RU2083567C1 - Derivatives of arylsulfoneamide or their salts and pharmaceutical composition showing antiprotective, antihypertension and vasospamolytic, in part, antiischemic action - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: derivatives of arylsulfoneamide of the formula:

where: R¹ - H, halogen; R² - H, halogen, CF₃; R³ - halogen, lower thioalkyl, trifluoromethoxy, lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, C₅-C₈-cycloalkyl, CF₃, phenyl-lower alkoxy, lower alkenyl, oxo-lower alkyl, hydroxyimini-lower alkyl, hydroxy-lower alkyl; or R² and R³ together form butadienyl; R⁵ - hydrogen, tetrahydropyrane-2; R⁶ - phenyl substituted with R⁷,R⁸ or benzyl substituted with R⁹,R¹⁰; R⁷ - hydrogen, lower alkyl; R⁸ - halogen, lower alkyl, lower alkoxy, lower thioalkyl, nitro-group; R⁹ - halogen, lower alkylhydroxy, lower thioalkyl, trifluoromethyl; R¹⁰ - hydrogen, lower thioalkyl, lower alkoxy; n = 2, 3, or their salts. Synthesized compounds were used as drugs. EFFECT: improved method of synthesis. 5 cl

Description

 The invention relates to new derivatives of arylsulfonamide and their salts having the properties of an endothelin binding inhibitor, which can be used for pharmaceuticals in the treatment of diseases associated with processes that increase vascular spasms, in particular, for the treatment of cardiovascular diseases such as hypertension, ischemia, blood vessels and angina pectoris, and also relates to angioprotective, antihypertensive and vasospasmolytic, in particular, anti-ischemic drugs based on them.

где R¹ водород, галоген; R² водород, трифторметил; R³ галоген, низший алкилтио, трифторметокси, низший алкил, низший алкокси-низший алкокси, низший алкокси, C₅-C₅-циклоалкил, трифторметил, фенил-низший алкокси, низший алкенил, оксо-низший алкил, гидроксимино-низший алкил, гидрокси-низший алкил, или R² и R³ вместе образуют бутадиенил; R⁴ водород, низший алкил; R⁵ - водород, тетрагидропиран-2-ил; R⁶ представляет радикал формулы

где R⁷ водород, низший алкил; R⁸ галоген, низший алкил, низший алкокси, низший алкилтио, нитро; R⁹ галоген, низший алкокси, низший алкилтио, трифторметил; R¹⁰ водород, низший алкилтио, низший алкокси; n 2 или 3, или их соли.Derivatives of the aryl sulfonamide according to the present invention correspond to the general structural formula I

where R ^{1 is} hydrogen, halogen; R ^{2 is} hydrogen; trifluoromethyl; R ³ halogen, lower alkylthio, trifluoromethoxy, lower alkyl, lower alkoxy lower alkoxy, lower alkoxy, C ₅ -C ₅ cycloalkyl, trifluoromethyl, phenyl lower alkoxy, lower alkenyl, oxo lower alkyl, hydroxyimino lower alkyl, hydroxy lower alkyl or R ² and R ³ together form butadienyl; R ⁴ hydrogen, lower alkyl; R ⁵ is hydrogen, tetrahydropyran-2-yl; R ⁶ represents a radical of the formula

where R ^{7 is} hydrogen, lower alkyl; R ⁸ halogen, lower alkyl, lower alkoxy, lower alkylthio, nitro; R ⁹ halogen, lower alkoxy, lower alkylthio, trifluoromethyl; R ^{10 is} hydrogen, lower alkylthio, lower alkoxy; n 2 or 3, or their salts.

 From German patent publications DE 1,545,944, sulfonamides are known which are very close to those proposed and have a similar general structural formula. These known sulfonamides act as lowering blood sugar.

 Unexpectedly, it was found that the compounds of the above formula I are inhibitors for endothelin receptors. The compounds of the formula can be used to treat diseases associated with endothelin activity, in particular diseases of the cardiovascular system such as hypertension, ischemia, vascular spasms and Angina pectoris (angina pectoris).

 The expression "lower" as used herein means groups with 1 to 7 carbon atoms, preferably with 1 to 4 carbon atoms. Alkyl groups, alkoxy, alkylthio and alkenyl groups, as well as alkyl groups as components of alkanoyl groups can be of normal or iso-structure. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, secondary and tertiary butyl. Examples of alkenyl groups are vinyl and allyl. The phenyl lower alkoxy radical is, for example, benzyloxy. Halogen means fluoro, chloro, bromo and iodo, with chloro being preferred.

Preferred compounds of formula I selected from the group:
N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] p-methoxybenzosulfonamide;
N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] p-methylthiobenzenesulfonamide;
N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] α, α, α-trifluoro-p-toluenesulfonamide;
as well as compounds of formula I selected from the group:
N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] trifluoro-p-toluenesulfonamide;
N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] p- (trifluoromethoxy) 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] benzylsulfonamide;
N- [5- (p-bromophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] p-chloro-benzenesulfonamide:
p-chloro-N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] benzenesulfonamide;
N- [6- (2-hydroxyethoxy) -5- (p-methoxyphenyl) -4-pyrimidinyl] p- (methylthio) benzenesulfonamide;
N- [6- (2-hydroxyethoxy) -5- (p-methoxyphenyl) -4-pyrimidinyl] p-isopropylbenzenesulfonamide;
p-tert-butyl-N- [6- (2-hydroxyethoxy) -5- (p-methoxyphenyl) -4-pyrimidinyl] benzenesulfonamide;
N- [6- (2-hydroxyethoxy) -5- [p- (methylthio) phenyl] -4-pyrimidinyl] p-isopropylbenzenesulfonamide;
N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] p-isopropylbenzene sulfonamide;
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] p- (2-methoxyethoxy) benzenesulfonamide;
N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] p- (trifluoromethoxy) benzenesulfonamide;
N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] p-toluenesulfonamide;
N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] a, α, α-trifluoro-p-toluenesulfonamide;
N- [6- (2-hydroxyethoxy) -5- (a, α, α-trifluoro-p-tolyl) -4-pyrimidinyl-p-isopropylbenzenesulfonamide;
N- [5- (p-bromophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] p-isopropylbenzenesulfonamide;
N- [6- (2-hydroxyethoxy) -5- (p-ethylphenyl) -4-pyrimidinyl] p-isopropyl-benzosulfonamide;
p-cyclopentyl-N- [6- (2-hydroxyethoxy) -5- (p-ethylphenyl) -4-pyrimidinyl] benzenesulfonamide.

где R¹, R², R³, R⁴ и R⁶ имеют вышеназванное значение, а Hal означает галоген, взаимодействует с соединением формулы
MO(CH₂)_nOR⁵
где 14 R⁵ имеет вышеназванное значение, M является щелочным металлом, заместители, присутствующие в полученном соединении формулы I, можно модифицировать и/или переводить полученное соединение формулы I в соль.Compounds of formula I can be prepared in this way when a compound of formula

where R ¹ , R ² , R ³ , R ⁴ and R ⁶ have the above meaning, and Hal means halogen, interacts with a compound of the formula
MO (CH ₂ ) _n OR ⁵
where 14 R ⁵ has the above meaning, M is an alkali metal, the substituents present in the obtained compound of formula I can be modified and / or the resulting compound of formula I can be converted into a salt.

 In a preferred embodiment of the method, the compounds of formula II or V.

 The interaction of the compounds of formula II with the compound of formula III, it is advisable to carry out the use of glycol, used mainly as compound III, for example, in ethylene glycol, including when n 2. As the alkali metal M, sodium is mainly used.

It is advisable to carry out the reaction by heating, for example, to 70-120 ^° C. In a preferred embodiment, the monosodium salt of ethylene or propylene glycol is used as the compound of formula III.

In the compound of formula I thus obtained, the substituents present in it can be modified. The hydroxyl group may, for example, be esterified (to ether). The nitro group can be reduced to an amino group. The lower alkenyl group R ³ can, for example, be oxidized with OsO ₄ or NaJO ₄ to a carbonyl group or alkanone group; such a carbonyl group formed can, for example, be reduced to a hydroxyl group using sodium borohydride or converted to the corresponding tert alcohol with the Grignard compound or converted to oxime with hydroxylamine. These reactions can be carried out in a known manner, wherein the hydroxyl group R ^{5 is} first converted to an ether group (ether), for example, tetrahydropyran. These groups may, if necessary, be cleaved again in a conventional manner. At the same time, if R ^{5 is a} hydroxyl group, it is transferred by etherification into ether without the subsequent modification of other reactive groups in the molecule. The compounds of formula I can be converted into salts, for example, to alkaline salts, such as sodium and potassium salts, by conventional methods.

 The compounds of formula II and III, used as starting materials, since they are not known and their preparation is described below, are obtained by analogy with the known or by analogy with the methods described below.

Конденсация соединения IV с формамидинацетатом или с его аналогом, таким как ацетат ацетамидина или хлоргидрат ацетамидина, дает пиримидиндион V. С помощью оксихлорида фосфора получат дихлорсоединение VI, которое при взаимодействии с соединением VII дает соединение II. Все эти реакции являются стандартными и могут быть проведены при условиях, обычных для таких реакций и известных специалистам. Соединения IV, в которых R⁶ представляют собой радикал (a), могут быть получены из соответствующих эфиров фенилуксусной кислоты формулы R⁶CH₂COOE_t взаимодействием с диэтилкарбонатом в присутствии этилацетата натрия. Соединения IV, в которых R⁶ представляют собой радикал (б), могут быть получены конденсацией Кневенагеля (Knoevenalgel) диэтилового эфира малоновой кислоты с соответствующим альдегидом R⁶CHO и путем последующего гидрирования продукта конденсации.Compounds of formula II can be prepared according to the following reaction scheme:

The condensation of compound IV with formamidine acetate or its analogue, such as acetamidine acetate or acetamidine hydrochloride, gives pyrimidinedione V. Using phosphorus oxychloride, dichloro compound VI is obtained which, when reacted with compound VII, gives compound II. All of these reactions are standard and can be carried out under conditions common to such reactions and known to those skilled in the art. Compounds IV in which R ⁶ is radical (a) can be prepared from the corresponding phenylacetic acid esters of the formula R ⁶ CH ₂ COOE _{t by} reaction with diethyl carbonate in the presence of sodium ethyl acetate. Compounds IV in which R ⁶ is radical (b) can be prepared by condensation of a Knoevenalgel of malonic acid diethyl ester with the corresponding R ⁶ CHO aldehyde and subsequent hydrogenation of the condensation product.

 Another object of the invention is an angioprotective, antihypertensive and vasospasmolytic, in particular anti-ischemic agent, comprising the active substance a compound of formula I in an effective amount and pharmaceutically acceptable additives.

The inhibitory effect of the compounds of formula I on endothelin receptors can be shown in the experiment described below:
I: Inhibition of endothelin binding on the membrane of the human placenta (cf. Life Sci 44: 1429 (1989))
The human placenta is homogenized in 5 mmol Tris buffer at pH 7.4 containing 1 mmol MgCl ₂ and 250 mmol sucrose. The homogenizate is centrifuged at 3000 g for 15 min at 4 ^° C, the supernatant contained in the plasma membrane fraction is centrifuged at 72000 g for 30 min, and the precipitate is washed with 75 mmol Tris buffer at pH 7.4, which contains 25 mmol MgCl ₂ . Then the precipitate obtained from 10 g of the main tissue is suspended in 1 ml of a 75 mmol Tris buffer at pH 7.4 containing 25 mmol of MgCl ₂ and 250 mmol of sucrose, and 1 ml of an aliquot is frozen at 20 ^° C.

For binding according to the Assay method, the frozen membrane fraction is thawed and after 10 min centrifugation at 25,000 g resuspended at 20 ^° C in Assey buffer (50 mmol tri-buffer, pH 7.4, containing 25 mmol MnCl ₂ , 1 mmol ethylenediaminetetraacetic acid and 0.5% bovine serum albumin). 100 μl of this membrane suspension containing 70 μg of protein is incubated with 50 μl of ¹²⁵ I-endothelin (specific activity 2200 Ci / mmol in Assay buffer (25,000 cpm, final concentration of 20 pM) and 100 ml Assey buffer containing varying concentration of the test compounds Incubation is carried out for 2 hours at 20 ^° C or for 24 hours at 4 ^° C. Separation of the free or bound membrane of the radioligand is carried out by filtration over a glass fiber filter.

In the table. 1 shows the inhibitory effect of the compounds of formula I, considered in this experiment, as IC ₅₀ , that is, as the concentration (mmol) necessary to inhibit 50% of the specific bonds of ¹²⁵ I-endothelin (endothelin labeled ¹²⁵ I).

означает необходимую эндотелин-концентрацию для половины максимального сокращения. Чем больше это отношение дозы, тем тест-соединение потенциальнее тормозит биологическое действие эндотелина-1. EC₅₀ эндотелина в присутствии тест-соединения составляет 0,3 ммол.II: Inhibition of endothelin-induced contractions on isolated rat aortic rings
5 mm long rings were excised from the thoracic aorta of an adult Wistar-Kyoto rat. The endothelium was removed by lightly grinding the inner surface. Each ring was immersed in an isolated bath at a temperature of 37 ^° C in 10 ml of Krebs-Hanselight solution by fumigation with 95% O ₂ and 5% CO ₂ . The isometric voltage of the ring was measured. The rings were stretched to a prestress of 3 g. After 10 minutes of incubation with a test compound or binder, cumulative doses of endothelin-1 were added. The activity of the test compounds was determined by calculating the dose ratio, that is, a shift to the right, induced by a 100 mmol test compound (shift to large values), EC ₅₀ endothelin, and

means the necessary endothelin concentration for half the maximum contraction. The larger this dose ratio, the more likely the test compound inhibits the biological effect of endothelin-1. The EC _{50 of} endothelin in the presence of the test compound is 0.3 mmol.

