MXPA97005385A - Derivatives of n- (4-aril-tiazol-2-il) -sulfonam - Google Patents

Abstract

The invention relates to the use of sulfonamide derivatives of the general formula (I), wherein R means lower alkyl, phenyl, benzyl, naphthyl, pyridyl or thienyl, optionally substituted by one or more substituents of lower alkyl, lower alkoxy, alkyl lower carbonyl amino, halogen, cycloalkyl, nitro, amino, methylenedioxyl, phenoxy or benzyloxy, and the aromatic rings may be substituted, in turn, by nitro, halogen or amino, R1-R4 signify hydrogen, halogen, hydroxyl, alkyl lower, nitro, cyano, amino, lower alkoxy, benzyloxy, trifluoromethyl or phenyl, optionally substituted by one or more substituents of lower alkyl, trifluoromethyl, nitro, amino or hydroxyl, and wherein R1 and R2 or R2 and R3 together can form a benzene ring which can optionally be substituted by halogen, trifluoromethyl, nitro, lower alkyl or lower alkoxy, and their pharmaceutically acceptable salts as inhibitors n-3-hydroxylase in the control or prevention of neurodegenerative disorders, neurological disorders resulting from an activation of the immune system, or psychiatric diseases and, respectively, for the production of corresponding medicaments

Description

Description of the invention The invention relates to the use of sulfonamide derivatives of the general formula wherein R means lower alkyl, phenyl, benzyl, naphthyl, pyridyl or thienyl, optionally substituted by one or more substituents of lower alkyl, lower alkoxy, lower alkyl-carbonyl-amino, halogen, cycloalkyl, nitro, amino, methylenedioxyl, phenoxy or benzyloxy, and the aromatic rings may be substituted, in turn, by nitro, halogen or amino, R! -R4 means hydrogen, halogen, hydroxyl, lower alkyl, nitro, cyano, amino, lower alkoxy, benzyloxy, trifluoromethyl or phenyl, optionally substituted by one or more lower alkyl, trifluoromethyl, nitro, amino or hydroxyl substituents, and wherein R ^ - and R ^ OR ^ and R3 together can form a benzene ring which can optionally be substituted by halogen, trifluoromethyl, nitro, lower alkyl or lower? coxyl, and their pharmaceutically acceptable salts as quinurenin inhibitors. 3-hydroxylase in the control or prevention of neurodegenerative disorders, neurological disorders resulting from an activation of the immune system or psychiatric diseases and, respectively, for the production of corresponding drugs. The 2-thiazolyl-sulfonamides have been known for a long time. US 2,611,770 describes, for example, N- (2-thiazolyl) -2-hydroxypyrimidine-5-sulfonamides as active compounds against viral diseases or diseases caused by microorganisms. Isoxazolyl sulfonamides having endo-telin-antagonistic activity, among others for the treatment of central nervous system disorders, are described in EP 569 193. WO 94/27979 describes sulfonamide derivatives containing different heterocycles and having endotelin-antagonistic activity. A series of specific 2-arylsulfonamido-4-fluoroarylthiazoles with antifungal activity are exposed in Agr. Biol. Chem., 40 (6), 1129-1135, 1976. Jour. Indian Chem. Soc, Vol. 39, No. 2, 1962 describes, among others, a series of specific thiazolyl sulfonamides having pesticidal activity. In accordance with the invention it has now been found that the 2-thiazolyl sulfonamides of the formula I and their salts have a surprisingly high activity as inhibitors of quinu-renin-3-hydroxylase. The quinurenin-3-hydroxylase inhibitors, alone or in combination with quinurenin or tryptophen, are of therapeutic interest in all disorders and conditions that are associated with a glutamatergic neurotransmission malfunction and / or that lead to excessive production of quinolinic acid. These disorders include not only neurodegenerative disorders (Huntington's chorea, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, epilepsy), consequences of attack and / or cerebral ischemia, hypoxia, multi-infarct dementia, consequences of trauma or injury cerebral, as well as trauma and spinal cord injury, neurological disorders resulting from an activation of the immune system (for example AIDS-dementia complex, infections such as for example viral or bacterial meningitis and cancers with cerebral localization), autoimmune diseases (sclerosis multiple), as well as psychiatric illnesses (schizophrenia, chronic anxiety). In addition, the compounds have been found to have antibacterial activity, for example against Staphylococcus aureus and Streptococcus pyogenes. This makes these compounds especially interesting, since a double attack in a pharmaceutical application is advantageous for certain types of disease, for example in the case of bacterial meningitis or infections that are caused by the AIDS dementia complex. Objects of the present invention are the use of compounds of formula I and their pharmaceutically usable salts in the control or prevention of diseases of the aforementioned type and, respectively, for the production of corresponding medicaments, new compounds of formula I and their salts of yes and for use as therapeutically active substances, the preparation of the new compounds and salts, as well as medicaments containing a new compound of formula I or salt and the production of corresponding medicaments.

When the compounds of the general formula I are used in the control or prevention of diseases of the type described above, those compounds are preferred wherein R means 4-methylphenyl, 4-methoxyphenyl, 4-aminophenyl, 3,4-dimethoxyphenyl or 2- Naphthyl and R1-R4 mean hydrogen, fluorine, nitro or trifluoromethyl or R2 and R3 together form a benzene ring. The following are examples of preferred compounds: 4-methoxy-N- (4-naphthalen-2-yl-thiazol-2-yl) -benzenesulfonamide, 4-amino-N- [4- (3-nitro-phenyl) ) -thiazol-2-yl] -benzenesulfonamide, 4-methyl-N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide, 3,4-dimethoxy-N- [ 4- (3-nitro-phenyl) thiazol-2-yl] benzenesulfonamide, 4-methoxy-N- [4- (3-nitro-pheny1) -thiazol-2-yl] benzenesulfonamide, [4- ( 3-Nitro-phenyl) -thiazol-2-yl] -amide of naphthalene-2-sulfonic acid, N- [4- (2-fluoro-5-trifluoromethyl-phenyl-thiazol-2-yl] -4-methy1- benzenesulfonamide, N- [4- (3-fluoro-5-trifluoromethyl-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide, 4-methyl-N- [4- (4-nitro-phenyl) -thiazole -2-yl] -benzenesulfonamide, 4-amino-N- [4- (2-fluoro-5-trifluoromethyl-phenyl) -thia-zol-2-yl] -benzenesulfonamide and 3,4-dimethoxy-N- [4- (2-fluoro-5-trifluoromethyl-phenyl) -thiazol-2-yl] -benzenesulfonamide The term "alkyl" used in the present description denotes saturated straight or branched chain hydrocarbon groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl and the like. The term "lower" denotes in this connection 1-7 carbon atoms, preferably 1-4. The term "alkoxy" denotes an alkyl group in the sense of the preceding definition linked via an oxygen atom. The term "leaving group" used in the present disclosure preferably includes metal-alkyl groups such as tributyltin or metal halogen groups such as, for example, the zinc chloride group or a boric acid group. "Halogen" means fluorine, chlorine, bromine or iodine. The new compounds that fall under the general formula I, ie compounds of general formulas IA-IE, and their salts are also an object of the invention: wherein RÍ-R 4 has the meaning indicated above, R 5 signifies hydrogen or lower alkyl, R 6 signifies hydrogen, lower alkyl, lower alkoxy, cycloalkyl or benzyl and n means 0 or 1 and wherein R ^ and R * > together they can form a methylene dioxyl group, and with the proviso that R5 and R ^ can not simultaneously be hydrogen; wherein R7-R ^ signify hydrogen, halogen, lower alkoxy or 4-N02 ~ phenoxy, with the proviso that at least one of R7-R9 is halogen; wherein R 10 signifies amino or -NHCOR 12, R 12 signifies lower alkyl, R 1, R 3 and R 4 have the meaning indicated above and R 0 signifies hydrogen, hydroxyl, nitro, cyano, amino, trifluoromethyl, benzyloxy or phenyl, optionally substituted by one or more substituents of lower alkyl, trifluoromethyl, nitro, amino or hydroxyl, and R11 and R3 together can form a phenyl ring; where R -R4 and R-1-2 have the meaning indicated above; where RÍ-R4 and R12 have the meaning indicated above. The novel compounds of formula I can be prepared according to the invention a) by reacting a compound of the general formula with an appropriate sulfonyl halide of the general formula S02X III wherein R and R ^ -R4 have the meaning indicated above and X means halogen, or b) dissociating the protecting group of a compound of the general formula wherein R ^ -R4 has the meaning indicated above and R ^ -3 means a sulfonamide protecting group, or c) by reacting a compound of the general formula O R \ V NH-C-NH2 where R has the meaning indicated above, with an appropriate compound of the general formula wherein R ^ -R4 and X have the meaning indicated above, to give a thiazole derivative of formula I, or d) by reacting an appropriate compound of formula IV wherein R2 or R3 mean bromine or iodine and R and / or R4 is / is different from bromine or iodine with a compound of the general formula wherein L means an appropriate leaving group and R ^ -4 are the same or different and mean lower alkyl, lower alkoxy, trifluoromethyl, nitro, amino or hydroxyl, or e) hydrolyzing a compound of the general formula I wherein R means phenyl substituted by lower alkylcarbonylamino and R ^ -R4 have the meaning indicated above to a compound of general formula I wherein R means phenyl substituted by amino, and f) if desired, converting a compound of general formula I into a pharmaceutically acceptable salt. According to variant a) of the process, a compound of general formula II is treated with a corresponding sulfonyl halide of formula III and stirred for several hours in the presence of pyridine. The following are especially well suited as sulfonyl halides: p-toluenesulfonyl chloride, p-methoxybenzenesulfonyl chloride, p-Cl-benzenesulfonyl chloride, 3,4-dichlorobenzenesulfonyl chloride, benzo- [1, 3] dioxol chloride -5-sulfonyl, 5-isopropyl-pyridine-2-sulfo-nyl chloride, 3,5-dichloro-4-nitrophenoxy-benzoyl chloride, naphthalene-2-sulfonyl chloride, 4-cyclohexyl-benzenesulfonyl chloride, chloride of 4-isopropyl-benzenesulfonyl, 4-acetamino-benzenesulfonyl chloride, 3,4-dimethoxy-benzenesulfonyl chloride, 5-tert-butyl-thiophene-2-sulfonyl chloride, butanesulfonyl chloride and the like. according to variant b) of the process, a compound of the general formula IV is deprotected. Suitable protecting groups and methods for dissociation will be familiar to one of ordinary skill in the art, with preferred protective groups being those that can be dissociated by methods involving conditions under which other structural elements are not affected in the compounds of formula IV. »All known sulfonamide protecting groups are suitable as the sulfonamide protecting group, with the methoxymethylene group (MOM) being preferred. The dissociation is carried out in the acidic range, for example by the addition of hydrochloric acid. Variant c) of the process, wherein a compound of formula V and a compound of formula VI react together to form the thiazole ring, represents another possibility for the preparation of compounds of formula I. Conveniently, a compound of Appropriately substituted sulfonyl thiourea dissolved in an alcohol, for example ethanol, with an appropriate 2-halo-1-phenyl-1-ethanone compound and the reaction mixture is boiled for a short period. According to variant d) of the process, a compound of general formula IV is reacted with a compound of general formula VII. Conveniently this reaction is carried out in the presence of a catalyst, for example tetrakis (triphenylphosphine) -palladium and lithium chloride with an aryl metal compound, for example phenylboronic acid, in the presence of potassium carbonate. Toluene is conveniently used as the solvent. Compounds of formula I are obtained wherein R2 is phenyl optionally substituted by one or more substituents of lower alkyl, lower alkoxy, trifluoromethyl, nitro, amino or hydroxyl. The salt formation according to variant f) of the process according to the invention is carried out according to methods which are generally customary and which will be familiar to any person skilled in the art. The basic compounds of formula I can be converted into pharmaceutically acceptable acid addition salts, for example with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, citric acid, p-toluenesulfonic acid and the like. The acidic compounds of formula I can form pharmaceutically acceptable salts with appropriate bases, for example alkali metal salts such as sodium or potassium salts or alkaline earth metal salts such as magnesium or calcium salts. The starting materials of formulas II, III, IV, V, VI and VII required for the preparation of the compounds of formula I are known compounds or can be prepared analogously to known processes. These reactions will be familiar to any expert in the art. In addition, the pre-paration of some intermediates is described in Example 52-65. Scheme 1 below shows the preparation of compounds of general formula II.

