KR850000757B1 - Process for preparing thiazoline derivatives - Google Patents

Abstract

Thiazolines I (R1 = C1-8 alkyl, C3-8 cycloalkyl, C3-4 alkenyl; R2-R4 = H, halogen, C1-4 alkyl or alkoxy, OCH2O, OCH2CH2O, CF3, dimethylamino, diethylamino; R5 = H, C1-3 alkyl; R6 = H, C1-6 alkyl; R7 = H, C1-12 alkyl, C3-12 cycloalkyl, allyl, phenylethyl, optionally substituted CH2Ph; Y = H, halogen, C1-3 alkyl) were prepd. Thus, 3- methyl-1-phenylthiourea were reacted with 2-bromo-4'-chloro-3'- chlorosulphonylacetophenone, which was then cooled down to 0≰C and filtered to give 4-(4-chloro-3chlorosulphonyl phenyl)-3-methyl-2- phenyl-imino-thiazolidine-4olhydrobromide.

Description

Method for preparing thiazolin derivatives

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

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 and are hydrogen, halogen, each having 1 to C carbon atoms. Alkyl of 4 or alkoxy, methylenedioxy, ethylenedioxy, dimethyl- or diethyl-amino or trifluoromethyl, R ₅ is hydrogen or alkyl of 1 to 3 carbon atoms, R ₆ is hydrogen or 1 to 6 carbon atoms Is alkyl, 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 a total of 8 carbon atoms 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.

The compound of formula (I) according to the present invention is prepared as follows.

Reacting the compound of formula (II) with thiourea of formula (III) under condensation reaction conditions, and then reacting the resulting compound of formula (XI) with an amine of formula HNR ⁶ R ⁷ , If necessary, the resulting compound of formula (I) is converted to its acid addition salt using an organic or inorganic acid of general formula HA, or a salt of the compound of formula (I) Convert to the free basic compound of (I).

중에서 선택된 이탈 그룹이다.Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and Y are as described above, Z is halogen, X is halogen, CH ₃ SO ₂ -O- and

The exit group selected.

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

The process is advantageously carried out by reacting compound (II) with thiourea (III) in a molar ratio of 1: 1 to 1: 1.5. In general, very large amounts of thiourea do not yield any significant benefit.

The reaction is advantageously carried out in an inert polar organic solvent such as dimethylformamide, dimethylacetamide, ethylene glycol monomethyl ether or ethylene glycol dimethine ether, in particular with methanol, ethanol, isopropanol, n-butanol, acetic acid, propionic acid or formic acid It is advantageously carried out in the same strong polar protic solvent, or in a mixture of said solvent and water. Anhydrous mixtures of the solvents are also suitable. The reaction may be carried out by warming the reaction mixture to a temperature of 80 to 220 ° C, preferably 100 to 180 ° C, without using a solvent. When using a solvent, the reaction is preferably carried out at a temperature of 60 to 150 ° C.

The reaction time to a considerable extent depends on the solvent used and the reaction temperature and is generally 15 minutes to 24 hours. The quantitative reaction process for obtaining compound (I) according to the present invention is followed by thin layer chromatography on silica gel plates.

In many cases, the compound (I) according to the invention is separated in the form of acid addition salts during the reaction, which is poorly soluble and can be filtered. In other cases, the yield can be increased by evaporating the solvent and adding a suitable precipitant such as ethyl acetate, diethyl ether, diisopropyl ether, acetone or acetonitrile, if necessary.

When Z in formula (II) preferably represents chlorine, the resulting compound of formula (XI) is reacted with ammonia or amine HNR ⁶ R ⁷ to obtain compound (I). An aqueous solution of ammonia and amine or an excess of liquid ammonia or pure amine can be used for the reaction, and the excess ammonia or amine acts simultaneously as a solvent. The reaction can also be carried out in an organic solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, dioxane, tetrahydrofuran or diethylene glycol dimethyl ether. However, particularly suitable solvents are lower alcohols having 1 to 4 carbon atoms such as methanol, ethanol or isopropanol. To convert sulfonyl chloride (XI) to sulfonamide (I), theoretically one mole of ammonia or amine is required in the presence of two moles of auxiliary base. Therefore, more than 3 moles of ammonia or amine per mole of sulfonyl chloride (XI) can be used in this reaction. It is advantageous to use 3 to 7 moles of ammonia or amines per mole of sulfonyl chloride in this reaction, but much more excess of amines can be used. If the reaction is carried out in the presence of a cobase, the reaction can also be carried out with 1 or 2 moles of ammonia or amine, in which case about 1 to 6 molar equivalents of cobase are used. Suitable auxiliary bases are inorganic and organic hydroxides, carbonates and bicarbonates, and may be salt solutions of weak inorganic and organic acids, in all cases triethylamine, tri-n-butylamine, methyl-dicyclohexylamine or Tertiary amines, such as ethyldicyclohexylamine, are particularly advantageous. When used in excess, tertiary amines can serve as reaction medium without further solvent portion. Since the reaction proceeds spontaneously, the reaction mixture is cooled and the reaction is preferably performed at -35 ° C to 100 ° C, preferably at + 10 ° C to + 60 ° C. The reaction time should be at least 30 minutes, and the reaction can be stopped at least two days later if no further benefit is achieved. A reaction time of 6 to 20 hours is preferred. The finishing process is advantageously dilution with water, distilling the amine and concentrating the reaction mixture if necessary and then precipitating compound (I) as a poorly soluble compound.

