New sulfonamides

 

(57) Abstract:

Describes the new sulfonamides of General formula I, where R1denotes hydrogen, lower alkyl; R2denotes hydrogen, lower alkyl; R3denotes hydrogen, lower alkyl; R2and R3indicate together methylendioxy, Ethylenedioxy or isopropylidenedioxy; R4denotes hydrogen, lower alkyl, lower alkoxyl, lower alkylthio, hydroxy-lower alkyl, hydroxy-lower alkoxy, hydroxy-lower alkoxy-lower alkyl, hydroxy-lower alkoxy-lower alkoxy, alkoxy-lower alkyl, alkoxy-lower alkyloxy, amino-lower alkyl, lower alkylamino-lower alkyl, morpholino, 2-pyrimidinyl, -Cho, -CH2HE or-CH2Cl; R5-R8denote hydrogen, halogen, lower alkoxy, lower alkylthio; X denotes-O - or-S-; Y represents-Cho,1-4-alkyl, -(CH2)1-4-Z-R9, -(CH2)0-3C(O)OR SIG9, -(CH2)1-4-OC(O) (CH2)1-4CH3, -(CH2)1-4OS(O)het, -(CH2)1-4OCH2CH(OH)CH2HE and his cyclic ketals, -(CH2)1-4NR9CH2CH(OH)CH2OH, -(CH2)1-4O(CH2)1-4-ZH, -(CH2)1-4NR9(CH2)1-4ZH, -(CH2)1-4O(CH212represents a C1-4-alkyl or -(CH2)0-4-aryl; Z represents-O-, het is a heterocyclic residue such as thienyl, furyl, pyridinyl, Gal-halogen, and n denotes 0 or 1. The compounds are inhibitors endothelially receptors and can be used for the treatment of diseases associated with the processes that contribute to the narrowing of blood vessels. 12 C.p. f-crystals, 2 PL.

The invention relates to new sulfonamides and their use as therapeutic drugs. Primarily the invention relates to new compounds of the formula

< / BR>
where R1denotes hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen or trifluoromethyl;

R2denotes hydrogen, lower alkyl, halogen, lower alkoxy, trifluoromethyl or-OCH2COOR9;

R3denotes hydrogen, lower alkyl, halogen, lower alkylthio, trifluoromethyl, lower alkoxy or triptoreline;

R2and R3indicate together butadienyl, methylenedioxy, Ethylenedioxy or isopropylidenedioxy;

R4denotes hydrogen, lower alkyl, trifluoromethyl, lower alkoxy, lower alkylthio, hydroxy-lower alkyl, hydroxy-lower alkoxy, hydroxy-lower alkoxy-lower alkyl, hydroxy-nor is kilalanin, 2-methoxy-3-oxopropoxy, 2-hydroxy-3-phenylpropyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, amino, lower alkylamino, di-lower alkylamino, arylamino, aryl, aaltio, aryloxy, aryl-lower alkyl, heterocyclyl, heterocyclyl-lower alkyl, heterocyclisation, heterocyclic, heterocyclic, -CHO, -CH2OH or-CH2Cl;

R5-R8denote hydrogen, halogen, trifluoromethyl, lower alkoxy, lower alkylthio, cyano;

R6together with R5or R7means butadienyl, methylenedioxy, Ethylenedioxy or isopropylidenedioxy;

X denotes-O - or-S-;

Y represents-CHO, C1-4-alkyl, -(CH2)1-4-Z-R9,

-(CH2)1-4-OC(O) (CH2)1-4CH3,

-(CH2)1-4OC(O)gets, -(CH2)1-4NHC(O)R10,

-(CH2)1-4OCH2CH(OH)CH2OH and its cyclic ketals,

-(CH2)1-4NR9CH2CH(OH)CH2HE, -(CH2)1-4OCH2CH2SCH3,

-(CH2)1-4OCH2CH2S(O)CH3, -(CH2)1-4O(CH2)1-4-ZH,

-(CH2)1-4O(CH2)1-4OC(O)R10, -(CH2)1-4NR9(CH2)1-4ZH,

H2)1-4ZH,

-(CH2)0-3CH(OH)CH2SCH3, -(CH2)0-3CH(OH)CH2S(O)CH3< / BR>
-(CH2)0-3CH(OH)OCH2CH2OH, -(CH2)0-3C(O)(CH2)1-4CH3,

-(CH2)0-3C(O)(CH2)1-4ZR11, -(CH2)0-3C(O)CH2Gal, -(CH2)1-4Gal, -(CH2)1-4CN,

-(CH2)0-3C(O)OR9, -OR12or-SR12,

R9represents hydrogen or C1-4-alkyl,

R10represents a C1-4-alkyl,

R11represents hydrogen, C1-4-alkanoyl or heterocalixarenes,

R12represents a C1-4-alkyl or -(CH2)0-4-aryl,

Z represents-O-, -S - or-NR9-,

het is a heterocyclic residue,

Gal - halogen and

n denotes 0 or 1;

and salts of these compounds.

Used herein, the term "lower" means a group with 1-7 carbon atoms, preferably 1-4. Alkyl-, alkoxy -, alkylthio groups, and alkyl groups as components alkanoyl groups can be unbranched or branched. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec - and tertbutyl. Halogen out to call phenyl and substituted phenyl residues, moreover, the substituents can be halogen, lower alkyl, lower alkoxy, carboxy and trifluoromethyl. Examples of heterocyclic residues are substituted, in particular one - or disubstituted, for example, lower alkyl, lower alkoxy, halogen, aryl, aryl - lower alkyl, or unsubstituted mono - or bicyclic 5 - and 6-tier heterocyclic residues with oxygen, nitrogen or sulfur as heteroatom as 2 - and 3-furyl, 2-, 4 - and 5-pyrimidinyl, 2-, 3 - and 4-pyridyl and pyridyl-N-oxide, 1,2 - and 1,4-diazines, morpholino, 2 - and 3-thienyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzofuranyl, benzothiazol, indolyl, purinol, hinely, ethanolic and chinadoll. As examples of salts can be called alkali metal salts like sodium and potassium salts, and salts of alkaline earth metals as calcium salts and magnesium.

Compounds of the above formula I are inhibitors of endothelium-receptors. Therefore they can be used to treat diseases associated with increased activity of the endothelium, primarily cardiovascular diseases, such as hypertension, ischemia, vasospasm and angina.

In a preferred group of compounds within formula I consists of compounds is denotes lower alkoxy, above all methoxy; R5and R7represent hydrogen and R8is halogen, preferably chlorine.

The preferred substituent R1and R2is hydrogen, the preferred substituent R3- lower alkyl, primarily tertbutyl. Preferred substituents R4are hydrogen, 2-pyrimidinyl, 2 - and 3-furyl, 2 - and 3-thienyl, p-methoxyphenyl, and primarily morpholino.

Preferred substituents Y are-CHO, C1-4-alkyl, -(CH2)1-4-Z1-R9, -(CH2)1-4NHC(O)R10, -CH2OCH2CH(OH)CH2OH and its cyclic ketals, -CH2NR9CH2CH(OH)CH2OH, -CH2OCH2CH2S(O)CH3, -CH2O(CH2)1-4-ZH, -CH2O(CH2)1-4OC(O)R10, -CH2O(CH2)1-4OC(O)het, -CH2Gal, primarily oximeter, 2-hydroxy-ethoxymethyl and 2,3-deoxypyridoxine.

