG
The amount of F2a produced remains unchanged or increases. Then the next TX
When measuring the B2 production amount, the P G E2 production amount is RI
Measure by method A to calculate the increase in PGEz production compared to the control. After drying, the ratio of the amount of inhibition of TXB2 production was determined and this was used as an index of selectivity for inhibition of TXA2 synthesis.

The larger this value is, the higher the selectivity is.

The compound of the present invention had selective TXA2 synthesis inhibitory activity. In addition, its activity strength and selectivity are known to be TXA2.
It was superior to daxixiben, which has a synthesis inhibitory effect.

The present invention will be explained below using reference examples, examples, and test examples.

Most of the compounds of formula (V) and formula (b), which are raw materials for producing the compound of formula (I) of the present invention, are novel metals. Representative examples of methods for producing these compounds are shown in Reference Examples.

Reference Example 16-amino-l, 2.3.4-tetrahydro-2-naphthalenecarboxylic acid ethyl (1) 6-amino-1,2,8,4-tetrahydro-4
-Ethyl oxo-2-su7talenecarboxylate 8.69 ethyl 6-nitro-1,2,8,4-tetrahydro-4-oxo-2-naphthalenecarboxylate to 150 ethanol
- Add 0.29 g of 10% radium charcoal and perform catalytic reduction. When the absorption of hydrogen is completed, the catalyst is also filtered off, and the filtrate is concentrated under reduced pressure to obtain the title compound as an oily product.
(Yield quantitative) (2) 6-amino-1,2,8,4-tetrahydro-2
-Ethyl naphthalenecarboxylate hydrochloride Ethyl 6-amino-1,2,8,4-tetrahydro-4-oxo-2-naphthalenecarboxylate prepared above8.
2 g of glacial acetic acid 18 (IL/, 95% sulfuric acid, rgOD &
Dissolve in liquid and catalytically reduce using 10% Tsucladium charcoal 0.79%. After hydrogen absorption has ended, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. After neutralizing the residue with sodium bicarbonate.

Extract with chloroform. The extract is washed with water, dried, and concentrated under reduced pressure. Dissolve the residual liquid in ethanol and add hydrogen chloride to
Add ethanol solution and dry under reduced pressure. The residual liquid was recrystallized from a mixture of ethanol and ether, and the melting point was 117-18.
2.57 g (73% yield) of the title compound at 0°C (decomposition)
get.

Reference example 2 6-(2-formylethyl) -5,6°7
．． Ethyl 8-tetrahydro-2-naphthalenecarboxylate (1) 6-bromo-1,2,3,4-tetrahydro-2
- Ethyl naphthalenecarboxylate 6-amino-1,2,3,4-tetrahydro-2-naphthalenecarboxylate ethyl hydrobromide 7.52 to 50% water
The suspension is suspended in a mixture of -9 hydrobromic acid and 4-, and a solution of 1.789 of sodium nitrate and water is added dropwise to this under water cooling. After dropping, the mixture is stirred and diazotized while cooling with water.

On the other hand, 15.69% of copper sulfate pentahydrate and 7.59% of sodium bromide were dissolved in 50% of water, and 8.889% of sodium acid sulfite was dissolved therein. A solution of 2.28 g of sodium hydroxide and 25 g of water is added at 60°C. After stirring for several minutes, the mixture is cooled, and the precipitated powder is separated by a decanting method. Hydrobromic acid (50°C) is added to this powder, and the mixture is cooled on ice. The above diazotized solution was added dropwise to the mixture and stirred for 80 minutes under water cooling, then at room temperature for 80 minutes, and finally at 60°C for 80 minutes. Then add 200ml of water and extract with chloroform. Wash the extract with water.

After drying, it is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography. From the chloroform eluate, 4.609 g of the title compound (yield: 65%) was obtained as a colorless oil.