The right shift value of EC ₅₀ endothelin obtained using the compounds of formula I are presented in table. 2.

III: The inhibitory effect of the compounds of formula I on vasoconstriction can be observed in vivo in rats in the following experiment:
Rats were anesthetized with sodium thiobutabarbital 100 mg / kg ip (intrapectorally). A catheter was inserted through the femoral artery to measure systemic arterial blood pressure, and a catheter was inserted through the femoral vein into the vena cava inferior vein to inject the test compound. A Doppler probe was placed around the left kidney artery and connected to a Doppler measuring instrument. 45 minutes after the compression of the left kidney artery, renal ischemia formed at the exit site. Test compounds were administered ia (intraarterially) 10 minutes before the onset of ischemia at doses of 5 mg / kg or intravenously (iv) at doses of 10 mg / kg. In control experiments, renal blood supply was reduced by 43 ± 4% compared with the pre-ischemic value
The measurement values obtained using the two compounds of formula I are presented in table. 3.

 The compounds of formula I, on the basis of their ability to inhibit the binding of endothelin, can be used as agents for the treatment of diseases associated with processes that increase vascular spasm. Examples of such diseases are high blood pressure, coronary artery disease, heart failure, renal and myocardial ischemia, renal failure, dialysis, cerebral ischemia, cerebral infarction, migraine, subarachnoid hemorrhage, Raynaud's syndrome and pulmonary high blood pressure. They can also be used for atherosclerosis, elimination of restenosis by vascular dilatation induced by Ballon, for inflammation, gastric and duodenal ulcer, ulcer (Ulcusruris), gram-negative sepsis, shock, inflammation of the renal glomeruli, renal colic, glaucoma, in the treatment and prevention of diabetic complications and complications when taking cyclosporine, as well as in other diseases associated with endothelin activity.

 The compounds of formula I can be administered orally, rectally and parenterally, for example, intravenously, intramuscularly, subcutaneously, intracapsular, transdermally; or may be administered sublingually or as an ophthalmic agent or as an aerosol. Examples of application forms are capsules, tablets, oral suspension, or solutions, suppositories, injectable solutions, eye drops, ointments or spray solutions.

 The preferred form is intravenous, intramuscular or oral administration. The dosage at which the compounds of formula I are taken in effective amounts depends on the type of specific active substance, on the age and needs of the patient, as well as on the method of application. Dosages of approximately 0.1 to 100 mg / kg body weight per day are generally used. Preparations containing compounds of formula I may contain inert or pharmacodynamic active additives. Tablets or granules may contain binders, excipients, carriers or diluents. Liquid preparations can be presented, for example, in the form of sterile solutions mixed with water. Capsules may, in addition to the active substance, additionally contain a filler or thickener. In addition, there may be additives that improve the taste, as well as substances used as preserving, stabilizing, moisturizing and emulsifying agents, as well as salts for changing the osmotic pressure, buffers and other additives.

 The above carriers and diluents may consist of organic or inorganic substances, for example, water, gelatin, milk sugar, starch, magnesium stearate, talc, gum arabic, polyalkylene glycol and the like. A prerequisite for all this is the fact that upon receipt of the preparations all the excipients used are non-toxic.

Example 1. A solution of 0.046 g of Na in 1.5 ml of abs. ethylene glycol is stirred with 0.216 g of N- [6- (2-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] α, α, α-trifluoro-p-toluenesulfonamide in the absence of moisture and heated for 3 hours to 100 ^o C, then cooled to room temperature and mixed with 2.3 ml of 1N HCl, the mixture was dissolved in ethyl acetate, the organic extracts were washed with water, dried and evaporated under reduced pressure.The remaining precipitate was recrystallized from CH ₂ Cl ₂ , isopropyl alcohol and n-hexane to give N - [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] a, α, α-trifluoro-p-toluenesulfonamide with a melting point of 160 162 ^o C.

The starting material is prepared as follows:
A solution of 1,052 g of potassium a, α, α-trifluorobenzenesulfonamide and 0.520 g of 4,6-dichloro-5- (p-chlorophenyl) pyrimidine (Chem. Absir. 63, 18078-HO ₄ ) in 6 ml of abs. dimethylformamide was heated for 4 hours to 100 ^° C, then cooled to room temperature and mixed with 5 ml of 1N HCl. The mixture was dissolved in ethyl acetate, the organic extracts were mixed with water, dried and evaporated under reduced pressure. N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] a, α, α-trifluoro-p-toluenesulfonamide was obtained as a white substance with a melting point of 275 ^° C. (from acetonitrile).

Example 2. Analogously to example 1, from N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] p- (trifluoromethoxy) benzenesulfonamide and sodium ethylene glycolate, N- [5-p-chlorophenyl) -6- ( 2-hydroxyethoxy) -4-pyrimidinyl] p- (trifluoromethoxy) benzosulfonamide with a melting point of 152 ^° C. (from isopropyl ether).

The starting material was obtained from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and potassium p- (trifluoromethoxy) benzenesulfonamide, melting point 240 - 242 ^o C.

Example 3. Analogously to example 1 from p-chloro-N- [6-chloro-5- (m-chlorophenyl) -4-pyrimidinyl] benzenesulfonamide and sodium ethylene glycolate received p-chloro-N- [5- (m-chlorophenyl) - 6- (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide with a melting point of 178 180 ^° C (from acetone and isopropyl ether).

The starting material was prepared as follows:
a) To a solution of 3.96 g of Na and 100 ml of abs. 5.97 g of formamidine acetate are added to methanol. After cooling the solution to 10 ^° C., 15.51 g of diethyl (m-chlorophenyl) malonate are added. After 2.5 hours, the solvent was evaporated under reduced pressure, the precipitate was dissolved in water and the solution was adjusted with glacial acetic acid to pH 5.0. The resulting precipitate was filtered under vacuum, 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 solution of 10.6 g of 5- (m-chlorophenyl) -4.6 (1H.5H) -pyrimidinedione, 36 ml of POCL ₃ and 5.8 ml of N, N-dimethylaniline is boiled for 3 hours on a reflux condenser. After evaporating the solvent under reduced pressure, the precipitate was mixed with ice and the mixture was extracted with ether. The organic solvents were dried and evaporated under reduced pressure. The oily precipitate dissolves in n-hexane, with 4,6-dichloro-5- (m-chlorophenyl) pyrimidine crystallizing out. The melting point is 93 94 ^o C.

c) From 4,6-dichloro-5- (m-chlorophenyl) pyrimidine and potassium p-chlorobenzenesulfonamide, p-chloro-N- [6-chloro-5- (m-chlorophenyl) -4-pyrimidinyl] benzenesulfonamide is obtained with a melting point 226 228 ^o C (from CH ₃ CN).

Example 4. Analogously to example 1 from p-chloro-N- [5- (p-fluorophenyl) -6- (2-hydroxyethoxy) -4-primidinyl] benzenesulfonamide with a melting point of 208 212 ^o C (from CH ₃ CN).

The starting material is prepared as follows:
a) Analogously to example 3, section a), from diethyl- (p-fluorophenyl) malonate and formamidine acetate, 5- (p-fluorophenyl) -4,6 (1H, 5H) -pyrimidinedione is obtained in the form of a solid, which is used directly on next stage.

b) Analogously to example 3, section b), from 5- (p-fluorophenyl) -4,6 (1H, 5H) -primidinedione and POCL ₃ receive 4,6-dichloro-5- (p-fluorophenyl) pyrimidine with a melting point 98 99 ^o C (from n-hexane).

c) Analogously to example 3, section c), from 4,6-dichloro-5- (p-fluorophenyl) pyrimidine and potassium p-chlorophenylsulfonamide receive p-chloro-N- [6-chloro-5- (p-fluorophenyl) - 4-pyrimidinyl] benzenesulfonamide with a melting point of 251 254 ^o C (from isopropyl ether-methylene chloride).

Example 5. Analogously to example 1, from N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] p-fluorobenzosulfonamide and sodium ethylene glycolate, N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy ) -4-pyrimidinyl] -p-fluorobenzenesulfonamide with a melting point of 181 183 ^o C (from isopropyl ether and methylene chloride).

The starting material is obtained from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and p-fluorophenylsulfonamide. Melting point 244 245 ^o C (from isopropyl ether and methylene chloride).

Example 6. Analogously to example 1, from o-chloro-N- [6-chloro-5- (p-chlorophenyl) -4-primidinyl] benzosulfonamide and sodium ethylene glycolate, o-chloro-N- [5- (p-chlorophenyl) - is obtained 6- (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide with a melting point of 183 185 ^° C (from acetone and isopropyl ether).

The starting material is obtained from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and o-chlorophenylsulfonamide. Melting point 230 234 ^o C (from CH ₃ CN).

Example 7. Analogously to example 1 of N- [6-chloro-5- (p-ethylphenyl) -4-pyrimidin]
p-cyclopentylbenzenesulfonamide and sodium ethylene glycolate give p-cyclopentyl-N- [6- (2-hydroxyethoxy) -5- (p-ethylphenyl) -4-pyrimidinyl] benzenesulfonamide with a melting point of 145-146 ^° C (from acetone and isopropyl ether).

The starting material is obtained from 4,6-dichloro-5- (p-ethylphenyl) pyrimidine and p-cyclopentylbenzenesulfonamide; melting point 178 180 ^o C (from acetonitrile and isopropyl ether).

Example 8. Analogously to example 1, from p-chloro-N- [6-chloro-5- (3,4-dimethoxyphenyl) -4-pyrimidinyl] benzenesulfonamide and sodium ethylene glycolate, p-chloro-N- [5- (3.4 -dimethoxyphenyl) -6 - (2-hydroxyethyl) -4-pyrimidinyl] benzene sulfonamide with a melting point of 232,234 ^° C (from CH ₃ CN).

The starting material is prepared as follows:
analogously to example 3, section b), from 5- (3,4-dimethoxyphenyl) - 4,6 (1H, 5H) -pyrimidinedione and POCL ₃ , receive 4,6-dichloro-5- (3,4-dimethoxyphenyl) pyrimidine with a melting point of 151 - 152 ^o C (from cyclohexane ether), from which p-chloro-N- [6-chloro-5- (3,4-dimethoxyphenyl) -4-pyrimidinyl] benzosulfonamide is obtained with p-chlorophenylsulfonamide with a temperature melting point 201 203 ^o C (from CH ₃ CN).

Example 9. Analogously to example 1, from 3,4-dichloro-N- [6-chloro-5- (p-chlorophenyl) pyrimidinyl] benzosulfonamide and sodium ethylene glycolate, 3,4-dichloro-N- [5- (p-chlorophenyl) is obtained -6- (2-hydroxyethoxy) -4-pyrimidinyl] benzosulfonamide with a melting point of 181 ^o c (from CH ₃ CN and isopropyl ether).

Example 10. Analogously to example 1, from N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] a, α, α, α ′, α ′, α ′ hexafluoromethylxylene sulfonamide, N- (p-chlorophenyl) - is obtained 6- (2-hydroxyethoxy) -4-pyrimidinyl] -α, α, α, α′-α ′, α′-hexafluoro-3,5-xylene sulphonamide with a melting point of 156 158 ^o C (from methylene chloride / n-hexane) .

The starting material was obtained from 4,6-dichloro-5- (p-chlorophenylpyrimidine and 2,4-bis-trifluoromethylphenylsulfonamide. Melting point 132 135 ^o C (from isopropyl ether); purity 92% (determined by high pressure liquid chromatography by HPLC) .

Example 11. Analogously to example 1, from 3-chloro-N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] -4-fluorobenzenesulfonamide and an excess of sodium ethylene glycolate, 3-chloro-N- [5- ( p-chlorophenyl) - 6- (2-hydroxyethoxy) -4-pyrimidinyl] -4- (2-hydroxyethoxy) benzenesulfonamide with a melting point 138 140 ^° C (from acetone / isopropyl ether).

The starting material is obtained from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and 3-chloro-4-fluorophenylsulfonamide. Melting point 239 ^o C (from acetonitrile / methylene chloride).

Example 12. Analogously to example 1 from p-chloro-N [6-chloro-5- (p-nitrophenyl) -4-pyrimidinyl] benzenesulfonamide and sodium ethylene glycolate receive p-chloro-N- [6- (2-hydroxyethoxy) -5 - (p-nitrophenyl) -4-pyrimidinyl] benzenesulfonamide with a melting point of 223,225 ^° C (from isopropyl ether / methylene chloride).

The starting material is obtained from 4-chloro-5- (p-nitrophenyl) pyrimidine and p-chlorophenlisulfonamide; melting point 282 285 ^o C (from CH ₃ CN).

Example 13. Analogously to example 1 from p-butoxy-N- [6-chloro- (p-chlorophenyl) -4-primidinyl] benzenesulfonamide and sodium ethylene glycolate receive p-butoxy-N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide with a melting point> 300 ^° C. (from isopropyl ether) and a purity of 97.7% (HPLC).

The starting material was obtained from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and 4-n-butoxyphenylsulfonamide. Melting point 234 ^o C (from CH ₃ CN).