When R ⁶ or R ⁷ of the prepared compound (I) represents a hydrogen atom, the pH should be adjusted to 7.5 to 8.5 as much as possible.

The compound of general formula (XI) can be obtained by removing water from the following compound of general formula (XI) or a salt thereof.

In the formula, R ¹ to R ⁵ , X, Y and Z are as defined in the general formula (XI).

The reaction is carried out by the action of heat, preferably by proton catalysis, to give a compound of formula (XI). This reaction is advantageously carried out in polar organic solvents and suitable solvents include lower alcohols having 1 to 6 carbon atoms (e.g. methanol, ethanol, propanol, iso-propanol or 1- or 2-butanol), ethylene glycol monomethyl ether, di Protic solvents such as ethylene glycol mono methyl ether or lower aliphatic carboxylic acids such as acetic acid, propionic acid or formic acid or mixtures of the above solvents. It is particularly advantageous to use mixtures of such solvents with water.

Catalysts that can be used are inorganic or organic positives such as hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, one of the aliphatic carboxylic acids mentioned as solvents, or aromatic carboxylic acids (eg salicylic acid or benzoic acid). In principle, dehydration of compound (XI) can also be carried out without using a catalyst and without using a solvent.

The reaction is carried out in the temperature range of 0 to 200 ℃, the lower the temperature, the longer the reaction time, the higher the temperature increases the formation of by-products. Preferably, the reaction is carried out at a temperature of 50 ^° C. to 150 ° C., in particular the reaction is advantageously carried out in boiling methanol, ethanol, propanol or glacial acetic acid. The reaction is preferably carried out in glacial acetic acid or in a solvent which is distilled as an azeotropic mixture with water such as methylene chloride, chloroform, dichloroethane, chlorobenzene, nitro benzene, nitromethane, toluene or xylene, if necessary water formed during the reaction. Is measured by analysis. Advantageously, the reaction is carried out in a boiling solvent. Particularly advantageously, compound (XI) is obtained by heating anhydrous compound (XI) to a temperature of from 100 ^° C to 250 ° C, preferably from 150 ^° C to 220 ° C. If necessary, the water during the condensation reaction which is hindered can preferably be distilled off rapidly in the air stream or removed by applying an effective vacuum and using a desiccant.

In addition, the compound of general formula (XI) and salts thereof can be obtained by a known method by diazotizing the following aniline derivative (XIIII) and then performing a Meerwein reaction.

Compound (XIII) is halogenated with the following amino ketone (XIV) or acid addition salt thereof, preferably bromine or chlorine element, and then halogenogen ketone (VIV) in which V is Cl or Br is subjected to general It can manufacture by reacting with the thiourea of (III).

Wherein T and R ⁵ are as defined above and V is H.

Most of the thiourea (III) used are described in the literature. They are prepared by known methods by reacting amines with isothiocyanates, carbon disulfides or thiophosgene (Houben-Weyl, "Methoden der organischen Chemie" ("Methods of Organic Chemistry"), Volume 9, Page 384, 4th edition, Georg-Thieme-Verlag, Stuttgart, 1955).

Compounds of general formula (II) can be obtained by a variety of methods described in the literature (see eg German Publication No. 2,436,263).

The compound of formula (I) can be reversibly reacted with the acid of formula HA in a suitable solvent. In this reaction, if the acid is a liquid or has a melting point not higher than 60 ° C. and does not cause any side reactions, compound (I) may 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 HA 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 ^o to 120 ° C, preferably 10 ^o to 60 ° C. The reaction is moderately exothermic.

When the reaction is carried out in an aqueous solution, generally compound (I) dissolves immediately after addition of acid H-A and in rare cases the corresponding acid addition compound precipitates 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. When a solution is obtained, the acid addition compound is first concentrated, if necessary, followed by precipitation with a suitable precipitant. Suitable precipitants are the solvents described for the same purpose in the above process.

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 treating with an organic solvent and, if necessary, warming to 40 ^° C. to 80 ° C. Suitable crystallization-promoting solvents include, in particular, lower alkyl acetates with 1 to 4 carbon atoms in the alkyl moiety (eg methyl acetate, ethyl acetate and n-butylacetate), lower dialkyl ketones (eg 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 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 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 out 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 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. The reaction is carried out at a temperature of -35 ° C to 100 ° C, preferably 0 ^o to 60 ° C. If a water-miscible organic solvent is used, the free base of general 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.

When one or more moles of sufficiently strong base are acted on a compound of formula (I) in which R ⁶ and / or R ⁷ represents hydrogen, deprotonation of the sulfonamide group occurs and a salt of the following general formula is obtained.

