KR850000758B1 - Process for preparing thiazoline derivatives - Google Patents

Abstract

Thiazolines I (R1 = C1-6 alkyl, C3-6 cycloalkyl; R2-R4 = H, halogen, C1-4 alkyl or alkoxy, OCH2O, OCH2CH2O, NMe2, NEt2, CF3; R5 = H, R6 = C1-6 alkyl; R7 = C1-6 alkyl; Y = H, halogen (no Br, I), C1-3 alkyl, M = Li), useful in lowering lipoprotein in serum, were prepd. Thus, the resultant solns, which included 3-methyl-4-oxo-2- phenyliminothiazolidine hydrobromide in ethanol, were reacted with triethylamine and were stirred for 3hrs. to remove the ethanol, and then were extracted with ethylacetate to give 3-methyl-4-oxo-2- phenylimino thiazolidine.

Description

Method for preparing thiazolin derivatives

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

(여기에서 R⁸및 R⁹는 같거나 다르며 수소, 메틸, 염소 또는 메톡시이다)이거나, R⁶및 R⁷은 알킬렌쇄로 결합되며, 이 알킬렌 쇄는 측쇄일 수 있고 총 탄소수 8까지 가지며 여기에서 하나의 메틸렌 그룹은 산소원자 또는 N-CH₃그룹으로 치환될 수 있고, Y는 수소, 할로겐 또는 탄소수 1 내지 3의 알킬이다.Wherein 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, hydrogen, halogen, each having 1 carbon atom Alkyl of 4 to 4 or alkoxy, methylenedioxy, echelenedioxy, dimethyl- or diethylamino, or trifluoromethyl, R ⁵ is hydrogen or alkyl of 1 to 3 carbon atoms, R ⁶ is hydrogen or 1 to carbon carbon Alkyl of 6, R ⁷ is hydrogen, alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, allyl, phenylethyl or benzyl radical

(Where R ⁸ and R ⁹ are the same or different and are hydrogen, methyl, chlorine or methoxy) or R ⁶ and R ⁷ are joined by an alkylene chain, which may be branched and has up to 8 carbon atoms in total Wherein one methylene group may be substituted with an oxygen atom or an N—CH ₃ group, and 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 (IX) is then reacted with the compound of formula (X) and the resulting reaction product is hydrolyzed and dehydrated, if necessary, using an organic or inorganic acid of formula HA, The compound of I) is converted to its acid addition salt or the base is used to convert the salt of the compound of formula (I) to the free basic compound of formula (I).

R in the above formula^One, R², R³, R⁴And R⁵Is as described above, and R⁶And R⁷Is as described above except for hydrogen, Y is as described above except for bromine or iodine, and M is lithium or MgBr group.

Inorganic acids H-A which can be used, for example hydrochloric acid (eg 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, a compound of formula (IX) is reacted with a compound of formula (X), wherein Y is not bromine or iodine and R ⁶ and R ⁷ are not hydrogen. Compounds (IX) and (X) are advantageously at a preferred temperature of -30 ° to + 60 ° C. in a molar ratio of 1: 1 to 1: 1.5 in an inert anhydrous solvent, preferably tetrahydrofuran, which is customary for metal-organic reactions. React. After completion of the reaction, the reaction product is hydrolyzed in the usual manner for metal-organic reactions. For example, the reaction mixture is placed in saturated aqueous ammonium chloride solution at a temperature of -5 ° to + 20 ° C to maintain a pH of 6-8. In order to complete the conversion to compound (I) according to the invention, the hydrolysis mixture can be warmed to a temperature of 40 to 100 ° C., preferably 60 to 80 ° C. while examining the progress of the reaction with thin layer chromatography. However, it is advantageous to finish by filtering the mixture of products which have not yet been completely converted to compound (I) or extracting with a suitable solvent such as methyl acetate, ethyl acetate or nitromethane.

In many cases the compound (I) according to the invention is separated in its acid addition salt form during the reaction, which is poorly soluble and easily filtered. In other cases, the solvent may be evaporated and the yield may be increased if necessary by the addition of suitable precipitating agents, for example ethyl acetate, diethyl ether, diisopropyl ether, acetone or acetonitrile.