Example 14. Analogously to example 1, from N-6-chloro- [5- (p-chlorophenyl) -4-pyrimidinyl] -3,4-dimethoxybenzenesulfonamide and sodium ethylene glycolate, N- [5- (p-chlorophenyl) -6- ( 2-hydroxyethyl) -4-pyrimidinyl] -3,4-dimethoxybenzenesulfonamide with a melting point of 130,132 ^° C (from isopropyl ether).

The starting material was obtained from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and 3,4-dimethoxyphenylsulfonamide. Melting point 226 ^o C (from CH ₃ CN).

Example 15. Analogously to example 1 from o-chloro-N- [6-5- (p-chlorophenyl) -4-pyrimidinyl] -α, α, α-trifluoro-p-toluenesulfonamide and sodium ethylene glycolate receive 2-chloro- N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -a, α, α-trifluoro-p-toluenesulfonamide with a melting point of 131 ^° C. (from isopropyl ether).

The starting material is prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and 2-chloro-a, α, α-trifluoro-p-toluenesulfonamide; melting point 234 ^o C (from acetonitrile and methylene chloride).

Example 16. Analogously to example 1 from 6-chloro-N- [6-chloro-5- (n-chlorophenyl) -4-pyrimidinyl] -a-α-α-trifluoro-m-toluenesulfonamide and sodium ethylene glycol get 6-chloro- N- [5- (n-chlorophenyl) 6- (2-hydroxyethoxy) -4-pyrimidinyl] -a-α-α-trifluoro-m-toluenesulfonamide with a melting point of 185 - 186 ^° C (from isopropyl ether).

The starting material is prepared from 4,6-dichloro-5- (n-chlorophenyl) pyrimidine and a, α, α, trifluoro-3-methyl-6-chlorophenylsulfonamide; melting point 232 ^o C (from isopropyl ether).

Example 17. Analogously to example 1, from 2,3,4-trichloro-N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] benzenesulfonamide and sodium ethylene glycolate, 2,3,4-trichloro-N- [ 6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] benzenesulfonamide and sodium ethylene glycolate give 2,3,4-trichloro-N - [(5-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide with a melting point of 209,211 ^° C (from isopropyl ether and methylene chloride).

The starting material is prepared from 4,6-dichloro-5- (p-chlorophenyl) -pyrimidine and 2,3,4-trichlorophenylsulfonamide; melting point 278 - 280 ^o C (from CH ₃ CN).

Example 18. Analogously to example 1, from m-chloro-N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] benzenesulfonamide and sodium ethylene glycolate, m-chloro-N- (p-chlorophenyl) -6- ( 2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide with a melting point of 179 181 ^o C (from isopropyl ether and acetonitrile).

The starting material is prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and 3-chlorophenylsulfonamide; melting point 219 221 ^o C (from CH ₃ CN).

Example 19. Analogously to example 1, from 2,4-dichloro-N- [6-chloro-5 (p-chlorophenyl) -4-pyrimidinyl] benzenesulfonamide and sodium ethylene glycolate, 2,4-dichloro-N- [5- (p- chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide with a melting point of 165 167 ^o C (from CH ₃ CN).

The starting material is prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and 2,4-dichlorophenylsulfonamide; melting point 252 254 ^o C (from CH ₃ CN).

Example 20. Analogously to example 1, from N- [6-chloro-5- (p-chlorophenyl) -4-primidinyl] -a, α, α-trifluoro-m-toluenesulfonamide and sodium ethylene glycolate receive N- [5- (p- chlorophenyl) -6- (2-hydroxyethoxy) -4-pyramidinyl] -a, α, α-trifluoro-m-toluenesulfonamide with a melting point of 148 150 ^o C (from isopropyl ether).

The starting material is prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and a, α, α-trifluoro-m-toluenesulfonamide; melting point 197 198 ^o C.

Example 21. Analogously to example 1, from N-6-chloro-5- (p-chlorophenyl) -a, α, α-trifluoro-o-toluenesulfonamide and sodium ethylene glycolate, N- [5- (p-chlorophenyl) -6- ( 2-hydroxyethoxy) -4-pyrimidinyl] -a, α, α-trifluoro-o-toluenesulfonamide with a melting point of 182 184.198> C (from CH ₃ CN and isopropyl ether).

The starting material is prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and a, α, α-trifluoro-o-toluenesulfonamide; melting point 191 193 ^o C (from CH ₃ CN).

Example 22. Analogously to example 1, from N- [6-chloro-5- (p-ethylphenyl) -4-pyrimidinyl] p-isopropylbenzenesulfonamide and sodium ethylene glycolate, N- [6- (2-hydroxyethoxy) -5- (p- ethylphenyl) -4-pyrimidinyl] -p-isopropyl] benzenesulfonamide with a melting point 137 138 ^° C (from acetonitrile and isopropyl ether).

The starting material is prepared as follows:
From diethyl (p-ethylphenyl) malonate and formamidine acetate, 5- (p-ethyl) -4,6 (1H, 5H) -pyrimidinedione with a melting point> 270 ^° C. is obtained, and then 4 are obtained from it using POCl ₃ . 6-dichloro-5- (p-ethylphenyl) pyrimidine with a melting point of 48-49 ^o C (from n-hexane).

The interaction of this compound with p-isopropylbenzenesulfonamide gives N- [6-chloro-5- (p-ethylphenyl) -4-pyrimidinyl] p-isopropylbenzenesulfonamide with a melting point of 187-188 ^° C (from acetonitrile and isopropyl ether).

Example 23. Analogously to example 1, from N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] -2-naphthalenesulfonamide and sodium ethylene glycolate, N- [5- (p-chlorophenyl) -6- (2- hydroxyethoxy) -4-pyrimidinyl] -2-naphthalenesulfonamide with a melting point of 196-198 ^o C (from CH ₃ CN and isopropyl ether).

The starting material is prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and 2-naphthalenesulfonamide; melting point 265-269 ^o C (from CH ₃ CN).

Example 24. Analogously to example 1 from p-chloro-N- [6-chloro-5- (m-nitrophenyl) -4-pyrimidinyl] benzenesulfonamide and sodium ethylene glycolate receive p-chloro-N- [6- (2-hydroxyethoxy) - 5- (m-nitrophenyl) -4-pyrimidinyl] benzenesulfonamide with a melting point of 186-187 ^o C (from CH ₃ CN and isopropyl ether).

The starting material is prepared from 466-dichloro-5- (m-nitrophenyl) -4-pyrimidinyl and p-chlorophenylsulfonamide; melting point 261-263 ^o C (from CH ₃ CN).

Example 25. Analogously to example 1, from N- [6-chloro-5- (m-nitrophenyl) -4-pyrimidinyl] -a, α, α-trifluoro-p-toluenesulfonamide and sodium ethyl glycolate receive a, α, α-trifluoro- N- [6- (2-hydroxyethoxy) -5- (m-nitrophenyl) -4-pyrimidinyl] p-toluenesulfonamide with a melting point of 194-195 ^° C (from acetic acid ester / n-hexane).

The starting material is prepared from 4,6-dichloro-5- (m-nitrophenyl) pyrimidine and a, α, α-trifluoro-p-toluenesulfonamide; melting point 246-250 ^o C (from CH ₃ CN).

Example 26. Analogously to example 1, from p- (benzyloxy) -N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] benzenesulfonamide and sodium ethylene glycolate, p- (benzyloxy) -N- [5- (p -chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide with a melting point of 162-163 ^o C (from acetone and isopropyl ether).

The starting material is prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and p- (benzyloxy) benzenesulfonamide; melting point 233-236 ^o C (from acetone and ether of acetic acid).

Example 27. A solution of 512 mg of p- (benzyloxy) -N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] benzenesulfonamide in 30 ml of glacial acetic acid is mixed with 2 ml of 4n HCl in dioxane ISO 100 mg of 10% palladium on charcoal. The mixture was hydrogenated with stirring, then the solution was filtered under vacuum, evaporated under reduced pressure, and the precipitate was recrystallized from isopropyl ether and again from CH ₃ CN. Get N- [5- (p-chlorophenyl) -4-pyrimidinyl] -p-hydroxybenzenesulfonamide with a melting point of 231-232 ^o C.

Example 28. Analogously to example 1, from N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidinyl] p- (2-methoxy) benzenesulfonamide and sodium ethylene glycolate, N- [5- (p-chlorophenyl) - 6- (2-hydroxyethoxy) -4-pyrimidinyl] p- (2-methoxyethoxy) benzenesulfonamide with a melting point of 151-152 ^o C (from CH ₃ CN and isopropyl ether).

The starting material is prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and p- (2-methoxyethoxy) benzenesulfonamide; melting point 212-215 ^o C (from CH ₃ CN).

Example 29. Analogously to example 1, from N- [5- (p-bromophenyl) -6-chloro-4-pyrimidinyl] p-chlorobenzenesulfonamide and sodium ethylene glycolate, N- [5- (p-bromophenyl) -6- (2- hydroxy) -4-pyrimidinyl] -p-chlorobenzenesulfonamide with a melting point of 179-180 ^o C (from acetone and isopropyl ether).

The starting material is prepared as follows:
Analogously to example 3, section a), from diethyl p-bromophenylmalonate and formamidine acetate, 5- (p-bromophenyl) -4,6 (1H, 5H) -pyrimidinedione with a melting point> 270 ^° C was obtained. After drying under reduced pressure at 80 ^° C. overnight, the compound was fed to the next step.

Analogously to example 3, section b), from 5- (p-bromophenyl) -4,6 (1H, 5H) -pyrimidinedione and POCl ₃ , 5- (p-bromophenyl) -4,6-dichloropyrimidine was obtained with a melting point of 99-100 ^o C (from hexane) and from it using p-chlorophenyl sulfonamide, N- [5- (p-bromophenyl) -6-chloro-4-pyrimidinyl] p-chlorobenzenesulfonamide was obtained with a melting point of 266-268 ^o C (from CH ₃ CN).

Example 30. Analogously to example 1, from p-chloro-N- (6-chloro-5-p-tolyl-4-pyrimidinyl) benzenesulfonamide and sodium ethylene glycolate, p-chloro-N- [6- (2-hydroxyethoxy) -5- was obtained p-tolyl-4-pyrimidinyl] benzenesulfonamide with a melting point of 162-165 ^o C (from acetone and isopropyl ether).

The starting product is prepared as follows:
Analogously to example 3, section a), from diethyl p-tolyl malonate and formamidine acetate, 5-p-tolyl-4,6 (1H, 5H) -pyrimidinedione is obtained with a melting point> 270 ^o C. After drying under reduced pressure at 80 ^o C substance was supplied to the next stage.

Analogously to example 3, section b), from 5-p-tolyl-4,6 (1H, 5H) -pyrimidinedione and POCl ₃ received 4,6-dichloro-5-p-tolylpyrimidine with a melting point of 81-82 ^o C (from hexane) and from it using p-chlorophenylsulfonamide p-chloro-N- (6-chloro-5-p-tolyl-4-pyrimidinyl) benzenesulfonamide was obtained with a melting point of 229-230 ^o C (from acetonitrile).

Example 31. A solution of 237 mg of N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -a, α, α-trifluorosulfonamide in 5 ml of methanol was mixed with 27.0 mg of sodium methylate and then with 5 ml of isopropyl ether. The white precipitate was filtered under vacuum and dried under reduced pressure at 50 ^° C. N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -a, α, α-trifluoro-p- was obtained toluenesulfonamide Na-salt as a white solid.

Example 32. 60 mg of sodium was added to 2 mm ethylene glycol at 70 ^° C. Then, 223 mg of N- [6-chloro-5- (2,6-dimethoxybenzyl) -4-pyrimidinyl] -p-vinyl-benzenesulfonamide was added and the reaction was heated the mixture was 4.5 hours to 150 ^° C. Ethylene glycol was distilled off under reduced pressure, the residue was dissolved in EtOAc / H ₂ O and extracted once with ethyl acetate. Next, the aqueous phase was acidified with 1N HCl and extracted 4 times with ethyl acetate. The organic phase was dried, filtered and concentrated under reduced pressure. The precipitate was chromatographed over 50 g of SiO ₂ with methylene chloride / acetic acid ester (1: 1). Received 50 mg of N- [5- (2,6-dimethoxybenzyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] p-vinylbenzenesulfonamide with a melting point of 138-139 ^o C.