Wherein A is a cation of an alkali metal or an 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 metals and alkaline earth metals (preferably NaOH and KOH), alkylolitic alcoholates and alkaline earth metal alcoholates (eg NaOCH ₃ and NaOC ₂ H ₅ ), NaH, sodium methylsulfinyl Metade, etc.

The solvent used is water or a polar organic solvent such as methanol, ethanol, isopropanol, n-butanol, dimethylformamide, dimethyl sulfoxide, 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 salts can also be used to prepare compounds of general formula (I) which are correspondingly converted in sulfonamide groups by alkylation reactions.

The compound of the following general formula (VII) is new.

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.

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 adducts listed in Table 3 below can also be obtained according to the present invention.

TABLE 3

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

The compounds of general formula (I) according to the invention are important agents and stand out with very favorable effects on serum lipoproteins. Therefore, they can be used as a medicament particularly affecting serum lipoproteins. Accordingly, the present invention also relates to pharmaceutical preparations based on the compounds of formula (I) and pharmacologically toxic salts thereof, and to their use as medicaments.

It is reported in the literature that 4-phenyl-2,3-dihydrothiazoline derivatives have edible decay, central nervous system excitability and diuresis, and derivatives in the literature do not have sulfonamide substituents at the phenyl site and are 2-amino. 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-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 are mentioned in the same way, in particular as diuretics (see "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 exhibits 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 is a significant risk enzyme for increasing atherosclerotic vascular changes, especially 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 protects against. 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 significant 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 hyperlipoproteinemia in diabetes. While relative liver weight does not change with 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 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 a weak ether anesthesia at the end of the treatment, and blood was collected from the orbital plexus, and the serum obtained therefrom was collected using a preliminary ultracentrifuge according to a widely used method. To separate. 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, almost no value is shown for clofibrate LDL fractions and significant decreases 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 the 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 materials and methods which are converted into suitable dosage forms, ie tablets, gelatin capsules, water-soluble or oily suspensions or aqueous or oily solutions. Inert excipients that can 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 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.

For the treatment of adipose biopsies, the compositions may, in addition to conventional fillers and excipients, include, for example, salt excretion agents, resselpin, hydrazine, guanetinine, α-methyl-dopa, clonidine or β-sympathetic blockers. It may contain a high blood pressure treatment agent, an agent having an antihyperacidosis action, an oral diabetes treatment 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-chlorosulfonylphenyl) -3-methyl-2-phenyl-imino-thiazolidin-4ol hydrobromide

A 3-methyl-1-phenylthiourea solution was added to a solution of 6.64 g (0.02 mol) of 2-bromo-4'-chloro-3'-chlorosulfonylacetophenone in 40 ml of acetone with stirring, and crystals were released when the heat was released appropriately. The title compound precipitates. The reaction mixture is stirred at room temperature for 4 hours, then cooled to 0 ° C. and the colorless crystals are filtered off.

1.decomposition temperature 220 ℃ (stock solidification)

2. Melting point 264-265 degreeC (decomposition)

The following compounds of the general formula (XII) in which Z is halogen are, for example, by the same method as in Example 1 from the corresponding substituted compounds of the general formula (II) in which Z is halogen and thiourea of general formula (III) Obtained.

a) 4- (4-chloro-3-chlorosulfonylphenyl) -2- (4-methoxyphenyl-imino) -3-methylthiazolidin-4-ol hydrobromide,

b) 4- (4-chloro-3-chlorosulfonylphenyl) -3-methyl-2- (2-methylphenyl-imino) -thiazolidin-4-ol hydrobromide,

c) 4- (4-chloro-3-chlorosulfonylphenyl) -2- (2-chlorophenyl-imino) -3-methylthiazolidin-4-ol hydrobromide,

d) 4- (4-chloro-3-chlorosulfonylphenyl) -3-methyl-2- (2, 4-dimethylphenyl-imino) -thiazolidin-4-ol hydrobromide,

e) 3-ethyl-4- (4-chloro-3-chlorosulfonylphenyl) -2- (2-methylphenyl imino) -thiazolidin-4-ol hydrobromide,

f) 2- (2, 4-diethylphenyl-imino) -4- (4-chloro-3-chlorosulfonylphenyl) -3-methylthiazolidin-4-ol hydrobromide,

g) 4- (4-chloro-3-chlorosulfonylphenyl) -2- (4-chlorophenyl-imino) -3-methylthiazolidin-4-ol hydrobromide,

h) 4- (4-chloro-3-chlorosulfonylphenyl) -2- (4-fluorophenyl-imino) -3-methylthiazolidin-4-ol hydrobromide.

