JPS5833870B2 - Thiazoline derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel thiazoline derivative, and its purpose is to provide a novel thiazoline derivative useful as a pharmaceutical or veterinary drug that exhibits excellent anti-inflammatory, anti-rheumatic, analgesic and antipyretic effects. It's about doing.

The thiazoline derivatives according to the present invention are compounds represented by the following general formula and their esters, (wherein Xl
represents hydrogen or a methyl group, Yl and Y2 each represent hydrogen, halogen, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, or a trifluoromethyl group, and R1 represents hydrogen or a methyl group. or represents an ethyl group, the bird represents an alkyl group having 1 to 3 carbon atoms or an alkenyl group having 3 to 5 carbon atoms, and 2 represents hydrogen, a carboxy group or a carboxy ester group.

) Further includes pharmaceutically acceptable salts thereof.

As shown in the above general formula (, the thiazoline derivative according to the present invention may be substituted with a methyl group at the 4th or 5th position of the thiazoline ring, and the nitrogen of the thiazoline ring is an alkyl group having 1 to 3 carbon atoms. groups (e.g. methyl,
ethyl, propyl, inopropyl, etc.) or alkenyl groups having 3 to 5 carbon atoms (e.g., 2-propenyl, 2-butenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, etc.) and one or two identical or different substituents may be present on the benzene ring.

Substituents on the benzene ring include halogen (e.g., fluorine, chlorine, bromine, etc.), alkyl groups having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, inopropyl groups, etc.), and 1 to 3 carbon atoms. an alkoxy group (e.g.
methoxy, ethoxy, propoxy, isopropoxy groups, etc.) and trifluoromethyl groups.

In the above general formula, the substituent represented by -CR1ZCOOH may substitute either the thiazoline ring or the benzene ring.

However, a compound in which 2 is a carboxy group or a carboxy ester group is used as an intermediate for a pharmacologically active compound in which 2 is hydrogen, like the ester of compound (I) above.

Note that the carboxy ester group refers to commonly used carboxylic acid ester residues (eg, alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl groups, etc.).

The ester of compound (I) refers to a compound in which the carboxyl group of the above general formula (I) is substituted with an ester residue, and the pharmaceutically acceptable salt of compound (■) and its ester refers to an alkali metal salt. (e.g., sodium, potassium, lithium salts, etc.), alkaline earth metal salts (e.g., calcium, magnesium, barium salts, etc.) and aluminum salts, as well as hydrochlorides, hydrobromides, hydroiodic acids. salts, sulfates, nitrates, phosphates, thiocyanates, carbonates, acetates, oxalates, succinates, maleates, tartrates, citrates, benzoates,
Salts such as salicylates and phthalates may be mentioned.

One method for producing the compound of the present invention includes a process represented by the following general formula.

(In the formula, Xl, Yl, Y2, R1, and R2 have the same meanings as above, R represents hydrogen or an ester residue, and X represents an acid residue.

) The raw material compound (In) for this method is disclosed in Patent Publication No. 50-6.
9075, 1976-69076 and 1982-70
It is obtained by the method described in 363.

The compound is quaternized using a quaternization reagent (step ①).

Alkyl halides (e.g., methyl iodide, ethyl iodide, propyl iodide, isopropyl iodide and the corresponding chlorides, bromides, etc.), alkenyl halides (e.g., 2-7"lopenyl iodide, iodide, etc.) as quaternization reagents. z
-1tenyl iodide, 2-methyl-2-gropenyl iodide, 3-#-2-butenyl iodide and the corresponding chlorides, bromides, etc.), aromatic sulfonic acid alkyl esters (e.g. benzenesulfonic acid alkyl ester, p -Toluenesulfonic acid alkyl ester (nato) and dialkyl sulfates (eg, dimethyl sulfate, diethyl sulfate, etc.) are exemplified.

Although the reaction can be carried out without a solvent, an inert neutral solvent may also be used.

For example, alcohols (e.g. methanol, ethanol, etc.), hydrocarbons (e.g. benzene, toluene,
xylene, etc.), ethers (eg, ether, tetrahydrofuran, etc.), dimethylformamide, acetonitrile, ethyl acetate, acetone, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide, and mixtures thereof.

The reaction is carried out by heating at room temperature or below 150° C. for 1 to 180 hours, but the reaction temperature and reaction time can be changed as appropriate depending on the mutual conditions and other reaction conditions.

The reaction may be accelerated by conducting it under pressure.

