JPS61186348A - Naphthalene derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R is lower alkyl; n is 1-6). EXAMPLE:6-(Hydroxymethyl)-5,6,7,8-tetrahydro-2-naphthalenecarbox-ylic acid ethyl ester. USE:An intermediate for the synthesis of the compound of formula II and formula III (R1 is H or lower alkyl) effective to suppress the synthesis of thromboxane A2. PREPARATION:The compound of formula I can be produced by reacting the compound of formula IV (R2 is lower alkyl) with sodium borohydride and trifluoroacetic acid in a solvent (e.g. THF) at a temperature between room temperature and the boiling point of the solvent. As an alternative method, the compound is obtained by reacting the compound of formula V with metallic magnesium in a solvent such as ether in the presence of an alkyl halide, treating the resultant Grignard reagent with carbon dioxide gas, reacting the product with dilute hydrochloric acid or dilute sulfuric acid, and finally reacting with an alcohol and sulfuric acid.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound represented by general formula (1) (wherein R represents a lower alkyl group and n represents an integer of 1 to 6).

<Industrial Application Field> The compound of formula (1) of the present invention is an excellent thromboxane A
2 (hereinafter, TXA2) synthesis inhibitory effect
a) and (mb) Cm1 (To) (wherein, Fh represents a hydrogen atom or a lower alkyl group.

n is useful as a synthetic intermediate for the compound represented by ◇) as described above.

<Problems to be Solved by the Invention> As a result of intensive studies on intermediates of the compounds of formulas (Ia) and (nb), the present inventors discovered a compound of formula 9 (1) and completed the present invention.

<Structure of the Invention> The compound of formula (1) can be produced as follows.

(In the formula, R and n are the same as above, and the formula 1 represents a lower alkyl group.) In other words, the compound of the formula 1 is treated with borohydride in a solvent such as tetrahydro7rane, dioxane or 1,2-dimethoxyethane. The compound of formula (1) can be produced by reacting sodium and trifluoroacetic acid in a temperature range from room temperature to the boiling point of the solvent.

The compound of formula (1) can also be produced as follows.

(In the formula, n is the same as above.) That is, Formula 9 (The cup compound is ether or tetrahydrogen. This is treated with carbon dioxide gas or dry ice, and the obtained product is treated with dilute hydrochloric acid or dilute sulfuric acid.) After that, the compound of formula (I) can be produced by reacting with alcohol and sulfuric acid.

The obtained compound of formula (1) of the present invention can be expressed as follows (
The final compound, a compound of formula (Ila) or (mb), can be produced by reacting in the method shown in a) or (b).

(a) Process for producing a compound of formula (I[a)>ff> (In the formula, Ts represents a tosyl group, and R and n are the same as above.) That is, 1 a compound of formula (I) is dissolved in para-toluenesulfonyl in pyridine. When reacted with chloride, a compound of formula (V') is produced. This is reacted with sodium hydride and imidazole in dimethylformamide and then optionally hydrolyzed in a conventional manner to give the desired formula (Ha
) can be produced.

(b) Process for producing the compound of formula (Ilb) [2] (In the formula, R and n are the same as above.) That is, when the compound of formula (1) is oxidized by a conventional method, the compound of formula (9) is produced. generate. This is treated with a complex of bromine and dioxane in dichloromethane to produce a compound of formula (4), which is then treated with thiourea in alcohol to produce a compound of formula (4). This is reacted with a nitrite ester such as tertiary butyl nitrite in a solvent such as dimethylformamide in a conventional deamination reaction 9, and then, if desired, hydrolyzed by a conventional method to obtain the desired compound of formula (nb). compounds can be manufactured.

<Effects of the Invention> The compound of formula (1) of the present invention is an extremely important compound as a synthetic intermediate for compounds of formulas (Ila) and (+tb), which have an excellent T X A2 synthesis inhibitory effect.

<Examples> The present invention will be further explained below with reference to Examples, Reference Examples, and Test Examples, but the present invention is not limited by these.

Example 16-(hydroxymethyl)-5,8,7,8
-Ethyl tetrahydro-2-naphthalenecarboxylate (1) 6-amino-1,2,8,4-tetrahydro-2
-S7talenecarboxylic acid ethyl ester hydrobromide 6-nitro-4-oxo-1,2,3,4-tetrahydro-2-su7talenecarboxylic acid ethyl ester 24.5
9 in 450 d of ethanol with 0.5 g of 10% palladium charcoal
is catalytically reduced to a catalyst. When 7.0 mm of hydrogen has been absorbed, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. Dissolve the residue in 1 part of acetic acid and add 5.2 parts of concentrated sulfur. 10% palladium on charcoal 79 was added, heated by irradiation with an infrared lamp, and catalytically reduced under hydrogen. When hydrogen absorption is completed, the catalyst is removed by filtration and the filtrate is concentrated under reduced pressure. The residue was dissolved in 300ml of water, neutralized with sodium bicarbonate, and then extracted with chloroform. The extract is washed with water, dried over sodium sulfate, and concentrated under reduced pressure. Dissolve the residue in 100% ethanol and cool on ice.
% hydrogen bromide@aO- was added and the mixture was dried under reduced pressure. The obtained crystals were recrystallized from a mixed solution of ethanol and ether to obtain 19.39 g of the title compound as a colorless powder. Melting point 163-166"C
(Disassembly).

