JPS6094974A - Omega-(p-(2-substituted-4-thiazolyl)phenyloxy)alkanecarboxylic acid and derivative thereof - Google Patents

Abstract

NEW MATERIAL:An omega-[p-( 2-substituted-4-thiazolyl )phenyloxy]alkanecarboxylic acid expressed by formula I [R<1> is 5--6-membered heterocyclic ring containing 1-2N atoms, alkyl, amino, phenyl, carbamoyl, etc.; R<2> is H or alkyl; X is expressed by formula IV (R<3> and R<4> are H or alkyl; R<5> is OH, alkoxyl or amino) or formula IV (R<6> is OH or alkoxyl); m is an integer 1-4] and a derivative thereof. EXAMPLE:Ethyl2,2-dimethyl-5-{p-[2-(3-pyridyl)-4-thiazolyl]phenoxy}pent anoate. USE:A preventing and treating agent for arteriosclerosis, cerebral infract, transient ischemic attack, angina pectoris, peripheral thrombus and obstruction having antilipemic action and inhibitory action on blood platelet agglutination. PREPARATION:A nicotinic acid amide expressed by formula II or hydroxyphenylthiourea is reacted with an omega-(halogenoacetylphenyloxy)alkanecarboxylic acid expressed by formula III or an ester thereof to afford the aimed compound expressed by formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides ω-[p-(2-ft
The present invention relates to (4-thiazolyl)phenyloxycorealkane carboxylic acid and its derivatives.

The symbols in the above formula have the following meanings.

R1: 6-membered heterocyclic group containing 1 or 2 nitrogen atoms; lower alkyl group; amine 7 group; lower alkyl group, phenyl group, substituted or unsubstituted carbamoyl group, acyl group R2 : hydrogen atom; lower alkyl group R3 or Ryomino group); or a group represented by the formula -〇-Q-COR6 (
In the formula, R6 means a hydroxyl group or a lower alkoxy group)
Group m: an integer from 1 to 4 The meanings of the symbols in the above general formula are further explained as follows.

[6-membered heterocyclic group containing 1 or 2 nitrogen atoms] in R1 is, for example, a 2-1 or 3-pyrrolyl group, a 2-
or 4-imidazolyl group.

2-93- or 4-pyridyl group, 2-. 4- or 5
-pyrimidinyl group.

"Lower alkyl group 1 means a straight or branched carbon chain having 1 to 5 carbon atoms. Preferred examples include methyl group, ethyl group, and inglovir group.

"Substituted carbamoyl group" is a lower alkyl group.

It is a lower alkyl group substituted with an imidazolyl group or a carbamoyl group substituted with a cyclohexyl group.

The "substituted amine group" in R4 is a amine group substituted with a lower alkyl group or a lower ester group (acetyl group, globionyl group, butyryl group, etc.).

The compounds of the present invention may have tautomers based on prototropy and optical isomers based on asymmetric carbon atoms.

These isomers and mixtures thereof are included.

Furthermore, the compounds of the present invention are capable of forming salts with acids or bases, and include pharmacologically acceptable salts thereof. Suitable salts with acids include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, formic acid, acetic acid,
Examples include salts with organic acids such as lactic acid, oxalic acid, succinic acid, fumaric acid, benzoic acid, and benzenesulfonic acid, and quaternary ammonium salts with alkyl rogens such as methyl iodide. In addition, salts with bases include sodium,
Salts with potassium etc. are used.

The object compound of the present invention has a lipid-lowering effect, particularly a sulfur cholesterol and triglyceride-lowering effect, and also has a platelet aggregation-inhibiting effect, causing arteriosclerosis, cerebral infarction, transient ischemic attack, and angina. It is effective in preventing and treating peripheral thrombosis, peripheral thrombosis, and occlusion.

According to animal experiments, the object compound of the present invention.

