SI9200268A - Use sulfonamides as drug and new sulfonamides - Google Patents

Abstract

Use of sulfonamides of the formula: Sl 9200268 A in which the symbols R1 to R6, X, Y and n are in the description said meaning and which are in part novel compounds; and salts thereof, as active substances in the preparation of medicaments for treatment of circulatory disorders, especially hypertension, ischemia, vasospasm and angina.

Description

F.HOFFMANN-LA ROCHE AG

USE OF SULFONAMIDES FOR THE PREPARATION OF MEDICINAL PRODUCTS AND NEW SULFONAMIDES

The present invention relates to the use of sulfonamides for drug preparation and to novel sulfonamides. The invention relates in particular to the use of compounds of formula

in which

R1 represents hydrogen, lower-alkyl, lower-alkoxy, lower-alkylthio, halogen or trifluoromethyl,

R ² represents hydrogen, halogen, lower-alkoxy, hydroxy-lower alkoxy or trifluoromethyl,

R4 represents hydrogen, hydroxy, halogen, alkylthio, cycloalkyl, hydroxy-lower-alkyl, hydroxy-lower-alkoxy, hydroxyimino-lower-alkyl, lower-alkenyl, oxo-lower-alkyl, trifluoromethyl, trifluoromethoxy, lower-alkoxy, lower -alkoxy-lower-alkoxy or aryl-lower-alkoxy;

R ² and R ² together represent butadienyl;

R 4 represents hydrogen, lower alkyl, aryl or heteroaryl;

R 5 represents hydrogen, lower alkanoyl, benzoyl, heterocyclyl-carbonyl or tetrahydropyran-2-yl;

R 6 represents a residue of formula

R7 represents hydrogen, lower-alkoxy or nitro;

R 5 represents hydrogen, halogen, lower-alkyl, lower-alkoxy, lower-alkylthio, nitro, hydroxy, amino or trifluoromethyl;

R ^ and r8 together represent butadienyl;

R4 represents hydrogen, halogen, lower-alkyl, lower-alkoxy, lower-alkylthio or trifluoromethyl;

R10 represents hydrogen, halogen, lower-alkyl, lower-alkoxy or lower-alkylthio;

X and Y independently represent O, S or NH; and n represents 2,3 or 4;

and their salts as active ingredients in the preparation of medicaments for the treatment of circulatory disorders, in particular hypertension, ischemia, vasospasms and angina.

The term used herein refers to groups of 1 to 7 C atoms, preferably 1 to 4 C atoms. Alkyl, alkoxy, alkylthio and alkenyl groups as well as alkyl groups as constituents of alkanoyl groups may be straight or branched. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec. and tert.butyl. Examples of alkenyl groups are vinyl and allyl. Aryl-lower-alkoxy is e.g. benzyloxy. Halogen denotes fluorine, chlorine, bromine and iodine, with chlorine being preferred. Examples of aryl radicals are phenyl and substituted phenyl radicals, with halogen, alkyl and alkoxy being the substituents. Examples of heteroaryl residues are, in particular, monocyclic 5- and 6-membered heteroaromatic residues with nitrogen or sulfur as the hetero atom, such as pyrimidinyl, pyridyl, pyrazenyl, pyridazinyl and thienyl. Heterocyclyl-carbonyl residues are e.g. 2-, 3- or 4-pyridylcarbonyl, 3-methylisoxazol-5-ylcarbonyl, 2- or 3-furoyl and 2- or 3-thenoyl.

DE 1 545 944 discloses sulfonamides known to fall within the above formula I. These known sulfonamides have a blood pressure lowering effect. However, it has now surprisingly been found that the compounds of Formula I above are endothelin receptor inhibitors. The compounds of formula I can therefore be used for the treatment of diseases related to endothelin activities, in particular diseases of the bloodstream, such as hypertonia, ischemia, vasospasms and angina.

A preferred group of compounds of formula I are those wherein it represents a residue of formula

and R1l represents halogen, lower-alkoxy, lower-alkylthio or trifluoromethyl, Rl2 represents hydrogen or lower-alkoxy, and R1 to R4, X, Y and n have the meanings indicated above.

A further preferred group of compounds within the formula I are those wherein R1 represents the residue of the formula

and R13 is hydrogen, lower-alkoxy or nitro and R4 is hydrogen, halogen, lower-alkyl, lower-alkoxy, lower-alkylthio or nitro, or R4 and R14 are total butadienyl and R1 to R4, X, Y, and n the meaning given above.

Compounds of formula I can be prepared by treating a compound of formula

in which R1, R4, r3, r4 and _n r6 have the above meaning and Hal is halogen, converted with the compound of formula

MX (CH ₂ ) _n YR ⁵ III in which X, Y, n and the above meanings and M represents an alkali metal, and optionally in the resultant compound of formula I, convert the present substituents and / or translate the resulting compound of formula I into salt;

In one of the preferred embodiments of the process, the compounds of formulas II or V are derived, wherein R1 represents one of the residues (c) or (d) defined above.

Conversion of a compound of formula II with a compound of formula III is efficiently carried out using the glycol that is the basis for compound III, e.g. in ethylene glycol if n = 2. The alkali metal M is preferably sodium. The reaction is conveniently carried out by heating, e.g. at 70 -120 ° C. In a preferred embodiment, the mono-sodium salt of ethylene, propylene or butylene glycol is used as the compound of formula III.

In the compound of formula I thus obtained, the substituents present therein can be converted. So e.g. the hydroxy group of R4 can be esterified or esterified. The nitro group can be reduced to the amino group. The lower alkenyl group R4 can be e.g. with OSO4 or NaJC> 4 oxidize to the carbonyl group, resp. to the alkanone group; the carbonyl group thus formed may e.g. with sodium borohydride is reduced to a hydroxy group, or with an alkyl-Grignard compound converted to the corresponding tertiary alcohol or converted with hydroxylamine to oxime. These transformations can be carried out in a manner known per se, wherein the hydroxy group R1 is previously converted to an ether group, e.g. tetrahydropyranylether, or to an ester group, e.g. to the acetate.These groups can optionally be cleaved in a manner known per se; on the other hand, the conversion of the hydroxy group R1 can be carried out by esterification or etching without further conversion of other reactive groups in the molecule. The compounds of formula I can in themselves be converted into salts in a known manner, e.g. alkali salts as Na- and K- salts.

Compounds of formulas II and III used as starting material, unless known or prepared, are prepared analogously to known methods or methods. to those described below.

The compounds of formula II can be prepared in the sense of the following reaction scheme:

IV /

R ⁶ —CH .COOEt

COOEt

II

Condensation of compound IV with formamidine acetate or a homologous compound such as acetamidine acetate or hydrochloride gives pyrimidinedione V. With phosphorus oxychloride, dichloro compound VI is obtained, which gives compound II when converted with compound VII. All of these conversions are standard operations and can be performed under conditions customary for such reactions and evident to one skilled in the art. Compounds IV, where R.6 represents the residue (a), can be obtained from the corresponding phenylacetic acid esters of the formula R ^C ^ CCOOEt by conversion with diethyl carbonate in the presence of sodium ethylate. Compounds IV in which R4 represents the residue (b) can be prepared by the Knoevenagel condensation of the malonic acid diethyl ester with the corresponding R ^ CHO aldehyde and subsequent hydrogenation of the condensation product.

The inhibitory effect of the compounds of formula I on endothelin receptors can be demonstrated by the arrangement of the experiments described below:

I: Inhibition of endothelin binding to human placental membranes (Cf. Life Sci 44: 1429 (1989))

The human placenta was homogenized in 5 mM Tris buffer pH 7.4 containing 1 mM MgCl2 and 250 mM sucrose. The homogenate was centrifuged at 3000 g for 15 minutes at 4 ° C, the top layer containing the plasma membrane fraction was centrifuged at 72 000 g for 30 minutes and the body washed at the bottom with 75 mM Tris buffer, pH 7.4 containing 25 mM MgCl2. Subsequently, the body from the bottom obtained from each 10 g of original tissue was suspended in 1 ml of 75 mM Tris buffer, pH 7.4 containing 25 mM MgCl2 and 250 mM sucrose, and frozen in 1 ml aliquots at -20 ° C.

For the binder experiment, frozen membrane preparations were thawed and, after 10 minutes of centrifugation at 25,000 g at 20 ° C, were resuspended in assay buffer (50 mM Tris buffer, pH 7.4 containing 25 mM MnQ2>

mM EDTA and 0.5% bovine serum albumin). 100 μ] of this membrane suspension containing 70 µg of protein was incubated with 50 μ \ ¹²⁵ J-endothelin (specific activity 2200 Ci / mmol) in assay buffer (25 000 cpm, final concentration 20 pM) and 100 μϊ assay buffer containing variable concentrations of the test compound. The incubation was performed for 2 hours at 20 ° C or 24 hours at 4 ° C. Separation of free and membrane bound radioligands was performed by filtration through a glass fiber filter.

In Table 1, the inhibitory effect of the compounds of formula I as IC50, i.e., the concentration [μΜ] required to inhibit 50% specific binding of ¹²⁵ J-endothelin, is indicated in this assay arrangement.

Table 1

The compound of the Example IC ₅₀ [μΜ] 1 5 54 3 63 1.6 64 2 66 0.5 83 0.7 84 1

II. Inhibition of endothelin-induced contractions on isolated rat aortic rings

Thorax aorta of adult Wistar-Kyoto rats were cut into 5 mm rings. The endothelium was removed by lightly rubbing the inner surface. Each ring was immersed in 10 ml Krebs-Henseleit solution at 37 ° C when poured with 95% O2 and 5% CO2 in an insulated bath. The isometric tension of the rings was measured. The rings were stretched to a prestress of 3 g. After 10 minutes of incubation with the test compound or medium, cumulative doses of endothelin-1 were added. The activity of the test compound was determined by calculating the dosage ratio, i.e. moving to the right, (moving to higher values) for the Εθ5θ of endothelin evoked by 100 μΜ of the test compound, with EC50 indicating the endothelin concentration required for the maximal contraction. The higher the dose ratio, the more strongly the test compound inhibits the biological effect of endothelin-1. The EC5q of endothelin in the absence of test compounds is 0.3 nM.

The compounds of formula I thus obtained values for the EC50 shift of the endothelin to the right are listed in Table 2.

Table 2

The compound of the Example Dose ratio (scroll right) 1 30 54 21 63 23 64 19 66 96 83 86 84 106

III. The inhibitory effect of the compounds of Formula I on vasoconstriction can be observed in vivo in the rat in the arrangement of the experiment described below.

Rats were anesthetized with Na-thiobutabarbital (100 mg / kg i.p.). A catheter was placed over the femoral artery to measure systemic arterial blood pressure, and over the femoral vein, a catheter was inserted into the vena cava inferior to inject these test compounds. We placed a Doppler probe in the left renal artery and connected to a Doppler meter. Renal ischemia was induced by 45 minutes of compression of the left renal artery at the exit site. The test compounds were administered 10 minutes before the introduction of ischemia intraarterially (i.a.) at doses of 5 mg / kg or intravenously (i.v.) at doses of 10 mg / kg. In the control experiments, renal blood flow was reduced in comparison with the pre-ischemic value by 43 +. 4%.

The measured values obtained with the two compounds of formula I are listed in Table 3.

Table 3

The compound of the Example % reduction in renal blood flow 1 i.a. 7 83 i.v. 29

The compounds of formula I can be used as agents for the treatment of diseases associated with vasoconstriction-enhancing processes, based on their ability to inhibit endothelin binding. Examples of such disorders are high blood pressure, coronary heart disease, heart failure, renal and myocardial ischemia, renal failure, dialysis, cerebral ischemia, heart attack, migraine, subarachnoid hemorrhage, Raynaud's syndrome and pulmonary high pressure. They can also be used in atherosclerosis, restenosis inhibition after balloon-induced vascular dilation, inflammation, gastric and duodenal ulcers, ulcus cruris, Gram-negative sepsis, shock, glomerulonephritis, renal colic, glaucoma, asthma, therapy and profile diabetic complications and complications with ciclosporin administration, as well as other diseases associated with endothelin activity.

The compounds of formula I may be administered orally, rectally, parenterally, e.g. intravenously, intramuscularly, subcutaneously, intrathecally or transdermally; or sublingually or as an ophthalmic preparation or as an aerosol. Examples of the application forms are capsules, tablets, suspensions or solutions for oral administration, suppositories, injectable solutions, eye drops, ointments or spray solutions.

The preferred route of administration is intravenous, intramuscular or oral administration. The dosages in which the compounds of Formula I are administered in effective amounts depend on the type of specific active ingredient, the age and needs of the patient and the mode of administration. Generally, dosages of 0.1 to 100 mg / kg body weight per day are appropriate. Formulations containing compounds of formula I may contain inert or also pharmacodynamically effective additives. The tablets or granules may e.g. they contain a variety of binders, fillers, carriers or thinners. Liquid preparations may be e.g. in the form of a sterile, water-miscible solution. However, the capsules may also contain, in addition to the active ingredient, a filler material or thickener. In addition, flavor enhancers may be present as well as substances commonly used for preserving, stabilizing, moisturizing and emulsifying purposes, as well as osmotic pressure salts, buffers and other additives.

The carriers and diluents mentioned above may exist from organic or inorganic substances, e.g. of water, gelatin, milk sugar, starch, magnesium stearate, talc, arabic gum, polyalkylene glycols and the like. The prerequisite, however, is that all the excipients used in the preparation of the preparations are non-toxic.

Example 1

A solution of 0.046 g Na in 1.5 ml abs. of ethylene glycol was added 0.216 g of N- [6-chloro-5 (p-chlorophenyl) -4-pyrimidinyl-a,?, -trifluoro-p-toluenesulfonamide under moisture exclusion and then heated to 100 ° C for 3 hours, then cooled to room temperature temperature and 2.3 ml of IN HCl were added. The mixture was taken up in ethyl acetate, washed with organic extracts with water, dried and evaporated under reduced pressure. The remaining precipitate was recrystallized from CH2Cl2, isopropylether and n-hexane to give N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl-a, a, a-trifluoro-p-toluenesulfonamide. m.p. 160-162 ° C.