(2) 6-bromo-2-hydroxymethyl-1, 8
．． 5.4 g of the ester obtained with 4-tetrahydronaphthalene (1) was dissolved in 20 g of tetrahydrofuran, and this was added dropwise to a suspension of 0.72 g of lithium aluminum hydride and 40 g of tetrahydrofuran. After stirring at room temperature for 1 hour, the reaction mixture was cooled with ice, and 1 ml of water, 1 wLt of 15% aqueous sodium hydroxide solution and 8-liter of water were sequentially added dropwise. Filter off the precipitated insoluble matter,
Concentrate the filtrate under reduced pressure. Dissolve the residue in chloroform.

After washing with water, drying, and concentrating under reduced pressure, the title compound was obtained as a colorless oil '4.
．． 89 (yield 98%) is obtained.

(3) Compound 24.19 obtained with 6-bromo-2-(p-)luenesulfonyloxymethyl)-1,2,8,4-tetrahydronaphthalene (2) was mixed with 5 ootsd of pyridine.
.

of p-toluenesulfonyl chloride 8 under cooling with water.
Add 8.19 and stir at room temperature for 16 hours. The reaction solution was poured into ice water 21, and the precipitated crystals were collected by filtration and washed with water to obtain 36.59 g of the title compound as a colorless powder (yield: 92%). Melting point 87-89°C.

(4) Sodium 2-(6-bromo-1,2,8,4-tetrahydronaphthalen-2-ylmethyl)malonate 2
．． Add 20.49 g of ethyl malonate to a solution of alflate made from 19.19 and 100 g of ethanol. continue,(
After adding compound 369 obtained in 3) and stirring at room temperature for 20 hours.

Heat to reflux for 24 hours. Concentrate under reduced pressure, extract the residue with chloroform, wash the extract with water, and dry.

Concentrate under reduced pressure to obtain 44.59% of a red oil. This was mixed with 10 g of sodium hydroxide and 100 g of water, and heated under reflux for 4 hours. Afterwards, acidify with 50% sulfuric acid, collect the precipitated powder by filtration, and wash with water to obtain powder 189 of the title compound (yield 60%).
get.

(s) After heating compound 189 obtained with ethyl a-(e-bromo-1,2,8,4-tetrahydronaphthalen-2-yl)propionate (4) to 180°C for 20 minutes, ethanol 2501+1/ , concentrated sulfuric acid 5- was added, and the mixture was heated under reflux for 4 hours. Concentrate under reduced pressure, add ice water and extract with chloroform. Add the extract to water.

Wash sequentially with 2N hydroxide solution and water. After drying, it was concentrated under reduced pressure to obtain the title compound as an oil (17.4).
9 (yield quantitative) is obtained.

(6) 6-bromo-1,2,8,4-tetrahydro-2
-Compound 17.89 obtained with (8-hydroxypropyl)naphthalene (5) and lithium aluminum hydride 2
．． This reference example (2) in tetrahydrofuran using 19
Powder of the title compound was prepared in the same manner as in 14. z9 (yield 95
%). Melting point 60-64°C.

(7) 6-bromo 2-(3-(tetrahydropyran-
2-yloxy)propyl) -1, 3. Mix 14.29 of the compound obtained with 4-tetrahydronaphthalene (6) and 4.44 of 2,8-dihydrobyran, and then add 6 drops of concentrated hydrochloric acid. , stir at room temperature for 18 hours. The reaction solution was added to ether, washed with water, dried, and concentrated under reduced pressure to obtain an oily product of the title compound (18.5%).
9 (yield 99%) is obtained.

(8) Compound obtained with ethyl 6-(8-hydroxypropyl)-5,6,7°8-tetrahydro-2-naphthalenecarboxylate (7) 18.59. A solution of 11.5 ml of ethyl bromide and 100 ml of tetrahydrofuran is added dropwise at 70 to 80° C. into a suspension of 7 g of magnesium and 50 ml of tetrahydrofuran under a nitrogen gas stream. After dropping, the mixture was heated under reflux for 3 hours and poured onto dry ice 1009. water 5
0i, 6N hydrochloric acid (50°C) was added, and the mixture was concentrated under reduced pressure. The residual liquid is extracted with benzene. The extract is washed with water, dried, and concentrated under reduced pressure. Add 250% of ethanol and 4% of concentrated sulfuric acid to the residue, and heat under reflux for 24 hours. Afterwards, concentrate under reduced pressure and extract the residue with chloroform. The extract was washed with water, dried, and concentrated under reduced pressure to obtain the title compound as an oil xt, a9 (yield 84%).
get.

