Derivatives of pyrimidine, pharmaceutical composition and method for prevention and treatment of disease

 

(57) Abstract:

The invention relates to new pyrimidine derivative or its pharmaceutically acceptable salts, pharmaceutical composition having the effect of inhibitor endothelin and method of prevention and treatment of diseases induced endothelium, particularly diseases associated with circulatory disorders such as hypertension, hypertension, asthma, angina and other pyrimidine Derivatives correspond to the General formula 1, where R1represents a hydroxyl, lower CNS, phenyl-lower CNS, benzyloxy or NR2R3; X represents an oxygen atom or NR4; m is 2 or 3; n is 1 or 2; R2is hydrogen; R3represents lower alkyl, phenylethylene, phenyl group which may be substituted by lower alkyl, lower Haloxylon, or pyridyl; R4represents a lower alkyl group, phenyl group, formyl group or a lower alkoxycarbonyl group. The pharmaceutical composition comprises a pyrimidine derivative of formula 1 or its salt and a pharmaceutically acceptable carrier. Method of prevention and treatment is the introduction of an effective amount of a pyrimidine and their salts and pharmaceutical preparations containing these compounds as active ingredients.

Background of the invention

It is believed that endothelin, showing a strong vasoconstrictor action and raise the blood pressure effect, is a substance that contributes to various diseases and disorders, including heart disease, such as ischemic heart attack, congestive heart failure, arrhythmia, unstable angina; diseases of the respiratory tract, such as asthma; hypertension, such as pulmonary hypertension and renal hypertension; hypofunction of the authorities, which may occur in connection with their operation or transplantation; diseases associated with the circulatory disorders, such as subarachnoid hemorrhage, re-narrowing of the blood vessels after RTSA and vasospasm; kidney disease, such as acute and chronic renal insufficiency; diabetes, hyperglycemia and other diseases that are accompanied by vascular damage; atherosclerosis; liver disease such as alcohol-induced disorders of the liver; gastrointestinal disorders, such as disorders of the mucous membrane of the stomach; bone disease; prostatic hypertrophy and urinary disorders; cancer [Saishin-Igaku (can be the(1994)].

It was found that various actions of endothelin are driven by the binding of endothelin to its receptors in the organs of the body, and that the narrowing of blood vessels caused by endothelin, is induced by meditirovaniya at least two different receptors (ETAand ETB-receptors). Therefore, a compound that prevents the binding of endothelin to these two receptors should be useful as a preventive and terapevticheskii funds for the above diseases, with the participation of endothelin. Still describes a series of compounds with the antagonism of endothelin [J. Med. Chem., 36, 2585 (1993); Nature, 365, 759 (1993); Circulation, 88, 1-316 (1994); Sashin-Igaku, 94, 424-431, (1994); J. Med. Chem., 37, 1553, (1994) and patent applications (Japan kokai) NN 5-222003, 6-211810, 7-17972 and 8-99961)].

However, no connection is found, which has satisfactory endothelin antagonism.

In accordance with this present invention is directed to the detection of a compound that has a strong antagonism of endothelin and provision of pharmaceutical preparations containing such a compound as an active ingredient.

Disclosure of the invention

Considering the uke is proizvodnye pyrimidine, represented by the following formula (1), and their salts have excellent endothelin antagonism and is therefore useful as medicines, especially medicines for diseases, flowing with blood circulation. The present invention was carried out on the basis of this discovery.

In accordance with this present invention represents a pyrimidine derivative of the following formula (1) or

< / BR>
where R1represents a hydroxyl group, a lower alkoxygroup, fenoxaprop, which may have a Deputy, aralkylated, which may have a Deputy, or NR2R3;

X represents an oxygen atom or N-R4;

m is 2 or 3;

n is 1 or 2

where each of R2and R3which may be identical or may differ from each other, represents a hydrogen atom, hydroxyl group, lower alkyl group which may have a Deputy, a phenyl group which may have a Deputy, aracelio group which may have a Deputy, or a heterocyclic group which may have a Deputy;4represents a lower alkyl group, phenyl group, formyl group or a lower alokasi pyrimidine derivative of the formula (1) or its salt as an active ingredient.

The present invention predstavljaet also a pharmaceutical composition comprising a pyrimidine derivative of the formula (1) or its salt and a pharmaceutically acceptable carrier.

The present invention is also the use of pyrimidine derivative of the formula (1) or its salts as a drug.

The present invention also provides a method for the treatment and prevention of diseases induced by endothelin, where the method is characterized by the introduction to the patient an effective amount of a derivative of a pyrimidine of formula (1) or its salt.

The best way of carrying out the invention

In the present invention, the term "lower" is used to denote that the number of carbon atoms is between 1 and 6 inclusive.

In the formula (1) low alkoxygroup represented by R1include unbranched, branched or cyclic alkoxygroup having 1-6 carbon atoms, examples of which include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentox, n-hexyloxy, cyclopropylamine, cyclopentyloxy, cyclohexyloxy.

Fenoxaprop, which may have substituents and which before the MOU carbon alkoxygroup having 1-6 carbon atoms, or halogen atoms. Specific examples of such fenoxaprop include methylphenoxy, ethyleneoxy, isopropylphenoxy, methoxyphenoxy, ethoxyphenoxy, chlorphenoxy, bromfenac, torpedolike.

Aralkylated, which may have substituents and which are represented by R1include phenylalkylamine, afterarraycopy, biphenylcarboxylic and Indaselassie. These groups may be substituted by hydroxy, C1-C6-alkyl, C1-C6-alkoxy, C1-C3-alkylenedioxy, halogen, nitro, trifluoromethyl or cyano groups. Examples of alkyl residues aralkylated include C1-C6is an alkyl group. Aralkylated may have as substituents with one to three groups. These substituents may be substituted for either the aryl portion or the alkyl portion. Specific examples of aralkylated, which may have substituents, include benzyloxy, penetrate, phenylpropoxy, aftermarket, naftiliaki, biphenylmethane and Indaselassie, and these groups may have as substituents with one to three groups selected from the group comprising chlorine, fluorine, methoxy, atoxin and which are represented by R2or R3, alkyl parts include unbranched, branched or cyclic alkyl group having 1-6 carbon atoms, examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclopentyl and cyclohexyl. Alkyl part may be substituted by one or more (a total of from one to three hydroxyl groups and halogen atoms. Examples of alkyl groups substituted by the above groups include chloroethyl, bromacil, chloropropyl, bromopropyl, chlorbutol, bromobutyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and chlorhydroxide.

In the formula (1) examples of the phenyl group which may have a substituent and which is represented by R2or R3include phenyl groups which may be substituted C1-C6-alkyl groups, C1-C6-CNS groups or halogen atoms. Specific examples of such phenyl groups include were, ethylphenyl, isopropylphenyl, methoxyphenyl, ethoxyphenyl, chlorophenyl, bromophenyl and forfinal.

Kalkilya group which may have substituents and which are represented by R2or R3include phenylaniline is hydroxy, C1-C6-alkyl, C1-C6-alkoxy, C1-C3-alkylenedioxy, halogen, nitro, trifluoromethyl or cyano groups. Examples of the alkyl parts Uralkalij groups include C1-C6is an alkyl group which may have one to three substituents either the aryl portion or the alkyl portion. Specific examples Uralkalij groups which may have substituents include benzyl, fenetylline, phenylpropionyl, naphthylmethyl, naphthylethylene, biphenylmethanol and indan-1-ilen group. These groups may be substituted by groups from one to three, selected from the group comprising chlorine, fluorine, methoxy, ethoxy, methyl, ethyl, nitro, cyano and trifluoromethyl.