The compounds of formula I can be obtained due to the fact that

a) compound of the formula

< / BR>
where X, n and R have the above significance and Gal is halogen, convert the compound of the formula

R12AM, III

where A represents oxygen or sulfur, and M is an alkaline metal, is connected to the R>
< / BR>
where R4-R8, R10, X and n have the above values,

convert the compound of the formula

< / BR>
where M represents a cation,

in the compound of formula I, where Y is the remainder R10, a R1-8, X and n have the above significance, under certain conditions, the obtained compound of the formula I in which Y and/or R4are the rest of CH3by oxidation is converted into the compound of the formula I in which Y and/or R4are the rest of CHO, and under certain conditions, the remainder CHO convert in the other, above the rest of Y and/or R4or

C) carry out the reaction between the compound of the formula

< / BR>
and the compound of the formula

< / BR>
and R1-R9, R12, n, A and X have the above meaning, and, under certain conditions, the obtained compound of the formula I is converted into salt.

The reaction between the compound of formula II and compound of formula III is preferably carried out with application forms the basis of compound III (thio)alcohol, i.e., for example, in ethanol, if a is a hydrogen, a R12the ethyl. The alkali metal M preferably represents sodium. The reaction is expediently carried out with heating, for example, to teousness using known methods, used when receiving sulfonamides, for example, in an inert organic solvent like dimethyl sulfoxide, preferably by heating in inert gas, for example argon. In the compounds of formula V cation is preferably a cation of alkali metal, such as Na+or+.

When the reaction between the compound of the formula VI and a compound of formula VII in this latter under certain conditions existing as of the substituents R4-R9hydroxy - and amino group is preferably protected. Actigraphy can be protected, for example, silylamine groups, such as dimethyl-tertbutylamine groups, or acyl groups as acetyl; amino group can be protected by tertbutoxycarbonyl or benzyloxycarbonyl. These protective groups can be introduced in a known manner and after the reaction between compounds VI and VII again to leave.

Obtained above by the compounds of formula I in which Y and/or R4represent the balance of CH3for example, methyl, thanks to the modification of substituents may be converted to other compounds of formula I. Thus, representing the Deputy Y and/or R4the group CH3through oxidation can p the scientists in this way the connection formyl group can be restored in oxymethylene group. Such recovery can be carried out in a known manner, for example by using reducing agents, as NaBH4. Oximetry (alkyl) group by processing the halogenation agent POCl3/PCl5can be transformed into halogenation (alkyl) group, of which through reaction with alcohols or aminoalcohols obtain the compounds of formula I in which Y is a residue -(CH2)1-4ZR9, -CH2OCH2CH(OH)CH2OH and its cyclic ketals, -CH2NR9CH2CH(OH)CH2OH or-CH2O(CH2)1-4ZH. In the thus obtained compounds of the formula I is contained in Y is hydroxy or amino groups can tarifitsirovatsja, resulting in a gain of compounds of formula I in which Y represents one of the above residues, in which the residue R11contained in the value of C1-4-alkanoyl or heterocalixarenes.

On the other hand, formyl group, using the Grignard reaction alkalinity halides can be converted to the compound of formula I in which Y is a residue -- CH(OH)R11. Formyl group can further react with Grignard compounds of the formula the new ether), with the aim of obtaining (after removal of HE - and SH-protective groups of the compounds of the formula I with Y=-CH(OH)(CH2)1-4-Z-h through the reaction between the compound of the formula I and dimethyl sulfide/Li can be obtained the compounds of formula I with Y= -CH(OH)CH2SCH3which by oxidation NaJO4can be converted into compounds of the formula I with Y=-CH(OH)CH2S(O)CH3.

The compounds of formula I with Y=-C(O)R10or-C(O)(CH2)1-4-Z-R11can be obtained by oxidation of the corresponding compounds in which Y is a residue -- CH(OH)R10or - CH(OH)(CH2)1-4ZR11and OH - or SH-group ZR11during the reaction preferably is protected, for example, as a benzyl ether. As a means of oxidation in the above reaction can be used, for example, CrO3/pyridine.

All these reactions may be carried out by well-known methods. And, finally, the compounds of formula I can in a known manner be converted into salts, for example alkali metal salts, as salts of sodium and potassium.

Used as the starting material compounds, if they are known or if they are receiving is described below, can be obtained similarly is Holocene according to the following scheme:

< / BR>
By alkylation of the phenol (1) complex in diethyl ether hormonology acid get connection (2), which by condensation with formamidine or any homologene connection, as acetamidine get pyrimidinetrione (3). From this last with phosphoroxychloride get dichloroethylene (4) from which, using the exchange reaction with the stoichiometric quantity of compound (5) to obtain compound II with n=1. The compounds of formula II in which n=0 can be obtained according to the following scheme:

< / BR>
All of these reactions are standard and can be carried out under the usual reaction conditions known to every expert.

The compounds of formula IV with n = 1 can be obtained in the following way:

< / BR>
Phenol or thiophenol formula (6) in the presence of sodium in an appropriate solvent, such as toluene, can be transformed complex ethyl ester, 2-chloroacetoxy acid compound of the formula (7), which by condensation with amidino R4C(NH)NH2can be obtained hydroxy-pyrimidinedione (8), respectively its tautomer-NH-CO-. As a result of currency actigraphy to chlorine using POCl3get R>
< / BR>
The inhibitory effect of the compounds of formula I on endothelial receptors can be illustrated by the following experiments carried out according to the following scheme.

1. Braking endotelialnogo binding placentero man

(see Life Sci 44:1429 (1989))

The membrane person homogenious in 5 mm Tris buffer solution, pH of 7.4, containing 1 mm MgCl2and 200 mm sucrose. Homogenized handle on the centrifuge, the centrifugal acceleration 3000g for 15 minutes at 4oC, the residue containing the membrane fraction plasma, centrifuged with a centrifugal acceleration 72000g for 30 min and the precipitate washed with 75 mm Tris-buffer solution pH of 7.4, containing 25 mm MgCl2. Then get out of every 10 g of original tissue residue suspended in 1 ml of 75 mm Tris buffer solution, pH of 7.4, containing 25 mm MgCl2and 250 mm sucrose, and frozen in 1 ml aliquots at -20oC.

To test the binding of the frozen membrane preparations was thawed after centrifugation with a centrifugal acceleration 25000g for 10 min at 20oC in a test buffer solution (50 mm Tris-buffer solution, pH of 7.4, containing 25 mm MnCl2, 1 mm EDTU and 0.5% serum larger the endothelium (specific activity 2200 CI/mmol) in a test buffer solution (25000 counts/min, the final concentration of 20 PM) and 100 ál of buffer solution containing the test compound in various concentrations. Incubation is carried out for 2 h at 20oC or for 24 h at 4oC. Separation of free and membrane-bound radio is produced by filtering through a filter made of fiberglass.

II. Braking-induced endothelium contractions on isolated aortic rings of rats

From the aorta in the chest adult rats Wistar-Kyoto carved rings with a length of 5 mm, the Endothelium was removed with a light rubbing of the inner surface. Each ring was immersed at 37oC in an isolated bath with 10 ml of Krebs-Henseleit simultaneous processing gas containing 95% O2and 5% CO2. Isometric tension rings was measured. Stretching with a load of 3 g ring was attached to the initial tension. After incubation for 10 min with the test compound or binder was added to the cumulative dose of endothelium-1. The activity of the test compounds was determined by the dose ratio, i.e., caused by 100 μm of the test compound to the right shift (a shift towards large figures) EC50the placements. The higher the dose ratio, the more effective the test compound inhibits the biological activity of endothelium-1. EC50endothelium in the absence of the test compound is 0.3 nm.

