Derivatives arylsulfonamides or their salts and a pharmaceutical composition exhibiting angioprotective, antihypertensive and vazospasticescoe, in particular anti-ischemic action

 

(57) Abstract:

Usage: as a healing agent. The inventive product: derivatives arylsulfonamides: C6H2-(R1, R2, R3)-SO2- where R1- H, halogen; R2- H, halogen, CF3; R3halogen, lower alkylthio, triptoreline, lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, C5-C6- cycloalkyl, CF3, vanillasky alkoxy, lower alkenyl, oxo-lower alkyl, hydroxymyristic alkyl, hidrogenesse alkyl, or R2and R3together form butadienyl; R5is hydrogen, tetrahydropyran-2-R6is phenyl, substituted R7, R8or benzyl, substituted R9, R10, R7is hydrogen, lower alkyl; R8halogen, lower alkyl, lower alkoxy, lower alkylthio, nitro; R9halogen, lower alkyloxy, lower alkylthio, trifluoromethyl; R10is hydrogen, lower alkylthio; lower alkoxy; n = 2, 3, or their salts. 2 S. and 3 C.p. f-crystals, 5 PL.

The invention concerns new derivatives of arylsulfonamides and their salts, having the properties of an inhibitor of binding of endothelin, which can be used for pharmaceuticals for treatment of diseases of the th, such as hypertension, ischemia, vascular and angina, as well as concerns angioprotective, antihypertensive and vazospasticescoe, in particular, anti-ischemic funds based on them.

Proposed according to the present invention derivatives of arylsulfonamides correspond to the General structural formula I

< / BR>
where R1hydrogen, halogen; R2hydrogen, trifluoromethyl; R3halogen, lower alkylthio, triptoreline, lower alkyl, lower alkoxy-lower alkoxy, lower alkoxy, C5-C5-cycloalkyl, trifluoromethyl, phenyl-lower alkoxy, lower alkenyl, oxo-lower alkyl, hydroxyimino-lower alkyl, hydroxy-lower alkyl, or R2and R3together form butadienyl; R4hydrogen, lower alkyl; R5is hydrogen, tetrahydropyran-2-yl; R6represents a radical of the formula

< / BR>
where R7hydrogen, lower alkyl; R8halogen, lower alkyl, lower alkoxy, lower alkylthio, nitro; R9halogen, lower alkoxy, lower alkylthio, trifluoromethyl; R10hydrogen, lower alkylthio, lower alkoxy; n is 2 or 3, or their salts.

From German patent publications DE 1 545 944 known sulfonamides, which are very close to the offer and have the lectern.

It has been unexpectedly found that the compounds of the above formula I are inhibitors for endothelin receptors. The compounds of formula can be applied for the treatment of diseases associated with the activity of endothelin, in particular, diseases of the cardiovascular system such as hypertension, ischemia, vasospasm and Angina pectoris (angina).

Applied here, the expression "lower" means a group with 1 to 7 carbon atoms, preferably with 1 to 4 carbon atoms. Alkyl groups, alkoxy-, alkylthio and altergroup, as well as alkyl groups as components alkanoyl groups may be normal or ISO-structure. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, secondary, and tertiary butyl. Examples alkenyl groups are vinyl and allyl. Phenyl-lower alkoxy radical is, for example, benzyloxy. Halogen means fluorine, chlorine, bromine and iodine, preferably chlorine is.

Preferred compounds of formula I, 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-methyldibenzothiophene;

N-[6-(2-mules I, selected from the group:

N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl] -Cryptor-p-toluensulfonate;

N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl] -n-(triptoreline)benzosulfimide;

p-chloro-N-[5-(p-forfinal)-6-(2-hydroxyethoxy)-4 - pyrimidinyl]benzosulfimide;

N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl] - p-forbindelsesfaneblad;

o-chloro-N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4 - pyrimidinyl]benzylmalonate;

N-[5-(p-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl] -p-chloro-benzosulfimide:

p-chloro-N-[6-(2-hydroxyethoxy)-5-p-tolyl-4 - pyrimidinyl]benzosulfimide;

N-[6-(2-hydroxyethoxy)-5-(p-methoxyphenyl)-4-pyrimidinyl]- p-(methylthio)benzosulfimide;

N-[6-(2-hydroxyethoxy)-5-(p-methoxyphenyl)-4-pyrimidinyl]- p-isopropylbenzenesulfonyl;

p-tert.-butyl-N-[6-(2-hydroxyethoxy)-5-(p-methoxyphenyl)-4 - pyrimidinyl] benzosulfimide;

N-[6-(2-hydroxyethoxy)-5-[p-(methylthio)phenyl] -4-pyrimidinyl]- p-isopropylbenzenesulfonyl;

N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl] - p-isopropylbenzenesulfonyl;

N-[6-(hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl] -p-isopropylbenzene - sulfonamide;

p-tert.-butyl-N-[6-(2-hydroxyethoxy)-5-p-tolyl-4 - pyrimidinyl]benzo is N-[6-(2-hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl]-n- (triptoreline)benzosulfimide;

N-[6-(2-hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl]-p - toluensulfonate;

N-[6-(2-hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl] a, , -Cryptor-p-toluensulfonate;

N-[6-(2-hydroxyethoxy)-5-( a, , -Cryptor-p-tolyl)-4 - pyrimidinyl-p-isopropylbenzenesulfonyl;

N-[5-(p-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl] - p-isopropylbenzenesulfonyl;

N-[6-(2-hydroxyethoxy)-5-(p-ethylphenyl)-4-pyrimidinyl] -n-isopropyl-benzosulfimide;

p-cyclopentyl-N-[6-(2-hydroxyethoxy)-5-(p-ethylphenyl)-4 - pyrimidinyl]benzosulfimide.

The compounds of formula I can thus be obtained when the compound of the formula

< / BR>
where R1, R2, R3, R4and R6have the abovementioned meaning and Hal means halogen, interacts with the compound of the formula

MO(CH2)nOR5< / BR>
where 14 R5has the above value, M is an alkaline metal, the substituents present in the resulting compound of formula I, it is possible to modify and/or translate the obtained compound of formula I in salt.

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

The interaction of the compounds of formula II with the compound of the formula III suitable PR including when n is 2. As the alkali metal M is mainly used sodium.

It is advisable to conduct the reaction under heating, for example, up to 70 - 120oC. In a preferred embodiment, use monosodium salt of ethylene or propylene glycol as the compounds of formula III.

In the thus obtained compound of formula I can be modified present in the substituents. A hydroxyl group can be, for example, etherification (simple ether). The nitro-group can be restored to the amino group. Lower alkenilovyh group R3may be, for example, oxidized using OsO4or NaJO4to the carbonyl group or groups alkenone; formed such carbonyl group may, for example, using sodium borohydride to be restored to a hydroxyl group or with Grignard compounds converted into the corresponding tert.alcohol or hydroxylamine can be converted into the oxime. These reactions can be carried out in a known manner, and a hydroxyl group, R5pre-turns into the ether group (simple ether), for example, in tetrahydropyran. These groups can, if necessary, re-split common way is blowing modification of other reactive groups in the molecule. The compounds of formula I, the conventional methods can be converted into salts, for example, alkaline salts such as sodium and potassium salts.

The compounds of formula II and III used as starting materials, since they are not known and obtaining them are described below, receive by analogy with known or by analogy with the ways described below.

The compounds of formula II can be obtained according to the following reaction scheme:

< / BR>
Condensation of compound IV with formamidine or its equivalent, such as the acetate of acetamidine or hydrochloride of acetamidine, gives pyrimidinedione V. using phosphorus oxychloride will receive dichloroethylene VI, which when interacting with the compound VII gives compound II. All of these reactions are standard and can be carried out under the conditions customary for such reactions known in the art. Compounds IV in which R6represent a radical (a), can be obtained from the corresponding esters of phenylacetic acid of the formula R6CH2COOEtinteraction with diethylmalonate in the presence of sodium acetate. Compounds IV in which R6represent a radical (b), can be obtained by condensation of knoevenagel (Knoe the work product of condensation.

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

The inhibitory effect of compounds of the formula I on the endothelin receptors may be shown in the following experience:

I: Inhibition of endothelin-communication on the membrane of human placenta (see Life Sci 44: 1429 (1989))

Human placenta homogenized in 5 mmol Tris-buffer at pH of 7.4, containing 1 mmol MgCl2and 250 mmol of sucrose. Homogenized centrifuged at 3000 g for 15 min at 4oC, nedostatek contained in plasmamembrane fraction centrifuged at 72000 g for 30 min and the precipitate is washed with 75 mmol of Tris-buffer at pH of 7.4, containing 25 mmol MgCl2. Then the precipitate obtained from 10 g main fabric suspended in 1 ml of 75-Smolnogo Tris buffer at a pH of 7.4, containing 25 mmol MgCl2and 250 mmol of sucrose, and freeze 1 ml aliquots at 20oC.

To associate a method Assay (Assay) thawed frozen membrane fraction, and after 10 min centrifugation at 25000 g resuspended at 20oC Assay-buffer (50 m is Buena cattle). 100 μl of this membrane suspension containing 70 μg protein are incubated with 50 μl of125I-endothelin (specific activity 2200 CI/mmol in Assay-buffer (Assay) (25000 cpm, final concentration 20 pM) and 100 ml Assay-buffer containing varying concentrations of test compounds. Incubation carried out for 2 h at 20oC or for 24 h at 4oC. Separation of free or associated with a membrane, the radio is performed by filtration over glass fiber filter.

In table. 1 shows the inhibitory effect of compounds of the formula I, are considered in this experience, as the IC50that is , as the concentration (mmol) needed to inhibit 50% of specific links125I-endothelin(endothelin, labeled125I).

II: Inhibition of endothelin-induced contractions on isolated aortic rings of rats

From the thoracic aorta of adult rats Wistar-Kyoto carved rings with a length of 5 mm, the Endothelium was removed with a light rubbing of the inner surface. Each ring was immersed in an isolated bath at a temperature of 37oC in 10 ml Krebs-Henseleit when fumigation 95% O2and 5% CO2. Was measured the isometric tension of the ring. Rings were stretched to predvaritelnogo the ina-1. The activity of test compounds was determined by calculation of the ratio of the dose, i.e. a shift to the right, induced 100 mmol test connection (shift to higher values), EC50endothelin, and means necessary endothelin-concentration for half maximal contraction. The higher the dose, the test connection potentsialnye inhibits the biological activity of endothelin-1. EC50endothelin in the presence of the test compound is 0.3 mmol.

The value of the right shift EC50endothelin obtained by using compounds of formula I are presented in table. 2.

III: the Inhibitory effect of the compounds of formula I, vasoconstriction may occur in vivo in rats in the following experience:

Rats were shot by thiobutabarbital sodium 100 mg/kg i.p. (vnutriplevralno). Through the femoral artery catheter was introduced for measurement of systemic arterial blood pressure and through the femoral vein catheter was introduced into the vein Vena cava inferior to injection of the test compounds. The Doppler probe was superimposed around the left renal artery and was associated with measuring Doppler. After 45 min since the compression of the left renal artery at the place of exit was formed renal v.) doses of 10 mg/kg In control experiments renal blood flow compared with predications value reduced by 434%

Values of measurements 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 a tool for the treatment of diseases associated with processes that enhance vasospasm. Examples of such diseases are high blood pressure, coronary artery disease, cardiac insufficiency, renal and myocardial ischemia, renal failure, dialysis, cerebral ischemia, cerebral infarction, migraine, subarachnoid, gamarala, Raynaud's phenomenon (Raynaud) and high pulmonary pressure. They can also be applied in case of atherosclerosis, the elimination of recensione by vascular dilatation induced by Balloon, inflammation, gastric ulcer and duodenal ulcer, the ulcer (Ulcusruris), gram-negative sepsis, shock, inflammation of the renal glomeruli, renal colic, glaucoma, asthma, and for treatment and prevention of diabetic complications and complications during therapy with cyclosporine, as well as other diseases associated with the activity of endothelin is intramuscularly, subcutaneously, intracapsular, transdermal; or may be potasico or as ophthalmological preparations or in the form of an aerosol. Examples of applications can include capsules, tablets, used by mouth suspensions, or solutions, suppositories, injectable solutions, eye drops, ointments or solutions for spraying.