Example 2

4- (4-Chloro-3-methylsulfamoylphenyl) -2- (4-methoxyphenyl-imino) -3-methyl-4-thiazolyl hydrochloride

4- (4-chloro-3-chlorosulfonylphenyl) -2- (4-methoxyphenyl-imino) -3-methyl-thiazolidine-4ol hydrobromide 10.6 g (0.02 mol) 40% methyl To a mixture of 10 ml aqueous amine solution and 150 ml methanol is added and the resulting mixture is stirred at room temperature for 20 hours. The solvent is distilled off and the residue is taken up in 100 ml of ethanol and the solution is acidified with methanolic or ethanolic hydrogen chloride solution and heated to boiling for 2 hours. The solvent is distilled off and the residue is crystallized under ether, ethyl acetate or diisopropyl ether to filter the crystals. Melting point 257 ° C. (decomposition) (from isopropanol)

The compounds of formula (I) below are analogous to Example 2 by reacting, for example, the corresponding substituted compounds of formula (XII) wherein Z is halogen with the corresponding substituted amine HNR ⁶ R ⁷ or ammonia Manufactured by

Example 3

4- (4-Chloro-3-sulfamoylphenyl) -3-methyl-2- (4-methoxyphenyl-imino) -4-thiazoline hydrochloride, melting point 267 ° C. (decomposition)

Example 4

4- (4-chloro-3-sulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline hydrochloride, melting point 242 ° C. (decomposition) (from methanol)

Example 5

4- (4-Chloro-3-dimethylsulfamoylphenyl) -3-methyl-2-phenyl-imino-4-thiazoline hydrochloride, melting point 228-231 ° C. (decomposition)

Example 6

4- (3-n-butylsulfamoyl-4-chlorophenyl) -2- (4-methoxy-phenyl-imino) -3-methyl-4-thiazoline hydrochloride, decomposed at 120 ° C. or higher.

Example 7

4- (4-Chloro-3- (1-hexylsulfamoyl) -phenyl) -2- (4-methoxy-phenyl-imino) -3-methyl-4-thiazoline hydrochloride, decomposed at 98 ° C. or higher .

Example 8

4- (3-benzylsulfamoyl-4-chlorophenyl) -2- (4-methoxyphenyl-imino) -3-methyl-4-thiazoline hydrochloride, decomposed at 135 ° C. or higher

Example 9

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

Example 10

4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline methanesulfonate 4- (4-chloro-3-dimethyl-sulfamoylphenyl) -3- Methyl-2-phenylimino-4-thiazoline and 0.02 mole of methanesulfonic acid are obtained in a similar manner as in Example 9. Colorless crystals; Melting Point 198 ~ 199 ℃

The acid addition salts of general formula (I) described in the following examples are obtained from the action of protonic acid of general formula HA on the basic compounds of general formula (I) by a method analogous to Example 9.

Example 11

4- (4-Chloro-3-sulfamoylphenyl) -3-methyl-2- (3-trifluoromethylphenyl-imino) -4-thiazoline hydrochloride, melting point: 222 캜

Example 12

4- (4-Chloro-3-n-propylsulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline hydrochloride, Melting point: 239 ° C

Example 13

4- [4-Chloro-3- (4-methylbenzylsulfamoyl) -phenyl] -3-methyl-2-phenyl-imino-4-thiazoline, melting point: 92-100 deg.

Example 14

4- (4-Chloro-3-sulfamoylphenyl) -2- (4-methoxyphenyl-imino) -3-methyl-4-thiazoline hydrochloride, melting point: 276 ° C

Example 15

4- (4-Chloro-3-dimethylsulfamoylphenyl) -3-methyl-2-phenyl-imino-4-thiazoline amidosulfonate, melting point: 296 to 298 ° C

Example 16

4- (4-chloro-3-chlorosulfonylphenyl) -3-methyl-2-phenyl-imino-4-thiazoline hydrobromide 4- (4-chloro-3-chloro-sulfonylphenyl) -3- 2.5 g (50 mmol) of methyl-2-phenyliminothiazolin-4-ol hydrobromide are rapidly heated on phosphorus pentoxide under vacuum (0.1 mm Hg) in a jacket preheated to 220 ° C. This material loses water, melts with bubbles and solidifies by recrystallization immediately after the reaction. Slight green crystal: melting point: 264 ℃

Thiazoline derivatives of the general formula (XI) are prepared by methods analogous to Example 16, for example, from correspondingly substituted thiazolidin-4-ol derivatives of the general formula (XII).

a) 4- (4-chloro-3-chlorosulfonylphenyl) -2- (4-methoxyphenyl-imino) -3-methyl-4-thiazoline hydrobromide

b) 4- (4-chloro-3-chlorosulfonylphenyl) -3-methyl-2- (2-methyl-phenyl-imino) -4-thiazoline hydrobromide melting point: 250 ° C. (decomposition)

c) 4- (4-chloro-3-chlorosulfonylphenyl) -2- (2-chloro-phenyl-imino) -3-methyl-4-thiazoline hydrobromide

d) 4- (4-chloro-3-chlorosulfonylphenyl) -3-methyl-2- (2, 4-dimethylphenyl-imino) -4-thiazoline hydrobromide

e) 3-ethyl-4- (4-chloro-3-chlorosulfonylphenyl) -2- (2-methyl-phenyl-imino) -4-thiazoline hydrobromide

f) 2- (2, 4-dimethylphenyl-imino) -4- (4-chloro-3-chloro-sulfonylphenyl) -3-methyl-4-thiazoline hydrobromide

g) 4- (4-chloro-3-chlorosulfonylphenyl) -2- (4-chlorophenyl-imino) -3-methyl-4-thiazoline hydrobromide

h) 4- (4-chloro-3-chlorosulfonylphenyl) -2- (4-fluorophenyl-imino) -3-methyl-4-thiazoline hydrobromide