Examples of heterocyclic groups which may have substituents and which are represented by R2or R3include foreline group, thienyl group, pyrazolidine group, thiazolidine group, thiadiazolyl group, imidazolidine, peredelnye, piramidalnyi and personilnya group. These groups may be substituted C1-C6-alkyl groups, C1-C6-CNS groups, C1-C6-halogenoalkane groups or halogen atoms. Specific examples include Furi the e group and personilnya group. These groups may be substituted by groups selected from the group comprising methyl, ethyl, methoxy, ethoxy, chlorine, fluorine and trifluoromethyl.

In the formula (1) lower alkyl groups which may have substituents and which are represented by R4include unbranched, branched or cyclic alkyl group having 1-6 carbon atoms, examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclopentyl and cyclohexyl. Lower alkoxycarbonyl groups include unbranched or branched alkoxycarbonyl group having 2-7 carbon atoms, examples of which include methoxycarbonyl, etoxycarbonyl and tert-butoxycarbonyl.

Salts of the compounds (1) according to the present invention in detail is not limited to, if they are pharmaceutically acceptable. Examples of such salts include salts of mineral acids, such as hydrochloride and sulfates; organic acid salts such as acetates, oxalates and citrates; salts of alkaline metals such as sodium and potassium salts; salts of alkaline earth metals such as calcium salts and magnesium salts; and salts of organic bases, such as salts of 1,8-diazabicyclo[5.4.0]undec-="ptx2">

Connection (1) according to the present invention can be obtained in accordance with the following reaction scheme at the end of the description,

where R2, R3, X, m and n have the same meanings as above,

R1ais lower alkoxygroup, substituted or unsubstituted fenoxaprop or substituted or unsubstituted aralkylated defined in the relation R1.

In short, the compound (2) is subjected to reaction with urea to obtain compound (3), which is then subjected to reaction with phosphorus oxychloride to obtain the compound (4). Thus obtained compound (4) is subjected to reaction with 4-tert-butylbenzenesulfonamide potassium, receiving the usual intermediate compound (5). The compound (6) are obtained by reaction of compound (5) and cyclic amino compounds. The compound (6) is subjected to reaction with glycol [HO(CH2)nCH2OH] to obtain compound (7), which is then oxidised to produce the compound (1a) of the present invention. Etherification of the compound (1a) gives compound (1b) of the present invention, while the reaction between the compounds (1a) and Amin [other2R3] gives compound (1c) of the present invention. The compound (1c) are also group the s transformation connection (2) connection (5) suitable known method.

The method of obtaining the compound (6) from the compound (5):

The compound (5) is subjected to reaction with a cyclic aminoguanidinium without using any solvent or in a solvent such as N,N-dimethylformamide (DMF) and dimethylsulfoxide (DMSO), optionally in the presence of a base, such as sodium, sodium hydride, potassium, potassium hydride, tert-piperonyl potassium and potassium carbonate, to obtain the compound (6).

The method of obtaining the compound (7) from compound (6):

The compound (6) is subjected to reaction with a glycol in a solvent such as DMF and DMSO, or without using any solvent, in the presence of a base, such as sodium, sodium hydride, potassium hydride and potassium tert-piperonyl potassium, to obtain compound (7).

A method of obtaining compound (1c) of the present invention from compound (6):

The compound (6) is subjected to reaction with Amida hydroxyzine acid in the presence of a base, such as sodium, sodium hydride, potassium hydride and tert-piperonyl potassium and potassium carbonate, to obtain compound (1c) of the present invention.

The method of producing compound (1a) of the present invention from compound (7):

Compound (7) are oxidized in a polar solvent such as Dramat pyridinium (DHP) and Jones reagent, chloride ruthenium-periodate sodium, etc.

The method of obtaining the compound (1b) of the present invention from the compound (1a) of the present invention:

The compound (1a) of the present invention can be atrificial by use of the following materials or methods: (1) use of an acid catalyst (e.g. sulfuric acid, hydrochloric acid, p-toluensulfonate acid), (2) the use of a dehydrating-condensing agent (the use of a dehydrating-condensing means, such as dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC), and so on), in the presence or absence of dimethylaminopyridine, (3) method via the acid chloride by using thionyl chloride, oxalicacid and so on, (4) method via a mixed anhydride by using atilglukuronida, isobutylparaben and so on, or (5) the way in which the alcohol portion activate the thionyl chloride, etc.

A method of obtaining compound (1c) of the present invention from the compound (1a) of the present invention:

The compound (1a) of the present invention can be lidirovat by use of the following materials or methods: (a) use dehydratation (WSC), and so on, (b) method via active esters (phenyl ester, such as p-nitrophenolate ether, ester of N-hydroxybenzotriazole, ester with N-hydroxysuccinimide and so on), obtained by using the above-mentioned dehydrating-condensing agent, (c) method via the acid chloride by using thionyl chloride, oxalicacid etc., (d) method via a mixed anhydride by using atilglukuronida, isobutylparaben and so on, (e) the way in which use reagent Woodward To, or (f) the way in which the use of the reagent, usually used for amidation (such as triptorelin N-ethyl-2'-hydroxybenzotriazole, N-ethyl-5-phenylisoxazole-3'-sulfonate, 1-etoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline, hexaflurophosphate benzotriazolyl-N-hydroxytrimethylene and diphenylphosphoryl).

Typical compounds of formula (1) according to the present invention is shown in the table. 1 and 2. In table.1 Me means methyl, Et means ethyl, Ph denotes phenyl,iPr represents isopropyl andtBu represents tert-butyl.

A derivative of pyridine (1) of the present invention or its salt after treatment together with a pharmaceutically acceptable carrier in accordance with a customary method Verdugo type or liquid type.

Examples of oral preparations include tablets, pills, granules, hard and soft capsules, powders, fine granules, powders, emulsions, syrups, balls and elixirs. Examples of parenteral drugs include drugs for injection, instillation, transfusion, ointments, lotions, tonic preparations, sprays, suspensions, oils, emulsions and suppositories. Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention, is not specifically limited and, if necessary, the composition add the following materials: surfactants, fillers, coloring agents, agents that improve the smell, preservatives, stabilizers, buffers, suspendresume agents, isotonic agents, etc.