The preferred form is intravenous, intramuscular or oral administration. The dosage at which accept the compounds of formula I in effective amounts depend on the specific active ingredient, the age and needs of the patient, and the method of application. Mainly used dosage of about 0.1 to 100 mg/kg of body weight per day. Preparations containing the compounds of formula I can contain inert or pharmacodynamic supplements. Tablets or granules can contain binders, fillers, carriers, or diluents. Liquid preparations can be represented, for example, in the form of sterile, mixed with water solutions. Capsules may, in addition to the active substance, optionally contain a filler or thickener. In addition, there may be additives that improve taste and substances used in the AC is the critical pressure, buffers and other additives.

The above carriers and diluents may consist of organic or inorganic substances, for example, water, gelatin, lactose, starch, magnesium stearate, talc, gum Arabic, polyalkyleneglycols and similar substances. The whole premise is the fact that when getting drugs used excipients are non-toxic.

Example 1. The solution of the 0,046 g Na 1.5 ml of abs. ethylene glycol is stirred with 0,216 g of N-[6-(2-chloro-5-(p-chlorophenyl)-4-pyrimidinyl] , , -Cryptor - p-toluensulfonate in the absence of moisture and heated for 3 h to 100oC, then cooled to room temperature and mixed with 2.3 ml of 1N HCl. The mixture is dissolved in ethyl acetate, the organic extracts washed with water, dried and evaporated under reduced pressure. The remaining residue is recrystallized from CH2Cl2, isopropyl alcohol and n-hexane and receive N-[5-(p-chlorophenyl)-6- (2-hydroxyethoxy)-4-pyrimidinyl] a, , -Cryptor-p-toluensulfonate with a melting point of 160 162oC.

The source material was obtained as follows:

The solution of 1,052 g a, , -tripersonality potassium and 0,520 g of 4,6-dichloro-5-(p-chlorophenyl)pyrimidine (Chem. Absir. 63, 18078-HOoC (from acetonitrile).

Example 2. Analogously to example 1 from N-[6-chloro-5-(p-chlorophenyl)-4 - pyrimidinyl]-n-(triptoreline)benzosulfimide, etilenglikolya sodium was obtained N-[5-p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-n- (triptoreline) benzosulfimide with a melting point of 152oC (from isopropyl ether).

The original material was prepared from 4,6-dichloro-5- (p-chlorophenyl)pyrimidine and p-(triptoreline)benzosulfimide potassium, melting point 240 - 242oC.

Example 3. Analogously to example 1 from n-chloro-N-[6-chloro-5-(m-chlorophenyl)-4 - pyrimidinyl] benzosulfimide, etilenglikolya sodium was obtained p-chloro-N-[5-(m-chlorophenyl)-6-(2-hydroxyethoxy)-4 - pyrimidinyl] benzosulfimide with a melting point of 178 180oC (from acetone and isopropyl ether).

The original material was prepared as follows:

a) To a solution of 3.96 g of sodium and 100 ml of abs. methanol add 5,97 g of the acetate of formamidine. After cooling rest the pressure, the precipitate is dissolved in water and bring the solution using glacial acetic acid to pH 5.0. The precipitate is filtered under vacuum, washed with water, ethanol and ether and dried under reduced pressure at 70oC. Receive 5-(m-chlorophenyl)-4,6(1H, 5H)-pyrimidinedione, which is used directly in the next stage.

b) a Solution of 10.6 g of 5-(m-chlorophenyl)-4,6(1H.5H)-pyrimidinedione, 36 ml of POCL3and 5.8 ml of N,N-dimethylaniline boiled for 3 h at reflux. After evaporation of the solvent under reduced pressure the residue is mixed with ice and the mixture extracted with ether. The organic solvent is dried and evaporated under reduced pressure. The oily residue is dissolved in n-hexane and distilled 4,6-dichloro-5-(m-chlorophenyl)pyrimidine. Melting point equal to 93 94oC.

in) FROM 4,6-dichloro-5-(m-chlorophenyl)pyrimidine and p-chlorobenzenesulfonamide get potassium p-chloro-N-[6-chloro-5-(m-chlorophenyl)-4-pyrimidinyl]benzosulfimide with a melting point of 226 228oC (CH3CN).

Example 4. Analogously to example 1 from n-chloro-N-[5-(p-forfinal)-6-(2-hydroxyethoxy)-4 - pyrimidinyl] benzosulfimide with a melting point 208 212oC (CH3CN).

The source material of polyamidine receive 5-(p-forfinal)-4,6(1H,5H)-pyrimidinedione in the form of solids, which is used directly in the next stage.

b) Analogously to example 3, section b), from 5-(p-forfinal)-4,6(1H,5H)-pyrimidinedione and POCL3get 4,6-dichloro-5-(p-forfinal)pyrimidine with a melting point 98 99oC (from n-hexane).

C) Analogously to example 3, section b), from 4,6-dichloro-5-(p-forfinal)pyrimidine and p-chlorophenylsulfonyl get potassium p-chloro-N-[6-chloro-5-(p-forfinal)-4-pyrimidinyl]benzosulfimide with a melting point of 251 254oC (from isopropyl ether-methylene chloride).

Example 5. Analogously to example 1 from N-[6-chloro-5-(p-chlorophenyl)-4-pyrimidinyl] p-fermentatively, etilenglikolya sodium get N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl] -p-forbindelsesfaneblad with a melting point of 181 183oC (from isopropyl ether and methylene chloride).

The source material was obtained from 4,6-dichloro-5-(p-chlorophenyl)pyrimidine and p-torpedoshaped. Melting point 244 245oC (from isopropyl ether and methylene chloride).

Example 6. Analogously to example 1 from o-chloro-N-[6-chloro-5-(p-chlorophenyl)-4 - primidone] benzosulfimide, etilenglikolya sodium get on-chloro - N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl] benzolsulfonat which are square from 4,6-dichloro-5-(p-chlorophenyl)pyrimidine and o-chlorophenylsulfonyl. Melting point 230 234oC (CH3CN).

Example 7. Analogously to example 1 from N-[6-chloro-5-(p-ethylphenyl)-4-pirimidine]

p-cyclopentylpropionate, etilenglikolya sodium get p-cyclopentyl-N-[6-(2-hydroxyethoxy)-5-(p-ethylphenyl)-4 - pyrimidinyl] benzosulfimide with a melting point 145 146oC (from acetone and isopropyl ether).

The source material was obtained from 4,6-dichloro-5-(p-ethylphenyl)pyrimidine and p-cyclopentadecanolide; melting point 178 180oC (from acetonitrile and isopropyl ether).

Example 8. Analogously to example 1 from n-chloro-N-[6-chloro-5-(3,4-acid)-4-pyrimidinyl] benzosulfimide, etilenglikolya sodium get p-chloro-N-[5-(3,4-acid)-6--(2-hydroxyethyl)-4-pyrimidinyl]benzene - sulfonamide with a melting point 232 234oC (CH3CN).

The source material was obtained as follows:

analogously to example 3, section b), from 5-(3,4-acid) 4,6(1H, 5H)-pyrimidinedione and POCL3get 4,6-dichloro-5-(3,4-acid)pyrimidine with a melting point of 151 - 152oC (from ether cyclohexane) using p-chlorophenylsulfonyl get p-chloro - N-[6-chloro-5-(3,4-acid)-4-pyrimidinone 1 from 3,4-dichloro-N-[6-chloro-5-(p-chlorophenyl)pyrimidinyl]benzosulfimide, etilenglikolya sodium get 3,4-dichloro-N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl] benzosulfimide with a melting point 181oc (CH3CN and isopropyl ether).

Example 10. Analogously to example 1 from N-[6-chloro-5-(p-chlorophenyl)-4-pyrimidinyl] a, , , , , hexabromocyclododecane get N-(p-chlorophenyl)-6- (2-hydroxyethoxy)-4-pyrimidinyl] -, , , -, -hexaplar-3,5-killsometime with a melting point of 156 158oC (from methylene chloride/n-hexane).

The source material was obtained from 4,6-dichloro-5-(p-chlorophenylpiperazine and 2,4-bis-triftormetilfullerenov. Melting point 132 135oC (from isopropyl ether); the degree of purity of 92% (determined by liquid chromatography high pressure ghvd).

Example 11. Analogously to example 1 from 3-chloro-N-[6-chloro--5-(p-chlorophenyl)-4-pyrimidinyl]-4-forbindelsesfaneblad and excess of etilenglikolya sodium get 3-chloro-N-[5-(p-chlorophenyl)- 6-(2-hydroxyethoxy)-4-pyrimidinyl]-4-(2-hydroxyethoxy)benzosulfimide with a melting point 138 140oC (from acetone/isopropyl ether).

The source material was obtained from 4,6-dichloro-5-(p-chlorophenyl)pyrimidine and 3-chloro-4-torpedoshaped. Melting point 239oC (acetonitrile/methylene chloride).

Example 12. Analogously to example 1 from n-chloro-N - [6-chloro-5-(p-nitrophenyl)-4-pyrimidinyl] benzosulfimide and melting point 223 225oC (from isopropyl ether/methylene chloride).

The source material was obtained from 4-hldr-5-(p-nitrophenyl)pyrimidine and p-chlorpheniramine; melting point 282 285oC (CH3CN).

Example 13. Analogously to example 1 from n-butoxy-N-[6-chloro-(p-chlorophenyl)-4 - pyrimidinyl] benzosulfimide, etilenglikolya sodium get p-butoxy-N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl] benzosulfimide with a melting point >300oC (from isopropyl ether) and the degree of purity of 97.7% (ghvd).

The source material was obtained from 4,6-dichloro-5-(p-chlorophenyl)pyrimidine and 4-n-butoxybenzaldehyde. Melting point 234oC (CH3CN).

Example 14. Analogously to example 1 from N-6-chloro-[5-(p-chlorophenyl)-4-pyrimidinyl] -3,4-dimethoxybenzenesulfonamide, etilenglikolya sodium get N-[5-(p-chlorophenyl)-6-(2-hydroxyethyl)-4-pyrimidinyl] -3,4-dimethoxybenzene - sulfonamide with a melting point of 130 132oC (from isopropyl ether).

The source material was obtained from 4,6-dichloro-5-(p-chlorophenyl)pyrimidine and 3,4-dimethoxybenzenesulfonamide. Melting point 226oC (CH3CN).

Example 15. Analogously to example 1 from o-chloro-N-[6-5-(p-chlorophenyl)-4-pyrimidone)-4-pyrimido - Neil]-a, -Cryptor-p-toluensulfonate with a melting point 131oC (from isopropyl ether).

The source material was prepared from 4,6-dichloro-5-(p-chlorophenyl)pyrimidine and 2-chloro-a , -Cryptor-p-toluensulfonate; melting point 234oC (from acetonitrile and methylene chloride).

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

The source material was prepared from 4,6-dichloro-5-(n - chlorophenyl)pyrimidine and a,,,-Cryptor-3-methyl-6-chlorophenylsulfonyl; melting point 232oC (from isopropyl ether).

Example 17. Analogously to example 1 from 2,3,4-trichloro-N-[6-chloro-5-(p-chlorophenyl)-4-pyrimidinyl] benzosulfimide, etilenglikolya sodium get 2,3,4-trichloro-N-[6-chloro-5- (p-chlorophenyl)-4-pyrimidinyl]benzosulfimide, etilenglikolya sodium get 2,3,4-trichloro-N-[(5-chlorophenyl)-6-(2-hydroxyethoxy)- 4-pyrimidinyl] benzosulfimide with a melting point of 209 211oC (from isopropyl ether and methylene chloride).

Izhora melting 278 - 280oC (CH3CN).

Example 18. Analogously to example 1 from m-chloro-N-[6-chloro-5-(p-chlorophenyl)-4 - pyrimidinyl] benzosulfimide, etilenglikolya sodium get m-chloro-N-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl] benzosulfimide with a melting point of 179 181oC (from isopropyl ether and acetonitrile).

The source material was prepared from 4,6-dichloro-5-(p - chlorophenyl)pyrimidine and 3-chlorophenylsulfonyl; melting point 219 221oC (CH3CN).

