KR850000766B1 - Process for preparing thiazoline derivatives - Google Patents

Abstract

Thiazolines I (R1 = C1-8 alkyl, C3-4 cycloalkyl, C3-4 alkenyl; R2-R4 = H, halogen, C1-4 alkyl or alkoxy, OCH2O, OCH2CH2O, NMe2, NEt2, CF3, R5 = H, C1-3 alkyl; R6 = H, C1-6 alkyl; R7 = C1-12 alkyl, C3-12 cycloalkyl, allyl, CH2CH2Ph, benzylradical), useful in lowering cholesterol in serum and low d. lipoproteins with little or no effect on high d. lipoproteins and thus useful in treating atherosclerosis, were prepared. Thus, 1-methyl-3- phenylthiourea was added into a phosgen in THF with stirring to give 4-(4-chloro-3- dimethylsulphamoylphenyl)-3-methyl-2-phenylimino-4thiazoline.

Description

Method for preparing tazozoline derivatives

The present invention relates to a compound of formula (I) and a pharmacologically toxic acid addition salt thereof.

In the above formula

R ¹ is C ₁ -C ₈ -alkyl, cycloalkyl of 3 to 8 carbon atoms or alkenyl of 3 to 4 carbon atoms

R ² , R ³ and R ⁴ are the same or different and are hydrogen, halogen, alkyl having 1 to 4 carbon atoms or alkoxy, methylenedioxy, ethyleneoxy, dimethyl- or diethyl amino, or trifluoromethyl

R ⁵ is hydrogen or alkyl of 1 to 3 carbons

R ⁶ is hydrogen or alkyl of 1 to 6 carbon atoms

이거나,R ⁷ is hydrogen, alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, allyl, phenylethyl or benzyl radicals

Or

R ⁶ and R ⁷ are joined by an alkylene chain which may be branched and has up to 8 carbon atoms in which one methylene group may be substituted with an oxygen atom or an N—CH ₃ group

Y is hydrogen, halogen or alkyl of 1 to 3 carbon atoms.

The compounds (in free form or in the form of pharmacologically toxic acid addition salts) have important pharmacological properties and are therefore suitable as medicaments.

Compounds of formula (I) according to the invention are prepared as follows:

The compound of formula (V) is then reacted with the compound of formula (VII) and, if necessary, the organic or inorganic acid of formula HA is used to convert the resulting compound of formula (I) to acid addition salt thereof. Alternatively, the base is used to convert the salt of the compound of formula (I) to a free basic compound of formula (I).

In the above formula

R ¹ ,, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as described above

X 'is a leaving group selected from halogen, methoxy and methylthio.

Inorganic acids H-A which can be used are, for example, hydrochloric acid (such as hydrochloric acid and bromic acid), sulfuric acid, phosphoric acid and amido sulfonic acid.

Organic acids H-A which may be mentioned are, for example, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and P-toluenesulfonic acid.

The compounds of general formula (I) according to the invention may also exist in possible isomeric forms, but for simplicity only one of the possible isomeric forms of the particular substance is pointed out.

According to this method, the compound of general formula (V) is added to the compound of general formula (VI) and advantageously to a polar organic solvent, for example lower alcohols having 1 to 4 carbon atoms, ethylene glycol monomethyl ether or ethylene glycol dimethyl. React in tar, diethylene glycol monomethyl ether or diethylene glycol dimethyl ether, acetone, ethyl acetate or dimethyl formamide.

The reaction is advantageously carried out at 0 to 80 ° C., preferably 15 to 40 ° C., and after the exothermic reaction is completed, the reaction mixture is heated to a temperature of 60 to 140 ° C. to complete the formation of the compound of general formula (I). Let's do it. The reaction is followed by thin layer chromatography on silica gel plates, if necessary. The reaction time is 5 to 60 hours. Compounds (V) which have proven to be particularly suitable for this reaction are compounds with hydrogen as large organic radicals R ⁷ and R ⁶ , in particular on sulfamoyl groups, for example tert-butyl, or R ⁶ and R ⁷ It is a compound which has an organic radical as a substituent.

Compounds of the general formula (V) used in the above process can be prepared according to methods known in the literature (e.g., publication 2436263). The preparation of compounds of general formula (VI) is also described in, for example, Chem, Ber, 97,1232 (1964), Bull, chem, Soc, Jap, 46,1765 (1973), Angew, Chem. 74,214 (1962) and Bull, Soc, Chim, Jap. 38, 1806 (1965) ,.