Methods for the preparation of compound (IX) and precursors thereof are described in the literature, for example in German Publication 2436263.

The compound of formula (X) is obtained by a known method, for example, by reacting the α-halogenocarboxylic acid ester of formula (XVI) with thiourea of formula (III).

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and X are as described above, B is OR ⁸ , wherein R ⁸ is preferably phenyl or lower alkyl (methyl or ethyl). Also suitable are α-halogenocarboxylic acid (B = OH) and α-halogenocarboxylic acid chloride (B = CI).

The compound of formula (I) can be reversibly reacted with the acid of formula H-A in a suitable solvent. In this reaction, if the acid is a liquid or has a melting point not higher than 60 ° C. and no side reactions occur, compound (I) can be introduced into the pure acid, preferably at 0 ° to 60 ° C. However, the reaction is carried out in organic solvents such as water, dioxane, tetrahydrofuran, ether, lower alkyl acetate having 1 to 4 carbon atoms, acetonitrile, nitromethane, acetone, methyl ethyl ketone, etc. Lower alcohols and carboxylic acids having 2 to 4 carbon atoms have proven particularly suitable. 1 to 1.5 moles of acid H-A per mole of compound (I) are used but higher amounts of acid may be used. If necessary, the reaction is carried out at a temperature of 0 ° to 120 ° C, preferably 10 ° 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 salt according to the invention is separated off by evaporating 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 poorly soluble 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, followed by precipitation with a suitable precipitant. Suitable precipitants are, for example, ethyl acetate, diethyl ether, diisopropyl ether, acetone or acetonitrile.

Acid adducts 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 include, in particular, lower alkyl acetates (e.g. methyl acetate, ethyl acetate and n-butyl acetate) having 1 to 4 carbon atoms in the alkyl moiety, lower dialkyl ketones (e.g. acetone or methyl ethyl ketone), 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 adduct can be deprotonated by treatment with a base in a suitable solvent to afford the 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 or bicarbonate, ammonia and triethylamine, di Amines such as cyclohexylamine, piperidine and methyldicyclohexylamine.

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 medium may include lower alcohols having 1 to 4 carbon atoms, preferably methanol and ethanol, ethyl acetate, diethyl ether, tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, dimethylformamide, and the like. . The reaction to obtain compound (I) occurs spontaneously. Half is carried out at a temperature of -35 ° to 100 ° C, preferably 0 ° to 60 ° C. If a water-miscible organic solvent is used, the free base of formula (I) is precipitated by concentrating the reaction mixture beforehand and then adding water if necessary. 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 mole of 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 the salt of formula (XVII) is obtained.

Wherein A is a cation of an alkali metal or alkaline earth metal, R ¹ to R ⁵ and Y are as described above, and 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 methylsulphenylmetha It is id.

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 an ammonium salt 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 sulfoamide groups by alkylation reactions.

The compound of formula (XVII) is novel.

Wherein R ¹ to R ⁵ and Y are as described above, R has the meaning of R ⁶ or R ⁷ , and 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

R ¹ = methyl, ethyl or cyclopropyl

R ² = hydrogen, methyl, ethyl, bromine, chlorine, fluorine, trifluoromethyl, methoxy, ethoxy, -N (CH ₃ ) ₂ or N (C ₂ H ₅ ) ₂

R ³ = hydrogen, methyl, ethyl or chlorine

R ⁴ = hydrogen or methyl

R ⁵ = hydrogen

R ⁶ and R ⁷ = hydrogen, methyl or ethyl (R ⁶ and R ⁷ are the same or different)

Y = bromine, chlorine or methyl in the 2-, 3- or 4- position of the thiazole ring

[Table 2]

R ¹ = methyl or ethyl R ⁴ = hydrogen

R ² = hydrogen, ethyl, chlorine, methoxy, fluorine or R ⁵ = hydrogen

Trifluoromethyl R ⁶ and R ⁷ = methyl or ethyl

R ³ = hydrogen or methyl

Y = chlorine at 2-, 3- or 4- position of the thiazole ring

In addition to the thiazolin derivatives described in the examples, the compounds of the general formula (I) and their acid addition products listed in Table 3 below can also be obtained according to the invention.