The ammonium salt (I[) produced in the above step (2) is isolated or subjected to the next step (2) without isolation.

This step is a deacidification reaction, in which hydrohalic acid or aromatic sulfonic acid is eliminated from compound (II).

As a deoxidizing agent, alkali hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), alkali carbonate (e.g.,
Examples include sodium carbonate, potassium carbonate, etc.), alkali hydrogen carbonates (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), and ammonia.

The reaction is carried out without a solvent or by shaking the compound (n) and the above deoxidizing agent in an inert solvent.

The solvents used include water, halogenated hydrocarbons (
(e.g., chloroform, methylene chloride, etc.), heynes (e.g., evaporation, benzene, toluene, xylenato) and ethers (e.g., ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, ethylene glycol dialkyl ether, diethylene glycol dialkyl ether, diglyme) etc.) are exemplified.

In addition, in the above step, if a deoxidizing agent such as lithium carbonate, calcium carbonate, sodium hydrogen carbonate, potassium fluoride, etc. is added together with the quaternization reagent and the reaction is carried out, compound (■') can be obtained directly. .

The obtained compound (■') is further subjected to a hydrolysis reaction if necessary.

This hydrolysis reaction may be carried out using a method commonly used to convert an ester into the corresponding carboxylic acid, such as an acid (e.g., hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, etc.) or an alkali in water or a water-containing solvent. (for example, alkali hydroxide, alkali carbonate, etc.) at room temperature or under heating.

When the raw material compound represented by the general formula (m) is a malonic acid derivative, that is, when 2 in the general formula is a carboxy group or a carboxy ester group, and when an acetic acid derivative, that is, a compound where 2 is hydrogen, is desired, The compound obtained in the above step is further subjected to a decarboxylation reaction.

Decarboxylation is easily accomplished by heating.

However, if the conditions for the deacidification reaction or the hydrolysis reaction are made stricter, the decarboxylation reaction will also be completed at the same time, so there may be cases where there is no need to carry out decarboxylation treatment again.

The compounds of the present invention have anti-inflammatory, anti-rheumatic, analgesic and antipyretic effects.Next, the results of pharmacological experiments on 2.30 representative compounds will be shown.

1. Experimental method (1) Acetic acid writhing method The test drug was orally administered to DS mice (20-231, male), and 60 minutes later, 0.6% acetic acid was administered. IT/'Ll/10S' was administered intraperitoneally, the number of distress symptoms exhibited within 10 minutes was counted, and ED5o was calculated by the Bliss method.

(2) Yeast edema method Immediately after oral administration of the test drug to Wistar rats (180-200P, female), 20% yeast suspension was applied to the hind limbs.
Inject 1 rrtl subcutaneously.

Two hours later, the same hind limb was compressed and the pain threshold was calculated using the Litchfield-Wilcochnon method.

CJ, Parmacol, Exp, Ther, 96.
99113 (1949)] (3) Adjuvant Arthritis Killed Mycobacterium tuberculosis was subcutaneously injected into arthritic Wistar rats (140-160?, female) 21 days after injection twice a day.
The test drug will be orally administered for 5 consecutive days.

The volume of arthritic edema is measured 5 hours after the final drug administration.

ED3o was calculated by the Bliss method.

(4) Carrageenin edema The test drug is orally administered to Wistar rats (180-200P, female), and 30 minutes later, a 1% carrageenan aqueous solution (0.05 mA) is injected subcutaneously into the hopping hind limb.

The edema volume is measured 3 hours after carrageenan administration, and the anti-inflammatory effect is calculated by comparing the edema volume between the treated and untreated paws.

ED5o was calculated by the Bliss method.

(5) Antipyretic effect 1 on the buttocks of Wistar rats (180-200g, female)
2TLl of 5% yeast suspension is injected subcutaneously, and 16 hours later, the test drug is orally administered.

Rectal temperature is measured every hour for 5 hours.

The effective amount was calculated by the Bliss method.

(6) Ten acutely toxic DS mice (20-23f, male) or Wistar rats (180-200?, female) were used as a group for one drug dose.

The test drug was orally administered, and 72 hours later, the 50% lethal dose was determined.

The LD50 value was calculated by the Pris method.

2. Experimental results 2-[2-fluoro-4-(3,4-dimethyl-4-thiazolin-2-ylideneamino)phenyl]propionate calcium salt and 2-[3-methyl-2-phenylimino-4-thiazoline -4-yl)propionate calcium salt has an ED3o value of 7.1 using the carrageenan edema method.
/ky and 16,4 /ky, and the other compounds provided by the present invention similarly exhibit anti-inflammatory, anti-rheumatic, analgesic or antipyretic effects.