The compound of formula (I) can be reversibly reacted with the acid of formula H-A in a suitable solvent. In this reaction, it is said that the acid is liquid or has a melting point not higher than 60 ° C. and does not cause any side reactions, so that compound (I) can be introduced into the pure acid at preferably 0 ° to 60 ° C. However, the reaction is carried out in an organic solvent such as water, dioxane, tetrahydrofuran, ether, lower alcohol acetate having 1 to 4 carbon atoms, acetonitrile, nitromethane, acetone, methyl ethyl ketone, and the like. Lower alcohols and carboxylic acids having 2 to 4 carbon atoms have proven particularly suitable. 1 to 1.5 moles of acid H-A are used per mole of compound (I), although higher amounts of acid may be used. If necessary, the reaction is carried out at a temperature of 0 ° to 120 ° C, preferably 10 ° C to 60 ° C. The reaction is moderately exothermic.

When the reaction is carried out in aqueous solution, compound (I) is generally dissolved immediately after addition of acid H-A and in rare cases the corresponding acid adduct is precipitated out. Once a solution is obtained, the water according to the invention is separated off by evaporating off the water under moderate conditions, preferably by lyophilization. When the reaction is carried out in an organic solvent, the acid addition salt precipitates out as a refractory compound as soon as the specific acid H-A is added. Once a solution is obtained, the acid addition compound is first concentrated, if necessary, and then precipitated using a suitable precipitant. Suitable precipitants are, for example, ethyl acetate, diethyl ether, diisopropyl ether, acetonitrile or acetone.

Acid addition products are very often obtained in the form of viscous oils or amorphous glassy products even at significant high purity. These amorphous products can be crystallized by treatment with an organic solvent and, if necessary, warmed to 40 ° to 80 ° C. Suitable crystallization-promoting solvents are, in particular, lower alkyl acetates (e.g. methyl acetate, ethyl acetate and n-butyl acetate), lower dialkyl ketones (e.g. acetone or methyl ethyl ketone) having 1 to 4 deatomization atoms in the alkyl moiety. , Lower dialkyl ethers (eg diethyl ether, diisopropyl ether or di-n-butyl ether), acetonitrile and nitromethane and in some cases lower alcohols such as methanol, ethanol, isopropanol or n-butanol.

The acid addition product can be deprotonated by treating with a base in a suitable solvent to obtain a compound of formula (I). Examples of bases that can be used are solutions of inorganic hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide or barium hydroxide, carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, ammonia, and triethylamine Amines such as dicyclohexylamine, piperidine and methyl dicyclohexylamine.

When the reaction is carried out in an aqueous medium, the free basic compound (I) precipitates as a poorly soluble compound, which can be separated by filtration or extraction with an organic solvent, preferably ethyl acetate. Suitable organic reaction media are, in particular, lower alcohols of 1 to 4 carbon atoms, preferably methanol and ethanol, but also ethyl acetate, diethyl ether, tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, dimethylformamide and the like. have. The reaction to obtain compound (I) occurs spontaneously. The reaction is carried out at temperatures between −35 ° and 100 ° C., preferably between 0 ° and 60 ° C. If a water-miscible organic solvent is used, the free base of formula (I) is precipitated by concentrating the reaction mixture in advance, if necessary, and then adding water. If a water-immiscible solvent is used, the process used is advantageously, after the reaction has taken place, the reaction mixture is washed with water and optionally dried before the organic solvent is evaporated off.

The action of at least one sufficiently strong base on a compound of formula (I) in which R ⁶ and / or R ⁷ represents hydrogen results in deprotonation of the sulfonamide group and a salt of (XVII) is obtained.

In the above formula

A is a cation of an alkali or alkaline earth metal

R ¹ to R ⁵ and Y are as described above

R has the meaning of R ⁶ or R ⁷ .

Bases that can be used are hydroxides of alkali and alkaline earth metals (preferably NaOH and KOH), alkali metal alcoholates and alkaline earth metal alcoholates (eg NaOCH ₃ and NaOC ₂ H ₅ ), NaH, sodium methylsulfinylmetha Droid and so on.