(9) 6-(2-formylethyl) -5,6,7,8
Compound 11.69 obtained with ethyl -tetrahydro-2-naphthalenecarboxylate (8) and dichloromethane 2
A solution of 01111j was added dropwise to a suspension of pyridinium chlorochromate 14.89 and dichloromethane 90 while cooling with water, and the mixture was stirred at room temperature for 1.5 hours. ether 1
00- is added and the supernatant liquid is separated, washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the title compound was obtained as a pale yellow oil from the chloroform eluate.
59 (yield 91%) is obtained.

NMR spectrum (CDGIs): δ1.86 (
t+ aH, J-7Hz, 000CHaOJi3)4.
82 (q, 2H, J-7Hz, -〇〇〇c3CH
3) 7.05 ((1, IH, J-9Hz, hydrogen at the 4th position of naphthalene) 7.60-7.80 (m, 2H, hydrogen at the 1,8th position of naphthalene) 9.75 (s, IH, -0°) 0
) Reference Example 8 5-(3-formylpropyl)-S.

Ethyl 6,7.8-tetrahydro-1-naphthalenecarboxylate (1) 5-bromo-1,2,8,4-tetrahydro-1
-(2-(p-)luenesulfonyloxy)ethyl]naphthalene 5-bromo-1-(2-hydroxyethyl)-1,2,
Using 12 g of 8,4-tetrahydronaphthalene, 19.29 g of the title compound as an oil (yield quantitative) was obtained in the same manner as in Reference Example 2 (3).

(2) 2-(2-(5-bromo-1,2,8,4-tetrahydronaphthalen-1-yl)ethylcomalonic acid) Using the compound 19.29 obtained above, the reaction was carried out as shown in Reference Example 2 (4). The oil of the title compound xx, o9 was prepared in a similar manner to the method.
(yield 78%).

(3) 4-(5-bromo-1,2,8,4-tetrahydronaphthalen-1-yl) butyric acid x f k The method shown in Reference Example 2 (5) using compound 11.69 obtained above 1 The title compound was obtained as an oily product in a yield of 9.57% (yield: 8.
6%).

(4) 5-bromo-1-(4-hydroxybutyl)-1
, 2,8,4-tetrahydronaphthalene Using 9.5 ml of the compound obtained above, the procedure was carried out in the same manner as in Reference Example 2 (6) to obtain an oily product of the title compound s, B (yield 98%).
).

(5) 5-bromo-1-(4-(tetrahydropyran-
(2-yloxy)butyl)-1,2,8,4-tetrahydronaphthalene Using 8.1 g of the compound obtained above, the procedure was repeated in the same manner as in Reference Example 2 (7) to obtain 1. Oily substance of the title compound 7. ．．
69 (yield 72%) is obtained.

(6) 5-(4-hydroxybutyl)-5,6,7,8
= Ethyl tetrahydro-1-naphthalenecarboxylate Using the compound 7.59 obtained above, the oily substances a and a9 (yield 59%) of the title compounds were obtained in the same manner as in the method shown in Reference Example 2 (8). .

(7) s-(a-formylpropyl)-5,6,7,8
-Ethyl tetrahydro-1-naphthalenecarboxylate Using the compound 3.89 obtained above, 2.7 g of the title compound as an oil (yield 82%) was prepared in the same manner as in the method shown in Reference Example 2 (9). obtain.