TABLE 3

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

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

It is reported in the literature that 4-phenyl-2,3-dihydrothiazoline derivatives have anorexia, central nervous system excitability and diuresis, and derivatives in the literature do not have sulfonamide substituents at the phenyl site and are 2-amino. A group is a compound in which the group is not substituted by aryl (see US Patent Specification No. 3671533 and German Publication No. 1938674). 3-alkyl-4-phenyl-2-phenylimide-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-methyl) -3-alkyl-2-imino-4-thiazoline and thiazolidine with different substituents are mentioned in the same way, in particular as diuretics, in 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 the type of lipoprotein, the thiazolin derivatives described in this document have no effect or only a minor effect which is clearly low in quantitative and normal terms. The fact that I could not do was surprising.

It is generally recognized that hyperlipoproteinemia poses a significant risk factor for increasing atherosclerotic vascular changes, particularly in coronary heart disease. Therefore, lowering elevated serum lipoprotein 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 acts as a protection. Therefore, hypolipidemic agents should lower the levels of VLDL-cholesterol and LDL-cholesterol in the serum, but should have no effect or rather increase the HDL-cholesterol concentration 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 tremendous progress when compared to the comparative compound clofibrate, as can be seen in the following test. They can therefore be used to prevent and recover atherosclerotic changes because they eliminate causal risk factors. This risk factor includes primary hyperlipoproteinemia as well as secondary hyperlipoproteinosis in diabetes. While the relative liver weight does not change with the example of compound (I), clofibrate used as a hypolipidemic standard results in a substantial increase in relative liver weight.

The effects of the compounds listed in the following table on the serum lipoproteins were studied by treating Wistar male rats in polyethylene glycol 400 with a throat throat for 7 days. The study also included a control group that received only 4 million solvents of polyethylene glycol, and the 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 orbital nerve layer, and the serum obtained therefrom was collected and fat was prepared using a precentral ultracentrifuge according to a widely used method. Isolate the protein. Serum lipoproteins are separated in the ultracentrifuge into the following density categories: VLDL 1.006; LDL 1.006 to 1.04; HDL 1.04-1.21.

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

[table]

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

Therapeutic compositions of the compounds of formula (I) may in particular be present in the form of tablets, dragees, capsulants, suppositories or syrups. The novel compounds can be used alone or in admixture with pharmacologically toxic excipients. Oral dosage forms are preferred. For this purpose, it is preferred to mix the active compound with known materials and methods which are converted into suitable dosage forms, ie tablets, capsulants, water soluble or oily suspensions, or aqueous or oily solutions. Inert excipients that may be used are, for example, magnesium carbonate, lactose or corn starch and may also add other materials such as magnesium stearate. 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 oils 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.

In addition to conventional fillers and excipients, the compositions may be used for the treatment of hyperlipidemia, for example, in hypertension, such as salinary excreta, reselpin, hydralazine, guanetinine, α-methyl-dopa, clonidine, or β-sympathetic blockers. It may contain an agent having an antiperiodic action, an oral diabetic agent, an agent for treating geriatric symptoms, or an agent for improving circulation.

Pure precursors of the general formula (IV) according to the invention, compared to the compounds of the general formula (I) according to the present invention, have a slightly weaker effect on serum lipoproteins, if at least slightly effective, but structurally related thiazoli Like the dean derivatives (see German Publication 2436263), they have very good salt excretion in some cases.

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

Example 1

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

a) 3-methyl-4-oxo-2-phenyliminothiazolidine hydrobromide

10 g of ethyl bromoacetate and 9.95 g of 1-methyl-3-phenylthiourea in 150 ml of acetone are boiled under a reflux condenser for 1 hour. Cool the reaction mixture, filter the crystals and wash with acetone.