The solvent used is water or a polar organic solvent such as methanol, ethanol, isopropanol, n-butanol, dimethylformamide, dimethylsulfoxide, diethylene glycol dimethyl ether or acetonitrile.

Upon addition of 1 mole of a suitable acid H-A, compound (I) of the present invention is obtained again, and ammonium may be used as the acid.

This reversible acid / base reaction can be used for the purification of compound (I). The salt (XVII) can also be used to prepare compounds of formula (I) which are correspondingly converted in sulfonamide groups by alkali reactions.

The compound of formula (XVII) is novel.

In the above formula

R ¹ to R ⁵ and Y are as described above

R has the meaning of R ⁶ or R ⁷

A is a cation of an alkali metal or an alkaline earth metal. They are particularly suitable as intermediates for the alkylation of compounds of formula (I) wherein R ⁶ and / or R ⁷ is hydrogen.

Preferred compounds according to the invention are compounds of formula (I) in which the substituents have the meanings set forth in Table 1 below, and particularly preferred compounds are compounds of formula (I) in which the substituents have the meanings given in Table 2 below.

TABLE 1

TABLE 2

In addition to the thiazolin derivatives described in the examples, compounds of the general formula (I) and their acid addition products listed below in the following also can be obtained according to the present invention.

TABLE 3

(Legend: Me = methyl, Et = ethyl, Prop = propyl, But = butyl, Pent = pentyl, Hea = hexyl, i = iso, Sec = secondary C = cyclo, the value given before substitution is Y on phenylradical Position, where the thiazole ring is in the 1-position and the sulfamoyl radical is in the 3-position)

Compounds of formula (I) according to the invention are important agents and stand out with very favorable effects on serum fat proteins. Thus they can be used in particular as agents which affect serum lipoproteins. Accordingly, the present invention also relates to pharmaceutical preparations based on the compounds of formula (I) and their pharmacologically unfavorable salts, and to their use as medicaments.

It is reported in the literature that 4-phenyl-2,3-dihydrothiazoline derivatives have anorexia, central nervous system excitement and inosiocytic activity, and derivatives in the literature do not have sulfonamide substituents in the phenyl moiety and have 2- Amino groups are compounds in which no aryl is substituted (see US Patent Specification No. 3671533 and German Publication No. 1938674). 3-alkyl-4-phenyl-2-phenylimino-4-thiazolines, in which the phenyl radical at the 4-position does not have a sulfonamide group, are also described in Univ. Kansas Sci. Bull. 24 , 45-49 (1936). 4- (3-Sulfamoyl-phenyl) -3-alkyl-2-imino-4-thiazoline and thiazolidine with different substituents in the same way, in particular as diuretics, Reference is made to the literature ("Diuretic Agents". EJ Cragoe. Jr., Editor: ACS-Symposium series 83, page 24, Washington DC, 1978).

Whereas the compound of formula (I) according to the present invention shows a very potent and beneficial effect on serum fat proteins, the thiazolin derivatives described in this document have no effect or only a minor effect which is clearly low in terms of quantitative and qualitative. The fact that it was not revealed was surprising.

It is generally recognized that hyperlipoproteinemia poses a significant risk factor for increasing atherosclerotic vascular changes, especially in coronary heart disease. Therefore, lowering elevated serum fat protein levels is very important for the prevention and recovery of atherosclerotic changes. However, this is a very specific category of serum lipoproteins involved, because low density lipoproteins (LDL) and lower density lipoproteins (VLDL) are atherosclerotic risk factors, while high density lipoproteins (HDL) are associated with coronary heart disease. Because it protects against. Therefore, hypolipidemic agents should lower the levels of VLDL-cholesterol and LDL-cholesterol in the serum, but should increase or decrease HDL-cholesterol as much as possible. The compounds according to the invention have important therapeutic properties. They therefore, in particular, lower the concentrations of LDL and VLDL, while reducing or even increasing the HDL fraction to a very small extent. Thus, they show significant progress when compared to the comparative compound Clofibrate, as can be seen in the following test. Therefore, they can be used for the prevention and recovery of atherosclerotic changes because they eliminate causal risk factors. This risk factor includes primary hyperlipoproteinemia as well as secondary hyperlipoproteinemia in diabetes. While relative hepatic does not change with Compound (I), clofibrate, which is used as a hypolipidemic standard, results in a substantial increase in relative hepatic gain.