The starting material was prepared as follows:

A solution of 1,052 g of potassium α, α, α-trifluorobenzenesulfonamide and 0.520 g

4,6-Dichloro-5- (p-chlorophenyl) pyrimidine (Chem. Abstract. 63, I8O78-HO4) in 6 ml abs. of dimethylformamide was heated at 100 ° C for 4 hours, then cooled to room temperature and 5 ml of IN HCl were added. The mixture was taken up in ethyl acetate, the organic extracts were washed with water, dried and evaporated under reduced pressure. N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] -a, a,? -Trifluoro-p-toluenesulfonamide was obtained as a white solid from m.p. 275 ° C (from acetonitrile).

Example 2

Analogous to Example 1, N- [5- (p-chlorophenyl) -6- (N-[6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] -β- (trifluoromethoxy) benzenesulfonamide and Na-ethylene glycol) was obtained. 2hydroxyethoxy) -4-pyrimidinyl] -β-trifluoromethoxy) benzenesulfonamide; m.p. 152 ° C (from isopropyl ether).

The starting material was prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and potassium p- (trifluoromethoxy) benzenesulfonamide, m.p. 240 - 242 ° C.

Example 3

Analogous to Example 1, p-chloro-N- [5- (m-chlorophenyl) -6 was obtained from p-chloro-N- [6-chloro-5- (m-chlorophenyl) -4-pyrimidinyl] benzenesulfonamide and Na-ethylene glycol - (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide;

m.p. 178-180 ° C (from acetone-isopropyl ether).

The starting material was prepared as follows:

a) A solution of 3.96 g Na and 100 ml abs. of methanol was added 5.97 g of formamidinacetate. After cooling the solution to 10 ° C, 15.51 g of diethyl (m-chlorophenyl) malonate was gradually added. After 2.5 hours, the solvent was evaporated under reduced pressure, the residue was dissolved in water and the solution was adjusted with ice to pH 5.0. The resulting precipitate was filtered off, washed with water, ethanol and ether and dried under reduced pressure at 70 ° C. 5- (m-Chlorophenyl) -4,6 (1H, 5H) -pyrimidinedione was obtained, which was used directly in the next step.

b) A mixture of 10.6 g of 5- (m-chlorophenyl) -4,6 (1H, 5H) -pyrimidinedione, 36 ml of POCl3 and 5.8 ml of Ν, dim-dimethylaniline was boiled under reflux for 3 hours. After evaporation of the solvent under reduced pressure, ice was added to the residue and the mixture was extracted with ether. The organic solvent was dried and evaporated under reduced pressure. The oily residue was taken up in n-hexane, crystallizing 4,6-dichloro-5- (m-chlorophenyl) -pyrimidine;

m.p. 93 - 94 ° C.

c) p-Chloro-N- [6-chloro-5- (m-chlorophenyl) -4-pyrimidinyl] benzenesulfonamide was obtained from 4,6-dichloro-5- (m-chlorophenyl) pyrimidine and potassium p-chlorobenzenesulfonamide; m.p. 226 - 228 ° C (from CH3CN).

Example 4

Analogous to Example 1, p-chloro-N- [5- (p-fluorophenyl) -6- (2 -) was obtained from p-chloro-N- [6-chloro-5- (p-fluorophenyl) -4-pyrimidinyl] benzenesulfonamide. hydroxyethoxy) -4pyrimidinylbenzenesulfonamide; m.p. 208-212 ° C (from CH3CN).

The starting material was prepared as follows:

a) Analogous to Example 3, paragraph a), 5- (p-fluorophenyl) -4,6 (1H, 5H) -pyrimidinedione was obtained from diethyl- (p-fluorophenyl) malonate and formamidinacetate as a solid, which was used directly at the next level.

b) Analogous to Example 3, paragraph b), 4,6-dichloro-5- (p-fluorophenyl) -pyrimidine was obtained from 5- (p-fluorophenyl) -4,6 (1H, 5H) pyrimidinedione and POCl 3; m.p. 98 -99 ° C (from n-hexane).

c) Analogous to Example 3, paragraph c), p-chloro-N- [6-chloro-5- (p-fluorophenyl) was obtained from 4,6-dichloro-5- (p-fluorophenyl) pyrimidine and potassium p-chlorophenylsulfonamide -4pyrimidinylbenzenesulfonamide;

m.p. 251-254 ° C (from methylene chloride-isopropyl ether).

Example 5

Analogous to Example 1, N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) was obtained from N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] -p-fluorobenzenesulfonamide and Na-ethylene glycol ) -4pyrimidinyl] -β-fluorobenzenesulfonamide; m.p. 181-183 ° C (from methylene chloride isopropyl ether).

starting material was prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and pfluorophenylsulfonamide. Tal. 244-246 ° C (from methylene chloride-isopropyl ether).

Example 6

Analogous to Example 1, o-chloro-N- [5- (p-chlorophenyl) -6 was obtained from o-chloro-N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] benzenesulfonamide and Na-ethylene glycol - (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide;

m.p. 183 - 185 ° C (from acetone and isopropyl ether).

The starting material was prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and o-chlorophenylsulfonamide. Tal. 230 - 234 ° C (from CH3CN).

Example 7

In analogy to Example 1, p-cyclopentyl-N- [6- (2-hydroxyethoxy) -5- was obtained from N- [6-chloro-5- (p-ethylphenyl) -4-pyrimidinyl] -p-cyclopentylbenzenesulfonamide and Na-ethylene glycol (p-ethylphenyl) -4-pyrimidinyl] benzenesulfonamide;

m.p. 145 - 146 ° C (from acetone and isopropyl ether).

The starting material was prepared from 4,6-dichloro-5- (p-ethylphenyl) pyrimidine and p-cyclopentyl-benzenesulfonamide;

m.p. 178 - 180 ° C (from acetonitrile and isopropyl ether).

Example 8

Analogous to Example 1, p-chloro-N- [5- (3,4-) was obtained from p-chloro-N- [6-chloro-5- (3,4-dimethoxyphenyl) -4-pyrimidinyl] benzenesulfonamide and Na-ethylene glycol. dimethoxyphenyl) -6 (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide;

m.p. 232-234 ° C (from CH ₃ CN).

The starting material was prepared as follows:

Analogous to Example 3, paragraph b), 4,6-dichloro-5- (3,4-dimethoxyphenyl) pyrimidine was obtained from [5- (3,4-dimethoxyphenyl) -4,6- (1H, 5H) pyrimidinedione and POCl3 , tal. 151-152 ° C (from cyclohexane-ether) from which p-chlorophenylsulfonamide gave p-chloro-N-6-chloro- [5- (3,4-dimethoxyphenyl) -4-pyrimidinyl] benzenesulfonamide;

m.p. 201 - 203 ° C (from CH3CN).

Example 9

Analogous to Example 1, 3,4-dichloro-N- [5- (p-chlorophenyl) was obtained from 3,4-dichloro-N- [6-chloro-5- (p-chlorophenyl) pyrimidinyl] benzene sulfonamide and Na-ethylene glycol ) 6- (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide;

m.p. 181 ° C (from CH3CN and isopropyl ether).

Example 10

Analogous to Example 1, N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] -a, o; _J aα ', α', α'-hexafluoromethyl-xylenesulfonamide to give N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -a, a, a-a ', a', a '-hexafluoro-3,5-xylenesulfonamide; m.p. 156 - 158 ° C (from methylene chloride / n-hexane).

The starting material was prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and 2,4-bistrifluoromethylphenylsulfonamide;

m.p. 132-135 ° C (from isopropyl ether); purity 92% (HPLC analysis).

Example 11

Analogous to Example 1, we are from 3-chloro-N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] 14

4-Fluorobenzenesulfonamide and excess Na-ethylene glycol gave 3-chloro-N- [5- (chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -4- (2-hydroxyethoxy) benzenesulfonamide;

m.p. 138-140 ° C (from acetone-isopropyl ether).

The starting material was prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and 3-chloro 4-fluorophenylsulfonamide;

m.p. 239 ° C (from methylene chloride-acetonitrile).

Example 12

Analogous to Example 1, p-chloro-N-6- (2-hydroxyethoxy) -5- was obtained from p-chloro-N- [6-chloro-5- (p-nitrophenyl) -4-pyrimidinyl] benzenesulfonamide and Na-ethylene glycol. (pnitrophenyl) -4-pyrimidinyl] benzenesulfonamide;

m.p. 223-225 ° C (from methylene chloride-isopropyl ether).

The starting material was prepared from 4-chloro-5- (p-nitrophenyl) pyrimidine and p-chlorophenylsulfonamide; m.p. 282 - 285 ° C (from CH3CN).

Example 13

Analogous to Example 1, p-butoxy-N- [5- (p-chlorophenyl) 6- was obtained from p-butoxy-N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] benzenesulfonamide and Na-ethylene glycol (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide; m.p. > 300 ° C (from isopropyl ether), 97.7% purity by HPLC analysis.

The starting material was prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and 4-nbutoxyphenylsulfonamide;

m.p. 234 ° C (from CH ₃ CN).

Example 14

Analogous to Example 1, N- [5- (p-chlorophenyl) 6- (2-hydroxyethoxy) was obtained from N-6-chloro- [5- (p-chlorophenyl) -4-pyrimidinyl] -3,4 dimethoxybenzenesulfonamide and Na-ethylene glycol -4-pyrimidinyl] -3,4-dimethoxybenzenesulfonamide; m.p. 130-132 ° C (from isopropyl ether).

The starting material was prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and

3,4-dimethoxyphenylsulfonamide; m.p. 226 ° C (from CH3CN).

Example 15

Analogous to Example 1, 2-chloro-N- was obtained from o-chloro-N- [6-chloro- [5- (p-chlorophenyl) -4-pyrimidinyl] -a, a, oitrifluoro-p-toluenesulfonamide and Na-ethylene glycol. [5- (p-Chlorophenyl) 6- (2-hydroxyethoxy) -4-pyrimidinyl] -a, a, α-trifluoro-p-toluenesulfonamide; m.p. 131 ° C (from isopropyl ether).

The starting material was prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and 2-chloroα, α, α-trifluoro-p-toluenesulfonamide; m.p. 234 ° C (from methylene chloride-acetonitrile).

Example 16

Analogous to Example 1, 6-chloro-N- [6] was obtained from 6-chloro-N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] -a, atrifluoro-m-toluenesulfonamide and Na-ethylene glycol. 5- (p-chlorophenyl) 6- (2-hydroxyethoxy) -4-pyrimidinyl] -α, α, α-trifluoro-m-toluenesulfonamide; m.p. 185 - 186 ° C (from isopropyl ether).

The starting material was prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and -α, α, αtrifluoro-3-methyl-6-chlorophenylsulfonamide;

m.p. 232 ° C (from isopropyl ether).

Example 17

Analogous to Example 1, 2,3,4-trichloro-N - [(2) was obtained from 2,3,4-trichloro-N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] benzenesulfonamide and Na-ethylene glycol. 5-chlorophenyl) -6- (2hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide;

m.p. 209 - 211 ° C (from methylene chloride-isopropyl ether).

The starting material was prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and 2,3,4 trichlorophenylsulfonamide;

m.p. 278-280 ° C (from CH ₃ CN).

Example 18

Analogous to Example 1, m-chloro-N- [5- (p-chlorophenyl) 6- was obtained from m-chloro-N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] benzenesulfonamide and Na-ethylene glycol (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide;

m.p. 179-181 ° C (from acetonitrile isopropyl ether).

The starting material was prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and 3-chlorophenylsulfonamide; m.p. 219-221 ° C (from CH3CN).

Example 19

Analogous to Example 1, 2,4-dichloro-N- [5- (5) was obtained from 2,4-dichloro-N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] benzene sulfonamide and Na-ethylene glycol. p-chlorophenyl) 6- (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide;

m.p. Mp 165-167 ° C (from CH3CN).

The starting material was prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and 2,4 dichlorophenylsulfonamide;

m.p. 252 - 254 ° C (from CH3CN).

Example 20

Analogous to Example 1, N- [5- (p-chlorophenyl) -6- (N- [6-chloro-5- (p-chlorophenyl) -a, a, α-trifluoro-m-toluenesulfonamide and Na-ethylene glycol) was obtained. 2-hydroxyethoxy) α, α, α-trifluoro-m-toluenesulfonamide; m.p. 148-150 ° C (from isopropyl ether).

The starting material was prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and α, α, αtrifluoro-m-toluenesulfonamide; m.p. 197 -198 ° C.

Example 21

Analogous to Example 1, N-5- (p-chlorophenyl) -6- (2 - (2-) was obtained from N-6-chloro-5- (p-chlorophenyl) -α, α, α-trifluoro-o-toluenesulfonamide and Na-ethylene glycol. hydroxyethoxy) 4-pyrimidinyl] -a, a, α-trifluoro-o-toluenesulfonamide;

m.p. 182 - 184 ° C (from CH3CN-isopropyl ether).

The starting material was prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and

-α, α, α-trifluoro-o-toluenesulfonamide;

m.p. 191 -193 ° C (from CH3CN).

Example 22

Analogous to Example 1, N- [6- (2-hydroxyethoxy) -5- (pethylphenyl) - was obtained from N- [6-chloro-5- (p-ethylphenyl) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide and Na-ethylene glycol. 4-pyrimidinyl] -β-isopropyl] benzenesulfonamide;

m.p. 137-138 ° C (from acetonitrile and isopropyl ether).

The starting material was prepared as follows:

From diethyl- (p-ethylphenyl) malonate and formamidinacetate 5- (p-ethyl) 4,6 (1H, 5H) -pyrimidinedione were obtained, m.p. > 270 ° C, and from this with POCl 3, 4,6-dichloro5- (p-ethylphenyl) pyrimidine, m.p. 48-49 ° C (from n-hexane).

Conversion of this compound with p-isopropylbenzenesulfonamide gave N- [6-chloro 5- (p-ethylphenyl) -4-pyrimidinyl] -p-isopropyl] benzenesulfonamide;

m.p. 187 -188 ° C (from acetonitrile and isopropyl ether).

Example 23

Analogous to Example 1, N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) was obtained from N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] -2-naphthalenesulfonamide and Na-ethylene glycol 4-pyrimidinyl] -2-naphthalenesulfonamide;

m.p. 196-198 ° C (from CH3CN and isopropyl ether).

The starting material was prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and 2 naphthalenesulfonamide; m.p. 265 - 269 ° C (from CH3CN).