Example 19. Analogously to example 1 from 2,4-dichloro-N-[6-chloro-5(p-chlorophenyl)-4 - pyrimidinyl] benzosulfimide, etilenglikolya sodium get 2,4 - dichloro-N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl] benzosulfimide with a melting point of 165 167oC (CH3CN).

The source material was prepared from 4,6-dichloro-5-(p - chlorophenyl)pyrimidine and 2,4-dichlorophenylisocyanate; melting point 252 254oC (CH3CN).

Example 20. Analogously to example 1 from N-[6-chloro-5-(p-chlorophenyl)-4 - pyrimidinyl] -a,-Cryptor-m-toluensulfonate, etilenglikolya sodium get N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl] -a,- Cryptor-m-toluensulfonate with a melting point 148 150oC (from isopropy the-m-toluensulfonate; melting point 197 198oC.

Example 21. Analogously to example 1 from N-6-chloro-5-(p-chlorophenyl)-a-Cryptor - o-toluensulfonate, etilenglikolya sodium get N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl] -a,-Cryptor - o-toluensulfonate with a melting point 182 184,198>C (CH3CN and isopropyl ether).

The source material was prepared from 4,6-dichloro-5-(p - chlorophenyl)pyrimidine and a,,-Cryptor-o-toluensulfonate; melting point 191 193oC (CH3CN).

Example 22. Analogously to example 1 from N-[6-chloro-5-(p-ethylphenyl)-4-pyrimidinyl] -p-isopropylbenzenesulfonyl, etilenglikolya sodium get N-[6-(2-hydroxyethoxy)-5-(p-ethylphenyl)-4-pyrimidinyl] -n - isopropyl]benzosulfimide with a melting point 137 138oC (from acetonitrile and isopropyl ether).

The source material was obtained as follows:

Of diethyl-(p-ethylphenyl)malonate and acetate of formamidine receive 5-(n-ethyl)-4,6(1H, 5H)-pyrimidinedione with a melting point >270oC, and then from it, using POCl3get 4,6-dichloro-5-(p-ethylphenyl)pyrimidine with a melting point 48-49oC (from n-hexane).

The interaction of this compound with p-isopropylbenzenesulfonyl the second melting point 187-188oC (from acetonitrile and isopropyl ether).

Example 23. Analogously to example 1 from N-[6-chloro-5-(p-chlorophenyl)-4-pyrimidinyl] -2-naphthalenesulfonate, etilenglikolya sodium get N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl] -2-naphthalenesulfonate with a melting point 196-198oC (CH3CN and isopropyl ether).

The source material was prepared from 4,6-dichloro-5-(p-chlorophenyl)pyrimidine and 2-naphthalenesulfonate; melting point 265-269oC (CH3CN).

Example 24. Analogously to example 1 from n-chloro-N-[6-chloro-5-(m-nitrophenyl)-4-pyrimidinyl] benzosulfimide, etilenglikolya sodium get p-chloro-N-[6-(2-hydroxyethoxy)-5-(m-nitrophenyl)-4-pyrimidinyl] benzosulfimide with a melting point of 186-187oC (CH3CN and isopropyl ether).

The source material is prepared from 466-dichloro-5-(m-nitrophenyl)-4-pyrimidinyl and p-chlorophenylsulfonyl; melting point 261-263oC (CH3CN).

Example 25. Analogously to example 1 from N-[6-chloro-5-(m-nitrophenyl)-4-pyrimidinyl] -a,-Cryptor-p-toluensulfonate and ethylglycol sodium get an a,,, trifter-N-[6-(2-hydroxyethoxy)-5-(m-nitrophenyl)-4-pyrimidinyl]-p-toluensulfonate with the temperature of the 4,6-dichloro-5-(m-nitrophenyl)-pyrimidine and a,,-Cryptor-p-toluensulfonate; melting point 246-250oC (CH3CN).

Example 26. Analogously to example 1 from n-(benzyloxy)-N-[6-chloro-5-(p-chlorophenyl)-4-pyrimidinyl] benzosulfimide, etilenglikolya sodium get p(benzoyloxy)-N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl] benzosulfimide with a melting point 162-163oC (from acetone and isopropyl ether).

The source material was prepared from 4,6-dichloro-5-(p-chlorophenyl)pyrimidine and p-(benzyloxy)benzosulfimide; melting point 233-236oC (from acetone and ether acetic acid).

Example 27. A solution of 512 mg of p-(benzyloxy)-N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl] benzosulfimide 30 ml of glacial acetic acid is mixed with 2 ml of 4n HCl in dioxane ISO 100 mg of 10% palladium on coal. The mixture hydronaut under stirring, then the solution is filtered under vacuum, reduced pressure, evaporated and the residue is recrystallized from isopropyl ether and again from CH3CN. Receive N-[5-(p-chlorophenyl)-4-pyrimidinyl]-p-hydroxybenzenesulfonate with a melting point 231-232oC.

Example 28. Analogously to example 1 from N-[6-chloro-5-(p-chlorophenyl)-4-pyrimidinyl] -n-(2-methoxy)benzosulfimide, etilenglikolya sodium is Oh melting point 151-152oC (CH3CN and isopropyl ether).

The source material was prepared from 4,6-dichloro-5-(p-chlorophenyl)pyrimidine and p-(2-methoxyethoxy)benzosulfimide; melting point 212-215oC (CH3CN).

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

The source material was obtained as follows:

Analogously to example 3, section a) of diethyl-p-bromophenylacetate and acetate of formamidine received 5-(p-bromophenyl)-4,6(1H,5H)-pyrimidinedione with a melting point >270oC. After drying under reduced pressure at 80oC through the night the connection was submitted to the next stage.

Analogously to example 3, section b), from 5-(p-bromophenyl)-4,6(1H,5H)-pyrimidinedione and POCl3received 5-(p-bromophenyl)-4,6-dichloropyrimidine with a melting point 99-100oC (from hexane) and from it, using the p-chlorophenylsulfonyl was obtained N-[5-(p-bromophenyl)-6-chloro-4-pyrimidinyl]-p-chlorobenzenesulfonamide with a melting point 266-268oC (CH3CN).

the sodium was obtained p-chloro-N-[6-(2-hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl] benzosulfimide with a melting point of 162 to 165 of theoC (from acetone and isopropyl ether).

The original product was obtained as follows:

Analogously to example 3, section a) of diethyl-p-tolylacetate and acetate of formamidine get 5-p-tolyl-4,6(1H,5H)-pyrimidinedione with a melting point >270oC. After drying under reduced pressure at 80oC substance was supplied to the next stage.

Analogously to example 3, section b), from 5-p-tolyl-4,6(1H,5H)-pyrimidinedione and POCl3was obtained 4,6-dichloro-5-p-tolylboronic with a melting point 81-82oC (from hexane) and from it, using the p-chlorophenylsulfonyl was obtained p-chloro-N-(6-chloro-5-p-tolyl-4-pyrimidinyl)benzosulfimide with a melting point 229-230oC (from acetonitrile).

Example 31. A solution of 237 mg of N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-a-triptoreline in 5 ml of methanol was mixed with 27.0 mg of sodium methylate and then with 5 ml of isopropyl ether. White precipitate was filtered under vacuum and dried under reduced pressure at 50oC. was Obtained N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-a-Cryptor-p - toluensulfonate Na-salt in the form of a white solid.

Example 32. 60 mg of sodium made in 2 mm ethylene glycol at 70oC. Then doba is camping within 4.5 hours up to 150oC. the ethylene Glycol was subjected to distillation under reduced pressure, the residue was dissolved in EtOAc/H2O and was extracted once with ethyl acetate. Next, the aqueous phase was acidified using 1N HCl and was extracted 4 times with ethyl acetate. The organic phase was dried, filtered, and concentrated under reduced pressure. The precipitate was chromatographically over 50 grams of SiO2using methylene chloride/ether acetic acid (1: 1). Received 50 mg of N-[5-(2,6-dimethoxybenzyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl] -p - vinylbenzenesulfonic with a melting point 138-139oC.

The original material was prepared as follows:

a) a Mixture of 1.52 ml diethyl ester of malonic acid, 1.66 g of 2,6-dimethoxybenzaldehyde, 0.1 ml of piperidine of 0.11 ml of glacial acetic acid and 100 ml of toluene was heated at 110oC separator for 3.5 hours. The solution was extracted with 10% solution of NaHCO3and then washed with saturated solution of NaCl. The organic phase was dried, filtered under vacuum and evaporated under reduced pressure. Got 2.8 g of diethyl-(2,6-dimethoxybenzamide)malonate in the form of a dark yellow oil.

b) a Mixture of 2.8 g diethyl-(2,6-dimethoxybenzamide)malonate, 0.6 g of coal on palladium, 50 ml of methanol and 50 ml ladenosama was dissolved in ethyl acetate and was extracted with 20% solution of NaHCO3and a small amount of ice. Then the mixture was subjected to extraction with 1N HCl, then washed with a saturated solution of HCl, the organic phase was dried and evaporated under reduced pressure. The crude product was subjected to distillation in a high vacuum at 170oC/0.6 mbar. Received 2.1 g diethyl-(2,6-dimethoxybenzyl)malonate.

C) To 0.14 g of sodium in 15 ml of ethanol is added to 0.23 g of the acetate of formamidine in 15 ml of ethanol. The reaction mixture was stirred for 30 min at 25oC and mixed dropwise with 0.62 g of diethyl-(2,6-dimethoxybenzyl)malonate in 10 ml of ethanol. After 2 days of starting material were not readily available. The precipitate is filtered under vacuum, dissolved in a small amount of water and acidified with 1N HCl. The precipitated crystals are filtered under vacuum and dried in high vacuum at 90oC. Get 0,175 g of 5-(2,6-dimethoxybenzyl)-4,6-pyrimidinedione with a melting point >245oC.

g) a Mixture of 1.04 g of 5-(2,6-dimethoxybenzyl)-4,6-pyrimidinedione and 12 ml of phosphorus oxychloride was heated at 85oC under reflux for 3 hours the Reaction solution was poured into ice and extracted twice with methylene chloride. The organic phase was washed with a saturated solution of HCl, dried, filtered and concentrer-5-(2,6-dimethoxybenzyl)pyrimidine with a melting point 152-153oC.

d) a Mixture of 80 mg of 4,6-dichloro-5-(2,6-dimethoxybenzyl)pyrimidine and 170 mg of montalieu salt of n-vinylbenzenesulfonic(J. Am. Chem. Soc. 1956, 78, 2169), corresponding sulfonamida with tetrabutyltin potassium in the abs. MeOH and 10 ml of dimethylformamide is heated to 100oC for 6 hours Then left overnight to cool to 25oC. was Added to the reaction solution with stirring, 30 ml of 0.5 n HCl. Precipitated 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-vinylbenzenesulfonic with a melting point 197-198oC.

Example 33. To 10 ml of ethylene glycol (distilleria in fresh condition over Na) is added by portions with the exception of water 29 mg of sodium. Then add 123 mg of N-[6-chloro-(o-trifluoromethyl)-benzyl-4-pyrimidinyl]-a,--trifter-p - toluensulfonate and heat the mixture to 150oC for 3 hours. The excess glycol is evaporated under reduced pressure; the residue is dissolved in water and washed with ethyl acetate. The aqueous phase is extracted with 1N hydrochloric acid to pH 3.0 and extracted with ethyl acetate. The organic phase is washed with water and saturated common salt solution, dried and evaporated under reduced pressure is hydroxyethoxy)-6-[(o-trifluoromethyl)benzyl] pyrimidinyl] -p-toluensulfonate in the form of a white foam. MS (mass spectrum): 521 (M); 456 (M-SO2+H).