The starting material was prepared as follows:
a) A mixture of 1.52 ml of malonic acid diethyl ether, 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 ,5:00. The solution was extracted with 10% NaHCO ₃ solution and then washed with saturated NaCl solution. The organic phase was dried, filtered off under vacuum and evaporated under reduced pressure. 2.8 g of diethyl- (2,6-dimethoxybenzylidene) 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 charcoal, 50 ml of methanol and 50 ml of glacial acetic acid was stirred overnight at 25 ^° C. The solution was filtered and concentrated, the precipitate was dissolved in ethyl acetate and extracted with 20% NaHCO ₃ solution and a little ice. The mixture was then extracted with 1N HCl, then washed with a saturated HCl solution, the organic phase was dried and evaporated under reduced pressure. The crude product was subjected to distillation in high vacuum at 170 ^o C / 0.6 mbar. 2.1 g of diethyl- (2,6-dimethoxybenzyl) malonate were obtained.

c) 0.23 g of formamidine acetate in 15 ml of ethanol is added to 0.14 g of sodium in 15 ml of ethanol. The reaction mixture was stirred for 30 minutes at 25 ^° C. and was added dropwise with 0.62 g of diethyl- (2,6-dimethoxybenzyl) malonate in 10 ml of ethanol. After 2 days, the starting material was not available. The precipitate was filtered under vacuum, dissolved in a small amount of water and acidified with 1N HCl. The precipitated crystals are filtered off with suction and dried under high vacuum at 90 ^° C. 0.175 g of 5- (2,6-dimethoxybenzyl) -4,6-pyrimidinediol is obtained with a melting point> 245 ^° C.

d) A mixture of 1.04 g of 5- (2,6-dimethoxybenzyl) -4,6-pyrimidinediol and 12 ml of phosphorus oxychloride was refluxed for 3 hours at 85 ^° C. The reaction solution was poured onto ice and extracted twice with methylene chloride. The organic phase was washed with saturated HCl, dried, filtered and concentrated under reduced pressure. The crude product was recrystallized from toluene / n-hexane. 0.41 g of 4,6-dichloro-5- (2,6-dimethoxybenzyl) pyrimidine was obtained with a melting point of 152-153 ^° C.

e) A mixture of 80 mg of 4,6-dichloro-5- (2,6-dimethoxybenzyl) pyrimidine and 170 mg of the monopotassium salt of n-vinylbenzenesulfonamide (J. Am. Chem. Soc. 1956, 78, 2169) corresponding to the sulfonamide with tetrabutylate potassium in abs. MeOH and 10 ml of dimethylformamide were heated to 100 ^° C. for 6 hours. They were then allowed to cool to 25 ^° C. overnight. 30 ml of 0.5 N HCl were added to the reaction solution with stirring. The precipitated substance was filtered under vacuum and recrystallized from toluene / n-hexane. Received 25 mg of N- [6-chloro-5- (2,6-dimethoxybenzyl) -4-pyrimidinyl] -n-vinylbenzenesulfonamide with a melting point of 197-198 ^o C.

Example 33. To 10 ml of ethylene glycol (distilled in a fresh state over Na) was added in portions with the exception of water 29 mg of sodium. Then 123 mg of N- [6-chloro- (o-trifluoromethyl) benzyl-4-pyrimidinyl] -a, α, α-trifluoro-p-toluenesulfonamide are added and the mixture is heated to 150 ^° C. for 3 hours. Excess ethylene glycol is evaporated under reduced pressure; the residue was dissolved in water and washed with ethyl acetate. The aqueous phase is extracted with 1N hydrochloric acid to a pH of 3.0 and extracted with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution, dried and evaporated under reduced pressure. The precipitate was chromatographed over 30 g of SiO ₂ with methylene chloride / ethyl acetate (1: 1). Obtain α, α, α - trifluoro-N- [6- (2-hydroxyethoxy) -6 - [(o-trifluoromethyl) benzyl] pyrimidinyl] p-toluenesulfonamide in the form of a white foam. MS (mass spectrum): 521 (M); 456 (M-SO ₂ + H).

The starting material is prepared as follows:
a) To a solution of 14 g of o-trifluoromethylbenzyl alcohol in 80 ml of abs. toluene is added dropwise at a temperature of from 20 to 30 ^o C a solution of 30 ml of phosphoric tribromide in 60 ml of abs. toluene. Then the reaction mixture was stirred for 2 hours at room temperature, toluene was distilled off under reduced pressure, the precipitate was dissolved in methylene chloride, mixed with water and adjusted to pH 8.0 with potassium bicarbonate. The aqueous phase is extracted three times with CH ₂ Cl ₂ , and the organic phase is washed twice with water and once with a saturated NaCl solution, dried over Na ₂ SO ₄ and evaporated under reduced pressure. O-trifluoromethylbenzyl bromide is obtained in the form of a precipitate.

b) 40 ml of malonic acid diethyl ether in 350 ml of ethyl alcohol are mixed in portions at room temperature with 12 g of o-trifluoromethylbenzyl bromide. The reaction mixture was stirred overnight at room temperature, the alcohol was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed twice with water and once with a NaCl solution, dried under reduced pressure and evaporated. The precipitate was chromatographed over 300 g of SiO ₂ with CH ₂ Cl ₂ / AcOEt (95: 5) to give 11 g of diethyl - [(o-trifluoromethyl) benzyl] malonate as a colorless oil.

c) 0.63 g of formamidine acetate in 40 ml of abs. ethyl alcohol is mixed with 1.2 g of sodium ethylate, stirred for 30 minutes at room temperature, and then dropwise mixed at room temperature with a solution of 1.6 g of diethyl- [o- (trifluoromethyl) benzene] malonate in 8 ml of abs. ethyl alcohol. After being stirred for 4 hours at 50 ^° C., the reaction mixture was worked up to give 5- [o- (trifluoromethyl) benzyl] -4,6 (1H, 5H) pyrimidinedione with a melting point> 290 ^° C.

d) From 5- [o- (trifluoromethyl) benzyl] -4,6 (1H, 5H) pyrimidinedione and phosphorus oxychloride, 5- [o- (trifluoromethyl) benzyl] 4,6-dichloropyrimidine with a melting point of 60-63 ^o C .

d) 295 mg of 4,6-dichloro-5- [o- (trifluoromethyl) benzyl] pyrimidine in 10 ml of freshly distilled dimethyl sulfoxide is mixed with 342 mg of monopotassium salt of α, α, α-trifluoro-p-toluenesulfonamide (obtained from the corresponding sulfonamide with KOH and abs. ethyl alcohol) and stirred for 5 hours at 150 ^° C. After the final reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate and the solution was washed with 10% potassium bicarbonate solution, 0.5N HCI and reduced pressure. The precipitate was chromatographed with ethyl acetate over 30 g of SIO _{2 to} give 135 mg of N- [6-chloro-6- [o- (trifluoromethyl) benzyl] -4-pyrimidinyl] a, α, α-trifluoro-p-toluenesulfonamide as a white foam. MS: 495 (M), 431 (-SO ₂ ), 430 (-SO ₂ + H), 362 (-CF ₃ + SO ₂ ).

Example 34. Analogously to example 33, from N- [6-chloro-5- [o- (trifluoromethyl) benzyl] -4-pyrimidinyl] p-methoxybenzenesulfonamide and sodium ethylene glycolate, N- [6- (2-hydroxyethoxy) -5- is obtained [o- (trifluoromethyl) benzyl] -4-pyrimidinyl] -p-methoxybenzenesulfonamide with a melting point of 100-107 ^o C.

The starting material is prepared as follows:
Analogously to example 33, section e), from 4,6-dichloro-5- [o- (trifluoromethyl) benzyl] pyrimidine and the potassium salt of p-methoxybenzenesulfonamide, N- [6-chloro-5- (trifluoromethyl) benzyl] -4- is obtained pyrimidinyl] -p-methoxybenzenesulfonamide in the form of a white foam with a melting point of 68-70 ^o C.

Example 35. Analogously to example 33, from p-chloro-N- [6-chloro-5- [o- (trifluoromethyl) benzyl] -4-pyrimidinyl] benzenesulfonamide and sodium ethylene glycolate, p-chloro-N- [6- (2 - hydroxyethoxy) -5- [o- (trifluoromethyl) benzyl] -4-pyrimidinyl] benzenesulfonamide with a melting point of 134-135 ^o C.

The starting material is prepared analogously to example 66, section e), from 4,6-dichlo-5- [o- (trifluoromethyl) benzyl] pyrimidine and the potassium salt of p-chlorobenzenesulfonamide; melting point> 210 ^o C (decomposition).

Example 36. Analogously to example 33, from N- [6-chloro-5- (o-methoxybenzene) -4-pyrimidinyl] -n-vinylbenzenesulfonamide and sodium ethylene glycolate, N- [6- (2-hydroxyethoxy) -5- (o- methoxybenzyl) -4-pyrimidinyl] - n-vinylbenzenesulfonamide with a melting point of 93-102 ^o C.

The starting material is prepared analogously to example 33, section d) from 4,6-dichloro-5- (o-methoxybenzyl) pyrimidine and the potassium salt of n-vinylbenzenesulfonamide; melting point 125-129 ^o C.

 Example 37. Analogously to example 33, from N- [6-chloro-5- [o- (trifluoromethyl) benzyl] -4-pyrimidinyl] p- (methylthio) benzenesulfonamide and sodium ethylene glycol, N- [6- (2-hydroxyethoxy) was obtained -5- [o- (trifluoromethyl) benzyl] -4-pyrimidinyl] p- (methylthio) benzenesulfonamide as a yellow gum.

The starting material is prepared analogously to example 33, section e), from 4,6-dichloro-5- [o- (trifluoromethyl)] benzylpyrimidine and p- (methylthio) benzenesulfonamide: IR 3433 cm _-1 (NH); 1313 (SO ₂ ); 1137 and 1094 (F ₃ C).

Example 38. Analogously to example 32, from N- [6-chloro-5- (2,4-dimethoxybenzyl) -4-pyrimidinyl] p-isopropylbenzenesulfonamide, ethylene glycol and sodium, N- [5- (2,4-dimethoxybenzyl) - 6- (3-hydroxypropyl) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide with a melting point of 97 ^o C.

The starting material was prepared as follows:
Analogously to example 32, section a), diethyl- (2,4-dimethoxybenzylidene) malonate was obtained from 2,4-dimethoxybenzaldehyde, malonic acid diethyl ether, glacial acetic acid, piperidine and toluene. From it, analogously to example 32, section b), diethyl- (2,4-dimethoxybenzyl) malonate was obtained in the form of a clear oil; boiling point 160 ^o C / 0.4 mbar.

Analogously to example 32, section c), from diethyl- (2,4-dimethoxybenzyl) malonate, formamidine acetate and the sodium salt of the standard, 5- (2.4-dimethoxybenzyl) -4,6-pyrimidinediol was obtained and from it analogously to example 32, section d) received 4,6-dichloro-5- (2,4-dimethoxybenzyl) pyrimidine with a melting point of 130-131 ^o C.

Analogously to example 32, section e), finally, from 4,6-dichloro-5- (2,4-dimethoxybenzyl) pyrimidine, potassium p-isopropylbenzenesulfonamide (from the corresponding sulfonamide with potassium tert-butylate in abs. MeOH and dimethyl sulfoxide, N - [6-chloro-5- (2,4-dimethoxybenzyl) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide with a melting point of 132-134 ^o C.

 Example 39. A solution of 110 mg of N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] p- (vinylbenzenesulfonamide) in 3 ml of abs. tetrahydrofuran was mixed with 0.3 ml of 3,4-dihydro-2H-pyran and four drops of trifluoroacetic acid.

After refluxing 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) -ethoxy] -4-pyrimidinyl] -p-vinylbenzenesulfonamide was obtained in the form of a white gum; MS: 460 (M-SO ₂ + H); 430 (M-SO ₂ + OCH ₃ ).

 Example 40. To a mixture of 1.5 ml of water and 4 ml of dioxin were added successively at room temperature 318 mg of rac-N- [5- (o-methoxybenzyl) -6 - [2 - [(tetrahydro-2H-pyran-2- il] oxy] ethoxy] -4-pyrimidinyl] -p-vinylbenzenesulfonamide, 5.3 mg of osmium tetroxide and 270 mg of sodium metaperiodate After 1 h of stirring at room temperature, dioxane was distilled off under reduced pressure, then the aqueous phase was extracted three times with ethyl acetate, washed twice ethyl acetate with water and once with (saturated) NaCl solution, dried and distilled off under reduced pressure.

The precipitate was chromatographed over 30 g of SiO ₂ CH ₂ C1 / ethyl acetate to give 150 mg of rac-p - [[5- (o-methoxybenzyl) -6- [2 - [(tetrahydro-2H-pyran-2-yl) oxy] - 4-pyrimidinyl] sulfamoyl] benzaldehyde as a white foam. MS: 527 (M); 443, 432 (-OCH ₃ + SO ₂ ).

Example 41. To a Grignard solution of 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] is added at room temperature -2-yl] oxy] ethoxy] -4-pyrimidinyl] sulfamoyl] benzaldehyde, and after 30 minutes 1 ml of abs. tetrahydrofuran. After 3 hours of stirring at room temperature, the reaction was interrupted by the addition of a saturated solution of ammonium chloride, the reaction mixture was diluted with ethyl acetate and the aqueous phase was extracted two more times with ethyl acetate. The organic phase is washed with water and saturated NaCl, dried and distilled off under reduced pressure. The precipitate was chromatographed over 35 g of SiO ₂ with CH ₂ C1 ₂ / ethyl acetate (8: 2) and (1: 1) to obtain 135 mg of p - [(RS) -1-hydroxyethyl] -N- [5- (methoxybenzyl) -6 - [[2 - [[(RS) -tetrahydro-2H-pyran-2-yl] oxy] ethoxy] -4-pyrimidinyl] benzenesulfonamide with a melting point> 56 ^° C (sublimation).

Example 42. 53 mg of rac-p - [[5- (o-methoxybenzyl) -6- [2 - [(tetrahydro-2H-pyran-2-yl] oxy] ethoxy] -4-primidinyl] sulfamoyl] benzaldehyde was dissolved in 3 ml of methyl alcohol and mixed with 37 sodium borohydrite at room temperature After 1 hour stirring at room temperature, methanol was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and NaC1 solution (saturated), dried and distilled off under reduced pressure. mg rac-a-hydroxy-N- [5- (o-methoxybenzyl) -6-12 - [(tetrahydro-2H-pyrin-2-yl) oxy] ethoxy] -4-pyrimidinyl] -n-tonuulsul onamida as a colorless oil MC% 529 (M);. 445 (tetrahydro-2H-pyran-2-yl); 434 (-OCH ₃ + SO _2).