The number of input pyrimidine derivative (1) or its salt varies in accordance with the individuality of this connection, a disease that must be treated or prevented by the method of administration, the age and symptoms of the patient, duration of treatment, etc., In the case of parenteral administration, the number of input connections is preferably between 0.01 and 30 mg/kg, more preferably 0.1 to 10 mg/kg for subcutaneous, vnutrivennogo of 0.01-100 mg/kg, more preferably 0.3 to 30 mg/kg

Examples

The present invention will be then described in more detail by means of examples, which should not be construed as limiting the invention

The SYNTHESIS EXAMPLE 1: Synthesis of 4-tert-butyl-N-[2,6-dichloro-5-(2 - methoxyphenoxy)-4-pyrimidinyl]benzosulfimide (5)

1) Sodium (3.2 g, 160 mmol) is dissolved in ethanol (200 ml). To the mixture while cooling on ice, add diethyl (2-methoxyphenoxy)malonate (2) (11.2 g, 160 mmol) and urea (2.6 g, 44 mmol). The mixture is stirred for 4 hours at boiling under reflux. After cooling, the ethanol is evaporated and the residue is dissolved in a small amount of water and acidified with hydrochloric acid. Mixture is allowed to stand over night at room temperature. The crystals which precipitate is separated by filtration and dried, to thereby obtain a 7.1 g of 5-(2-methoxyphenoxy)pyrimidine-2,4,6-trione (3). This connection is added phosphorus oxychloride (70 ml) and kallidin (14 ml) and the mixture stirred for 10 h at boiling under reflux with heating. Once was evaporated oxychloride phosphorus, the remainder is added to ice water and the mixture extracted with ethyl acetate. The reaction mixture p is imagele (a mixture of ethyl acetate:hexane, 1:2), thereby obtaining 4.8 g (yield: 39%) of 5-(2-methoxyphenoxy)-2,4,6-trichloropyridine (4) in the form of a colorless solid.

1H-NMR (CDCl3, M. D., tetramethylsilane was (TMS): 3.86 (3H, s), 6.73 (1H, DD, J = 1.5, 8.1 Hz), 6.90 (1H, dt, J = 1.5, 8.1 Hz), 7.00 (1H, DD, J = 1.5, 7.3 Hz), 7.13 (1H, dt, J = 1.5, 7.3 Hz).

2) 5-(2-methoxyphenoxy)-2,4,6-trichloropyridin (4) (4.8 g, 15.6 mmol) dissolved in dimethyl sulfoxide (45 ml). To the mixture, while it is cooled on ice, add 4-tert-butylbenzenesulfonamide potassium (8.0 g, 32 mmol) and the mixture stirred for 30 min at room temperature. The reaction mixture was poured into water, acidified with hydrochloric acid and extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and evaporated. The residue is recrystallized from ether, thereby obtaining 4.9 g (yield: 65%) indicated in the title compounds as colorless needles.

1H-NMR (CDCl3:, M. D., TMS): 1.35 (9H, s), 3.92 (3H, s), 6.78 (1H, DD, J = 1.7, 8.3 Hz), 6.89 (1H, dt, J = 1.7, 7.3 Hz), 7.03 (1H, DD, J = 1.7, 8.3 Hz), 7.13 (1H, dt, J = 1.7, 7.3 Hz), 7.51 (2H, d, J = 8.8 Hz), 7.96 (2H, d, J = 8.8 Hz).

IR (KBr) cm-1: 3220, 2954, 1549, 1350, 1179

EXAMPLE of SYNTHESIS 2: Synthesis of 4-tert-butyl-N-[6-chloro-5-(2 - methoxyphenoxy)-2-morpholino-4-pyrimidinyl]benzosulfimide

4-tricolporate (5 ml). To the solution was added morpholine (175 mg, 2.0 mmol) and the resulting mixture is stirred over night at 100oC. After cooling, the reaction mixture was poured into water, acidified with hydrochloric acid and extracted with ethyl acetate, the extract washed with water, dried over anhydrous sodium sulfate and evaporated. The residue is purified column chromatography on silica gel (mixture of ethyl acetate: hexane, 1:2), thus receiving 240 mg (yield: 45%) indicated in the title compound as a white powder.

1H-NMR (CDCl3, M. D. , TMS): 1.33 (9H, s), 3.64 (8H, m), 4.04 (3H, s), 6.88 (1H, dt, J = 1.5, 8.1 Hz), 6.97 (1H, DD, J = 1.7, 8.1 Hz), 7.04 (1H, DD, J = 1.5, 8.1 Hz), 7.14 (1H, dt, J = 1.7, 8.1 Hz), 7.45 (2H, d, J = 8.8 Hz), 7.80 (2H, d, J = 8.8 Hz), 8.69 (1H, s).

IR (KBr) cm-1: 2965, 1605, 1540, 1495, 1440, 1340, 1115, 955, 755.

The SYNTHESIS EXAMPLE 3: Synthesis of 4-tert-butyl-N-[6-(3-hydroxypropoxy)- 5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyl]benzosulfimide

1,3-Propandiol (580 mg) was dissolved in dimethyl sulfoxide (15 ml). To the solution was added sodium hydride (297 mg) and 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-morpholino-4 - pyrimidinyl] benzosulfimide (1.1 g). The resulting mixture is stirred for 4 h at 120oC. To the reaction mixture are added ethyl acetate and then about who is evaporated. The residue is purified column chromatography on silica gel (mixture of chloroform: methanol, 50:1), thereby obtaining 802 mg (yield: 68%) indicated in the title compound as a white powder.

1H-NMR (CDCl3, M. D. , TMS): 1.33 (9H, s), 1.88 (2H, q, J = 6.0 Hz), 3.52-3.67 (10H, m), 4.01 (3H, s), 4.41 (2H, t, J = 6.0 Hz), 6.84 (1H, dt, J = 1.7, 8.1 Hz), 6.94 (1H, DD, J = 1.7, 8.1 Hz), 6.99 (1H, DD, J = 1.7, 8.2 Hz), 7.08 (1H, dt, J = 1.7, 8.2 Hz), 7.45 (2H, d, J = 8.8 Hz), 7.86 (2H, d, J = 8.8 Hz), 8.52 (1H, s).

IR (KBr) cm-1: 3495, 2965, 1615, 1580, 1500, 1440, 1170, 1110, 1085, 755.

EXAMPLE 1: Synthesis of 3-[6-(4-tert-butylphenylphosphine)-5-(2 - methoxyphenoxy)-2-morpholino-4-pyrimidinone]propionic acid

4-tert-Butyl-N-[6-(3-hydroxypropoxy)-5-(2-methoxyphenoxy)-2 - morpholino-4-pyrimidinyl] benzosulfimide (800 mg) is dissolved in dimethylformamide (40 ml). To the solution was added pyridinium dichromate (2,63 g) and the resulting mixture is stirred for 14 h at room temperature. To the reaction mixture are added ethyl acetate and then washed sequentially with 0.5 N. HCl, water and brine. The organic layer is dried over anhydrous sodium sulfate and evaporated. The residue is purified column chromatography on silica gel (mixture of chloroform: methanol 25: 1), thereby obtaining 128 mg (yield: 16%) specified in the header connect the 1 (3H, s), 4.53 (2H, t, J = 6.4 Hz), for 6.81 (1H, dt, J = 1.5, 7.6 Hz), 6.93-7.09 (3H, m), 7.44 (2H, d, J = 8.6 Hz), 7.84 (2H, d, J = 8.6 Hz).

IR (KBr) cm-1: 3210, 2965, 1720, 1615, 1560, 1500, 1440, 1250, 1170, 1110, 1085, 750.