The compound according to the present invention is administered to humans and animals by adding pharmaceutically acceptable carriers, excipients, adjuvants, and other drugs as appropriate.

The carrier used can vary depending on the administration method and purpose, but solid carriers include lactose, sucrose,
Examples include starch, dextrin, sodium bicarbonate sugar powder, talc, kaolin, bentonite, calcium carbonate, paraffin, etc., and liquid carriers include gelatin, water,
Examples include ethanol, ingropanol, chloroform, and glycerin.

Freon (trademark) and the like can also be used as carriers for aerosols.

When administering these, they can be administered orally in the form of tablets, capsules, powders, etc., or parenterally as injections, liniments, single agents, etc.

The compounds of the invention are generally administered at 1/30 of the dose of mefenamic acid.
It is administered orally to humans in about the same amount, i.e. 20 to 1000 μ/day, but it can also be used as a one-time drug.

Next, the method for producing the compound of the present invention will be shown in Examples.
These examples are not intended to limit the invention.

Example 1 Ethyl-2-(4-N-thiazol-2-ylamino)
phenyl]propio, 1-)(6,3S'), methyl iodide (30rrLO and ethanol (30rrLl)
is heated at 50-55° C. for 20 hours in a nitrogen stream.

After distilling off ethanol and methyl iodide, the residue was washed with ether and ethyl acetate,
-Methyl-2-(4-(1-ethoxycarbonylethyl)anilinophthiazolium iodite (8,0?) (yield 84%) is obtained.

Dissolve this product in methylene chloride, shake with a 10% aqueous potassium chloride solution, and then distill off the methylene chloride.

The residue was dissolved in ether, dried over potassium carbonate, and the ether was distilled off to give ethyl 2-(4-(3-methyl-4-thiazolin-2-ylideneamino)phenyl]propionate (5,5P) (yield 83%). obtain.

CI IRv 'crrt' 1735.1615
, aX 1590oNMRτCDCl32.9 (4H.

Aromatic), 3.5 (a, IH), 4
．． 2 (d, LH), 5.9 (q12H), 6.3 (q
, 2H), 6.6 (s, 3H), s, 5 (dl 1H
), s, s(t, 3H).

This product (5,5P) was added to a 20% potassium hydroxide aqueous solution (28
Dissolve in a mixture of 1rLl) and ethanol (28rIll) and leave at room temperature for 1 hour.

After distilling off the ethanol, the distillate was neutralized with hydrochloric acid, made alkaline with sodium bicarbonate, and washed with methylene chloride.

After neutralizing with hydrochloric acid, the pH was adjusted to 5 with acetic acid, salted out with sodium chloride, and extracted with ether.

After drying the ether extract over magnesium sulfate, the ether is distilled off to obtain a residue.

The ether-extracted mother liquor was treated in the same manner, and the resulting residue was combined with the previous residue and recrystallized from ethyl acetate to give m9130-13.
2-(4-(3-methyl-4-thiazoline-2-
ylideneamino)phenyl]propionic acid (4,3S'
).

(Contraction rate 73%).

IB, Nujol 1 crrt 1710.1595゜aX Elemental analysis Calculated value as C13H1402N2S C1
59,52; H, 5,36; N, 10.64;
S112.18 Experimental value C, 59, 79; H", 5.3
6; N110.41; Sl 12.18 The hydrochloride of the same compound exhibits a mp of 154 to 155°C (recrystallized from ethanol).

Engineering RνNuj01-11708, C is aX 2470 (broad).

Example 2 Ethyl 2-[3,5-dichloro-4-(N-thiazol-2-ylamino)phenyl]gropionate (3,0
S') and calcium carbonate (2,702) were suspended in acetonitrile (20 m) and dimethyl sulfate (3,3P)
Add an acetonitrile solution (5 ml) of and stir on a 60°C oil bath for 5 hours.

After distilling off the acetonitrile, a 20% aqueous potassium carbonate solution is added to decompose excess dimethyl sulfate, followed by extraction with ether.

The extract was washed successively with a 20% aqueous potassium carbonate solution and water, dried over potassium carbonate, and then the ether was distilled off.

Ethyl 2-[3,5dichloro-4-(3
-Methyl-4-thiazolin-2-ylideneamino)phenyl]propionate (2,96S') (yield 95%)
get.