NMR spectrum (CDCl13) δ: 1j37 (3
H, t, -CiOzCH2C equivalent) 1.4 to 8.0 (8
H, m, methylene hydrogen) 2.8 to 2.55 (2H, m
, -GIj2 (IHO) 2.6 to 2.9 (IH, Naphthalene 5th position hydrogen) 2,9 to 8.1 (2H, m, 7 grain 8th position hydrogen) 4, +38 (2H, q, - CO2
C diC mountain) 7.0 to 7.85 (28, m, hydrogen at 3 and 4 positions of naphthalene) 7.62 (IH, da, naphthalene 2
position hydrogen) 9.77 (1B, t, -coo) Example 1 6-(thiazol-5-ylmethyl)-5,6,
Ethyl 7,8-tetrahydro-2-naphthalenecarboxylate (1) 6-(2-aminothiazol-5-ylmethyl)
Ethylbromine 2-5,6,7,8-tetrahydro-2-su7talenecarboxylate is added dropwise to 6 ml of dioxane. After stirring for 10 minutes, it is dissolved in dichloromethane 25-. This solution was added to 6-(2-formylethyl)-5,6,7,8-
Ethyl tetrahydro-2-naphthalenecarboxylate 10.
-10 in a solution of 5 g dissolved in dichloromethane 20-
Drop it under a stream of nitrogen gas at ~-5°C. After dropping -5
After stirring for 1 hour at °C, a solution consisting of 3.19 m of sodium carbonate and 13 m of water is added dropwise. Extract with chloroform, wash the extract with water, dry, and concentrate under reduced pressure. Dissolve the residue in 180% of ethanol, add 8g of thiourea and add 1
Heat to reflux for 0 hours.

Neutralize with saturated sodium bicarbonate water and concentrate under reduced pressure.

The residue is extracted with chloroform, and the extract is washed with water, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and 5.789 g of the title compound (yield: 44.9%) was obtained as a colorless powder from the chloroform eluate. Melting point 150-1
5.9℃.

(2) 6-(thiazol-5-ylmethyl)-5゜6,
7. Dissolve the compound 2.12 obtained with ethyl 8-tetrahydro-2-su7talenecarboxylate (1) in 28-phosphoric acid,
Concentrated nitric acid (12) is added, and a solution of 0.46 ml of sodium nitrite and water is added dropwise at -10 to -5"C. After further stirring for 20 minutes at -8°C, the reaction solution is diluted with cuprous chloride. 5.28
9 and concentrated hydrochloric acid 7- at -5°C. -8
After stirring at ~θ°C for 1.5 hours, add 100 ml of ice water, add carbonate, neutralize with IJum, and extract with chloroform.

The extract was washed with water, dried, concentrated under reduced pressure, and the residue was dissolved in 15 ml of acetic acid.
! ! Add 1.41 g of zinc powder little by little while heating. After heating under reflux for 2 hours, the mixture was cooled and insoluble materials were filtered off.

The filtrate is concentrated under reduced pressure, and the residue is dissolved in chloroform, washed with water, dried, and concentrated under reduced pressure. Purify the residue using silica gel column chromatography. 1.27 g (68%) of the title compound as an oil is obtained from the chloroform eluate containing 2% methanol.

NMR spectrum (CDCl3) δ: 1.87 (3
H, t, -CO2C) bc le) 4.84 (2H, q,
-CO20H2CH3) 7.0 s (IH, a, hydrogen at position 4 of naphthalene ring) 7.60 (IH, S, hydrogen at position 4 of thiazole ring)? , 6 (1-7.70 (2H, m,
8.68 (LH, s, hydrogen at 2nd position of thiazole ring) In addition, 2 to 4 ppm of hydrogen at 5th, 6th, 7th, and 8th positions of naphthalene ring
Signals of methylene group hydrogen substituted at the 2-position and the 2-position of the naphthalene ring are observed.

Example 26-(thiazol-5-ylmethyl)-5,6
, 7,8-tetrahydro-2-naphthalenecarboxylic acid sodium 6-(thiazol-5-ylmethyl)- obtained in Example 1
8.929 of ethyl 5,6,7,8-tetrahydro-2-su7talenecarboxylate was added to a mixture of 10% aqueous sodium hydroxide solution IO and 80 of methanol;
After heating under reflux for an hour, the two reaction solutions were dried under reduced pressure. The residual solution is dissolved in water, a small amount of insoluble matter is filtered off, and the filtrate is adjusted to pH approximately 6 with hydrochloric acid. The precipitated powder was filtered to obtain 2.71 of the free carboxylic acid powder of the title compound. Add this powder to 20 m of water.
Suspended in water, added 0.429% sodium hydroxide and filtered.
Concentrate the filtrate under reduced pressure.