Example 17

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

4.8 g (0.01 mol) of 4- (4-chloro-3-chloro-sulfonylphenyl) -3-methyl-2-phenylimino-4-thiazoline hydrobromide was added to 5 ml (40 mol) of 40% aqueous dimethyl solution. And to a mixture of 50 ml of methanol (or ethanol) little by little with external cooling and stirring so that the temperature does not rise to 35 ° C. or higher as much as possible. The reaction mixture is further stirred for 14 hours at room temperature, the solvent is distilled off under a water pump vacuum and the residue is crystallized with stirring with a magnetic stirrer under 50 ml of water. Colorless crystals; Melting Point 178-181 ° C

The thiazolin derivatives of the general formula (I) are for example prepared by analogous methods to those of Example 17 from correspondingly substituted compounds of general formula (XI) and correspondingly substituted amines or ammonia of general formula HNR ⁶ R ⁷ Obtained.

a) 4- (3-dimethylsulfamoyl-4-chlorophenyl) -3-methyl-2-imino-4-thiazoline

b) 4- (4-chloro-3-sulfamoylphenyl) -3-methyl-2-phenyl-imino-4-thiazoline

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

d) 4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (2-methylphenyl-imino) -4-thiazoline, melting point: 158 to 162 캜

e) 4- (3-diethylsulfamoyl-4-chlorophenyl) -3-methyl-2- (2-methylphenylimino) -4-thiazoline

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

g) 4- (4-chloro-3-methylsulfamoylphenyl) -3-methyl-2- (4-methoxyphenyl-imino) -4-thiazoline

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

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

j) 4- (4-chloro-3-dimethylsulfamoylphenyl) -2- (4-fluorophenyl-imino) -3-methyl-4-thiazoline

Example 18

4- (4-Chloro-3-N-methyl-N-cyclohexylsulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline

Obtained by the method similar to Example 2 using N-methyl-N-cyclohexylamine as an amine component. Colorless crystals; 180 to 181 ° C

Example 19

4- [4-Chloro-3- (1-methyl-4-piperazinylsulfonyl) -phenyl] -3-methyl-2-phenylimino-4-thiazoline N-methylpiperazine as amine component To obtain by a method similar to Example 2. Colorless crystals; Melting Point: 160 ℃ (Decomposition)

Example 20

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-phenyl imino-4-thiazoline hydro in 200 ml of methanol. To the bromide (melting point: 258-260 ° C.) suspension is added. The mixture is stirred at about 20-30 ° C. for 3 hours and the solvent is removed under reduced pressure. The residue is stirred in 100 ml of water for 2 hours and the crystals are filtered off. Melting Point: 179 ~ 181 ℃

Example 21

4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline-p-toluenesulfonate 4- (4-chloro-3-dimethylsulfamoylphenyl)- From 3-methyl-2-phenylimino) -4-thiazoline and 0.02 mole of p-toluenesulfonic acid are obtained according to a similar method as in Example 9. Colorless crystals; Melting Point: 196 ℃

Example 22

4- (4-chloro-3-dimethylsulfamoylphenyl) -2- (4-fluorophenyl-imino) -3-methyl-4-thiazoline 4- (4-chloro-3-dimethylsulfamoylphenyl) From 2- (4-fluorophenylimino) -3-methyl-4-thiazoline hydrobromide, obtained according to a method analogous to Example 20. Colorless to pale yellow crystals; Melting Point: 144 to 145 ° C

Example 23

2- (4-diethylaminophenyl in 2- (4-diethylaminophenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline methanol Mino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline hydrobromide and triethylamine are obtained according to a method analogous to Example 20 at room temperature. Melting Point: 184 to 185 ° C

Example 24

4- (4-chloro-3-dimethylsulfamoylphenyl) -2- (2-chlorophenyl-imino) -3-methyl-4-thiazoline from the hydrobromide and triethylamine of the title compound, Obtained according to a similar method. Colorless crystals; Melting Point: 152-154 DEG C (from Ethanol)

Example 25

4- (4-Chloro-3-dimethylsulfamoylphenyl) -2- (4-methoxyphenyl-imino) -3-methyl-4-thiazoline from hydrobromide and triethylamine of the title compound in ethanol Obtained according to a method analogous to example 20. Colorless crystals; Melting Point: 198 ~ 199 ℃