The source material is prepared as follows:

a) To a solution of 14 g of o-triftormetilfosfinov alcohol in 80 ml of abs. toluene is added dropwise at a temperature of from 20 to 30oC a solution of 30 ml of phosphoribosyl in 60 ml of abs. of toluene. Then the reaction mixture is stirred for 2 hours at room temperature distilled off toluene under reduced pressure, dissolve the residue in methylene chloride, mixed with water and set the pH to 8.0 with potassium bicarbonate. The aqueous phase is extracted three times with CH2Cl2and the organic phase is washed twice with water and once with saturated NaCl solution, dried over Na2SO4and evaporated under reduced pressure. Get o-triftormetilfosfinov in the form of sediment.

b) 40 ml of diethyl ester of malonic acid in 350 ml of ethanol is mixed in portions at room temperature with 12 g of o-triftormetilfosfinov. The reaction mixture during the night stirred at room temperature, distilled alcohol under reduced pressure and dissolve the residue in ethyl acetate. The solution is washed twice with water and once with NaCl solution, dried under reduced pressure and evaporated. Sludge chromatographica in the form of a colorless oil.

in) 0,63 g of the acetate of formamidine in 40 ml of abs. ethyl alcohol is mixed with 1.2 g of ateleta sodium, stirred for 30 min at room temperature and then added dropwise at room temperature is mixed with a solution of 1.6 g of diethyl-[o-(tinformation)benzene] malonate in 8 ml of abs. ethyl alcohol. After stirred for 4 hours at 50oC the reaction mixture is processed and receive 5-[o-(tinformation)benzyl] -4,6(1H,5H)pyrimidinedione with a melting point > 290oC.

g) From 5-[o-(trifluoromethyl)benzyl]-4,6(1H,5H)pyrimidinedione and phosphorus oxychloride get 5-[o-(trifluoromethyl)benzyl] 4,6-dichloropyrimidine with a melting point 60-63oC.

d) 295 mg of 4,6-dichloro-5-[o-(trifluoromethyl)benzyl]pyrimidine in 10 ml swietojanska of dimethyl sulfoxide is mixed with 342 mg of montalieu salt, trifter-p-toluensulfonate (obtained from the corresponding sulfonamida with CON and abs. ethanol) and stirred for 5 hours at 150oC. After the final interaction between the solvent is distilled off under reduced pressure, dissolve the residue in ethyl acetate and washed with a solution of 10% solution of potassium bicarbonate, 0.5 n HCI and reduced pressure. Sediment chromatorgraphy the ethyl acetate over 30 g of SIO2is received. MS: 495(M), 431 (SO2), 430 (SO2+H), 362(-CF3+SO2).

Example 34. Analogously to example 33 N-[6-chloro-5-[o-(trifluoromethyl)benzyl] -4-pyrimidinyl] -p-methoxybenzenesulfonamide, etilenglikolya sodium get N-[6-(2-hydroxyethoxy)-5-[o-(trifluoromethyl)benzyl]-4-pyrimidinyl] -p-methoxybenzenesulfonamide with a melting point 100-107oC.

The source material was obtained as follows:

Analogously to example 33, section d), from 4,6-dichloro-5-[o-(trifluoromethyl)benzyl] pyrimidine and sodium salt of p-methoxybenzenesulfonamide receive N-[6-chloro-5-(trifluoromethyl)benzyl]-4-pyrimidinyl]-p - methoxybenzenesulfonamide in the form of a white foam with a melting point 68-70oC.

Example 35. Analogously to example 33, from p-chloro-N-[6-chloro-5-[o-(trifluoromethyl)benzyl] -4-pyrimidinyl] benzosulfimide, etilenglikolya sodium get p-chloro-N-[6-(2-hydroxyethoxy)-5-[o-(trifluoromethyl)benzyl] -4-pyrimidinyl] benzosulfimide with a melting point 134-135oC.

Starting material is prepared analogously to example 66, section d), from 4,6-dichlo-5-[o-(trifluoromethyl)benzyl] pyrimidine and sodium salt of p-chlorobenzenesulfonamide; melting point > 210oC (decomposition).

Example 36. Similarly, ucaut N-[6-(2-hydroxyethoxy)-5-(o-methoxybenzyl)-4-pyrimidinyl] - n-vinylbenzenesulfonic with a melting point 93-102oC.

Starting material is prepared analogously to example 33, section d) of 4,6-dichloro-5-(o-methoxybenzyl)pyrimidine and the potassium salt of n-vinylbenzenesulfonic; melting point 125-129oC.

Example 37. Analogously to example 33 N-[6-chloro-5-[o-(trifluoromethyl)benzyl] -4-pyrimidinyl] -p-(methylthio)benzosulfimide and ethylene glycol sodium was obtained N-[6-(2-hydroxyethoxy)-5-[o-(trifluoromethyl)benzyl]-4-pyrimidinyl]-p-(methylthio)benzosulfimide in the form of a yellow resin.

Starting material is prepared analogously to example 33, section d), from 4,6-dichloro-5-[o-(trifluoromethyl)]benzylpyrimidines and p-(methylthio)benzosulfimide: IR 3433 cm-1(NH); 1313 (SO2); 1137 and 1094 (F3C).

Example 38. Analogously to example 32 N-[6-chloro-5-(2,4-dimethoxybenzyl)-4-pyrimidinyl]-p-isopropylbenzenesulfonyl, ethylene glycol and sodium was obtained N-[5-(2,4-dimethoxybenzyl)-6-(3-hydroxypropyl)-4-pyrimidinyl] -p-isopropylbenzenesulfonyl with a melting point 97oC.

The original material is prepared as follows:

Analogously to example 32, section a), from 2,4-dimethoxybenzaldehyde, diethyl ester of malonic acid, ice uimenu 32, section b) received diethyl-(2,4-dimethoxybenzyl)malonate in the form of a clear oil; boiling point 160oC/0.4 mbar.

Analogously to example 32, section b) of diethyl-(2,4-dimethoxybenzyl)malonate, acetate of formamidine and sodium salt of the standard was obtained 5-(2.4-dimethoxybenzyl)-4,6-pyrimidinyl and out analogously to example 32, section g), was obtained 4,6-dichloro-5-(2,4 - dimethoxybenzyl)pyrimidine with a melting point 130-131oC.

Analogously to example 32, section d) finally, from 4,6-dichloro-5-(2,4 - dimethoxybenzyl)pyrimidine, p-isopropylbenzenesulfonyl potassium (from the corresponding sulfonamida with tert.-the butyl potassium in the abs. MeOH and DMSO was obtained N-[6-chloro-5-(2,4-dimethoxybenzyl)-4-pyrimidinyl]-p-isopropylbenzenesulfonyl with a melting point 132-134oC.

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

After boiling under reflux during the night were stripped of solvent under reduced pressure, and the residue was subjected to chromatography with a mixture of methylene chloride-ethyl acetate (9:1) -vinylbenzenesulfonic in the form of a white resin; MS: 460 (M-SO2+H); 430 (M-SO2+OCH3).

Example 40. To a mixture of 1.5 ml of water and 4 ml of dioxin were added sequentially at room temperature 318 mg rat-N-[5-(o-methoxybenzyl)-6 -[2-[(tetrahydro-2H-Piran-2-yl]oxy]ethoxy]-4-pyrimidinyl]-p-vinylbenzenesulfonic, 5.3 mg of osmium tetroxide and 270 mg of metaperiodate sodium. After 1 h stirring at room temperature drove the dioxane under reduced pressure, and then the aqueous phase three times were extracted with ethyl acetate, washed with ethyl acetate twice with water and once with saturated) solution of NaC1, dried and put away under reduced pressure.

The precipitate was chromatographically over 30 g of SiO2CH2C1/ethyl acetate, received 150 mg rat-n-[[5-(o-methoxybenzyl)-6-[2-[(tetrahydro-2H-Piran-2-yl)oxy]-4-pyrimidinyl] sulfamoyl] benzaldehyde as a white foam. MS: 527 (M); 443, 432 (-OCH3+SO2).

Example 41. To a solution of Grigera 60 mg of magnesium and 0.15 ml under the conditions in diethyl ether is added at room temperature to 170 mg rat-n-[[5-(o-methoxybenzyl)-6-[2-[tetrahydro-2H-Piran-2-yl] oxy]ethoxy]-4-pyrimidinyl] sulfamoyl]benzaldehyde, and after 30 min, 1 ml of abs. tetrahydrofuran (THF). After 3 h stirring at room temperature the reaction is terminated by adding nasusunog the shape with ethyl acetate. The organic phase is washed with water and saturated NaC1 solution, dried and evaporated under reduced pressure. Sediment chromatographic over 35 g of SiO2with the help of CH2C12/ethyl acetate (8:2) and (1:1) and obtain 135 mg of p-[(RS)-1-hydroxyethyl] -N-[5-(methoxybenzyl)-6 -[[2-[[(RS)-tetrahydro-2H-Piran-2-yl]oxy]ethoxy]-4-pyrimidinyl] benzosulfimide with a melting point >56oC (sublimation).

Example 42. 53 mg rat-n-[[5-(o-methoxybenzyl)-6-[2-[(tetrahydro-2H-Piran-2-yl] oxy] ethoxy]-4-pyrimidinyl]sulfamoyl]benzaldehyde was dissolved in 3 ml of methanol and mixed with 37 borhydride sodium at room temperature. After 1 hour stirring at room temperature drove the methanol under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and NaC1 solution (saturated), dried and put away under reduced pressure. Received 42 mg rat-a-hydroxy-N-[5-(o-methoxybenzyl)-6-12-[(tetrahydro-2H-Pirin-2-yl) oxy]ethoxy]-4-pyrimidinyl]-n-toluolsulfonic in the form of a colorless oil. MC% 529 (M); 445 (tetrahydro-2H-Piran-2-yl); 434 (-OCH3+SO2).

Example 43. 534 mg rat-n-[[5-(o-methoxybenzyl)-6-[2-[(tetrahydro-2H-Piran-2-yl)oxy] ethoxy] - 4-pyrimidinyl]sulfamoyl]benzaldehyde was dissolved in 3 ml of ethanol and dare powder). After 3 h stirring at room temperature drove the ethanol under reduced pressure, the residue was dissolved in ethyl acetate and washed with water and (saturated) solution of NaCl. The organic phase is dried and evaporated under reduced pressure, and get rat-a-[(>E/Z)-hydroxyimino-N-[5-(o-methoxybenzyl)-6-[2-[tetrahydro-2H-Piran - 2-yl)oxy]ethoxy]-4-pyrimidinyl]-n-toluensulfonate. Melting point 49-52oC.

Example 44. A solution of 60 mg of n-[(RS)-1-hydroxyethyl]-M-5[-(o-methoxybenzyl)-6-[2-[[(RS)-tetrahydro-2H-Piran - 2-yl] oxy] ethoxy] -4-pyrimidine-Neil] benzosulfimide in 3 ml of tetrahydrofuran is mixed with two drops of 3n HCl. After 4 hours stirring at room temperature the reaction mixture is evaporated under reduced pressure. The remainder chromatographic using methylene chloride/ethyl acetate (1:1) and ethyl acetate on silica gel. Get rat-N-6-(2-hydroxyethoxy)-5-(o-methoxybenzyl)-n-(1-hydroxyethyl) benzosulfimide in the form of a white resin. MS: 459 (M); 394 (SO2/H); 364 (SO2M/OCH3).

Example 45. Analogously to example 44 and rat-a-[(E/Z)-hydroxyimino]-N-[5-(o-methoxybenzyl)-6-[2-[(tetrahydro-2H-Piran - 2-yl)oxy] -4-pyrimidinyl]-n-toluensulfonate received a-[(E/Z)-hydroxyimino]-N-{6-(2-hydroxyethoxy)-5-(o-methoxybenzyl)- 4-Piri is 46. Analogously to example 44 from rat-a-hydroxy-N-[5-(o-methoxybenzyl)-6-[2-[(tetrahydro-2H-Piran-2-yl)oxy] ethoxy] -4-pyrimidinyl]-n-toluensulfonate get a-hydroxy-N-[6-(2-hydroxyethoxy)-5-(o-methoxybenzyl)-4-pyrimidinyl] -p - toluensulfonate in the form of a light brown resin. MS: 445 (M); 380 (SO2/H); 274.

Example 47. Analogously to example 44 from rat-n-[[5-[(o-methoxybenzyl)-6-[2-[tetrahydro-2H-Piran-2-yl)oxy]ethoxy]- 4-pyrimidinyl]sulfamoylbenzoic receive n-[[(2-hydroxyethoxy)-5-(o-methoxybenzyl)-4-pyrimidinyl]sulfamoyl] benzaldehyde as a white resin. MS: 443 (M); 348 (SO2/OCH3); 274.