EXAMPLE 2: Synthesis of N-(2-isopropylphenyl)-3-[6-(4- tert-butylphenylphosphine)-5-(2-methoxyphenoxy)-2-morpholino-4 - pyrimidinone]propionamide

3-[6-(4-tert-Butylphenylphosphine)-5-(2-methoxyphenoxy)-2 - morpholino-4-pyrimidinone]propionic acid (80 mg) dissolved in a mixture of dimethylformamide-methylene chloride (1: 1, 6 ml). To this mixture N-hydroxybenzotriazole2O (42.2 mg), 2-isopropylaniline (133,2 mg) and 1-(3-dimethylaminopropyl)-3-HCl (32,6 mg). The reaction mixture was stirred over night at room temperature. After evaporation of the solvent added ethyl acetate. The organic layer is successively washed with saturated aqueous NaHCO3, 0,5 N. HCl and brine, dried over anhydrous sodium sulfate and evaporated. The residue is purified column chromatography on silica gel (mixture of chloroform: methanol = 30: 1), thereby obtaining 97,2 mg (yield: 100%) specified in the title compounds as colorless oils.

1H-NMR (CDCl3, M. D., TMS): 1.09 (6H, d, J = 6.8 Hz), 1.32 (9H, s), 2.76 (2H, t, J = 5.7 Hz), 2.89 (1H, Sep., J = 6.8 Hz), 3.60 (8H, m), 3.90 (3H, s), 4.66 (2H, t, J = 5.7 KBr) cm-1: 2965, 1670, 1615, 1560, 1520, 1500, 1440, 1340, 1250, 1170, 1085, 755.

EXAMPLE 3: Synthesis of N-(2-pyridyl)-3-[6-(4- tert-butylphenylphosphine)-5-(2-methoxyphenoxy)-2-morpholino-4 - pyrimidinone]propionamide

3-[6-(4-tert-Butylphenylphosphine)-5-(2-methoxyphenoxy)-2 - morpholino-4-pyrimidinone] propionic acid (121 mg) was dissolved in methylene chloride (0.9 ml). Add oxalicacid (27 mg) and dimethylformamide (1 drop) and the mixture stirred for 30 min at room temperature. Add 2-aminopyridine (38 ml) and the mixture is stirred over night at room temperature. After evaporation of the solvent added ethyl acetate. The organic layer is successively washed with 0.5 N. HCl, saturated aqueous NaHCO3and brine, dried over anhydrous sodium sulfate and evaporated. The residue is purified column chromatography on silica gel (mixture of chloroform:methanol = 10:1), thereby obtaining 51 mg (yield: 37%) indicated in the title compound as a white powder.

1H-NMR (CDCl3, M. D., TMS): 1.32 (9H, s), 3.53-3.67 (8H, m), 3.95 (3H, s), 4.63 (1H, t, J = 6.1 Hz), 6.62 (1H, DDD, J = 2.4, 6.6, 8.1 Hz), 6.84-6.97 (3H, m), 7.03 (1H, DDD, J = 1.0, 4.9, 7.3 Hz), 7.44 (2H, d, J = 8.6 Hz), 7.68 (1H, dt, J = 2.0, 7.3 Hz), 7.83 (2H, d, J = 8.6 Hz), 8.14 (1H, d, J = 8.6 Hz), 8.23 (2H, m), 8.68 (1H, Shir.C).

IR (KBr) cm-1: Tin)-4-pyrimidinyl]benzosulfimide

The procedure described in the synthesis example 2, again using 4-tert-butyl-N-[2,6-dichloro-5-(2-methoxyphenoxy)-4 - pyrimidinyl] benzosulfimide (5) and 1-phenylpiperazine, thereby obtaining specified in the header of the connection.

The SYNTHESIS EXAMPLE 5: Synthesis of 4-tert-butyl-N-[6-(3-hydroxypropoxy)- 5-(2-methoxyphenoxy)-2-(4-phenylpiperazine)-4-pyrimidinyl]benzosulfimide

The method described in synthesis example 3, again using 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4 - phenylpiperazine)-4-pyrimidinyl]benzosulfimide and 1,3-propane diol, thereby obtaining specified in the title compound as a pale yellow oil.

1H-NMR (CDCl3, M. D., TMS): 1.31 (9H, s), 1.90 (2H, Sep., J = 5.9 Hz), 3.13 (4H, t, J = 4.6 Hz), 3.60 (2H, t, J = 5.9 Hz), 3.78

(4H, t, J = 4.6 Hz), 4.45 (2H, t, J = 5.9 Hz), 6.81-7.11 (8H, m), 7.31 (1H, d, J = 7.3 Hz), 7.47 (2H, d, J = 8.3 Hz), 7.89 (2H, d, J = 8.3 Hz).

EXAMPLE 4: Synthesis of 3-[6-(4-tert-butylphenylphosphine)-5-(2 - methoxyphenoxy)-2-(4-phenylpiperazine)-4-pyrimidinone]propionic acid

The procedure described in example 1 is repeated using 4-tert-butyl-N-[6-(3-hydroxypropoxy)-5-(2-methoxyphenoxy)-2-(4 - phenylpiperazine)-4-pyrimidinyl]benzosulfimide, thereby obtaining the specified B1.31 (9H, s), 2.71 (2H, t, J = 5.7 Hz), 3.80-4.11 (8H, W), 4.02 (3H, s), 4.62 (2H, t, J = 5.7 Hz), 6.70-7.36 (9H, m), 7.51 (2H, d, J = 8.5 Hz), 7.85 (2H, d, J = 8.5 Hz), 8.31 (1H, s), 9.33 (1H, s).

EXAMPLE 5: Synthesis of N-(2-isopropylphenyl)-3-[6-(4- tert-butylphenylphosphine)-5-(2-methoxyphenoxy)-2-(4 - phenylpiperazine)-4-pyrimidinone] propionamide

The procedure described in example 2 is repeated using 3-[6-(4-tert-butylphenylphosphine)-5-(2-methoxyphenoxy)-2-(4 - phenylpiperazine)-4-pyrimidinone] propionic acid and 2-isopropylaniline, thereby obtaining specified in the title compound as a pale yellow oil.

1H-NMR (CDCl3, M. D., TMS): 1.13 (6H, d, J = 6.3 Hz), 1.31 (9H, s), 2.92 (2H, t, J = 5.7 Hz), 3.00 (1H, Sep., J = 6.3 Hz), 3.90-4.12 (8H, s), 4.02 (3H, s), 4.79 (2H, t, J = 7.5 Hz), 6.87 (1H, t, J = 6.0 Hz), 6.96-7.57 (11H, m), 7.51 (2H, d, J = 8.6 Hz), 7.85 (2H, d, J = 8.6 Hz).

The SYNTHESIS EXAMPLE 6: Synthesis of 4-tert-butyl-N-[6-chloro-2-(4 - isopropylpiperazine)-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzosulfimide

The procedure described in the synthesis example 2, again using 4-tert-butyl-N-[2,6-dichloro-5-(2-methoxyphenoxy)-4 - pyrimidinyl] benzosulfimide (5) and 1-isopropylpiperazine, thereby obtaining specified in the title compound as a pale yellow oil.

1H-NMR (CDCl3, M. D. , TMS): 1, the d, J = 1.5, 7.8 Hz), 7.36 (2H, d, J = 8.3 Hz), 7.51 (2H, d, J = 8.3 Hz).

The SYNTHESIS EXAMPLE 7: Synthesis of 4-tert-butyl-N-[6-(3-hydroxypropoxy)- 2-(4-isopropylpiperazine)-5-(2-methoxyphenoxy)-4 - pyrimidinyl] benzosulfimide

The method described in synthesis example 3, again using 4-tert-butyl-N-[6-chloro-2-(4-isopropylpiperazine)-5-(2 - methoxyphenoxy)-4-pyrimidinyl]benzosulfimide and 1,3-propane diol, thereby obtaining specified in the title compound as a pale yellow oil.