It has been recognized to have excellent cholesterol and triglyceride lowering effects and to selectively increase high density lipoprotein (HDL) in the blood. It is known that the amount of HDL decreases during arteriosclerosis compared to normal levels, and that it prevents excessive accumulation of cholesterol in arterial walls and promotes the flow of cholesterol from arterial walls. It is a substance. In addition, 9 target compounds of the present invention are:

It has the effect of inhibiting platelet aggregation caused by arachidonic acid. This effect, together with the lipid-lowering effect, is effective in preventing and treating the above-mentioned diseases such as arteriosclerosis.

The pharmacological effects of the present invention were confirmed as follows.

Lipid lowering effect: Sprague - 3 weeks old
Cholesterol 1.5 in male rats (Dawley)
A diet containing 0.5% and bile acids was given for 7 days, and for the last 4 days, the compound of the present invention, which had been dissolved in methylcellulose (0.5% water), was administered orally once a day by red rubbish, and - at night. After fasting, blood was collected under ether anesthesia.

Measure the amount of serum total cholesterol and HDL.

Cholesterol measurement Schettler, G &Nuetsel;
Arubaits Medicincial Medicin Preventive Medicine Vol. 10, p. 25, 1975 (5chett
ler, G &N1rssel; Arbe i
tsmed.

Sozialmed, PrKventivmed,
1025 (1975)),
HDL measurement is also available in Lipid Volume 11, page 628, 197
6th year (T, T, Ishikawa et al,
; Lipids, 11628 (1976)). According to this experiment, the compound of the present invention was administered at 25 to IO01Qg/kg (1
It was found that the daily dose was significantly effective.

Platelet-rich plasma (PRP') and platelet-poor plasma (PPP) used were prepared from the venous blood of a Japanese white rabbit. Measurement of platelet aggregation ability was performed by Bourne G, V, R,;
Volume 194, page 927, 1962 (Born, G, V.

R; Nature, 194', 927 (19
The platelet aggregation inhibitory effect of the compound on the platelet aggregation induced by arachidonic acid (final concentration 0.3 mM) was measured using an Ablibometer (manufactured by Priceton) using the method described in 62). As a result, the target compound of the present invention 9 exhibited an inhibitory effect at an IC concentration of 10 to 100 μM.

The compound of the present invention can be formulated into powders, granules, and capsules using commonly used pharmaceutical additives.

It can be made into preparations such as injections. The method of administration is preferably oral, and the dosage varies depending on the patient's condition, age, etc., but in the case of oral administration.

1 to 100111 g/kg per day for adults, preferably 5
~251118/kg.

The target compound of the present invention can be produced by the method shown by the following reaction formula.

(Former (III) (1) (in the formula, Hal) means a rogen atom, R',
The meanings of RjX and m are the same as above. ) To produce the compound of the present invention by this method, (■) nicotinic acid thioamide or hydroxyphenylthiourea and ω-()・rogeno acetylphenyloxy)
This is carried out by reacting an alkane carboxylic acid or its ester (III) in a solvent that does not participate in the reaction.

As the solvent, alcoholic solvents such as alcoholic acid, methanol, and ethanol are preferred. Both raw material compounds are used in approximately equimolar proportions.

The reaction proceeds easily at room temperature, but may be carried out with heating if necessary.

To isolate the target compound from the reaction mixture.

This is carried out using various operations such as extraction with a solvent, recrystallization, and chromatography.

The compound thus obtained can be converted into a salt by reacting with the above-mentioned acid or base, if necessary.

I cut it. When the target compound is a free acid, it can be converted into an ester by the conjugation method.

Next, in order to further explain the present invention, Examples will be given.

In addition, the manufacturing method of the raw material compound used in an Example is demonstrated as a reference example.

Reference example 1 p-hydroxyacetate 1 pheno 730g, potassium carbonate 3
Add 500 ml of ethanol to 0 g and stir for 60 minutes.
After heating at ℃ for 30 minutes and cooling to room temperature, 5-bromo-2,2-
52 g of dimethylpentanoic acid ethyl ester was added, and the mixture was heated to reflux overnight while stirring. The solvent was distilled off from the reaction mixture, 500 ml of chloroform and 300 ml of 1.5% aqueous sodium hydrogen carbonate solution were added to the residue, and after stirring to a brown color, the chloroform layer was separated, washed sequentially with water and a saturated aqueous sodium chloride solution, and washed with anhydrous sodium sulfate. Dry. Distilling off the chloroform gave an oily residue. This oil was subjected to silica gel column chromatography using chloroform as the eluent.