Example 24

Analogous to Example 1, p-chloro-N- [6- (2-hydroxyethoxy) 5- was obtained from p-chloro-N- [6-chloro-5- (m-nitrophenyl) -4-pyrimidinyl] benzenesulfonamide and Na-ethylene glycol. (m-nitrophenyl) -4-pyrimidinyl] benzenesulfonamide;

m.p. 186-187 ° C (from CH3CN and isopropyl ether).

The starting material was prepared from 4,6-dichloro-5- (m-nitrophenyl) pyrimidine and pchlorophenylsulfonamide; m.p. 261-263 ° C (from CH3CN).

Example 25

Analogously to Example 1, N, [6-chloro-5- (m-nitrophenyl) -4-pyrimidinyl] -a, a, atrifluoro-p-toluenesulfonamide and Na-ethylene glycol were obtained from a, a, a-trifluoro-N- [ 6- (2-hydroxyethoxy) -5- (m-nitrophenyl) -4-pyrimidinyl] -β-toluenesulfonamide; m.p. 194 - 195 ° C (from acetone / n-hexane).

The starting material was prepared from 4,6-dichloro-5- (m-nitrophenyl) pyrimidine and α, α, α-trifluoro-β-toluenesulfonamide; m.p. 246-250 ° C (from CH3CN).

Example 26

Analogous to Example 1, p- (benzyloxy) -N- [5- (p-chlorophenyl) was obtained from p- (benzyloxy) -N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinylbenzenesulfonamide and Na-ethylene glycol; -6 (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide;

m.p. 162-163 ° C (acetone and isopropyl ether).

The starting material was prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and p (benzyloxy) benzenesulfonamide; m.p. 233 - 236 ° C (from acetone and acetone).

Example 27

To a solution of 512 mg of p- (benzyloxy) -N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide in 30 ml of ice was added 2 ml of 4N HCl in dioxane and 100 mg of 10% palladium on charcoal. The mixture was hydrated with stirring, then the solution was filtered off, evaporated under reduced pressure, and the residue was recrystallized from isopropyl ether and again from CH3CN. N- [5- (p-Chlorophenyl) -4-pyrimidinyl] p-hydroxybenzenesulfonamide was obtained; m.p. 231-232 ° C.

Example 28

In analogy to Example 1, N- [5- (p-chlorophenyl) 6- (2 was obtained from N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] -p- (2methoxyethoxy) benzenesulfonamide and Na-ethylene glycol) -hydroxyethoxy) -4-pyrimidinyl] -β- (2-methoxyethoxy) benzenesulfonamide; m.p. 151-152 ° C (from CH3CN and isopropyl ether).

The starting material was prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and p- (2methoxyethoxy) benzenesulfonamide;

m.p. 212 - 215 ° C (from CH3CN).

Example 29

In analogy to Example 1, N- [5- (p-bromophenyl) 6- (2-hydroxyethoxy) -4 was obtained from N- [5- (p-bromophenyl) -6-chloro-4-pyrimidinyl] -chlorobenzenesulfonamide and Na-ethylene glycol -pyrimidinyl] -β-chlorobenzenesulfonamide;

m.p. 179 - 180 ° C. (from acetone and isopropyl ether).

The starting material was prepared as follows:

Analogous to Example 3, paragraph a), 5- (p-bromophenyl) -4,6 (1H, 5H) -pyrimidinedione, mp., Was prepared from diethyl-p-bromophenylmalonate and formamidinacetate. > 270 ° C. After drying under reduced pressure at 80 ° C overnight, the compound was used in the next step.

Analogous to Example 3, paragraph b), 5- (p-bromophenyl) -4,6-dichloro-pyrimidine, mp., Was prepared from 5- (p-bromophenyl) -4,6 (1H, 5H) pyrimidinedione and POCl3. 99-100 ° C (from hexane) and from that with p- chlorophenylsulfonamide N- [5- (p-bromophenyl) -6-chloro-4-pyrimidinyl] -p-chlorobenzenesulfonamide; m.p. 266-268 ° C (from CH ₃ CN).

Example 30

Analogous to Example 1, p-chloro-N- [6- (2-hydroxyethoxy) -5- was obtained from p-chloro-N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -benzenesulfonamide and Na-ethylene glycol. p-tolyl4-pyrimidinyl] benzenesulfonamide; m.p. 162 -165 ° C. (from acetone and isopropyl ether).

The starting material was prepared as follows:

Analogous to Example 3, paragraph a), 5-p-tolyl-4,6 (1H, 5H) -pyrimidinedione, mp., Was prepared from diethyl-p-tolylmalonate and formamidinacetate. > 270 ° C.

After drying under reduced pressure at 80 ° C, the compound was used in the next step.

Analogous to Example 3, paragraph b), 4,6-dichloro-5-p-tolylpyrimidine, mp., Was prepared from 5-p-tolyl-4,6 (1H, 5H) -pyrimidinedione and POCl3. 81-82 ° C (from hexane) and from that with p-chlorophenylsulfonamide p-chloro-N- (6-chloro-5-p-tolyl-4-pyrimidinyl) benzenesulfonamide; m.p. 229 - 230 ° C (from acetonitrile).

Example 31

To a solution of 237 mg of N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -a, atrifluoro-p-toluenesulfonamide in 5 ml of methanol was added 27.0 mg of sodium methylate and then 5 ml. isopropyl ether. The white precipitate was filtered off and dried under reduced pressure at 50 ° C. N- [5- (p-Chlorophenyl) -6- (2hydroxyethoxy) -4-pyrimidinyl] -a, a, o-trifluoro-p-toluenesulfonamide sodium salt was obtained as a white solid.

Example 32 mg of sodium was added to 2 ml of ethylene glycol at 70 ° C. 223 mg of N- [6-chloro-5- (2,6-dimethoxybenzyl) -4-pyrimidinyl] -β-vinyl-benzenesulfonamide were added and the reaction mixture was heated to 150 ° C for 4.5 hours. Ethylene glycol was distilled off under reduced pressure, the residue was taken up in EtOAc / H2O and extracted once with ethyl acetate. The iodine phase was then acidified with IN HCl and extracted four times with ethyl acetate. The organic phase was dried, filtered and evaporated under reduced pressure. The residue was chromatographed over 50 g of S1O2 with methylene chloride / acetone 1: 1.

50 mg of N- [5- (2,6-dimethoxybenzyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] p-vinyl-benzenesulfonamide, m.p. 138 -139 ° C.

The starting material was prepared as follows:

a) A mixture of 1.52 ml of malonic acid diethyl ester, 1.66 g of 2,6-dimethoxybenzaldehyde, 0.1 ml of piperidine, 0.11 ml of glacial acetic acid and 100 ml of toluene was boiled at 110 ° C on a water separator for 3.5 hours. The solution was extracted with 10% NaHCO3 solution and washed with saturated NaCl solution. The organic phase was dried, filtered off and evaporated under reduced pressure. 2.8 g of diethyl- (2,6-dimethoxy-benzylidene) 20 malonate were obtained as a dark yellow oil.

b) A mixture of 2.8 g of diethyl- (2,6-dimethoxybenzylidene) malonate, 0.6 g of palladium on charcoal, 50 ml of methanol and 50 ml of ice was dried at 25 ° C overnight. The solution was filtered and evaporated, the residue taken up in ethyl acetate and extracted with 20%

NaHCOj and some ice. It was then extracted with 1 N HCl, washed with saturated NaCl solution, dried and evaporated under reduced pressure. The crude product was distilled under high vacuum at 170 ° C (0.6 mbar). We got

2.1 g of diethyl- (2,6-dimethoxybenzyl) malonate.

c) To 0.14 g of sodium in 15 ml of ethanol was added 0.23 g of formamidinacetate in 15 ml of ethanol. The reaction mixture was stirred for 30 minutes at 25 ° C and 0.62 g of diethyl- (2,6-dimethoxybenzyl) malonate in 10 ml of ethanol was added dropwise. After two days, no starting material was present. The residue was drained, dissolved in a little water and acidified with 1NHC1. The separated crystals were filtered off and dried under high vacuum at 90 ° C.

0.175 g of 5- (2,6-dimethoxybenzyl) -4,6-pyrimidindiol were obtained from m.p. > 245 ° C.

d) A mixture of 1.04 g of 5- (2,6-dimethoxybenzyl) -4,6-pyrimidindiol and 12 ml of phosphorus oxychloride was boiled at 85 ° C at reflux for three hours. The reaction solution was poured onto ice and extracted twice with methylene chloride. The organic phase was washed with saturated NaCl solution, dried, filtered and evaporated under reduced pressure. The crude product was recrystallized from toluene / n-hexane. 0.41 g of 4,6-dichloro-5 (2,6-dimethoxybenzyl) pyrimidine, m.p. 152 - 153 ° C.

e) A mixture of 80 mg of 4,6-dichloro-5- (2,6-dimethoxybenzyl) pyrimidine and 170 mg of the p-vinylbenzenesulfonamide mono-potassium salt (J. Am. Chem. Soc. 1956,78,2169) obtained from the corresponding sulfonamide with potassium tert.butylate in abs. MeOH, and 10 ml of dimethylformamide were heated at 100 ° C for 6 hours. Thereafter, it was allowed to cool to 25 ° C overnight. 30 ml of 0.5N HCl was added while stirring to the reaction solution. The recovered substance was filtered off and recrystallized from toluene / n-hexane. 25 mg of N- (6-chloro-5- (2,6-dimethoxybenzyl) -4-pyrimidinyl) -p-vinylbenzenesulfonamide, m.p. 197 -198 ° C.

Example 33

To 10 ml of ethylene glycol (freshly distilled over Na), 29 mg of sodium was added by exclusion of moisture. 123 mg of N- [6-chloro-6- [o (trifluoromethyl) benzyl] -4-pyrimidinyl] -Q 1, α, α-trifluoro-β-toluenesulfonamide were then added and the reaction mixture was heated to 150 ° C for 3 hours. Subsequently, excess ethylene glycol was evaporated under reduced pressure; the residue was dissolved in water and washed with ethyl acetate. The aqueous phase was adjusted with 1N hydrochloric acid to pH 3.0 and extracted with ethyl acetate. The organic phase was washed with water and brine, dried and evaporated under reduced pressure. The residue was chromatographed over 30 g of SiO2 with methylene chloride / ethyl acetate (1: 1).

We obtained α, α, α-trifluoro N- [6- (2-hydroxyethoxy) -6- [o- (trifluoromethyl) benzyl] pyrimidinyl-β-toluenesulfonamide as a white foam. MS: 521 (M); 456 (M - SO2 + H).

The starting material was prepared as follows:

a) A solution of 14 g of o-trifluoromethylbenzyl alcohol in 80 ml abs. toluene was added dropwise at 20-30 ° C, a solution of 30 ml phosphorus tribromide in 60 ml abs. toluene. The reaction mixture was then stirred for 2 hours at room temperature, distilled off the toluene under reduced pressure, the residue dissolved in methylene chloride, water was added and the mixture was adjusted with potassium hydrogen carbonate to pH 8.0. The aqueous phase was extracted three times with CH2Cl2 and the organic phases were washed twice with water and once with saturated NaCl solution, dried over Na2SO4 and evaporated under reduced pressure. O-trifluoromethyl-benzyl bromide was obtained as a residue.

b) 40 ml of malonic acid diethyl ester in 350 ml of ethyl alcohol was added 18.6 g of sodium ethylate in portions at room temperature and then 12 g of o-trifluoromethyl-benzyl bromide were added over 30 minutes. The reaction mixture was stirred overnight at room temperature, the alcohol distilled off under reduced pressure and the residue dissolved in ethyl acetate. The solution was washed twice with water and once with NaCl solution, dried under reduced pressure and evaporated. The residue was chromatographed over 300 g of SiO2 with CH2Cl2 / AcOEt 95: 5 and gave 11 g of diethyl- [o- (trifluoromethyl) benzyl] malonate as a colorless oil.

c) 0.63 g formamidinacetate in 40 ml abs. of ethyl alcohol at room temperature was added 1.2 g of sodium ethylate, stirred for 30 minutes at room temperature and then a solution of 1.6 g of diethyl- [o- (trifluoromethyl) benzyl] malonate in 8 ml of abs was added dropwise. of ethyl alcohol at room temperature. After stirring at 50 ° C for 4 hours, the reaction mixture was treated to give 5- [o- (trifluoromethyl) benzyl] -4,6 (1H, 5H) pyrimidinedione, m.p. > 290 ° C.

d) From 5- [o- (trifluoromethyl) benzyl] -4,6 (1H, 5H) pyrimidinedione and phosphorus oxychloride 5- [o- (trifluoromethyl) benzyl] -4,6-dichloropyrimidine, m.p. 60 - 63 ° C.

e) 292 mg of 4,6-dichloro-5- [o- (trifluoromethyl) benzyl] pyrimidine in 10 ml of freshly distilled dimethyl sulfoxide were added 342 mg of the mono-potassium salt of α, α, α-trifluoro-β-toluenesulfonamide (from the corresponding sulfonamide) with KOH and abs. ethyl alcohol) and stirred for 5 hours at 150 ° C. After complete conversion, the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate and the solution was washed with 10% potassium hydrogen carbonate solution, 0.5N HCl, water and saturated NaCl solution. The organic phase was dried and evaporated under reduced pressure. The residue was chromatographed with ethyl acetate over 30 g S1O2 and gave 135 mg of N- [6-chloro-6- [o- (trifluoromethyl) benzyl] -4-pyrimidinyl] -a, a, α-trifluoro-p-toluenesulfonamide as white foam.

MS: 495 (M), 431 (-SO ₂ ), 430 (-SO ₂ + H), 362 (-CF 3 + SO ₂ ).

Example 34

Analogous to Example 33, N- [6- (2-hydroxyethoxy) 5- [o- (trifluoromethyl) was obtained from N- [6-chloro-5- [o- (trifluoromethyl) benzyl] -4-pyrimidinyl] -methoxybenzenesulfonamide and Na ethylene glycol. ) benzyl] -4-pyrimidinyl] -β-methoxybenzenesulfonamide; m.p. 100 -107 ° C.

The starting material was prepared as follows:

Analogous to Example 33, paragraph e), N- [6-chloro-5 [o- (trifluoromethyl) benzyl] was obtained from 4,6-dichloro-5- [o- (trifluoromethyl) benzyl] pyrimidine and the potassium salt of p-methoxybenzenesulfonamide. -4-Pyrimidinyl] -β-methoxybenzenesulfonamide as a white foam; m.p. 68 - 70 ° G.