The effects of the compounds listed in the following table on serum lipoproteins were studied by treating the Wistar males with polyethylene glycol 400 in suspension of the following compounds for 7 days with throat throat. The study also included a control group administered with only 0.4 grams of polyethylene glycol, a solvent, and a group of rats that received clofibrate, the standard hypolipidemic agent, in most trials. In general, 10 animals per group were used, and these rats were introduced into weak ether anesthesia at the end of the treatment, blood was collected from the plexus plexus, and the serum obtained therefrom was collected and fat was prepared using a preliminary ultracentrifuge according to a widely used method. Isolate the protein. Serum lipoproteins are separated in the ultracentrifuge in the following density categories: VLDL 1.006; LDL 1.006 to 1.04; HDL 1.04 to 1.21.

Cholesterol content of the lipoprotein fraction separated by ultracentrifuge was fully enzymatically determined by the CHOD-PAP method with the Beringer-Mannheim test and the resin obtained was changed to μg / ml of serum. Under the same conditions, the change in lipoprotein cholesterol of the treatment group is shown in the table. As can be seen from the table, clofibrate shows almost the same degradation for LDL fractions and significant degradation for HDL fractions, while new compounds show strong selective degradation for atherosclerotic lipoprotein fractions (VLDL and LDL). It does not fundamentally affect the protective HDL fraction or rather increases this fraction.

[table]

Changes in Serum Lipoprotein Concentration in Rats After Oral Administration of Compounds for 7 Days

Therapeutic compositions of compounds of formula (I) may be present in the form of tablets, dragees, capsules, suppositories or syrups, in particular. The novel compounds can be used alone or in admixture with pharmacologically toxic excipients. Oral dosage forms are preferred. To this end, it is preferred to mix the active compound with known substances and with suitable dosage forms, i.e. tablets, gelatin capsules, aqueous or oily suspensions, or substances which are converted to aqueous or oily inhibition by known methods. . Inert excipients that may be used are, for example, magnesium carbonate, lactose or corn starch and other materials such as magnesium stearate may also be added. The composition may be prepared in the form of anhydrous granules or wet granules. Oily excipients or solvents that can be used are especially vegetable and animal oils, for example sunflower oil or cod liver oil. The daily dose may be about 50 mg to 5 g. It is preferable that a single dose contains 250-500 mg.

For the treatment of fat metabolism, the composition is used in addition to conventional fillers and excipients, for example, for treatment of hypertension, such as salt excretion agents, reselpin, hydralazine, guanetinine, α-methyl-dopa, clonidine or β-sympathetic blockers. It may also contain a medicament having an action against antiperiodic acid, an oral diabetic agent, a geriatric disease treatment agent, or an agent for improving circulation.

The melting point and decomposition temperature given in the examples below do not change.

Example 1

4- (4-chloro-3-dimethyl sulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline

a) N-methyl-N'-phenyl-chloroformamidine hydrochloride

After passing 6.3 g of phosgene through 40 ml of anhydrous tetrahydrofuran at room temperature, 8 g of 1-methyl-3-phenylthiourea was added with stirring, and the color of the suspension turned yellow immediately. After adding 0.5 ml of dimethylformamide, the mixture was stirred at room temperature for 20 hours, nitrogen was passed through the reaction mixture for about 30 minutes to remove phosgene, and the crystals were filtered and washed with tetrahydrofuran. Crystal; Melting Point 169 ° C (Decomposition)

b) 4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline

A mixture of 2 g of triethylamine in 10 ml of isopropanol, 3 g of 4'-chloro-3'-dimethylsulfamoyl-acetophenone-2-thiol and 2.1 g of N-methyl-N'-phenyl-chloroformamidine hydrochloride in 50 ml of isopropanol Over 30 minutes, excluding moisture during the addition, external cooling and maintaining the reaction temperature at 10-15 ° C.

After adding 50 ml of chloroform, the mixture was stirred overnight at room temperature and 20 ml of glacial acetic acid was added and boiled under reflux for 1 hour. The solvent was distilled off under reduced pressure, and the residue was taken up in 10 ml of chloroform, and the organic phase was washed with water, dried over MgSO _4, and subjected to column chromatography (silkkagel, eluent; 1: 1 ethyl acetate / toluene).

