JPH04173782A - 2-sulfonamido-4,5-diphenylthiazole derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel 2-sulfonamido-4,5-diphenylthiazole derivatives and pharmaceutically acceptable salts thereof.

More specifically, the present invention relates to 2-sulfonamide-4,5-diphenylthiazole derivatives and pharmaceutically acceptable salts thereof having anti-inflammatory, antipyretic, analgesic, and antiallergic effects. .

Regarding 2-amino-4,5-diphenylthiazole derivatives, see JP-A-50-121269 and JP-A-54-16.
No. 0369, JP-A No. 64-75475, etc.
There is no disclosure whatsoever regarding the 2-sulfonamido-4,5-diphenylthiazole derivative of the present invention.

Conventional acidic non-steroidal anti-inflammatory drugs, which Ming is trying to solve, have had clinical side effects, particularly gastrointestinal disorders. An object of the present invention is to provide a highly safe drug that has few side effects and can withstand long-term administration.

Means to Solve the Problems As a result of intensive studies aimed at the above-mentioned purpose, the present inventors found that it has anti-inflammatory, antipyretic, analgesic, and antiallergic effects, so it can be used as an anti-inflammatory, antipyretic, analgesic, and antiallergic agent. The present invention was completed by discovering a highly safe compound that is useful, has few side effects such as gastrointestinal disorders, and has a high degree of safety.

R') (In the formula, R1 is a lower alkyl group substituted with a halogen atom, and R1, R1, R4, and R5 may be the same or different, and a hydrogen atom, a halogen atom, a lower alkyl group, a halogen atom) a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfonyl group, a dil-ro group, a phenyl group or a phenyl group substituted with
It is a xyl group. ) 2-Sulponamide-4
, 5-diphenylthiazole derivatives and pharmaceutically acceptable salts thereof.

Specific examples of the above various definitions that are within the scope of the present invention are given below.

Lower alkyl groups substituted with halogen atoms are fluorine,
An alkyl group having 1 to 4 carbon atoms substituted with chlorine, bromine, etc., such as chloromethyl group, dichloromethyl group, trichloromethyl group, bromomethyl group, difluoromethyl group, 1-lifluoromethyl group, etc. be.

A halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

A lower alkyl group is a linear or branched alkyl group having 1 to 5 carbon atoms, such as a methyl group, an ethyl group,
Examples include n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, and n-pentyl group.

A lower alkoxy group is a linear or branched alkoxy group having 1 to 5 carbon atoms, such as methoxy group, ethoxy group, n-propoxy group, impropoxy group, n-butoxy group, imbutoxy group, Examples include t-butoxy group and n-pentyloxy group.

A lower alkylthio group is a linear or branched alkylthio group having 1 to 5 carbon atoms, such as methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, n-pentylthio group. etc.

A lower alkylsulfonyl group is a linear or branched alkylsulfonyl group having 1 to 5 carbon atoms, such as methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-butylsulfonyl group. group, n-pentylsulfonyl group, etc.

Pharmaceutically acceptable salts include salts with alkali metals such as lithium, sodium, and potassium, and salts with organic amines such as 1-ethylamine and ethanolamine.

The compound of the present invention can be produced, for example, from a known compound by the method shown below.

(1) A compound represented by the formula (wherein R2, R1, R4 and R5 have the same meanings as above) in the presence of a halogenating agent,
By reacting with thiourea, the formula (where R', R
8, R4 and R5 have the same meanings as above. ) is obtained.

The halogenating agents used in this reaction include bromine, iodine, N-
Bromosuccinimide, pyridinium bromide perbromide, etc., and can be carried out without a solvent or in a solvent such as chloroform, back tetrachloride, pyridine, N,N-dimethylformamide, dioxane, etc.

Next, the compound of formula
In the formula, R1 has the same meaning as above. ) or its reactive derivatives (e.g., acid halides, acid anhydrides, etc.).
The compound of the present invention represented by can be obtained.