III. The inhibitory effect on vasoconstriction in rats

Rats were anestesiologi thiobutabarbital sodium (100 mg/kg orally). Through the femoral (thigh) artery is injected with a catheter for measurement of systemic arterial blood pressure, and through the femoral vein was entered another catheter in the inferior caval vein for injection of the test compounds. The artery of the left kidney were applied to the probe, which was connected with the measuring instrument Doppler. Clip for 45 min artery of the left kidney at the output caused renal ischemia. 10 minutes before ischemia intraarterially (C. A.) doses of 5 mg/kg or intravenously (centuries) doses of 10 mg/kg was injected compound. In control experiments the renal blood flow was decreased in comparison with predications indicator 434%.

Table 1 lists identified in experiment I, the inhibitory effect of the compounds of formula 1 in the abbreviation IC50that means the concentration [µm] required for 50% of specific binding125I-endothelium.

The compounds of formula I can be used for oral, rectal, parenteral, for example intravenous, intramuscular, subcutaneous, transdermal injection or injection within the CSF space; or for sublingual injection or ophthalmic preparations, or in the form of aerosols. Preparaion, injection solutions, eye drops, ointments or aerosol solutions.

The preferred form of application are intravenous, intramuscular injections and introduction oral route. The effective dosage amounts of the compounds of the formula I depends on the specifics of biologically active substances, the age and needs of the patient, as well as the method of application. Generally, the daily dosage is determined by the rate of 0.1-100 mg/kg body weight. Preparations containing the compounds of formula I may also contain inert or having pharmacodynamic activity of the additive. Tablets or pellets, for example, may contain a number of binding agents, fillers, carriers or diluents. Liquid preparations can be produced, for example, in the form of sterile, mixed with water solution. Capsules can along with a biologically active material to contain as additives filler or thickener. In addition, can be used to improve the taste additives and substances which are usually used as preservatives, stabilizers, emulsifiers and moisture retaining means hereinafter, also salts for modifying the osmotic pressure, buffers and other additives.

For p is, the example gelatin, lactose, starch, magnesium stearate, talc, gum Arabic, polyalkylene glycols, etc., the Necessary condition is that all used in the manufacture of preparations auxiliary substances were not toxic.

The following examples explain the invention in detail. Used in these abbreviations mean the following:

because the boiling point of

so pl. - melting point

MS is mass spectrum, and

M - mass of a mole

Example 1

10.7 g of 4-[4-chloro-5-(2-chloro-5-methoxy-phenoxy)-6-methyl-pyrimidine-2-yl]- the research and 21.6 g of p-t-butyl-benzosulfimide-potassium in 150 ml of dry dimethyl sulfoxide was heated in argon for 16 h to 120oC. Then the sulfoxide drove away, the residue was distributed between ethyl acetate and 1N. hydrochloric acid and the organic phase was washed neutralizing substance. The organic phase was dried, the solution evaporated and the residue was recrystallized from dichloromethane/ethanol. He got to 14.7 g of 4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-methyl-2- (morpholine-4-yl)-pyrimidine-4-yl]-benzosulfimide, so pl. 154oC, MS:M=546.

The original material was prepared as follows:

a) In a solution containing 17.1 g of 2-chloro-5-methoxyphenol in toluene, to which, then treated with a solution of 19,57 g complex ethyl ester of 2-chloro-acetoxyl acid in toluene. The reaction mixture was continued to stir for another 3 hours at 110oC and distributed between acetic acid/water 20% and toluene. The organic phase was dried and the solution was away. The residue was purified over silica gel with dichloromethane. The result was of 18.2 g of complex ethyl ester of (RS)-(2-chloro-5-methoxy-phenoxy)-acetoxyl acid in the form of a yellowish oil. MS:M=286.

b) In a solution of nutrimedical containing 10 ml of methanol and to 0.19 g of sodium was added 0.8 g of morpholinepropanesulfonic and 1 g of ester (RS)-(2-chloro-5-methoxy-phenoxy)acetoxyl acid. The reaction mixture was stirred for 16 hours at a temperature of 80oC, set at pH 6 and concentrated. The residue was distributed between chloroform and water. After drying and evaporation of the solvent the residue was led from ethanol/dichloromethane. The result was obtained 0.45 g of 5-(2-chloro-5-methoxy-phenoxy)-6 - methyl-2-(morpholine-4-yl)-pyrimidine-4-ol, I. pl. 252oC, MS:M=351.

in) 1,72 g of 5-(2-chloro-5-methoxy-phenoxy)-6-methyl-2-(morpholine-4-yl)- pyrimidine-4-ol was treated with 3.3 ml of POCl3. The reaction mixture was stirred at tema and washed with water, 1H. NaOH. The organic phase was dried, concentrated and the residue was recrystallized from a simple ether. The results were obtained 1.48 g of 4-[4-chloro-5- (2-chloro-5-methoxy-phenoxy)-6-methyl-pyrimidine-2-yl]-the research, so pl. 134oC, MS:M=369.

Example 2

14.6 g of 4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-methyl-2- (morpholine-4-yl)-pyrimidine-4-yl]-benzosulfimide and 15.9 g dioxide villages in 500 ml of dioxane was stirred in an autoclave at a temperature of 170oC for 6 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was distributed between chloroform and water. The organic phase was dried, the solvent evaporated and the residue was recrystallized from dichloromethane/ethanol. The results were obtained 10.3 g of 4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy) -6-formyl-2-(morpholine-4-yl)-pyrimidine-4-yl] -benzosulfimide, so pl. 235-236oC, MS:M=561.

Example 3

7 g of 4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-formyl-2- (morpholine-4-yl)-pyrimidine-4-yl] -benzosulfimide in 300 ml of ethanol was treated with 0.9 g of detribalized. The reaction mixture was stirred at a temperature of 80oC for one hour. The ethanol is then drove away, and the residue was distributed between chloroform and 1N. NaCl. The organic phase was washed with water and solitarii from dichloromethane/ethanol obtained 4.6 g of 4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6 - oxymethyl-2-(morpholine-4-yl)-pyrimidine-4-yl]-benzosulfimide, so pl. 103oC, MS:M=536.

Example 4

of 4.57 g of 4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-oxymethyl - 2-(morpholine-4-yl)-pyrimidine-4-yl] -benzosulfimide in 50 ml of POCl3that was stirred up from 2.03 g PCl5for two hours at a temperature of 20oC. Then POCl3drove away, and the residue was distributed between acetic ether and water 1H. NaOH. The organic phase was washed with water, dried and the solvent evaporated. The residue was chromatographically over silica gel with dichloromethane and chloroform, and then recrystallized from dichloromethane/ethanol. The result was a 3.01 g of 4-tertbutyl-N- [5-(2-chloro-5-methoxy-phenoxy)-6-chloromethyl-2-(morpholine-4-yl) - pyrimidine-4-yl]-benzosulfimide, so pl. 170oC, MS:M=581.

Example 5

In the solution nitroglycol containing 2.5 g of ethylene glycol and 0.12 g of sodium was added 1 g of 4-tertbutyl-N-[5-(2 - chloro-5-methoxy-phenoxy)-6-chloromethyl-2-(morpholine-4-yl) - pyrimidine-4-yl] -benzosulfimide. The reaction mixture was stirred in an argon atmosphere for 72 hours at a temperature of 80oC. Then drove ethylene glycol, and the residue was distributed between ethyl acetate and 1N. of hydrochloric acid. The organic phase was washed with water, dried over sodium sulfate, and the solvent drove away. The remainder chromatograph-hydroxy-ethoxymethyl)-2-(morpholine-4-yl)-pyrimidine-4-yl]- benzosulfimide, so pl. 162-164oC, MS:M=606.