Colorless crystals; Melting Point 178-180 ° C (from Ethanol / Ethyl Acetate)

Example 2

4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline

10 ml of triethylamine was added to 9.8 g (0.02 mol) of 4- (4-chloro-3-dimethylsulfamoyl-phenyl) -3-methyl-2-phenylimino-4-thiazoline hydro in 200 ml of methanol. To a bromide (melting point 258-260 ° C.) suspension. The mixture is stirred at about 20-30 ° C. for 3 hours and the solvent is removed under reduced pressure. The transcription is stirred in 100 ml of water for 2 hours and the crystals are filtered off. Melting Point 179 ~ 181 ℃

Example 3

4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline hydrochloride 8.9 g (0.02 mole) of 4- (4-chloro- in 150 ml methanol 3-Dimethyl-sulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline is acidified with a saturated ether solution of hydrogen chloride, the solvent is distilled off and the residue is recrystallized from ethanol. Melting Point 229-233 ℃ (Decomposition)

Example 4

4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline methanesulfonate

From 4- (4-chloro-3-dimethyl-sulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline and 0.02 moles of methanesulfonic acid, obtained according to a method analogous to Example 3. Colorless crystals; Melting Point 198 ~ 199 ℃

Example 5

4- (4-Chloro-3-dimethylsulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline-P-toluenesulfonate

From 4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline and 0.02 mol of P-toluenesulfonic acid, obtained according to a method analogous to Example 3 . Colorless crystals; Melting Point 196 ℃

Example 6

4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl- (2-methylphenylimino) -4-thiazoline

From 4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl- (2-phenylimino) -4-thiazoline hydrobromide and triethylamine in methanol, according to a method analogous to Example 2 Obtained. Colorless crystals from methanol / ethyl acetate; Melting Point 158-162 ℃

Example 7

4- (4-chloro-3-dimethylsulfamoylphenyl) -2- (4-fluorophenylimino) -3-methyl-4-thiazoline

From 4- (4-chloro-3-dimethyl-sulfamoylphenyl) -2- (4-fluorophenylimino) -3-methyl-4-thiazoline hydrobromide, obtained according to a method analogous to Example 2 . Colorless to light yellow crystals; Melting Point 144-145 ℃

Example 8

2- (4-dimethylaminophenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline

Example 2 from 2- (4-dimethylaminophenylimino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline hydrobromide and triethylamine in methanol at room temperature Obtained according to a similar method. Melting Point 184 ~ 185 ℃

Example 9

4- (4-chloro-3-dimethylsulfamoylphenyl) -2- (2-chlorophenyl-imino) -3-methyl-1-thiazoline

From hydrobromide and triethyl-amine of the title compound, it is obtained according to a method analogous to Example 2. Colorless crystals; Melting point 152-154 ° C (from ethanol)

Example 10

4- (4-chloro-3-dimethylsulfamoylphenyl) -2- (4-methoxyphenyl-imino) -3-methyl-4-thiazoline

From hydrobromide and triethylamine of the title compound in ethanol, it is obtained according to a method similar to that of Example 2. Colorless crystals; Melting Point 198 ~ 199 ℃

Example 11

4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (4-trifluoromethylphenyl-imino) -4-thiazoline

From hydrobromide and triethyl-amine of the title compound, it is obtained according to a method analogous to Example 2. Colorless crystals; Melting Point 147-151 ℃

Example 12

4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (2,4-dimethylphenyl-imino) -4-thiazoline

4- (4-Chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (4-dimethylphenyl-imino) -4-thiazoline hydrobromide, obtained according to a similar method as in Example 2. Colorless crystals; Melting Point 152-154 ℃

Example 13

2- (4-chloro-2-methylphenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline

From 2- (4-chloro-3-methylphenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline hydrobromide and triethylamine Obtained according to a similar method.

Melting Point 137-141 ℃

Example 14

4- (4-chloro-3-dimethylsulfamoylphenyl) -2- (4-chlorophenyl-imino) -3-methyl-4-thiazoline

From hydrobromide and triethyl-amine of the title compound, it is obtained according to a method analogous to Example 2.