(2) 6-bromo-1,2,3,4-tetrahydro-2
- Compound 7.59 prepared with naphthalenecarboxylic acid ethyl ester (1) is suspended in 50% water and 48% hydrobromic acid 4%. Ice-cold sodium nitrite 1.
A solution of 789 dissolved in water was added dropwise.

Stir for 20 minutes while cooling with water to obtain a diazonium salt solution.

Copper sulfate pentahydrate 15.69 and bromide) IJum7.
Dissolve 5g in 50ml of water, heat to 60-80"C with stirring, add hydrogen sulfite, add a solution of 3.389 IJum and 2.239% sodium hydroxide dissolved in 25trLt of water, and heat to 60-80"C. After stirring for 10 minutes, the mixture is cooled, and the precipitated crystals are collected by a decanting method and further washed with water.To this is added 48% hydrobromic acid 5Q+nt, cooled on ice, and the above diazonium salt solution is added dropwise thereto. After stirring under water cooling for 80 minutes,
Stir at room temperature for 80 minutes, then warm to 60"C for 3
Stir for 0 minutes.

The reaction solution was cooled with water, 20,011 tons of water was added, and the mixture was extracted with chloroform. The extract was washed with water, dried over sulfuric acid, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4.69 g of the title compound as a pale yellow oil from the chloroform eluate.

(3) 6-bromo 2-hydroxymethyl-1,2,8
Compound 5.49 prepared from 4-tetrahydronaphthalene (2) was added to tetrahydrofuran 2
A solution of lithium aluminum hydride dissolved in 0.
729 and 40% of tetrahydrofuran. After stirring for 1 hour at room temperature.

The reaction mixture was cooled with ice, and 11d of water, 1-2 of a 15% aqueous sodium hydroxide solution, and 8- of water were sequentially added thereto, and insoluble materials were filtered off. The filtrate is concentrated under reduced pressure, and the residue is extracted with chloroform. The extract was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain 4.289 g of the title compound as a colorless oil.

(4) 6-bromo-2-(tetrahydropyran-2-
4.289 of the compound prepared from 1,2,3,4-tetrahydronaphthalene (3) was mixed with 1.69 of 2,8-dihydropyran, 2 drops of concentrated hydrochloric acid was added thereto, and the mixture was kept at room temperature for 15 hours. Stir at . The reaction solution was extracted with ether. The extract was washed with IJ hydroxide, water, and sulfuric acid. The extract was dried over IJ hydroxide and concentrated under reduced pressure to obtain 5.489 g of the title compound as a pale yellow oil.

(5) 1 g of magnesium 2-(tetrahydropyran-2-yloxymethyl)-1,2,3,4-tetrahydro-6-naphthalenecarboxylate and 10-tetrahydro7ran were heated at 60 to 70°C under a nitrogen stream. Heat to. A mixed solution of 2.449 g of the compound prepared in (4), 1.65 g of ethyl bromide, and 20 g of tetrahydrofuran was added dropwise to the mixture.

After the dropwise addition, the mixture was further heated under reflux for 2 hours under a nitrogen stream, cooled with ice, and dry ice 159 was added. Add 7m of water to the reaction solution, Q
After adding 7-N hydrochloric acid and stirring, concentrate under reduced pressure. The residue was extracted with ethyl acetate at °C, and the extract was washed with water, dried over sulfuric acid, concentrated under reduced pressure, and crystallized with petroleum ether to give 1.52 kg of the title compound as a colorless powder. This product was used crude in the next reaction.

(e) a-(hydroxymethyl L/)-5,6, fu, 8
-Tetrahydro-2-naphthalenecarboxylic acid ethyl ester 0.9 g of the crude compound prepared in (5) was added with 0.0 g of concentrated sulfuric acid.
54 and 60 gLt of ethanol and heated under reflux for 18 hours. Add 40% of water to the reaction solution, concentrate under reduced pressure, and extract the residue with chloroform. The extract was washed successively with IN sodium hydroxide and water, dried over sodium sulfate, and concentrated under reduced pressure to obtain 0.78 g of the title compound as a pale yellow oil.

IH-N M R (cnc13) δ: 1.16 (IH, t) 121-8.1 (8H, m) 8.61 (2H, d) 442 (2H, q) 7.08 (LH, d) 7.68-7.8 (2H,m) Example 2 e-(hydroxymethyl)-5,@? , 8
-tetrahydro-2-naphthalenecarboxylic acid methyl trifluoroacetic acid 57 sodium borohydride 18
．． The mixture was added to a suspension of 99% of tetrahydrofuran and 200% of tetrahydrofuran, and stirred at room temperature for 80 minutes. Next, add 12 g of dimethyl 1.2.3.4-tetrahydro-2,6-naphthalenedicacarboxylate and heat under reflux for 48 hours. After cooling, add dilute hydrochloric acid and extract with chloroform. The extract was washed with water, dried, and dried under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 11 g of colorless crystals of the title compound. Melting point 74~
76℃.