Example 6

In the same way as described in example 1 from 4-chloro-5-(2-chloro - 5-methoxy-phenoxy)-6-methyl-pyrimidine is obtained 4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-methyl-pyrimidine-4 - yl]-benzosulfimide. So pl. 191oC, MS:(M-Cl*)=426.

The original material was prepared as follows:

Analogously to example 1, paragraph (a) of the complex ethyl ester of (RS)-(2-chloro-5-methoxy-phenoxy)-acetoxyl acid and formamidine received 5-[2-chloro-5-methoxy-phenoxy]-6-methyl-pyrimidine-4-ol in the form of wax, MS:M=266, which was treated similarly to example 1, paragraph b) POCl3.

Example 7

In the same way as described in example 2, obtained in example 6, the compound was converted into 4-tertbutyl-N- [-5-(2-chloro-5-methoxy-phenoxy)-6-formyl-pyrimidine-4-yl] - benzosulfimide. So pl. 99-101oC, MS:M=475.

Example 8

In the same way as described in example 3, obtained in example 7 compound was 4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)- 6-hydroxy-methyl-pyrimidine-4-yl]-benzosulfimide, so pl. 188oC, MS:M=477.

Example 9

In the same way as described in example 4, obtained in example 8 compound was 4-tertbutyl-N-[6-x the tx2">

Example 10

In the same way as described in example 5 from 4-tertbutyl-N- [6-chloromethyl-5-(2-chloro-5-methoxy-phenoxy)-pyrimidine-4-yl] -benzosulfimide got a 4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)- 6-(2-hydroxy-ethoxy-methyl)-pyrimidine-4-yl]-benzosulfimide. So pl. 80oC, MS:(M+N)+= 522.

Example 11

100 mg of 4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy - methyl)-2-(morpholine-4-yl)-pyrimidine-4-yl] -benzosulfimide was atrificial 3-thiophencarboxylic acid under the following conditions: first dissolved 100 mg sulfonamida, 175 mg of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide-hydrochloride, 150 mg of triethylamine and 5 mg dimethylaminopyridine in 10 ml of dichloromethane and the solution was kept for 2 hours at room temperature. Then evaporated until dry. The residue was treated with toluene and distributed between acetic ether and 1N. HCl, then washed with water and was isolated in the usual manner. The compound was purified over silica gel with chloroform as the mobile phase. In the received 90 mg of 2-[6-(4 - tertbutyl-phenylsulfonyl)-5-(2-chloro-5-methoxy-phenoxy)-2 - morpholine-4-yl)-pyrimidine-4-yl-methoxy] -complex ethyl ester thiophene-3-carboxylic acid as an amorphous powder, MS:M=716.

oC, MS:M=676.

Example 13

In a solution containing 100 mg obtained in example 12 compound in 2 ml of dioxane, was added 1.5 ml 1N. HCl and within 15 minutes the mixture was heated up to 80oC. After evaporation the residue was chromatographically over silica gel using a simple ether as mobile phase and received 85 mg of (RS)-4-tertbutyl-N-[5- (2-chloro-5-methoxy-phenoxy)-6- (2,3-dioxy-propoxymethyl)-2-(morpholine-4-yl)-pyrimidine-4-yl] - benzosulfimide in the form of a foam, MS:(M+N)+= 637.

Example 14

By exchange reaction between 4-tertbutyl-N-[6-chloromethyl-5-(2-chloro-5 - methoxy-phenoxy)-pyrimidine-4-yl]-benzosulfimide and ethanolamine got a 4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6- (2-hydroxy-ethylaminomethyl)-pyrimidine-4-yl]-benzosulfimide.

Example 15

By exchange reaction between 4-tertbutyl-N-[6-chloromethyl-5-(2-chloro-5 - methoxy-phenoxy)-pyrimidine-4-yl] -benzosulfimide and propane diol-Na got a 4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6- (3-hydroxy-propoxymethyl)-pyrimidine-4-yl]-benzosulfimide. MS:M(Cl*+HC(O)CH2CH2OH)=436.

Example 16

By exchange reaction between 4-tertbutyl-N-[6-(chloromethyl-5-(2-chloro-5 - methoxy-phenoxy)-pyrimidine-4-yl] -benzoylmethyl)-pyrimidine-4-yl]-benzosulfimide. MS:(M+N)+=551.

Example 17

In the same way as described in example 12, from 4-tertbutyl-N-[6-chloromethyl-5-(2-chloro-5-methoxy-phenoxy)-pyrimidine-4-yl]- benzosulfimide received (RS)-4-tertbutyl-N-[5-(2-chloro-5-methoxy - phenoxy)-6-(2,2-dimethyl-1,3-dioxolane-4-ileocecal) -pyrimidine-4-yl]-benzosulfimide. MS: (M+N)+= 592.

Example 18

In the same way as described in example 13 from (RS)-4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2,2-dimethyl - 1,3-dioxolane-4-yl-methoxymethyl)-pyrimidine-4-yl] - benzosulfimide received (RS)-4-tertbutyl-N-[5-(2-chloro-5 - methoxy-phenoxy)-6-(2,3-dioxy-propoxymethyl)-pyrimidine-4-yl] - benzosulfimide. MS:M = 551.

Example 19

By exchange reaction between 4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)- 6-(2-hydroxy-ethoxy-methyl)-pyrimidine-4-yl] -benzosulfimide and nicotinic acid had a complex 2-[6-(4-tertbutyl-phenylcarbonylamino)- 5-(2-chloro-5-methoxy-phenoxy) -pyrimidine-4-ylethoxy] -ethyl ester pyridine-3-yl-acetic acid. MS:M=626.

Example 20

By exchange reaction between 4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)- 6-(2-hydroxy-ethoxy-methyl)-pyrimidine-4-yl]-benzosulfimide and isonicotinic acid had a complex 2-[6-(4-tertbutyl-Penisula">

Example 21

By exchange reaction between 4-tertbutyl-N-[5-(2-chloro-5-methoxy - phenoxy)-6-(2-hydroxy-ethoxy-methyl)-pyrimidine-4-yl] -benzosulfimide and 3-frankenboob acid had a complex 2-[6-(4-tertbutyl-phenylcarbonylamino)-5-(2-chloro-5-methoxy-phenoxy)- pyrimidine-4-ylethoxy]-ether furan-3-carboxylic acid. MS:(M+N)+=618.

Example 22

By exchange reaction between 4-tertbutyl-N-[5-(2-chloro-5-methoxy - phenoxy)-6-(2-acetoxy-methyl)-pyrimidine-4-yl] -benzosulfimide and 3-thiophencarboxylic acid had a complex 2-[6-(4-tertbutyl-phenylcarbonylamino)-5-(2-chloro-5-methoxy-phenoxy)- pyrimidine-4-ylethoxy] -ethyl ester thiophene-3-carboxylic acid. MS:M=631.