The resulting residue was recrystallized from a mixture of ethanol and ether to give 1.929 g of the title compound as a colorless powder (yield 50%).
get. Melting point 280°C or higher.

Elemental analysis value Calculated value as IC1sH+4t403Na C61,00, H4,77, N 4.74 Experimental value C
60,95,H4,91,N 4.78NMR spectrum (D20) δ: 6.99 (IH, d, J-8Hz, 7 turns, hydrogen at 4th position) 8.4-8.7 (3H, m, naphthalene 1,3
8.78 (IH, s, hydrogen at 2nd position of thiazole) 8.78 (IH, s, hydrogen at 2nd position of thiazole) In addition, 1.5 to 4 ppm of hydrogen at the 5,6°7.8 position of naphthalene and a methylene group substituted at the 6th position of naphthalene. Water emergency signals are recognized.

Example 8 Ethyl 5-(2-(thiazol-5-yl)ethyl)-5,6,7,8-tetrahydro-1-naphthalenecarboxylate (1) 5-(: 2-(2-aminothiazole-5
-yl)ethyl)-5,6,7,8-tetrahydro-1
-ethyl 7talenecarboxylate 5-(3-formylpropyl) -5,6,7,8-tetrahydro-1-ethyl 7talenecarboxylate 2.79
2.29 (yield: 68%) of the title compound as an oil is obtained in the same manner as in Example 1 (1).

(2) 5-(2-(thiazol-5-yl)ethyl)
-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid ethyl 0.87 of cuprous chloride was suspended in 20 td of acetonitrile, 0.829 of tert-butyl nitrite was added, and then at 60°C ( Compound 1.89 obtained in 1). A solution of acetonitrile 5- is added dropwise. After the gas generation has subsided, 15% hydrochloric acid is added and extracted with chloroform. The extract is washed with water, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography. An oily substance is obtained from the chloroform eluate.

This was dissolved in 30% of acetic acid, and 0.49% of zinc powder was divided into 4 portions and added every hour under heating and reflux. Insoluble matters were removed by filtration, the filtrate was concentrated under reduced pressure, the residue was dissolved in chloroform, washed with water,
After drying, concentrate under reduced pressure.

The residue was purified by silica gel column chromatography to obtain 1.89 g of the title compound as an oil (yield: 70%).

NMR spectrum (CDC13) δ: 187 (8H, t, C102CH2(!a) 1.6
~2.2 (6H, m, methylene hydrogen)2.8 (LH
, m, naphthalene 5-position hydrogen) 2.95 (4M, t,
methylene hydrogen, naphthalene hydrogen at position 8) 4.84 (2H
,q, -GO2Cμ2CI83)7.0~7.4 (2
H, rtr, naphthalene 8-position, 4-position hydrogen) 7.62 (
2H, m, hydrogen at 4th position of thiazole, hydrogen at 2nd position of naphthalene) 8.66 (LH,s, hydrogen at 2nd position of thiazole) Example 4
5-(2-(thiazol-5-yl)ethyl) -5
,6,7,8-tetrahydro-1-naphthalenecarboxylic acid sodium 5-(2-(thiadyl-5-yl) prepared in Example 3
ethyl)-5,6,7,8-tetrahydro-1-naphthalenecarboxylate (1.89 g) was dissolved in a mixture of 5 g. of water and 30 g. of methanol.

After adding 0.8:39 of sodium hydroxide and heating for 4 hours, the mixture was concentrated under reduced pressure. Add 50% of water to the residue, wash with 50% of chloroform, and adjust the aqueous layer to pH 7 with concentrated hydrochloric acid. The precipitated powder is filtered, washed with water, dissolved in an aqueous solution containing the calculated amount of sodium hydroxide, and dried under reduced pressure. The obtained powder is washed with a small amount of ethanol to obtain a colorless powder of the title compound o, asB (Yi ratio: 81%). Melting point 104-11
5°C8 Elemental analysis value Calculated value as C+aH+aNO2SNa
C62, 12, H5, 21, N 4.5B experimental value C6
1, +8. H5,8B, 84.57 NM) l spectrum (D20) δ.