Dissolve this product in a mixture of ethanol (15m7) and 20% potassium hydroxide aqueous solution (157711), and
After standing for a period of time, ethanol is distilled off.

When the residual solution is neutralized with hydrochloric acid and adjusted to pH 5 with acetic acid, 2-[3.
5-dichloro-4-(3-methyl-4-thiazoline-2
-ylideneamino)phenyl]propionic acid precipitates.

When this precipitate is recrystallized from ethyl acetate, the mp165~
Crystals (2,32f) (yield 85%) are obtained at 167°C.

Engineering RνNujO1-1 crn 3125.3075, aX 1710 16000 Elemental analysis Calculated value as C13H1202N2SC12 C, 47, 13; H, 3, 65; N, 8.46
;S, 9.68;C1,21,40 Experimental value C,47,37;H,3,69;N, 8.
67; S, 9.56; CI, 21.17 This product (2,4S') is dissolved in an aqueous solution of sodium hydroxide (0,3P) (33I71Q) and the solution is washed with ether.

Aqueous solution of calcium chloride dihydrate (533■) (2rf
When adding Ll) and collecting the resulting precipitate, the mp is 265~
2-(3-5-dichloro-4-(3
-Methyl-4-thiazolin-2-ylideneamino)phenyl]propionate calcium salt (2,5P) is obtained.

Example 3 Ethyl 2-[3-chloro-4-(N-thiazole-2-
ylamino)phenyl]propionate (3,8P),
Methyl iodide (11,4m) and ethanol (11,4m)
Heat 4 mA at 100° C. for 6 hours in a sealed tube.

Ethanol and methyl iodide are distilled off, and the residue is washed with benzene and then dissolved in methylene chloride.

After shaking with a 20% potassium carbonate aqueous solution, methylene chloride was distilled off and the following treatment was carried out in the same manner as in Example 1 to obtain ethyl 2-[3-chloro-4-(3-methyl-4-thiazolin-2-ylideneamino)phenyl] flobionate ( 2,45P)(
yield of 62%).

CCl4.

IRv crrt 1735.1615,
aX 1585° This product was subjected to a hydrolysis reaction in the same manner as in Example 1, and when recrystallized from ether/hexane, a 2-
[3-chloro-4-(3-methyl-4-thiazoline-2
-ylideneamino)phenyl]propionic acid (2,08
P) is obtained.

I Rv Nujol” 2500 (broad
), aX 1950 (broad), 1720.15800 elemental analysis Calculated value as C13H1302N2SC1 C
152,61; H, 4,42; N, 9.44; S
110.80; C1,11,95 Experimental value C152,83; H, 4,61; N, 9.
40; S, 10.90; C1,11,84 Example 4 Ethyl 2-(2-chloro□-4-(N-(4-methylthiazol-2-yl)aminocophenyl)propionate (96σi?) and Methyl iodide (5Qm0 at 50℃
Reflux for 20 hours with stirring on an oil bath.

Thereafter, the same treatment as in Example 1 was carried out to obtain ethyl 2-[2-chloro-4-(3,4-dimethyl-4-thiazolin-2-ylideneamino)phenyl].

Ropionate (5,6r) is obtained.

■Rshi CC14CrrL-11733.1615゜ax Add this product (5,6S') to a mixture of ethanol (30rIL0 and 20% potassium hydroxide aqueous solution (30mQ),
After standing at room temperature for 1 hour, ethanol is distilled off.

The residual solution was neutralized with hydrochloric acid, adjusted to pH 5, and extracted with ether.

After washing and drying the extract, the ether was distilled off and the residue was dissolved in acetone/
When recrystallized from hexane, the 2-
[2-chloro-4-(3,4-dimethyl-4-thiazolin-2-ylideneamino)phenyl]propionic acid (4
, 4f ) (yield 86%).

Engineering RνNuj01-12450, aπ aX 1900 (broad), 1718.1608° Elemental analysis Calculated value as C14H1502N2SC1 C
,54,10;H,4,86;N,9.01;S,1
0.32; C1, 11, 41 Experimental value C, 54, 38; H14, 84; N, 8.9
5 ; S, 10.38 ; C311,40 Example 5 Treated in the same manner as in Example 1 to obtain ethyl 2-[3-fluoro-4
-(3-Methyl-4-thiazolin-2-ylideneamine)phenyl]propionate is obtained.

CCl4.