Example 48. 208 mg of N-[6-(2-hydroxyethoxy)-5-(o-methoxybenzyl)-4-pyrimidinyl] -p - vinylbenzenesulfonic was dissolved in 4 ml of abs. tetrahydrofuran (THF) was mixed with 0.06 ml of pyridine and 0.07 ml of acetic anhydride was heated for 3 h at reflux. After removal of the solvent under reduced pressure the residue was dissolved in ethyl acetate and washed with a solution of water and common salt solution, dried and evaporated. After chromatography of the residue over kieselgel with methylene chloride and methylene chloride/ethyl acetate (19:1 and 9:1) was obtained 2-[[5-(o-methoxybenzyl)-6-[n-vinylphenol)sulfamoyl]-4-pyrimidinyl] oxy] acetate as a white resin.

oC (from acetone and isopropyl ether).

The source material was prepared from 4,6-dichloro-5-a,,-Cryptor-p-tolylenediamine and n-isopropylbenzenesulfonyl; melting point 266-269oC (from acetonitrile).

Example 50. Sodium glycolate, sodium 46 mg of sodium in 1 ml of ethylene glycol added 190 mg of N-[6-chloro-5-(n-methoxyphenyl)-4-pyrimidinyl]-n-toluensulfonate. After 5 h the reaction mixture was evaporated to dryness at 100oC under reduced pressure, the residue is distributed between ethyl acetate and 1N hydrochloric acid, the organic phase is washed until neutral, dried and evaporated under reduced pressure. The remainder chromatographic with methylene chloride and ethyl acetate (4:1 V/V) on kieselgel. Obtain 175 mg of n-[6-(2-hydroxyethoxy)-5-(n-methoxyphenyl)-4-pyrimidinyl] -p - toluensulfonate with a melting point 147-149oC (from methylene chloride/hexane).

The source material was obtained as follows:

To a solution of 41,55 g n-methoxyphenylacetic acid in 150 ml of abs. ethanol, add 150 ml of ethyl ether of ortho-formic acid and 1 g methanesulfonic acid. The mixture is heated for 20 h to 85oC. ethyl formate Formed continuously distilled off from the reaction mixture. Then the reaction to shift the Gain of 46.7 g of ethyl ester (p-methoxy)phenylacetic acid as a colourless liquid; boiling point 84oC/0.025 mm RT.article.

To and 19.4 g of a previously received broadcast add 7.5 g of ateleta sodium and 120 ml of diethylmalonate. The resulting slurry is thoroughly mixed with 230oC, and the resulting ethanol is distilled off from the mixture. The mixture is then cooled to room temperature and the reaction mixture is poured on ice water and hydrochloric acid (10% excess). After extraction with ethyl acetate and processing of the extract product is purified by distillation. Get 25 g of diethyl ether (n-methoxy)phenylmalonate acid; boiling point 115oC/0.05 mm RT.article.

10,9 g ethylate sodium are suspended in 125 ml of dried ethanol, here is under ice cooling add 4.83 g of the hydrochloride of formamidine and 13.3 g of malonic ester, obtained according to the above paragraph. The reaction mixture while removing water is stirred for 3 h at room temperature, then evaporated the solvent, dissolve the residue in 100 ml of water, washed with toluene, the aqueous phase is acidified. Get 8 g of 5-(p-methoxy)phenyl-6-hydroxy-4(3H)-pyrimidinone with a melting point >250oC.

1 g of pyrimidinone described in the parent paragraph, suspended in 5 ml of phosphoroxychloride. The suspension is stirred at udaleniya in methylene chloride, then shaken with an aqueous solution of potassium bicarbonate until then, until you stop the secretion of carbonic acid. After evaporation of the solvent is filtered with methylene chloride over kieselgel. Obtain 0.7 g of 4,6-dichloro-5-(n-methoxyphenyl) pyrimidine with a melting point 95-96oC.

To boiling ethanolic solution of potassium hydroxide (2 g 80% potassium hydroxide in 50 ml of abs. ethanol) is added to 5,15 g dissolved in ethanol p-toluensulfonate. Then add 50 ml of abs. benzene and most of the solvent mixture is distilled off at normal pressure. Obtain 4.6 g of n-toluensulfonate potassium.

510 g of dichloropyrimidine named in the above paragraph, and 840 mg of n-toluensulfonate potassium dissolved in 3 ml of dry dimethylformamide. The solution is maintained at 120oC for 3 h, then distilled dimethylformamide and the residue distributed between ethyl acetate and 1N hydrochloric acid, the organic phase is washed until neutral and evaporated. After adding methanol obtain 540 mg of N-[6-chloro-5-(p-methoxyphenyl)-4-pyrimidinyl]-p-toluensulfonate with a melting point 210-212oC.

Example 51. Analogously to example 50 from 400 mg of N-[6-chloro-5-(p-methoxyphenyl)-4-pyrimidinyl] -p-methoxybenzoyl; melting point 132-134oC.

The source material is prepared as follows:

To a solution of 7.3 g of n-methoxybenzenesulfonamide in 50 ml tetrahydrofurane added dropwise 25 ml of 25% aqueous NH4OH while cooling in an ice bath. Then the reaction mixture is thoroughly stirred for 30 min at 70oC (bath temperature), then distilled tetrahydrofuran.

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

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

Example 52. Analogously to example 50 N-[6-chloro-5-(p-methoxyphenyl)-4-pyrimidinyl] -p-(methylthio) benzosulfimide receive N-[6-(2-hydroxyethoxy)-5-(p-methoxyphenyl)-4-pyrimidinyl] -p-(methylthio) benzosulfimide with a melting point 171-172oC.

The source material was obtained analogously to example 50 and 4,6-dichloro-5-(p-methoxy)phenylpyrimidine and (t-metalis N-[6-chloro-5-(p-methoxyphenyl)-2-methyl-4-pyrimidinyl] -p - methoxybenzenesulfonamide receive N-[6-(2-hydroxyethoxy)-5-(p-methoxyphenyl)-2-methyl-4-pyrimidinyl]-p - methoxybenzenesulfonamide with a melting point 138-139oC.

The source material was obtained as follows:

To a solution of 5.6 g of sodium methylate in 75 ml of abs. ethanol added to 2.94 g of the hydrochloride of acetamidine and 6.9 g of diethyl ether n-methoxyphenylalanine acid. The reaction mixture is stirred for 3 hours while removing water at room temperature and for 1.5 h at 50oC. and Then distilled ethanol, the residue is dissolved in water and the suspension is acidified with 5N hydrochloric acid. The solid is filtered off and washed with water until until the washing solution reaches a pH of 4.5 to 5.7. Thus obtained product interacts with phosphorus oxychloride and obtain 2.8 g of 4,6-dichloro-2-methyl-(p-methoxy)phenylpyrimidine with a melting point 114-116oC. In the interaction of this compound with p-methoxybenzenesulfonamide get potassium N-[6-chloro-5-(p-methoxyphenyl)-2-methyl-4-pyrimidinyl]-p - methoxybenzenesulfonamide with a melting point 152-154oC.

Example 54. Analogously to example 50 from 615 mg of N-[6-chloro-5-(p-methoxyphenyl)-4-pyrimidinyl] -p - isopropylbenzenesulfonyl obtain 350 mg of N-[6-(2-hydroxyethoxy)-5-(p-methoxyphenyl)-4-pyrimidinyl]-p - isopropylbenzenesulfonyl with a melting point 128-129oC.

To translate the lat sodium, the solvent is distilled off and add diisopropyl ether.

The source material is prepared as follows:

p-Isopropylbenzenesulfonyl with a boiling point 105oC/0.25 mm RT. senior derived from cumene and transferred to the corresponding sulfonamide; melting point 104-105oC. When interacting 765 mg of 4,6-dichloro-5-(p-methoxyphenyl)pyrimidine from 1925 mg p-isopropylbenzenesulfonyl potassium obtain 720 mg of N-[6-chloro-5-(p-methoxyphenyl)-4-pyrimidinyl]-p - isopropylbenzenesulfonyl with a melting point 181-182oC.

Example 55. Analogously to example 50 from 700 mg of p-tert.-butyl-N-[6-chloro-5-(p-methoxyphenyl)-4-pyrimidinyl] benzosulfimide receive 600 mg of p-tert. -butyl-N-[6-(2-hydroxyethoxy)-5-(p-methoxyphenyl)-4-pyrimidinyl] benzosulfimide with a melting point 165-166oC.

The source material was obtained from p-tert.-butylbenzenesulfonamide potassium and 4,6-dichloro-5-(p-methoxyphenyl)pyrimidine. Melting point is 204-205oC.

Example 56. Analogously to example 50 from 216 mg rat-u-Deut.-butyl-N-[6-chloro-5-(p-methoxyphenyl)-4-pyrimidinyl] benzosulfimide obtain 185 mg of rat-u-Deut. -butyl-N-[6-(2-hydroxyethoxy)-5-(p-methoxyphenyl)-4-pyrimidinyl] benzosulfimide with sulfonamida and potassium 2,6-dichloro-5-(p-methoxyphenyl) pyrimidine; melting point is 172-173oC.

Example 57. Analogously to example 50 from 280 mg of N-[6-chloro-5-[(p-methylthio)phenyl] -4-pyrimidinyl] -p - isopropylbenzenesulfonyl obtain 240 mg of N-[6-(2-hydroxyethoxy)-5-[p-(methylthio)phenyl] -4-pyrimidinyl] -p - isopropylbenzenesulfonyl with a melting point 135-136oC (from diisopropyl ether).

The source material was obtained as follows:

15.2 g (p-methylthio)benzaldehyde was dissolved in 50 ml of isopropanol. To this solution was added dropwise while cooling in an ice bath to 1.31 g of sodium borohydride in 150 ml of isopropanol in half an hour. After 1 h stirring at room temperature, add 5 ml of acetone, after which the solvent is distilled off. The residue is distributed between methylene chloride and water. After processing gain (p-methylthio)benzyl alcohol with a melting point 40-41oC (from isopropanol).

Dissolve 7,71 g (p-methylthio)benzilovogo alcohol in 25 ml dry methylene chloride. To this solution is added within 30 min to 4 ml of SOCl2while cooling in an ice bath. After removal of the solvent and excess reagent sucked off the methylene chloride over kieselgel. After distillation obtain 4.3 g (p-methylthio)benzylchloride of dimethylformamide add 9 g of benzylchloride, obtained as described in the previous paragraph. The reaction mixture was stirred at removing moisture for 1 h at 90oC. then distilled dimethylformamide and the residue partitioned between toluene and water. Treatment of the organic phase gives (p-methylthio)benzylcyanide with a melting point 28-30oC.

In 30 ml etilenglikola dissolve 12 g (p-methylthio)benzylcyanide and mixed with 9 g of NaOH (30% solution). The reaction mixture was stirred at 140oC 3 h After cooling to room temperature the mixture was acidified with 25% hydrochloric acid, dissolve the residue in ethyl acetate and shaken out with water. Get 11.5g (p-methylthio)phenylacetic acid with a melting point of 94-96oC.

11 g of the acid obtained as described above, dissolved in 50 ml of abs. ethanol and 25 ml of ethyl orthomorphisms acid and 1 g methanesulfonic acid. Formate formed during the reaction is continuously distilled off. After 4 h the completion of the reaction. The acidic catalyst is neutralized stoichiometric quantity of ateleta sodium, the solvent is distilled off, the residue is dissolved in methylene chloride and filtered over kieselgel. Get 12 grams ethyl ester (p-methylthio)phenylacetic acid with tempera 50, transferred to diethyl ether (p-methylthio)phenylmalonate acid. Boiling point 120oC/0.05 mm RT.article.

From the above diethyl ester of malonic acid get similar to the method described in example 50, 5-(p-methylthio)-phenyl-6-hydroxy-4(3H)-pyrimidinone.

Above pyrimidine transferred by means of sodium methylate in dialkoxybenzene, from which, by interaction with phosphoroxychloride get 4,6-dichloro-5-(p-methylthio)phenylpyrimidine.