1.5~2.1 (6H, m, methylene hydrogen) 2.5~
3.1 (5H, m, hydrogen at 5.8 position of naphthalene.

- proboscis) 7.0 to 7.3 (8H, naphthalene 2.8.4-position hydrogen) 7.58 (IH, s, thiazole 4-position hydrogen) 8.7
0 (IH, s, thiazole 2-position hydrogen) Example 5 a-
Ethyl (thiazol-5-ylmethyl)-1,2,8,4-tetrahydro-2-naphthalenecarboxylate (1) 6-(2-aminothiazol-5-ylmethyl-1.2.3.4-tetrahydro-2- Ethyl naphthalenecarboxylate 11 g of ethyl 6-amino-1,2,3,4-tetrahydro-2-naphthalenecarboxylate hydrochloride prepared in Reference Example 1
was mixed with 4 tt of concentrated hydrochloric acid and 40 ml of acetone and cooled on ice.

This 4-3.89 of sodium nitrite at 0 to 5°C is added to 4 of water.
-Drop the solution dissolved in -. After 20 minutes, 25-9 cuprous chloride (200 ml) was added, and the mixture was stirred at 85-40°C for 3 hours. Concentrate under reduced pressure and extract the residue with benzene. The extract is washed with water, dried, and concentrated under reduced pressure. The obtained residue was dissolved in 100% of ethanol, and 8.64% of thiourea was added.
9 was added and heated under reflux for 16 hours.

The reaction solution was concentrated under reduced pressure, the residue was neutralized with sodium hydrogen carbonate, and extracted with chloroform. The extract is washed with water, dried, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to obtain 6.0 g of the title compound as a powder (yield: 44%) from the eluate of chloroform containing 2% ethanol.

(zz 6-(thiazol-5-ylmethyl)-1゜2
, 3. Add a small amount of compound 1.07 obtained with ethyl tetrahydro-2-naphthalenecarboxylate (1) to a mixture of tert-butyl nitrite 0.499 and dimethylformamide 5@z heated to 50 °C. Add them one by one and stir at 60°C for 1 hour. Thereafter, ethyl acetate is added, washed with water, dried, concentrated under reduced pressure, and the residue is purified using silica gel column chromatography. From the eluate of a mixture of methanol and chloroform (1:50), 720 ml of the title compound as an oil is obtained.

NMR spectrum (CDC7a) δ: 1.26 (8
H, t, -Co2CHtCHs) 1.6 to 2.4
(2H, m, hydrogen at 8-position of naphthalene) 2.5-8.1 (
5H, 10, naphthalene 1st, 2nd, 4th hydrogen) 3.8
6 (2H,s, methylene hydrogen)4.15 (2H,q
, -C020shaCH3)6.8~7.1 (3H,m,
Naphthalene 5th, 7th, 8th hydrogen) 7.85 (IH,
s, thiazole 4-position hydrogen) 8.71 (1) 1.8. Hydrogen at 2-position of thiazole) Example 6 6-(thiazole-5-
Sodium 6-(thiazol-5-ylmethyl)-1,2,3,4-tetrahydro-2-naphthalenecarboxylate prepared in Example 5
-145 m9 of a colorless powder of the title compound was prepared in the same manner as in Example 4 using 720+119 ethyl 1,2,8,4-tetrahydro-2-naphthalenecarboxylate.
get. Melting point 256-262°C.