Melting Point 212-215 ° C

b) 3-methyl-4-oxo-2-phenyliminothiazolidine

4 g of 3-methyl-4-oxo-2-phenyliminothiazolidine hydrobromide are suspended in 100 ml of ethanol and 8.4 g of triethylamine are added. The resulting solution was stirred at room temperature for 3 hours, ethanol was distilled off, water was added to the residue, the mixture was extracted several times with ethyl acetate, the organic phase was dried over sodium sulfate and the solvent was distilled off. Yellow viscous oil

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

20 mmol of tert-butyl-lithium in pentane are added to a 3 g solution of 5-bromo-2-chlorobenzene-dimethylsulfonamide in 40 ml of anhydrous tetrahydrofuran over 10 minutes and the solution is stirred at -78 ° C under argon. . The solution was held at −78 ° C. for about 60 minutes, then 2 g of 3-methyl-4-oxo-2-phenyl-iminothiazoline were added and the reaction mixture was stirred at room temperature overnight. It is poured into 15 ml of saturated ammonium chloride solution and the resulting solution is washed several times with chloroform, the organic phases are combined, washed with water and dried over magnesium sulfate. After drying the filtrate, 60 ml of glacial acetic acid was added, the mixture was boiled for 2 hours, heated, the solvent was distilled off, the residue was dissolved in 5 ml of chloroform, and the resulting solution was prepared using a 1: 1 mixture of ethyl acetate / toluene. Chromatography on column. Crystal; Melting point 177 to 179 ° C

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 hydrobromide in 200 ml of methanol. (Melting point 258-260 ° C.) is added to the suspension. The mixture is stirred at about 20-30 ° C. for 3 hours and the solvent is removed under reduced pressure. The residue is stirred for 2 h in 100 ml of water and the crystals are filtered off. Melting point 179-181 ° C

Example 3

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

8.9 g (0.02 mol) of 4- (4-chloro-3-dimethyl-sulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline in 150 ml of methanol are acidified with a saturated ether solution of hydrogen chloride The solvent is distilled off and the residue is recrystallized from ethanol. Melting Point: 229 to 233 ° C (Decomposition)

Example 4

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

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

Example 5

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

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

Example 6

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

A method similar to Example 2 from 4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (2-methylphenylimino) -4-thiazoline hydrobrohydride and triethylamine in methanol Obtained accordingly. Colorless crystals from methanol / ethyl acetate; Melting point 158-162 캜

Example 7

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

4- (4-Chloro-3-dimethyl-sulfamoylphenyl) -2- (4-fluorophenylimino) -3-methyl-4-thiazoline hydrobromide is obtained according to a method analogous to Example 2. Colorless to pale yellow crystals; Melting point 144-145 캜

Example 8

2- (4-diethylaminophenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-mitel-4-thiazoline

It is carried out from 2- (4-diethylaminophenylimino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline hydrobromide and triethylamine in methanol at room temperature. Obtained in a similar manner to Example 2.

Melting Point: 184 to 185 ° C

Example 9

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

Obtained according to a method similar to Example 2 from hydrobromite and triethylamine of the title compound.

Colorless crystals; Melting point 152 to 154 ° (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 are obtained following a similar method as in Example 2. Colorless crystals; Melting Point: 198 ~ 199 ℃

Example 11

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

Obtained according to a method similar to Example 2 from hydrobromide and triethylamine of the title compound.

Melting Point: 147-151 ° C

Example 12

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

Obtained from 4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (2, 4-dimethylphenyl-imino) -4-thiazoline hydrobromide according to a method analogous to Example 2 . Colorless crystals; Melting Point 152-154 ° C

Example 13

2- (4-Chloro-2-methylphenyl-imino) -4- (4-chloro-3-dimethylsulfamoyl-phenyl) -3-methyl-4-thiazoline

Similar to Example 2 from 2- (4-chloro-2-methylphenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline hydrobromide and triethylamine Obtained according to the method. Melting point 137-141 ° C

Example 14

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

Obtained according to a method similar to Example 2 from hydrobromide and triethylamine of the title compound.