In this reaction, when using a sulfonic acid compound, it is preferable to carry out the reaction in the presence of a condensing agent such as N,N'-dicyclohexylcarbodiimide, and when using a reactive derivative, triethylamine, - Carry out the reaction in the presence of a base such as methylmorpholine, 1-methylpiperidine, pyridine, N,N-dimethylaminopyridine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, etc. is preferable.

In addition, the organic solvent in this reaction includes dichloromethane,
These include chloroform, diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, pyridine, acetone, acetonitrile, ethyl acetate, N,N-dimethylbormamide, and the like.

(2) The intermediate represented by the above formula (2) can also be produced by the following method.

That is, by reacting the compound of formula (1) with a halogenating agent in water or an organic solvent, a compound of the formula (wherein X is a chlorine atom, a bromine atom, or an iodine atom,
and R'' have the same meanings as above.) A compound represented by the following formula is obtained.

The halogenating agents used in this reaction include chlorine, sulfuryl chloride, bromine, N-bromosuccinimide, pyridinium bromide perbromide, and iodine, and the organic solvents include dichloromethane, chloroform, back tetrachloride, and diethyl ether. , tetrahydrofuran, dioxane, pyridine, acetic acid, etc.

Then, a compound of formula (■) is dissolved in water and/or an organic solvent,
A compound of formula (1) can be obtained by reaction with thiourea.

The organic solvents used in this reaction include alcohols such as methanol, ethanol, and isopropyl alcohol, ethers such as diethyl ether, tetrahydrofuran, and dioxane, benzene, toluene, hexane, pyridine,
N,N-dimethylformamide, acetic acid and the like.

(3) A pharmaceutically acceptable salt of a compound of formula I is a compound of formula I
can be obtained by treating the compound with a base in water or an organic solvent. Examples of the base in this reaction include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, and organic amines such as triethylamine and ethanolamine.

The compound of the present invention exhibits anti-inflammatory, antipyretic, analgesic, and antiallergic effects, and has fewer side effects than conventional compounds in toxicity tests mainly for gastrointestinal disorders. Therefore, the compounds of the present invention are useful as anti-inflammatory agents, antipyretics, analgesics, and antiallergic agents.

For this purpose, the compounds can be administered orally or parenterally in customary dosage forms. these are,
Examples include tablets, powders, granules, powders, capsules, liquids, emulsions, suspensions, and injections, all of which can be manufactured using conventional formulation techniques. anti-inflammatory drugs for humans,
When used as an antipyretic, analgesic, or antiallergic agent, the dosage varies depending on age, body weight, symptoms, route of administration, number of administrations, etc., but is usually 20 to 1000 mg.

Hereinafter, a more detailed explanation will be given using test examples.

Test Example 1 [Edema suppression test using carrageenan] Winter et al.'s method using carrageenan [Jour-rn
al of Pharmacology and Ex
peripheral Thera-peutics
, Vol. 141, p. 369 (1963)]. A suspension of the compound of the present invention in a 5% aqueous gum arabic solution was orally administered to male Wistar rats (6 rats per group) at a dose of 50 mg/kg at a dose of 1 ml per 100 g of body weight, 1 hour before carrageenan administration. Using ibuprofen as a control drug, its anti-inflammatory effect was investigated by determining its edema suppression rate.

The results are shown in Table 1.

Table 1 a: N-[4-(4-methoxyphenyl)-5-phenylthiazol-2-yl]trifluoromethanesulfonamide b: N-[4-(4-chlorophenyl)-5-phenylthiazol-2- yl]trifluoromethanesulfonamide c: N-[5-(4-nitrophenyl)-4-phenylthiazol-2-yl]trifluoromethanesulfonamide d: N-[5-phenyl-4-(4- trifluoromethylphenyl)thiazol-2-yl]trifluoromethanesulponamide e: N-[4-(4-methoxyphenyl)-5-(4-
trifluoromethylphenyl)thiazol-2-yl]
Trifluoromethanesulfonamide Examples The present invention will now be explained in more detail with reference to Examples.

Example 1 (1) 4.61 g of 1-(4-chlorophenyl)-2-phenylethanone, 3.04 g of thiourea and 5 iodine,
08 g were mixed and stirred at 110-120°C for 8 hours.