In this scheme, R1-R4 have the meaning indicated above and X means halogen. As indicated above the sulfonamide derivatives of the formula I have valuable pharmacological properties and are therefore suitable for the control or prevention of diseases or conditions that are associated with a malfunction of glutamatergic neurotransmission and / or which leads to an excessive production of quinolinic acid. Kynurenic acid and quinolinic acid, two specific body substances from the pathway of degradation of tryptophan through kynurenine, influence the binding sites of N-methyl-D-aspartate (NMDA) of the glutamate receptor. Changes in the tissue level of these two substances are associated with neurological disorders and psychiatric illnesses. Quinolinic acid is strongly neurotoxic, whereas kynurenic acid exhibits neuroprotective activities. The enzyme quinurenin-3-monooxy-genase (quinurenin-3-hydroxylase) is responsible for the conversion of kynurenine into 3-hydroxyquinurenine, a precursor of quinolinic acid, in the tryptophen degradation pathway. The inhibitors of this enzyme on the one hand reduce the formation of the neurotoxin quinolinic acid and on the other hand lead to an increased formation of the kynurenic acid with neuroprotective activity through the increased availability mediated by inhibition of kynurenine. The compounds according to the invention have as quinurenin-3-hydroxylase inhibitors a higher activity than known inhibitors such as m-nitrobenzoylalanine, 3,4-dichlorobenzoylalanine and / or nicotinilalanine. The compounds according to the invention are active in rodents not only after intraperitoneal injection, but also after oral administration. Determination of quinurenin-3-hydroxy1ase in vitro ex vivo The quinurenin-3-hydroxylase inhibitory activity of the compounds according to the invention can be determined in vitro and ex vivo using standard methods. The preparations to be tested were examined in the tests described below, which are based on the methods published by J.B. Erickson, E.M. Flanagan, S. Russo and J.F. Reinhard [Anal. Biochem. 1992, 205: 257-262). In vitro: The enzyme source is a mitochondrial preparation of crude rat kidney that, taken in the ratio of 1:70 (weight / volume) in a potassium phosphate buffer of pH 7.4, containing EGTA, is maintained in the state frozen at -80 ° C until used. The enzymatic test for the in vitro determination differs from the ex vivo determination described below with the use of the aforementioned mitochondrial preparation instead of tissue homogenates as an enzymatic source and by pre-incubation of the enzyme with the substances to be tested at 37 ° C for 15 minutes. ex vivo: The substances to be tested are administered orally to male rats of 100-140 g of body weight in a dose of 30 umol / kg. The kidneys and a part of the liver that is decapitated after 2 hours are separated from the animals and frozen at -80 ° C until they are used. In order to measure the enzymatic activity, the organs are homogenized in the ratio 1:10 (weight / volume) in sucrose, containing TRIS / HC1, pH 7.4 and PMSF. Measurement of enzyme activity Schematic of a typical procedure carried out in an appropriately sized incubation tube or on a microtitre plate: - 25 μl of the substance to be tested in an appropriate concentration (in vitro) or homogenization buffer ( ex vivo) - 25 μl of 0.2 M potassium phosphate buffer containing 0.4 units of glucose-6-phosphate dehydrogenase - 25 μl of the mitochondrial preparation (in vitro) or of the kidney or liver homogenate (ex vivo) - pre -incubation: 15 min at 37 ° C (only in vitro) - 25 ul of the substrate L-kynurenine containing L-3 H -3-kynurenine (0.1 uCi) 100 μmol, magnesium chloride 4 mmol, NADPH 200 umol, glucose-6-phosphate 3 mmol (concentration data as final concentrations) - incubation: 10 min (in vitro) or 2 min (ex vivo) at 37 ° C on a shaker - 150 μl of a 10% suspension of activated carbon (norit A) in water (to separate substrate labeled unreacted) - shaking for about one minute - centrifugation for 4 minutes at 4000 revolutions / min - transfer of 50 μl of the carbon-free supernatant in a counting vessel - addition of 150 μl of an appropriate scintillator for count the radioactivity of the water now tritiated, which is a measurement of the enzymatic activity that exists. The IC50 value is a measurement of the resistance of the in vitro enzymatic inhibition that is provided by the tested substances. It is the concentration of the test substance that provides an inhibition of approximately 50% of the enzymatic activity. The ED50 value or, when this is not obtained, the percentage of inhibition after administration of a single dose, is a measure of the resistance of the ex vivo enzymatic inhibition that is provided by the tested substances. The ED50 value is the dose of the test substance that leads to 50% enzyme inhibition in the tissue homogenates investigated.

Example n °% control a | Control% IC50 DE50 Mol / kg compound 1 μM [μMI 30 M / kg p.o. p.o. in the liver liver 3 0.04 43.00 A 6 4.58 O.Odd 54.00 B 8 5.00 0.044 23.00 9.0 C 4. 00 0.03 20.00 D 21 2.00 0.026 10.00 4.7 E 32 2.50 0.043 17.0 F 41 18.00 0.050 17.0 G 42 1.40 0.015 4.6 H 46 4.70 0.022 5.3 I A 4-Methyl-N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide B N- [4- (3,4-dimethoxy-phenyl) -thiazole-2-yl] 4-Methyl-benzenesulfonamide C 4-methoxy-N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide D [4- (3-nitro-phenyl) -thiazole-2- il) -naphthalene-2-sulfonic acid amide E 3,4-dimethoxy-N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide F N- [4- (2-fluoro- 5-trifluoromethyl-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide G N- [4- (2-fluoro-5-trifluoromethyl-phenyl) -thiazol-2-yl] -4-methoxy- benzenesulfonamide H 4-amino-N- [4- (2-fluoro-5-trifluoromethyl-phenyl) -thia-zol-2-yl] -benzenesulfonamide I 3,4-dimethoxy-N- [4- (2-fluoro- 5-trifluoromethyl-phenyl) -thiazol-2-yl] -benzenesulfonamide As indicated above some new compounds also have antibacterial activity, for example against Staphylococcus aureus and Streptococcus pyogenes. From the following Table it will be apparent that the antibacterial activity of two chosen compounds is comparable with that of the known antibacterial compound sulfamethoxazole (SMZ). In addition, the comparison was made with trimethoprim (TMP). ?to Method for the determination of antibacterial activity The minimum inhibitory concentration (MIC in μg / ml) was determined with the microdilution method where an Isosensotest tracing (Oxoid) was used and supplemented with 3% horse blood for Streptococcus and Listeria. The inoculation amount was approximately 5 x 10 5 CFU / ml. After incubation at 37 ° C for 18 hours the plates were evaluated at 650 nm. The MIC was determined as the lowest concentration of active substance that provided a growth inhibition of = 80% compared to the control. The compounds of the formula I and their pharmaceutically acceptable salts can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be carried out rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions.