Elemental analysis value cps positive <NOBS? Calculated value as Ja: C61,00, H4,78,N 4.74 Experimental value: C60,95,)+4.91. N 4.73N
MR spectrum (D20) δ: 1.5-2.8 (7H, m, naphthalene 1.2.3.
4-position hydrogen) 4.03 (2H, s, -C total σ) 6.90 to 7.10 (8H, m, 7 talene 5, 7.
Hydrogen at 8th position) 7.85 (IH, s, hydrogen at 4th position of thiazole) 8.72 (IH, s, hydrogen at 2nd position of thiazole) Test example Male Wistar Kondo rats weighing 280 to 820 kg under bendoparbital anesthesia citrated blood (8.18% sodium citrate per 9 volumes of blood) during cardiac puncture.
(added volume) and centrifuged at 280×9 for 7 minutes at room temperature.

The obtained supernatant (PRP) was diluted with ppp (platelet poor plasma) to adjust the platelet count to 5 x 108/-.

ppp was prepared by centrifuging the residual liquid after PRP separation at 1.500X for 10 minutes.

TXA2 and PG: 2 production reaction and its measurement Add 90 μl of the above PRP to 10 μl of the sample solution, shake for 1 minute, then take 90 μl of this mixture and combine with 10 μl of 5u+M arachidone-55 Na solution, and mix at room temperature. I shook it. After shaking for 5 minutes, 10 μl of this mixture
Take 90 μM of 100 μM flurbiprone 7-solution!
The reaction was stopped. The reaction solution was centrifuged at 1000×9 for 5 minutes.

The average concentration of TXB2 (a stable decomposition product of TXA2) and PO in the obtained supernatant was determined using the radioimmunoassay method of Morris et al.
1). 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 TXA2 synthesis inhibition rate was calculated using the following formula, and the TX~synthesis inhibition activity was determined by the concentration of the sample showing a 50% inhibition rate (rcso
).

In platelets, TX is reduced by suppressing cyclooxygenase.
The production of not only B2 but also PG& and PG F2a is suppressed (Hamberg et al., Proc, N
at.

Aca6. Sci, USA, 71.8824.1
974), on the contrary.

PG & due to deficiency or inhibition of TXA2 synthase.

Increased production of P G F2a and PGD2 (
Defreyn et al., Brot, J.) (aemato
l, 49.29. 1981) is known. Therefore, the selectivity index of TXA2 synthesis inhibition was calculated using the following formula, and the relationship between the effects on both TXA2 synthase and cyclooxygenase was shown.

Selectivity index of TXA2 synthesis inhibition: The larger this value is, the stronger the TXA2 synthesis inhibition effect is.
This means that the cyclooxygenase inhibitory effect is weak.

5. Contents of the amendment (1) The words "platelet aggregation inhibition" in lines 6 to 5 from the bottom of page 2 of the specification are corrected to "platelet aggregation promotion".

(2) The last line of page 8, "Thromboxane" is corrected to [T X A2J.

(3) On page 8, lines 9 to IO, the phrase "Thromboxane synthesis inhibition effect" is corrected to "About TxA2 synthesis inhibition effect."

(4) On page 9, line 10, [ratio of the amount of inhibition of TXB2 production] should be corrected to "ratio of the amount of inhibition of TX82 production."

(5) 3 lines from the bottom of page 11 "Water cooling after dripping" should be corrected to "Water cooling after dripping."

(6) 4 lines from the bottom of page 22 Correct "2nd place" to 1st-6th place].

(7) 5th line from the bottom of page 28 rc+sH+4No 5NaJ r IC+sH
Corrected to +4NOxSNaJ.

(8) Page 25, line 1 The text "Liaohua cupric" is corrected to "cupric monochloride."

(9) On page 81, line 4, "prepared" should be corrected to "the supernatant was used."

(101, p. 81, line 8 [Corrected "NaJ arachidonic acid" to read "sodium arachidonic acid".

(11) The 4th line from the bottom of the same page 32, "TXB2 production amount of control, TXB2 production amount of one sample" is corrected to European language [TXB2 production amount of control, TXB2 production amount when one sample is added] (b) The first line of the table on page 88 is corrected as follows.

Claims (1)

[Scope of Claims] General formula [In the formula, one of R1 and W represents a lower alkyl dicarbonyl group or a carboxyl group, and the other is a group represented by the following general formula (wherein R1 and W represent an integer of 1 to 6). Compounds represented by ] and their salts