1H-NMR (CDCl3, M. D., TMS): 1.06 (6H, d, J = 6.6 Hz), 1.32 (9H, s), 1.88 (2H, t, J = 6.1 Hz), 2.50 (4H, t, J = 4.9 Hz), 2.76 (1H, Sep., J = 6.6 Hz), 3.58 (2H, t, J = 6.1 Hz), 3.66 (4H, t, J = 4.9 Hz), 4.00 (3H, s), 4.41 (2H, t, J = 6.1 Hz), 6.77-7.14 (4H, m), 7.45 (2H, d, J = 8.7 Hz), 7.87 (2H, d, J = 8.7 Hz).

EXAMPLE 6: Synthesis of 3-[6-(4-tert-butylphenylphosphine)-2-(4 - isopropylpiperazine)-5-(2-methoxyphenoxy)-4-pyrimidinone]propionic acid

The procedure described in example 1 is repeated using 4-tert-butyl-N-[6-(3-hydroxypropoxy)-2-(4-isopropylpiperazine)- 5-(2-methoxyphenoxy)-4-pyrimidinyl]benzosulfimide, thereby obtaining specified in the header of the connection.

EXAMPLE 7: Synthesis of N-(2-isopropylphenyl)-3-[6-(4- tert-butylphenylphosphine)-2-(4-isopropylpiperazine)-5-(2 - detoxifier-butylphenylphosphine)-2-(4-isopropylpiperazine)-5-(2 - methoxyphenoxy)-4-pyrimidinone]propionic acid and 2-isopropylaniline, so getting listed in the title compound as a pale yellow oil.

1H-NMR (CDCl3, M. D., TMS): 1.12 (6H, d, J = 6.8 Hz), 1.24 (6H, d, J = 6.8 Hz), 1.32 (9H, s), 2.70 (4H, t, J = 4.9 Hz), 2.91-3.28 (4H, m), 3.31 (4H, t, J = 4.9 Hz), 4.03 (3H, s), 4.91 (2H, t, J = 7.1 Hz), 6.60-7.25 (8H, m), 7.52 (2H, d, J = 8.6 Hz), 7.87 (2H, d, J = 8. 6 Hz).

EXAMPLE 8 SYNTHESIS: Synthesis of 4-tert-butyl-N-[6-chloro-5-(2 - methoxyphenoxy)-2-(4-methylpiperazine)-4-pyrimidinyl]benzosulfimide

The procedure described in the synthesis example 2, again using 4-tert-butyl-N-[2,6-dichloro-5-(2-methoxyphenoxy)-4 - pyrimidinyl] benzosulfimide (5) and N-methylpiperazine, thereby obtaining specified in the title compound as a pale yellow oil.

1H-NMR (CDCl3, M. D., TMS): 1.33 (9H, s), 2.31 (3H, s), 2.36 (4H, t, J = 4.6 Hz), 3.68 (4H, t, J = 4.6 Hz), 4.04 (3H, s), 6.88 (1H, dt, J = 1.5, 6.4 Hz), 6.96 (1H, DD, J = 1.5, 6.4 Hz), 7.04 (1H, DD, J = 1.5, 6.5 Hz), 7.11 (1H, dt, J = 1.5, 6.5 Hz).

EXAMPLE 9 SYNTHESIS: Synthesis of 4-tert-butyl-N-[6-(3-hydroxypropoxy - 5-(2-methoxyphenoxy)-2-(4-methylpiperazine)-4-pyrimidinyl]benzosulfimide

The method described in synthesis example 3, again using 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4 - phenylpiperazine)-4-pyrimidinyl]benzosulfimide and 1,3-propane diol, thus polucha.32 (9H, C) of 1.84-1.92 (2H, m), 2.31 (3H, s), 2.36 (4H, t, J = 4.9 Hz), 3.58 (2H, t, J = 6.0 Hz), 3.64 (4H, t, J = 4.9 Hz), 4.01 (3H, s), 4.41 (2H, t, J = 6.0 Hz), 6.84 (1H, dt, J = 1.5, 7.1 Hz), 6.94 (1H, DD, J = 1.5, 7.1 Hz), 6.99 (1H, DD, J = 1.5, 7.1 Hz), 7.07 (1H, dt, J = 1.5, 7.1 Hz), 7.45 (2H, d, J = 8.6 Hz), 7.87 (2H, d, J = 8.6 Hz).

EXAMPLE 8: Synthesis of 3-[6-(4-tert-butylphenylphosphine)-5-(2 - methoxyphenoxy)-2-(4-methylpiperazine)-4-pyrimidinone]propionic acid

The procedure described in example 1 is repeated using 4-tert-butyl-N-[6-(3-hydroxypropoxy)-5-(2-methoxyphenoxy)-2-(4 - methylpiperazine)-4-pyrimidinyl]benzosulfimide, thereby obtaining specified in the header of the connection.

EXAMPLE 9: Synthesis of N-(2-isopropylphenyl)-3-[6-(4- tert-butylphenylphosphine)-5-(2-methoxyphenoxy)-2-(4 - methylpiperazine)-4-pyrimidinone] propionamide

The procedure described in example 2 is repeated using 3-[6-(4-tert-butylphenylphosphine)-5-(2-methoxyphenoxy)-2-(4 - methylpiperazine)-4-pyrimidinone] propionic acid and 2-isopropylaniline, thereby obtaining specified in the title compound as a pale yellow solid.

1H-NMR (CDCl3, M. D., TMS): 1.13 (6H, d, J = 6.8 Hz), 1.32 (9H, s), 2.32 (3H, s), 2.49 (4H, t, J = 4.9 Hz), 2.90 (2H, t, J = 5.8 Hz), 2.99 (1H, Sep., J = 6.8 Hz), 3.60 (4H, t, J = 4.9 Hz), 4.01 (3H, s), 4.75 (2H, t, J =is ethoxyphenoxy)-2-(4-methylhomopiperazine)-4-pyrimidinyl]benzosulfimide

The procedure described in the synthesis example 2, again using 4-tert-butyl-N-[2,6-dichloro-5-(2-methoxyphenoxy)-4 - pyrimidinyl] benzosulfimide (5) and N-methylhomopiperazine, thereby obtaining specified in the title compound as a pale yellow oil.

1H-NMR (CDCl3, M. D., TMS): 1.32 (9H, s), 1.98-2.10 (2H, W), 2.45 (3H, s), 2.65-2.81 (4H, W), 3.6-3.88 (4H, W), 4.04 (3H, s), 6.87-7.16 (4H, m), 7.46 (2H, t, J = 8.3 Hz), 7.79 (2H, d, J = 8.3 Hz).

EXAMPLE 11 SYNTHESIS: Synthesis of 4-tert-butyl-N-[6-(3 - hydroxypropoxy)-5-(2-methoxyphenoxy)-2-(4-methylhomopiperazine)-4 - pyrimidinyl]benzosulfimide

The method described in synthesis example 3, again using 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4 - methylhomopiperazine)-4-pyrimidinyl]benzosulfimide and 1,3-propane diol, thereby obtaining specified in the title compound as a pale yellow oil.