IH-NMR (CDC; 1B) δ: 1.20-8
．． 12 (8H, m) 3.63 (2H, d, -C and 20H) 3.89 (
3H,s, -COzCH3)7.14 (IH,d,
Naphthalene 4-position hydrogen) 7.60-7.84 (2H, m
, Naphthalene 1st and 3rd position hydrogen) Example a s a-(a-
and droxypropyl) -5゜ethyl 6,7.8-tetrahydro-2-naphthalenecarboxylate (1) 6-bromo-2-(p-)luenesulfonyloxymethyl) -1,2,3,4-tetrahydro Naphthalene 6-bromo-2-(hydroxymethyl)-1,2°8.
4-Tetrahydronaphthalene24. 30% of pyridine
88.1 g of 1)-) luenesulfonyl chloride was added to the solution under water cooling, and the mixture was stirred 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. Melting point 87~
89”(:0(2)2-(6-bromo-1,2,3,4
-Tetrahydronaphthalen-2-ylmethyl) To a solution of alcoholade made from 2.1 parts of sodium malonate and 100 parts of ethanol are added 20.49 parts of ethyl malonate. Subsequently, 36 g of the compound obtained in (1) was added, stirred at room temperature for 20 hours, and then heated under reflux for 24 hours. Concentrate under reduced pressure, extract the residue with chloroform, wash the extract with water, dry, and concentrate under reduced pressure to obtain 44.5 g of a red oil.

This is 10g of sodium hydroxide and 1001 parts of water! Mix with It and heat under reflux for 4 hours. After cooling, acidify with 50% sulfuric acid, collect the precipitated powder by filtration, and wash with water to obtain powder 18 of the title compound.
get the benefits.

(8) Compound 189 obtained with 3-(6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)propionic ethyl (2) was heated to 180°C for 20 minutes, and then ethanol 250117. Add concentrated sulfuric acid and heat under reflux for 4 hours. Concentrate under reduced pressure, add ice water and extract with chloroform. The extract is washed successively with water, a 2N hydroxide solution, and water. After drying, the mixture was concentrated under reduced pressure to obtain 1 and 4 oils of the title compound.

(4) 6-(3-hydroxypropyl)-5,6,7
, 8-Tetrahydro-2-naphthalenecarboxylic acid ethyl (3) Example 1 (3), (4),
The reaction is carried out in the same manner as in (s) and (6) to obtain the title compound as an oil.

1M-NMR(CDCl2)δ: 1.87(3
H, t, J-7Hz, -Co2CH2Cjj3)1
．． 4-3.5 (11H, m, methylene and methine hydrogen) 8.67 (2H, t, J-6Hz, -cB3-
OH) 4.34 (2H, q, J=7 Hz, -C
02CHjOHs )7, I Q (XI(, +1.
J-9Hz, naphthalene 4th position hydrogen) 7.66-7.80
(2H, m, 7 turns 1st and 3rd position hydrogen) Example 4
5-(4-Hydroxybutyl)-5,6゜7.8-Tetrahydro-1-su7talenecarboxylic acid ethyl 5-bromo 1-(2-hydroxyethyl) = 1,2.
3. 4-Tetrahydronaphthalene is reacted in the same manner as in Example 8 to obtain the title compound as an oil.

IH-N M R (CDCl3) δ: 1, Jl 7 (3H, t, -GO20H20Ha
) 1.4-2.0 (IOH, m, methylene hydrogen)2.
6-2.9 (2H, m, hydrogen at 8-position of 7talene) 2.9
~8J (I Hj m, hydrogen at the 5th position of naphthalene) 8.6
6 (2H,t,-(,cell-0H)-4,83(2H,
q, -Co2 Season CH3) 7.0~F, 4 (2H,
m, naphthalene hydrogen at position 8.4) 7.61 (II(, d
(1, hydrogen at 2-position of naphthalene) Example 5 5-(2- and droxyethyl)-5,6°7.8-tetrahydro-2-
Suspend 3.2 g of 50% sodium hydride in 90% of anhydrous tetrahydrofuran. , triethylphosphonoacetate 169. After stirring at room temperature for 30 minutes, 14.8 g of 6-bromo-1-oxo-1,2,3,4-tetrahydronaphthalene was added and stirred at room temperature for 2 days.
After stirring at 50°C for 20 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in benzene, washed with water, dried, and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography to obtain a small amount of ethyl 2-(6-promo'3.4-dihydro-1-su7tyl)acetate. 15.5 g of an oil containing the title compound are obtained. This will be used as is for the next reaction.

(2) 6-bromo 1-(2- and droxyethyl)-1
, 2,3,4-tetrahydrobyranlene (1) is reacted in the same manner as in Example (3) to obtain an oily substance 11.79. This is 6-bromo-1-(2-hydroxyethyl)-8 produced from a small amount of a compound contained as a raw material in addition to the title compound.
, 4-dihydronaphthalene, which is used as it is in the next reaction.

(3) 6-bromo 1-(2-(tetrahydrobilane-
Compound 11. Compound prepared with (2-yl)oxyethyl)-1,2,3,4-tetrahydronaphthalene (2). Oily product 14 of the title compound containing a small amount of 6-bromo-1-(2-(tetrahydropyran-2-yl)oxyethyl)-3,4-dihydronaphthalene by reacting Kuku in the same manner as in Example-(4) .3
get g. This will be used as is for the next reaction.