The target p-acetylphenoxy-2,2-dimethylpentanoic acid ethyl ester is an oily substance,! : then 4
I got 2g. This obtained oil was mixed with anhydrous methylene chloride for 1
．． Dissolve in 6 Otsu and dropwise add 24 g of bromine while cooling with water.

The reaction was allowed to proceed for 3 hours while stirring. Add ice water IL to the reaction solution.

After stirring well, wash sequentially with water and saturated saline.

Dry with anhydrous sulfuric acid (IJum). When methylene chloride is distilled off, the target 5-4p-(bromoacetyl)
An oil of phenoxy)-2,2-dimethylpentanoic acid ethyl ester was obtained.

Reference Example 2 In Reference Example 1, 6-bromo-2,2-
The same reaction and treatment as in Reference Example 1 were carried out using dimethyl hexa/acid ethyl ester as the starting material (
Ethyl i-[p-bromoacetylphenoxy]-2,2-dimethylbexanoate Reference Example 3 In Reference Example 1, 7-bromo 2,
Using 2-dimethylpebutanoic acid ethyl ester as a starting material, the same reaction and treatment as in Reference Example 1 were carried out to obtain the desired 7-(p-bromoacetylphenoxy)-2,2-dimethylhebutanoic acid ethyl ester in the form of an oil. I got it as a thing.

Reference Example 4 In Reference Example 1, the same reaction treatment as in Reference Example 1 was carried out using p-hydroxypropiophenone as a starting material for the conversion of p-hydroxyacetophenone, and the desired 5-Co-(2-bromo propionyl) phenoxy]
-2.2-Dimethylpentanoic acid ethyl ester was obtained as an oil.

Reference Example 5 In Reference Example 3, the same reaction treatment as in Reference Example 3 was carried out using p-hydroxypropiophenone as a starting material for p-hydroxyacetophenone, and the desired 74:p-(2-bromo Propionyl)phenoxy)-2,2-dimethylheptanoic acid ethyl ester was obtained as an oil.

Example 1 5-(1)-(2-bromo acetyl) obtained in Reference Example 1
18 g of (phenoxy)-2,2-dimethylpentanoic acid ethyl ester and 0.7 g of 3-pyridylthioamide were stirred in 20 mZ of methanol at room temperature for 5 hours.

The solvent was distilled off from the reaction solution, and 30ml of chloroform was added to the residue.
1. After adding 1'l of 5% sodium bicarbonate aqueous solution [30mA] and stirring, separate the chloroform layer and add water.

Wash sequentially with an aqueous solution of IJ (saturated chloride) and dry over anhydrous sodium sulfate. Distill off the chloroform.

An oily residue was obtained.

This product was subjected to silica gel column chromatography to elute the target product using chloroform-methanol (10:1 volume ratio) as an eluent, and the solvent was distilled off from the eluate under reduced pressure to obtain the target 2,2 -dimethyl-5-(p-1
:2-(3-pyridyl)-4-thiazolyl]phenogyshi]pentanoic acid ethyl ester was obtained as an oil.

Nuclear magnetic resonance spectrum (CDCI) (internal standard TM
S) δ (ppm): 1.22 (6H,s, C
H, -C-CH3) ~ 1 ~ 1.26 (3H, L, J = 7.27 C00CH
2-Cdan,)1.5-1.9(4H,m,C-CH2-
CH, -C) 3.99 (2H, t, J"5.4H
z, φ-o -CH2-C)4.12 (2H, q,
J=7.2Hz, COOCH2-C)6.94(2
H, d, J=8.3. Hz, Eo-c >7.38 (
IH,s,-i)[:”) In Example 1, 5[p
-(2-bromoacetyl)phenoxy) -'2.2-
Reference example 3 instead of dimethylpentanoic acid ethyl ester
7-[p-(bromoacetyl)phenoxy]-2 obtained in
, 2-dimethylhebutanoic acid ethyl ester as a raw material was subjected to the same reaction treatment as in Example 1, and the obtained residue was recrystallized from petroleum ether to obtain the desired 2,2-
Dimethyl-7[P-[2-(3-pyridyl)-4-thiazolyl]phenoxychohebutanoic acid ethyl ester was obtained as white crystals.