Colorless crystals; Melting point 184 ℃

Example 15

4- (4-chloro-3-dimethylsulfamoyl) -3-methyl-2- (2,3-dimethylphenyl-imino) -4-thiazoline

From 4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (2,3-dimethylphenyl-imino) -4-thiazoline hydrobromide and triethylamine in methanol Obtained according to a method analogous to Example 2. Melting point 226 ℃

Example 16

2- (3-chloro-2-methylphenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline

From 2- (3-chloro-3-methylphenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline hydrobromide, following a similar method as in Example 2 The reaction mixture is obtained, made alkaline with 20% methanolic ammonia solution instead of triethylamine and finished as in Example 2.

Colorless Crystals: 144 ~ 146 ℃

Example 17

2- (4-chloro-2-methoxyphenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline

Similar to Example 2 from 2- (4-chloro-3-methoxyphenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline hydrobromide Obtained according to.

Colorless crystals: 148 to 150 ℃

Example 18

4- (4-Chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (3,4-methylenedioxyphenyl-imino) -4-thiazoline

From 4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (3,4-methylenedioxyphenyl-imino) -4-thiazoline hydrobro-amide, similar to Example 2 Obtained according to the method. Colorless crystals; Crystalline having melting point of 171 to 173 ℃

Example 19

2- (3,4-ethylenedioxyphenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline

From 2- (3,4-ethylenedioxyphenyl-imino) -4- (chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline hydrobro-amide in a similar manner to Example 2 Obtained accordingly. Colorless crystals; Melting Point 200 ~ 203 ℃

Example 20

4- (4-Chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (3,4,5-trimethoxyphenyl-imino) -4-thiazoline

a) 4- (4-Chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (3,4,5-trimethoxyphenyl-imino) -4-thiazoline hydrobromide and tri From ethylamine, following a method analogous to Example 2, or

b) obtained by stirring in a mixture of 100 ml of ethyl acetate / 50 ml of toluene and 100 ml of sodium bicarbonate solution (pH 8-8.5). The organic phase can be separated off after 4 hours and the solvent can be distilled off under a water pump vacuum and the residue is treated with diisopropyl ether or water to filter the crystals. Melting Point 119 ~ 122 ℃

Example 21

3-ethyl-4- (4-chloro-3-dimethylsulfamoylphenyl) -2- (2-methylphenyl-imino) -4-thiazoline

From 3-ethyl-4- (4-chloro-3-dimethylsulfamoylphenyl) -2- (2-methylphenyl-imino) -4-thiazoline hydrobromide, obtained according to a similar method as in Example 2.

Colorless crystals; Melting Point 164 ~ 166 ℃

Example 22

4- (4-chloro-3-dimethylsulfamoylphenyl) -3-cyclopropyl-2-phenylimino-4-thiazoline

From 4- (4-chloro-3-dimethylsulfamoylphenyl) -3-cyclopropyl-2-phenylimino-4-thiazoline hydrobromide, obtained according to a similar method as in Example 2. Crystal with melting point of 156-159 ℃

[Example 23]

3-tert-butyl-4- (4-chloro-3-dimethylsulfamoylphenyl) -2-phenylimino-4-thiazoline

Tert-butyl-4- (4-chloro-3-dimethylsulfamoyl) -2-phenyl

From mino-4-thiazoline hydrobromide, prepared according to a similar method as in Example 2 or 20b). Colorless crystals; Melting point 138 ℃

Example 24

4- (4-chloro-3-dimethylsulfamoylphenyl) -3-n-hexyl-2-phenylimino-4-thiazoline

From 4- (4-chloro-3-dimethylsulfamoylphenyl) -3-n-hexyl-2-phenylimino-4-thiazoline hydrobromide, prepared according to a similar method as in Example 2. Melting point 86 ℃

Example 25

4- (4-chloro-3-dimethylsulfamoylphenyl) -3-cyclohexyl-2-phenylimino-4-thiazoline

From 4- (4-chloro-3-dimethylsulfamoylphenyl) -3-cyclo hexyl-2-phenylimino-4-thiazoline hydrobromide, obtained according to a method analogous to Example 2 or 20b). Colorless crystals; Melting point 148 ℃

[Example 26]

3-n-butyl-4- (4-chloro-3-dimethylsulfamoylphenyl) -2- (2-methylphenyl-imino) -4-thiazoline