(4) 5-(2-hydroxyethyl) -5,6,7,
Ethyl 8-tetrahydro-2-naphthalenecarboxylate (
Example + (5) and (6) except that methyl iodide was used instead of ethyl bromide for compound 14.39 prepared in 3).
) to form 5-(2-hydroxyethyl)-
An oil of the title compound containing a small amount of ethyl 7,8-dihydro-2-naphthalenecarboxylate is obtained.

Dissolve this in ethanol 10-10% palladium charcoal 0
．． Catalytic reduction is carried out using 5 g. After the absorption of hydrogen is completed, it is filtered and the filtrate is concentrated to obtain 1.49 g of the title compound as an oil.

IH-N MR (cDats) δ: 3.60 (l
H,! 11. 7talene 5-position hydrogen) 3.63 (2H,
t, -0j3)OH)7.16 (1)1. 7.68 (IH, s, hydrogen at 1st position of naphthalene) 7.7 (IH, +1.Hydrogen at 3rd position of naphthalene) Example 6 5-(2-hydroxyethyl)-5,6
7. Ethyl 8-tetrahydro-1-naphthalenecarboxylate 5-bromo-1-oxo-1,2,3,4-tetrahydronaphthalene is reacted in the same manner as in Example 5 to obtain the title compound.

1B-NMR(cDals)δ:IJ7(
53H,t, -0020HzCl 01.60~2.1
0 (6H, m, 7talene 6.7th position hydrogen.

-Cdan, O)1.0)! ) 2.7 (1~8.20 (3H, m, s7 talen 5.
Hydrogen at position 8) 3.76 (2H, t, -c and 20H) 4.
31 (2M, q, -CO2Cdan2cH3) 7.04~
7.48 (2H, rn, 7talene hydrogen at 3 and 4 positions → 7
．． 68 (IH, aa, hydrogen at 2-position of 7-talene) Example 7
Ethyl 7-(hydroxymethyl)-5,6,7,8-tetrahydro-2-naphthalenecarboxylate (1) ? -Promo 2-[Bis(methylthio)methylene-1-oxo-1,2,3,4-tetrahydronaphthalenepotassium tert-butoxide (11.89 g) is added to N,N-dimethylformamide (30-) and cooled on ice. 7 in this solution
-114 g of bromo-1-oxo-1,2,3,i-tetrahydronaphthalene, 5 g of carbon disulfide and 8 g of anhydrous benzene
The mixed solution of 0- is added dropwise under a nitrogen gas stream. After stirring at room temperature for 4 hours, 15 g of methyl iodide was added dropwise, and the mixture was stirred at room temperature for 4 hours.

Next, the mixture is heated under reflux for 8 hours. After cooling, the reaction solution was added to 300 ml of ice water and stirred. The reaction solution was extracted with benzene. The extract is washed with water, dried, and concentrated under reduced pressure. Remove the residue with silica gel 3
00g was purified in a column column to obtain 10.59 g of the title compound as an oil.

(2) Compound 10.52 prepared from 2-(bis(methylthio)methylene]-7-promo-1-hydroxy-1,2,3,4-tetrahydronaphthalene (1) was dissolved in chloroform 40-
Dissolve in a mixture of 80% and ethanol. Sodium borohydride 67 was added to this solution and heated under reflux for 1 hour. Furthermore, 49% of sodium borohydride was added and the mixture was heated under reflux for 1 hour. Afterwards, concentrate under reduced pressure, add water to the residue, and extract with chloroform. The extract was washed with water, dried, and concentrated under reduced pressure to obtain 10.39 g of the title compound as an oil.

(3) Compound 10.32 prepared from methyl 7-bromo-3,4-dihydro-2-naphthalenecarboxylate (2) is mixed with boron trisulfide etherate 22- and stirred at room temperature for 5 minutes. Next, 70 methanol is added and the mixture is heated under reflux for 18 hours. Afterwards, concentrate under reduced pressure, add water to the residue, and extract with chloroform. The extract was washed with water, dried, and concentrated under reduced pressure to obtain the title compound as an oil 82.

(4)? -(Hydroxymethyl) -5,6,7,8-
Ethyl tetrahydro-2-naphthalenecarboxylate (3)
The compound prepared in Example 1 (sL (4), (5) and (6) was reacted in the same manner as in Example 1 (sL) (4), (5) and (6) to obtain an oily substance of the title compound. 8H,t, CogCH2Ci3)1.
80-2.70 (8H, m, naphthalene 6.7-position hydrogen) 2.76-2.96 (4H, m, naphthalene 5,8
position hydrogen) 3.63 (2H, +1.-0 0H) 4.8
5 (2H,q, -GOzC-diCH3)'7.12
(IH, d, hydrogen at 4-position of naphthalene) 7.68-7.88
, (2H, m, naphthalene 1,8-position hydrogen) Reference Example 1 (1) 6-(p-toluenesulfonyloxymethyl)-
5,6,7,8-tetrahydro-2-naphthalenecarboxylic acid ethyl ester 6-(hydroxymethyl)-5,6, prepared in Example 1
0.97 g of ethyl 7,8-tetrahydro-2-naphthalenecarboxylate was dissolved in pyridine 15- and cooled with water (p-).
Add 1.58 g of luenesulfonyl chloride and stir at room temperature for 6 hours. The reaction solution was poured into 70°C of ice water and stirred for 20 minutes. The precipitated powder was collected in one batch to obtain 1.459 ml of colorless powder of the title compound.