The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts and the like can be used, for example, as carriers such as tablets, coated tablets, dragees and hard gelatine capsules. Suitable vehicles for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active ingredient, however, vehicles are not usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Coadjuvants such as alcohols, polyols, glycerol, vegetable oils and the like can be used, for aqueous injection solutions of water-soluble salts of compounds of formula I, but are usually not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like. The pharmaceutical preparations may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

As indicated above, medicaments containing a new compound of formula I or a respective pharmaceutically acceptable salt and a therapeutically inert excipient are also the subject of the present invention, in addition to a process for the production of these medicaments comprising administering galenic form to one or more of the novel compounds of formula I or their pharmaceutically acceptable salts and, if desired, one or more other therapeutically valuable substances together with one or more therapeutically inert carriers. The dosage can vary within wide limits and will, of course, be adjusted to the individual requirements in each particular case. In general, in the case of intravenous administration, a daily dose of about 1 mg to 1000 mg should be appropriate. The object of the invention in its broadest aspect is, as indicated above, the use of compounds of formula I and their pharmaceutically usable salts in the control or prevention of neurodegenerative diseases, neurological disorders resulting from an activation of the immune system or diseases psychiatrists and, respectively, for the production of corresponding medicines. The following examples illustrate the present invention in greater detail, but do not limit its scope in any way. EXAMPLE 1 N- [4- (4-Hydroxy-3-methyl-phenyl) -thiazol-2-yl] -4-methyl-benzenesulphonamide A solution of 26 g of 4-toluenesulfonyl-thiourea in 225 ml of ethanol with 25.9 g of 2-bromo-l- (4-hydrox? -3-methyl-phenyl) -ethanone was allowed to stand at room temperature for 3 days and then boiled for a short period. The reaction mixture was evaporated to dryness in vacuo and then partitioned between water and ethyl acetate. The aqueous phase was extracted once with ethyl acetate, the organic phases were combined, dried with sodium sulfate and concentrated. The residue was chromatographed on 500 g of Keselgel 60 with ethyl acetate / hexane (1: 1) as the eluent. The fractions containing product were concentrated and, after recrystallization from 50% ethanol, gave 10.1 g of N- [4- (4-hydroxy-3-methyl-phenyl) -thiazol-2-yl] -4-methyl -benzenesulfonamide in the form of colorless crystals. Melting point 168-170 ° C (dec). EXAMPLE 2 N- [4- (3-cyano-phenyl) -thiazol-2-yl] -4-methyl-benzenephonamide A mixture of 0.5 g of 3- (2-amino-thiazol-4-yl) -benzonitrile With 0.52 g of p-toluenesulfonyl chloride, it was stirred overnight with 2 ml of pyridine. The resulting red suspension was poured into 50 ml of IN hydrochloric acid and the solid thus separated was filtered off and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. The product was separated after neutralization with concentrated hydrochloric acid. Recrystallization from 80 ml of 50% ethanol gave 0.35 g of N- [4- (3-cyano-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide as colorless crystals.

Melting point: > 250 ° C. EXAMPLE 3 4-Methyl-N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide A mixture of 0.5 g of 4- (3-nitro-phenyl) -thiazole-2 hydrochloride -amine with 0.42 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red suspension was poured into 50 ml of IN hydrochloric acid and the solid thus separated was filtered off and dissolved in a mixture of 109 ml of ethanol and 10 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. The product was separated after neutralization with concentrated hydrochloric acid. Recrystallization from 40 ml of 50% ethanol gave 0.35 g of N-methyl-N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide as yellowish crystals. Melting point: 187-189 ° C. EXAMPLE 4 N- [4- (4-benzyloxy-3-methoxy-phenyl) -thiazol-2-yl) -benzenesulfonamide A mixture of 0, 5 g of 4- (4-benzyloxy-3-methoxy-phenyl) -thiazol-2-ylamine hydrobromide with 0.27 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red solution was poured into 50 ml of IN hydrochloric acid and extracted three times with 50 ml of methylene chloride each time. The organic extracts were combined, dried with magnesium sulfate and concentrated. The residue was chromatographed on 40 g of Kieselgel 60 with diethyl ether / hexane (2: 1) as the eluent. The concentration of the fractions containing product gave 0.35 g of N- [4- (4-benzyloxy-3-methoxy-phenyl) -thiazol-2-yl) -benzenesulfonamide as colorless crystals. Melting point: 152-155 ° C. EXAMPLE 5 N- [4- (3, 4-bis-benzyloxy-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide A mixture of 0.5 g of hydrobromide of 4- (3,4- bis-benzyloxy-phenyl) -thiazole-2-ylamine with 0.23 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red solution was poured into 50 ml of IN hydrochloric acid and extracted three times with 50 ml of methylene chloride each time. The organic extracts were combined, dried with magnesium sulfate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 15 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. The product was then separated by neutralization with concentrated hydrochloric acid, recrystallization from 50 ml of 60% ethanol gave 0.33 g of N- [4- (3,4-bis-benzyloxy-phenyl) -thiazole-2-. il] -4-methyl-benzenesulfonamide in the form of colorless crystals Melting point: 185-161 ° C. EXAMPLE 6 N- [4- (3,4-dimethoxy-phenyl) -thiazole-2-yl] -4- methyl-benzenesulfo-namide A mixture of 0.5 g of 4- (3, -dimethoxy-phenyl) -thiazole-2-ylamine hydrobromide with 0.33 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml. The resulting red solution was poured into 50 ml of IN hydrochloric acid and extracted three times with 50 ml of methylene chloride each time, the organic extracts were combined, dried with magnesium sulfate and concentrated. The residue was chromatographed on 35 g of Kieselgel 60 with diethyl ether as the eluent, the fractions containing product were concentrated, dissolved in 40 ml of 50% ethanol by addition of a the amount of 2N sodium hydroxide solution was precipitated and precipitated with 2N hydrochloric acid at pH 6. 0.4 g of N- [4- (3,4-dimethoxy-phenyl) -thiazol-2-yl] -4- was obtained. methyl-benzenesulfonamide in the form of colorless crystals. Melting point: 85-87 ° C (dec). EXAMPLE 7 N- [4- (4-methoxy-3-methyl-phenyl) -thiazol-2-yl-1-4-methyl-benzenesulfonamide A mixture of 0.5 g 4- (4-methoxy-3- hydrobromide. methyl-phenyl) -thiazole-2-ylamine with 0.5 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red color solution was poured into 50 ml of IN hydrochloric acid and the solid which was thus segregated was filtered off and dissolved in a hot mixture of 20 ml of etnaol and 50 ml of water. After cooling, 0.006 g of N- [4- (4-methoxy-3-methyl-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide were separated in the form of beige crystals. Melting point: 94-96 ° C.