Melting point 41-42℃ Elemental analysis value (as C, N3., N203S) C (%)
H (%) N (%) S (%) Theoretical value 68.46 6
,89 6.39 7.31Experimental value 68.60 6.
87 6.36 7.11 Example 3 5-[p-(bromoacetyl)phenoxy]-2.2-dimethylpentanoic acid ethyl ester obtained in Reference Example 13.
After stirring 6 g of 4-imidazolylthioamide and 1 g of 4-imidazolylthioamide in a methanol 40 + nZn chamber for 15 minutes, the mixture was heated under reflux at 70°C for 2 hours, the solvent was distilled off from the reaction solution, and the residue was mixed with 200 mZ of chloroform and 5% After adding 100 mZ of an aqueous sodium hydrogen carbonate solution and stirring, the chloroform layer was separated, washed successively with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Chloroform was distilled off to obtain an oily substance. This product was subjected to silica gel column chromatography to elute the target product using chloroform-methanol (20:1 volume ratio) as an eluent, and the solvent was distilled off from the eluate under reduced pressure to obtain the product. The residue was recrystallized from ethyl acetate to obtain the desired 5-['p-[2-(4-imidazolyl)-
4-thiazolyl]phenoxy]-2,2-dimethylpentanoic acid ethyl ester was obtained as white crystals.

Melting point 122-123℃ Elemental analysis value (as C21H25N30S) C (%)
I((%) N(%) S(%) Theoretical value 63,14
6.31 10.52 8.02 Experimental value 63.21'
6.25 10.4'6 8.14 Example 4 In Example 3, 7-[ obtained in Reference Example 3 was used instead of 5-[p-(promoacel)phenoxy]-2,2-dimethylpentanoic acid ethyl ester. The same reaction treatment as in Example 3 was carried out using p-(bromoacetyl)phenoxy]-2,2-dimethylhebutanoic acid ethyl ester as a raw material compound (however.

(recrystallized from ethyl acetate-hexane) desired 5-[,
p-[2-(4-imidazolyl)-4-thiolzolyl]phenoxy]-2,2-dimethylhebutanoic acid ethyl ester was obtained as white crystals.

Melting point N4~1.15℃ Elemental analysis value (as C23H2o N303S) C (%
) H (%) N (%) S (%) Theoretical value 64,61
6,84 9,837.50 Experimental value 64,69 7
,02 9.75 7.40 Example 5 In Example 3, thioacetamide was used as a raw material compound instead of 4-imidazolylthiolamide, and Example 3
The obtained oil was subjected to silica gel column chromatography, the target product was eluted using chloroform as an eluent, and the solvent was distilled off from the eluate under reduced pressure to obtain the target product 5. -[p-('2-methyl-4
-thiasolyl)phenoxy]-2,2-dimethylpentanoic acid ethyl ester was obtained as an oil.

Nuclear magnetic resonance spectrum CDCl, ) (internal standard T
MS) δ (ppm); 1.20 (6H, S, CH,
, -C-CH3)1.22 (3H,t, J=7.
2, C00C-CH31,5-1.9 (4H, rn,
C-CH,,-CH2-C'~1 2.73(3H,8,CI(3<))3.94(2
H, t, J=6.1Hz, φ-0-CH2-C)4
．． 08(2H,q, J=7.2Hz, Coo
CH2-C) 6.86 (2H, d, J=8.3H
z, Tsukio-c) 7.12 (IH, s, Su-,) Example 6 In Example 2, the same procedure as in Example 1 was carried out using thioacetamide as the raw material compound instead of 3-pyridylacetamide. The reaction treatment was carried out, and the obtained oily residue was subjected to silica gel column chromatography using n-hegizan-ethyl acetate (8:1 volume ratio) as the eluent.
Elute the target product, distill off the solvent from the eluent, and
7-[p-(2-Methyl-4-thiazolyl)phenoxy]=2.2-dimethylhebutanoic acid ethyl ester was obtained as an oil.