Melting point 76-78"C0 (2) 6-(1-imidazolylmethyl)-5,6,7,
8-tetrahydro-2-naphthalenecarboxylic acid ethyl ester 50% sodium hydride 0.569 was suspended in anhydrous dimethylformamide 60-, and imidazole 0.7
After adding 9 g and stirring at room temperature for 20 minutes.

Compound 4.59 obtained in (1) was added little by little, and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform. The extract is washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with a 98:2 mixed solution of chloroform and methanol.

2.31 volumes of the title compound are obtained as a colorless oil.

IH-NMR (CDCl5) δ: 1, 37 (3
H, t, -GO20H2C and 3) now 3.94 (2H, d, -C dan 2-NN) return = shi 4.85 (2H, q, -GOzOH2C dan 3) 6.
98 (IH,s, imidazole 2-position hydrogen) 7.08
(LH,s, imidazole 4th-position hydrogen)? -48(I
H, 8, imidazole 5th-position hydrogen)'1. 'l～'1.8
(2H, m, hydrogen at 5.7 position of naphthalene) (3) 2-(
Compound prepared from 1-imidazolylmethyl)-1, 8,4-tetrahydro-6-7talenecarboxylic acid hydrochloride (2) 2. Hydroxylate C19) IJ
um0.499. 4 with methanol 60-2 water 20-2
Heat to reflux for an hour. Methanol was distilled off under reduced pressure.

Add 50% of water and extract with chloroform. The aqueous layer was separated and adjusted to pH 6 with 2N hydrochloric acid. The precipitated crystals were collected by filtration and washed with water to give 6-(l-imidazolylmethyl)-5,6,7
, 1.149 of a colorless powder of 8-tetrahydro-2-naphthalenecarboxylic acid is obtained. Melting point 224-226°C.

The educt 1.149 obtained here is suspended in a small amount of ethanol, concentrated hydrochloric acid is added, and the suspension is dried under reduced pressure. The residue was recrystallized from a mixture of ethanol and ether to obtain 5 g of a colorless powder of the labeled compound. Melting point 240-252°C0 Elemental analysis value c, S Hl 6 Calculated value as N202・HCl C61,54, H5,85, N 9.57 Experimental value catao, H5,84, N 9.50 Reference example 2 (1 )8-(1-imidazolylmethyl) -5,6,7
, 8-tetrahydro-2-naphthalenecarboxylic acid methyl 6-(hydroxymethyl)-5,6, prepared in Example 2
Methyl 7,8-tetrahydro-2-naphthalenecarboxylate is reacted in the same manner as in Reference Example 1 (1) and (2) to obtain the title compound as an oil.

'H-N M R (CDCl2) δ: 1.1 to 8.05 (7H, m) 3.89 (3H, s, -0020H3) 3.95
(2B, a, -C)12- )6.95(IH,s
) 7.0 s (LH, a, hydrogen at the 4th position of naphthalene) 7.0
9 (IH, s) 7.50 (IH, s, imidazole 2-position hydrogen) 7.6
5-7.9 (2H, m, 7talene 1.3-position hydrogen) (
2) 6-(1-imidazolylmethyl)-5,8, fluoro8
9.9 g of the compound prepared from -tetrahydro-2-naphthalenecarboxylic hydrochloride (1) is dissolved in 30 mL of ethanol, a solution of 2.4 g of sodium hydroxide in 30 d of water is added thereto, and the mixture is heated under reflux for 4 hours. from now on.

Concentrate under reduced pressure and neutralize with concentrated hydrochloric acid. The precipitated powder is combined to obtain a powder of the free base of the title compound. This was suspended in 800 tnl of ethanol, added with concentrated hydrochloric acid, and dried under reduced pressure. The residue was recrystallized from a mixture of ethanol and ether to obtain 7.3 g of colorless crystals of the title compound.

Reference example 3 (1) 6-(2-formylethyl) -5,6,7,8
-ethyl tetrahydro-2-naphthalenecarboxylate 11
．． A solution of 12 and dichloromethane 20 was added dropwise to a suspension of pyridinium chlorochrome) 14.39 and dichloromethane 90 under ice cooling.

Stir for 1.5 hours at room temperature. Add 100% ether, separate the supernatant, wash with water, dry, and concentrate under reduced pressure. The residue was purified by silica gel column chromatography to obtain 10.59 g of the title compound as a pale yellow oil from the chloroform eluate.

(2) 6-(2-aminothiazol-5-ylmethyl)
-5,6,7,8-tetrahydro-2-su7talenecarboxylic acid ethylbromine 2- is added dropwise to dioxane 6-. After stirring for 10 minutes, it is dissolved in dichloromethane 25-. This solution was mixed with 10.5 g of the compound obtained in (1) in dichloromethane 2
It is added dropwise into the solution dissolved in 011Lt at -10 to 5"C under a stream of nitrogen gas. After the dropwise addition, it is stirred at -5°C for 1 hour, and a solution consisting of 8.19 of sodium carbonate and 18 of water is added. Extract with chloroform, wash the extract with water, and dry.