EXAMPLE 8 4-methoxy-N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide A mixture of 0.5 g of 4- (3-nitro-phenyl) -thiazole-2 hydrochloride -amine with 0.44 g of 4-methoxybenzene-sulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red suspension was poured into 50 ml of IN hydrochloric acid and the solid thus segregated was filtered off and dissolved in a mixture of 40 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. The product was separated after neutralization with concentrated hydrochloric acid. Recrystallization from 40 ml of 50% ethanol gave 0.31 g of 4-methoxy-N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide as yellowish crystals. Melting point: 157-159 ° C. EXAMPLE 9 4-Chloro-N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide A mixture of 0.5 g of 4- (3-nitro-phenyl-1-thiazole-2-hydrochloride -amine with 0.45 g of 4-chlorobenzenesulfonyl chloride was stirred overnight with 2 ml of pyridine, the resulting red suspension was poured into 50 ml of hydrochloric acid, and the solid which was thus segregated. it was separated by filtration and dissolved in a mixture of 40 ml of ethanol and 20 ml of 2N sodium hydroxide solution After the addition of 0.5 g of activated carbon, the mixture was stirred at room temperature. > for 30 minutes and then separated by filtration • > active carbon. The product was separated after neutralization with concentrated hydrochloric acid. Recrystallization from 40 ml of 50% ethanol gave 0.43 g of 4-chloro-N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide as colorless crystals. Melting point: 195-197 ° C. EXAMPLE 10 3, 4-dichloro-N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide A mixture of 0.5 g of 4- (3-nitro-phenyl) -thiazole hydrochloride -2-ylamine with 0.52 g of 3,4-dichloro-benzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red suspension was poured into 25 ml of IN hydrochloric acid and the solid thus segregated was filtered off and dissolved in a mixture of 30 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. The product was separated after neutralization with concentrated hydrochloric acid. Recrystallization from 80 ml of 50% ethanol gave 0.39 g of 3,4-dichloro-N- [4- (3-nitrophenyl) -thiazol-2-yl] -benzenesulfonamide in the form of yellowish crystals. Melting point: 189-191 ° C. EXAMPLE 11 Benzo [1,3] -d? -oxo-5-sulfonic acid [4- (3-nitro-phenyl) -thiazol-2-yl] -amide A mixture of 0.5 g of 4- hydrochloride (3-nitro-phenyl) -thiazol-2-ylamine with 0.52 g of benzo [1,3] dioxol-5-sulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red suspension was poured into 25 ml of IN hydrochloric acid and the solid thus segregated was filtered off and dissolved in a mixture of 30 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. The product was separated after neutralization with concentrated hydrochloric acid. Recrystallization from 100 ml of 60% ethanol gave 0.30 g of benzo [1,3] dioxol-5-sulfonic acid [4- (3-nitro-phenyl) -thiazol-2-yl] -amide in the form of yellowish crystals. Melting point: 221-224 ° C. EXAMPLE 12 [4- (3-nitro-phenyl) -thiazol-2-yl] -amide of 5-isopropyl-pyridine-2-sulfonic acid A mixture of 0.5 g of 4- (3-nitro-phenyl) hydrochloride ) -thiazole-2-ylamine with 0.46 g of 5-isopropyl-pyridine-2-sulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red suspension was poured into 25 ml of IN hydrochloric acid and the solid thus segregated was filtered off and dissolved in a mixture of 30 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0, 5 g of activated charcoal was stirred at room temperature for 30 minutes and then activated carbon was filtered off. The product was separated after neutralization with concentrated hydrochloric acid. Recrystallization from 40 ml of ethanol and 20 ml of ethyl acetate gave 0.31 g of 5-isopropylpyridine-2-sulfonic acid [4- (3-nitro-phenyl) -thiazole-2-ylamide in the form of yellowish crystals. . Melting point: 208-210 ° C. EXAMPLE 13 3, 5-Dichloro-4- (4-nitro-phenoxy) -N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide A mixture of 0.26 g of hydrochloride of 4 - (3-nitro-phenyl) -thiazol-2-ylamine with 0.42 g of 3,5-dichloro-4-nitro-phenoxybenzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The red-colored suspension was poured into 50 ml of IN hydrochloric acid and the solid thus separated was filtered off and dissolved in a mixture of 50 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. The product was separated after neutralization with concentrated hydrochloric acid, recrystallization from 50 ml of ethanol and 20 ml of ethyl acetate gave 0.11 g of 3,5-dichloro-4- (4-nitro-phenoxy) -N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide in the form of yellowish crystals. Melting point: >250 ° C. EXAMPLE 14 N- [4- (4-chloro-phenyl) -thiazol-2-yl) -4-methyl-benzenesulfonamide A mixture of 0.3 g of 4- (4-chlorophenyl) -thiazole-2-ylamine hydrobromide. with 0.22 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red suspension was poured into 30 ml of IN hydrochloric acid and the solid thus segregated was filtered off and dissolved in a hot mixture of 20 ml of ethanol and 30 ml of water. Upon cooling, 0.05 g of N- [4- (4-chlorophenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide was separated in the form of colorless crystals. Melting point: 237-239 ° C. EXAMPLE 15 N- [4- (4-bromo-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide A mixture of 4.0 g of 4- (4-bromophenyl) -thiazole-2-ylamine hydrobromide. with 2.5 g of p-toluenesulfonyl chloride was stirred overnight with 15 ml of pyridine. The resulting red suspension was poured into 180 ml of IN hydrochloric acid and the solid thus segregated was separated by filtration and chromatographed on 100 g of Kieselgel 60 with diethyl ether / hexane / methylene chloride (1: 1: 1) as the eluent The fractions containing product were concentrated and the residue was recrystallized two times in 60% ethanol. 0.8 g of N- [4- (4-bromophenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide was separated in the form of colorless crystals with cooling. Melting point: 227-230 ° C EXAMPLE 16 N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide A mixture of 0.5 g of 4- (3-nitro-phenyl) hydrobromide ) -thiazole-2-ylamine with 0.21 g of benzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red suspension was poured into 25 ml of IN hydrochloric acid and the solid thus segregated was filtered off and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then filtered off from the activated carbon. The product after neutralization was separated as an oil and then treated again with activated charcoal. The product was separated after neutralization renewed with concentrated hydrochloric acid. Recrystallization from 10 ml of 50% ethanol gave 0.06 g of N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide as yellowish crystals. Melting point: 141-142 ° C. EXAMPLE 17 4-Cyclohexyl-N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide A mixture of 0.5 g of 4- (3-nitro-phenyl) -thiazole-2-hydrobromide. -amine with 0.46 g of 4-cyclohexyl-benzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red suspension was poured into 25 ml of IN hydrochloric acid and the organic phase was separated and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and < * then activated carbon was filtered off. After neutralization, the product was separated in the form of an oil. Then 20 ml of ethanol were added, the mixture was boiled and the insoluble material was filtered off. With cooling, the crystals were separated and, after crystallization in 40 ml of 50% ethanol, 0.15 g of 4-cyclohexyl-N- [4- (3-nitro-phenyl) -thiazol-2-yl] was obtained. -benzenesulfonamide in the form of beige crystals.Melting point: 180-182 ° C. EXAMPLE 18 4-Isopropyl-N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide A mixture of 0.5 g of 4- (3-nitro-phenyl) -thiazole-2-hydrobromide. -amine with 0.36 g of 4-isopropyl-benzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red color was poured into 25 ml of IN hydrochloric acid and the organic phase was separated and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. The product was separated in the form of an oil after neutralization. The mixture was then boiled with 0.5 g of active carbon and the activated carbon and the insoluble constituents were separated or filtered. The crystals were separated with cooling, and, after recrystallization from 40 ml of 50% ethanol, gave 0.17 g of 4-isopropyl-N- [4- (3-nitro-phenyl) -thiazole-2-yl. ] -benzenesulfonamide in the form of colorless crystals. Melting point: 144-145 ° C. EXAMPLE 19 4-Methyl-N- [4- (4-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamy A A mixture of 0.5 g of 4- (4-nitro-phenol) hydrobromide - thiazol-2-ylamine with 0.35 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red suspension was poured into 30 ml of IN hydrochloric acid and the mixture was extracted three times with 100 ml of ethyl acetate each time. The organic phases were combined, dried with magnesium sulfate and the solvent was separated on a rotary evaporator. The residue was chromatographed on 60 g of Kieselgel 60 with diethyl ether / ethyl acetate (1: 1) as the eluent. The fractions containing the product were concentrated and the residue was digested with a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. The product was separated after neutralization of the filtrate with concentrated hydrochloric acid. Recrystallization from 50 ml of 60% ethanol gave 0.10 g of 4-methyl-N- [4- (4-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide in the form of yellowish crystals. Melting point: > 250 ° C. EXAMPLE 20 N-. { 4- [4- (3-nitro-phenyl) -thiazol-2-ylsulfamoyl] -phenyl} acetamide A mixture of 0.5 g of 4- (3-nitro-phenyl) -thiazole-2-ylamine hydrobromide with 0.43 g of 4-acetamino-benzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red suspension was poured into 30 ml of IN hydrochloric acid and the solid thus segregated was filtered off and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. After neutralization with concentrated hydrochloric acid, 0.60 g of N- were separated. { 4- [4- (3-nitro-phenyl) -thiazol-2-ylsulfamoyl] -phenyl} -acetamide in the form of yellowish crystals. Melting point: > 250 ° C.

EXAMPLE 21 3, 4-dimethoxy-N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide A mixture of 0.5 g of hydrobromide of 4% was stirred overnight with 2 ml of pyridine. - (3-nitro-phenyl) -thiazole-2-ylamine with 0.43 g of 3,4-dimethoxy-benzenesulfonyl chloride. The resulting red suspension was poured into 30 ml of IN hydrochloric acid and the organic phase was separated and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. After neutralization, the product was separated in the form of an oil and then treated once more with activated carbon. The product was separated after further neutralization with concentrated hydrochloric acid. Recrystallization from 25 ml of 60% ethanol gave 0.12 g of 3,4-dimethoxy-N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide as colorless crystals. Melting point: 185 ° C. EXAMPLE 22 [4- (3-nitro-phenyl) -thiazole-2-y1] -amide of 5-tert-butyl-thiophene-2-sulfonic acid A mixture of 0, 5 g of 4- (3-nitro-phenyl) -thiazol-2-ylamine hydrobromide with 0.43 g of 5-ger-butyl-thiophene-2-sulfonyl chloride was stirred overnight with 2 ml of pyridine. . The resulting red suspension was poured into 30 ml of IN hydrochloric acid and the mixture was extracted three times with 30 ml of ethyl acetate each time. The organic phases were combined, dried with magnesium sulfate and the solvent was separated on a rotary evaporator. The residue was chromatographed on 50 g of * < Kieselgel 60 with ethyl acetate / hexane (1: 2) as the eluent. The fractions containing product were concentrated and the residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of activated carbon the mixture was stirred at room temperature '< for 30 minutes and then activated carbon was filtered off. After neutralization with concentrated hydrochloric acid and repeated boiling, 0.20 g of [4- (3- (10-nitro-phenyl) -thiazol-2-yl] -amide of 5-tert-butyl-thiophene was separated off. 2- sulfonic. * Melting point: 176-178 ° C. EXAMPLE 23 N- [4- (4-Methoxy-phenyl) -thiazole-2-yl-4-methyl-benzenesulfonamide I A mixture of 0.5 g of 4- (4-methoxy-phenyl) -thiazole-2-hydrobromide. -amine with 0.37 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red color suspension was poured into 30 ml of g & amp; hydrochloric acid and the mixture was extracted twice with 40 ml of ethyl acetate each time. The organic phases were combined, dried with magnesium sulfate and the solvent was removed on a rotary evaporator. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of activated carbon, the The mixture was mixed at room temperature for 30 minutes and then activated carbon was filtered off. The product was separated after neutralization with concentrated hydrochloric acid. Recrystallization from 30 ml of 50% ethanol gave 0.24 g of N- [4- (4-methoxyphenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide as beige crystals. Melting point: 85-88 ° C (dec). EXAMPLE 24 4-Methyl-N- [4- (3-trifluoromethyl-phenyl) -thiazol-2-yl-3-benzenesulfonamide A mixture of 0.5 g of 4- (3-trifluoromethyl-phenyl) -thiazole-2- hydrobromide. Ilamine with 0.42 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red suspension was poured into 30 ml of IN hydrochloric acid and the mixture was extracted twice with 40 ml of ethyl acetate each time. The organic phases were combined, dried with magnesium sulfate and the solvent was separated on a rotary evaporator. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of activated carbon, the mixture was stirred at room temperature for 309 minutes and then activated carbon was filtered off. After neutralization with centric-concentrated hydrochloric acid, 0.23 g of 4-methyl-N- [4- (3-trifluoromethyl-l-phenyl) -thiazol-2-yl] -benzenesulfonamide was separated in the form of colorless crystals. Melting point: 157-159 ° C. EXAMPLE 25 4-Methyl-N- [4- (4-methyl-phenyl) -thiazol-2-yl] -benzenesulfonamide A mixture of 0.5 g of 4- (4-methyl-phenyl) -thiazole-2-hydrobromide. -amine with 0.39 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red suspension Li was poured into 30 ml of IN hydrochloric acid and the mixture was extracted twice with 50 ml of ethyl acetate each time. The organic phases were combined, dried with magnesium sulfate and the solvent was separated on a rotary evaporator. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. After neutralization with concentrated hydrochloric acid, 0.46 g of 4-methyl-N- [4- (4-methylphenyl) -thiazol-2-yl] -benzenesulfonamide was obtained in the form of colorless crystals. Melting point: 186-189 ° C. EXAMPLE 26 4-Methyl-N- [4- (2-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide A mixture of 0.5 g of 4- (2-nitro-phenyl) -thiazole-2-hydrobromide. -amine with 0.47 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red suspension was poured into 30 ml of IN hydrochloric acid and extracted twice with 40 ml of ethyl acetate each time. The organic extracts were combined, dried with magnesium sulfate and concentrated. The residue was dissolved in a mixture of 30 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. After neutralization with concentrated hydrochloric acid and boiling, 0.58 g of 4-methyl-N- [4- (2-nitrophenyl) -thiazol-2-yl] -benzenesulfonamide was separated in the form of yellow crystals with cooling. Melting point: 172-174 ° C. EXAMPLE 27 4-Methyl-N- (4-naphthalen-1-yl-thiazolo-2-yl) -benzenesulfonamide. A mixture of 0.5 g of 4- (1-naphthyl) -thiazole-2-ylamine hydrobromide with 0.34 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red suspension was poured into 30 ml of IN hydrochloric acid and extracted twice with 40 ml of ethyl acetate each time. The organic extracts were combined, dried with magnesium sulfate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. The product was separated after neutralization with concentrated hydrochloric acid. Recrystallization from 60 ml of 50% ethanol gave 0.46 g of 4-methyl-N- (4-naphthalen-1-yl-thiazol-2-yl) -benzenesulfonamide as colorless crystals. Melting point 196-197 ° C. EXAMPLE 28 N- [4- (3,4-dichloro-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide A mixture of 0.5 g of 4- (3,4-dichlorophenyl) hydrobromide) -thiazole-2-ylamine with 0.50 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red suspension was poured into 30 ml of IN hydrochloric acid and the solid thus separated was filtered off and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. 0.33 g of N- [4- (3, -dichloro-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide was obtained as colorless crystals after neutralization with concentrated hydrochloric acid. Melting point: 205-206 ° C EXAMPLE 29 N- [4- (2,4-dichloro-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide A mixture of 0.5 g of 4- (2,4-dichloro-phenyl) -thiazole-2-ylamine hydrobromide with 0.32 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red suspension was poured into 30 ml of IN hydrochloric acid and extracted three times with 40 ml of ethyl acetate each time. The organic extracts were combined, dried with magnesium sulfate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. After neutralization with concentrated hydrochloric acid, 0.50 g of N- [4- (2,4-dichloro-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide was removed. Melting point: 218-219 ° C. EXAMPLE 30 N- [4- (3-Bromo-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide A mixture of 0.5 g of 4- (3-bromo-phenyl) -thiazole-2 hydrobromide. -amine with 0.31 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red suspension was poured into 30 ml of IN hydrochloric acid and the solid secreted in this way was filtered off and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. After neutralization with concentrated hydrochloric acid, 0.40 g of N- [4- (3-bromo-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide was separated in the form of colorless crystals. Melting point: 199-200 ° C. EXAMPLE 31 4-amino-N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide 0.47 g of N- was suspended. { - [4- (3-nitro-phenyl) -thiazol-2-yl-sulfamoyl] -phenyl} -acetamide in 10 ml of hydrochloric acid cN and was heated to boiling overnight. The cooled mixture was treated with 35 ml of sodium hydroxide solution 2. After the addition of 0.4 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. The product was separated after neutralization with concentrated hydrochloric acid. Recrystallization from 50 ml of 40% etabnol and 0.16 g of 4-amino-N- [4- (3-nitro-phenyl) -thiazol-2-yl] benzenesul f (-namide in the form of yellowish crystals. Melting point 191-193 ° C.