Nuclear magnetic resonance spectrum (CDCl2) (inner tank iTM
s) δ (ppm): 1.16 (611, s, CI,
, -C-CH31,23(31(,t, J=7.
2Hz, CH3-CH2-0-)e 1.1-1.9 (8H, m -C-CHz-C'H!
-CHz-Chui, -C)J.

2.76 (3H, 11, cH2) 3.98 (2H, t, J=6.1Hz,) O-C! ! ,
, -C) 4.12 (2H, q, J=7.2Hz, C
oo CruC) 6.92 (2u, d, J=9.01
1z, Eo-c) Examples 7 to 9 (m = 2 to 4) Promoacetyl phenoxycarboxylic acid ethyl ester and thiourea obtained in Reference Examples 1 to 3 were used as raw material compounds in different combinations, and Example 1 Compounds of Examples 7 to 9 were produced by carrying out the same reactions and treatments.

Examples 10 to 11 (m = 3.4) The same reaction as in Example 1 was carried out using different combinations of bromoacetyl phenoxycarboxylic acid ethyl ester and methylthiourea obtained in Reference Examples 1 and 2 as starting compounds,
Example 10. '11 compound was prepared.

Examples 12 to 13 (m=3.4) Using bromoacetyl phenoxycarboxylic acid ethyl ester and l-phenyl-2-thiourea obtained in Reference Examples 4 and 5 as raw material compounds by changing the rough combination, Examples were prepared. The same reaction treatment as in step 1 was carried out.

Examples 12-1: Two compounds were prepared.

Examples 14 to 16 7-[p-(2-bromopropionyl)phenoxy]-2.2-9 methylhebutanoic acid ethyl ester obtained in Reference Example 5 and 3-pyridylthioamide, thioacetamide,
The same reactions and treatments as in Example 3 were carried out using different combinations of thiourea as raw material compounds to produce compounds of Examples 14 to 16.

Example 17 In Example 15, ethyl 7-[p-(bromoacetyl)phenoxy]-2,2-dimethylhephthanoate/l
/ester instead of 2,2-dimethyl-5-[p-(bromoacetyl)phenoxy]pentanoic acid ethyl ester obtained in Reference Example 1 as a starting material, Example 1
Perform the same reaction and treatment as in step 5, apply the obtained oily residue to silica gel column chromatography, use chloroform as an eluent to elute the target product, and distill off the solvent from the eluent under reduced pressure. Then, the desired 5-[p
-(2,5-dimethyl-4-thiazolyl)phenoxy]
-2,2-dimethylpenconic acid ethyl ester was obtained as an oil.

Nuclear magnetic resonance spectrum (CDCl 3-) (internal standard TMS) δ (ppm); 1.20 (6H, s, CH3-C-CH8)' 1 to 1.22 (3H, t, J-7, 2Hz, -COOC-C
H3) 2.48 (3H, s, -XJ'"")2
．． 65(3H,!1.CH,<1)3.98(2H
, q, φ0CH2-C) 4.12 (2H, q, J=
7.2 Hz, C00CH2C) Example 18 1.13 g of 7-[p-(2-minor-4-thiazolyl)phenoxy]-2,2-dimethylhebutanoic acid ethyl ester obtained in Example 9 and cyclohexyl insia Nee)
0.38 g was reacted in 15 mt of tetrahydrofuran for 4 hours under heat reflux overnight.

Add ice water to the reaction solution and extract with methylene chloride.

After drying the methylene chloride layer with anhydrous magnesium sulfate.

The solvent is distilled off, and the resulting residue is subjected to silica gel column chromatography. n-hexane-ethyl acetate (4:
After distilling off the solvent, the obtained crystals were recrystallized from a mixed solvent of n-hexane-ether to give 7-[p-[2-(:3- cyclohexylureido)-4-thiolzolyl]phenoxy]-
2,2-dimethylhebutanoic acid ethyl ester was obtained as white crystals.