IRv ctrt 173011620
, aX 6000 When this product is subjected to a hydrolysis reaction and recrystallized from 10% acetone/ethyl acetate, it shows m9151-152℃ 2-[3
-Fluoro-4-(3-methyl-4-thiazoline-2-
Ylideneamino)phenyl]propionic acid is obtained.

IRvNujo” 2500 (broad), aπ aX 1900 (broad), 1710.1580° Elemental analysis C13H1302N2 Calculated value as SF C
,55,70;H14,64;N, 9.99;S
, 11.44; F, 6.78 Experimental value C, 55, 60; H14, 93; N, 9.93
, S, 11.57; F6.84 Example 6 2-[3-chloro-4-(1-jethoxycarbonylethyl)anilinofthiazole (6,5P), methyl iodide (40mA') and ethanol (40TLl ) to 5
Heat at 0'C for 24 hours.

Thereafter, the same procedure as in Example 1 was carried out to obtain 3-methyl-2-[3-chloro-4-(1-jethoxycarbonylethyl)anilino]thiazolium iodite (5,2S').

When recrystallized from ethanol, it shows a mp of 192-193°C.

This product (8,8f) is suspended in methylene chloride and shaken with a 20% aqueous potassium carbonate solution.The reaction solution is washed with water, dried, and the solvent is distilled off.

The residue was subjected to alumina column chromatography, and diethyl 2-methyl-2-[2-chloro-4-(3
-Methyl-4-thiazolin-2-ylideneamino)phenyl]malomate (6,3S') is obtained.

This product (6,3f) was mixed with ethanol (331rL0 and 2
Dissolve in a mixture of 0% potassium hydroxide aqueous solution (33TL7) and leave at room temperature for 16 hours.

After distilling off the ethanol, the distillate was neutralized with hydrochloric acid, adjusted to pH 6 with sodium bicarbonate, and then evaporated to dryness.

The residue was digested with acetone and the acetone was distilled off to give 2-methyl-2-[2-chloro-4-(3-methyl-4-thiazolin-2-yritenamino)phenylcomalonic acid (90
(decomposed at ℃) is obtained.

After heating the product on a water bath for 10 minutes, add dilute aqueous sodium bicarbonate solution and wash with chloroform and ether.

After treatment with activated carbon, the pH was adjusted to 6 with hydrochloric acid and evaporated to dryness.

When the residue is digested with acetone, the acetone is distilled off, and recrystallized from 10% ethanol/acetone, the mp is 215-250.
'C (decomposition) of 2-[2-chloro-4-(3-methyl-
4-thiazolin-2-ylideneamino)phenyl]propionic acid (3,1') is obtained.

■R Nuj01-12775.2450゜ax 2000~1900 (broad), 1730゜1
715.1610° Elemental analysis Calculated value as C13H1302N2SC1
C152,61; N14.42; N, 9.44.51
10.80; C1,11,95 Experimental value C,52,83; H14,48;N, 9.2
8 ; S, 10.84 ; CL 12.08 Example 7 Treated in the same manner as in Example 1 to give ethyl 2-[3-chloro-4-
(3-methyl-4-thiazolin-2-ylideneamine)
Obtain [phenyl]acetate.

IB, Nujol 1 crfl, 1740, 1620, aX 1595゜When this product is subjected to a hydrolysis reaction and recrystallized from acetone, m
2-[3-chloro-4-(3-
Methyl-4-thiazolin-2-ylideneamino]phenyl]acetic acid is obtained.

IRvNujo” 2500 (broad), aX 1700.15700 Elemental analysis Calculated value as C1□H1,02N2SC1
C, 50,98; H, 3,92; N, 9.91; S
, 11.34; C1,12,54 Experimental value C, 50,98; H, 3,97; N, 9°7
1; Sl 11.31; CL 12.66 Example 8 Ethyl 2-[3-chloro-4-(N-thiazole-2-
Heat ylamino)phenyl]propionate (12P), allyl bromide (6, IP) and ethanol (25 mA) at 70-75°C for 8 days.

Thereafter, ethyl 2-[3-chloro-
4-(3-allyl-4-thiazolin-2ylideneamino)phenyl]propionate (3,af) (yield 24.
5%).

IRνCC14cIn-11735,1610, aX 1590° When this compound was subjected to a hydrolysis reaction in the same manner as in Example 1, 2-
[3-chloro-4-(3-allyl-4thiazoline-2-
ylideneamino)phenyl]flopionic acid (3,0P)
get.

mpH 4-115 when recrystallized from ether/hexane
Indicates °C.