EXAMPLE 32 N- [4- (2-Fluoro-5-trifluoromethyl-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide A mixture of 0.5 g of 4- (2-fluoro-5-hydrobromide) trifluoromethylphenyl) -thiazole-2-ylamine with 0.30 g of p-toluenesulfonyl chloride was stirred for 3 hours with 2 ml of pyridine. The resulting red suspension was poured into 30 ml of IN hydrochloric acid and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulfate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.3 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. 0.36 g of N- [4- (2-fluoro-5-trifluoromethyl-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide was separated in the form of colorless crystals after neutralization with concentrated hydrochloric acid. Melting point 136-140 ° C EXAMPLE 33 4-benzyloxy-N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide A mixture of 0.5 g of 4- (3-nitro-phenyl) -thiazol-2-ylamine hydrobromide with 0.51 g of 4-phenylmethoxy-benzenesulfonyl chloride was stirred overnight with 2 ml of pyridine.

The resulting red suspension was poured into 30 ml of IN hydrochloric acid. The mixture was extracted three times with ethyl acetate. The organic phases were combined, dried with magnesium sulfate and freed of solvent. The residue was boiled with 30 ml of ethyl acetate, the insoluble constituents were filtered off and the solution was treated with boiling with 20 ml of hexane. After cooling 0 was separated, 5 g of 4-benzyloxy-N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide. Melting point: 214-216 ° C EXAMPLE 34 N- [4- (3-nitro-phenyl) -thiazol-2-yl] -C-phenyl-methanesulfonamide A mixture of 0.5 g of hydrobromide of 4- (3 -nitro-phenyl) -thiazole-2-ylamine with 0.35 g of phenylmethanesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red suspension was poured into 30 ml of IN hydrochloric acid and the solid thus segregated was filtered off and dissolved in a mixture of 25 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. After neutralization with concentrated hydrochloric acid, the mixture was concentrated and the aqueous residue was extracted twice with ethyl acetate. The organic phases were combined dried with magnesium sulfate and freed of solvent. The residue was chromatographed on 30 g of Kieselgel 60 with ethyl acetate / hexane (1: 2 as eluent) The fractions containing product were concentrated, recrystallization of the residue from 5 ml of ethyl acetate gave 60 mg of N- [4- (3-nitrophenyl) -thiazol-2-yl] -C-phenyl-methanesulfonamide in the form of colorless crystals Melting point 219-221 ° C EXAMPLE 35 N- [4- (4-cyclohexyl-phenyl) -thiazole-2 -yl] -4-methyl-benzenesulfonamide A mixture of 0.5 g of 4- (4-cyclohexyl-phenyl) -thiazole-2-ylamine hydrobromide with 0.31 g of p-toluenesulphonyl chloride was stirred for 3 hours with 2 ml of pyridine The resulting red suspension was poured into 30 ml of IN hydrochloric acid and the mixture was extracted with ethyl acetate.The organic phase was dried with magnesium sulfate and concentrated. in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution After the addition of 0.5 g of active carbon, the mixture was stirred at room temperature. for 30 minutes and then activated carbon was filtered off. The product was separated in an amorphous form after neutralization with concentrated hydrochloric acid. After chromatography on 70 g of Kieselgel 60 with ethyl acetate / hexane (1: 2) the fractions containing product were concentrated. Recrystallization from 50% ethanol gave 0.22 g of N- [4- (4-cyclohexyl-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide as colorless crystals. Melting point: 197-199 ° C. EXAMPLE 36 N- [4- (3-Fluoro-5-trifluoromethyl-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide A mixture of 0.5 g of 4- (3-fluoro-5- hydrobromide. trifluoromethyl-phenyl) -thiazole-2-ylamine with 0.34 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red suspension was poured into 30 ml of IN hydrochloric acid and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulfate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. After neutralization with concentrated hydrochloric acid, 0.38 g of N- [4- (3-fluoro-5-trifluoromethyl-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide was separated in the form of colorless crystals. Melting point: 165-167 ° C EXAMPLE 37 N- [4- (2-benzyloxy-phenyl) -thiazol-2-yl3-4-methyl-benzenesulfonamide A mixture of 0.5 g of 4- (2- hydrobromide. benzyloxy-phenyl) -thiazole-2-ylamine with 0.29 g of p-toluenesulfonyl chloride was stirred for 2 hours with 2 ml of pyridine. The resulting red color suspension was poured into 30 ml of IN hydrochloric acid and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulfate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. After neutralization with concentrated hydrochloric acid, the mixture was concentrated and the aqueous residue was extracted twice with ethyl acetate. The organic phases were combined, dried with magnesium sulfate and freed of solvent. The residue was chromatographed over 60 g of Kieselgel 60 with ethyl acetate / hexane (1: 2) as the eluent. The product-containing fractions were concentrated and gave 0.28 g of N- [4- (2-benzyloxy-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide as a colorless amorphous solid. NMR (CDC13) ppm: 10.5 (bs, 1H), 7.83 (d, 2H), 7.48 ("d", 1H), 7.34 (m, 6H) 7.25 (d, 2H ), 7.03 ("t", 2H), 6.59 (s, 1H), 5.26 (s, 2H), 2.40 (s, 3H). EXAMPLE 3J3 N- [4- (3-benzyloxy-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide A mixture of 3.0 g of 4- (3-benzyloxy-phenyl) -thiazole-2 hydrobromide -amine with 1.8 g of p-toluenesulfonyl chloride was stirred for 2 hours with 12 ml of pyridine. The resulting red suspension was poured into 100 ml of 2N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulfate and concentrated. The residue was dissolved in a mixture of 120 ml of ethanol and 120 ml of 2N sodium hydroxide solution. After the addition of 2.4 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. After neutralization with concentrated hydrochloric acid, the mixture was concentrated and the aqueous residue was extracted twice with ethyl acetate. The organic phases were combined, dried with magnesium sulfate and freed of solvent. The residue was chromatographed on 300 g of Kieselgel 60 with ethyl acetate / hexane (1: 2) as the eluent. The product-containing fractions were concentrated and gave 2.2 g of N- [4- (3-benzyloxy-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide as a colorless amorphous solid.