Concentrate under reduced pressure. The residue was dissolved in 180111t of ethanol, 8 g of thiourea was added, and the mixture was heated under reflux for 10 hours.

Saturated hydrogen carbonate) Neutralize with IJum water and concentrate under reduced pressure. The residue was extracted with chloroform, the extract was washed with water, dried, and concentrated under reduced pressure.The residue was purified using silica gel column chromatography, and the title compound was extracted as a colorless powder from the chloroform eluate.5. Get '139. Melting point: 150-158°C.

(3) Compound 2.19 obtained from ethyl 6-(thiazol-5-ylmethyl)-5,6°7.8-tetrahydro-2-naphthalenecarboxylate (2) was dissolved in phosphoric acid 23-.

Concentrated nitric acid (12) is added, and a solution of sodium nitrite (0.469) and water (4) is added dropwise at -10 to -5°C.

After further stirring for 20 minutes at -8°C, 1 reaction solution was diluted with 5 cuprous chloride,
Add to a solution of 28 g and 7 WLt of concentrated hydrochloric acid at -5"C. After stirring for 1.5 hours at -8 to O"C, add 100% of ice water.
is added, neutralized with sodium carbonate, and extracted with chloroform. The extract is washed with water, dried, and concentrated under reduced pressure. The residue is dissolved in 15-acetic acid, and 1.44% of zinc powder is added little by little while heating. After heating under reflux for 2 hours, the mixture was cooled and insoluble materials were filtered off. The filtrate was concentrated under reduced pressure, and the residue was dissolved in chloroform.
Wash with water.

After drying, concentrate under reduced pressure. The residue is purified by silica gel column chromatography. 1.27 g of the title compound as an oil was obtained from the chloroform eluate containing 2% methanol.

IH-NMR(cnc)3) δ:1.3
7 (3H,t, -(jozcHzc!L3)4.3
4 (2H, q, -002C and 2CH3) 7.05
(IH, a, hydrogen at position 4 of naphthalene ring) 7.60 (1)
1. s, hydrogen at position 4 of thiazole ring) 7.60-7.70
(2H, m, hydrogen at positions 1 and 8 of naphthalene ring) 8.68
(LH, s, hydrogen at 2-position of thiazole ring) In addition, 2 to 4
ppm 7 talene ring 5th and 6th positions.

Signals of methylene group hydrogen substituted at the 7th and 8th positions and the 6th position of the naphthalene ring are observed.

(4) 6-(thiazol-5-ylmethyl)-5,6
゜7. Add 3.02 g of the compound obtained from sodium 8-tetrahydro-2-naphthalenecarboxylate (3) to a mixture of 10% aqueous sodium hydroxide solution and 30 methanol, and heat this under reflux for 1 hour. 1. Dry the reaction solution under reduced pressure. The residue is dissolved in water, a small amount of insoluble matter is filtered off, and the filtrate is brought to pH approximately 6 with hydrochloric acid. The precipitated powder is collected in one batch to obtain 2.71 pieces of free carboxylic acid powder of the title compound. This powder is suspended in 20 g of water, 0.42 g of sodium hydroxide is added and filtered, and the filtrate is concentrated under reduced pressure. The resulting residual liquid was recrystallized from a mixture of ethanol and ether to obtain 1.929 g of the title compound as a colorless powder. Melting point over 280°C.

Elemental analysis value Calculated value as C+sH+4NO28Na
061.00. H4,77, N 4.74 experimental value
060.95. H4,91,N 4.73'H-N
M R (DzO) δ: 6.99 (IH, d, J" 8 Hz, hydrogen at the 4th position of the 7 talene) 8.4 - 8.7 (3 H, m, the hydrogen at the 4th position of the 7 talene 1,
8th place hydrogen.

Hydrogen at the 4th position of thiazole) 8.73 (IH,s, hydrogen at the 2nd position of thiazole) In addition, 1.5 to 4 ppm of hydrogen at the 8th position of 7talene 5,6,7°! : A signal of methylene group hydrogen substituted at the 6th position of naphthalene is observed.

Reference example 4 (1) 5- (2-(2-aminothiazole-5-
yl)ethyl) -5,6,7,8-tetrahydro-1
-5-(4-hydroxybutyl) obtained at the ethyl naphthalenecarboxylate example session -
Ethyl 5,6,7,8-tetrahydro-1-naphthalenecarboxylate is reacted in the same manner as in Reference Examples I(x) and (2) to obtain the title compound as an oil.

(2>5-(2-(thiazol-5-yl)ethyl) 5.6. Ethyl ethyl 8-tetrahydro-1-su7talenecarboxylate Suspend 0.879 cupric chloride in 20 WLt of acetonitrile, add nitrous acid Add tertiary butyl 0.829.

Next, a solution of 1.8 g of the compound prepared in (1) and 5-acetonitrile was added dropwise at 60°C. 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. Add this to 80% acetic acid
- and add 0.4 g of zinc powder in 4 portions every hour under heated distant current. Filter off insoluble matter.