Example 35

Analogous to Example 33, p-chloro-N- [6- (2hydroxyethoxy) -5- [o- from p-chloro-N- [6-chloro-5- [o- (trifluoromethyl) benzyl] -4-pyrimidinylbenzenesulfonamide and Na ethylene glycol was obtained. (trifluoromethyl) benzyl] -4-pyrimidinyl] benzenesulfonamide; m.p. 134-135 ° C.

The starting material was prepared analogously to Example 33, paragraph e), from 4,6-dichloro5- [o- (trifluoromethyl) benzyl] pyrimidine and the K-salt of p-chlorobenzenesulfonamide; m.p. > 210 ° C (decomposition).

Example 36

Analogous to Example 33, N- [6- (2-hydroxyethoxy) -5 (o-methoxybenzyl) -4- was obtained from N- [6-chloro-5- (o-methoxybenzyl) -4-pyrimidinyl] -pinylbenzenesulfonamide and Na ethylene glycol. pyrimidinyl] -β-vinylbenzenesulfonamide; m.p. 93 -102 ° C.

The starting material was prepared, analogously to Example 33, paragraph e), from 4,6-dichloro5- (o-methoxybenzyl) pyrimidine and the K-salt of p-vinylbenzenesulfonamide; m.p. 125 - 129 ° C.

Example 37

Analogous to Example 33, N- [6- (2-hydroxyethoxy) 5 was obtained from N- [6-chloro-5- [o- (trifluoromethyl) benzyl] -4-pyrimidinyl] 24 p- (methylthio) benzenesulfonamide and Na-ethylene glycol 5 - [o- (trifluoromethyl) benzyl] -4-pyrimidinyl] -β- (methylthio) benzenesulfonamide as a yellowish resin.

The starting material was prepared, analogously to Example 33, paragraph e) from

4,6-dichloro-5- [o- (trifluoromethyl)] benzylpyrimidine p- (methylthio) benzenesulfonamide; IR: 3433 cm ^-1 (NH); 1313 (SO ₂ ); 1137 and 1094 (F ₃ C).

Example 38

Analogous to Example 32, N * [5-2,4-dimethoxybenzyl) -6- (3 was obtained from N- [6-chloro-5- (2,4-dimethoxybenzyl) -4-pyrimidinyl] p-isopropylbenzenesulfonamide, ethylene glycol and sodium) -hydroxypropyl) -4-pyrimidinyl] -β-isopropylbenzene sulfonamide; m.p. 97 ° C.

The starting material was prepared as follows:

Analogous to Example 32, paragraph a), diethyl- (2,4-dimethoxybenzylidene) malonate was prepared from 2,4-dimethoxybenzaldehyde, diethyl ester of malonic acid, glacial, piperidine and toluene. From this, analogous to Example 32, paragraph b), diethyl- (2,4-dimethoxybenzyl) malonate was prepared as a clear oil, boiling. 160 ° C / 0.4 mbar.

In analogy to Example 32, paragraph e), 5- (2,4-dimethoxybenzyl) -4,6 pyrimidinediol was prepared from diethyl- (2,4-dimethoxybenzyl) malonate, formamidine acetate and Na-salts of ethanol and from this analogous to Example 32, paragraph d), 4,6-Dichloro-5- (2,4dimethoxybenzyl) pyrimidine, m.p. 130 -131 ° C.

Analogous to Example 32, paragraph e), finally N, 4,6-dichloro-5- (2,4-dimethoxybenzyl) pyrimidine, potassium p-isopropylbenzenesulfonamide (from the corresponding sulfonamide with potassium tert.butylate in abs. MeOH) and DMSO were prepared - [6chloro-5- (2,4-dimethoxybenzyl) -4-pyrimidinyl] -β-isopropyl] benzene sulfonamide, m.p. 132 - 134 ° C.

Example 39

A solution of 110 mg of N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] -vinylbenzenesulfonamide in 3 ml abs. 0.3 ml of 3,4-dihydro-2H-pyran and 4 drops of trifluoroacetic acid were added to tetrahydrofuran. After boiling under reflux overnight, the solvent was distilled off under reduced pressure and the residue was chromatographed with methylene chloride / ethyl acetate (9: 1) on silica gel. 100 mg of rac-N- [5- (o-methoxybenzyl) -6- [2 - [(tetrahydro-2H-pyran-2-yl) oxy] ethoxy] -4-pyrimidinyl] -p-vinylbenzenesulfonamide were obtained as a white resin.

MS: 460 (M-SO2 + H); 430 (M - SO ₂ + OCH ₃ ).

Example 40

To a mixture of 1.5 ml of water and 4 ml of dioxane, 318 mg of rac-N- [5- (o-methoxybenzyl) -6- [2 - [(tetrahydro-2H-pyran-2-yl) oxy] ethoxy was added successively at room temperature. ] -4pyrimidinyl] -β-vinylbenzenesulfonamide, 5.3 mg of osmium tetroxide and 270 mg of sodium (meth) peiodate. After stirring at room temperature for one hour, the dioxane was distilled off under reduced pressure, then the aqueous phase was extracted three times with ethyl acetate, the ethyl acetate was washed twice with water and once with a (saturated) NaCl solution, dried and distilled off under reduced pressure. The residue was chromatographed over 30 g of SiO ₂ with CH ₂ Cl ₂ / ethyl acetate and gave 150 mg of rac-p - [[5- (omethoxybenzyl) -6- [2 - [(tetrahydro-2H-pyran-2-yl) oxy] ethoxy] -4-pyrimidinyl] sulfamoylbenzaldehyde as a white foam,

MS: 527 (M); 443 (); 432 (-OCH3 + SO ₂ ).

Example 41

To Grignard's solution prepared from 60 mg of magnesium and 0.15 ml of methyl iodide in diethyl ether, 170 mg of rac-p - [[5- (o-methoxybenzyl) -6 [2 - [(tetrahydro-2H-pyran-2) was added at room temperature -yl) oxy] ethoxy] -4-pyrimidinyl] sulfamoyl] benzaldehydeine after 30 minutes 1 ml abs. tetrahydrofuran. After stirring at room temperature for 3 hours, the reaction was quenched by the addition of saturated ammonium chloride solution, the reaction was diluted with ethyl acetate and the aqueous phase extracted twice again with ethyl acetate. The organic phase was washed with water and saturated NaCl solution, dried and distilled off under reduced pressure. The residue was chromatographed over 35 g of SiO _{2 and} CH ₂ Cl ₂ / ethyl acetate (8.2) and (1: 1) to give 135 mg of p - [(RS) -1-hydroxyethyl] -N- [5 - (- methoxybenzyl) ) -6- [2 - [[(RS) -tetrahydro-2H-pyran-2-yl] oxy] ethoxy] -4pyrimidinylbenzenesulfonamide, m.p. > 56 ° C (sublimation).

'Ž6'

Example 42 mg of rac-p - [[5- (o-methoxybenzyl) -6- [2 - [(tetrahydro-2H-pyran-2-yl) oxy] ethoxy] -4pyrimidinylsulfamoylbenzaldehyde was dissolved in 3 ml of methyl alcohol and at room temperature 37 mg of sodium borohydride were added. After stirring at room temperature for 1 hour, the methanol was evaporated under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and a (saturated) NaCl solution, dried and distilled off under reduced pressure. 42 mg of rac-a-hydroxy-N- [5- (o-methoxybenzyl) -6- [2 [(tetrahydro-2H-pyran-2-yl) oxy] ethoxy] -4-pyrimidinyl] -p-toluenesulfonamidacate were obtained colorless oil.

MS: 529 (M); 445 (tetrahydro-2H-pyran-2-yl); 434 (—OCH3 + SO2).

Example 43 mg of rac-p - [[5- (o-methoxybenzyl) -6- [2 - [(tetrahydro-2H-pyran-2-yl) oxy] ethoxy] -4pyrimidinylsulfamoylbenzaldehyde was dissolved in 3 ml of ethyl alcohol and at room temperature 7 mg hydroxylamine hydrochloride and 14 mg finely powdered potassium carbonate were added. After stirring at room temperature for 3 hours, the ethanol was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and a (saturated) NaCl solution. The organic phase was dried and evaporated under reduced pressure to give rac-a - [(> E / Z) -hydroxyimino-N- [5- (omethoxybenzyl) -6- [2 - [(tetrahydro-2H-pyran- 2-yl) oxy] ethoxy] -4-pyrimidinyl] -ptoluenesulfonamide, m.p. 49 - 52 ° C.

Example 44

60 mg solution of p - [(RS) -1-hydroxyethyl] -N- [5- (o-methoxybenzyl) -6- [2 - [[(RS) tetrahydro-2H-pyran-2-yl] oxy] ethoxy] of benzenesulfonamide in 3 ml of tetrahydrofuran was added to 2 drops of 3N HCl. After stirring at room temperature for 4 hours, the reaction mixture was evaporated under reduced pressure. The residue was chromatographed with methylene chloride / ethyl acetate (1: 1) and ethyl acetate on silica gel to give rac-N-6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -p- (1-hydroxyethyl) benzenesulfonamide like white resin.

MS: 459 (M); 394 (- SO2 / H); 364 (-SO ₂ O / OCH ₃ ).

Example 45

Analogous to Example 44, rac - [(E / Z) -hydroxyimino] -N- [5- (o-methoxybenzyl) 6- [2-tetrahydro-2H-pyran-2-yl) oxy] ethoxy] -4 -pyrimidinyl] -β-toluenesulfonamide gave α - [(E / Z) -hydroxyimino] -N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] -β-toluenesulfonamide as a yellow resin.

IR: 3403 and 3193 cm -1 (W, OH); 2607 (W, NH); 1729 (W, C = N).

Example 46

Analogous to Example 44, rac-a-hydroxy-N- [5- (o-methoxybenzyl) -6- [2-tetrahydro-2H-pyran-2-yl) oxy] ethoxy] -4-pyrimidinyl] -p-toluenesulfonamide -hydroxy-N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] -p-toluenesulfonamide as a light-brown resin.

MS: 445 (M), 380 (-SO2 / H), 274.

Example 47

Analogous to Example 44, p- [6- (6- (6- (2-methoxybenzyl) -6- [2-tetrahydro-2H-pyran-2-yl) oxy] ethoxy] -4-pyrimidinyl] sulfamoyl) benzaldehyde was obtained from rac-p- [6- 2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] sulfamoyl] benzaldehyde as a white resin. MS: 443 (M), 348 (-SO2 / OCH3), 274.

Example 48

208 mg of N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] -p-vinylbenzenesulfonamide were dissolved in 3 ml abs. tetrahydrofuran, 0.06 ml of pyridine and 0.07 ml of acetic anhydride were added and boiled for 3 hours in reflux. After the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and brine, dried and evaporated. The residue was obtained by chromatography over silica gel with methylene chloride and methylene chloride / ethyl acetate (19: 1 and 9: 1) 2 - [[5- (o-methoxybenzyl) 6 - [(p-vinylphenyl) sulfamoyl] -4-pyrimidinyl] oxy-thylacetate as a white resin.

Example 49

Analogous to Example 1, N- [6- (2-hydroxyethoxy) 5 was obtained from N- [6-chloro-5- (a, a,? -Trifluoro-p-tolyl) -4-pyrimidinyl] -isopropylbenzenesulfonamide and Na-ethylene glycol 5 - (a, a, α-Trifluoro-p-tolyl) -4-pyrimidinyl] -β-isopropylbenzenesulfonamide; m.p. 222 - 223 ° C (from acetone and isopropyl ether).

The starting material was prepared from 4,6-dichloro-5-a, α, α-trifluoro-β-tolyl-pyrimidine and β-isopropylbenzenesulfonamide; m.p. 266-269 ° C (from acetonitrile).

Example 50

To a solution of sodium glycolate from 46 mg of sodium and 1 ml of ethylene glycol was added 190 mg of N- [6-chloro-5- (p-methoxyphenyl) -4-pyrimidinyl] -p-toluenesulfonamide. After 5 hours of reaction at 100 ° C, the reaction mixture was evaporated under reduced pressure to dryness, the residue was partitioned between ethyl acetate and 1N hydrochloric acid, the organic phase was washed to neutral, dried and evaporated under reduced pressure. The residue was chromatographed with methylene chloride and ethyl acetate (4: 1 vol./vol.) On silica gel. 175 mg of N- [6- (2-hydroxyethoxy) -5- (p-methoxyphenyl) 4-pyrimidinyl] -p-toluenesulfonamide were obtained; m.p. 147 -149 ° C (from methylene chloride / hexane).

The starting material was prepared as follows:

A solution of 41.55 g of p-methoxyphenylacetic acid in 150 ml of abs. ethanol was added 150 ml of orthoformic acid ethyl ester and 1 g of methanesulfonic acid. The reaction mixture was heated to 85 ° C for 20 hours. The resulting ethylformate was continuously distilled off from the reaction mixture. The reaction mixture was then neutralized with sodium ethylate, the solvent was evaporated and the residue taken up in methylene chloride and distilled. 46.7 g of ethyl (p-methoxy) phenylacetic acid were obtained as a colorless liquid, boiling. 84 ° C / 3.3 Pa.

7.5 g of sodium ethylate and 120 ml of diethyl carbonate were added to 19.4 g of the ester obtained above. The resulting suspension was stirred vigorously at 130 ° C and the ethanol formed was distilled off from the reaction mixture. It was then cooled to room temperature and the reaction mixture was poured onto ice and aqueous hydrochloric acid (10% excess). After extraction with ethyl acetate and treatment of the extract, the product was purified by distillation. 25 g of diethyl (p-methoxy) phenylmalonic acid, boiling point, were obtained. 115 ° C / 6.6 Pa.

10.9 g of sodium ethylate were suspended in 125 ml of dried ethanol. 4.83 g of formamidine hydrochloride and 13.3 g of the malonester obtained in the above paragraph were added to it under ice-cooling. The reaction mixture was stirred at room temperature for 3 hours and then the solvent was evaporated. The residue was dissolved in 100 ml of water, the aqueous phase was washed with toluene and acidified. 8 g of 5- (pmethoxy) phenyl-6-hydroxy-4 (3H) -pyrimidinone were obtained, m.p. > 250 ° C.