NMR (CDCl 3) ppm: 9.6 (bs, 1H), 7.85 (d, 2H), 7.36 (m, 6H) 7.24 (d, 2H), 7.01 (m, 3H), 6.50 (s, 1H), 5.08 (s, 2H), 2.39 (s, 3H). EXAMPLE 39 N- [4- (3-Amino-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide A solution of 1.5 g of 4-methyl-N- [4- (3-nitro-phenyl) ) -thiazol-2-yl] -benzenesulfonamide in 150 ml of methanol and 70 ml of ethyl acetate was hydrogenated at room temperature after the addition of 0.15 g of palladium on active carbon (10%). The catalyst was filtered off and the filtrate was concentrated. Crystallization from ethyl acetate / hexane (1: 1) gave 1.1 g of N- (4- (3-amino-phenyl) -thiazol-2-yl] -4-methylbenzenesulfonamide as a colorless solid Melting point: 180-182 ° C EXAMPLE 40 N- (4-diphenyl-3-yl-thiazol-2-yl) -4-methyl-benzenesulfonamide A solution of 0.29 g of N- (4-diphenyl- 3-yl-thiazol-2-yl) -N-methoxymethyl-4-methyl-benzenesulfonamide in 6 ml of tetrahydrofuran was stirred at room temperature for 6 hours after the addition of 1.5 ml of 6N hydrochloric acid. Reaction mixture was added to 40 ml of water and extracted with ethyl acetate, the organic phases were combined, dried with magnesium sulfate and concentrated, recrystallization from 10 ml of 50% ethanol gave 120 mg of N- (4-). diphenyl-3-yl-t-azol-2-yl) -4-methyl-benzenesulfonamide in the form of colorless crystals PF: 153-155 ° C EXAMPLE 41 N- [4- (2-fluoro-5-trifluoromethyl) -fen l) -thiazol-2-yl] -4-methox? -benzenesulfonamide A mixture of 0.5 g of 4- (2-fluoro-5-trifluoromethyl) hydrobromide phenyl) -thiazole-2-ylamine with 0.33 g of 4-methoxy-benzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red suspension was poured into 30 ml of IN hydrochloric acid and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulfate and concentrated. The residue was dissolved in a mixture of 30 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. The product was separated after neutralization with concentrated hydrochloric acid. Recrystallization from 30 ml of 50% ethanol gave 0.26 g of N- [4- (2-fluoro-5-trifluoromethyl-phenyl) -thiazol-2-yl] -4-methoxy-benzenesulfonamide in the form of colorless crystals. P.F. : 112 ° C, dec. EXAMPLE 42 4-amino-N- [4-2-fluoro-5-trifluoromethyl-phenyl) -thiazol-2-yl] benzenesulfonamide A mixture of 0.5 g of 4- (2-fluoro-5-trifluoromethylphenyl) hydrobromide) -thiazole-2-ylamine with 0.38 g of 4-acetaminobenzenesulfonyl chloride was stirred for 2 hours with 2 ml of pyridine. The resulting red suspension was poured into 30 ml of IN hydrochloric acid and stirred at room temperature for 30 minutes. The secreted solid was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active carbon, the mixture was stirred at room temperature for 30 minutes and then the acivive carbon was filtered off. The 4-acetamino-N- [4- (2-fluoro-5-trifluoromethyl-phenyl) -thiazol-2-yl] -benzenesulfonamide, which was separated after neutralization with concentrated hydrochloric acid, was suspended in 9 ml of hydrochloric acid 6N and boiled for 36 hours. The mixture was cooled, treated with 30 ml of ethanol and neutralized with 2N sodium hydroxide solution. Recrystallization of the product, which was thus separated, from 20 ml of 50% ethanol gave 0.21 g of 4-amino-N- [4- (2-fluoro-5-trifluoromethyl-phenyl) -thiazole-2. -yl] benzenesulfonamide in the form of colorless crystals. Melting point: 150-152 ° C. EXAMPLE 43 N- [4- (4-benzyloxy-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide A mixture of 0.5 g of 4- (4-benzyloxy-phenyl) -thiazole-2 hydrobromide. -amine with 0.29 g of p-toluenesulfonyl chloride was stirred for 4 hours with 2 ml of pyridine. The resulting red suspension was poured into 30 ml of IN hydrochloric acid and the mixture was extracted with methylene chloride. The organic phase was dried with magnesium sulfate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0, 7 g of active charcoal was stirred at room temperature for 30 minutes and then activated carbon was filtered off. After neutralization with concentrated hydrochloric acid, the mixture was concentrated and the residue was chromatographed on 100 g of Kieselgel 60 with diethyl ether as the eluent. The fractions containing product were concentrated and, after recrystallization from ethyl acetate, gave 0.22 g of N- [4- (4-benzyloxy-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide in the form of colorless crystals. Melting point: 166-167 ° C. EXAMPLE 44 4-methoxy-N- (4-naphthalen-2-yl-thiazol-2-yl) -benzenesulfonamide A mixture of 0.5 g of 4- (2-naphthyl) -thiazol-2-ylamine hydrobromide with 0 34 g of 4-methoxy-benzenesulfonyl chloride was stirred for 3 hours with 2 ml of pyridine. The resulting red suspension was poured into 30 ml of IN hydrochloric acid and extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulfate and freed of solvent. The residue was dissolved in a mixture of 25 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. The product was separated after neutralization with concentrated hydrochloric acid. Recrystallization from 10 ml of ethyl acetate and 15 ml of n-hexane gave 0.19 g of 4-methoxy-N- (4-naphthalen-2-yl-thiazol-2-yl) -benzenesulfonamide as colorless crystals. . Melting point: 163-165 ° C. EXAMPLE 45 N- [4- (3,4-Dihydroxy-5-nitro-phene) -thiazol-2-yl] -4-methylbenzenesulfonamide A mixture of 0.24 g of N- (aminothioxomethyl) -4-methyl-benzenesulfonamide and 0.2 g of 2-bromo-l- (3,4-dihydroxy-5-nitrophenyl) ethanone was dissolved in 5 ml of ethanol and boiled under reflux for 1 hour. 0.26 g of N- [4- (3,4-dihydroxy-5-nitrophenyl) -thiazole ^ -yl-methyl-benzenesulfonamide in the form of red crystals was removed on cooling. Melting point: 252-254 ° C (dec). EXAMPLE 46 3,4-dimethoxy-N- [4- (2-fluoro-5-trifluoromethyl-phenyl) -thiazole-2-yl] benzenesulfonamide A mixture of 0.5 g of 4- (2-fluorohydrobromide) 5-trifluoromethyl-phenyl) -thiazol-2-ylamine with 0.38 g of 3,4-dimethoxy-benzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting red suspension was poured into 30 ml of IN hydrochloric acid and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulfate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. After neutralization with concentrated hydrochloric acid, the mixture was concentrated and the residue was chromatographed on 40 g of Kieselgel 60 with ethyl acetate / hexane (1: 1 as the eluent) The fractions containing product were concentrated and, after recrystallization in 15 ml. of 50% ethanol gave 0.16 g of N- [4- (3-fluoro-5-trifluoromethyl-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide in the form of colorless crystals. of fusion: 123-125 ° C.