Example 23

a) Analogously to that described in example 1, by exchange reactions between complex ethyl ester, 2,6-sodium dichloro-5-phenoxy-pyrimidine - 4-carboxylic acid and p-tertbutyl-benzosulfimide-potassium salt get complicated ethyl ester of 6-(4-tertbutyl-phenylcarbonylamino)-2 - chloro-5-phenoxy-pyrimidine-3-carboxylic acid. MS:(M+N)+=490.

b) Required as starting compound dichloride was prepared as follows:

130 mg of the complex of ethyl ether 2,6-dioxo-5-phenoxy-1,2,3,6 - tetrahydro-pyrimidine-4-carb is grebaut under reflux. POCl3removed in a water jet vacuum, the residue is distributed between water and acetic ether. After customary treatment of the organic phase the residue chromatographic on silica gel (solvent: CH2Cl2/simple ether: 6/1). The result is 44 mg complex ethyl ester 2,6-sodium dichloro-5-phenoxy-pyrimidine-4-carboxylic acid in the form of oil. MS:M=312.

b) Required as starting compound was prepared as follows: 1.8 g of 2,6-dioxo-5-phenoxy-1,2,3,6-tetrahydro-pyrimidine-4 - carboxylic acid (receiving is described in "Chemical heterocycle. Conn-I", 1974, page 1527) emuleret in 65 ml of ethanol, then add to 0.92 ml of concentrated H2SO4, and 0.92 ml SOCl2; and the mixture heated for 12 hours under reflux. Then concentrated using a rotary evaporator and filtered by suction drawn a solid residue, which chromatographic on silica gel (solvent: CH2Cl2a simple ether: 3/1). The result is 520 mg complex ethyl ester 2,6-dioxo-5-phenoxy-1,2,3,6-tetrahydro-pyrimidine - 4-carboxylic acid in the form of solids. MS:M = 276.

Example 24

In a solution containing 69 mg Na 5.0 ml of abs. ethanol was added 526 mg 4-tertbutyl-N-[6-Chlo for 4 hours using a heating under reflux. After evaporation of the solvent under reduced pressure the residue was distributed between acetic ether and 1 M aqueous tartaric acid, the organic phase was dried and evaporated, then the residue was recrystallized from alcohol. The result was a 4-tertbutyl-N- [6-ethoxy-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin - 4-yl] -benzosulfimide in the form of white crystals. So pl. 140-141oC.

4-tertbutyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-pyrimidine-2-yl)- pyrimidine-4-yl] -benzosulfimide received on the basis of the pyrimidine-2-carboxamide-hydrochloride through the rat-5-(2-methoxy - phenoxy)-2-pyrimidine-2-yl-tetrahydro-pyrimidine-4,6-dione and 4,6 - dichloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin.

Example 25

In the same way as described in example 24 4-tertbutyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(pyrimidine-2 - yl)-pyrimidine-4-yl] -benzosulfimide and sodium methylate in methanol was obtained 4-tertbutyl-N-[6-methoxy-5-(2-methoxy-phenoxy) -2-bipyrimidin-4-yl] -benzosulfimide in the form of a solid substance.

Example 26

In the same way as described in example 1 from 4-chloro-5-(2-chloro-5-methoxy-phenoxy)-6-methyl-2,2'-bipyrimidine got a 4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-methyl - 2,2'-bipyrimidin-4-yl] -benzosulfimide, so pl. 122it is written in example 1B), 2 - pyrimidinamine-hydrochloride obtained 5-(2-chloro-5-methoxy - phenoxy)-6-methyl-2,2'-bipyrimidin-4-ol. MS:M=344.

b) Analogously to that described in example 1B), from the above substance was obtained 4-chloro-5- (2-chloro-5-methoxy-phenoxy)-6-methyl-2,2'-bipyrimidine, so pl. 110oC, MS:M=363.

Example 27

In the same way as described in example 12, was obtained (S)-4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2,2 - dimethyl-1,3-dioxolane-4-ileocecal)-2-morpholine-4-yl) - pyrimidine-4-yl]-benzosulfimide. MS:M=677.

Example 28

In the same way as described in example 12, was obtained (R)-4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2,2 - dimethyl-1,3-dioxolane-4-yl-methoxymethyl)-2-(morpholine-4-yl) - pyrimidine-4-yl]-benzosulfimide. MS:M= 677.

Example 29

In the same way as described in example 13, obtained in example 28 compound was obtained (S)-4-tertbutyl-N-[5-(2-chloro-4-methoxy - phenoxy)-6-(2,3-deoxypyridoxine)-2-(morpholine-4-yl)-pyrimidine-4-yl]- benzosulfimide. MS:M=637.

Example 30

In the same way as described in example 13, obtained in example 28 compound was obtained (R)-4-tertbutyl-N-[5- (2-chloro-5-methoxy-phenoxy)-6-(2,3-dioxy-propoxymethyl)-2- (morpholine-4-yl)-pyrimidine-4-yl]-b is l-N-[6-chloromethyl-5-(2-chloro-5-methoxy-phenoxy) - pyrimidine-4-yl]-benzosulfimide and 2,3-O-isopropylidene-L - trait received (4S,5S)-4-tertbutyl-N-[5-(2-chloro-5-methoxy - phenoxy)-6-(5-oximeter-2,2-dimethyl-1,3-dioxolane-4 - ileocecal)-pyrimidine-4-yl]-benzosulfimide. MS:M=622.

Example 32

In the same way as described in example 18, obtained in example 31 compound was obtained (2S,3S)-4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6- (2,3,4-trihexyphenidyl)-pyrimidine-4-yl]-benzosulfimide. So pl. 192oC, MS:M=582.

Example 33

In the same way as described in example 2, obtained in example 26 compound was obtained 6-(4-tertbutyl - phenylsulfonyl)-5-(2-chloro-5-methoxy-phenoxy)-2,2'- bipyrimidin-4-carboxaldehyde, so pl. 211oC.

Example 34

In the same way as described in example 3 obtained in example 33 aldehyde got a 4-tertbutyl-N-[5-(2-chloro-5-methoxy - phenoxy)-6-oximeter-2,2'-bipyrimidin-4-yl]-benzosulfimide, MS:M=556.

Example 35

In the same way as described in example 4, obtained in example 34 alcohol got a 4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)- 6-chloro-methyl-2,2'-bipyrimidin-4-yl]-benzosulfimide, MS:M=574.

Example 36

In the same way as described in example 5, from Poluden-4-yl]-benzosulfimide, MS:(MH)-=598.

Example 37

In the same way as described in example 25 from 4-tertbutyl-N-[6-chloro-5-(2-chloro-5-methoxy-phenoxy-2-methyl - pyrimidine-4-yl] -benzenesulfonamide and sodium methylate in methanol was obtained 4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-methoxy - 2-methyl-pyrimidine-4-yl]-benzosulfimide, so pl. 174oC, MC:M- (SO2+Cl)=392.

Example 38

In the same way as described in example 2, obtained in example 37 compound was 4-tertbutyl-N-[5-(2-chloro-5-methoxy - phenoxy)-2-formyl-6-methoxypyridine-4-yl] -benzosulfimide, so pl. 163oC, MS:(M-N)-= 503.

Example 39

In the same way as described in example 3 obtained in example 38 compound was 4-tertbutyl-N-[5-(2-chloro-5-methoxy - phenoxy)-2-oxymethyl-6-methoxy-pyrimidine-4-yl] -benzosulfimide, so pl. 167oC, MS:M+N+= 508.

Example 40

In the same way as described in example 4, obtained in example 39 compound was 4-tertbutyl-N-[5-(2-chloro-5-methoxy - phenoxy)-2-chloromethyl-6-methoxy-pyrimidine-4-yl] -benzosulfimide, so pl. 165oC, MS:M= 526.

Example 41

In the same way as described in example 5, obtained in example 40 compound was 4-of treb
C, MS:M=552.

Example 42

In the same way as described in example 27, from the obtained in example 40 compound was obtained (RS)-4-tertbutyl-N-[5-(2-chloro-5-methoxy - phenoxy)-2-(2,2-dimethyl-1,3-dioxolane-4-ylethoxy-methyl)-6-methoxy - pyrimidine-4-yl] -benzosulfimide, so pl. 162oC, MS:M=622.