From 3-n-butyl-4- (4-chloro-3-dimethylsulfamoylphenyl) -2- (2-methylphenyl-imino) -4-thiazoline hydrobromide, obtained according to a method analogous to Example 2 . Crystal; Melting point 104 ℃

Example 27

4- (3-Diethylsulfamoyl-4-chlorophenyl) -2- (4-chlorophenyl-imino) -3-methyl-4-thiazoline)

From the corresponding hydrobromide, it is obtained according to a method analogous to Example 2. Colorless crystals; Melting Point 198 ℃

Example 28

4- (3-Diethylsulfamoyl-4-chlorophenyl) -3-methyl-2- (2-methyl-imino) -4-thiazoline

From the corresponding hydrobromide, it is obtained according to a method analogous to Example 2. Colorless crystals; Melting point 166 ℃

Example 29

4- (3-N-butyl-N-methylsulfamoyl-4-chlorophenyl) -3-methyl-2-phenylimino4-thiazoline hydrobromide

From the corresponding thiazolin, it is obtained according to a method analogous to Example 3.

Colorless solid; Melting Point 84 ~ 87 ℃ (Decomposition)

Example 30

4- (4-chloro-3-diprosulfamoylphenyl) -3-methyl-2- (2-methylphenyl-imino) -4-thiazoline

From the corresponding hydrobromide and triethylamine, it is obtained according to a method analogous to Example 2.

Colorless crystals; Melting Point 114-116 ℃

Example 31

4- (4-Chloro-3-dipropylsulfamoylphenyl) -3-methyl-2- (2,4-dimethylphenyl-imino) -4-thiazoline

From the corresponding hydrobromide, it is obtained according to a method analogous to Example 2.

Colorless crystals; Melting Point 139-141 ℃

Example 32

4- (4-chloro-3-dipropylsulfamoylphenyl) -3-methyl-2- (2,3-dimethylphenyl-imino) -4-thiazoline

From hydrobromide of the title compound, it is obtained according to a method analogous to Example 2.

Colorless crystals; Melting Point 184 ~ 187 ℃

Example 33

2- (5-chloro-2,4-dimethoxyphenyl-imino) -4- (4-chloro-3-dipropylsulfamoylphenyl) -3-methyl-4-thiazoline

From the corresponding hydrobromide, it is obtained according to a method analogous to Example 2.

Colorless crystals; Melting Point 173 ~ 175 ℃

The basic compounds of formula (I) described in the following examples can be obtained according to a method analogous to Example 2 by acting a base on the acid addition salt of the compound of formula (I).

Example 34

4- [4-chloro-3- (1-piperidylsulfonyl) -phenyl] -3-methyl-2-phenylimino-4-thiazoline, melting point 189-195 ° C.

Example 35

4- [4-Chloro-3- (1-pyrrolidinylsulfonyl) -phenyl] -3-methyl-2-phenyl-imino-4-thiazoline, melting point 191-194 ° C.

Example 36

4- (3-Diethylsulfamoyl-4-chlorophenyl) -3-methyl-2-phenyl-imino-4-thiazoline with melting point 173 to 175 ° C

The acid addition salts of general formula (I) described in the following examples are obtained by acting on the basic compound of general formula (I) the positive asset of general formula HA according to a method analogous to Example 3.

Example 37

4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2-phenyl-imino-4-thiazoline amidosulfonate,

Melting Point 296 ~ 298 ℃

The basic compounds of formula (I) described in the following examples can be obtained according to a method analogous to Example 2 by acting a base on the acid addition salt of the compound of formula (I).

Example 38

3-methyl-4- (3-dimethylsulfamoylphenyl) -2-phenylimino-4-thiazoline, melting point 254 ° C

Example 39

2- (4-methoxyphenylimino) -3-methyl-4- (3-dimethylsulfamoylphenyl) -4-thiazoline, melting point 234 ° C

Example 40

4- (4-Chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (3-trifluoromethylphenyl-imino) -4-thiazoline, melting point 226 DEG C

Example 41

2- (4-bromophenylimino) -4- (4-chloro-3-dimethylsulfamoyl-phenyl) -3-methyl-4-thiazoline, melting point 185-188 ° C.

Example 42

2- (2-bromophenyl-imino) -4- (4-chloro-3-dimethylsulfamoyl-phenyl) -3-methyl-4-thiazoline, melting point 155 ° C.