Example 26

4- (4-Chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (4-trifluoromethylphenyl-imino) -4-thiazoline From the hydrobromide and triethylamine of the title compound, Examples Obtained according to a method analogous to 20. Melting Point: 147-151 ° C

Example 27

4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (2, 4-dimethylphenyl-imino) -4-thiazoline 4- (4-chloro-3-dimethylsulfamoylphenyl ) -3-methyl-2- (2, 4-dimethylphenyl-imino) -4-thiazoline hydrobromide, obtained according to a method analogous to Example 20. Colorless crystals; Melting Point 152-154 ° C

Example 28

2- (4-chloro-2-methylphenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline 2- (4-chloro-3-methylphenyl-imi From no) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline hydrobromide and triethylamine, obtained according to a method analogous to Example 20. Melting Point: 137 ~ 141 ℃

Example 29

4- (4-Chloro-3-dimethylsulfamoylphenyl) -2- (4-chlorophenyl-imino) -3-methyl-thiazoline From the hydrobromide and triethylamine of the title compound, a method similar to that of Example 20 Obtained according to. Colorless crystals; Melting Point: 184 ℃

Example 30

4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (2, 3-dimethylphenyl-imino) -4-thiazoline methanol 4- (4-chloro-3-dimethylsulfa From moylphenyl) -3-methyl-2- (2, 3-dimethylphenyl-imino) -4-thiazoline hydrobromide and triethylamine, obtained according to a method analogous to Example 20. Melting Point: 226 ℃

Example 31

2- (3-chloro-2-methylphenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline 2- (3-chloro-2-methylphenyl-imi No) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline hydrobromide is obtained according to a method analogous to Example 20, wherein the reaction mixture is 20% instead of triethylamine. Made alkaline with methanolic ammonia and finished as in Example 20. Colorless crystals; Melting Point: 144 to 146 ° C

Example 32

2- (4-chloro-2-methoxyphenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline 2- (4-chloro-2-meth From oxyphenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline hydrobromide, obtained according to a method analogous to Example 20. Colorless crystals; Melting Point: 148-150 ℃

Example 33

4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (3, 4-methylenedioxyphenyl-imino) -4-thiazoline 4- (4-chloro-3-dimethylsulfa Moylphenyl) -3-methyl-2- (3, 4-methylenedioxyphenyl-imino) -4-thiazoline hydrobromide, obtained according to a method analogous to Example 31. Melting point: 171-173 ° C. crystals

Example 34

2- (3,4-ethylenedioxyphenyl-imino) -4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline 2- (3, 4-ethylenedioxyphenyl -Imino) -4-) chloro-3-dimethylsulfamoylphenyl) -3-methyl-4-thiazoline hydrobromide obtained according to a method analogous to Example 20. Colorless crystals; Melting Point: 200-203 ℃

Example 35

4- (4-chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (3, 4, 5-trimethoxyphenyl-imino) -4-thiazoline a) 4- (4 in methanol Similar to Example 20 from -chloro-3-dimethylsulfamoylphenyl) -3-methyl-2- (3, 4, 5-trimethoxyphenyl-imino) -4-thiazoline hydrobromide and triethylamine Or b) by stirring in a mixture of 100 ml of ethyl acetate / 50 ml of toluene and 100 ml of aqueous sodium bicarbonate solution (pH 8 to 8.5). The organic phase can be separated off after 4 hours and the solvent is distilled off under a water pump vacuum and the residue is treated with diisopropylether or water to filter off the crystals. Melting Point: 119 to 122 ° C

Example 36

3-ethyl-4- (4-chloro-3-dimethylsulfamoylphenyl) -2- (2-methylphenyl-imino) -4-thiazoline 3-ethyl-4- (4-chloro-3-dimethylsulfamoyl Phenyl) -2- (2-methylphenyl-imino) -4-thiazoline hydrobromide, obtained according to a method analogous to Example 20. Colorless crystals; Melting Point: 164 ~ 166 ℃

Example 37

4- (4-chloro-3-dimethylsulfamoylphenyl) -3-cyclopropyl-2-phenylimino-4-thiazoline 4- (4-chloro-3-dimethylsulfamoylphenyl) -3-cyclopropyl- From 2-phenylimino-4-thiazoline hydrobromide, obtained according to a method analogous to Example 20. Melting Point: 156 to 159 ° C

Example 38

Tert-butyl-4- (4-chloro-3-dimethylsulfamoylphenyl) -2-phenylimino-4-thiazoline tert-butyl-4- (4-chloro-3-dimethylsulfa Moyl) -2-phenylimino-4-thiazoline hydrobromide, according to a method analogous to Example 20 or 35b). Colorless crystals; Melting Point: 138 ℃

Example 39

4- (4-chloro-3-dimethylsulfamoylphenyl) -3-n-hexyl-2-phenylimino-4-thiazoline 4- (4-chloro-3-dimethylsulfamoylphenyl) -3-n- From hexyl-2-phenylimino-4-thiazoline hydrobromide, it is prepared according to a method analogous to Example 20. Melting Point: 86 ℃