Melting point 106-108℃ Elemental analysis value (C2? H39Na 04 S) C
(%) H (%) N (%) S (%) Theoretical value 64.
64 7.84 13:38 6.39 Experimental value 64.
438.04 8.24 6.40 Example 19 In Example 18, in place of 7-[p-(2-amino-4-thiazolyl)phenoxy]-2,2-dimethylhebutanoic acid ethyl ester, Example 7-[p obtained in 16
-(2-dimethyl-5-methyl-4-thiol-zolyl)phenoxy]-2,2-dimethylhebutanoic acid ethyl ester using as starting material.

The same reaction treatment as in Example 18 was carried out to obtain the desired 7-
[p-[27(3-cyclohexylureido)-5-methyl-4-thiazolyl]phenoxy]-2,2-dimethylhebutanoic acid ethyl ester was obtained as white crystals.

Melting point 79-81"C Elemental analysis value (as C2g H41N304"')C
(%) H (%) N (%) S (%) Theoretical value 65.2
1 8.01 8.1j 6.22 Experimental value 65.33
8.22 B, 03 6.20 Example 20 0.39 g of 4-(1-imidazolyl)butyric acid and 0.37 g of 1-hydroxybenzotrizolyzole were dried with N, N
-Dissolve in 15 ml of dimethylformamide (DMF) and add 0.57 g of dicyclohexylcarbodiimide to this solution at 40-45°C while stirring. After precipitating dicyclohexylurea in the reaction solution, D
7-[p-(2-amino-4-thiazolyl)phenoxy]-2. dissolved in MF5mt. 0.94 g of 2-dimethylhebutanoic acid ethyl ester was added dropwise, and the mixture was stirred overnight at the same temperature. After adding dicyclohexylurea to P, the solvent is distilled off under reduced pressure. Ice water was added to the residue, extracted with chloroform, and the chloroform layer was washed successively with saturated aqueous sodium bicarbonate and water.

Dry with anhydrous magnesium sulfate. Chloroform was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. Chloroform-methanol (40:
The target product was eluted using an eluent of 7-[P-[2-[4-(1 -imidazolyl)butyramide]-4-thiazolylcophenoxy]-2°2-dimethylhebutanoic acid ethyl ester was obtained as white crystals.

Melting point 148~150"C Elemental analysis value (C2? H36N404S and shite) C (%)
H (%) N (%) S (%) Theoretical value 63.26
7.08 10.93 6.25 Experimental value 63.01
7.08 10.85 6.13 Example 21 In Example 20, Example 16 was used instead of 7-[p-(2-amino-4-thiazolyl)phenoxy]-2,2-dimethylhebutanoic acid ethyl ester. 7 −[
A similar reaction treatment was carried out using p-(2-amino-5-methyl-4-thiazolyl)phenoxy]-2,2-dimethylhebutanoic acid ethyl ester as a starting material to obtain the desired 7-[p-[2 -'[4-(1-imidazolyl)phthyramide]-5-methyl-4-thyrozolyl]phenoxy]-2,2-dimethylhebutanoic acid ethyl ester was obtained as white crystals.

Melting point 85-87゛C Elemental analysis value (as C, 8H3, N404S) C (%)
■(%) N(%) S(%) Theoretical value 63,85 7
．． 27 10.64 6.09 Experimental value 63,87 7
．． 47 10.62 6.25 Example 22 Obtained in Example 5. 2.2-dimethyl-5,-[p-(2
-Methyl-4-thiazolyl)femexopentanoic acid ethyl ester (1.4 og) was dissolved in 5 ml of ethanol, and this was dissolved in an aqueous sodium hydroxide solution (hydroxidized).
0.4 g of IJum, 5 ml of water) and heated under reflux for 10 minutes.
Allow time to react. After cooling, the precipitated crystals are washed with water to obtain the desired 2,2-dimethyl-5-[p (2-no-1-
4-thiazolyl)phenoxy]pentanoic acid sodium salt was obtained as white crystals.