Anhydrous crystals; Melting point 184 ℃

Example 15

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

Example 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 2. Melting point 226 ℃

Example 16

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

Obtained according to a method similar to Example 2 from 2- (3-chloro-2-methylphenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline hydrobromide The reaction mixture is made alkaline using 20% methanolic ammonia solution instead of triethylamine and is finished as in Example 2.

Colorless crystals; Melting Point: 144 to 146 ° C

Example 17

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

In a method similar to Example 2 from 2- (4-chloro-2-methoxyphenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline hydrobromide Obtained accordingly. Colorless crystals; Melting point 148 to 150 ° C

Example 18

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

4- (4-Chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (3,4-methylenedioxyphenyl-imino) -4-thiazoline hydrobromide according to a method analogous to Example 16 To obtain. Crystalline with melting point of 171-173 ° C

Example 19

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

Obtained from 2- (3,4-ethylenedioxyphenyl-imino) -4- (chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazolinehydrobromide according to a method analogous to Example 2 . Colorless crystals; Melting Point 200-203 ° C

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 triethyl Obtained from an amine according to a method analogous to Example 2, or

b) obtained by stirring in a mixture of 100 ml of ethyl acetate 150 ml of toluene and 100 ml of aqueous solution of tartium bicarbonate (pH 8-8.5). The organic phase can be separated off after 4 hours and the solvent is distilled off under vacuum in a water pump and the residue can be filtered off with diisopropyl ether or water to filter off the crystals. Melting Point: 119 to 122 ° C

Example 21

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

Obtained according to a method analogous to Example 2 from 3-ethyl-4- (4-chloro-3-dimethylsulfamoylphenyl) -2- (2-methylphenyl-imino) -4-thiazoline hydrobromide. Colorless crystals; Melting Point: 164 ~ 166 ℃

Example 22

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

Obtained according to a method analogous to Example 2 from 4- (4-chloro-3-dimethylsulfamoylphenyl) -3-cyclopropyl-2-phenylamino-4-thiazoline hydrobromide. Melting Point 156-159 ° C

Example 23

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

Prepared according to a method analogous to Example 2 or 20b) from tert-butyl-4- (4-chloro-3-dimethylsulfamoyl) -2-phenylimino-4-thiazoline hydrobromite. Colorless crystals; Melting Point: 138 ℃

Example 24

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

Prepared according to a method similar to that of Example 2 from 4- (4-chloro-3-dimethylsulfamoylphenyl) -3-n-hexyl-2-phenylimino-4-thiazoline hydrobromide. Melting Point: 86 ℃

Example 25

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

Prepared according to a method analogous to Example 2 or 20b) from 4- (4-chloro-3-dimethylsulfamoylphenyl) -3-cyclohexyl-2-phenylimino-4-thiazoline hydrobromide. Colorless crystals; Melting Point: 148 ℃

Example 26

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

Obtained according to a method analogous to Example 2 from 3-n-butyl-4- (4-chloro-3-dimethylsulfamoylphenyl) -2- (2-methylphenyl-imino) -4-thiazoline hydrobromide. Crystal; Melting Point: 104 ℃

Example 27

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

Obtained according to a method analogous to Example 2 from the corresponding hydrobromide. Colorless crystals; Melting Point: 198 ℃

Example 28

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

Obtained according to a method analogous to Example 2 from the corresponding hydrobromide. Colorless crystals; Melting Point: 166 ℃

Example 29

4- (3-N-butyl-N-methylsulfamoyl-4-chlorophenyl-3-methyl-2-phenylimino-4-thiazoline hydrochloride

Obtained according to a method analogous to Example 3 from the corresponding thiazolin.

Colorless solid; Melting Point 84-87 ° C (Decomposition)

Example 30

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

Obtained according to a method analogous to Example 2 from the corresponding hydrobromide and triethylamine.

Colorless crystals; Melting point 114-116 ° C

Example 31

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

Obtained according to a method analogous to Example 2 from the corresponding hydrobromide.