Example 43. 534 mg of rac-p - [[5- (o-methoxybenzyl) -6- [2 - [(tetrahydro-2H-pyran-2-yl) oxy] ethoxy] - 4-pyrimidinyl] sulfamoyl] benzaldehyde was dissolved in 3 ml of ethyl alcohol and mixed at room temperature with 7 mg of hydroxylamine hydrochloride and 14 mg of potassium carbonate (fine powder). After 3 hours of stirring at room temperature, ethanol was distilled off under reduced pressure, the residue was dissolved in ethyl acetate and washed with water and a (saturated) NaCl solution. The organic phase is dried and evaporated under reduced pressure to give rac-a - [(> E / Z) -hydroximino-N- [5- (o-methoxybenzyl) -6- [2- [tetrahydro-2H-pyran-2- yl) oxy] ethoxy] -4-pyrimidinyl] -n-toluenesulfonamide. Melting point 49-52 ^o C.

Example 44. A solution of 60 mg of n - [(RS) -1-hydroxyethyl] -M-5 [- (o-methoxybenzyl) -6- [2 - [[(RS) -tetrahydro-2H-pyran-2-yl ] hydroxy] ethoxy] -4-pyrimidin-nyl] benzenesulfonamide in 3 ml of tetrahydrofuran is mixed with two drops of 3n HCl. After 4 hours stirring at room temperature, the reaction mixture was evaporated under reduced pressure. The residue was chromatographed using methylene chloride / ethyl acetate (1: 1) and ethyl acetate on silica gel. Rac-N-6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -n- (1-hydroxyethyl) benzenesulfonamide was obtained in the form of a white gum. MS: 459 (M); 394 (-SO ₂ / H); 364 (-SO _2M / OCH ₃ ).

Example 45. Analogously to example 44 and rac-a - [(E / Z) -hydroximino] -N- [5- (o-methoxybenzyl) -6- [2 - [(tetrahydro-2H-pyran-2-yl) oxy ] -4-pyrimidinyl] -n-toluenesulfonamide received a - [(E / Z) -hydroximino] -N- {6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] -n-toluenesulfonamide in the form of a yellow gum; IR: 3403 and 3193 cm ^-1 (w, OH); 2607 (w, NH); 1729 (w, C = N).

Example 46. Analogously to example 44 of rac-a-hydroxy-N- [5- (o-methoxybenzyl) -6- [2 - [(tetrahydro-2H-pyran-2-yl) oxy] ethoxy] -4-pyrimidinyl] -n-toluenesulfonamide receive a-hydroxy-N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] -p-toluenesulfonamide as a light brown gum. MS: 445 (M); 380 (-SO ₂ / H); 274.

Example 47. Analogously to example 44, from rat-n - [[5 - [(o-methoxybenzyl) -6- [2- [tetrahydro-2H-pyran-2-yl) oxy] ethoxy] - 4-pyrimidinyl] sulfamoylbenzaldehyde, n - [[(2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] sulfamoyl] benzaldehyde as a white resin. MS: 443 (M); 348 (-SO ₂ / OCH ₃ ); 274.

 Example 48. 208 mg of N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] p-vinylbenzenesulfonamide was dissolved in 4 ml of abs. tetrahydrofuran, mixed with 0.06 ml of pyridine and 0.07 ml of acetic anhydride and boiled for 3 hours at reflux condenser. After distilling off the solvent under reduced pressure, the residue was dissolved in ethyl acetate and the solution was washed with water and sodium chloride solution, dried and evaporated. Chromatography of the residue over silica gel with methylene chloride and methylene chloride / ethyl acetate (19: 1 and 9: 1) gave 2 - [[5- (o-methoxybenzyl) -6- [n-vinylphenyl) sulfamoyl] -4-pyrimidinyl] oxy] ethyl acetate in in the form of white resin.

Example 49. Analogously to example 1, from N- [6-chloro-5-a, α, α-trifluoro-p-tolyl) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide and sodium ethylene glycolate, N- [6 - [(2- hydroxyethoxy) -5- (a, α, α-trifluoro-p-tolyl) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide with a melting point of 222-223 ^o C (from acetone and isopropyl ether).

The starting material is prepared from 4,6-dichloro-5-a, α, α-trifluoro-p-tolylpyrimidine and n-isopropylbenzenesulfonamide; melting point 266-269 ^o C (from acetonitrile).

Example 50. To a solution of sodium glycolate from 46 mg of sodium in 1 ml of ethylene glycol was added 190 mg of N- [6-chloro-5- (n-methoxyphenyl) -4-pyrimidinyl] -n-toluenesulfonamide. After 5 hours, the reaction mixture was evaporated to dryness at 100 ^° C. under reduced pressure, the residue was partitioned between ethyl acetate and 1N hydrochloric acid, the organic phase was washed until neutral, dried and evaporated under reduced pressure. The residue was chromatographed with methylene chloride and ethyl acetate (4: 1 v / v) on silica gel. 175 mg of n- [6- (2-hydroxyethoxy) -5- (n-methoxyphenyl) -4-pyrimidinyl] p-toluenesulfonamide are obtained with a melting point of 147-149 ^° C. (from methylene chloride / hexane).

The starting material is prepared as follows:
To a solution of 41.55 g of n-methoxyphenylacetic acid in 150 ml of abs. ethanol add 150 ml of ethyl ester of ortho-formic acid and 1 g of methanesulfonic acid. The mixture was heated to 85 ^° C. for 20 hours. The resulting ethyl formate was continuously distilled off from the reaction mixture. Then the reaction mixture was neutralized with sodium ethyl acetate, the solvent was evaporated, the residue was dissolved in methylene chloride and distilled off. 46.7 g of (p-methoxy) phenylacetic acid ethyl ester are obtained as a colorless liquid; boiling point 84 ^o C / 0,025 mm RT.article

7.5 g of sodium ethylate and 120 ml of diethyl carbonate are added to 19.4 g of the previously obtained ether. The resulting suspension was thoroughly stirred at 230 ^o C, and the resulting ethanol was distilled off from the mixture. Then the mixture was cooled to room temperature and the reaction mixture was poured onto ice and aqueous hydrochloric acid (10% excess). After extraction with ethyl acetate and processing of the extract, the product is purified by distillation. 25 g of (n-methoxy) phenylmalonic acid diethyl ester are obtained; boiling point 115 ^o C / 0.05 mm Hg

10.9 g of sodium ethylate are suspended in 125 ml of dried ethanol, and 4.83 g of formamidine hydrochloride and 13.3 g of malonic ester obtained in accordance with the above paragraph are added thereto under ice cooling. The reaction mixture was stirred for 3 hours at room temperature while removing water, 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- (p-methoxy) phenyl-6-hydroxy-4 (3H) -pyrimidinone are obtained with a melting point> 250 ^° C.

1 g of pyrimidinone described in the above paragraph is suspended in 5 ml of phosphoroxychloride. The suspension is stirred while removing water at 80 ^° C., whereby a clear solution is obtained. After 30 minutes, the excess reagent was distilled off and the residue was dissolved in methylene chloride, then shaken with an aqueous solution of potassium bicarbonate until the evolution of carbonic acid ceased. After evaporation of the solvent, it is filtered with methylene chloride over silica gel. Obtain 0.7 g of 4,6-dichloro-5- (n-methoxyphenyl) pyrimidine with a melting point of 95-96 ^o C.

 To a boiling ethanol solution of potassium hydroxide (2 g of 80% potassium hydroxide in 50 ml of abs. Ethanol) is added to 5.15 g of p-toluenesulfonamide dissolved in ethanol. Then add 50 ml of abs. benzene and most of the solvent mixture is distilled off at normal pressure. 4.6 g of potassium n-toluenesulfonamide are obtained.

510 g of dichloropyrimidine, referred to in the above paragraph, and 840 mg of potassium n-toluenesulfonamide are dissolved in 3 ml of dry dimethylformamide. The solution was kept at 120 ^° C. for 3 hours, then dimethylformamide was distilled off and the residue was partitioned between ethyl acetate and 1N hydrochloric acid, the organic phase was washed until neutral and evaporated. After adding methanol, 540 mg of N- [6-chloro-5- (p-methoxyphenyl) -4-pyrimidinyl] -p-toluenesulfonamide are obtained with a melting point of 210-212 ^o C.

Example 51. Analogously to example 50, from 400 mg of N- [6-chloro-5- (p-methoxyphenyl) -4-pyrimidinyl] -p-methoxybenzenesulfonamide, 200 mg of N- [6- (2-hydroxyethoxy) -5- (p -methoxyphenyl) -4-pyrimidinyl] p-methoxybenzenesulfonamide; melting point 132-134 ^o C.

The starting material is prepared as follows:
To a solution of 7.3 g of n-methoxybenzenesulfonyl chloride in 50 ml of tetrahydrofunar was added dropwise 25 ml of 25% NH ₄ OH while cooling in an ice bath. Then the reaction mixture was thoroughly stirred for 30 min at 70 ^o C (bath temperature), then tetrahydrofuna was distilled off.

 The residue was extracted with ethyl acetate. Get n-methoxybenzenesulfonamide, which, as described in example 50, is converted into potassium salt.

A solution of 510 mg of 4,6-dichloro-5 (p-methoxyphenyl) pyrimidine and 690 mg of potassium p-methoxybenzenesulfonamide in 3 ml of dimethylformamide is heated to 130 ^° C. for 1 hour. After processing the reaction mixture, 690 mg of N- [6-chloro- 5 (p-methoxyphenyl) -4-pyrimidinyl] methoxybenzenesulfonamide with a melting point of 165-167 ^o C.

Example 52. Analogously to example 50, from N- [6-chloro-5- (p-methoxyphenyl) -4-pyrimidinyl] p- (methylthio) benzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (p- methoxyphenyl) -4-pyrimidinyl] p- (methylthio) benzenesulfonamide with a melting point of 171-172 ^o C.

The starting material is obtained analogously to example 50 and 4,6-dichloro-5- (p-methoxy) phenylpyrimidine and (p-methylthio) potassium benzenesulfonamide; melting point 204-205 ^o C.

Example 53. Analogously to example 50, from N- [6-chloro-5- (p-methoxyphenyl) -2-methyl-4-pyrimidinyl] -p-methoxybenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (p -methoxyphenyl) -2-methyl-4-pyrimidinyl] -p-methoxybenzenesulfonamide with a melting point of 138-139 ^o C.

The starting material is prepared as follows:
To a solution of 5.6 g of sodium methylate in 75 ml of abs. ethanol add 2.94 g of acetamidine hydrochloride and 6.9 g of n-methoxyphenylmalonic acid diethyl ether. The reaction mixture was stirred for 3 hours while removing water at room temperature and for 1.5 hours at 50 ^° C. Ethanol was then distilled off, the residue was dissolved in water and the suspension was acidified with 5N hydrochloric acid. The solid is filtered off and washed with water until the wash solution reaches a pH of 4.5-5.7. The product thus obtained is reacted with phosphorus oxychloride to give 2.8 g of 4,6-dichloro-2-methyl- (p-methoxy) phenylpyrimidine with a melting point of 114-116 ^° C. When this compound is reacted with potassium p-methoxybenzenesulfonamide, N - [6-chloro-5- (p-methoxyphenyl) -2-methyl-4-pyrimidinyl] -p-methoxybenzenesulfonamide with a melting point of 152-154 ^o C.

Example 54. Analogously to example 50 of 615 mg of N- [6-chloro-5- (p-methoxyphenyl) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide, 350 mg of N- [6- (2-hydroxyethoxy) -5- (p -methoxyphenyl) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide with a melting point of 128-129 ^o C.

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

The starting material is prepared as follows:
p-Isopropylbenzenesulfonyl chloride with a boiling point of 105 ^o C / 0.25 mm RT. Art. obtained from cumene and transferred to the corresponding sulfonamide; melting point 104-105 ^o C. The interaction of 765 mg of 4,6-dichloro-5- (p-methoxyphenyl) pyrimidine with 1925 mg of potassium p-isopropylbenzenesulfonamide gives 720 mg of N- [6-chloro-5- (p-methoxyphenyl) -4-pyrimidinyl] -p- isopropylbenzenesulfonamide with a melting point of 181-182 ^o C.

Example 55. Analogously to example 50, from 600 mg of p-tert.-butyl-N- [6-chloro-5- (p-methoxyphenyl) -4-pyrimidinyl] benzenesulfonamide, 600 mg of p-tert are obtained. -butyl-N- [6- (2-hydroxyethoxy) -5- (p-methoxyphenyl) -4-pyrimidinyl] benzenesulfonamide with a melting point of 165-166 ^o C.

The starting material was prepared from potassium p-tert-butylbenzenesulfonamide and 4,6-dichloro-5- (p-methoxyphenyl) pyrimidine. The melting point is 204-205 ^o C.

Example 56. Analogously to example 50 of 216 mg of rac-p-sec.-Butyl-N- [6-chloro-5- (p-methoxyphenyl) -4-pyrimidinyl] benzenesulfonamide, 185 mg of rac-p-sec. -butyl-N- [6- (2-hydroxyethoxy) -5- (p-methoxyphenyl) -4-pyrimidinyl] benzenesulfonamide with a melting point of 120-122 ^o C.

The starting material was prepared from rac-p-sec.-Butylbenzenesulfonamide potassium and 2,6-dichloro-5- (p-methoxyphenyl) pyrimidine; melting point is 172-173 ^o C.