The pyrimidinone described above was suspended in 5 ml of phosphorus oxychloride. The slurry was stirred at 80 [deg.] C. to exclude moisture to give a clear solution. After 30 minutes, the excess reagent was distilled off, the residue was taken up in methylene chloride and shaken with an aqueous solution of potassium hydrogen carbonate until carbonic acid developed. After evaporation of the solvent, it was filtered with methylene chloride over silica gel. 0.7 g of 4,6-dichloro-5- (p-methoxyphenyl) -pyrimidine, m.p. 95 - 96 ° C.

5.15 g of p-toluenesulfonamide dissolved in ethanol was added to boiling ethanol solution of potassium hydroxide (2 g of 85% potassium hydroxide in 50 ml of abs. Ethanol). We then added 50 ml of abs. of benzene and most of the solvent mixture was distilled off under normal pressure. 4.6 g of potassium p-toluenesulfonamide were obtained.

The 510 mg of dichloropyrimidine described above and 840 mg of potassium ptoluenesulfonamide were dissolved in 3 ml of dry dimethylformamide. The solution was maintained at 120 ° C for 3 hours, then distilled off with dimethylformamide, the residue partitioned between ethyl acetate and 1N hydrochloric acid, the organic phase was washed to neutral and evaporated. After the addition of methanol, 540 mg of N- [6-chloro-5 (p-methoxyphenyl) -4-pyrimidinyl] -p-toluenesulfonamide, m.p. 210-212 ° C.

Example 51

The starting material was prepared as follows:

Analogously to Example 50, 300 mg of N- [6-chloro-5- (p-methoxyphenyl) -4pyrimidinyl] -β-methoxybenzenesulfonamide, 200 mg of N- [6- (2-hydroxyethoxy) -5 (p-methoxyphenyl) - 4-Pyrimidinyl] -β-methoxybenzenesulfonamide, m.p. 132 - 134 ° C.

To a solution of 7.3 g of p-methoxybenzenesulfochloride in 50 ml of tetrahydrofuran, 25 ml of 25% NH 4 OH was added dropwise while cooling on an ice bath, then the reaction mixture was stirred vigorously for 30 minutes at 70 ° C (bath temperature), then distilled off with tetrahydrofuran. The residue was extracted with ethyl acetate. P-Methoxybenzenesulfonamide was obtained, which was converted to the potassium salt as described in Example 50.

A solution of 510 mg of 4,6-dichloro-5- (p-methoxyphenyl) pyrimidine and 680 mg of potassium pmethoxybenzenesulfonamide in 3 ml of dimethylformamide was heated at 130 ° C for 1 hour. After treatment of the reaction mixture, 690 mg of N- [6-chloro-5- (pmethoxyphenyl) -4-pyrimidinyl] -β-methoxybenzenesulfonamide, m.p. Mp 165 - 167 ° C.

Example 52

Analogous to Example 50, N- [6- (2-hydroxyethoxy) -5- (p-methoxyphenyl) - N- [6-chloro-5- (p-methoxyphenyl) -4-pyrimidinyl] -p (methylthio) benzenesulfonamide was obtained. 4pyrimidinyl] -β- (methylthio) benzenesulfonamide, m.p. 171 -172 ° C.

The starting material was obtained as described in Example 50 from 4,6-dichloro- (pmethoxy) phenylpyrimidine and potassium (p-methylthio) benzenesulfonamide, m.p. 204 - 205 ° C.

Example 53

Analogous to Example 50, N- [6- (2-hydroxyethoxy) -5- (pmethoxyphenyl) -2-methyl was obtained from N- [6-chloro-5- (p-methoxyphenyl) 2-methyl-4-pyrimidinyl] -p-methoxybenzenesulfonamide. -4-Pyrimidinyl] -β-methoxybenzenesulfonamide, m.p. 138 -139 ° C.

The starting material was prepared as follows:

A solution of 5.6 g of sodium methylate in 75 ml of abs. of ethanol was added 2.94 g of acetamidine hydrochloride and 6.9 g of p-methoxyphenylmalonic acid diethyl ester. The reaction mixture was stirred for 3 hours at humidity at room temperature and

1.5 hours at 50 ° C. The ethanol was then distilled off, the residue was taken up in water and the suspension was acidified with 5N hydrochloric acid. The solid was filtered off and washed with water until the rinse solution reached pH 4.5 - 5.7. The products thus obtained were converted with phosphorus oxychloride and gave 2.8 g of 4,6-dichloro-2-methyl- (p-methoxy) '31 'phenylpyrimidine, m.p. 114-116 ° C. Conversion of this compound to potassium p-methoxybenzenesulfonamide gave N- [6-chloro-5- (p-methoxyphenyl) 2-methyl-4-pyrimidinyl] p-methoxybenzenesulfonamide, m.p. 152-154 ° C.

Example 54

Analogous to Example 50 was obtained from 615 mg of N- [6-chloro-5- (p-methoxyphenyl) -4pyrimidinyl] -β-isopropylbenzenesulfonamide, 550 mg of N- [6- (2-hydroxyethoxy) -5- (pmethoxyphenyl) -4 -pyrimidinyl] -β-isopropylbenzenesulfonamide, m.p. 128 -129 ° C.

To convert this sulfonamide to the sodium salt, 87 mg was dissolved in methanol, a stoichiometric amount of sodium methylate was added, the solvent was distilled off and diisopropylether was added.

The starting material was prepared as follows:

p-Isopropylbenzenesulfochloride, ref. 105 ° C / 33 Pa, was prepared from cumene and converted to the corresponding sulfonamide, m.p. 104 -105 ° C. Conversion of 765 mg of 4,6-dichloro-5 (p-methoxyphenyl) pyrimidine and 925 mg of potassium p-isopropylbenzenesulfonamide gave 720 mg of N- [6-chloro-5- (p-methoxyphenyl) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide , tal. 181 -182 ° C.

Example 55

Analogous to Example 50 was obtained from 700 mg of p-tert-butyl-N- [6-chloro-5- (p-methoxyphenyl) -4-pyrimidinyl] benzenesulfonamide, 600 mg of p-tert-butyl-N- [6- (2 -hydroxyethoxy) -5- (p-methoxyphenyl) -4-pyrimidinyl] benzenesulfonamide, m.p. Mp 165-166 ° C.

The starting material was obtained from potassium p-tert-butyl-benzenesulfonamide and 4,6 dichloro-5- (p-methoxyphenyl) pyrimidine; m.p. 204 - 205 ° C.

Example 56

Analogous to Example 50 was obtained from 216 mg of rac-p-sec.butyl-N- [6-chloro-5- (p-methoxyphenyl) -4-pyrimidinyl] benzenesulfonamide, 185 mg rac-p-sec.butyl-N- [ 6- (2-hydroxyethoxy) -5- (p-methoxyphenyl) -4-pyrimidinyl] benzenesulfonamide, m.p. 120 -122 ° C.

v 32.

The starting material was obtained from potassium rac-p-sec. butyl-benzenesulfonamide and

2,6-Dichloro-5- (p-methoxyphenyl) pyrimidine, m.p. 172 - 173 ° C.

Example 57

Analogous to Example 50 was obtained from 280 mg of N- [6-chloro-5 - [(p-methylthio) phenyl] -4-pyrimidinyl-p-isopropylbenzenesulfonamide, 240 mg of N- [6- (2-hydroxyethoxy) -5- [p ( methylthio) phenyl] -4-pyrimidinyl] -β-isopropylbenzenesulfonamide, m.p. 135-136 ° C (from diisopropylether).

The starting material was prepared as follows:

15.2 g of (p-methylthio) benzaldehyde were dissolved in 50 ml of isopropanol. To this solution, 1.31 g of sodium borohydride in 150 ml of isopropanol was added dropwise during cooling in an ice bath over 0.5 hours. After stirring at room temperature for 1 hour, 5 ml of acetone was added and the solvent was then distilled off. The residue was partitioned between methylene chloride and water. (P-methylthio) benzyl alcohol, m.p. 40 - 41 ° C (from isopropanol).

7.71 g of (p-methylthio) benzyl alcohol was dissolved in 25 ml of dry methylene chloride. While cooling in an ice bath, 4 ml of SOCI2 was added to this solution ^for 30 minutes. After the solvent and excess reagent were distilled off, the residue was filtered with methylene chloride over silica gel. Distillation gave 4.3 g (p-methylthio) benzyl chloride, boiling point. 92 ° C / 6.6 Pa.

To a suspension of 10 g of potassium cyanide and 0.1 g of sodium iodide in 100 ml of dimethylformamide was added 9 g of the previous paragraph of the obtained benzyl chloride. The reaction mixture was stirred at 90 ° C for 1 hour with the humidity off. Dimethylformamide was then distilled off and the residue partitioned between toluene and water. Organic phase treatment gave (p-methylthio) benzyl cyanide, m.p. 28 - 30 ° C.

g (p-methylthio) benzyl cyanide was dissolved in 30 ml ethylene glycol and 9 g NaOH (as 30% solution) was added. The reaction mixture was stirred for 3 hours at 140 ° C. After cooling to room temperature, it was acidified with 25% hydrochloric acid, the precipitate was taken up in ethyl acetate and shaken with water. 11.5 g of (p-methylthio) phenylacetic acid were obtained, m.p. 94 - 96 ° C.

of the above acid was dissolved in 50 ml abs. ethanol and 25 ml of orthorubic acid ethyl ester and 1 g of methanesulfonic acid. During the reaction, your formate was continuously distilled off. After 4 hours the conversion was complete. The acid catalyst was neutralized with a stoichiometric amount of sodium ethylate, the solvent was distilled off, the residue was taken up in methylene chloride and filtered through silica gel. 12 g of (p-methylthio) phenylacetic acid ethyl ester were obtained, m.p. 46 - 47 ° C.

The above compound was converted into the (p-methylthio) phenylmalonic acid diethyl ester by analogy to the procedure described in Example 50. Hot. 120 ° C / 6.6 Pa.

From the malonic acid diethyl ester obtained above, 5- (p-methylthio) phenyl-6-hydroxy-4 (3H) -pyrimidinone was obtained analogously to the procedure described in Example 50.

The pyrimidinone described above was converted with sodium methylate into a dialkoxy compound from which 4,6-dichloro-5 (p-methylthio) phenyl-pyrimidine was obtained by conversion with phosphorus oxychloride.

From the 4,6-dichloro-compound described above, N- [6-chloro-5- [p- (methylthio) phenyl- [4-pyrimidinyl] -isopropylbenzenesulfonamide was obtained by conversion with potassium p-isopropylbenzenesulfonamide; m.p. 193 - 195 ° C.

Example 58

Analogously to Example 50, 160 mg of N- [6- (2 (2) was obtained from 230 mg of N- [6-chloro-5- [p- (methylthio) phenyl- [4-pyrimidinyl] α, α, α-trifluoro-p-toluenesulfonamide). -hydroxyethoxy) -5- [p (methylthio) phenyl] -4-pyrimidinyl] -a, a, α-trifluoro-p-toluenesulfonamide, m.p. 266-268 ° C.

The starting material was prepared from 4,6-dichloro-5-p- (methylthio) phenylpyrimidine and potassium α, α, α-trifluoro-p-toluenesulfonamide, m.p. 250 - 252 ° C.

Example 59

To a solution of sodium glycolate from 1 ml of dry ethylene glycol and 46 mg of sodium was added 300 mg of N- [6-chloro-5- (o-methoxybenzyl) -4-pyrimidinyl] -p-methoxybenzenesulfonamide. The reaction mixture was heated to argon at 125 ° C for 4 hours. The ethylene glycol was then distilled off under reduced pressure, the residue partitioned between ethyl acetate and 1N hydrochloric acid, the organic phase was washed to neutral, dried and evaporated. The residue was chromatographed with methylene chloride / ethyl acetate (1: 1 vol./vol) on silica gel. N- [6- (2-hydroxyethoxy) -5- (omethoxybenzyl) -4-pyrimidinyl] -β-methoxybenzenesulfonamide was obtained; m.p. 161 -162 ° C.

The starting material was prepared as follows:

Knoevenagel condensation of o-methoxybenzaldehyde with diethylmalonate gave the o-methoxybenzylidene-malonic acid diethyl ester, boiling point. 140 ° C / 6.6 Pa ..

Hydrogenation of the above compound in ethanol in the presence of palladium on charcoal gave o-methoxybenzylmalonic acid diethyl ester, ref. 115 ° C / 1.3 Pa.

Conversion of o-methoxybenzylmalonic acid diethyl ester with formamidine hydrochloride gave 5- (o-methoxybenzyl) -6-hydroxy-4 (3H) pyrimidinone from which 4,6-dichloro-5- (omethoxybenzyl) pyrimidinone was obtained by conversion with phosphorus oxychloride , tal. 95 - 96 ° C.

Conversion of 4,6-dichloro-5- (o-methoxybenzyl) -4-pyrimidine and potassium p-methoxybenzenesulfonamide gave N- [6-chloro-5- (o-methoxybenzyl) -4-pyrimidinyl] -methoxybenzenesulfonamide, m.p. 149 -151 ° C.

Example 60

Analogous to Example 59, N- [6- (2-hydroxyethoxy) -5- (o-chlorobenzyl) -4-pyrimidinyl] was obtained from N- [6-chloro-5- (o-chlorobenzyl) -4-pyrimidinyl] -ptoluenesulfonamide] -ptoluenesulfonamide.

The starting material was prepared as follows:

Malonic acid diethyl ester and o-chlorobenzyl chloride were converted to o-chlorobenzylmalonic acid diethyl ester, boiling. 115 ° C / 6.6 Pa.

Condensation of o-chlorobenzylmalonic acid diethyl ester with formamidine gave 5- (o-chlorobenzyl) -6-hydroxy-4 (3H) -pyrimidinone which, by conversion with phosphorus oxychloride, gave 4,6-dichloro-5- (o-chlorobenzyl) ) pyrimidine, m.p. 110-112 ° C.

Analogous to Example 59, N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) 4 was obtained from N- [6-chloro-5- (o-methoxybenzyl) -4-pyrimidinyl] -p (methylthio) benzenesulfonamide 4 -pyrimidinyl] -β- (methylthio) benzenesulfonamide, m.p. 134 - 136 ° C.

The starting material was prepared from 4,6-dichloro-5- (o-methoxybenzyl) -pyrimidine and potassium (p-methylthio) benzenesulfonamide; m.p. 157-159 ° C.