1H-NMR (CDCl3, M. D., TMS): 1.33 (9H, s), 1.81-1.99 (4H, m), 1.32 (9H, s), 2.36 (3H, s), 2.44-2.60 (4H, W), 3.59 (2H, t, J = 6.1 Hz), 3.64-3.79 (4H, Shir. ), 4.01 (3H, s), 4.43 (2H, t, J = 6.1 Hz), 6.85 (1H, t, J = 8.1 Hz), 6.95-7.11 (3H, m), 7.46 (2H, d, J = 8.5 Hz), 7.86 (2H, d, J = 8.5 Hz).

EXAMPLE 10: Synthesis of 3-[6-(4-tert-butylphenylphosphine)-5-(2 - methoxyphenoxy)-2-(4-methylhomopiperazine)-4-pyrimidinone]propionic acid

is noxy)-2-(4 - methylhomopiperazine)-4-pyrimidinyl]benzosulfimide, so getting listed at the beginning of the connection.

EXAMPLE 11: Synthesis of N-(2-isopropylphenyl)-3-[6-(4- tert-butylphenylphosphine)-5-(2-methoxyphenoxy)-(4 - methylhomopiperazine)-4-pyrimidinone] propionamide

The procedure described in example 2 is repeated using 3-[6-(4-tert-butylphenylphosphine)-5-(2-methoxyphenoxy)-2-(4 - methylhomopiperazine)-4-pyrimidinone]propionic acid and 2-isopropylaniline, thereby obtaining specified in the title compound as a pale yellow oil.

1H-NMR (CDCl3, M. D. , TMS): 1.13 (6H, d, J = 6.8 Hz), 1.33 (9H, s), 1.85-2.01 (2H, W), 2.36 (3H, s), 2.49-2.89 (6H, m), 2.99 (1H, Sep., J = 6.8 Hz), 3.60-3.85 (4H, Shir. ), 4.00 (3H, s), 4.75 (2H, t, J = 5.9 Hz), 6.89-7.25 (8H, m), 7.48 (2H, d, J = 8.5 Hz), 7.86 (2H, d, J = 8.5 Hz).

EXAMPLE 12 SYNTHESIS: Synthesis of 4-tert-butyl-N-[6-chloro-2-(4 - formylpiperazine)-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzosulfimide

The procedure described in the synthesis example 2, again using 4-tert-butyl-N-[2,6-dichloro-5-(2-methoxyphenoxy)-4 - pyrimidinyl]benzosulfimide (5) and 1-formylpiperazine, thereby obtaining specified in the title compound as a pale yellow oil.

1H-NMR (CDCl3, M. D., TMS): 1.33 (9H, s), 3.33 (2H, t, J = 4.9 Hz), 3.50 (2H, t, J = 4.9 Hz), 3.65 (2H, t, J = 4.9 Hz), 3 J = 8.5 Hz), 7.81 (2H, d, J = 8.5 Hz), 8.12 (1H, s).

EXAMPLE 13 SYNTHESIS: Synthesis of 4-tert-butyl-N-[2-(4-formylpiperazine)- 6-(3-hydroxypropoxy)-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzosulfimide

The method described in synthesis example 3, again using 4-tert-butyl-N-[6-chloro-2-(4-formylpiperazine)-5-(2 - methoxyphenoxy)-4-pyrimidinyl]benzosulfimide and 1,3-propane diol, thereby obtaining specified in the title compound as a pale yellow solid.

1H-NMR (CDCl3, M. D., TMS): 1.31 (9H, s), 1.87 (1H, m), 3.03 (4H, Shir.s), 3.57 (2H, t, J = 5.9 Hz), 3.82 (4H, Shir.s), 3.99 (3H, s), 4.38 (2H, t, J = 5.9 Hz), 6.83 (1H, dt, J = 1.5, 8.1 Hz), 6.92 (1H, DD, J = 1.5, 8.1 Hz), 6.98 (1H, DD, J = 1.5, 8.1 Hz), 7.06 (1H, d, J = 1.5, 8.1 Hz), 7.45 (2H, d, J = 8.5 Hz), 7.82 (2H, d, J = 8.5 Hz).

EXAMPLE 14 SYNTHESIS: Synthesis of 4-tert-butyl-N-[2-(4-formylpiperazine)- 6-(3-hydroxypropoxy)-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzosulfimide

4-tert-Butyl-N-[6-(3-hydroxypropoxy)-5-(2-methoxyphenoxy)-2 - piperazinil-4-pyrimidinyl]benzosulfimide (80 mg, 0.14 mmol), WSC HCl (61,6 mg, 0.28 mmol), N-hydroxybenzotriazole (75,6 mg of 0.56 mmol) and formic acid (6.5 mg, 0.15 mmol) dissolved in a mixture of dimethylformamide-methylene chloride (1: 1.1 ml). The mixture is stirred over night at room temperature. The reaction sorayut water, dried over anhydrous sodium sulfate and evaporated. The residue is purified column chromatography on silica gel (mixture of chloroform:methanol = 15:1), thereby obtaining 20 mg (yield: 23.8 per cent) indicated in the title compounds as a pale yellow oil.

1H-NMR (CDCl2, M. D., TMS): 1.33 (9H, s), 1.82-1.95 (2H, m), 3.29 (2H, t, J = 4.9 Hz), 3.47 (2H, t, J = 4.9 Hz), 3.53-3.78 (6H, m), 4.01 (3H, s), 4.41 (2H, t, J = 6.1 Hz), 6.82-7.11 (4H, m), 7.47 (2H, d, J = 8.8 Hz), 7.86 (2H, d, J = 8.8 Hz), 8.10 (1H, s).

EXAMPLE 12: Synthesis of 3-[6-(4-tert-butylphenylphosphine)-2-(4 - formylpiperazine)-5-(2-methoxyphenoxy)-4-pyrimidinone]propionic acid

The procedure described in example 1 is repeated using 4-tert-butyl-N-[2-(4-formylpiperazine)-6-(3-hydroxypropoxy)-5-(2 - methoxyphenoxy)-4-pyrimidinyl] benzosulfimide, thereby obtaining specified in the title compound as a pale yellow solid.

1H-NMR (CDCl3, M. D., TMS): 1.31 (9H, s), 2.78 (2H, t, J = 6.6 Hz), 3.27 (2H, t, J = 6.3 Hz), 3.41 (2H, t, J = 6.3 Hz), 3.67-3.79 (4H, m), 4.04 (3H, s), 4.37 (2H, t, J = 6.6 Hz), 6.73 (1H, DD, J = 1.5, 8.0 Hz), 6.86 (1H, dt, J = 1.5, 8.0 Hz), 7.05 (1H, DD, J = 1.5, 8.0 Hz), 7.10 (1H, dt, J = 1.5, 8.0 Hz), 7.45 (2H, d, J = 8.6 Hz),7.81 (2H, d, J = 8.6 Hz), 8.01 (1H, s).

EXAMPLE 13: Synthesis of N-(2-isopropylphenyl)-3-[6-(4- tert-butylphenylphosphine)-2-(4-formylpiperidine 3-[6-(4-tert-butylphenylphosphine)-2-(4-formylpiperazine)-5-(2 - methoxyphenoxy)-4-pyrimidinone]propionic acid and 2-isopropylaniline, so getting listed in the title compound as a pale yellow solid.