Melting point 259-261℃ Elemental analysis value (as C17H2oNO3SNa) C (%
) H (%) N (%) s (%) Theoretical value 59.81
5.90 4,10 9.39 Experimental value 58.72 5
,73 4.12 9.34 Example 23 2,2-dimethyl-5-' [p
-(2-Methyl-4-thiazolyl)phenoxy]pentanoic acid sodium salt 1 og was dissolved in 50 mZ of water.

Neutralize with 10% hydrochloric acid. The precipitated crystals were collected and washed with water to obtain the desired 2,2-dimethyl-5-[p-(2
-Methyl-4-thiazolyl)phenoquine]pentanoic acid was obtained as white crystals.

Melting point 150~153"C Elemental analysis value (as C10H21NOs S)C (%)
11 (%) N (%) S (%) Theoretical value 63,92
6,63 4.39 10.04 Experimental value 63.67
6.65. 4.13 9.64 Example 24 2,2-dimethyl-5-[p-(2
-Methyl-4-thiazolyl)phenoxy]pentanoic acid 0
．． 7 g and 0.22 g of triethylamine were dissolved in 10 ml of dichloromethane, and heated to -20°C while stirring.
Cool to −15° C. and add dropwise 0.3 g of inbutyl chloroformate. After stirring at the same temperature for 30 minutes, 0.6 g of concentrated ammonia water (29% ammonia) was added dropwise.

After completion of the dropwise addition, the temperature was raised to room temperature, and the mixture was further stirred for 15 minutes.

Ice water is added to the reaction solution, and the organic layer is separated, washed successively with saturated aqueous sodium bicarbonate and water, and dried over anhydrous magnesium sulfate. The solvent is distilled off, and the resulting residue is subjected to silica gel column chromatography. The target product is eluted using chloroform-methanol (50:1 volume ratio) as an eluent, and after distilling off the solvent, the obtained crystals are recrystallized from a mixed solvent of ether-benzene to obtain the target 2,2-dimethyl -5-[p-(2-methyl-4-thiazolyl)phenoxy]pentanoic acid compound was obtained as white crystals.

Melting point 148-150"C Elemental analysis value (c, □ [as 52N20□S) C (%)
H (%) N (%) S (%) Theoretical value fi4.12
G, 96 8.80 10.07 Experimental value 64,20
7.04 8.78 9.95 Example 25 0.4 g of thioacetamide and p (4-[p-(2-
2.2 g of bromopropionyl) phenoxy] butoxy) benzoic acid ethyl ester and 30 ml of methanol.
The mixture was reacted in the same manner as in Example 3, and after cooling.

The crystals precipitated from the reaction mixture were collected and recrystallized from inpropyl alcohol to obtain the desired P-[4[p-(2,
White crystals of 5-dimethyl-4-thiazolyl)phenoxy]butoxy]benzoic acid ethyl ester/hydrogen salt were obtained.

Melting point 179-180℃ Elemental analysis value (as C24H27NO4S-HBr) C
(%) H (%) N (%) S (%) Br (%) Theoretical value 56,92 5.57 '2,77 6.33
15.78 Experimental value 56.70. 5,66 2.71
．． 6.37 Example 26
7 g of 2,2-dimethylpentanoic acid ethyl ester
The mixture was stirred for 1 hour at room temperature in 7 tons of 3OmZ, and then 20 ml of glacial acetic acid was added and stirred for 1 hour under reflux. The reaction product was concentrated under reduced pressure, and the precipitated crystals were recrystallized from ethanol to obtain the desired 5-[p-[2-(p-hydroxyphenylimino)-3-methyl-4-teacyly/-5-yl]phenoxy ]-2, z-dimethylpentanoic acid ethyl ester hydrogen salt is obtained.