Example 43

3-methyl-4- (4-methyl-3-dimethylsulfamoylphenyl) -2-phenylimino-4-thiazoline, melting point 175 ° C

Example 44

2- (4-methoxyphenyl-imino) -3-methyl-4- (4-methyl-3-dimethylsulfamoylphenyl) -4-thiazoline, melting point 180 deg.

Example 45

2- (4-chlorophenyl-imino) -3-methyl-4- (4-methyl-3-dimethylsulfamoylphenyl) -4-thiazoline, melting point 172 ° C

Example 46

3-ethyl-4- (4-methyl-3-dimesulfamoylphenyl) -2-phenyl-imino-4-thiazoline, melting point 175

℃

Example 47

4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (2,6-dimethylphenyl-imino) -4-thiazoline, melting point 180 deg.

The basic compounds of the general formula (I) described in the following examples can be obtained according to a method analogous to Example 2 by applying a base to the corresponding acid addition salt of the compound of the general formula (I).

Example 48

3-methyl-4- (2-methyl-5-dimethylsulfamoylphenyl) -2-phenylimino-4-thiazoline, melting point 190 ° C

Example 49

3-methyl-4- (3-methyl-5-dimethylsulfamoylphenyl) -2-phenylimino-4-thiazoline, melting point 166 ° C

Example 50

4- (2-Chloro-5-dimethylsulfamoylphenyl) -3-methyl-2-phenyl-imino-4-thiazoline, fused

197 ℃

Example 51

4- (3-Chloro-5-dimethylsulfamoylphenyl) -3-methyl-2-phenyl-imino-4-thiazoline, fused

167 ℃

Example 52

4- (2-chloro-5-dimethylsulfamoylphenyl) -2- (2-chlorophenyl-imino) -3-methyl-4-thiazoline, melting point 227 ° C

Example 53

3-ethyl-4- (2-chloro-5-dimethylsulfamoylphenyl) -2-phenylimino-4-thiazoline, melting point 201 ° C. (decomposition)

Example 54

4- (3-chloro-5-dimethylsulfamoylphenyl) -2- (2-chlorophenylimino) -3-methyl-4-thiazoline, melting point 163 deg.

Example 55

4- (2-Bromo-5-dimethylsulfamoylphenyl) -3-methyl-2-phenyl-imino-4-thiazoline, melting point 204 캜

Example 56

4- (2-Bromo-5-dimethylsulfamoylphenyl) -3-methyl-2- (2-chlorophenylimino) -4-thiazoline, melting point 242 DEG C (decomposition)

Example 57

4- (2-Bromo-5-dimethylsulfamoylphenyl) -3-methyl-2- (2,4-dimethylphenyl-imino) -4-thiazoline, melting point 260 ° C. (decomposition)

Example 58

3-ethyl-4- (2-bromo-5-dimethylsulfamoylphenyl) -2- (2-methylphenyl-imino) -4-thiazoline, melting point 209-210 ° C. (decomposition)

Example 59

2- (4-methoxyphenyl-imino) -3-methyl4- (2-methyl-5-dimethylsulfamoylphenyl) -4-thiazoline, melting point 186-189 ° C.

Example 60

3-ethyl-4- (3-methyl-5-dimethylsulfamoylphenyl) -2- (2-methylphenylimino) -4-thiazoline, melting point 155 deg.

Claims (1)

A method of preparing a thiazolin derivative of formula (I) and a pharmacologically toxic acid addition salt thereof, characterized by reacting a compound of formula (v) with a compound of formula (VI):

Wherein R ¹ is C ₁ -C ₆ -alkyl or cycloalkyl of 3 to 6 carbon atoms and R ² , R ³ and R ⁴ are ground or different, hydrogen, halogen, alkyl of 1 to 4 carbon atoms or alkoxy, methylenedi Oxy, ethylenedioxy, dimethyl- or diethyl-amino, or trifluoromethyl, R ⁵ is hydrogen, R ⁶ is hydrogen or alkyl of 1 to 6 carbon atoms and R ⁷ is hydrogen or alkyl of 1 to 6 carbon atoms, or R ⁶ and R ⁷ are joined by an alkylene chain which has up to 5 carbon atoms in total and Y is hydrogen, halogen or alkyl having 1 to 3 carbons and X 'is halogen.