Example 43

In the same way as described in example 29, obtained in example 42 compound was obtained (RS)-4-tertbutyl-N-(5-(2-chloro-5 - methoxy-phenoxy)-2-(2,3-hydroxy-propoxy-methyl)-6-methoxy-pyrimidine-4-yl]- benzosulfimide, so pl. 81oC, MS:M=582.

Example 44

A solution containing 100 mg obtained in example 40 compound in 20 ml of NH3-dioxane was heated in a thick-walled flask to work under pressure for 16 hours up to 80oC. After evaporation the residue was chromatographically over silica gel with chloroform/methanol, resulted in 30 mg 4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)- 2-aminomethyl-6-methoxy-pyrimidine - 4-yl]-benzosulfimide, MS:M=507.

Example 45

In the same way as described in example 24 N-[5-(2-chloro-5-methoxy-phenoxy)-2-methyl-6-chloro-pyrimidine-4-yl] - 1,3-benzodioxol-5-sulfonamida and 2-methoxyethanol sodium was obtained N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-methoxy-ATOX

In the same way as described in example 2, obtained in example 45 compound was obtained N-[5-(2-chloro-5 - methoxy-phenoxy)-2-formyl-6-(2-methoxy-ethoxy)-pyrimidine-4-yl] - 1,3-benzodioxol-5-sulfonamide, MS:M-(SO2+ Cl) = 438.

Example 47

In the same way as described in example 3 obtained in example 46 compound was obtained N-[5-(2-chloro-5 - methoxy-phenoxy)-2-oxymethyl-6-(2-methoxy-ethoxy)-pyrimidine-4-yl]- 1,3-benzodioxol-5-sulfonamide, MS:M-(SO2+ Cl) = 440.

Example 48

In the same way as described in example 4, obtained in example 47 compound was obtained N-[5-(2-chloro-5-methoxy-phenoxy)-2 - chloromethyl-6-(2-methoxy-ethoxy)-pyrimidine-4-yl] -1,3-benzodioxol-5 - sulfonamide, MS:M-(SO2+ Cl) = 458.

Example 49

In the same way as described in example 41, obtained in example 48 compound was obtained N-[5-(2-chloro-5-methoxy-phenoxy)-2- (2-hydroxy-ethoxymethyl)-6-(2-methoxy-ethoxy)-pyrimidine-4-yl]-1,3-benzodioxol - 5-sulfonamide, MS:M = 584.

Example 50

In the same way as described in example 25 from 4-tertbutyl-N-[6-(2-chloro-5-methoxy-phenylsulfanyl)-2-methyl - pyrimidine-4-yl]-benzosulfimide got a 4-tertbutyl-N-[6 - methoxy-5-(2-methoxy-phenylsulfanyl)-2-methyl-pyrimidine-4-yl] - benzo is 2.2 ml of 2-methoxythiophene in 30 ml of ethanol was added 1 g of KOH. The reaction mixture was subjected at room temperature to the interaction with the complex solution of dimethyl ether of hormonology acid in 5 ml of ethanol, continuing to stir for another hour, then evaporated. The residue was distributed between the simple ether and water. The organic phase was dried, concentrated and the residue was purified over silica gel with methylene chloride. The result was obtained 3.6 g of a complex of dimethyl ether (2-methoxy-phenylsulfanyl) -malonic acid, MS:M = 270.

b) Analogously to that described in example 1B, obtained in example 50A substances and acetamide-hydrochloride obtained 6-hydroxy-5-(2-methoxy-phenylsulfanyl)-2-methyl-3,4-dihydro - pyrimidine-4-one, so pl. 290oC, MS:M = 264.

C) Analogously to that described in example 1B, obtained in example 50B substances obtained 4,6-sodium dichloro-5-(2 - methoxy-phenylsulfanyl)-2-methyl-pyrimidine, T. pl. 140oC, MS:M=301.

d) Analogously to that described in example 1, obtained in example 50B substances received 4-tertbutyl-N-[6-chloro-5-(2 - methoxy-phenylsulfanyl)-2-methyl-pyrimidine-4-yl] - benzosulfimide, so pl. 155oC.

Example 51

In the same way as described in example 2, obtained in example 50 wisest.

Example 52

In the same way as described in example 3 obtained in example 51 substances received 4-tertbutyl-N-[2-oxymethyl-6-methoxy-5- (2-methoxy-phenylsulfanyl)-pyrimidine-4-yl]-benzosulfimide, so pl. 152oC, MS:M=490.

Example 53

In a solution of sodium phenolate containing 0,024 g of phenol and 0.06 g of NaOH in 2 ml of acetone and 1 ml of water was added 0,145 g of 4-tertbutyl-N- [5-(2-chloro-5-methoxy-phenoxy)-6-chloro-methyl-2-(morpholine-4-yl) -pyrimidine-4-yl] -benzosulfimide (example 4) in 3 ml of acetone. The reaction mixture was stirred in an argon atmosphere for 48 hours at a temperature of 80oC. thereafter, the acetone was off, and the residue was distributed between chloroform and water. The chloroform phase was washed with water, dried over sodium sulfate and the solvent drove away. The residue was chromatographically over silica gel using chloroform. The result was 0.07 g of 4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-2-morpholine - 4-yl-6-phenoxymethyl-pyrimidine-4-yl]-benzosulfimide, MS:M = 639.

Example 54

In the same way as described in example 53, 4-Bifrost sodium was obtained N-[6-biphenyl-4-intoximeter-5-(2-chloro-5 - methoxy-phenoxy)-2-morpholine-4-yl-pyrimidine-4-yl]-4-tertbutyl - benzosulfimide, MS:M=715.

Example 55

Analogically-4-yl] - 1,3-benzodioxol-5-sulfonamida from 520 mg of N-[6-chloro-5-methoxy-phenoxy)-2-methylsulfanyl-pyrimidine-4-yl] -1,3 - benzodioxol-5-sulfonamida and 270 mg of sodium methylate in abs. MeOH. So pl. 176oC (from ethanol).

Example 56

Other examples of compounds obtained according to the invention, are the following:

4-methoxy-N-[6-methoxy-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin - 4-yl]-3-(3-morpholine-4-yl-3-oxopropyl)-benzosulfimide;

complex 2-[4-[6-methoxy-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl-sulfamoyl] phenoxy]-ethyl ester of acetic acid;

4-(2-hydroxy-ethoxy)-N-[6-methoxy-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]- benzosulfimide;

N-[6-methoxy-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-4-(2-morpholine-4 - yl-2-oxo-ethoxy)-benzosulfimide;

N-[6-methoxy-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-4-(3-morpholine - 4-yl-3-oxo-propyl)-benzosulfimide;

4-methoxy-N-[6-methoxy-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl] -3-(2-oxoethyl)-benzosulfimide;

complex ethyl ester [2-methoxy-5-[6-methoxy-5-(2-methoxy - phenoxy)-2,2'-bipyrimidin-4-yl-sulfamoyl]phenoxy]-acetic acid;

4-tertbutyl-N-[6-methoxy-5-(2-methoxy-phenoxy)-2-methyl - pyrimidine-4-yl] -benzosulfimide;

4-tertbutyl-(6-methoxy-5-naphthalene-2-yloxy-2,2'-b which may be made in the usual way:

Ingredients per tablet

The compounds of formula I - 10,0 - 100,0 mg

Lactose - 125,0 mg

Corn starch is 75.0 mg

Talc - 4.0 mg

Magnesium stearate 1.0 mg

Example B

Capsules containing the following ingredients can be manufactured in the usual way:

Ingredients one capsule

The compounds of formula I - 25.0 mg

Lactose - 150,0 mg

Corn starch - 20.0 mg

Talc - 5.0 mg

The example IN

Injectable solutions may have the following composition:

The compound of formula I - 3.0 mg

Gelatin - 150,0 mg

Phenol - 4,7 mg

Water for injection solutions ad 1.0 ml

Example D

3.5 ml of megliola 812 and 0.08 g of benzyl alcohol are suspended 500 mg of the compounds of formula 1. The resulting suspension is placed in a canister with a metering valve. Through this valve into the canister serves under pressure of 5.0 g of freon 12. As a result of shaking the freon is dissolved in a mixture of megliola and benzyl alcohol. This spray contains approximately 100 single doses, which can be used separately.