Example 62

Analogous to Example 59, N- [6- (2-hydroxyethoxy) -5- (o was obtained from N- [6-chloro-5- (o-methoxybenzyl) -4-pyrimidinyl] -a, and, atrifluoro-p-toluenesulfonamide) -methoxybenzyl) -4-pyrimidinyl] -a, a, α-trifluoro-p-toluenesulfonamide, m.p. 133-134 ° C.

The starting material was prepared from 4,6-dichloro-5- (o-methoxybenzyl) -pyrimidine and potassium p-trifluoromethylbenzenesulfonamide; m.p. 163 ° C.

Example 63

In analogy to Example 59, N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] was obtained from N- [6-chloro-5- (o-methoxybenzyl) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide] -p-isopropylbenzenesulfonamide, m.p. 112-113 ° C.

Treatment with sodium methylate in methanol prepared the sodium salt, m.p. 225 ° C.

The starting material was prepared from 4,6-dichloro-5- (o-methoxybenzyl) pyrimidine and potassium isopropylbenzenesulfonamide; m.p. 138-139 ° C.

Example 64

Analogous to Example 59, p-tert-butyl-N- [6- (2-hydroxyethoxy) -5- (omethoxybenzyl) was obtained from p-tert-butyl-N- [6-chloro-5- (o-methoxybenzyl) -4-pyrimidinylbenzenesulfonamide -4-pyrimidinyl] benzenesulfonamide, m.p. 138-140 ° C (from diisopropylether).

The starting material was prepared from 4,6-dichloro-5- (o-methoxybenzyl) -pyrimidine and potassium p-tert.butylbenzenesulfonamide; m.p. 215 - 216 ° C.

Example 65

Analogous to Example 59, N- [6- (2-hydroxyethoxy) -5- (o-chlorobenzyl) -4-pyrimidinyl] -p was obtained from N- [6-chloro-5- (o-chlorobenzyl) -4-pyrimidinyl] -isopropylbenzenesulfonamide -isopropylbenzenesulfonamide.

The starting material was prepared from 4,6-dichloro-5- (o-chlorobenzyl) -pyrimidine and potassium p-isopropylbenzenesulfonamide; m.p. 166 -167 ° C.

Example 66

In analogy to Example 59, N- [6- (2-hydroxyethoxy) -5- (o- (methylthio) benzyl) was obtained from N- [6-chloro-5- (o- (methylthio) benzyl-4-pyrimidinyl] -isopropylbenzenesulfonamide) 4-Pyrimidinyl] -β-isopropylbenzenesulfonamide.

The starting material was prepared as follows:

By converting thiosalicylic acid with dimethylsulfate in the presence of tetrabutylammonium bromide, 2- (methylthio) benzoic acid methyl ester was prepared from the ground. 64 ° C. Reduction with lithium aluminum hydride in dry terahydrofuran gave 2- (methylthio) benzyl alcohol, which was converted to SOCPj by conversion to

2- (methylthio) benzyl chloride, boiling point. 90 ° C / 39.9 Pa. Conversion of the malonic acid diethyl ester with 2- (methylthio) benzyl chloride gave 2- (methylthio) benzylmalonic acid diethyl ester, boiling. 130 ° C / 6.6 Pa. Condensation with formamidine gave 5- [o- (methylthio) benzyl] -6-hydroxy-4 (3H) -pyrimidinone, which was converted to 4,6-dichloro-5- [o (methylthio) benzylpyrimidine, m.p. 91 ° C. From 4,6-dichloro-5- [o- (methylthio) -benzylpyrimidine and potassium p-isopropylbenzenesulfonamide, N- [6-chloro-5- (o- (methylthio) benzyl) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide was finally obtained. m.p. 145 - 146 ° C.

Example 67

Analogous to Example 59, N- [6- (2-hydroxyethoxy) -5- (o-chlorobenzyl) -4-pyrimidinyl] -p was obtained from N- [6-chloro-5- (o-chlorobenzyl) -4-pyrimidinyl] -isobutylbenzenesulfonamide -isobutylbenzenesulfonamide, m.p. 130 -131 ° C.

The starting material was prepared from 4,6-dichloro-5- (o-chlorobenzyl) -pyrimidine and potassium p-isobutylbenzenesulfonamide; m.p. 147 -149 ° C.

Example 69

Analogous to Example 50, N- [6- (2-hydroxyethoxy) -5- (o-chlorobenzyl) -4-pyrimidinyl] -p was obtained from N- [6-chloro-5- (o-chlorobenzyl) -4-pyrimidinyl] -picyclohexylbenzenesulfonamide -cyclohexylbenzenesulfonamide, m.p. 164 - 165 ° C.

The starting material was prepared from 4,6-dichloro-5- (o-chlorobenzyl) -pyrimidine and potassium p-cyclohexylbenzenesulfonamide; m.p. 107 -108 ° C.

Example 70

Analogous to Example 59, N- [6- (2-hydroxyethoxy) -5- (o-chlorobenzyl) -4- was obtained from N- [6-chloro-5- (o-chlorobenzyl) -4-pyrimidinyl] -p-isopentylbenzenesulfonamide. pyrimidinyl] p-isopentylbenzenesulfonamide, m.p. 127 -128 ° C (from diisopropylether).

The starting material was prepared from 4,6-dichloro-5- (o-chlorobenzyl) -pyrimidine and potassium p-isopentylbenzenesulfonamide; m.p. 139 -140 ° C.

Example 71

Analogous to Example 59, N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) - N - [6-chloro-5- (o-methoxybenzyl) -4-pyrimidinyl] -p (isopropylthio) benzenesulfonamide was obtained. 4-pyrimidinyl] -β- (isopropylthio) benzenesulfonamide, m.p. 127 - 128 ° C (from diisopropylether).

The starting material was prepared from 4,6-dichloro-5- (o-methoxybenzyl) -pyrimidine and potassium p- (isopropylthio) benzenesulfonamide.

Example 72 '38'

Analogous to Example 1, p-chloro-N- [5- (p-) was obtained from p-chloro-N- [6-chloro-5- (p-chlorophenyl) -2-methyl-4-pyrimidinyl] benzenesulfonamide and Na-ethylene glycol. chlorophenyl) -6- (2hydroxyethoxy) -2-methyl-4-pyrimidinyl] benzenesulfonamide, m.p. 163 -164 ° C (from ether).

The starting material was prepared as follows:

From diethyl-p-chlorophenylmalonate, acetamidine hydrochloride and sodium methylate 5- (p-chlorophenyl) -2-methyl-4,6 (1H, 5H) -pyrimidine-dione, m.p. ≫ 270 DEG C. and POCl3 therefor 4,6-dichloro-5- (p-chlorophenyl) -2-methylpyrimidine, m.p. 181-183 ° C (from methylene chloride and isopropyl ether).

Conversion of this compound with p-chlorophenylsulfonamide gave p-chloro-N- [6-chloro-5- (chlorophenyl) -2-methyl-4-pyrimidinyl] benzenesulfonamide, m.p. 196-197 ° C (from acetonitrile).

Example 73

Analogous to Example 1, p-chloro-N- [6- (2-hydroxyethoxy) -5- (p-chloro-N- [6-chloro-5- (p-nitrophenyl) -4-pyrimidinyl] benzenesulfonamide) and p-chlorophenylsulfonamide were obtained. p-nitrophenyl) -4-pyrimidinyl] benzenesulfonamide, m.p. 223-225 ° C (from methylene chloride and isopropyl ether).

The starting material was prepared as follows:

3.5 g of diethyl-p-nitrophenylmalonate and 1.6 g of formamidinacetate were heated at 100 ° C for 3 hours. Then 3.2 g of formamidinacetate, 5 ml of abs were added. of dimethylformamide and 1 ml of ice, and the reaction mixture was heated to 110 ° C for 16 hours. After evaporation of the solvent under reduced pressure, the residue was triturated with ether, drained and taken up in 1N NaOH solution. Some charcoal was added to the solution, filtered off and adjusted to pH 4.5 with ice. The precipitate was dried under reduced pressure at 80 ° C, then taken up in 20 ml of POCl 3 and 1 ml of dimethylaniline and boiled under reflux for 3 hours. After evaporation of the solvent under reduced pressure, the residue was taken up in acetone, the organic solution was washed with cold water, dried and evaporated. The residue was chromatographed on silica gel with cyclohexane-ether 9: 1 to give 4,6-dichloro-5- (p-nitrophenyl) -pyrimidine, m.p. 159 -161 ° C (from isopropyl ether). Conversion of this compound with p-chlorophenylsulfonamide gave p-chloro-N- [6-chloro-5- (pnitrophenyl) -4-pyrimidinyl] benzenesulfonamide, m.p. 282 - 285 ° C (from acetonitrile).

Example 74

200 mg of p-chloro-N- [6- (2-hydroxyethoxy) -5- (p-nitrophenyl) -4-pyrimidinyl] -benzenesulfonamide were hydrated in 15 ml of ice and 2 ml of 4N HCl in dioxane over 50 mg palladium on carbon (10%) at room temperature and normal pressure. After catalyst was removed, the solution was evaporated under reduced pressure, the residue was dissolved in 30 ml of methanol and 1 ml of dioxane - HCl was added to the solution. After 16 hours, the solution was evaporated under reduced pressure and the residue was recrystallized from methanol and acetonitrile. N- [5- (p-Aminophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] p-chlorobenzenesulfonamide hydrochloride, m.p. 206 ° C (decomposition).

Example 75

Analogous to Example 1, N- [5- (4-biphenyl) - (2-hydroxyethoxy) was obtained from p-chloro-N- [5- (4-biphenyl) -6-chloro-4-pyrimidinyl] benzenesulfonamide and Na-ethylene glycol. -4-pyrimidinyl] -β-chlorobenzenesulfonamide, m.p. 213 - 214 ° C (from acetone).

The starting material was prepared as follows:

From diethyl-4-biphenylmalonate, formamidine acetate and sodium methylate 5- (4-biphenyl) -4,6 (1H, 5H) -pyrimidine-dione, m.p. > 280 ° C and from this with POCl 3 5- (4-biphenyl) -4,6-dichloropyrimidine, m.p. 144 ° C (from methylene chloride and n-hexane).

Conversion of this compound with p-chlorophenylsulfonamide gave p-chloro-N- [5- (4-biphenyl) 6-chloro-4-pyrimidinyl] benzenesulfonamide, m.p. 234-235 ° C (from acetonitrile).

Example 76

Analogous to Example 1, p-chloro-N - [(6hydroxyethoxy) was obtained from p-chloro-N- (6-k] or-5-a, a, o; -trifluoro-p-tolyl-4-pyrimidinylbenzene-sulfonamide and Na-ethylene glycol. ) -5-a, a, α-trifluoro-p-tolyl) -4-pyrimidinyl] benzenesulfonamide, m.p. 171-174 ° C (from acetone and isopropyl ether).

The starting material was prepared as follows:

From α, α, α-trifluoro-β-tolyl-malonate and formamidinacetate, 5-a, α, atrifluoro-β-tolyl-4,6 (1H, 5H) -pyrimidine-dione, m.p. > 280 ° C and from that with POCI3

4,6-dichloro-5- (a, a, a-p-tolyl) -pyrimidine, m.p. 94 - 95 ° C (from n-hexane).

Conversion of this compound with p-chlorophenylsulfonamide gave p-chloro-N- (6-chloro-5-a, a, atrifluoro-p-tolyl) -4-pyrimidinyl] benzenesulfonamide, m.p. 262-264 ° C (from acetonitrile).

Example 77

Analogous to Example 27, p-chloro-N- [5- (p-hydroxyphenyl) -6 was obtained from N- [5- [p- (benzyloxy) phenyl] -6- (2-hydroxyethocos) -4pyrimidinyl] -p-chlorobenzenesulfonamide - (2hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide, m.p. 207 - 209 ° C (from acetonitrile and isopropyl ether).

Example 78

Analogous to Example 1, N- [5- [p (benzyloxy) phenyl] -6 (2 was obtained from N- [5- [p- (benzyloxy) phenyl] -6-chloro-4-pyrimidinyl] -chlorobenzenesulfonamide and Na-ethylene glycol -hydroxyethoxy) -4-pyrimidinyl] -β-chlorobenzenesulfonamide, m.p. 160-161 ° C (from ether).

The starting material was prepared as follows:

From diethyl- [p- (benzyloxy) phenyl] malonate and formamidinacetate 5- [p- (benzyloxy) phenyl] -4,6 (1H, 5H) dione, m.p. > 280 ° C and from this with POCl 3 5- [p- (benzyloxy) phenyl] -4,6-dichloropyrimidine, m.p. 115 -116 ° C (from methylene chloride and isopropyl ether). Conversion of this compound with p-chlorophenylsulfonamide gave N- [5 [p (benzyloxy) phenyl] -6-chloro-4-pyrimidinyl] -p-chlorobenzenesulfonamide, m.p. 234 - 236 ° C (from acetone).

Example 79

Analogously to Example 1, N- [6 was obtained from N- (6-chloro-4- (a, a, a-trifluoro-p-tolyl) -4-pyrimidinyl] a, a, atrifluoro-p-toluenesulfonamide and Na-ethylene glycol. - (2-hydroxyethoxy) -5 (a, a, a-trifluoro-p-tolyl) -4-pyrimidinyl] -a, a, a-trifluoro-p-toluenesulfonamide, mp 165-166 ° C (from methylene chloride and isopropyl ether).

The starting material was prepared from 4,6-dichloro-5- (a, a, a-p-tolyl) -pyrimidine and α, α, α-trifluoro-p-tolylsulfonamide, m.p. > 270 ° C (from acetonitrile).

Example 80

Analogous to Example 1, p-chloro-N- [6- (2-hydroxyethoxy) 5- was obtained from p-chloro-N- [6-chloro-5- (2-naphthylmethyl) -4-pyrimidinyl] benzenesulfonamide and Na-ethylene glycol. (2-naphthylmethyl) -4-pyrimidinyl] benzenesulfonamide, m.p. 161 ° C (from acetonitrile and isopropyl ether).

The starting material was prepared as follows:

From diethyl- [2-naphthylmethyl) malonate and formamidine acetate 5- (2naphthylmethyl) -4,6 (1H, 5H) pyrimidinedione, m.p. ≫ 270 ° C and from that with POCl 3 4,6-dichloro5- (2-naphthylmethyl) pyrimidine, m.p. 161 -162 ° C (from methylene chloride and isopropyl ether).