The filtrate was concentrated under reduced pressure, and the residue was dissolved in chloroform and washed with water.
After drying, it 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.

IH-N MR (cDats) δ: 1.87 (3
H9t+ C0zCH2CHa ) 1.6 to 2.2
(6H, m, methylene hydrogen)2.8 (11(, m,
(4H, t, methylene hydrogen, naphthalene hydrogen at 8 position) 4.84 (2H, q, -
co, ca, cH3)7, o ~? -4(2H+m
+ Natsuta 128th position, 4th position hydrogen) 7.62 (2H, m
, thiazole 4-position, su7talene 2-position hydrogen) 8, 66 (
I H9lit, thiazole 2-position hydrogen) (3) 5-(2
-(thiazol-5-yl)ethylcou 5.6. F, 8
Compound 1.89 prepared with sodium -tetrahydro-1-su7talenecarboxylate (2) is reacted in the same manner as in reference side number (4) to obtain 0.7399 of the title compound as a colorless powder.

Melting point 104-115”C0 Elemental analysis value Calculated value as 0ssHssNOzSNa
C62,12,H5,21,N 4.58 Experimental value CB
1.48. H5,8B, N 4.57'H-N
M R (D20) δ: 1,5~2-1 (6H,me methylene hydrogen)2-5~
3-1 (5L m, 7talene hydrogen at 5 and 8 positions.

? -0~? -3(3HT m + naphthalene 2.3.4
(Hydrogen at position 7.53) (IH, S, hydrogen at 4th position of thiazole)
8.70 (LH, s, hydrogen at 2-position of thiazole) Reference example 5 (1) 5- (2-(l-imidazolyl)ethyl)
-ethyl 5,6,7,8-tetrahydro-2-naphthalenecarboxylate 5-(2-and droxyethyl)-5 prepared in Example 5,
Ethyl 6,7,8-tetrahydro-2-naphthalenecarboxylate is reacted in the same manner as in Reference Example 1 (1) and (2) to obtain the title compound as an oil.

IH-NMR(C1D(Ja)δ:1.36 (
3H,t, -co2CH20H3)2,f! ~3.0
(3H, m, hydrogen at 5 and 8 positions in naphthalene) 3.99 (
2H, t, methylene hydrogen) 4J 2 (2H+ Q, G
OzO and 2CH3) 6.90 (IH, s, hydrogen at imidazole 5th position) 7.02 (IH, s, hydrogen at 4th position of imidazole) 7.04 (LH, d, +7 Talen 4th position water*>
7.70 (LH,s, 7talene 1st-position hydrogen) 7.72
(IH, d, hydrogen at 3-position of naphthalene) (2> 5-
(2-(1-imidazolyl)ethyl]-5, 6, 7, 8
Compound 1.29 prepared from -tetrahydro-2-naphthalenecarboxylic acid hydrochloride (1) was mixed with 1Qm7 of ethanol, 100% of water and 0.48g of sodium hydroxide.

Heat to reflux for 1 hour. Ethanol was distilled off under reduced pressure.

Adjust the pH to 5 with dilute hydrochloric acid. Filter the precipitated powder.

Wash with water. Suspend this in 10 - of water and add 0.4 - of concentrated hydrochloric acid.
Add and concentrate under reduced pressure. The precipitated crystals were collected in one group to obtain 0.79 of colorless crystals of the title compound. Melting point 242-244℃
.

'H-N M R (dimethyl sulfoxide-ds) δ:
1.4-2.2 (4H, m, hydrogen at 6.7th position in naphthalene) 2.6 (2H, m, hydrogen at 8th position in naphthalene) 2.8
(LH, ms Naphthalene 5th hydrogen) 4-8 (2H1m
, methylene hydrogen) 7.1 o (IH, a, naphthalene 4-position hydrogen) 7.4
2 (LH, m, imidazole 5th-position hydrogen) 7.48 (
IH, m, imidazole 4-position hydrogen) 7.56 (LH,
m, naphthalene 1-position hydrogen) 7.62 (IH, m, su7
Talen 8th position hydrogen) 8.65 (IH, m, imidazole 2nd position hydrogen) Elemental analysis value C5at (tsNzoz・1(
Calculated value as Ol C62, 64, H6, 24, N 9
．． 11 Experimental value C62, 81, H6, 24, N 9.0
7 Reference Example 6 (1) 5-(2-(1-imidazolyl)ethyl)
=5,6.7.8-Ethyl tetrahydro-1-naphthalenecarboxylate 5-(2-hydroxyethyl)-5, prepared in Example 6
Ethyl 6,7,8-tetrahydro-1-naphthalenecarboxylate is reacted in the same manner as in Reference Example 1 (1) and (2) to obtain the title compound as an oil.