From the above 4,6-dichloroaniline by interacting with p-isopropylbenzenesulfonyl get potassium N-[6-chloro-5-[p-(methylthio)phenyl]-4-pyrimidinyl]-p-isopropylbenzenesulfonyl with a melting point of 193-195oC.

Example 58. Analogously to example 50 from 230 mg of N-[6-chloro-5-[p-(methylthio)phenyl]-4-pyrimidinyl]-a,-Cryptor-p - toluensulfonate receive 160 mg of N-[6-(2-hydroxyethoxy)-5-[p-(methylthio)phenyl] -4-pyrimidinyl] -a,-Cryptor-p - toluensulfonate with a melting point 266-268oC.

The source material was obtained from 4, 6-dichloro-5-p-(methyl-thio) phenylpyrimidine and a,, -Cryptor-p-toluensulfonate potassium; melting point 250-252oC.

Example 59. Sodium glycolate, sodium of 1 ml dry ed. The reaction mixture is heated for 4 h in an argon atmosphere to a temperature of 125oC. the distilled ethylene glycol under reduced pressure, the residue is distributed between ethyl acetate and 1N hydrochloric acid, the organic phase is washed until neutral, dried and evaporated. The remainder chromatographic using methylene chloride-ethyl acetate (1:1 V/V) on kieselgel. Receive 250 mg of N-[6-(2-hydroxyethoxy)-5-(o-methoxybenzyl)-4-pyrimidinyl]-p - methoxybenzenesulfonamide with a melting point 161-162oC.

The source material is prepared as follows:

When condensation on Knowingly (Knovengel) o-methoxybenzaldehyde with diethylmalonate receive diethyl ether o- -methoxybenzylideneamino acid; boiling point 140oC/0.05 mm RT. Art.

Hydrogenation of the above compounds in ethanol in the presence of palladium on coal leads to the formation of diethyl ether on - methoxybenzeneboronic acid; boiling point 115oC/0.01 mm RT. Art.

In the interaction of diethyl ether on methoxybenzeneboronic acid hydrochloride of formamidine receive 5-(o-methoxybenzyl)-6-hydroxy-4-(3H)-pyrimidinone, which when interacting with phosphorus oxychloride poetiy 4, 6-dichloro-5-(o-methoxybenzyl)-4-pyrimidine with p-methoxybenzenesulfonamide get potassium N-[6-chloro-5-(o - methoxybenzyl)-4-pyrimidinyl]-p-methoxybenzenesulfonamide with temperature appears 149-151oC.

Example 60. Analogously to example 52 N-[6-chloro-5-(o-Chlorobenzyl)-4-pyrimidinyl] -p-toluensulfonate receive N-[6-(2-hydroxyethoxy)-5-(o-Chlorobenzyl)-4-pyrimidinyl] -p-toluensulfonate.

The source material is prepared as follows:

When the interaction of the diethyl ester of malonic acid and o-chlorobenzylchloride receive diethyl ether on chlorobenzylamino acid; boiling point 115oC/0.05 mm RT. Art.

By condensation of diethyl ether on chlorobenzylamino acid with formamidine receive 5-(o-Chlorobenzyl)-6-hydroxy-4(3H)-pyrimidinone that when interacting with the oxychloride gives 4, 6-chloro-5-(o-Chlorobenzyl) pyrimidine with a melting point 110-112oC.

4, 6-dichloro-5-(o-Chlorobenzyl) pyrimidine and p-toluensulfonate get potassium N-[6-chloro-5-(o-Chlorobenzyl)-4-pyrimidinyl]-p-toluensulfonate, which is used as a raw product.

Example 61. Analogously to example 59, from N-[6-chloro-5-(o-methoxybenzyl)-4-pyrimidinyl-p-(methylthio) benzols is the temperature of the melting point 134-136oC.

Example 62. Analogously to example 59, from N-[6-chloro-5-(o-methoxybenzyl)-4-pyrimidinyl] -a,-Cryptor-p-toluensulfonate receive N-[6-(2-hydroxyethoxy)-5-(o-methoxybenzyl)-4-pyrimidinyl] -a,-Cryptor- -p-toluensulfonate with a melting point of 133-134oC.

The source material was obtained from 4, 6-dichloro-5-(o-methoxybenzyl) pyrimidine and p-triftoratsetilatsetonom potassium. Melting point 163oC.

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

In the processing of sodium methylate in methanol receive sodium salt, melting point 225oC.

The source material is prepared from 4, 6-dichloro-5-(o-methoxybenzyl) pyrimidine and isopropylbenzenesulfonyl potassium; melting point 138-139oC.

Example 64. Analogously to example 59, from n-tert.-butyl-N-[6-chloro-5-(o-methoxy - benzyl)-4-pyrimidinyl] benzosulfimide get p-tert.-butyl-N -[6-(2-hydroxyethoxy)-5-(o-methoxybenzyl)-4-pyrimidinyl] benzosulfimide with a melting point 138-140oC amidine and p-tert. -butylbenzenesulfonamide potassium; melting point 215-216oC.

Example 65. Analogously to example 59, from N-[6-chloro-5-(o-Chlorobenzyl)-4-pyrimido- -Neil]-p-isopropylbenzenesulfonyl receive N-[6-(2-hydroxyethoxy)- -5-(o-Chlorobenzyl)-4-pyrimidinyl]-p-isopropylbenzenesulfonyl.

The source material was prepared from 4,6-dichloro-5-(o-Chlorobenzyl) pyrimidine and p-isopropylbenzenesulfonyl potassium; melting point 166-167oC.

Example 66. Analogously to example 59, from N-[6-chloro-5-(o-methyltin)benzyl)-4 - pyrimidine] -p-isopropylbenzenesulfonyl receive N-[6-(2-hydroc - setacci)-5-(o-(methylthio)benzyl)-4-pyrimidinyl]-p-isopropylbenzenesulfonyl.

The source material was obtained as follows:

When interacting thiosalicylic acid with dimethylsulfate in the presence of tetrabutylammonium receive the methyl ester of 2-(methylthio) benzoic acid with a melting point 64oC. By restoring aluminohydrides lithium in dry tetrahydrofuran get 2-(methylthio)benzyl alcohol, which when interacting with SOCl2transfer in 2-(methylthio) benzoylchloride; boiling point 90oC/0.3 mm RT. Art. In the interaction diethyl ester of malonic acid with 2 is 130oC/0.05 mm RT. Art. by condensation with formamidine get 5-[o-(methylthio)benzyl] -6-hydroxy-4-(3H)-pyrimidine, which translate into 4,6-dichloro-5-[o-(methylthio) benzyl] pyrimidine with a melting point 91oC. Finally, from 4,6-dichloro-5-(o-(methylthio)benzyl)pyrimidine and p-isopropylbenzenesulfonyl get potassium N-[6-chloro-5-(o-methylthio)benzyl)-4-pyrimidinyl]-p-isopropylbenzenesulfonyl with a melting point 145-146oC.

Example 67. Analogously to example 59, from N-[6-chloro-5-(o-Chlorobenzyl)-4-pyrimidinyl] -p-isobutylacetophenone receive N-[6-(2-hydroxyethoxy)-5-(o-Chlorobenzyl)-4-pyrimidinyl] -p-isobutylbenzene - named with a melting point 130-131oC.

The source material was prepared from 4,6-dichloro-5-(o-Chlorobenzyl) pyrimidine and p-isobutylacetophenone potassium; melting point 147-149oC.

Example 68. Analogously to example 50 N-[6-chloro-(o-Chlorobenzyl)-4-pyrimidinyl] -p-cyclohexanesulfonic receive N-[6-(2-hydroxyethoxy)-5- -(o-Chlorobenzyl)-4-pyrimidinyl]-p-cyclohexanesulfonic with a melting point 164-165oC.

The source material was prepared from 4,6-dichloro-5-(o-Chlorobenzyl)- pyrimidine and p-cyclohexanesulfonic potassium; temperature is l] -p-isopentenyladenine receive N-[6-(2-hydroxyethoxy)-5- -(o-Chlorobenzyl)-4-pyrimidinyl] -p-sometimesalcohol with a melting point 127-128oC (from diisopropyl ether).

The source material was prepared from 4,6-dichloro-5-(o-Chlorobenzyl) pyrimidine and p-isopentenyladenine potassium; melting point 139-140oC.

Example 70. Analogously to example 59, from N-[6-chloro-5-(o-methoxybenzyl)-4- -pyrimidinyl] -n-(isopropylthio)benzosulfimide receive N-[6-(2 - hydroxyethoxy)-5-(o-methoxybenzyl)-4-pyrimidinyl] -n-(isopropylthio) benzosulfimide with a melting point 127-128oC (from diisopropyl ether).

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

Example 71. Analogously to example 1 from n-chloro-N-[6-chloro-5-(p-chlorophenyl)-2-methyl-4-pyrimidinyl] benzosulfimide, etilenglikolya sodium get p-chloro-N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-2-methyl-4-pyrimidinyl] benzosulfimide with a melting point 163-164oC (from simple ether).

The source material was obtained as follows:

Of diethyl-p-chlorophenylalanine, hydrochloride of acetamidine and sodium methylate receive 5-(p-chlorophenyl)-2-methyl-4,6(1H,5H)- -pyrimidinedione with a melting point > 270oC and from it with POCl3get 4,6-dichloro-5-(p-chlorophenyl)-2-motivaional of this compound with p-chlorophenylsulfonyl get p-chloro-N-[6-chloro-5-(p-chlorophenyl)-2-methyl-4-pyrimidinyl] benzosulfimide; melting point 196-197oC (from acetonitrile).

Example 72. Analogously to example 1 from n-chloro-N-[6-chloro-5-(p-nitrophenyl)-4- -pyrimidinyl] benzosulfimide and p-chlorophenylsulfonyl get p-chloro-N-[6-(2-hydroxyethoxy)-5-(p-nitrophenyl)-4-pyrimidinyl] benzosulfimide with a melting point 223-225oC (from methylene chloride and isopropyl ether).

The source material was obtained as follows:

3.5 g of the diethyl-p-nitrophenylacetate and 1.6 g of the acetate of formamidine heated 3 h to 100oC. After that add a further 3.2 g of the acetate of formamidine, 5 ml of abs. of dimethylformamide and 1 ml of glacial acetic acid and heated the reaction mixture to 110oC for 16 hours. After evaporation of the solvent under reduced pressure the residue fray with ether (common), filtered under vacuum and dissolved in 1N NaOH-solution. The solution is mixed with a small amount of charcoal, filtered and pH adjusted to a value of 4.5 using glacial acetic acid. The residue is dried under reduced pressure at 80oC, and then dissolved and stirring for 3 h boil under reflux. After evaporation of the solvent under reduced pressure the residue is dissolved in ether, acetic acid, organic races is (9:1) and obtain 4,6-dichloro-5-(p-nitrophenyl)pyrimidine with a melting point 159-161oC (from isopropyl ether).

In the interaction of compounds with p-chlorophenylsulfonyl get p-chloro-N-[6-chloro-5-(p-nitrophenyl)-4-pyrimidinyl] benzosulfimide with a melting point 282-285oC (from acetonitrile).

Example 73. 200 mg of n-chloro-N-[6-(2-hydroxyethoxy)-5-(n-nitrophenyl)-4-pyrimidinyl] benzosulfimide hydronaut in 15 ml of glacial acetic acid and 2 ml of 4n HC1 in dioxane over 50 mg of palladium (10%) coal at room temperature and normal pressure. After filtration of the catalyst under vacuum, the solution is evaporated under reduced pressure, the residue is dissolved in 30 ml of methanol and the solution is mixed with 1 ml of dioxane-HC1. After 16 h, the solution evaporated under reduced pressure and the residue is recrystallized from methanol and acetonitrile. Receive hydrochloride N-[5-(n-AMINOPHENYL)-6- (2-hydroxyethoxy)-4-pyrimidinyl] -n-chlorobenzenesulfonamide with a melting point 206oC (decomposition).

Example 74. Analogously to example 1 from n-chloro-N-[5-(biphenylyl)-6-chloro-4 - pyrimidinyl] benzosulfimide, etilenglikolya sodium get N-[5-(4-biphenylyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl] -p-chlorobenzene - sulfonamide melting temperature 213-214oC (from ether acetic acid).