Conversion of this compound with p-chlorophenylsulfonamide gave p-chloro-N- [6-chloro-5- (2naphthylmethyl) -4-pyrimidinyl] benzenesulfonamide, m.p. 197-199 ° C (from acetonitrile).

Example 81

Analogous to Example 1, N- [5- (p-bromophenyl) -6- (2-hydroxyethoxy) was obtained from N- [5- [p-bromophenyl] -6-chloro-4-pyrimidinyl] -β-isopropylbenzenesulfonamide and Na-ethylene glycol ) -4-pyrimidinyl] isopropylbenzenesulfonamide, m.p. 207 - 208 ° C (from acetonitrile and isopropyl ether).

The starting material was prepared from 5- (p-bromophenyl) -4,6-dichloropyrimidine and pizopropylbenzenesulfonamide, m.p. 271-273 ° C (from acetonitrile).

Example 82

Analogous to Example 1, N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) was obtained from N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide and Na-ethylene glycol ) -4-pyrimidinyl] -β-isopropylbenzenesulfonamide, m.p. 162-164 ° C (from acetonitrile and isopropyl ether).

The starting material was prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and p-isopropylbenzenesulfonamide, m.p. 266-268 ° C (from acetonitrile).

Example 83

Analogous to Example 1, N- [6-hydroxyethoxy) -5-tolyl-4-pyrimidinyl] p- was obtained from N- [6-chloro-5- (p-tolyl-4-pyrimidinyl] -p-isopropylbenzenesulfonamide and Na-ethylene glycol. isopropylbenzenesulfonamide, m.p. 142 -144 ° C (from isopropyl ether).

With Na-methylate, Na-salt, an amorphous substance, was obtained.

Starting material N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -β-isopropylbenzenesulfonamide, m.p. 211 - 213 ° C (from acetonitrile) was obtained from 4,6-dichloro-5-p-tolylpyrimidine and pizopropylbenzenesulfonamide.

Example 84

Analogous to Example 1, p-tert-butyl-N- [6- (2-hydroxyethoxy) was obtained from p-tert-butyl-N- [6-chloro-5- (p-tolyl-4-pyrimidinyl] benzenesulfonamide and Na-ethylene glycol ) 5-p-tolyl-4-pyrimidinyl] benzenesulfonamide, mp 169-170 ° C (from isopropyl ether) and from this with Na-methylate an amorphous Na-salt.

The starting material was obtained from 4,6-dichloro-5-p-tolylpyrimidine and p-tert.butylbenzenesulfonamide, m.p. 222 - 224 ° C (from acetonitrile).

Example 85

Analogous to Example 1, N- [6- (2-hydroxyethoxy) 5-p- was obtained from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -β- (2-methoxyethocos) benzenesulfonamide and Na-ethylene glycol. tolyl-4-pyrimidinyl] -β- (2-methoxyethoxy) benzenesulfonamide, m.p. 155-156 ° C (from isopropyl ether).

The starting material was obtained from 4,6-dichloro-5-p-tolylpyrimidine and p- (2-methoxyethoxy) benzenesulfonamide, m.p. 172-173 ° C (from methylene chloride and isopropyl ether).

Example 86

Analogous to Example 1, N- [6- (2-hydroxyethoxy) -5-p was obtained from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -β- (trifluoro-methoxy) benzenesulfonamide and Na-ethylene glycol -tolyl-4-pyrimidinyl] -β- (trifluoromethoxy) benzenesulfonamide, m.p. 147 - 148 ° C (from isopropyl ether).

The starting material was obtained from 4,6-dichloro-5-p-tolylpyrimidine and p- (trifluoromethoxy) benzenesulfonamide, m.p. 205 DEG-206 DEG C. (from acetonitrile and isopropyl ether).

Example 87

Analogous to Example 1, p-butyl-N- [6- (2-hydroxyethoxy) -5-p was obtained from p-butyl-N- (6-chloro-5-p-tolyl-4-pyrimidinyl) benzenesulfonamide and Na-ethylene glycol -tolyl-4-pyrimidinylbenzenesulfonamide, m.p. 136 -137 ° C (from isopropyl ether).

The starting material was obtained from 4,6-dichloro-5-p-tolylpyrimidine and p-butylenzenesulfonamide, m.p. 168-169 ° C (from acetonitrile and isopropyl ether).

Example 88

Analogous to Example 1, N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] was obtained from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -2-naphthalenesulfonamide and Na-ethylene glycol -2-Naphthalene-benzenesulfonamide, m.p. 161-162 ° C (with acetone and isopropyl ether).

The starting material was obtained from 4,6-dichloro-5-p-tolylpyrimidine and 2-naphthalenesulfonamide, m.p. 198 - 202 ° C (from acetonitrile).

Example 89

Analogous to Example 1, N- [6- (2-hydroxyethoxy) -5-p-tolyl-4- was obtained from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -p-toluenesulfonamide and Na-ethylene glycol. pyrimidinyl] -ptoluenesulfonamide, m.p. 169 -170 ° C (from acetone and isopropyl ether).

The starting material was obtained from 4,6-dichloro-5-p-tolylpyrimidine and p-toluenesulfonamide, m.p. 213 - 214 ° C (from acetonitrile and isopropyl ether).

Example 90

Analogous to Example 1, N- [6- (2-hydroxyethoxy) -5- was obtained from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -α, α, α-trifluoro-ptoluenesulfonamide and Na-ethylene glycol. p-tolyl-4-pyrimidinyl] -a, a,? -trifluoro-p-toluenesulfonamide, m.p. 162-163 ° C (from acetonitrile and isopropyl ether).

The starting material was obtained from 4,6-dichloro-5-p-tolylpyrimidine and α, α, α-trifluoro-ptoluenesulfonamide, m.p. 231-233 ° C (from acetonitrile).

Example 91

Analogous to Example 1, p-fluoro-N- [6- (2hydroxyethoxy) -5-p- was obtained from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -p-fluorobenzenesulfonamide and Na-ethylene glycol. tolyl-4-pyrimidinyl] benzenesulfonamide, m.p. 167-168 ° C (from acetone and isopropylether), and p- (2-hydroxyethoxy) -N- [6- (2-hydroxyethoxy) 5-p-tolyl-4-pyrimidinyl] benzenesulfonamide, m.p. 174 -176 ° C (from acetone and isopropyl ether).

The starting material was obtained from 4,6-dichloro-5-p-tolylpyrimidine and p-fluorobenzenesulfonamide, m.p. 207 - 208 ° C (from acetonitrile and isopropyl ether).

Example 92

Analogous to Example 1, N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] was obtained from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -p-propylbenzenesulfonamide and Na-ethylene glycol -p-propylbenzenesulfonamide, m.p. 152-153 ° C (from isopropyl ether).

The starting material was prepared from 4,6-dichloro-5-p-tolylpyrimidine and p-propylbenzenesulfonamide, m.p. 171 -172 ° C (from acetonitrile).

Example 93

Analogous to Example 1, N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] was obtained from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -o-propylbenzenesulfonamide and Na-ethylene glycol -o-propylbenzenesulfonamide, m.p. 195-196 ° C (from methylene chloride and isopropyl ether).

The starting material was prepared from 4,6-dichloro-5-p-tolylpyrimidine and o-propylbenzenesulfonamide, m.p. 150-151 ° C (from isopropyl ether).

Example 94

Analogous to Example 1, p-ethyl-N- [6- (2-hydroxyethoxy) -5-p- was obtained from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -p-ethylbenzenesulfonamide and Na-ethylene glycol. tolyl-4-pyrimidinyl] benzenesulfonamide, m.p. 138-139 ° C (from methylene chloride and isopropyl ether).

The starting material was prepared from 4,6-dichloro-5-p-tolylpyrimidine and p-ethylbenzenesulfonamide, m.p. 180-181 ° C (from acetonitrile).

Example 95

Analogous to Example 1, o-ethyl-N- [6- (2-hydroxyethoxy) -5-p- was obtained from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -o-ethylbenzenesulfonamide and Na-ethylene glycol. tolyl-4-pyrimidinyl] benzenesulfonamide, m.p. 136-138 ° C (acetone and isopropyl ether).

The starting material was prepared from 4,6-dichloro-5-p-tolylpyrimidine and o-ethylbenzenesulfonamide, m.p. 159 -160 ° C (from acetonitrile and isopropyl ether).

Example 96

Analogous to Example 1, p-cyclopentyl-N- [6- (2-hydroxyethoxy) -5- was obtained from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -p-cyclopentylbenzene-sulfonamide and Na-ethylene glycol. ptolyl-4-pyrimidinyl] benzenesulfonamide, m.p. 179 -181 ° C (from acetone and isopropyl ether).

The starting material was prepared from 4,6-dichloro-5-p-tolylpyrimidine and p-cyclopentylbenzenesulfonamide, m.p. 192-194 ° C (from acetonitrile and isopropyl ether).

Example 97

Analogously to Example 1, N, (6-chloro-5-p-tolyl-4-pyrimidinyl) -α, α, α-trifluoro-otoluenesulfonamide and Na-ethylene glycol were obtained α, α, α-trifluoro-N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] -o-toluenesulfonamide, m.p. 166 - 167 ° C (from methylene chloride and isopropyl ether).

The starting material was prepared from 4,6-dichloro-5-p-tolylpyrimidine and -α, α, α-trifluoro-toluenesulfonamide, m.p. 129 -131 ° C (from methylene chloride and isopropyl ether).

Example 98

Analogous to Example 1, N- [6- (2-hydroxyethoxy) -5-p-tolyl-4- was obtained from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -o-toluenesulfonamide and Na-ethylene glycol. pyrimidinyl] -otoluenesulfonamide, m.p. 149 - 150 [deg.] C. (from acetone and isopropyl ether).

The starting material was prepared from 4,6-dichloro-5-p-tolylpyrimidine and otoluenesulfonamide, m.p. 198-199 ° C (from acetonitrile).

Example 99

Analogous to Example 1, N- [6- (2-hydroxyethoxy) -5-p-tolyl- from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -2,4-xylenesulfonamide and Na-ethylene glycol 4pyrimidinyl] -2,4-xylolsulfonamide, m.p. 158-159 ° C (from isopropyl ether).

The starting material was prepared from 4,6-dichloro-5-p-tolylpyrimidine and 2,4-xylenesulfonamide, m.p. 233 ° C (from acetonitrile and isopropyl ether).

Example 100

Analogous to Example 1, p-chloro-N- [6- (2-hydroxyethoxy) -5 was obtained from p-chloro-N- (6-chloro-5- (1-naphthylmethyl) -4-pyrimidinyl] benzenesulfonamide and Na-ethylene glycol - (naphthylmethyl) -4-pyrimidinyl] benzenesulfonamide, mp 204 - 205 ° C (from acetonitrile and isopropyl ether).

The starting material was prepared as follows:

From diethyl-1-naphthylmalonate and formamidinacetate 5- (1-naphthylmethyl) 4,6 (1H, 5H) -pyrimidinedione, m.p. > 270 ° C, and from this, after drying under reduced pressure at 80 ° C by conversion with POCl 3, 4,6-dichloro-5- (1-naphthylmethyl) pyrimidine was obtained, m.p. 111-112 ° C (from methylene chloride and isopropyl ether).

Conversion of this compound with p-chlorophenylsulfonamide gave p-chloro-N- [6-chloro-5- (naphthylmethyl) -4-pyrimidinyl] benzenesulfonamide, m.p. 202 - 203 ° C (from acetonitrile).

Example 101

Analogous to Example 1, N- [6- (2-hydroxyethoxy) 5- (p-isopropylphenyl) -4 was obtained from N- [6-chloro-5- (p-isopropylphenyl) -4-pyrimidinyl] -isopropylbenzenesulfonamide and Na-ethylene glycol -pyrimidinyl] -β-isopropylbenzenesulfonamide, m.p. 142 -144 ° C (from isopropyl ether).

The starting material was prepared as follows:

From diethyl- (p-isopropylphenyl) malonate and formamidinacetate 5- (pizopropylphenyl) -4,6 (1H, 5H) pyrimidinedione, m.p. ≫ 290 [deg.] C. and from this, by conversion with POCl3, 4,6-dichloro-5- (p-isopropyl-phenyl) pyrimidine was obtained, m.p. 69-70 ° C (from n-hexane). Conversion of this compound with p-isopropylbenzenesulfonamide gave N- [6-chloro-5- (p-isopropylphenyl) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide, m.p. 198-199 ° C (from acetonitrile and isopropyl ether).

Example 102

Analogous to Example 1, p-cyclopentyl-N- [6- (2-hydroxyethoxy) -5- (p-isopropylphenyl) was obtained from N- [6-chloro-5- (p-isopropylphenyl) -4-pyrimidinyl] -picyclopentylbenzenesulfonamide and Na-ethylene glycol. ) -4-pyrimidinyl] benzenesulfonamide, m.p. 132 ° C (decomposition) (acetone - isopropyl ether).

The starting material was prepared from 4,6-dichloro-5- (p-isopropylphenyl) pyrimidine and p-cyclopentylbenzenesulfonamide, m.p. 188-189 ° C (from methylene chloride and isopropyl ether).

Example 103

From p-tert-butyl-N- [6-chloro-5- (o-methoxybenzyl) -4-pyrimidinyl] benzenesulfonamide and pyridine-2-carboxylic acid was obtained by heating in methylene chloride in the presence of dicyclohexylcarbodiimide 4-tert-butyl-N - [6- [2- (pyridin-2-ylcarbonyloxy) -ethoxy] -5- (2-methoxybenzyl) pyrimidin-4-yl] benzenesulfonamide.

Analogically, we can obtain:

4-tert-butyl-N- [6- [2- (pyridin-3-ylcarbonyloxy) ethoxy] -5- (2-methoxybenzyl) pyrimidin4-ylbenzenesulfonamide;

4-tert-butyl-N- [6- [2- (pyridin-4-ylcarbonyloxy) ethoxy] -5- (2-methoxybenzyl) pyrimidin4-yl] benzenesulfonamide;

4-tert-butyl-N- [6- [2 - [(3-methylisoxazol-5-yl) carbonyloxy] ethoxy] -5- (2-methoxybenzyl) pyrimidin-4-yl] benzenesulfonamide;

4-tert-butyl-N- [6- [2- (furan-2-ylcarbonyl-oxy) ethoxy] -5- (2-methoxybenzyl) pyrimidin4-yl] benzenesulfonamide;

4-tert-butyl-N- [6- [2- (furan-3-ylcarbonyloxy) ethoxy] -5- (2-methoxybenzyl) pyrimidin4-yl] benzenesulfonamide;

4-tert-butyl-N- [6- [2- (thiophen-2-ylcarbonyl) ethoxy] -5- (2-methoxybenzyl) pyrimidin-10-yl] benzenesulfonamide;

4-tert-Butyl-N- [6- [2- (thiophen-3-ylcarbonyl) ethoxy-5- (2-methoxybenzyl) pyrimidin4-yl] benzenesulfonamide.