1. New sulfonamides

< / BR>
where R1denotes hydrogen, lower alkyl;

R2denotes hydrogen, lower alkyl;

R3ibupropen identix;

R4denotes hydrogen, lower alkyl, lower alkoxyl, lower alkylthio, hydroxy-lower alkyl, hydroxy-lower alkoxy, hydroxy-lower alkoxy-lower alkyl, hydroxy-lower alkoxy-lower alkoxy, alkoxy-lower alkyl, alkoxy-lower alkyloxy, amino-lower alkyl, lower alkyl-amino-lower alkyl, morpholino, 2-pyrimidinyl, -CHO, -CH2OH or-CH2Cl;

R5-R8denote hydrogen, halogen, lower alkoxy, lower alkylthio;

X denotes-O - or-S-;

Y represents-CHO, C1-4-alkyl, -(CH2)1-4-Z-R9, -(CH2)0-3C(O)OR9, -(CH2)1-4-OC(O)(CH2)1-4CH3, -(CH2)1-4-OC(O)het, -(CH2)1-4OCH2CH(OH)CH2OH and its cyclic ketals, -(CH2)1-4NR9CH2CH(OH)CH2OH, -(CH2)1-4O(CH2)1-4-ZH,

-(CH2)1-4NR9(CH2)1-4-ZH, -(CH2)1-4O(CH2)1-4-OC(O)het, -(CH2)1-4Gal-OR12; R9represents hydrogen or C1-4-alkyl,

R12represents a C1-4-alkyl or -(CH2)0-4-aryl;

Z represents-O-;

het is a heterocyclic residue such as thienyl, furyl, pyridinyl;

Gal - halogen;

n denotes 0 and is achene, specified in paragraph 1.

3. Connection on p. 1, where Y represents-CHO, C1- C4alkyl, -(CH2)1-4-Z-R9, -(CH2)1-4-OC(O)het, -C(O)OR9, -(CH2)1-4-OC(O)(CH2)1-4CH3,

-CH2OCH2CH(OH)CH2OH and its cyclic ketals, -CH2NR9CH2CH(OH)CH2OH, -CH2O(CH2)1-4-ZH, -CH2NR9(CH2)1-4-ZH, -CH2O(CH2)1-4-OC(O)het, -CH2Gal;

R1-R9, R11, gets, Gal, X, Z and n have the meanings specified in paragraph 1.

4. Connection PP.1 - 3, where n represents 1 and X represents 0.

5. Compounds according to any one of paragraphs.1 to 4, where R1and R2denote hydrogen; R3denotes lower alkyl.

6. Compounds according to any one of paragraphs.1 - 5, where R6denotes lower alkoxy; R5and R7denote hydrogen; R8denotes halogen.

7. Compounds according to any one of paragraphs.1 - 6, where R4denotes hydrogen, 2-pyrimidinyl, morpholino.

8. Compounds according to any one of paragraphs.1 to 7, where Y represents-CHO, C1-4alkyl, -(CH2)-Z-R9, -CH2O-CH2CH(OH)CH2OH and its cyclic ketals; -CH2NR9CH2CH(OH)CH2OH, -CH2O(CH2)1-4-ZH, -CH
4-tertbutyl-N-[6-methoxy-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl] -benzosulfimide.

10. Connection on p. 3:

4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-methyl-2-(morpholine-4-yl)-pyrimidine-4-yl]-benzosulfimide,

4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-formyl-2-(morpholine-4-yl)-pyrimidine-4-yl]-benzosulfimide,

4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-oxymethyl-2-(morpholine-4-yl)-pyrimidine-4-yl]-benzosulfimide,

4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-chloromethyl-2-(morpholine-4-yl)-pyrimidine-4-yl]-benzosulfimide,

4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-acetoxymethyl)-2-(morpholine-4-yl)-pyrimidine-4-yl]-benzosulfimide,

4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-methyl-pyrimidine-4-yl]-benzosulfimide,

4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-formyl-pyrimidine-4-yl] -benzosulfimide,

4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-hydroxy-methyl-pyrimidine-4-yl]-benzosulfimide,

4-tertbutyl-N-[5-(2-chloromethyl-5-(2-chloro-5-methoxy-phenoxy)-pyrimidine-4-yl]-benzosulfimide,

4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxymethyl)-pyrimidine-4-yl]-benzosulfimide,

complex 2-[6-(4-tertbutyl-phenylsulfonyl)-5-(2-chloro-5-methoxy-phenoxy)-2-(morphol the si-phenoxy)-6-(2,2-dimethyl-1,3-dioxolane-4-ileocecal)-2-morpholine-4-yl)-pyrimidine-4-yl] -benzosulfimide,

(RS)-4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2,3-deoxypyridoxine)-2-(morpholine-4-yl)-pyrimidine-4-yl]-benzosulfimide,

4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethylaminomethyl)-pyrimidine-4-yl]-benzosulfimide,

4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(3-hydroxy-propoxymethyl)-pyrimidine-4-yl]-benzosulfimide,

(RS)-4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2,3-dioxy-propylaminoethyl)-pyrimidine-4-yl]-benzosulfimide,

(RS)-4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2,2-dimethyl-1,3-dioxolane-4-ileocecal)-pyrimidine-4-yl]-benzosulfimide,

(RS)-4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2,3-dioxy-propoxymethyl)-pyrimidine-4-yl]-benzosulfimide,

complex 2-[6-(4-tertbutyl-phenylcarbonylamino)-5-(2-chloro-5-methoxy-phenoxy)-pyrimidine-4-ylethoxy]-ethyl ester pyridine-3-yl-acetic acid,

complex 2-[6-(4-tertbutyl-phenylcarbonylamino)-5-(2-chloro-5-methoxy-phenoxy)-pyrimidine-4-ylethoxy]-ethyl ester pyridine-3-yl-acetic acid,

complex 2-[6-tertbutyl-phenylcarbonylamino)-5-(2-chloro-5-methoxy-phenoxy)-pyrimidine-4-ylethoxy]-ethyl ester furan-3-carboxylic acid,

complex 2-[6-tertbutyl-phenylcarbonylamino)-5-(2-chloro-5-methoxy-phenoxy)-pyrimidine-4-ylethoxy-chloro-5-phenoxy-pyrimidine-3-carboxylic acid.