Example 57. Analogously to example 50, from 280 mg of N- [6-chloro-5 - [(p-methylthio) phenyl] -4-pyrimidinyl] -p-isopropylbenzenesulfonamide, 240 mg of N- [6- (2-hydroxyethoxy) -5 are obtained - [p- (methylthio) phenyl] -4-pyrimidinyl] -p-isopropylbenzenesulfonamide with a melting point of 135-136 ^o C (from diisopropyl ether).

The starting material is prepared as follows:
15.2 g of (p-methylthio) benzaldehyde are dissolved in 50 ml of isopropanol. To this solution, 1.31 g of sodium borohydride in 150 ml of isopropanol is added dropwise with cooling in an ice bath for half an hour. After 1 h of stirring at room temperature, 5 ml of acetone was added, after which the solvent was distilled off. The residue was partitioned between methylene chloride and water. After processing receive (p-methylthio) benzyl alcohol with a melting point of 40-41 ^o C (from isopropanol).

7.71 g of (p-methylthio) benzene alcohol are dissolved in 25 ml of dry methylene chloride. To this solution was added 4 ml of SOCl ₂ over 30 minutes while cooling in an ice bath. After distilling off the solvent and excess reagent, the precipitate is filtered off with methylene chloride over silica gel. After distillation, 4.3 g of (p-methylthio) benzyl chloride are obtained, boiling point 92 ^° C / 0.05 mm Hg,
To a suspension of 10 g of potassium cyanide and 0.1 g of sodium iodide in 100 ml of dimethylformamide, 9 g of benzyl chloride obtained as described in the previous paragraph are added. The reaction mixture was stirred while removing moisture for 1 h at 90 ^° C. After this, dimethylformamide was distilled off and the residue was partitioned between toluene and water. Processing the organic phase gives (p-methylthio) benzyl cyanide with a melting point of 28-30 ^o C.

12 g of (p-methylthio) benzyl cyanide are dissolved in 30 ml of ethylene glycol and mixed with 9 g of NaOH (as a 30% solution). The reaction mixture was stirred at 140 ^° C. for 3 hours. After cooling to room temperature, the mixture was acidified with 25% hydrochloric acid, the residue was dissolved in ethyl acetate and shaken with water. Obtain 11.5 g of (p-methylthio) phenylacetic acid with a melting point of 94-96 ^o C.

11 g of the acid obtained as described above are dissolved in 50 ml of abs. ethanol and 25 ml of ethyl orthoformic acid and in 1 g of methanesulfonic acid. The formate formed during the reaction is continuously distilled off. After 4 hours, the reaction is complete. The acidic catalyst is neutralized with a stoichiometric amount of sodium ethylate, the solvent is distilled off, the residue is dissolved in methylene chloride and filtered over silica gel. 12 g of (p-methylthio) phenylacetic acid ethyl ester are obtained with a melting point of 46-47 ^° C.

The compound obtained above, similar to that obtained by the method of example 50, is converted into diethyl ether (p-methylthio) phenylmalonic acid. Boiling point 120 ^o C / 0.05 mm Hg

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

 The pyrimidinone described above is converted, using sodium methylate, to a dialkoxy compound, from which 4,6-dichloro-5- (p-methylthio) phenylpyrimidine is obtained by reaction with phosphoroxychloride.

From the above 4,6-dichloro compound by reaction with potassium p-isopropylbenzenesulfonamide, N- [6-chloro-5- [p- (methylthio) phenyl] -4-pyrimidinyl] -p-isopropylbenzenesulfonamide is obtained with a melting point of 193-195 ^o C .

Example 58. Analogously to example 50, from 230 mg of N- [6-chloro-5- [p- (methylthio) phenyl] -4-pyrimidinyl] -a, α, α-trifluoro-p-toluenesulfonamide, 160 mg of N- [6 - (2-hydroxyethoxy) -5- [p- (methylthio) phenyl] -4-pyrimidinyl] -a, α, α-trifluoro-p-toluenesulfonamide with a melting point of 266-268 ^o C.

The starting material is obtained from 4, 6-dichloro-5-p- (methylthio) phenylpyrimidine and potassium a, α, α-trifluoro-p-toluenesulfonamide; melting point 250-252 ^o 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 for 4 hours under argon to a temperature of 125 ^° C. After that, ethylene glycol was distilled off under reduced pressure, the residue was partitioned between ethyl acetate and 1N hydrochloric acid, the organic phase was washed until neutral, dried and evaporated. The residue was chromatographed using methylene chloride-ethyl acetate (1: 1 v / v) on silica gel. Obtain 250 mg of N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] p-methoxybenzenesulfonamide with a melting point of 161-162 ^o C.

The starting material is prepared as follows:
Upon Knovengel condensation of o-methoxybenzaldehyde with diethyl malonate, o-α-methoxybenzylidene malonic acid diethyl ether is obtained; boiling point 140 ^o C / 0.05 mm RT. Art.

Hydrogenation of the above compound in ethanol in the presence of palladium on charcoal leads to the formation of o-β-methoxybenzylmalonic acid diethyl ester; boiling point 115 ^o C / 0,01 mm RT. Art.

The reaction of o-methoxybenzylmalonic acid diethyl ester with formamidine hydrochloride gives 5- (o-methoxybenzyl) -6-hydroxy-4- (3H) -pyrimidinone, from which, when reacted with phosphorus oxychloride, 4,6-dichloro-5- (o - -methoxybenzyl) pyrimidine with a melting point of 95-96 ^o C.

Reaction of 4, 6-dichloro-5- (o-methoxybenzyl) -4-pyrimidine with potassium p-methoxybenzenesulfonamide gives N- [6-chloro-5- (o-methoxybenzyl) -4-pyrimidinyl] p-methoxybenzenesulfonamide the temperature of occurrence of 149-151 ^o C.

 Example 60. Analogously to example 52, from N- [6-chloro-5- (o-chlorobenzyl) -4-pyrimidinyl] p-toluenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (o-chlorobenzyl) - 4-pyrimidinyl] p-toluenesulfonamide.

The starting material is prepared as follows:
The reaction of malonic acid diethyl ether and o-chlorobenzyl chloride gives o-chlorobenzylmalonic acid diethyl ether; boiling point 115 ^o C / 0.05 mm RT. Art.

Condensation of o-chlorobenzylmalonic acid diethyl ester with formamidine gives 5- (o-chlorobenzyl) -6-hydroxy-4 (3H) -pyrimidinone, which, when reacted with oxychloride, gives 4, 6-chloro-5- (o-chlorobenzyl) pyrimidine with a melting point of 110-112 ^o C.

 From 4, 6-dichloro-5- (o-chlorobenzyl) pyrimidine and potassium p-toluenesulfonamide, N- [6-chloro-5- (o-chlorobenzyl) -4-pyrimidinyl] -p-toluenesulfonamide is obtained, which is used as a raw material product.

Example 61. Analogously to example 59, from N- [6-chloro-5- (o-methoxybenzyl) -4-pyrimidinyl-p- (methylthio) benzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) is obtained ) -4-pyrimidinyl] -p- (methylthio) benzenesulfonamide with a melting point of 134-136 ^o C.

Example 62. Analogously to example 59, from N- [6-chloro-5- (o-methoxybenzyl) -4-pyrimidinyl] -a, α, α-trifluoro-p-toluenesulfonamide, N- [6- (2-hydroxyethoxy) - 5- (o-methoxybenzyl) -4-pyrimidinyl] -a, α, α-trifluoro-β-toluenesulfonamide with a melting point of 133-134 ^o C.

The starting material is obtained from 4, 6-dichloro-5- (o-methoxybenzyl) pyrimidine and potassium p-trifluoromethylbenzenesulfonamide. Melting point 163 ^o C.

Example 63. Analogously to example 59, from N- [6-chloro-5- (o-methoxybenzyl) -4-pyrimidinyl] p-isopropylbenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) - 4-pyrimidinyl] - p-isopropylbenzenesulfonamide with a melting point of 112-113 ^o C.

When processing with sodium methylate in methanol get sodium salt, melting point 225 ^o C.

The starting material is prepared from 4, 6-dichloro-5- (o-methoxybenzyl) pyrimidine and potassium isopropylbenzenesulfonamide; melting point 138-139 ^o C.

Example 64. Analogously to example 59, from p-tert.-butyl-N- [6-chloro-5- (o-methoxybenzyl) -4-pyrimidinyl] benzenesulfonamide, p-tert-butyl-N- - [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] benzenesulfonamide with a melting point of 138-140 ^o C (from diisopropyl ether).

The starting material is prepared from 4,6-dichloro-5- (o-methoxybenzyl) -pyrimidine and p-tert. potassium butylbenzenesulfonamide; melting point 215-216 ^o C.

 Example 65. Analogously to example 59, from N- [6-chloro-5- (o-chlorobenzyl) -4-pyrimidin-ynyl] -p-isopropylbenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (o -chlorobinzyl) -4-pyrimidinyl] p-isopropylbenzenesulfonamide.

The starting material is prepared from 4,6-dichloro-5- (o-chlorobenzyl) pyrimidine and potassium p-isopropylbenzenesulfonamide; melting point 166-167 ^o C.

 Example 66. Analogously to example 59, from N- [6-chloro-5- (o-methyltyl) benzyl) -4- pyrimidine] p-isopropylbenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- ( o- (methylthio) benzyl) -4-pyrimidinyl] p-isopropylbenzenesulfonamide.

The starting material is prepared as follows:
By reacting thiosalicylic acid with dimethyl sulfate in the presence of tetrabutylammonium bromide, 2- (methylthio) benzoic acid methyl ester is obtained with a melting point of 64 ^° C. By reduction with lithium aluminum hydride in dry tetrahydrofuran, 2- (methylthio) benzyl alcohol is obtained, which is reacted with SOCl ₂ 2- (methylthio) benzene chloride; boiling point 90 ^o C / 0.3 mm RT. Art. The reaction of malonic acid diethyl ether with 2- (methylthio) benzyl chloride gives 2- (methylthio) benzylmalonic acid diethyl ether; boiling point 130 ^o C / 0.05 mm RT. Art. Condensation with formamidine gives 5- [o- (methylthio) benzyl] -6-hydroxy-4- (3H) -pyrimidion, which is converted into 4,6-dichloro-5- [o- (methylthio) benzyl] pyrimidine with a temperature melting point 91 ^° C. Finally, from 4,6-dichloro-5- (o- (methylthio) benzyl) pyrimidine and potassium p-isopropylbenzenesulfonamide, N- [6-chloro-5- (o-methylthio) benzyl) -4- pyrimidinyl] -p-isopropylbenzenesulfonamide with a melting point of 145-146 ^o C.

Example 67. Analogously to example 59, from N- [6-chloro-5- (o-chlorobenzyl) -4-pyrimidinyl] p-isobutylbenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (o-chlorobenzyl) - 4-pyrimidinyl] -p-isobutylbenzenesulfonamide with a melting point of 130-131 ^o C.

The starting material is prepared from 4,6-dichloro-5- (o-chlorobenzyl) pyrimidine and potassium p-isobutylbenzenesulfonamide; melting point 147-149 ^o C.

Example 68. Analogously to example 50, from N- [6-chloro (o-chlorobenzyl) -4-pyrimidinyl] p-cyclohexylbenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- - (o-chlorobenzyl) -4 is obtained -pyrimidinyl] -p-cyclohexylbenzenesulfonamide with a melting point of 164-165 ^o C.

The starting material is prepared from 4,6-dichloro-5- (o-chlorobenzyl) -pyrimidine and potassium p-cyclohexylbenzenesulfonamide; melting point 107-108 ^o C.

Example 69. Analogously to example 59, from N- [6-chloro-5- (o-chlorobenzyl) -4-pyrimidinyl] -p-isopentylbenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- - (o-chlorobenzyl) is obtained -4-pyrimidinyl] -p-isopentylbenzenesulfonamide with a melting point of 127-128 ^o C (from diisopropyl ether).

The starting material is prepared from 4,6-dichloro-5- (o-chlorobenzyl) pyrimidine and potassium p-isopentylbenzenesulfonamide; melting point 139-140 ^o C.

Example 70. Analogously to example 59, from N- [6-chloro-5- (o-methoxybenzyl) -4- pyrimidinyl] p- (isopropylthio) benzenesulfonamide, N- [6- (2- hydroxyethoxy) -5- ( o-methoxybenzyl) -4-pyrimidinyl] p- (isopropylthio) benzenesulfonamide with a melting point of 127-128 ^o C (from diisopropyl ether).

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

Example 71. Analogously to example 1, from p-chloro-N- [6-chloro-5- (p-chlorophenyl) -2-methyl- -4-pyrimidinyl] benzenesulfonamide and sodium ethylene glycolate, p-chloro-N- [5- ( p-chlorophenyl) -6- (2-hydroxyethoxy) -2-methyl-4-pyrimidinyl] benzenesulfonamide with a melting point of 163-164 ^o C (from ether).

The starting material is prepared as follows:
From diethyl p-chlorophenyl malonate, acetamidine hydrochloride and sodium methylate, 5- (p-chlorophenyl) -2-methyl-4,6 (1H, 5H) - -pyrimidinedione with a melting point> 270 ^° C is obtained and from it POCl _{3 is} obtained 4,6-dichloro-5- (p-chlorophenyl) -2-methylpyrimidine with a melting point of 181-183 ^o C (from methylene chloride and isopropyl ether).