After returning the reaction mixture to room temperature, 10% aqueous ammonia
0ml was added and extracted with dichloromethane. The dichloromethane layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The crude crystals obtained by distilling off the solvent were recrystallized from dichloromethane-n-hexane to give 2-amino-
3.12 g of 4-(4-chlorophenyl)-5-phenylthiazole was obtained.

m, p, 187-189°C (2) 2-amino-4-(4-chlorophenyl)-5-
40 dichloromethane containing 2.0 g phenylthiazole
2.26 g of trifluoromethanesulfonic anhydride and 0.9 g of triethylamine in a water-cooled and stirred solution.
1 g were added one after another and stirred for 2 hours. Next, the mixture was extracted with dichloromethane, and the dichloromethane layer was washed successively with 2N hydrochloric acid, water, and saturated brine, and then dried over anhydrous magnesium sulfate.

The oil obtained by distilling off the solvent was subjected to silica gel column chromatography (elution solvent: n-hexane: ethyl acetate =
5:1 to 2:1), recrystallized from ethyl acetate-n-hexane to obtain N-[4-(4-chlorophenyl)-5-
1.12 g of phenylthiazol-2-yl]trifluoromethanesulfonamide was obtained.

m, p, 224-225℃ In the same manner as in Example 1, the following compounds were obtained.

The number in parentheses after the melting point indicates the recrystallization solvent.

N-[4-(4-methoxyphenyl)-5-phenylthiazol-2-yl]trifluoromethanesulfonamide m, p, 205-206°C (ethanol-n-hexane) N-(4,5-diphenylthiazole- 2-yl) trifluoromethanesulfonamide m, p, 191-1
93°C (ethanol-water) N-[4-(4-methylphenyl)-5-phenylthiazol-2-yl]trifluoromethanesulfonamide full, I), 188-189°C (ether-n-hexane) N- [4,5-bis(4-methoxyphenyl)thiazol-2-yl]trifluoromethanesulfonamide m, p, 236-237°C (ethyl acetate-n-hexane) N-[4-(2-methoxyphenyl) )-5-phenylthiazol-2-yl] trifluoromethanesulfonamide m, p, 205.5-206.5°C (ethanol)
N-[4-(3-methoxyphenyl)-5-phenylthiazol-2-yl]trifluoromethanesulfonamide m, p, 153-154°C (ethanol) N-[4-
(4-fluorophenyl)-5-phenylthiazole-
2-yl] trifluoromethanesulfonamide m, p, 174.5-175.5°C (ether-n-
hexane) N-[5-(4-methylphenyl)-4-phenylthiazol-2-yl]trifluoromethanesulfonamide m, p, 209.5-211°C (ethanol-n-hexane) N-[5-( 4-chlorophenyl)-4-phenylthiazol-2-yl]trifluoromethanesulfonamide m, p, 203.5-204.5°C (ethanol-n