1H-NMR (CDCl3, M. D., TMS): 1.10 (6H, d, J = 7.1 Hz), 1.32 (9H, s), 2.77 (2H, t, J = 5.7 Hz), 2.89 (1H, Sep, J = 7.1 Hz), 3.26 (2H, Shir.s), 3.45 (2H, Shir. s), 3.57-3.79 (4H, W), 3.94 (3H, s), 4.68 (2H, t, J = 5.7 Hz), 6.68 (1H, m), 6.82-7.29 (7H, m), 7.46 (2H, d, J = 8.3 Hz), 7.82 (2H, d, J = 8.3 Hz), 8.09 (1H, s).

EXAMPLE 15 SYNTHESIS: Synthesis of 4-tert-butyl-N-[2-(4 - tert-butoxycarbonylmethyl)-6-(3-hydroxypropoxy)-5-(2 - methoxyphenoxy)-4-pyrimidinyl] benzosulfimide

4-tert-Butyl-N-[6-(3-hydroxypropoxy)-5-(2-methoxyphenoxy)-2 - piperazinil-4-pyrimidinyl] benzosulfimide (55 mg, 0,096 mmol) dissolved in chloroform (2 ml). To the solution was added N,N-dimethylaminopyridine (1.5 mg, 0.01 mmol) and di-tert-BUTYLCARBAMATE (21,8 mg, 0.1 mmol). The resulting mixture is stirred over night at room temperature and then poured into water and extracted with chloroform. The organic layer is washed with water, dried over anhydrous sodium sulfate and evaporated. The residue is purified column chromatography on silica gel (chloroform:methanol = 10:1), thereby obtaining 61 mg (yield: 94%) indicated in the title compounds as a pale yellow oil.

1H-NMR (CDCl3, M. D., TMS): 1.33 (9H, s), 1.48 (9H, s), 1.86-1 Hz), 7.08 (1H, dt, J = 1.7, 8.1 Hz), 7.47 (2H, d, J = 8.5 Hz), 7.86 (2H, d, J = 8.5 Hz).

IR (KBr) cm-1: 3020, 2401, 1522, 1212, 1047.

EXAMPLE 14: Synthesis of 3-[2-(4-tert-butoxycarbonylmethyl)-6-(4 - tert-butylphenylphosphine)-5-(2-methoxyphenoxy)-4 - pyrimidinone] propionic acid

The procedure described in example 1 is repeated using 4-tert-butyl-N-[2-(4-tert-butoxycarbonylmethyl)-6-(3 - hydroxypropoxy)-5-(2-methoxyphenoxy)-4-pyrimidinyl] benzosulfimide, thereby obtaining specified in the title compound as a pale yellow oil.

1H-NMR (CDCl3, M. D., TMS): 1.33 (9H, s), 1.48 (9H, s), 2.75 (2H, t, J = 6.4 Hz), 3.34 (4H, Shir.s), 3.56 (4H, Shir.s), 4.01 (3H, s), 4.53 (2H, t, J = 6.4 Hz), 6.82 (1H, t, J = 7.1 Hz), 6.94-7.06 (3H, m), 7.46 (2H, d, J = 8.8 Hz), 7.85 (2H, d, J = 8.8 Hz).

EXAMPLE 15: Synthesis of N-(2-isopropylphenyl)-3-[2-(4- tert-butoxycarbonylmethyl)-6-(4-tert-butylphenylphosphine)- 5-(2-methoxyphenoxy)-4-pyrimidinone]propionamide

The procedure described in example 2 is repeated using 3-[2-(4-tert-butoxycarbonylmethyl)-6-(4 - tert-butylphenylphosphine)-5-(2-methoxyphenoxy)-4 - pyrimidinone]propionic acid and 2-isopropylaniline, thereby obtaining specified in the title compound as a pale yellow oil.

EXAMPLE 16: Synthesis of N-(1-phenylethyl)-[6-(4-tert-butylphenylphosphine)-2-(4-formylpiperazine)-5-(2 - methoxyphenoxy)-4-pyrimidinone]ndimethylacetamide

N-(1-Phenylethyl)hydroxyacetamido (50 mg, 0.3 mmol) was dissolved in dimethyl sulfoxide (0,56 ml). To the solution was added sodium (11.5 mg, 0.5 mmol) and the resulting mixture was stirred at room temperature for two hours. To the mixture is added 4-tert-butyl-N-[6-chloro-2-(4-formylpiperazine)-5-(2-methoxyphenoxy)-4 - pyrimidinyl] benzosulfimide (56 mg, 0.1 mmol) and the resulting mixture is stirred for 1 h at 120 C, then poured into water, acidified with hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous sodium sulfate and evaporated. The residue is purified column chromatography on silica gel (chloroform:methanol = 20: 1), thereby obtaining of 23.8 mg (yield: 34%) indicated in the title compounds as a pale yellow oil.

1H-NMR (CDCl3, M. D. , TMS): 1.18 (3H, d, J = 7.1 Hz), 1.22 (9H, s), 3.04-3.12 (2H, m), 3.26-3.35 (2H, m), 3.37-3.49 (4H, m), 3.80 (3H, s), 4.58 (2H, s), 4.97 (1H, m), 6.63-6.73 (2H, m), 6.84 (1H, DD, J = 1.5, 7.8 Hz), 6.89 - 6.98 (3H, m), 7.03-7.11 (3H, m), 7.39 (2H, d, J = 8.5 Hz), 7.77 (2H, d, J = 8.5 is-2-morpholino-4 - pyrimidinone]propionamide

The procedure described in example 2 is repeated using 3-[6-(4-tert-butylphenylphosphine)-5-(2-methoxyphenoxy)-2 - morpholino-4-pyrimidinone] propionic acid and 2-ethylaniline, thereby obtaining specified in the title compound as a colourless oil.

1H-NMR (CDCl3, M. D., TMS): 1.08 (3H, t, J = 7.6 Hz), 1.32 (9H, s), 2.41 (2H, K, J = 7.6 Hz), 2.74 (2H, t, J = 5.7 Hz), 3.60 (8H, s), 3.88 (3H, s), 4.64 (2H, t, J = 5.7 Hz), 6.66 (1H, m), 6.85-6.94 (2H, m), 7.14-7.26 (4H, m), 7.44 (2H, d, J = 8.8 Hz), 7.59 (1H, d, J = 7.8 Hz), 7.82 (2H, d, J = 8.8 Hz), 8.65 (1H, Shir.C).

IR (KBr) cm-1: 2970, 1670, 1615, 1560, 1500, 1440, 1340, 1250, 1170, 1110, 1080, 750.

EXAMPLE 18: Synthesis of N-(2,6-dimetilfenil)-3-[6-(4- tert-butylphenylphosphine)-5-(2-methoxyphenoxy)-2-morpholino-4 - pyrimidinone]propionamide

The procedure described in example 3 is repeated using 3-[6-(4-tert-butylphenylphosphine)-5-(2-methoxyphenoxy)-2 - morpholino-4-pyrimidinone] propionic acid, 2,6-dimethylaniline, thereby obtaining specified in the title compound as a colourless oil.