11. Connection on p. 1:

4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-methyl-2,2'-bipyrimidin-4-yl]-benzosulfimide,

(S)-4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2,2-dimethyl-1,3-dioxolane-4-ileocecal)-2-morpholine-4-yl)-pyrimidine-4-yl] -benzosulfimide,

(R)-4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2,2-dimethyl-1,3-dioxolane-4-ileocecal)-2-(morpholine-4-yl)-pyrimidine-4-yl] -benzosulfimide,

(S)-4-tertbutyl-N-[5-(2-chloro-4-methoxy-phenoxy)-6-(2,3-dioxy-propoxymethyl)-2-(morpholine-4-yl)-pyrimidine-4-yl]-benzosulfimide,

(R)-4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2,3-dioxy-propoxymethyl)-2-(morpholine-4-yl)-pyrimidine-4-yl]-benzosulfimide,

(4S, 5S)-4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(5-oximeter-2,2-dimethyl-1,3-dioxolane-4-ileocecal)-pyrimidine-4-yl] -benzosulfimide,

(2S, 3S)-4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2,3,4-trihexyphenidyl)-pyrimidine-4-yl]-benzosulfimide,

6-(4-tertbutyl-phenylsulfonyl)-5-(2-chloro-5-methoxy-phenoxy)-2,2'-bipyrimidin-4-carboxaldehyde,

4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-oximeter-2,2'-bipyrimidin-4-yl]-benzosulfimide,

4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-chloromethyl-2,2'-bipyrimidin-4-yl]-benzosulfimide,

4-what butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-methoxy-2-methyl-pyrimidine-4-yl]-benzosulfimide,

4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-2-formyl-6-methoxypyridine-4-yl]-benzosulfimide,

4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-2-oxymethyl-6-methoxy-pyrimidine-4-yl]-benzosulfimide,

4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-2-chloromethyl-6-methoxy-pyrimidine-4-yl]-benzosulfimide,

4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-2-(2-acetoxymethyl-6-methoxy-pyrimidine-4-yl]-benzosulfimide,

(RS)-4-tertbutyl-N-[5-(chloro-5-methoxy-phenoxy)-2-(2,2-dimethyl-1,3-dioxolane-4-ylethoxy-methyl)-6-methoxy-pyrimidine-4-yl]-benzosulfimide,

(RS)-4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-2-(2,3-deoxypyridoxine)-6-methoxy-pyrimidine-4-yl]-benzosulfimide,

4-tertbutyl-N-[5-(2-chloro-5-methoxy-phenoxy)-2-aminomethyl-6-methoxy-pyrimidine-4-yl]-benzosulfimide,

N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-methoxy-ethoxy)-2-methyl-pyrimidine-4-yl]-1,3-benzodioxol-5-sulfonamide,

N-[5-(2-chloro-5-methoxy-phenoxy)-2-formyl-6-(2-methoxy-ethoxy)-pyrimidine-4-yl]-1,3-benzodioxol-5-sulfonamide,

N-[5-(2-chloro-5-methoxy-phenoxy)-2-oxymethyl-6-(2-methoxy-ethoxy)-pyrimidine-4-yl]-1,3-benzodioxol-5-sulfonamide,

N-[5-(2-chloro-5-methoxy-phenoxy)-2-chloromethyl-6-(2-methoxy-ethoxy)-pyrimidine-4-yl]-1,3-benzodioxol-5-sulfonamide,

N-[5-(2R>
4-tertbutyl-N-[6-methoxy-5-(2-methoxy-phenylsulfanyl)-2-methyl-pyrimidine-4-yl]-benzosulfimide,

4-tertbutyl-N-[2-formyl-6-methoxy-5-(2-methoxy-phenylsulfanyl)-pyrimidine-4-yl]-benzosulfimide and

4-tertbutyl-N-[2-oxymethyl-6-methoxy-5-(2-methoxy-phenylsulfanyl)-pyrimidine-4-yl]-benzosulfimide.

12. Sulfonamides of formula I on PP.1 - 11, has an inhibitory effect on endothelial binding.

13. Sulfonamides of General formula I on PP.1 - 11 for the manufacture of medicinal products, which have a braking effect on endothelin receptors and affect the processes associated with increased vasoconstriction.

Priority points:

10.12.92 - PP.1, 3 - 7, 9 - 12;

14.10.93 - PP.2 and 8. Based on the originally filed.

 

Same patents:

The invention relates to new sulfonamide of General formula I, where R1-R8A and B have the meanings indicated in the formula, which are inhibitors of endothelin and can be used for the treatment of diseases associated with the activity of endothelin, such as high blood pressure, as well as to pharmaceutical compositions based on

The invention relates to a method for producing sodium and potassium salts of N-heterocyclization/arylsulfonamides General formula

< / BR>
where R1- Cl COOCH3; R2- CH3, OCH3, R3- CH3; X is N, CH, M is Na, K, and more particularly to a method of obtaining sodium and potassium salts of chlorsulfuron II and III sulfometuron

The invention relates to new derivatives of salicylic acid f-ly Gets-NR-SO2-Ph1A Ph2(COOH)(OH), (I), where Het represents (R1, R2, R3-Het1That gets1represents a cyclic systemin which the free valence is associated with a group NR; X is a group: a) -O-CH=CH-, -CH=CH-O-, -CH= CH-S - or b) -CH=CH-CH=CH-, -CH=CH-CH=N-, -CH=N-CH=CH-, -CH=CH-N=CH-, -N= CH-CH= CH-; R1, R2and R3are substituents at the carbon atom in Het and represent hydrogen, C1-C6- alkyl, halogen, hydroxy - or benzyloxy; R is hydrogen or C1-C6- alkyl; Ph1- phenylene, Ph2is phenyl which may be substituted with halogen, lower alkyl or benzyloxypropionic, provided that the carboxy - and hydroxy-group are in the ortho-position to each other; And a represents - CC-, -CH=CH-, -CH2-CH2-, -CO-CH=CH-, -CH=CH-CO-

The invention relates to methods seleting suppression of undesirable plant species in the presence of agricultural crops

The invention relates to new derivatives sulfonamida, method for their production and pharmaceutical compositions containing these compounds as active ingredient

The invention relates to new derivatives of arylsulfonamides, which can be used in agriculture as a herbicide for weed control in soybean crops, in particular in a mixture with other compounds

The invention relates to new compounds of the formula I

Y-(CmH2m-CHR1)n-CO- (NH-CHR2CO)r-Z

where Y denotes

< / BR>
or

< / BR>
Z denotes

< / BR>
or if Y

< / BR>
also means

< / BR>
R1, R2and R7each means-CtH2t-R9,

R3means H or H2N-C(=NH)-,

R4and R6each means (H,H) or =O,

R5means H2N-C(=NH) -, or H2N-C(=NH)-NH,

R8means OH or OA,

R9denotes H or COOH,

A denotes alkyl with 1-4 C-atoms,

m and t each is 0, 1 or 2,

n and r each denotes 0 or 1 and

p is 0, 1 or 2,

and their salts

The invention relates to medicine and veterinary medicine, namely to medical and veterinary helminthology, and can be used for larval treatment of hydatid cysts and other castadot human and animal
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The invention relates to new compounds with strong anti-tumor activity that meets the General formula (I), where the values of R1- R7, A, Z, Y, X specified in paragraph 1 of the formula

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

their pharmaceutically acceptable salts or solvates, or salt solvates wherein R1 represents (C1-C6)-alkyl, cycloalkyl, aryl, aliphatic or aromatic heterocyclyl substituted with one more basic group, such as amino-, amidino- and/or guanidine-group; R2 represents hydrogen atom (H), alkyl, alkylthio-, alkoxy- or cycloalkyl group; R3 represents COOR5, SO(OR5), SOR5 and others; R4 represents hydrogen atom (H) or (C1-C6)-alkyl; R6 represents hydrogen atom (H); X represents C(Z)2 or NR6CO; Y represents C(Z)2; Z represents hydrogen atom (H), (C1-C6)-alkyl, aryl or cycloalkyl. Indicated compounds inhibit activity of carboxypeptidase U and can be used for prophylaxis and treatment of diseases associated with carboxypeptidase U.

EFFECT: improved preparing method, valuable biochemical and medicinal properties of compounds.

14 cl, 36 ex

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