The reaction of this compound with p-chlorophenylsulfonamide gives p-chloro-N- [6-chloro-5- (p-chlorophenyl) -2-methyl-4-pyrimidinyl] benzenesulfonamide; melting point 196-197 ^o C (from acetonitrile).

Example 72. Analogously to example 1, from p-chloro-N- [6-chloro-5- (p-nitrophenyl) -4- pyrimidinyl] benzenesulfonamide and p-chlorophenylsulfonamide receive p-chloro-N- [6- (2-hydroxyethoxy ) -5- (p-nitrophenyl) -4-pyrimidinyl] benzenesulfonamide with a melting point of 223-225 ^o C (from methylene chloride and isopropyl ether).

The starting material is prepared as follows:
3.5 g of diethyl p-nitrophenyl malonate and 1.6 g of formamidine acetate are heated for 3 hours to 100 ^° C. After that, another 3.2 g of formamidine acetate, 5 ml of abs. dimethylformamide and 1 ml of glacial acetic acid and heat the reaction mixture to 110 ^° C. for 16 hours. After evaporation of the solvent under reduced pressure, the residue was triturated with ether (simple), filtered under vacuum and dissolved in a 1N NaOH solution. The solution was mixed with a small amount of coal, filtered off and adjusted to pH 4.5 with glacial acetic acid. The residue was dried under reduced pressure at 80 ^° C. and then dissolved and refluxed for 3 hours with stirring. After evaporation of the solvent under reduced pressure, the residue was dissolved in ethyl acetate, 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 with a melting point of 159-161 ^° C. (from isopropyl ether).

By reacting the compound with p-chlorophenylsulfonamide, p-chloro-N- [6-chloro-5- (p-nitrophenyl) -4-pyrimidinyl] benzenesulfonamide is obtained with a melting point of 282-285 ^° C. (from acetonitrile).

Example 73. 200 mg of n-chloro-N- [6- (2-hydroxyethoxy) -5- (n-nitrophenyl) -4-pyrimidinyl] benzenesulfonamide is hydrogenated in 15 ml of glacial acetic acid and in 2 ml of 4n HC1 in dioxane over 50 mg palladium (10%) on charcoal at room temperature and normal pressure. After filtering the catalyst under vacuum, the solution was evaporated under reduced pressure, the residue was dissolved in 30 ml of methanol and the solution was mixed with 1 ml of dioxane-HC1. After 16 hours, the solution was evaporated under reduced pressure, and the residue was recrystallized from methanol and acetonitrile. N- [5- (n-aminophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -n-chlorobenzenesulfonamide hydrochloride is obtained with a melting point of 206 ^° C. (decomposition).

Example 74. Analogously to example 1, from p-chloro-N- [5- (biphenylyl) -6-chloro-4-pyrimidinyl] benzenesulfonamide and sodium ethylene glycolate, N- [5- (4-biphenylyl) -6- (2-hydroxyethoxy ) -4-pyrimidinyl] -p-chlorobenzenesulfonamide with a melting point of 213-214 ^o C (from ester of acetic acid).

The starting material is prepared as follows:
From diethyl-4-bifenilmalonata, formamidine acetate and sodium methylate prepared 5- (4-biphenylyl) -4,6 (1H, 5H) -pyrimidinedione, melting at> 280 ^o C, therefrom by reaction with POC1 _3, 5- ( 4-biphenylyl) -4,6-dichloropyrimidine with a melting point of 144 ^° C. (from methylene chloride and n-hexane).

The reaction of this compound with p-chlorophenylsulfonamide gives p-chloro-N- [5- (4-biphenylyl) -6-chloro-4-pyrimidinyl] benzenesulfonamide with a melting point of 234-235 ^° C (from acetonitrile).

Example 75. Analogously to example 1, from p- chloro-N - [(6-hydroxyethoxy) from N- [6-chloro-5-a, α, α-trifluoro-p-tolyl) - 4-pyrimidinyl] benzenesulfonamide and sodium ethylene glycolate -5-a, α, α-trifluoro-p-tolyl) -4-pyrimidinyl] benzene sulfonamide with a melting point of 171-174 ^° C. (from acetone and isopropyl ether).

 The starting material is prepared as follows.

From a, α, α-trifluoro-p-tolyl malonate and formamidine acetate, 5-a, α, α-trifluoro-p-tolyl) -4,6 (1H, 5H) pyrimidinedione with a melting point> 280 ^° C. is obtained, and from it is obtained by reaction with POC1 ₃ 4,6-dichloro-5-a, α, α-p-tolyl) -pyrimidine with a melting point of 94-95 ^o C (from p-hexane).

The reaction of this compound with n-chlorophenylsulfonamide gives p-chloro-N - [(6-chloro-5-a, α, α-trifluoro-p-tolyl) -4-pyrimidinyl] benzenesulfonamide with a melting point of 262-264 ^o C ( from acetonitrile).

Example 76. Analogously to example 1, from p-chloro-N- [6-chloro-5-a, α, α-trifluoro-p-tolyl) -4-pyrimidinyl] benzenesulfonamide and sodium ethylene glycolate, p-chloro-N - [( 6-hydroxyethoxy) -5-a, α, α-trifluoro-p-tolyl) -4-pyrimidinyl] benzenesulfonamide with a melting point of 171-174 ^o C (from acetone and isopropyl ether).

The starting material is prepared as follows:
From a, α, α-trifroth-p-tolyl malonate and formamidine acetate, 5-a, α, α-trifluoro-p-tolyl) -4,6 (1H, 5H) -pyrimidinedione with a melting point> 280 ^° C is obtained, and 4,6-dichloro-5-a, α, α-trifluoro-p-tolyl) -pyrimidine with a melting point of 94-95 ^o C (from p-hexane) is obtained from it by reaction with POC1 ₃ .

The reaction of this compound with p-chlorosulfonamide gives p-chloro-N- [6-chloro-5-a, α, α-trifluoro-p-tolyl) -4-pyrimidinyl] benzene sulfonamide with a melting point of 262-264 ^o C (from acetonitrile).

Example 77. Analogously to example 27, from N- [5- [p- (benzyloxy) phenyl] -6- (2-hydroxyethoxy) -4-pyrimidinyl] p-chlorobenzenesulfonamide, p-chloro-N- [5- ( p-hydroxyphenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] benzene sulfonamide with a melting point of 207-209 ^° C (from acetonitrile and isopropyl ether).

Example 78. Analogously to example 1, from N- [5- [p- (benzyloxy) phenyl] -6-chloro-4-pyrimidinyl] p-chlorobenzenesulfonamide and sodium ethylene glycolate, N- [5- [p- (benzyloxy) phenyl] is obtained -6- (2-hydroxyethoxy) -4-pyrimidinyl] - p-chlorobenzenesulfonamide with a melting point of 160-161 ^o C (from ether).

The starting material is prepared as follows:
From diethyl [p- (benzyloxy) phenyl] malonate and formamidine acetate, a 5- [p- (benzyloxy) phenyl] -4,6 (1H, 5H) dione is obtained with a melting point> 280 ^° C. and is obtained from it by POC1 ₃ 5- [p- (benzyoxy) phenyl] -4,6-dichloropyrimidine with a melting point of 115-116 ^° C (from methylene chloride and isopropyl ether).

By reacting this compound with p-chlorophenylsulfonamide, N- [5- (benzyloxy) phenyl] -6-chloro-4-pyrimidinyl] p-chlorobenzenesulfonamide is obtained with a melting point of 234-236 ^° C. (from acetic acid ester).

Example 79. Analogously to example 1, from N- (6-chloro-4-a, α, α-trifluoro-p-tolyl) -4-pyrimidinyl] -a, α, α-trifluoro-p-toluenesulfonamide and sodium ethylene glycolate receive N - [(6- (2-hydroxyethoxy) -5-a, α, α-trifluoro-p-tolyl) - 4-pyrimidinyl] -a, α, α-trifluoro-p-toluenesulfonamide with a melting point of 165-166 ^o C (from methylene chloride and isopropyl ether).

The starting material is prepared from 4,6-dichloro-5-a, α, α-p-tolyl) pyrimidine and a, α, α-trifluoro-p-toluenesulfonamide; melting point> 270 ^o C (from acetonitrile).

Example 80. Analogously to example 1, from p-chloro-N- [6-chloro-5- (2-naphthylmethyl) -4-pyrimidinyl] benzenesulfonamide and sodium ethylene glycolate, p-chloro-N- [6- (2-hydroxyethoxy) - is obtained 5- (2-naphthylmethyl) -4-pyrimidinyl] benzene sulfonamide with a melting point of 161 ^° C. (from acetonitrile and isopropyl ether).

The starting material is prepared as follows:
From diethyl- (2-naphthylmethyl) malonate and formamidine acetate, 5- (2-naphthylmethyl) -4.6 (1H, 5H) -pyrimidinedione with a melting point> 270 ^° C. is obtained and is obtained from it when reacted with POC1 ₃ 4.6 -dichloro-5- (2-naphthylmethyl) pyrimidine with a melting point of 161-162 ^o C (from methylene chloride and isopropyl ether).

The reaction of this compound with p-chlorophenylsulfonamide gives p-chloro-N- [6-chloro-5- (2-naphthylmethyl) -4-pyrimidinyl] benzenesulfonamide with a melting point of 197-199 ^° C (from acetonitrile).

Example 81. Analogously to example 1, from N- [5- (p-bromophenyl) -6-chloro-4-pyrimidinyl] p-isopropylbenzenesulfonamide and sodium ethylene glycolate, N- [5- (p-bromophenyl) -6- (2- hydroxyethoxy) -4-pyrimidinyl] p-isopropylbenzenesulfonamide with a melting point of 207-208 ^o C (from acetonitrile and isopropyl ether).

The starting material is prepared from 5- (p-bromophenyl) -4,6-dichloropyrimidine and p-isopropylbenzenesulfonamide; melting point 271-273 ^o C (from acetonitrile).

Example 82. Analogously to example 1, from N- [6-chloro-5- (p-chlorophenyl) -4-pyrimidine] -p-isopropylbenzenesulfonamide and sodium ethylene glycolate, N- [5- (p-chlorophenyl) -6- (2- hydroxyethoxy) -4-pyrimidinyl] p-isopropylbenzenesulfonamide with a melting point of 162-164 ^° C (from acetonitrile and isopropyl ether).

The starting material is prepared from 4,6-dichloro-5- (p-chlorophenyl) pyrimidine and p-isopropylbenzenesulfonamide; melting point 266-268 ^o C (from acetonitrile).

Example 83. Analogously to example 1, from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) p-isopropylbenzenesulfonamide and sodium ethylene glycolate receive N- [6- (hydroxyethoxy) -5-p-tolyl) -4- pyrimidinyl] -p-isopropylbenzenesulfonamide with a melting point of 142-144 ^o C (from isopropyl ether).

 From this compound, sodium salt is obtained in the form of an amorphous substance together with sodium methylate.

The starting material N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -p-isopropylbenzenesulfonamide with a melting point of 211-213 ^o C (from acetonitrile) is obtained from 4,6-dichloro-5-p-tolylpyrimidine and p-isopropylbenzene sulfonamide.

Example 84. Analogously to example 1, from p-tert.-butyl-N- (6-chloro-5-p-tolyl-4-pyrimidinyl) benzenesulfonamide and sodium ethylene glycolate, p-tert.-butyl-N- [6- (2 -hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl) benzene sulfonamide with a melting point of 169-170 ^° C (from isopropyl ether) and amorphous sodium salt is obtained from it using sodium methylate.

The starting material is obtained from 4,6-dichloro-5-p-tolylpyrimidine and p-tert. -butylbenzenesulfonamide; melting point 222-224 ^o C (from acetonitrile).

Example 85. Analogously to example 1, from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -4- (2-methoxyethoxy) benzenesulfonamide and sodium ethylene glycolate, N- [6- (2-hydroxyethoxy) -5- is obtained p-tolyl-4-pyrimidinyl] p- (2-methoxyethoxy) benzene sulfonamide with a melting point of 155-156 ^° C (from isopropyl ether).

The starting material is prepared from 4,6-dichloro-5-p-tolylpyrimidine and p- (2-methoxyethoxy) benzenesulfonamide; melting point 172-173 ^o C (from methylene chloride and isopropyl ether).

Example 86. Analogously to example 1, from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -4- (trifluoromethoxy) benzenesulfonamide and sodium ethylene glycolate, N- [6- (2-hydroxyethoxy) -5-p- tolyl-4-pyrimidinyl] p- (trifluoromethoxy) benzene sulfonamide with a melting point of 147-148 ^° C (from isopropyl ether).

The starting material is prepared from 4,6-dichloro-5-p-tolylpyrimidine and p- (trifluoromethoxy) benzenesulfonamide; melting point 205-206 ^o C (from acetonitrile and isopropyl ether).

Example 87. Analogously to example 1 from p-butyl-N- (6-chloro-5-n-tolyl-4-pyrimidinyl) benzenesulfonamide and sodium ethylene glycolate receive p-butyl-N- [6- (2-hydroxyethoxy) -5- p-tolyl-4-pyrimidinyl] benzenesulfonamide with a melting point of 136-137 ^o C (from isopropyl ether).

The starting material is prepared from 4,6-dichloro-5-p-tolylpyrimidine and p-butylbenzenesulfonamide; melting point 168-169 ^o C (from acetonitrile and isopropyl ether).

Example 88. Analogously to example 1, from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -2-naphthalenesulfonamide and sodium ethylene glycolate, N- [6- (2-hydroxyethoxy) -5-p-tolyl-4 is obtained -pyrimidinyl] -2-naphthalenesulfonamide with a melting point of 161-162 ^o C (from acetone and isopropyl ether).