-hexane) N-[5-(4-nitrophenyl)-4-phenylthiazol-2-yl]trifluoromethanesulfonamide m, p, 207-208°C (ethanol-n-hexane) N-[4-(4 -Methylthiophenyl)-5-phenylthiazol-2-ylcotrifluoromethanesulfonamide m, p, 201-202°C (dichloromethane-n-hexane) N-[4-(4-ethylphenyl)-5-phenylthiazole- 2-ylkotrifluoromethanesulfonamide m, p, 164-165°C (ether-n-hexane) N-[4-(4-phenoxyphenyl)-5-phenylthiazol-2-yl]trifluoromethanesulfonamide m, p, 131.5-132°C (ether-n-hexane) N-[5-phenyl-4-(4-trifluoromethylphenyl)thiazol-2-yl]trifluoromethanesulfonamide m, p, 193-194°C (ether-n-hexane) N-[5-(4-methoxyphenyl)-4-phenylthiazol-2-yl]trifluoromethanesulfonamide m, p, 187.5-188°C (ethanol-n-hexane) N -[4-(4-biphenylyl)-5-phenylthiazol-2-ylcotrifluoromethanesulfonamide m, p, 215-215.5°C (ethanol-n-hexane) N-[4-(2,4- dimethylphenyl)-5-phenylthiazol-2-yl]trifluoromethanesulfonamide m, p, 162-162.5°C (ethanol-n-hexane) N-[5-(4-fluorophenyl)-4-(4 -Methoxyphenyl)thiazol-2-yl]trifluoromethanesulfonamide m, p, 209-210°C (dichloromethane-n-hexane) N-[5-(4-chlorophenyl)-4-(4-methoxyphenyl)thiazole- 2-yl]trifluoromethanesulfonamide m, p, 201-202°C (dichloromethane-n-hexane) N-[4-(4-methoxyphenyl)-5-(4-methylphenyl)thiazol-2-yl]trifluoro lomethanesulfonamide m, p, 214-215.5°C (dichloromethane-n
-hexane) N-[4-(4-bromophenyl)-5-phenylthiazol-2-ylcotrifluoromethanesulfonamide m, p, 229.5-230.5°C (dichloromethane-n-hexane) N-[ 5-(4-bromophenyl)-4-phenylthiazol-2-yl]trifluoromethanesulfonamide m, p, 198-200°C (dichloromethane-n-hexane) N-[5-(4-fluorophenyl)-4 -Phenylthiazol-2-ylcotrifluoromethanesulfonamide m, p, 190-191.5°C (dichloromethane-n
-hexane) N-[4,5-bis(4-methylphenyl)thiazol-2-ylcotrifluoromethanesulfonamide m, p, 215-217°C (ethanol-n-hexane) Example 2 (1) 1- To a chloroform 7ynQ solution containing 1.0 g of (4-methoxyphenyl)-2-(4-trifluoromethylphenyl)ethanone in the presence of a catalytic amount of anhydrous aluminum chloride, 0.60 g of bromine was slowly added and stirred for 1 hour. Next, 5 ml of a 5% aqueous sodium thiosulfate solution was added and stirred for 5 minutes, followed by extraction with chloroform. The chloroform layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. To the oily substance obtained by distilling off the solvent, 7 ml of ethanol and 0.39 g of thiourea were added, and the mixture was refluxed for 6 hours. After the reaction solution was returned to room temperature, 28% aqueous ammonia was added, and the precipitated crystals were collected by filtration, washed with water, and then dried. By recrystallizing the crude crystals from ethanol-n-hexane, 2-amino-4-(4-methoxyphenyl)-5-(
1.1 g of 4-trifluoromethylphenyl)thiazole
I got it.