Example 40

4- (4-chloro-3-dimethylsulfamoylphenyl) -3-cyclohexyl-2-phenylimino-4-thiazoline 4- (4-chloro-3-dimethylsulfamoylphenyl) -3-cyclohexyl- From 2-phenylimino-4-thiazoline hydrobromide, it is prepared according to a method analogous to Example 20 or 35b). Colorless Crystal: Melting Point: 148 ℃

Example 41

3-n-butyl-4- (4-chloro-3-dimethylsulfamoylphenyl) -2- (2-methylphenyl-imino) -4-thiazoline 3-n-butyl-4- (4-chloro-3 From -dimethylsulfamoylphenyl) -2- (2-methylphenyl-imino) -4-thiazoline hydrobromide, obtained according to a method analogous to Example 20. Crystal; Melting Point: 104 ℃

Example 42

4- (3-Diethylsulfamoyl-4-chlorophenyl) -2- (4-chlorophenyl-imino) -3-methyl-4-thiazoline From the corresponding hydrobromide, according to a method analogous to Example 20 Obtained. Colorless crystals; Melting Point: 198 ℃

Example 43

4- (3-Diethylsulfamoyl-4-chlorophenyl) -3-methyl-2- (2-methylphenylimino) -4-thiazoline obtained from the corresponding hydrobromide, according to a method analogous to Example 20 . Colorless crystals; Melting Point: 166 ℃

Example 44

4- (3-N-butyl-N-methylsulfamoyl-4-chlorophenyl) -3-methyl-2-phenylimino-4-thiazoline hydrochloride From the corresponding thiazoline, a method analogous to Example 9 Obtained accordingly. Colorless solid; Melting Point: 84-87 ° C (Decomposition)

Example 45

4- (4-Chloro-3-dipropylsulfamoylphenyl) -3-methyl-2- (2-methylphenylimino) -4-thiazoline from the corresponding hydrobromide and triethylamine, similar to Example 20 Is obtained according to. Colorless crystals; Melting Point: 114-116 ° C

Example 46

4- (4-Chloro-3-dipropylsulfamoylphenyl) -3-methyl-2- (2, 4-dimethylphenyl-imino) -4-thiazoline From the corresponding hydrobromide, a method similar to Example 20 Is obtained according to. Colorless crystals; Melting Point: 139 ~ 141 ℃

Example 47

4- (4-Chloro-3-dipropylsulfamoylphenyl) -3-methyl-2- (2,3-dimethylphenyl-imino) -4-thiazoline from hydrobromide of the title compound, similar to Example 20 Obtained according to the method. Colorless crystals; Melting Point: 184 ~ 187 ℃

Example 48

2- (5-chloro-2, 4-dimethoxyphenyl-imino) -4- (4-chloro-3-dipropylsulfamoylphenyl) -3-methyl-4-thiazoline from corresponding hydrobromide Obtained according to a method analogous to Example 20. 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 20, 31 and 35b) from acid addition salts of compounds of formula (I) by the action of a base.

Example 49

4- (4-chloro-3-sulfamoylphenyl) -3, 5-dimethyl-2-phenyl-imino-4-thiazoline, decomposed at 117 ° C. or higher

Example 50

4- (4-Bromo-3-sulfamoylphenyl) -2- (4-methoxyphenyl-imino) -3-methyl-4-thiazoline, melting point: 197 ° (from alcohol)

Example 51

2- (2-ethylphenyl-imino) -4- (4-chloro-3-sulfamoylphenyl) -3-methyl-4-thiazoline, melting point: 161 to 163 ° C

Example 52

4- (4-chloro-3-sulfamoylphenyl) -3-methyl-2- (4-methyl-phenyl-imino) -4-thiazoline, melting point 267 ° C

Example 53

4- [4-Chloro-3- (1-piperidylsulfonyl) -phenyl] -3-methyl-2-phenylimino-4-thiazoline, melting point 189-195 degreeC

Example 54

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

Example 55

4- (4-chloro-3-sulfamoylphenyl) -2-phenylimino-3-propyl-4-thiazoline, melting point 165 to 170 ° C

Example 56

3-tert-butyl-4- (4-chloro-3-sulfamoylphenyl) -2-phenylimino-4-thiazoline, melting point 80 占 폚

Example 57

4- [3- (1-butylsulfamoyl) -4-chlorophenyl] -3-methyl-2-phenylimino-4-thiazoline, melting point 130-135 degreeC

Example 58

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

Example 59

4- (4-Chloro-3-sulfamoylphenyl) -3-methyl-2- (3, 4, 5-trimethoxy-phenyl-imino) -4-thiazoline, melting point 187-189 degreeC

Example 60

2- (3,4-ethylenedioxyphenyl-imino) -4- (4-chloro-3-sulfamoylphenyl) -3-methyl-4-thiazoline, melting point 247-249 ° C.