Recognize the atrium receive 5-(4-biphenylyl)-4,6(1H, 5H)-pyrimidinedione with a melting point > 280oC, when interacting with POC13get 5-(4-biphenylyl)-4,6-dichloropyrimidine with a melting point 144oC (from methylene chloride and n-hexane).

In the interaction of this compound with p-chlorophenylsulfonyl get p-chloro-N-[5-(4-biphenylyl)-6-chloro-4-pyrimidinyl] benzene - sulfonamide melting temperature 234-235oC (from acetonitrile).

Example 75. Analogously to example 1 from N-[6-chloro-5-a,,-Cryptor-p-tolyl)- 4-pyrimidinyl] benzosulfimide, etilenglikolya sodium get p-chloro-N-[(6-hydroxyethoxy)-5-a,,-Cryptor-p-tolyl)-4-pyrimidinyl] benzene - sulfonamide melting temperature 171-174oC (from acetone and isopropyl ether).

The source material was obtained as follows.

A,,-Cryptor-p-tolylacetate and acetate of formamidine get 5-a,,-Cryptor-p-tolyl)-4,6(1H, 5H)pyrimidinedione with a melting point > 280oC, and from him receive when interacting with POC134,6-dichloro-5-a,,-p-tolyl)-pyrimidine with a melting point 94-95oC (from n-hexane).

In the interaction of this compound with n-chlorophenylsulfonyl get p-chloro-N-[(6-chloro-5-a,,-Cryptor-p-tolyl)-4-pyrimidinyl]benzolsulfonat is-N-[6-chloro-5-a,,-Cryptor-p-tolyl)-4-pyrimidinyl] benzosulfimide, etilenglikolya sodium get p-chloro-N-[(6-hydroxyethoxy)-5-a,,- -Cryptor-p-tolyl)-4-pyrimidinyl] benzosulfimide with a melting point 171-174oC (from acetone and isopropyl ether).

The source material was obtained as follows:

A,,-tripot-p-tolylacetate and acetate of formamidine get 5-a,,-Cryptor-p-tolyl)-4,6(1H, 5H)-pyrimidinedione with a melting point > 280oC, and from him receive when interacting with POC134,6-dichloro-5-a,,-Cryptor-p-tolyl)-pyrimidine with a melting point 94-95oC (from n-hexane).

In the interaction of this compound with p-chlorosulfonation get p-chloro-N-[6-chloro-5-a,,-Cryptor-p-tolyl)-4-pyrimidinyl] Ben - solarpanel with a melting point 262 to 264oC (from acetonitrile).

Example 77. Analogously to example 27 N-[5-[p-(benzyloxy)phenyl]-6-(2-hydro - xiaoxi)-4-pyrimidinyl]-p-chlorobenzenesulfonamide get p-chloro-N-[5-(p-gitoxigenin)-6-(2-hydroxyethoxy)-4-pyrimidinyl] benzene - sulfonamide with a melting point 207-209oC (from acetonitrile and isopropyl ether).

Example 78. Analogously to example 1 from N-[5-[p-(benzyloxy)phenyl]-6-chloro-4-pyrimidinyl] -p-chlorobenzenesulfonamide, etilenglikolya sodium get N-[5-[p-(benzyloxy)phenyl]-6-(2-hydroxyethoxy)-4-pyrimidinyl]- p-chlorobenzenesulfonamide with a melting point 160-161oC (from simple ether).

Source what are square-5-[p-(benzyloxy)phenyl] -4,6(1H, 5H)-dione with a melting point > 280oC and from it is obtained using POC135-[p-(antioxi)phenyl]-4,6-dichloropyrimidine with a melting point 115-116oC (from methylene chloride and isopropyl ether).

In the interaction of this compound with p-chlorophenylsulfonyl receive N-[5-(benzyloxy)phenyl]-6-chloro-4-pyrimidinyl]-p-chlorobenzenesulfonamide with a melting point 234-236oC (from ether acetic acid).

Example 79. Analogously to example 1 from N-(6-chloro-4-a,,-Cryptor-p-tolyl)- 4-pyrimidinyl] -a,-Cryptor-p-toluensulfonate, etilenglikolya sodium get N-[(6-(2-gynocritics)-5-a,,-Cryptor-p-tolyl)- 4-pyrimidinyl] -a,-Cryptor-p-toluensulfonate with a melting point 165-166oC (from methylene chloride and isopropyl ether).

The source material was prepared from 4,6-dichloro-5-a,,-p-tolyl)pyrimidine and a,,-Cryptor-p-toluensulfonate; melting point > 270oC (from acetonitrile).

Example 80. Analogously to example 1 from n-chloro-N-[6-chloro-5-(2-naphthylmethyl)-4 - pyrimidinyl] benzosulfimide, etilenglikolya sodium get p-chloro-N-[6-(2-hydroxyethoxy)-5-(2-naphthylmethyl)-4-pyrimidinyl] benzene - sulfonamide with a melting point 161oC (from acetonitrile and isop is of Lonate and acetate of formamidine receive 5-(2-naphthylmethyl)-4,6(1H, 5H)-pyrimidinedione with a melting point > 270oC and from him receive when interacting with POC134,6-dichloro-5-(2 - naphthylmethyl)pyrimidine with a melting point 161-162oC (from methylene chloride and isopropyl ether).

In the interaction of this compound with p-chlorophenylsulfonyl get p-chloro-N-[6-chloro-5-(2-naphthylmethyl)-4-pyrimidinyl] bansilal - foamed with a melting point 197-199oC (from acetonitrile).

Example 81. Analogously to example 1 from N-[5-(p-bromophenyl)-6-chloro-4-pyrimidinyl] -p-isopropylbenzenesulfonyl, etilenglikolya sodium get N-[5-(p-bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl] -p-isopropylbenzene - sulfonamide with a melting point 207-208oC (from acetonitrile and isopropyl ether).

The source material is prepared from 5-(p-bromophenyl)-4,6-dichloro - pyrimidine and p-isopropylbenzenesulfonyl; melting point 271-273oC (from acetonitrile).

Example 82. Analogously to example 1 from N-[6-chloro-5-(p-chlorophenyl)-4-pyrimidine] -p-isopropylbenzenesulfonyl, etilenglikolya sodium get N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl]-p-isopropylbenzene - sulfonamide with a melting point 162-164oC (from acetonitrile, isopro is eventoccurred; melting point 266-268oC (from acetonitrile).

Example 83. Analogously to example 1 from N-(6-chloro-5-p-tolyl-4-pyrimidinyl)-p-isopropylbenzenesulfonyl, etilenglikolya sodium get N-[6-(hydroxyethoxy)-5-p-tolyl)-4 - pyrimidinyl] -p-isopropylbenzenesulfonyl with a melting point 142-144oC (from isopropyl ether).

From this compound together with sodium methylate get sodium salt as an amorphous substance.

Starting material N-(6-chloro-5-p-tolyl-4-pyrimidinyl)-p-isopro - bilanzanalyse with a melting point 211-213oC (from acetonitrile) is obtained from 4,6-dichloro-5-p-tolylenediamine and p - isopro - eventsourcename.

Example 84. Analogously to example 1 from n-tert.-butyl-N-(6-chloro-5-p-tolyl-4 - pyrimidinyl)benzosulfimide, etilenglikolya sodium get p-tert.-butyl-N-[6-(2-hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl)benzene - sulfonamide with a melting point 169-170oC (from isopropyl ether) and out using sodium methylate receive amorphous sodium salt.

The source material was obtained from 4,6-dichloro-5-p-tolylenediamine and p-tert. -butylbenzenesulfonamide; melting point 222-224oC (from acetonitrile).

An example is at sodium get N-[6-(2-hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl] -n-(2-methoxyethoxy)Ben - solarpanel with a melting point 155-156oC (from isopropyl ether).

The source material was prepared from 4,6-dichloro-5-p-tolylenediamine and n-(2-methoxyethoxy)benzolsulfonat - Mead; melting point 172-173oC (from methylene chloride and isopropyl ether).

Example 86. Analogously to example 1 from N-(6-chloro-5-p-tolyl-4-pyrimidinyl)-4- (triptoreline)benzosulfimide, etilenglikolya sodium get N-[6-(2-hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl] -n-(triptoreline)Ben - solarpanel with a melting point 147-148oC (from isopropyl ether).

The source material was prepared from 4,6-dichloro-5-p-tolylenediamine and p-(triptoreline)benzosulfimide - Yes; the melting point of 205-206oC (from acetonitrile and isopropyl ether).

Example 87. Analogously to example 1 from n-butyl-N-(6-chloro-5-n-tolyl-4-pyrimidinyl)benzosulfimide, etilenglikolya sodium get n-butyl-N-[6-(2-hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl] benzosulfimide with a melting point of 136-137oC (from isopropyl ether).

The source material was prepared from 4,6-dichloro-5-p-tolylenediamine and p-butylbenzenesulfonamide; melting point 168-169oC (from acetonitrile and isopropyl ether).

Example 88. And the N-[6-(2-hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl] -2-naphthalenesulfonate with a melting point 161-162oC (from acetone and isopropyl ether).

The source material was prepared from 4,6-dichloro-5-p-tolylenediamine and 2-naphthalenesulfonate; melting point 198-202oC (from acetonitrile).

Example 89. Analogously to example 1 from N-(6-chloro-5-p-tolyl-4-pyrimidinyl)-p-toluensulfonate, etilenglikolya sodium get N-[6-(2-hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl]-p-toluensulfonate with a melting point 169-170oC (from acetone and isopropyl ether).

The source material was prepared from 4,6-dichloro-5-p-tolylenediamine and p-toluensulfonate; melting point 213-214oC (from acetonitrile and isopropyl ether).

Example 90. Analogously to example 1 from N-(6-chloro-5-p-tolyl-4-pyrimidinyl)-a,,-Cryptor-p-toluensulfonate, etilenglikolya sodium get N-[6-(2-hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl]-a,-Cryptor-p - toluensulfonate with a melting point 162-163oC (from acetonitrile and isopropyl ether).

The source material was prepared from 4,6-dichloro-5-p-tolylenediamine and a,,-Cryptor-p-toluensulfonate; melting point 231-233oC (from acetonitrile).

Example 91. Analogously to example 1 from N-(6-chloro-5-n-tolyl-4-pyrimidinyl)-n-forbindelse idini] benzosulfimide with a melting point 167-168oC (from acetone and isopropyl ether) and n-(2-hydroxyethoxy)-N-[6-hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl] benzosulfimide with a melting point 174-176oC (from acetone and isopropyl ether).

The source material was prepared from 4,6-dichloro-5-p-tolylenediamine and p-forbindelsesfaneblad; melting point 168-169oC (from acetonitrile and isopropyl ether).

Example 92. Analogously to example 1 from N-(6-chloro-5-p-tolyl-4-pyrimidinyl)-p-propylbenzenesulfonyl, etilenglikolya sodium get N-[6-(2-hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl] -p-propylbenzenesulfonyl with a melting point 171-172oC (from acetonitrile).

Example 93. Analogously to example 1 from N-(6-chloro-5-p-tolyl-4-pyrimidinyl)-o-propylbenzenesulfonyl, etilenglikolya sodium get N-[6-(2-hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl] -o-propylbenzenesulfonyl with a melting point 195-196oC (from methylene chloride and isopropyl ether).

The source material was obtained from 4,6-dichloro-5-p-tolylenediamine and o-propylbenzenesulfonyl; melting point 150-151oC (from isopropyl ether).

Example 94. Analogously to example 1 from N-(6-chloro-5-p-tolyl-4-pyrimidinyl)-p-ethylbenzyltoluidines melting point 138-139oC (from methylene chloride and isopropyl ether).

The source material was prepared from 4,6-dichloro-5-p-tolylenediamine and p-ethylbenzaldehyde; melting point 168-169oC (from acetonitrile).

Example 95. Analogously to example 1 from N-(6-chloro-5-p-tolyl-4-pyrimidinyl)-o-ethylbenzylamine, etilenglikolya sodium get o-ethyl-N-[6-(2-hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl] benzosulfimide with a melting point of 136-138oC (from acetone and isopropyl ether).