The starting material is prepared from 4,6-dichloro-5-p-tolylpyrimidine and 2-naphthalenesulfonamide; melting point 198-202 ^o C (from acetonitrile).

Example 89. Analogously to example 1, from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) p-toluenesulfonamide and sodium ethylene glycolate receive N- [6- (2-hydroxyethoxy) -5-p-tolyl-4 -pyrimidinyl] -p-toluenesulfonamide with a melting point of 169-170 ^o C (from acetone and isopropyl ether).

The starting material is prepared from 4,6-dichloro-5-p-tolylpyrimidine and p-toluenesulfonamide; melting point 213-214 ^o C (from acetonitrile and isopropyl ether).

Example 90. Analogously to example 1, from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -a, α, α-trifluoro-p-toluenesulfonamide and sodium ethylene glycolate receive N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] -a, α, α-trifluoro-p-toluenesulfonamide with a melting point of 162-163 ^° C (from acetonitrile and isopropyl ether).

The starting material is prepared from 4,6-dichloro-5-p-tolylpyrimidine and a, α, α-trifluoro-p-toluenesulfonamide; melting point 231-233 ^o C (from acetonitrile).

Example 91. Analogously to example 1, from N- (6-chloro-5-n-tolyl-4-pyrimidinyl) -n-fluorobenzenesulfonamide and sodium ethylene glycolate, after chromatography, p-fluoro-N- [6- (2-hydroxyethoxy) -5 is obtained -p-tolyl-4-pyrimidinyl] benzenesulfonamide with a melting point of 167-168 ^o C (from acetone and isopropyl ether) and p- (2-hydroxyethoxy) -N- [6-hydroxyethoxy) -5-p-tolyl-4- pyrimidinyl] benzenesulfonamide with a melting point of 174-176 ^o C (from acetone and isopropyl ether).

The starting material is prepared from 4,6-dichloro-5-p-tolylpyrimidine and p-fluorobenzenesulfonamide; melting point 168-169 ^o C (from acetonitrile and isopropyl ether).

Example 92. Analogously to example 1, from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) p-propylbenzenesulfonamide and sodium ethylene glycolate, N- [6- (2-hydroxyethoxy) -5-p-tolyl-4 is obtained -pyrimidinyl] -p-propylbenzenesulfonamide with a melting point of 171-172 ^o C (from acetonitrile).

Example 93. Analogously to example 1, from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -o-propylbenzenesulfonamide and sodium ethylene glycolate receive N- [6- (2-hydroxyethoxy) -5-p-tolyl-4 -pyrimidinyl] -o-propylbenzenesulfonamide with a melting point of 195-196 ^o C (from methylene chloride and isopropyl ether).

The starting material is obtained from 4,6-dichloro-5-p-tolylpyrimidine and o-propylbenzenesulfonamide; melting point 150-151 ^o C (from isopropyl ether).

Example 94. Analogously to example 1, from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) p-ethylbenzenesulfonamide and sodium ethylene glycolate receive p-ethyl-N- [6- (2-hydroxyethoxy) -5-p -tolyl-4-pyrimidinyl] benzenesulfonamide with a melting point of 138-139 ^o C (from methylene chloride and isopropyl ether).

The starting material is prepared from 4,6-dichloro-5-p-tolylpyrimidine and p-ethylbenzenesulfonamide; melting point 168-169 ^o C (from acetonitrile).

Example 95. Analogously to example 1, from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -o-ethylbenzenesulfonamide and sodium ethylene glycolate, o-ethyl-N- [6- (2-hydroxyethoxy) -5-p is obtained -tolyl-4-pyrimidinyl] benzenesulfonamide with a melting point of 136-138 ^o C (from acetone and isopropyl ether).

The starting material is prepared from 4,6-dichloro-5-p-tolylpyrimidine and o-ethylbenzenesulfonamide; melting point 159-160 ^o C (from acetonitrile and isopropyl ether).

Example 96. Analogously to example 1, from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) p-cyclopentylbenzenesulfonamide and sodium ethylene glycolate receive p-cyclopentyl-N- [6- (2-hydroxyethoxy) -5-p -tolyl] benzenesulfonamide with a melting point of 179-181 ^o C (from acetone and isopropyl ether).

The starting material is prepared from 4,6-dichloro-5-p-tolylpyrimidine and p-cyclopentylbenzenesulfonamide; melting point 192-194 ^o C (from acetonitrile and isopropyl ether).

Example 97. Analogously to example 1, from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -a, α, α-trifluoro-o-toluenesulfonamide and sodium ethylene glycolate receive a, α, α-trifluoro-N- [6- (2-Hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] -o-toluenesulfonamide, melting point 166-167 ^° C (from methylene chloride and isopropyl ether).

The starting material is prepared from 4,6-dichloro-5-p-tolylpyrimidine and a, α, α-trifluoro-o-toluenesulfonamide; melting point 129-131 ^o C (from methyl chloride and isopropyl ether).

Example 98. Analogously to example 1, from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -o-toluosulfonamide and sodium ethylene glycolate, N- [6- (2-hydroxyethoxy) -5-p-tolyl-4 is obtained -pyrimidinyl] -o-toluenesulfonamide with a melting point of 149 150 ^o C (from ester of acetic acid and isopropyl ether).

 The starting material is prepared from 4,6-dichloro-5-p-tolylpyrimidine and o-toluenesulfonamide; melting point 198 199.198> C (from acetonitrile).

Example 99. Analogously to example 1, from N- (6-chloro-5-p-tolyl-4-pyrimidinyl) -2,4-xylene sulfonamide and sodium ethylene glycolate, N- [6- (2-hydroxyethoxy) -5-p-tolyl is obtained -4-pyrimidinyl] -2,4-xylene sulphonamide with a melting point of 158 159 ^o C (from isopropyl ether).

The starting material is obtained from 4,6-dichloro-5-p-tolylpyrimidine and 2,4-xylene sulphonamide; melting point 233 ^o C (from acetonitrile and isopropyl ether).

Example 100. Analogously to example 1, from p-chloro-N- [6-chloro-5- (1-naphthylmethyl) -4-pyrimidinyl] benzenesulfonamide and sodium ethylene glycolate, p-chloro-N- [6- (2-hydroxyethoxy) - is obtained 5- (1-naphthylmethyl) -4-pyrimidinyl] benzenesulfonamide with a melting point of 204 205 ^o C (from acetonitrile and isopropyl ether).

The starting material is prepared as follows:
From diethyl-1-naphthylmalonate and formamidine acetate, 5- (1-naphthylmethyl) -4.6 (1H, 5H) -pyrimidinedione is obtained with a melting point> 270 ^° C. and from it, after drying under reduced pressure at 80 ^° C., in contact with POCL ₃ gave 4,6-dichloro-5- (1-naphthylmethyl) pyrimidine with a melting point of 111 112 ^° C. (from methylene chloride and isopropyl ether).

The reaction of this compound with p-chlorophenylsulfonamide gives p-chloro-N- [6-chloro-5- (1-naphthylmethyl) -4-pyrimidinyl] benzenesulfonamide with a melting point of 202 203 ^o C (from acetonitrile).

Example 101. Analogously to example 1, from N- [6-chloro-5- (p-isopropylphenyl) -4-pyrimidinyl] p-isopropylbenzenesulfonamide and sodium ethylene glycolate, N- [6- (2-hydroxyethoxy) -5- (p- isopropylphenyl) -4-pyrimidinyl] - p-isopropylbenzenesulfonamide with a melting point of 142 144 ^° C (from isopropyl ether).

The starting material is prepared as follows:
From diethyl- (p-isopropylphenyl) malonate and formamidine acetate, 5- (p-isopropylphenyl) -4.6 (1H, 5H) -pyrimidinedione with a melting point> 290 ^° C. is obtained and 4.6 is obtained from it when reacted with POCl ₃ -dichloro-5- (p-isopropylphenyl) pyrimidine with a melting point of 69 - 70 ^o C (from n-hexane).

The reaction of this compound with p-isopropylbenzenesulfonamide gives N- [6-chloro-5- (p-isopropylphenyl) -4-pyrimidinyl] p-isopropylbenzenesulfonamide with a melting point of 198 199 ^° C (from acetonitrile and isopropyl ether).

Example 102. Analogously to example 1, from N- [6-chloro-5- (p-isopropylphenyl) -4-pyrimidinyl] -p-cyclopentylbenzenesulfonamide and sodium ethylene glycolate, receive p-cyclopentyl-N- [6- (2-hydroxyethoxy) -5 - (p-isopropylphenyl) -4-pyrimidinyl] benzenesulfonamide with a melting point of 132 ^° C. (decomposition) (from acetone and isopropyl ether).

The starting material is prepared from 4,6-dichloro-5- (p-isopropylphenyl) pyrimidine and p-cyclopentylbenzenesulfonamide; melting point 188 189 ^o C (from methylene chloride and isopropyl ether).

 Example A. Tablets containing the following components can be obtained by conventional methods: (see table. 4).

 Example B. Capsules containing the following components can be obtained by conventional methods: (see table. 5).

Example C. Injection solutions have the following composition%
The compound of formula I 3.0 mg
Gelatin 150.0 mg
Phenol 4.7 mg
Water for injection up to 1.0 ml.

 Example D. 500 mg of a compound of formula I are suspended in 3.5 ml of migliol 812 and 0.08 g of benzyl alcohol. This suspension is introduced into a vessel with a metering valve. 5.0 g of Freon 12 is introduced into the vessel through the valve under pressure. When shaken, Freon is dissolved in a mixture of migliol-benzyl alcohol. This spray bottle contains approximately 100 single doses, which can be used alone.

Claims (4)

1. Derivatives of arylsulfonamide of the General formula

where R ^{1 is} hydrogen, halogen;
R ² hydrogen, halogen, trifluoromethyl;
R ³ halogen, lower alkylthio, trifluoromethoxy, lower alkyl, lower alkoxy-lower alkoxy, lower alkoxy, C ₅ -C ₆ -cycloalkyl, trifluoromethyl, phenyl-lower alkoxy, lower alkenyl, oxo-lower alkyl, hydroxy-lower alkyl, hydroxy lower alkyl or R ² and R ³ together form butadienyl;
R ⁴ hydrogen, lower alkyl;
R ^{5 is} hydrogen, tetrahydropyran-2-yl;
R ⁶ radical of the General formula

or

where R ^{7 is} hydrogen, lower alkyl;
R ⁸ halogen, lower alkyl, lower alkoxy, lower alkylthio, nitro;
R ⁹ halogen, lower alkoxy, lower alkylthio, trifluoromethyl;
R ^{1 0} hydrogen, lower alkylthio, lower alkoxy;
n 2 or 3,
or their salts. 2. The compound according to claim 1, selected from the group N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl) p-methoxybenzenesulfonamide; N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] p-methylthiobenzenesulfonamide; N- [6- (2-hydroxyethoxy) -5- (o-methoxybenzyl) -4-pyrimidinyl] -α, α, α - trifluoro-p-toluenesulfonamide;
3. The compound according to claim 1, selected from the group N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] trifluoro-p-toluenesulfonamide; N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] p- (trifluoromethoxy) benzenesulfonamide; p-chloro-N- [5- (p-chlorophenyl) -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; N- [5- (p-bromophenyl) -6 (2-hydroxyethoxy) -4-pyrimidinyl] p-chlorobenzenesulfonamide; p-chloro-N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] benzenesulfonamide; N- [6- (2-hydroxyethoxy) -5- (p-methoxyphenyl) -4-pyrimidinyl] p (methylthio) benzenesulfonamide; N- [6- (2-hydroxyethoxy) -5- (p-methoxyphenyl) -4-pyrimidinyl] p-isopropylbenzenesulfonamide; p-tert-butyl-N- [6- (2-hydroxyethoxy) -5- (p-methoxyphenyl) -4-pyrimidinyl] benzenesulfonamide; N- [6- (2-hydroxyethoxy) -5- (p- (methylthio) phenyl) -4-pyrimidinyl] p-isopropylbenzenesulfonamide; N- [5- (p-chlorophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] p-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] p- (2-methoxyethoxy) benzenesulfonamide; N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] p- (trifluoromethoxy) benzenesulfonamide; N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] p-toluenesulfonamide; N- [6- (2-hydroxyethoxy) -5-p-tolyl-4-pyrimidinyl] -α, α, α is trifluoro-p-toluenesulfonamide; N- [6- (2-hydroxyethoxy) -5- (α, α, α-trifluoro-p-tolyl) -4-pyrimidinyl-p-isopropylbenzenesulfonamide; N- [5- (p-bromophenyl) -6- (2-hydroxyethoxy) -4-pyrimidinyl] p-isopropylbenzenesulfonamide; N- [6- (2-hydroxyethoxy) -5- (p-ethylphenyl) -4-pyrimidinyl] p-isopropylbenzenesulfonamide; p-cyclopentyl-N- [6- (2-hydroxyethoxy) -5- (p-ethylphenyl) -4-pyrimidinyl] benzenesulfonamide.  4. Compounds according to claims 1 to 3, exhibiting angioprotective, antihypertensive and vasospasmolytic, in particular anti-ischemic activity.  5. A pharmaceutical composition exhibiting angioprotective, antihypertensive and vasospasmolytic, in particular anti-ischemic, action comprising an active substance and pharmaceutically acceptable additives, characterized in that it contains as an active substance a derivative of arylsulfonamide or its salt according to any one of claims 1-3 in effective quantity.

Images