IRvNujo” 2500 (broad), (1 m aX 1950 (broad), 1720.1600°1
570.15500 Elemental analysis Calculated value as C15H1502N2SC1
C, 55,81; H, 4,68; N18.68; S
, 9.93; C1,10,98 Experimental value C,55,94; H14,69;N, 8.
72; S, 9.90; C1, 11,02 Example 9 Treated as in Example 1 and recrystallized from ether/hexane to give ethyl 2(2-phenylimino-3-methyl -4-thiazolin-4-yl)propionate is obtained.

Cl4-1 1Rv crrt 1740, 1610,
aX 1580.690° This product was subjected to a hydrolysis reaction in the same manner as in Example 2, and then reacted with calcium chloride to form 2-(2-phenylimino 3-methyl-4- Thiazolin-4-yl)furopionic acid calcium salt is obtained.

I Rv Nujo” 3300 (broad)
, 0m aX 1550 (broad).

Elemental analysis (C13H1302N2S)2Ca・3H2
Calculated value as 0 C150, 63; H2S, 23; N19.0
8; Ca 16.50 Experimental value C, 50, 62; H2S, 21; N, 8.
95: Ca, 6.54 (However, the carboxylic acid has been eliminated.

) Example 10 The same procedure as in Example 1 was carried out to obtain ethyl 2-(2-(4**-chlorophenylimino), 3,4-dimethyl-4-thiazolin-5-yl)acetate.

mp
A calcium salt of 2-C2-(4-chlorophenylimino)-3,4-dimethyl-4-thiazolin-5-yl]acetate is obtained at 198-201°C.

Elemental analysis (C13H1□02N2SC1)2Ca・2.5H20
Calculated value as C, 46, 14; H, 4, 32; N, 8
．． 28; C1110,48; Ca15.92 Experimental value C, 46,42; H, 4,42; N, 8.2
8; C1,10,51; Ca, 5.53 Implementation/Example 11-25 The following compound is obtained by reacting in the same manner as in Example 1.

Example 26-29 The reaction was carried out in the same manner as in Example 9 to obtain the following compound.

Claims (1)

[Claims] (In the formula, Xl represents hydrogen or a methyl group, and Yl and Y2 are hydrogen, halogen, and 1 to 3 carbon atoms, respectively.
R1 represents hydrogen or a methyl group, and R2 represents an alkyl group having 1 to 3 carbon atoms or an alkyl group having 3 to 5 carbon atoms. represents an alkenyl group, and 2 represents hydrogen, a carboxy group or a carboxy ester group. ) and their esters or pharmaceutically acceptable salts thereof. 2. The compound of claim 1, wherein z is hydrogen. 3. The compound according to claim 1, wherein z is hydrogen and R1 is a methyl group. 4. The compound of claim 1, wherein z and R1 are each hydrogen. 5. The compound according to claim 1, wherein z is hydrogen, and R2 and R2 are each a methyl group. 6. The compound according to claim 1, wherein Z is hydrogen, R1 and R2 are each a methyl group, and the -CRlZCOOH group is substituted at the para position of the benzene ring. 2. The compound of claim 1, wherein γ2 is hydrogen, R1 and R2 are each a methyl group, a -CR12COOH group is substituted at the para position of the benzene ring, and Yl and Y2 are each hydrogen or halogen. The compound of claim 1 which is 82-(3-chloro-4-(3-methyl-4thiazolin-2-ylideneamine)phenyl]propionic acid and its pharmaceutically acceptable salts. 92-(2-chloro- The compound of claim 1 which is 4-(3-methyl-4thiazolin-2-ylideneamino)phenyl]propionic acid and its pharmaceutically acceptable salts. -4-thiazolin-2-ylideneamino)phenyl]propionic acid and its pharmaceutically acceptable salts Claim 1
compound. 112-(2-chloro-4-(3,4-dimethyl-4-
The compound of claim 1 which is thiazolin-2-ylideneamino)phenyl]propionic acid and its pharmaceutically acceptable salts. 122-(3-fluoro-4-(3,4-dimethyl-4
-thiazolin-2-ylideneamino)phenyl]propionic acid and its pharmaceutically acceptable salts. The compound of claim 1 which is 132-(3,5-dichloro-4-(3-methyl4-thiazolin-2-ylideneamine)phenyl]propionic acid and its pharmaceutically acceptable salts. 142-(3. The compound of claim 1 which is 5-dichloro-4-(3,4-dimethyl-4-thiazolin-2-indenamino)phenyl]propionic acid and its pharmaceutically acceptable salts.