The source material was prepared from 4,6-dichloro-5-p-tolylenediamine and o-ethylbenzylamine; melting point 159-160oC (from acetonitrile and isopropyl ether).

Example 96. Analogously to example 1 from N-(6-chloro-5-p-tolyl-4-pyrimidinyl)-p-cyclopentylpropionate, etilenglikolya sodium get p-cyclopentyl-N-[6-(2-hydroxyethoxy)-5-p-tolyl] benzosulfimide with a melting point 179-181oC (from acetone and isopropyl ether).

The source material was prepared from 4,6-dichloro-5-p-tolylenediamine and p-cyclopentadecanolide; melting point 192-194oC (from acetonitrile and isopropyl ether).

Example 97. Analogously to example 1 from N-(6-chloro-5-paragraph-that is toxi)-5-p-tolyl-4-pyrimidinyl] -o - toluensulfonate with a melting point 166-167oC (from methylene chloride and isopropyl ether).

The source material was prepared from 4,6-dichloro-5-p-tolylenediamine and a,,-Cryptor-o-toluensulfonate; the melting point of 129-131oC (methyl chloride and isopropyl ether).

Example 98. Analogously to example 1 from N-(6-chloro-5-p-tolyl-4-pyrimidinyl)- o-toluoyltartaric, etilenglikolya sodium get N-[6-(2 - hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl]-o-toluensulfonate with a melting point 149 150oC (from ether acetic acid isopropylalcohol ether).

The source material was prepared from 4,6-dichloro-5-p-tolylenediamine and o-toluensulfonate; 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 - cellculture, etilenglikolya sodium get N-[6-(2 - hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl]-2,4-killsometime with a melting point 158 159oC (from isopropyl ether).

The source material was obtained from 4,6-dichloro-5-p-tolylenediamine and 2,4-cellculture; melting point 233oC (from acetonitrile and isopropyl ether).

Example 100. Analogously to example 1 from n-chloro-N-[6-chloro-5-(1-naphthylmethyl)-4 - pyrimidinyl]Ben]benzosulfimide with a melting point 204 205oC (from acetonitrile and isopropyl ether).

The source material was obtained as follows:

Of diethyl-1-aftermonth and acetate of formamidine receive 5-(1-naphthylmethyl)-4,6(1H, 5H)-pyrimidinedione with a melting point >270oC, and of him, after drying under reduced pressure at 80oC when interacting with POCL3get 4,6-dichloro-5-(1-naphthylmethyl)pyrimidine with a melting point 111 112oC (from methylene chloride and isopropyl ether).

In the interaction of this compound with p-chlorophenylsulfonyl get p-chloro-N-[6-chloro-5-(1-naphthylmethyl)-4-pyrimidinyl] benzosulfimide with a melting point 202 203oC (from acetonitrile).

Example 101. Analogously to example 1 from N-[6-chloro-5-(p-isopropylphenyl)-4 - pyrimidinyl]-p-isopropylbenzenesulfonyl, etilenglikolya sodium get N-[6-(2-hydroxyethoxy)-5-(p-isopropylphenyl)-4-pyrimidinyl] - p-isopropylbenzenesulfonyl with a melting point of 142 144oC (from isopropyl ether).

The source material was obtained as follows:

Of diethyl-(p-isopropylphenyl)malonate and acetate of formamidine receive 5-(p-isopropylphenyl)-4,6(1H, 5H)-pyrimidinedione with a melting point >290oC and from him when in the UP>C (from n-hexane).

In the interaction of this compound with p-isopropylbenzenesulfonyl receive N-[6-chloro-5-(p-isopropylphenyl)-4-pyrimidinyl]-n-isopropyl - benzosulfimide with a melting point 198 199oC (from acetonitrile and isopropyl ether).

Example 102. Analogously to example 1 from N-[6-chloro-5-(p-isopropylphenyl)-4 - pyrimidinyl] -p-cyclopentylpropionate, etilenglikolya sodium get p-cyclopentyl-N-[6-(2-hydroxyethoxy)-5-(p-isopropylphenyl)-4 - pyrimidinyl]benzosulfimide with a melting point 132oC (decomposition) (from acetone and isopropyl ether).

The source material was prepared from 4,6-dichloro-5-(p-isopropylphenyl)pyrimidine and p-cyclopentadecanolide; melting point 188 189oC (from methylene chloride and isopropyl ether).

Example A. the Tablets containing the following components, can be obtained by standard methods: (see tab. 4).

Example B. the Capsules containing the following components, can be obtained by standard methods: (see tab. 5).

Example C. injectable Solutions have the following composition%

The compound of formula I 3.0 mg

Gelatin 150,0 mg

Phenol 4,7 mg

Water for injection Paradise of formula I. This suspension contribute in a container with a metering valve. Through the valve under pressure in the vessel is injected 5.0 g of freon 12. When shaken, the freon is dissolved in a mixture of miglyol-benzyl alcohol. This vessel with spray contains approximately 100 single doses, which can be applied separately.

1. Derivatives arylsulfonamides General formula

< / BR>
where R1hydrogen, halogen;

R2hydrogen, halogen, trifluoromethyl;

R3halogen, lower alkylthio, triptoreline, lower alkyl, lower alkoxy-lower alkoxy, lower alkoxy, C5- C6-cycloalkyl, trifluoromethyl, phenyl-lower alkoxy, lower alkenyl, oxo-lower alkyl, hydroxyimino-lower alkyl, hydroxy-lower alkyl, or R2and R3together form butadienyl;

R4hydrogen, lower alkyl;

R5hydrogen, tetrahydropyran-2-yl;

R6the radical of General formula

< / BR>
or

< / BR>
where R7hydrogen, lower alkyl;

R8halogen, lower alkyl, lower alkoxy, lower alkylthio, nitro;

R9halogen, lower alkoxy, lower alkylthio, trifluoromethyl;

R10hydrogen, lower alkylthio, lower alkoxy;

n is 2 or 3,

or their salts.

2. Connect named; N-[6-(2-hydroxyethoxy)-5-(o-methoxybenzyl)-4-pyrimidinyl]-p-methyldibenzothiophene; N-[6-(2-hydroxyethoxy)-5- (o-methoxybenzyl)-4-pyrimidinyl]-, , - Cryptor-p-toluensulfonate;

3. Connection on p. 1, selected from the group of N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4 - pyrimidinyl] -Cryptor-p-toluensulfonate; N-[5-(p-chlorophenyl)-6- (2-hydroxyethoxy)-4-pyrimidinyl]-n-(trottinette)- benzosulfimide; p-chloro-N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)- 4-pyrimidinyl]benzosulfimide; N-[5-(p-chlorophenyl)-6- (2-hydroxyethoxy)-4-pyrimidinyl]-p-forbindelsesfaneblad; o-chloro-N-[5-(p-chlorophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl]- benzosulfimide; N-[5-(p-bromophenyl)-6 (2-hydroxyethoxy)-4 - pyrimidinyl] -p-chlorobenzenesulfonamide; p-chloro-N-[6- (2-hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl] benzosulfimide; N-[6-(2-hydroxyethoxy)-5-(p-methoxyphenyl)-4-pyrimidinyl]-p(methylthio)benzosulfimide; N-[6-(2-hydroxyethoxy)- 5-(p-methoxyphenyl)-4-pyrimidinyl]-p-isopropylbenzenesulfonyl; p-tert-butyl-N-[6-(2-hydroxyethoxy)- 5-(p-methoxyphenyl)-4-pyrimidinyl]benzosulfimide; N-[6-(2-hydroxyethoxy)-5-(p-(methylthio)phenyl)-4-pyrimidinyl]-p-isopropylbenzenesulfonyl; N-[5-(p-chlorophenyl)-6- (2-hydroxyethoxy)-4-pyrimidinyl] -p-isopropylbenzenesulfonyl; N-[6-(hydroxyethoxy)-5-p-tol is alcolholic; N-[6-(2-hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl]-n-(2-methoxyethoxy) benzosulfimide; N-[6-(2-hydroxyethoxy)- 5-p-tolyl-4-pyrimidinyl] -n-(triptoreline)benzosulfimide; N-[6-(2-hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl] -p-toluensulfonate; N-[6-(2-hydroxyethoxy)-5-p-tolyl-4-pyrimidinyl] -, , - Cryptor-p-toluensulfonate; N-[6-(2-hydroxyethoxy)-5-(, , - Cryptor-p-tolyl)-4-pyrimidinyl-p-isopropylbenzenesulfonyl; N-[5-(p-bromophenyl)-6- (2-hydroxyethoxy)-4-pyrimidinyl]-p-isopropylbenzenesulfonyl; N-[6-(2-hydroxyethoxy)-5-(p-ethylphenyl)-4 - pyrimidinyl] -p - isopropylbenzenesulfonyl; p-cyclopentyl-N-[6-(2 - hydroxyethoxy)-5-(p-ethylphenyl)-4-pyrimidinyl]benzosulfimide.

4. Connection PP.1 to 3, showing angioprotective, antihypertensive and vazospasticescuu, in particular anti-ischemic activity.

5. The pharmaceutical composition exhibiting angioprotective, antihypertensive and vazospasticescoe, in particular anti-ischemic action, including an active ingredient and pharmaceutically acceptable additives, characterized in that it as the active substance contains a derivative of arylsulfonamides or its salt according to any one of paragraphs.1 3 in an effective amount.

 

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< / BR>
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FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an intermediate compound, i. e. tert.-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-yl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate that can be used in synthesis of compound of the formula (IV)

eliciting inhibitory effect on activity of HMG-CoA-reductase and, therefore, can be used for preparing pharmaceutical agents for treatment, for example, hypercholesterolemia, hyperproteinemia and atherosclerosis. Also, invention relates to a method for preparing indicated intermediate compound by reaction of the new parent compound - diphenyl-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-ylmethyl]phosphine oxide with tert.-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate in the presence of a strong base in simple ether or aromatic solvents or their mixtures at temperature in the range from -200C to -900C. Also, invention relates to a method for preparing of compound of the formula (IV) wherein R1 means hydrogen atom or pharmaceutically acceptable cation and to a method for preparing intermediate compounds of the formula (VI):

wherein each P1 and P2 represents independently (C1-C4)-alkyl or group:

and wherein P3 represents (C1-C8)-alkyl. Applying new intermediate compounds and proposed methods provide enhancing quality and yield of compounds.

EFFECT: improved preparing methods.

9 cl, 1 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for preparing 1,3-oxathiolan nucleosides or a method for preparing derivatives of 1,3-oxathiolanyl-5-one that involve effective methods for formation of 1,3-oxathiolan ring followed by condensation of 1,3-oxathiolan with pyrimidine or purine base. Using indicated methods these compounds can be synthesized as separate enantiomers with high selectivity.

EFFECT: improved preparing methods.

27 cl, 3 dwg, 16 ex

FIELD: medicine.

SUBSTANCE: method involves administering typical neuroleptics according to titration scheme and tricyclic antidepressants. Neuroleptics are applied according to titration scheme in the morning and tricyclic antidepressants are introduced as intravenous drop-by-drop infusion in the evening in combination with per os application of atypic neuroleptic risperidon. After having given 12-14 intravenous infusions, strategic supporting risperidon psychopharmacotherapy in combination with tricyclic antidepressants during 4-6 months.

EFFECT: enhanced effectiveness in overcoming pharmacological resistance; accelerated schizo-affective syndrome relief.

FIELD: medicine.

SUBSTANCE: method involves applying eradicative anti-helicobacterial therapy comprising Omeprazol administration at a dose of 20 mg twice a day and Ximedone at a dose of 500 mg twice a day in 12 days long course.

EFFECT: enhanced effectiveness of eradication; reduced adverse side effects risk.

FIELD: organic chemistry, medicine, pharmacy, pharmacotherapy.

SUBSTANCE: method involves administration in mammal the effective dose of 6-hydroxy-8-[4[4-(2-pyrimidinyl)piperazinyl]butyl]-8-azaspiro[4,5]-7,9-dione or its pharmaceutically acceptable salt of acid addition or its hydrate. Method expands arsenal of medicinal agents used for suppression of fear sensation.

EFFECT: valuable properties of agent.

3 tbl, 6 dwg, 4 ex

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