Example 61

4- (4-Chloro-3-sulfamoylphenyl) -2- (3, 4-methylenedioxy-phenyl-imino) -3-methyl-4-thiazoline, melting point 187-189 degreeC

Example 62

4- (4-chloro-3-sulfamoylphenyl) -2- (4-methoxyphenyl-imino) -3-methyl-4-thiazoline, melting point 210 to 214 ° C

Example 63

4- (4-chloro-3-sulfamoylphenyl) -2- (4-fluorophenylimino) -3-methyl-4-thiazoline, melting point 234 to 236 ° C

Example 64

2- (4-ethoxyphenyl-imino) -3-methyl-4- (4-chloro-3-sulfamoylphenyl) -4-thiazoline, melting point 233 ° C

Example 65

4- (4-chloro-3-sulfamoylphenyl) -3-methyl-2- (3-methyl-phenyl-imino) -4-thiazoline, melting point 193-194 ° C. (from methanol)

Example 66

2- (5-chloro-2, 4-dimethoxyphenyl-imino) -4- (4-chloro-3-sulfamoylphenyl) -3-methyl-4-thiazoline, melting point 204 to 206 캜

Example 67

4- (4-chloro-3-sulfamoylphenyl) -3-methyl-2- (3-dimethylaminophenyl-imino) -4-thiazoline, melting point 134-140 ° C

Example 68

4- (4-chloro-3-sulfamoylphenyl) -3-methyl-2- (2, 4-dimethyl-phenyl-imino) -4-thiazoline, melting point 270 to 275 ° C

Example 69

2- (2-ethoxy-5-methylphenyl-imino) -4- (4-chloro-3-sulfamoylphenyl) -3-methyl-4-thiazoline, melting point 194-197 ° C.

The basic compounds of formula (I) described in the following examples can be obtained according to methods analogous to examples 20, 31 and 35 b) by acting a base on the acid addition salts of compounds of formula (I):

Example 70

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

Example 71

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

Example 72

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

Example 73

4- (4-Chloro-3-methylsulfamoylphenyl) -3-methyl-2-phenyl-imino-4-thiazoline, melting point 274 ° C

Example 74

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

Example 75

2- (2-bromophenylimino) -4- (4-chloro-3-dimethylsulfamoyl-phenyl) -3-methyl-4-thiazoline, melting point 155 deg.

Example 76

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

Example 77

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

Example 78

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

Example 79

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

Example 80

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 methods analogous to Examples 20, 31 and 35, by acting a base on the corresponding acid addition salt of the compound of the general formula (I).

Example 81

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

Example 82

3-methyl-4- (3-methyl-5-dimethylsulfamoylphenyl) -2-phenylimino-4-thiazoline, melting point 165 deg.

Example 83

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

Example 84

4- (3-chloro-5-dimethylsulfamoylphenyl) -3-methyl-2-phenyl-imino-4-thiazoline, melting point 167 deg.

Example 85

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

Example 86

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

Example 87

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

Example 88

3-methyl-4- (2-methyl-5-sulfamoylphenyl) -2-phenylimino-4-thiazoline, melting point 188-191 ° C.

Example 89

3-methyl-4- (3-methyl-5-sulfamoylphenyl) -2-phenylimino-4-thiazoline, melting point 210 to 212 ° C

Example 90

4- (2-chloro-5-sulfamoylphenyl) -3-methyl-2-phenylimino-4-thiazoline, melting point 198 to 200 ° C

Example 91

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

Example 92

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

Example 93

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

Example 94

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

Example 95

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

Example 96

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

Example 97

2- (4-Chlorophenyl-imino) -3-methyl-4- (3-methyl-5-sulfamoylphenyl) -4-thiazoline, melting point 195 ° C.

TABLE 4

Some thiourea (III) prepared are shown. These compounds are obtained according to methods known in the following literature. , Stuttgart, 1955).

Claims (1)

Reacting a compound of formula (II) with a thiourea of formula (III) under condensation conditions, and then reacting the compound of formula (XI) with an amine of formula HNR ⁶ R ⁷ Characterized in that the thiazolin derivatives of the general formula (I) and pharmacologically toxic acid addition salts thereof.

Wherein R ¹ is C ₁ -C ₆ -alkyl, or cycloalkyl of 3 to 6 carbon atoms, R ² , R ³ and R ⁴ are the same or different, hydrogen, halogen, alkyl or alkoxy of 1 to 4 carbon atoms, Methylenedioxy, ethylenedioxy or trifluoromethyl, R ⁵ is hydrogen, R ⁶ is hydrogen or alkyl of 1 to 6 carbon atoms, R ⁷ is hydrogen, alkyl of 1 to 6 carbon atoms, cyclohexyl or benzyl radical

(Where R ⁸ and R ⁹ are the same or different and are hydrogen or methyl), or R ⁶ and R ⁷ are joined by an alkylene chain, which alkylene chain has a total of 5 carbon atoms, where one methylene group is

N-CH ₃ can be substituted, Y is hydrogen, halogen or alkyl of 1 to 3 carbon atoms, Z is halogen, X is halogen, CH ₃ -SO ₂ -O- and

The exit group selected.