1H-NMR(CDC)3) δ:L87
(8H, t, -COzCHzC and 3) 1.56-1
．． 96 (4H, m, hydrogen at 6.7 position of naphthalene) 1.9
6 to 2.82 (2H, m, -0diGH2-N”N
) (=Go 2.70 ~ 8.20 (8H, m, naphthalene? 5,8-position hydrogen) 4.02 (2H, t, to -CH2-N) (=Go 4.84 (2H, q, - CO2C dan2cHa )6
．． 92-7.80 (6H, m, aromatic ring hydrogen) (2)
5-(2-(1-imidazolyl)ethyl)-5, 6
, 7,8-tetrahydro-1-naphthalenecarboxylic hydrochloride (1) Compound 1.79 was used to prepare Reference Example 5 (2).
Colorless crystals of the title compound 1.2 were prepared in the same manner as shown in
Get 9. Melting point 219.5-220.5°C0IH-N
M R (dimethyl sulfoxide-ds) δ: 1.50
~2.00 (4H, m, hydrogen at position 6.7 of naphthalene)2
．． 00~2.40 (2H, m, -CHzCH2-6
) (=J 2.64~c1.12 (3H, m, naphthalene 5.8
position hydrogen) 4.86 (2H, t, -c degree 2-N"N) (
=ㅅ7.22 (LH, t, hydrogen at 3-position of naphthalene) 7.42
(IH, cld, naphthalene 4-position hydrogen) 7.49 (
LH, dd, naphthalene 2-position hydrogen) 7.63 (2H,
m, imidazole 4,5-position hydrogen) 9.86 (IH, m
, imidazole 2-position hydrogen) elemental analysis value 016H111
Calculated value as N202・HCj C62, 64, H6,
24, N 9.13 Experimental value C62,30, H6,41
, N 9.09 Reference Example 7 (1) 7-(1-imidazolylmethyl)-5,6,7,
Ethyl 8-tetrahydro-2-su7talenecarboxylate 7-(hydroxymethyl)-5,6, prepared in Example 7
Ethyl 7,8-tetrahydro-2-naphthalenecarboxylate is reacted in the same manner as in Reference Examples (1) and (2) to obtain the title compound as an oil.

”H-NMR(0DGIs)δ:1.38 (3
H, t, co2cHzcdan3) 1.50-8.1
0 (7H, m, naphthalene hydrogen at 5, 6, 7.8 positions) 3
．． 95 (2H, m, -GH2-N″N) ν=zo4.35 (2H, q, -COzC and 2.aH3)6
゜90~7.88 (6H, m, naphthalene 1.8.4
position hydrogen.

Imidazole 2.4.5-position hydrogen) (2>7-(1-imidazolylmethyl) -5,6,7
, 8-tetrahydro-2-su7talenecarboxylic hydrochloride (1) was reacted in the same manner as in Reference Example 1 (3) to obtain colorless crystals 1.2 as an earth hydrate of the title compound. . Melting point 269-271"C0'H-NMR (dimethyl sulfoxide-da) δ:
IJO ~ 2.20 (aH, rn, hydrogen at 6.7 position of naphthalene) 2.64 ~ L04 (4H, m, 7 talene 5,
Hydrogen at position 8) 4.2 e (2H, d, -aH2-N"N
)-=su 7.22 (IHI d, naphthalene 4-position hydrogen) 7.6
Q ~7.96 (4H, m, hydrogen at 1.8 position of naphthalene.

Imidazole 4,5 position hydrogen) 9.28 (IH, s, imidazole 2 position hydrogen) Elemental analysis value Cs5HxsNzOz・HCj-+1 (calculated value as 20 G 59.70. H6,01,N 9.
28 Experimental value C60,02, H5,82, N 9.20
Test Example Citrated blood (1 volume of 3613% sodium citrate was added to 9 volumes of ml solution) was collected from male Wistar Imamichi rats weighing 280 to 320 kg by cardiac puncture under bendoparbital anesthesia. ,room temperature.

Centrifugation was performed at 230X for 7 minutes. Obtained supernatant (PRP)
diluted with ppp (platelet poor plasma) to increase the platelet count by 5x.
It was adjusted to 108/- and used in the following tests. For PPP, the residue after PRP separation is centrifuged at 1.500X for 10 minutes, and the supernatant is used to add the above PRP to 10 μl of the sample solution.
After adding 90 μl of this mixture and shaking for 1 minute, 90 μl of this mixture was combined with 10 μt of 5 mM sodium arachidonic acid solution and shaken at room temperature. After shaking for 5 minutes, take 10 μl of this mixture and add 90 μl of 100 μM flurbiprofen solution! The reaction was stopped.

The reaction solution was centrifuged at 1009x for 5 minutes, and the concentrations of TXB2 (a stable decomposition product of TXA2) and PG E2 in the resulting supernatant were measured using the radioimmunoassay method (Proa) of Morris et al.
taglandins 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 TXA2 synthesis inhibition rate was calculated using the following formula, and the TXA2 synthesis inhibition activity was determined by the concentration of the sample showing a 50% inhibition rate (I 0
It is expressed as s(1).

In platelets, TX is reduced by suppressing cyclooxygenase.
The production of not only B2 but also PGE2 and PGF2a is suppressed (Hamberg et al., Proc, N
at, AcILd.

USA? 1,3824.1974), conversely, TXA2
PGF2. due to deficiency or inhibition of the synthase. P.G.
Increased production of F2a and PG (Defrey)
n et al., Brot.

J. Haematol, 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.

Claims (1)

[Claims] A compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R represents a lower alkyl group, and n represents an integer from 1 to 6.)