EXAMPLE 47 3-Bromo-4-methoxy-N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide A mixture of 5.0 g of 4- (3-nitro-phenyl) hydrobromide -thiazole-2-ylamine with 5.2 g of 3-bromo-4-methoxy-benzenesulfonyl chloride was stirred for 3 hours with 20 ml of pirdine. The resulting red suspension was poured into 300 ml of hydrochloric acid in 300 ml of IN hydrochloric acid and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulfate and concentrated. The residue was dissolved in a mixture of 300 ml of ethanol and 200 ml of 2N sodium hydroxide solution. After the addition of 4.5 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. After neutralization with concentrated hydrochloric acid, 4.4 g of 3-bromo-4-methoxy-N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide were separated in the form of yellow crystals. Melting point: 200-202 ° C. EXAMPLE 48 N- [4- (3-Hydroxy-4-methoxy-5-nitro-phenyl) -thiazol-2-yl] -4-methyl-1-benzenesulfonamide 50 mg of sodium hydride (60%) was added to a solution of 0.5 g of N- [4- (3,4-dihydroxy-5-nitro-phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide in 5 ml of dimethylformamide. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate and concentrated. The residue was chromatographed on 60 g of Kieselgel 60 with methylene chloride / acetone / formic acid (90: 10: 2.5) as the eluent. The fractions containing product were concentrated and, after boiling with 20 ml of diethyl ether, gave 0.17 g of N- [4- (3-hydroxy-4-methoxy-5-nitro-phenyl) -thiazole-2-yl. ] -4-methyl-benzenesulfonamide in the form of orange crystals. Melting point: 210-212 ° C. EXAMPLE 49 3,4-Dimethoxy-N- (4-naphthalen-1-yl-thiazol-2-yl) -benzenesulfonamide A mixture of 10 g of 4- (1-naphthyl) -thiazol-2-ylamine hydrobromide with 8 , 5 g of 3,4-dimethoxy-benzenesulfonyl chloride was stirred for 18 hours with 30 ml of pyridine. The resulting red suspension was poured into 400 ml of IN hydrochloric acid. The separated solid was dissolved in a mixture of 400 ml of ethanol and 400 ml of 2N sodium hydroxide solution. After the addition of 8 g of activated carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. After neutralization with concentrated hydrochloric acid, the mixture was concentrated and the residue was taken up in ethyl acetate, dried over magnesium sulfate and concentrated. Crystallization from 200 ml of ethyl acetate gave 11.5 g of 3,4-dimethoxy-N- (4-naphthalen-1-yl-thiazol-2-yl) -benzenesulfonamide as colorless crystals. Melting point: 132-133 ° C EXAMPLE 50 3, -dimethoxy-N- (4-naphthalen-2-yl-thiazol-2-yl) -benzenesulfonamide A mixture of 10 g of 4- (2-naphthyl) hydrobromide -thiazole-2-ylamine with 8.5 g of 3,4-dimethoxy-benzenesulfonyl chloride was stirred for 18 hours with 40 ml of pyridine. The resulting red suspension was poured into 400 ml of IN hydrochloric acid and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulfate and concentrated (sic). The residue was dissolved in a mixture of 500 ml of ethanol and 400 ml of 2N sodium hydroxide solution. After the addition of 10 g of acrylic carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. After neutralization with concentrated hydrochloric acid, 11.1 g of 3,4-dimethoxy-N- (4-naphthalen-2-yl-thiazol-2-yl) -benzenesulfonamide were separated as colorless crystals, which were recrystallized from ethanol /Water. Melting point: 114-117 ° C. EXAMPLE 51 4-methoxy-N- (4-naphthalen-1-yl-thiazol-2-yl) -benzenesulfonamide A mixture of 10 g of 4- (l-naphthyl) thiazol-2-ylamine hydrobromide with 7.4 g of 4-methoxy-benzenesulfonyl chloride was stirred for 16 hours with 40 ml of pyridine. The resulting red suspension was poured into 400 ml of IN hydrochloric acid and extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulfate and freed of solvent. The residue was dissolved in a mixture of 500 ml of ethanol and 400 ml of 2N sodium hydroxide solution. After the addition of 10 g of active carbon, the mixture was stirred at room temperature for 30 minutes and then activated carbon was filtered off. After neutralization with concentrated hydrochloric acid, the mixture was concentrated, the residue was taken up in ethyl acetate, dried over magnesium sulfate and concentrated. Crystallization from ethyl acetate / hexane gave 10.2 g of 4-methoxy-N- (4-naphthalen-1-yl-thiazol-2-yl) -benzenesulfonamide as colorless crystals, which was recrystallized once in acetate of ethyl / hexane. Melting point: 98-100 ° C. Intermediates EXAMPLE 52 3- (2-Amino-thiazol-4-yl) -benzonitrile 16.9 g of 3-bromoacetyl-benzonitrile were placed in 50 ml of methanol and treated at room temperature with 8 g of thiourea. The mixture was boiled for 2 and a half hours and then cooled to 0 ° C while stirring slowly. The product was separated as the salt, separated by filtration and converted to the base with the addition of 100 ml of 2N sodium hydroxide solution. The aqueous suspension was extracted with a total of 700 ml of methylene chloride and the organic phase was dried with magnesium sulfate. After concentration 9.6 g of 3- (2-amino-thiazol-4-yl) were separated. benzonitrile. Melting point: 195-198 ° C. EXAMPLE 53 4-Cyclohexyl-benzenesulfonyl chloride A solution of 10.6 ml of phenylcyclohexane in 100 ml of methylene chloride was added at 5 ° C within 30 minutes to 13.8 ml of chlorosulfonic acid. The mixture was stirred at 5 ° C for 1 hour, poured into 400 ml of a 20% ammonium chloride solution and extracted twice with 300 ml of methylene chloride each time. The organic phases were combined, dried with magnesium sulfate and the solvent was separated on a rotary evaporator. 13.6 g of 4-cyclohexyl-benzenesulfonyl chloride were separated in the form of a reddish oil, which was used without further purification. NMR (CDCl 3) ppm: 7.94 (d, 2 H), 7.43 (d, 2 H), 2.62 (m, 1 H), 2.0-1.2 (m, 10 H). EXAMPLE 54 4-Isopropyl-benzenesulfonyl chloride. A solution of 11.6 ml of isopropylbenzene in 100 ml of methylene chloride was added at 5 ° C within 30 minutes to 18.3 ml of chlorosulfonic acid. The reaction mixture was stirred at 5 ° C for 1 hour, poured into 500 ml of ice-water and, after stirring for 5 minutes, treated with 100 g of ammonium chloride. After extraction with methylene chloride (1 x 800 ml, 1 x 500 ml), the organic phases were combined, dried with magnesium sulfate and the solvent was removed on a rotary evaporator. isopropyl-benzenesulfonyl in the form of a reddish oil, which was used without further purification. NMR (CDCl 3) ppm: 7.96 (d, 2H), 7.46 (d, 2H), 3.04 (m, 1H), 1.30 (d, 6 H) EXAMPLE 55 Bromhydrate of 4- (3 -trifluoromethyl-phenyl) -thiazole-2-ylamine A solution of 8.1 g of 2-bromo-l- (3-trifluoromethylphenyl) -ethanone in 70 ml of methanol was treated at room temperature with 3.2 g of thiourea and It was boiled for 1 hour. Upon cooling to 0 ° C, 4.1 g of 4- (3-trifluoromethyl-phenyl) -thiazol-2-ylamine was separated in the form of colorless crystals. Melting point 206-208 ° C. EXAMPLE 56 4- (4-Benzyloxy-3-methoxy-phenyl) -thiazole-2-ylamine hydrobromide 4- (4-Benzyloxy-3-methoxy-phenyl) -thiazol-2-yl-amine hydrobromide was prepared in all the aspects analogously from 2-bromo-l- (4-benzyloxy-3-methoxy-phenyl) -ethanone. Melting point: 239-240 ° C. EXAMPLE 57 4- (3,4-Bis-benzyloxy-phenyl) -thiazole-2-ylamine Hydrobromide 4- (3,4-bis-benzyloxy-phenyl) -thiazol-2-ylamine hydrobromide was prepared in all respects analogously from 2-bromo-l- (3,4-bis-benzyloxy-phenyl) -ethanone. Melting point: 166-167 ° C. EXAMPLE 58 2-Bromo-l- (2-fluoro-5-trifluoromethyl-phenyl) -ethanone A solution of 5.0 g of 2-fluoro-5-trifluoromethyl-acetonfenone in 35 ml of acetic acid was treated with 0, 8 ml of bromine at room temperature within 10 minutes. The brown color disappeared after stirring at room temperature for 3 hours. The reaction mixture was added to 150 ml of ice-water and extracted twice with diethyl ether. The organic phases were washed twice with saturated sodium bicarbonate solution, combined, dried with sodium sulfate and concentrated. The residue weight 5.8 g, contained around 60% 2-bromo-l- (2-fluoro-5-trifluoromethyl-phenyl) -ethanone and was worked up without purification.

EXAMPLE 59 4- (2-Fluoro-5-trifluoromethyl-phenyl) -taizol-2-yl-amine hydrobromide A solution of 5.8 g of 2-bromo-l- (2-fluoro-5-trifluoromethyl-phenyl) Etanone in 44 ml of methanol was treated at room temperature with 2.2 g of thiourea and boiled for 1 hour. Upon cooling to 0 ° C and after the addition of 15 ml of diethyl ether, 2.8 g of 4- (2-fluoro-5-trifluoromethyl-phenyl) -thiazol-2-ylamine hydrobromide was removed. Melting point: 194-195 ° C. EXAMPLE 60 2-Bromo-l- (3-fluoro-5-trifluoromethyl-phenyl) -ethanone A solution of 5.8 g of 3-fluoro-5-trifluoromethyl-acetophenone in 35 ml of acetic acid was treated with 0.94. My bromine at room temperature within 10 minutes. The brown color disappeared after stirring at room temperature for 2 hours. The reaction mixture was added to 150 ml of ice-water and extracted twice with diethyl ether. The organic phases were washed twice with saturated sodium bicarbonate solution, combined, dried with magnesium sulfate and concentrated. The residue, weight 7.2 g, contained about 60% of 2-bromo-l- (3-fluoro-5-trifluoromethyl-phenyl) -ethanone and was processed without further purification. EXAMPLE 61 4- (3-Fluoro-5-trifluoromethyl-phenyl) -thiazol-2-yl-amine hydrobromide A solution of 7.2 g of 2-bromo-l- (3-fluoro-5-trifluoromethyl-phenyl) Etonone in 60 ml of methanol was treated at room temperature with 2.7 g of thiourea and boiled for 1 hour. Upon cooling to 0 ° C and after the addition of 15 ml of diethyl ether, 5.2 g of 4- (3-fluoro-5-trifluoromethyl-phenyl) -thiazol-2-ylamine hydrobromide was removed. Melting point: 219-221 ° C. EXAMPLE 62 4- (2-Benzyloxy-phenyl) -thiazole-2-ylamine hydrobromide A solution of 21.7 g of 2-bromo-l- (2-benzyloxy-phenyl) -ethanone in 150 ml of methanol was treated with room temperature with 7.6 g of thiourea and boiled for 1 hour. The reaction mixture was concentrated to a volume of 60 ml. After cooling to 0 ° C and after the addition of 250 ml of diethyl ether, 20.7 g of 4- (2-benzyloxy-phenyl) -thiazol-2-ylamine hydrobromide were separated. Melting point: 194-196 ° C. EXAMPLE 63 4- (3-Benzyloxy-phenyl) -thiazole-2-ylamine bromohydrate A solution of 22.5 g of 2-bromo-l- (3-benzyloxy-phenyl) ethanone in 150 ml of methanol was treated at room temperature. environment with 7.8 g of methylurea and boiled for 1 hour. Upon cooling to 0 ° C, 16.1 g of 4- (3-benzyloxy-phenyl) -thiazol-2-ylamine were separated in the form of colorless crystals. Melting point 168-170 ° C. EXAMPLE 64 N- [4- (3-Bromo-phenyl) -thiazol-2-yl] -N-methoxymethyl-4-methyl-ben-cenulphonamide A solution of 0.72 g of N- [4- (3-bromine phenyl) -thiazol-2-yl] -4-methyl-benzenesulfonamide and 0.6 ml of ethyldiisopropylamine in 10 ml of methylene chloride was cooled to 0 ° C and, after the addition of 0.13 ml of chloromethyl ether methyl, was stirred at 0 ° C for 2 hours. The mixture was then treated with 40 ml of water and extracted with methylene chloride. The organic phase was dried with magnesium sulfate and concentrated. After chromatography on 60 g of Kieselgel 60 with ethyl acetate / hexane (1: 3) as the eluent, the product-containing fractions were concentrated. 0.64 g of colorless N- [4- (3-bromo-phenyl) -thiazol-2-yl] -N-methoxymethyl-4-methylbenzenesulfonamide, obtained in amorphous form, was processed without further purification. NMR (CDC13) ppm: 7.89 (s, 1H), 7.85 (d, 2H), 7.56 (d, 1H), 7.38 (d, 1H) 7.31 (d, 2H), 7.23 (dd, 1H), 7.18 (s, 1H), 5.51 (s, 2H), 3.47 (s, 3H), 2.42 (s, 3H). EXAMPLE 65 N- (4-diphenyl-3-yl-thiazol-2-yl) -N-methoxymethyl-4-methylbenzenesulfonamide A solution of 0.5 g of N- (4- (3-bromo-phenyl) - thiazol-2-yl] -N-methoxymethyl-4-methyl-benzenesulfonamide in 8 ml of toluene was treated in succession with 0.1 g of anhydrous lithium chloride, 60 mg of tetra is (triphenylphosphine) palladium, 0.23 g of phenylboric acid and 2 ml of 2N potassium carbonate solution.The mixture was boiled overnight, it was cooled and, after the addition of water, extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulfate and concentrated. The residue was chromatographed on 80 g of Kieselgel 60 with ethyl acetate / hexane (1: 4) as the eluent. The product-containing fractions were concentrated and gave 0.29 g of colorless amorphous N- (4-diphenyl-3-yl-thiazol-2-yl) -N-methoxymethyl-4-methylbenzenesulphonamide, which was processed without further purification NMR (CDCl 3) ppm: 7.99 (s, 1H), 7.86 (d, 2H), 7.72 (d, 1H), 7.6-7.2 (m, 9H), 6.80 ( d, 1H), 5.53 (s, 2H), 3.48 (s, 3H), 2.38 (s, 3H). EXAMPLE A In the usual way tablets of the following composition are produced mg / tablet White corn starch 100 Lactose powder 95 White corn starch 35 Polyvinylpyrrolidone 8 Carboxymethyl starch of Na 10 Magnesium stearate 2 Weight of tablet 250 EXAMPLE B In the usual way tablets of the following composition are produced: mg / tablet White corn starch 200 Lactose powder 100 White corn starch 64 Polyvinylpyrrolidone 12 Carboxymethyl starch of Na 20 Magnesium stearate 4 Weight of the tablet 400 EXAMPLE C Capsules of the following composition are produced: mg / capsule White corn starch 50 Crystalline lactose 60 Microcrystalline cellulose 34 Talcum 5 Magnesium stearate 1 Weight of capsule filling 150 The active ingredient having an appropriate particle size, the crystalline lactose and the microcrystalline cellulose is homogenously mixed with each other, sieved and then talc and magnesium stearate are combined. The finished mixture is filled into hard gelatin capsules of appropriate size.