Melting point 208-210°C Elemental analysis value (as C25H3gN204S-HBr) C (%) former %) N (%>s<%) Br (%) theoretical value 56,07 5. s: 35.23 5.99 1
4.92 Experimental value 56,21 5.90 5.23
6.00 15.09 Patent applicant: Yamanouchi Pharmaceutical Co., Ltd. Agent: Patent attorney Shozo Nagai Continuation of page 1 ■Int, CI,' Identification code Office docket number 277:
00) Procedural amendment (voluntary) February 7, 1980] Case description 1982 Patent Application No. 201639 2 Name of the invention ω-[p-(2-Substituted-4-thianolyl)phenyloxy]alkanecarbon Acids and their derivatives 3 Relationship with the case of the person making the amendment Patent applicant address: 2-5 Nihonbashi Honmachi, Chuo-ku, Tokyo, 1st name (667) Yamanouchi Pharmaceutical Co., Ltd. Representative: Shigeo Morioka 4 Agent address: Tokyo 1-1-8 Azukizawa, Itabashi-ku, Miyako ＼＼－－〆・ Column 1 of ``Detailed explanation''? f-P? th 6. Contents of amendment 1) Amend the "Claims" as shown in the attached sheet.

11) Amend the "Detailed Description of the Invention" column as follows: ■ Change "6 members" to "5-6 members" in line 0 from the bottom of page 2 of the specification.
Correct.

■ Correct "6 members" in the 7th line from the bottom of the third page to "5-6 members."

■ Delete "1-imidazolyl group-substituted lower alkyl group" in line 3 of No. 4 Tei.

(2) On page 4, lines 6-9, ``7 groups in R4'' are corrected to ``'Acyl group' is a lower acyl group having 1 to 5 carbon atoms substituted with an imidahal group.''

■ Structural formula of Example 26, page 40 Correct as follows.

0 Claims ω-[p-(2-substituted-4-thiazolyl)phenyloxycorealkanecarboxylic acid and derivatives thereof represented by the general formula below. The symbols in the above formula have the following meanings.

RI=5- to 6-membered heterocyclic group containing 1 or 2 nitrogen atoms; lower alkyl group; amino group; lower alkyl group, phenyl group, substituted or unsubstituted carbamoyl group, amino group substituted with 7-syl group R2: hydrogen atom; lower alkyl group 3

In addition, RS means a hydroxyl group, a lower alkoxy group, or an amino group); a group represented by the formula -0-1S)-COR' (in the formula R
6 means hydroxyl group or lower alkoxy group) -
Indicated base m: integer from 1 to 4 Procedural amendment (voluntary) July I2, 1980 Manabu Shiga, Commissioner of the Japan Patent Office 1 Display of the case 1982 Patent Application No. 201639 2 Name of the invention ω-[p- (2-Substituted-4-thiazolyl)phenyloxycorealkanecarboxylic acid and its derivatives 3, relationship to the amended person case Patent applicant address 2-5-1 Nihonbashi Honmachi, Chuo-ku, Tokyo Name
(667) Yamanouchi Pharmaceutical Co., Ltd. Representative Shigeru Morioka
4th husband, Osamu (Address: 1-1-8 Azukizawa, Itabashi-ku, Tokyo) 6. Contents of amendment (!) Specification page 18, line 5 rC2+ H2s N5o
Correct sJ to "c,,H,N,0.SJ.

do.

Ru.

(4) On page 25, line 4, “In reference example 4.5” was changed to “Reference example 1.”
．． 2," and in the table starting from line 9 on the same page, the reference side layers of raw material compounds "4" and "5" are respectively corrected to "rlJ layer 2".

(5) On page 29, line 5 of the same document, change “In reference example 1” to “In reference example 4.”
rp-(bromo7sedil)" in the same 6th line is changed to rp-(2
- Glomobropionil Correct each month.

Claims (1)

[Claims] ω-[p-(2-substituted-4-thiazolyl)phenyloxycorekanecarboxylic acid and derivatives thereof represented by the following general formula. The symbols in the above formula have the following meanings. R1: 6-membered heterocyclic group containing 1 or 2 nitrogen atoms; lower alkyl group: amino group; lower alkyl group, phenyl group, substituted or unsubstituted carbamoyl group, amino group substituted with acyl group R2: hydrogen Atom; lower alkyl group 3 means an amino group); a group represented by the formula -0-(]←C0R6(
In the formula, R6 means a hydroxyl group or a lower alkoxy group)
Group m: an integer from 1 to 4