Example A 15

Tablets containing the following ingredients can be prepared in the usual way:

Ingredients_ compound of formula I lactose corn starch talc magnesium stearate (and isopropyl ether).

per tablet 10.0 -100.0 mg 125.0 mg

75.0 mg 4.0 mg 1.0 mg

Example B

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

Ingredients of compounds of formula I lactose corn starch talc capsule 25.0 mg 150.0 mg 20.0 mg 5.0 mg

Injectable solutions may have the following composition

Example C

Compound of Formula I_3.0 mg gelatin 150.0 mg phenol 4.7 mg water for solution for injection ad 1.0 ml

Example D

Suspend 500 mg of the compound of Formula I in 3.5 ml of Myglyol 812 and 0.08 g of benzyl alcohol. This suspension is filled into a container with a metering valve. Pour into a container of 5.0 g Freon 12 under pressure through a valve. By shaking, Freon melts in the Myglyola-benzyl alcohol mixture. This spray container contains about 100 single use dispensers.

Claims (10)

PATENT APPLICATIONS in which R1 represents hydrogen, lower-alkyl, lower-alkoxy, lower-alkylthio, halogen or trifluoromethyl, R 2 represents hydrogen, halogen, lower-alkoxy, hydroxy-lower alkoxy or trifluoromethyl, R4 represents hydrogen, hydroxy, halogen, alkylthio, cycloalkyl, hydroxy-lower-alkyl, hydroxy-lower-alkoxy, hydroxyimino-lower-alkyl, lower-alkenyl, oxo-lower-alkyl, trifluoromethyl, trifluoromethoxy, lower-alkoxy, lower -alkoxy-lower-alkoxy or aryl-lower-alkoxy; R2 and R4 together represent butadienyl; R 4 represents hydrogen, lower alkyl, aryl or heteroaryl; R 5 represents hydrogen, lower alkanoyl, benzoyl, heterocyclyl-carbonyl or tetrahydropyran-2-yl; R ^ represents a residue of formula R7 represents hydrogen, lower-alkoxy or nitro; r8 represents hydrogen, halogen, lower-alkyl, lower-alkoxy, lower-alkylthio, nitro, hydroxy, amino or trifluoromethyl; R ⁷ and R 8 together represent butadienyl; R4 represents hydrogen, halogen, lower-alkyl, lower-alkoxy, lower-alkylthio or trifluoromethyl; R10 represents hydrogen, halogen, lower-alkyl, lower-alkoxy or lower-alkylthio; X and Y independently represent O, S or NH; and n represents 2,3 or 4; and their salts as active ingredients in the preparation of medicaments for the treatment of circulatory disorders, in particular hypertension, ischemia, vasospasms and angina. Use according to claim 1 of the compounds of formula I and their salts, wherein hydrogen, lower alkyl or aryl and the other symbols in claim 1 have the meanings indicated. Compounds of formula I according to claim 1 and their salts, characterized in that R 1 represents a residue of formula and R 1 represents halogen, lower-alkoxy, lower-alkylthio or trifluoromethyl, R 1 represents hydrogen, or lower-alkoxy and have R 1 to R 1, X, Y and n in claim 1, the meaning indicated. Compounds of formula I and their salts, wherein R 1 is hydrogen, lower alkyl or aryl and the other symbols have the meaning indicated in claim 3. 5. Compounds: N- [5- (2,6-Dimethoxybenzyl) -6-3-hydroxypropyl) -4-pyrimidinyl] -p-vinylbenzenesulfonamide, a, a, a-trifluoro-N- [6- (2-hydroxyethoxy) -6- [o- (trifluoromethyl) benzyl] pyrimidinyl] -ptoluenesulfonamide, N- [6- (2-hydroxyethoxy) -5- [o- (trifluoromethyl) benzyl] -4-pyrimidinyl] -p-methoxybenzenesulfonamide, p-chloro-N- [6- (2-hydroxyethoxy) -5- [o - (trifluoromethyl) benzyl] -4-pyrimidinylbenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- [o- (methoxybenzyl) -4-pyrimidinyl] -p-vinylbenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- [o- (trifluoromethyl) benzyl] -4-pyrimidinyl] -β- (methylthio) benzenesulfonamide, N- [5- (2,4-dimethoxybenzyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -β-isopropylbenzenesulfonamide, rac-N- [5- (o-methoxybenzyl) -6- [2 - [( tetrahydro-2H-pyran-2-yl) oxy] ethoxy] -4-pyrimidinyl] -β-vinylbenzenesulfonamide, rac-p - [[5- (o-methoxybenzyl) -6- [2 - [(tetrahydro-2H-pyran-2 -yl) oxy] ethoxy] -4pyrimidinyl] sulfamoyl] benzaldehyde, p - [(RS) -1-hydroxyethyl] -N- [5 - (- methoxybenzyl) -6- [2 - [[(RS) -tetrahydro-2H -pyran2-yl) oxy] ethoxy] -4-pyrimidinyl] benzenesulfonanide, rac-a-hydroxy-N- [5- (o-methoxybenzyl) -6- [2 - [(tetrahydro-2H-pyran-2yl) oxy] ethoxy] -4-pyrimidinyl] -p-toluenesulfonamide, rac-a - [(> E / Z) -hydroxyimino-N- [5- (o-methoxybenzyl) -6- [2 - [(tetrahydro-2H-pyran2- yl) oxy] ethoxy] -4-pyrimidinyl] -p-toluenesulfonamide, rac-N-6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -p- (lidroxyethyl) benzenesulfonamide, a - [(> E / Z) -hydroxyimino-N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] -p-toluenesulfonamide, p - [[6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] sulfamoyl] benzaldehyde, 2 - [[5- (o-methoxybenzyl) -6 - [(p-vinylphenyl) sulfamoyl] -4-pyrimidinyl] oxy] ethyl acetate, N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] -β-methoxybenzenesulfonamide, N- [6- (2-Hydroxyethoxy) -5- (o-chlorobenzyl) -4-pyrimidinyl] -p-tohienesulfonamide, N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] -p-methylthiobenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] -a, a, α-trifluoro-ptoluenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] -β-isopropylbenzenesulfonamide, p-tert-butyl-N- [6- (2-hydroxyethoxy) -5- (o- methoxybenzyl) -4-pyrimidinyl] benzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (o-chlorobenzyl) -4-pyrimidinyl] -β-isopropylbenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (o-methylthiobenzyl) -4-pyrimidinyl] -β-isopropylbenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (o-chlorobenzyl) -4-pyrimidinyl] -p-isobutylbenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (o-chlorobenzyl) -4-pyrimidinyl] -picyclohexylbenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (o-chlorobenzyl) -4-pyrimidinyl] -β-isopentylbenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] -β-isopropylthiobenzenesulfonamide, Compounds of formula I according to claim 1, characterized in that it is a radical of formula and R 13 is hydrogen, lower-alkoxy or nitro, R 4 is hydrogen, halogen, lower-alkyl, lower-alkoxy, lower-alkylthio or nitro, or R 13 and R 4 together represent butadienyl and R 1 to R 4, X, Y and n have the meanings indicated in claim 1. Compounds of formula I and their salts, characterized in that R1 is hydrogen, lower-alkyl or aryl and the other symbols have the meaning indicated in claim 6. 8. Compounds: N- [5- (p-Chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] α, α, α-trifluoro-ptoluenesulfonamide, N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -p- (trifluoromethoxy) benzenesulfonamide, p-chloro-N- [5- (m-chlorophenyl) -6- ( 2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide, p-chloro-N- [5- (p-fluorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide, N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -p-fluorobenzenesulfonamide, o-chloro-N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide, p-chloro-N- [5- (3,4-dimethoxyphenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide, 3.4-Dichloro-N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide, N- [5- (p-Chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -a, a, a-a ', a', a'-hexafluoro-3,5xylenesulfonamide, 3-chloro-N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -4- (2-hydroxyethoxy) benzenesulfonamide, p-chloro-N- (6- (2'hydroxyethoxy) ) -5- (p-nitrophenyl) -4-pyrimidinyl] benzenesulfonamide, p-butoxy-N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide, N- [5- (p-Chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -3,4-dimethoxy) benzenesulfonamide, 2-chloro-N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -G, α ;, α-trifluoro-ptoluenesulfonamide, 6-chloro-N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -a, a, α-trifluoro-methylenesulfonamide, 2.3.4-Trichloro-N- (5-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide, m-chloro-N- (5-chlorophenyl) -6- (2-hydroxyethoxy) -4- pyrimidinyl] benzenesulfonamide, 2.4-dichloro-N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide, N-5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -a, a, α-trifluoro-m-toluenesulfonamide, N-5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl-a, a, α-trifluoro-o-toluenesulfonamide, N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -2-naphthalenesulfonamide, p-chloro-N- [6- (2-hydroxyethoxy) -5- (m-nitrophenyl) -4-pyrimidinyl] benzenesulfonamide, a, a, a-trifluoro-N- [6- (2-hydroxyethoxy) -5- (m-nitrophenyl) -4-pyrimidinyl] p-toluenesulfonamide, p- (benzyloxy) -N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide, N- [5- (p-Chlorophenyl) -4-pyrimidinyl] -β-hydroxybenzenesulfonamide, N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -β- (2-methoxyethoxy) benzenesulfonamide, N- [5- (p-bromophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -β-chlorobenzenesulfonamide, p-chloro-N- [6- (2-hydroxyethoxy) -5-p-tolyl-4 -pyrimidinyl] benzenesulfonamide, N-5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -a, o ;, a-trifluoro-p-toluenesulfonamide-Na-salt, N- [6- (2-hydroxyethoxy) -5- (p-methoxyphenyl) -4-pyrimidinyl] -p-toluenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (p-methoxyphenyl) -4-pyrimidinyl] -p-methoxybenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (p-methoxyphenyl) -4-pyrimidinyl] -β- (methylthio) benzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (p-methoxyphenyl) -2-methyl-4-pyrimidinyl] -β-methoxybenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (p-methoxyphenyl) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide, p-tert-butyl-N- [6- (2-hydroxyethoxy) -5- (p- methoxyphenyl) -4-pyrimidinyl] benzenesulfonamide, rac-p-sec-butyl-N- [6- (2-hydroxyethoxy) -5- (p-methoxyphenyl) -4-pyrimidinyl] benzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- [p- (methylthio) phenyl] -4-pyrimidinyl] -β-isopropylbenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- [p- (methylthio) phenyl] -4-pyrimidinyl] -a, a, α-trifluoro-ptoluenesulfonamide, p-chloro-N- [5- (p-chlorophenyl) ) -6- (2-hydroxyethoxy) -2-methyl-4-pyrimidinyl] benzenesulfonamide, p-chloro-N- [6- (2-hydroxyethoxy) -5- [p-nitrophenyl) -4-pyrimidinyl] benzenesulfonamide, N- [5- (p-Aminophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -β-chlorobenzenesulfonamide hydrochloride, N- [5- (4-Biphenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -β-chlorobenzenesulfonamide, p-chloro-N- [6-hydroxyethoxy) -5- (a, a, a-trifluoro) -p-tolyl) -4-pyrimidinyl] benzenesulfonamide, p-chloro-N- [5- (p-hydroxyphenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide, N- [5- (p- (benzyloxy) phenyl] -6- (2-hydroxyethoxy) -4-pyrimidinyl] -β-chlorobenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (a, a, a-trifluoro-p-tolyl) -4-pyrimidinyl] -a, a, a-trifluoro-ptoluenesulfonamide, N- [5- (p-Chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -β-isopropylbenzenesulfonamide, N- [6-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] -p-isopropylbenzenesulfonamide, p-tert-butyl-N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] benzenesulfonamide, N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] -β- (2-methoxyethoxy) benzenesulfonamide, N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] -β- (trifluoromethoxy) benzenesulfonamide, p-butyl-N- [6- (2-hydroxyethoxy) -5-p-tolyl -4-pyrimidinyl] benzenesulfonamide, N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] -2-naphthalenesulfonamide, N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] -p-toluenesulfonamide, N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] -a, a, α-trifluoro-ptoluenesulfonamide, p- (2-hydroxyethoxy) -N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] benzenesulfonamide, N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] p-propylbenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] -o-propylbenzenesulfonamide, p-ethyl-N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl ] benzenesulfonamide, o-ethyl-N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] benzenesulfonamide, p-cyclopentyl-N- [6- (2-hydroxyethoxy) -5-p-tolyl ] benzenesulfonamide, a, a, a-trifluoro-N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] -o-toluenesulfonamide, N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] -o-toluenesulfonamide, p-chloro-N- [6- (2-hydroxyethoxy) -5- (1-naphthylmethyl) -4 -pyrimidinyl] benzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (p-isopropylphenyl) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide, p-cyclopentyl-N- [6- (2-hydroxyethoxy) -5- (p-isopropylphenyl) -4-pyrimidinyl] benzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (a, a, α-trifluoro-p-tolyl) -4-pyrimidinyl] -β-isopropylbenzenesulfonamide, N- [5- (p-Bromophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -β-isopropylbenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (p-ethylphenyl) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide, p-cyclopentyl-N- [6- (2-hydroxyethoxy) -5- (p-ethylphenyl) -4-pyrimidinyl] benzenesulfonamide. A process for the preparation of compounds according to claims 3 to 8, characterized in that a compound of the formula wherein R 1, R 1, R 3 and R 4 have the meanings indicated in claim 1, Hal represents halogen and R 4 represents a residue and have RH , Rl2 _} r13 j _n r14 the meaning given _in claims 3 and 6, is converted to a compound of the formula MX (CH ₂ ) _n YR ⁵ ΙΠ in which X, Y, n and R $ are as defined in claim 1 and M represents an alkali metal, and optionally in the resultant compound of formula I, the substituents present are converted and / or the compound obtained with Formula I is converted into a salt. Pharmaceutical preparations containing the compounds according to claims 3 - 8 and conventional pharmaceutical auxiliaries.