Colorless crystals; Melting Point 139-141 ° C

Example 32

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

Obtained according to a method similar to Example 2 from hydrobromide of the title compound.

Colorless crystals; Melting Point 184-187 ° C

Example 33

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

Obtained according to a method analogous to Example 2 from the corresponding hydrobromide.

Colorless crystals; Melting Point 173 ~ 175 ℃

The basic compounds of formula (I) described in the following examples can be obtained according to methods analogous to examples 2, 16 and 20 b) by acting a base on acid addition salts of compounds of formula (I).

Example 34

4- [4-chloro-3- (1-piperidylsulfonyl) -phenyl] -3-methyl-2-phenylimino-4-thiazoline,

Melting Point: 189 ~ 195 ℃

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 melting point: 173 to 175 ° C

Acid addition salts of general formula (I) described in the following examples are obtained by acting on the basic compounds of general formula (I) a 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 are obtained according to methods analogous to examples 2, 16 and 20 b) by acting a base on the acid addition salts of compounds 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 ℃

Example 42

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

Melting Point: 155 ℃

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 ° C

Example 45

2- (4-Chlorophenyl-imino) -3-methyl-4- (4-methyl-3-dimethylsulfamoylphenyl) -4-thiazoline, melting point: 172 캜

Example 46

3-ethyl-4- (4-methyl-3-dimethylsulfamoylphenyl) -2-phenyl-imino-4-thiazoline, melting point: 175 ° C

Example 47

4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (2, 6-dimethylphenyl-imino) -4-thiazoline,

Melting Point: 180 ℃

The basic compounds of formula (I) described in the following examples can be obtained according to methods analogous to examples 2, 16, and 20 b) by reacting a base with the corresponding acid addition salt of the compound of formula (I). have.

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 deg.

Example 50

4- (2-chloro-5-dimethylsulfamoylphenyl) -3-methyl-2-phenyl-amino-4-thiazoline, melting point: 197 ° C

Example 51

4- (3-chloro-5-dimethylsulfamoylphenyl) -3-methyl-2-phenyl-imino-4-thiazoline, melting point: 167 ° C

Example 52

4- (2-chloro-5-dimethylsulfamoylphenyl) -2- (2-chlorophenyl-imino) -3-methyl-4-thiazoline,

Melting Point: 227 ℃

Example 53

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

Example 54

4- (3-chloro-5-dimethylsulfamoylphenyl) -2- (2-chlorophenylimino) -3-methyl-4-thiazoline,

Melting Point: 163 ℃

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 ℃ (decomposition)

Example 57

4- (2-bromo-5-dimethylsulfamoylphenyl) -3-methyl-2- (2, 4-dimethylphenyl-imino) -4-thiazoline,

Melting Point 260 ℃ (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-methyl-4- (2-methyl-5-dimethylsulfamoylphenyl) -4-thiazoline,

Melting Point 186-189 ° C

Example 60

3-ethyl-4- (3-methyl-5-dimethylsulfamoylphenyl) -2- (2-methylphenyl-imino) -4-thiazoline, melting point: 155 ° C

Claims (1)

And reacting the compound of formula (IX) with the compound of formula (X) and hydrolyzing and dehydrating the resulting reaction product, the thiazolin derivatives of formula (I) and their pharmacological To prepare nontoxic acid addition salts.

Wherein R ¹ is C ₁ -C ₆ -alkyl, cycloalkyl of 3 to 6 carbon atoms, R ² , R ³ and R ⁴ are the same or different, hydrogen, halogen, alkyl of 1 to 4 carbon atoms or alkoxy, methylene Dioxy, ethylenedioxy, dimethyl- or diethyl-amino or trifluoromethyl, R ⁵ is hydrogen, R ⁶ is alkyl of 1 to 6 carbon atoms, R ⁷ is alkyl of 1 to 6 carbon atoms, or R ⁶ and R ⁷ are joined by an alkylene chain, which chain has up to 5 carbon atoms, Y is hydrogen, halogen (except bromine or iodine) or alkyl of 1 to 3 carbon atoms, M is lithium to be.