Claims (15)

1. CLAIMS 1.- The use of compounds of the general formula

   wherein R means lower alkyl, phenyl, benzyl, naphthyl, pyridyl or thienyl, optionally substituted by one or more substituents of lower alkyl, lower alkoxy, lower alkyl-carbonyl-amino, halogen, cycloalkyl, nitro, amino, methylenedioxyl, phenoxy or benzyloxy, and the aromatic rings may be substituted, in turn, by nitro, halogen or amino, R * -R4 mean hydrogen, halogen, hydroxyl, lower alkyl, nitro, cyano, amino, lower alkoxy, benzyloxy, trifluoromethyl or phenyl, optionally substituted by one or more substituents of lower alkyl, trifluoromethyl, nitro, amino or hydroxyl, and wherein R 1 and R 2 or R 2 and R 3 together may form a benzene ring which may optionally be substituted by halogen, trifluoromethyl, nitro, lower alkyl or lower alkoxy, and its pharmaceutically acceptable salts as inhibitors of quinurenin-3-hydroxylase in the control or prevention of neurodegenerative disorders, tr neurological asthma resulting from an activation of the immune system or psychiatric illnesses and, respectively, for the production of corresponding medications.
2. 2. The use, according to claim 1, of compounds of formula I defined in claim 1, wherein R means 4-methoxyphenyl, 4-methylphenyl, 4-aminophenyl, 3,4-dimethoxyphenyl or 2-naphthyl and R1-R ^ mean hydrogen, fluorine, nitro or trifluoromethyl or R2 and R3 together form a benzene ring.
3. 3. The use according to claim 1 of
4. 4-methoxy-N- (4-naphthalen-2-yl-thiazol-2-yl) -benzenesulfonamide, 4-amino-N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide, 4-methyl-N- [4- (3-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide, 3,4-dimethoxy-N- [4- (3-nitro-phenyl) thiazol-2-yl] benzenesulfonamide, 4-methoxy-N- [4- (3-nitro-phenyl) -thiazol-2-yl] benzenesulfonamide, [4- (3-nitro-phenyl) -thiazol-2-yl] -amide of the acid Naphthalene-2-sulfonic acid, N- [4- (2-fluoro-5-trifluoromethyl-phenyl-thiazol-2-yl] -4- ethi-benzenesulfonamide, N- [4- (3-fluoro-5-trifluoromethyl-phenyl ) -thiazol-2-yl] -4-methyl-benzenesulfonamide, 4-methyl-N- [4- (4-nitro-phenyl) -thiazol-2-yl] -benzenesulfonamide, 4-amino-N- [4- (2-fluoro-5-trifluoromethyl-phenyl) -thia-zol-2-yl] -benzenesulfonamide and 3,4-dimethoxy-N- [4- (2-fluoro-5-trifluoromethyl-phenyl) -thiazole-2- il] -benzenesulfonamide 4.- New compounds from the group of compounds of the general formula I of claim 1

   R6 wherein R ^ -R4 have the meaning set forth in claim 1, R5 signifies hydrogen or lower alkyl, R6 signifies hydrogen, lower alkyl, lower alkoxy, cycloalkyl or benzyl and n means 0 or 1 and wherein R ^ and R ^ together they can form a methylenedioxyl group, with the proviso that R5 and R6 can not simultaneously be hydrogen.
5. 5.- New compounds of the group of compounds of the general formula I of claim 1

   wherein R7-R9 means hydrogen, halogen, lower alkoxy or 4-N02-phenoxy, with the proviso that at least one of R7-R9 is halogen.
6. 6.- New compounds of the group of compounds of the general formula I of claim 1

   wherein R 10 means amino or -NHCOR 12, R 12 means lower alkyl, R 1, R 5 and R 4 have the meaning set forth in claim 1 and R 1 means hydrogen, hydroxyl, nitro, cyano, amino, trifluoromethyl, benzyloxy or phenyl, optionally substituted by one or more substituents of lower alkyl, trifluoromethyl, nitro, amino or hydroxyl, and pll and p13 together may form a phenyl ring.
7. 7.- New compounds of the group of compounds Je 20 general formula I of claim 1

   25 where they have the meaning set forth in claim 1

   R12 has the meaning set forth in claim 6.
8. 8.- New compounds of the group of compounds of the general formula I of claim 1

   wherein Rl-R4 has the meaning set forth in claim 1 and R 2 has the meaning set forth in claim 6.
9. 9. a medicament characterized in that it contains one or more compounds according to any of claims 4-8 and an excipient therapeutically inert.
10. 10.- A medication, according to claim 9, especially for the control of diseases or conditions that are associated with a malfunction of glutamatergic neurotransmission and / or which lead to an excessive production of quinolic acid, such as neurodegenerative disorders (Huntington's chorea, Alzheimers disease). -r, Parkinson's disease, amyotrophic lateral sclerosis, epilepsy), consequences of attack and / or cerebral ischemia, hypoxia, multi-infarct dementia, consequences of trauma or brain injury, as well as trauma and spinal cord injury 1, disorders neurological resulting from an activation: the immune system (for example AIDS-dementia complex:?, infections such as for example viral or bacterial meningitis and cancers with cerebral localization), autoimmune diseases (multiple sclerosis), as well as psychiatric diseases (schizophrenia, chronic anxiety).
11. 11. A process for the preparation of compounds, according to any of claims 4-8, a process characterized in that a) reacting a compound of the general formula

    with an appropriate sulfonyl halide of the general formula

    S02X III

    wherein R and R1-R4 have the meaning indicated above and X means halogen, or b) dissociate the protecting group of a compound of the general formula

    wherein R ^ -R4 have the above meaning and R13 means a sulfonamide protecting group, or reacting a compound of the general formula

    where R has the meaning indicated above, with an appropriate compound of the general formula

    R "VI

    R1 R2

    wherein R ^ -R4 have the meaning set forth in claim 1 and X has the meaning set out above in this claim, to give a thiazole derivative of formula I, or d) to react an appropriate compound of formula IV wherein R2 or R3 means bromine or iodine and R1 and / or R4 are / is different (s) of bromine or iodine with a compound of the general formula

    R

    wherein L means an appropriate leaving group and R 14 are the same or different and mean lower alkyl, lower alkoxy, trifluoromethyl, nitro, amino or hydroxyl, or e) hydrolyze a compound of the general formula I wherein R means phenyl substituted by alkyl lower-carbonyl-amino and R ^ -R4 have the meaning indicated above to a compound of general formula I wherein R means phenyl substituted by amino, and f) if desired, convert a compound of the general formula I to a pharmaceutically acceptable salt .
12. 12. Compounds, according to any of claims 4-8, provided that they are prepared with the process according to claim 11 or an equivalent process.
13. 13. Compounds, according to any of claims 4-8 for use as therapeutically active substances, especially for the control or prevention of neurodegenerative disorders (Huntington's chorea, Alzheimer's disease, Parkinson's disease, amio-trophic lateral sclerosis, epilepsy), consequences of attack and / or cerebral ischemia, hypoxia, multi-infarct dementia, consequences of trauma or brain injury, as well as trauma and spinal cord injury, neurological disorders resulting from an activation of the immune system (for example, AIDS-dementia, infections such as for example viral or bacterial meningitis and cancers with cerebral localization), autoimmune diseases (multiple sclerosis), as well as psychiatric illnesses (schizophrenia, chronic anxiety).
14. 14. The use of the compound according to any of claims 4-8 as therapeutically active substances.
15. 15. The use of compounds according to any of claims 4-8 for the control or prevention of neurodegenerative disorders (Huntington's chorea, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, epilepsy), attack consequences and / or cerebral ischemia, hypoxia, multi-infarct dementia, consequences of trauma or brain injury, as well as trauma and spinal cord injury, neurological disorders resulting from an activation of the immune system (eg AIDS-dementia complex, infections such as as for example viral or bacterial meningitis and cancers with cerebral localization), autoimmune diseases (multiple sclerosis), as well as psychiatric illnesses (schizophrenia, chronic anxiety) and, respectively, for the production of corresponding medications.

    Summary of the Invention The invention relates to the use of sulfonamide derivatives of the general formula

    wherein R means lower alkyl, phenyl, benzyl, naphthyl, pyridyl or thienyl, optionally substituted by one or more substituents of lower alkyl, lower alkoxy, lower alkyl-carbonyl-amino, halogen, cycloalkyl, nitro, amino, methylenedioxyl, phenoxy or benzyloxy, and the aromatic rings may be substituted, in turn, by nitro, halogen or amino, R1-R4 mean hydrogen, halogen, hydroxyl, lower alkyl, nitro, cyano, amino, lower alkoxy, benzyloxy, trifluoromethyl or phenyl, optionally substituted by one or more substituents of lower alkyl, trifluoromethyl, nitro, amino or hydroxyl, and wherein R1 and R2 or R2 and R3 together can form a benzene ring which optionally can be substituted by halogen, trifluoromethyl, nitro, lower alkylene or lower alkoxy, and its pharmaceutically acceptable salts as inhibitors: e quinurenin-3-hydroxylase in the control or prevention of tra. >- neurodegenerative factors, neurological disorders resulting from an activation of the immune system, or psychiatric diseases and, respectively, for the production of corresponding drugs.