m, p, 175-178°C (2) 2-amino-4-(4-methoxyphenyl) -
By reacting 5-(4-trifluoromethylphenyl)thiazole in the same manner as in Example 1 (2), N-[
4-(4-methoxyphenyl)-5-(4-trifluoromethylphenyl)thiazol-2-yl]trifluoromethanesulfonamide was obtained.

m, p, 160-162°C (dichloromethane-n-hexane) In the same manner as in Example 2, the following compound was obtained.

N-[4-(4-nitrophenyl)-5-phenylthiazol-2-ylcotrifluoromethanesulfonamide m, p, 220-221°C (dichloromethane-n-hexane) N-[4-(4-methylsulfonyl) phenyl)-5-phenylthiazol-2-yl]trifluoromethanesulfonamide m, p, 264-266°C (ethyl acetate-n-hexane) N-[4-(2,4-dimethoxyphenyl)-5-phenylthiazole -2-yl] trifluoromethanesulfonamide m, p, 203-205°C (ethanol-n-hexane) N-[5-(4-bromophenyl)-4-(4-methoxyphenyl)thiazol-2-yl Cotrifluoromethanesulfonamide m, p, 196-198°C (decomposition) (dichloromethane-n-hexane) N-[4-(4-methoxyphenyl)-5-(4-nitrophenyl)thiazol-2-ylcotrifluoro Methanesulfonamide m, p, 234-235°C (dichloromethane-n-
hexane) N-[5-(4-nitrophenyl)-4-(4-phenoxyphenyl)thiazol-2-yl]trifluoromethanesulfonamide m, p, 173-175°C (dichloromethane-n-hexane) N-[ 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)thiazol-2-yl]trifluoromethanesulfonamide m, p, 243-244
°C (dichloromethane-n-hexane) N-[4-(4-methylthiophenyl)-5-(4-nitrophenyl)thiazol-2-yl]trifluoromethanesulfonamide m, p, 198-199 °C (dichloromethane-n -hexane) N-[5-(4-biphenylyl)-4-phenylthiazol-2-yl]trifluoromethanesulfonamide m, p, 209-210°C (ethanol-n-hexane) N-[5-(4- biphenylyl)-4-(4-methoxyphenyl)thiazol-2-yl]trifluoromethanesulfonamide m, p, 223-225°C (ethyl acetate-n-hexane) N-[5-(4-bromophenyl)-5 -(4-nitrophenyl)thiazol-2-yl]trifluoromethanesulfonamide m, p, 252-254°C (ethyl acetate-n-hexane) N-[4-(4-fluorophenyl)-5-(4- nitrophenyl)thiazol-2-yl]trifluoromethanesulfonamide m, p, 207-208°C (ethanol-n-hexane) N-[4-(4-chlorophenyl)-5-(4-nitrophenyl)thiazole-2 -ylkotrifluoromethanesulfonamide m, p, 245-247°C (ethanol-n-hexane) N-[5-(4-ethylphenyl)-4-phenylthiazol-2-ylkotrifluoromethanesulfonamide m, p , 181.5°C to 182.5°C (ethyl acetate-n-hexane) N-[5-(2-nitrophenyl)-4-phenylthiazol-2-yl]trifluoromethanesulfonamide m, p, 140. 5-142°C (ether-n-hexane) N-[4,5-bis(4-chlorophenyl)thiazol-2-ylcotrifluoromethanesulfonamide! 11. p, 221-222°C (ethyl acetate-n-hexane) N-[5-(4-ethylphenyl)-4-(4-methoxyphenyl)thiazol-2-yl]trifluoromethanesulfonamide fli, p, 192- 194°C (dichloromethane-n
-hexane) N-[4-(4-ethylphenyl)-5-(4-nitrophenyl)thiazol-2-ylcotrifluoromethanesulfonamide tll, I), 181-182°C (dichloromethane-
〇-hexane) N-[4-(4-biphenylyl)-5-(4-nitrophenyl)thiazol-2-yl]triple olomethanesulfonamide m, p, 238-239°C (chloroform) N-[5
-(2,4-dinitrophenyl)-4-phenylthiazol-2-yl]trifluoromethanesulfonamide m, p, 178-180°C (dichloromethane-n-hexane) N-[5-(4-methylsulfonylphenyl) -4-phenylthiazol-2-yl] trifluoromethanesulfonamide m, p, 235-237°C (dichloromethane-n-
Example 3 To a 5 mQ solution of ethanol containing 0.20 g of N-[4-(4-chlorophenyl)-5-(4-nitrophenyl)thiazol-2-yl]trifluoromethanesulfonamide, 17 m of sodium hydroxide was added. 0.45ml of water containing
The solution was added and stirred. By distilling off the solvent, N-
[0.18 g of 4-(4-chlorophenyl)-5-(4-nitrophenyl)thiazol-2-ylcotrifluoromethanesulfonamide sodium salt was obtained.

m, p, 121-135°C In the same manner as in Example 3, the following compound was obtained.

N-[4-(4-bromophenyl)-5-(4-nitrophenyl)thiazol-2-ylcotrifluoromethanesulfonamide sodium salt.

m, p, 143-155℃

Claims (1)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 is a lower alkyl group substituted with a halogen atom, and R^2, R^3, R^4 and R^5 are Hydrogen atoms, halogen atoms, lower alkyl groups, lower alkyl groups substituted with halogen atoms, lower alkoxy groups, lower alkylthio groups, which may be the same or different, respectively;
It is a lower alkylsulfonyl group, nitro group, phenyl group or phenoxy group. ) and a pharmaceutically acceptable salt thereof.