1H-NMR (CDCl3, M. D., TMS): 1.33 (9H, s), 2.02 (6H, s), 2.71 (2H, t, J = 5.7 Hz), 3.65 (8H, m), 3.67 (3H, s), 4.61 (2H, t, J = 5.7 Hz), 6.67-6.73 (2H, m), 6.81-6.85 (2H, m), 6.88-7.09 (3H, m), 7.45 (2H, d, J = 8.8 Hz), 7.85 (2H, d, J = 8.8 Hz), 8.45 (1H, Shir.C).

IR (KBr) cm-1: 2965, 1670, Mino)-5-(2-methoxyphenoxy)-2-morpholino-4 - pyrimidinone]propionamide

The procedure described in example 2 is repeated using 3-[6-(4-tert-butylphenylphosphine)-5-(2-methoxyphenoxy)-2 - morpholino-4-pyrimidinone]propionic acid and 2-methoxyaniline, thereby obtaining specified in the title compound as a colourless oil.

1H-NMR (CDCl3, M. D., TMS): 1.29 (9H, s), 2.40 (2H, t, J = 6.1 Hz), 3.56 (8H, m), 3.70 (3H, s), 3.93 (3H, s), 4.62 (2H, t, J = 6.1 Hz), 6.55 (1H, m), 6.78 (1H, d, J = 8.1 Hz), 6.80-7.01 (5H, m), 7.31 (2H, d, J = 8.6 Hz), 7.78 (2H, d, J = 8.6 Hz), 7.83 (1H, m), 8.28 (1H, d, J = 7.8 Hz).

IR (KBr) cm-1: 2965, 1685, 1600, 1560, 1500, 1440, 1335, 1250, 1170, 1115, 1085, 750.

EXAMPLE 20: Synthesis of N-(4-isopropylphenyl)-3-[6-(4- tert-butylphenylphosphine)-5-(2-methoxyphenoxy)-2-morpholino-4 - pyrimidinone]propionamide

The procedure described in example 2 is repeated using 3-[6-(4-tert-butylethylenediamine)-5-(2-methoxyphenoxy)-2 - morpholino-4-pyrimidinone]propionic acid and 4-isopropylaniline, thereby obtaining specified in the title compound as a colourless oil.

1H-NMR (CDCl3, M. D., TMS): 1.22 (6H, d, J = 6.8 Hz), 1.32 (9H, s), 2.66 (2H, t, J = 5.9 Hz), 2.86 (1H, Sep., J = 6.8 Hz), 3.50-3.65 (8H, m), 3.86 (3H, s), 4.59 (2H, t, J = 5.9 Hz), 6.63 (1H, dt, J = 7.7, 1.5 Hz), 6.81-6.98 (3H, m), 7.11 (2H, d, J = 8.5 Hz), 7.27 (2H, d, J 8.5 Hz), 7.43 (2H, d, J = 8.8 Hz), 7.82 (2H, d, J = 8.8 Hz), 8.71 (isopropylphenyl)-3-[6-(4- tert-butylphenylphosphine)-5-(2-methoxyphenoxy)-2-morpholino-4 - pyrimidinone]propionamide

The procedure described in example 2 is repeated using 3-[6-(4-tert-butylphenylphosphine)-5-(2-methoxyphenoxy)-2 - morpholino-4-pyrimidinone] propionic acid and 3-isopropylaniline, thereby obtaining specified in the title compound as a colourless oil.

1H-NMR (CDCl3, M. D., TMS): 1.21 (6H, d, J = 7.1 Hz), 1.32 (9H, s), 2.69 (2H, t, J = 6.0 Hz), 2.84 (1H, Sep., J = 7.1 Hz), 3.50-3.65 (8H, m), 3.93 (3H, s), 4.62 (2H, t, J = 6.0 Hz), 6.64 (1H, dt, J = 7.6, 1.5 Hz), 6.85-7.01 (4H, m), 7.14-7.22 (2H, m), 7.30 (1H, Shir.s), 7.43 (2H, d, J = 8.8 Hz), 7.82 (2H, d, J = 8.8 Hz), 8.72 (1H, Shir. C).

IR (KBr) cm-1: 2965, 1700, 1615, 1560, 1495, 1440, 1340, 1250, 1170, 1115, 1085, 755.

EXAMPLE 22: Synthesis of methyl 3-[6-(4-tert-butylphenylphosphine)- 5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinone]propionate

Methanol (0.5 ml) and concentrated sulfuric acid (two drops) are added to 3-[6-(4-tert-butylphenylphosphine)-5-(2 - methoxyphenoxy)-2-morpholino-4-pyrimidinone] propionic acid (50 mg) and the mixture stirred for 4 h at room temperature, then poured into water and extracted with ethyl acetate. The extract is washed successively with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified preparative thin-layer chromatogr is inane in the form of a colorless oil.

1H-NMR (CDCl3, M. D., TMS): 1.32 (9H, s), 2.71 (2H, t, J = 6.4 Hz), 3.62 (3H, s), 3.52-3.69 (8H, m), 4.02 (3H, s), 4.54 (2H, t, J = 6.4 Hz), 6.84 (1H, DDD, J = 8.1, 7.3, 1.5 Hz), 6.99 (1H, DD, J = 8.1, 1.5 Hz), 7.00 (1H, DD, J = 8.1, 1.5 Hz), 7.08 (1H, DDD, J = 8.1, 7.3, 1.5 Hz), 7.44 (2H, d, J 8.8 Hz), 7.84 (2H, d, J = 8.8 Hz), 8.70 (1H, Shir.C).

IR (KBr) cm-1: 2965, 1740, 1615, 1560, 1500, 1440, 1340, 1250, 1170, 1115, 1085, 750.

EXAMPLE 23: Synthesis of benzyl 3-[6-(4-tert-butylphenylphosphine)- 5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinone]propionate

The procedure described in example 22, is repeated using 3-[6-(4-tert-butylphenylphosphine)-5-(2-methoxyphenoxy)-2 - morpholino-4-pyrimidinone] propionic acid and benzyl alcohol, thereby obtaining specified in the title compound as a colourless oil.

1H-NMR (CDCl3, M. D., TMS): 1.32 (9H, s), 2.75 (2H, t, J = 6.4 Hz), 3.62 (3H, s), 3.50-3.65 (8H, m), 4.01 (3H, s), 4.56 (2H, t, J = 6.4 Hz), 5.04 (2H, s), 6.80 (1H, DDD, J = 8.1, 7.3, 1.5 Hz), 6.97 (1H, DD, J = 8.3, 1.5 Hz), 6.98 (1H, DD, J = 8.1, 1.5 Hz), 7.06 (1H, DDD, J = 8.3, 7.3, 3.1 Hz), 7.30 (5H, m), 7.44 (2H, d, J = 8.5 Hz), 7.84 (2H, d, J = 8.5 Hz), 8.70 (1H, Shir.C).

IR (KBr) cm-1: 2965, 1740, 1595, 1500, 1440, 1340, 1250, 1170, 1110, 1085, 750.

Example 1 tests: Experiment on inhibition of binding of endothelin

Obtaining the crude membrane samples of the receptor (ETAfrom smooth m the th was removed with gauze endothelium, crushed and then homogenized in three volumes of buffer Tris-HCl (pH of 7.4) (buffer A) containing 0.25 M sucrose, 3 mm ethylenediaminetetraacetic acid, 5 μg/ml Aprotinin, 10 μg/ml of pepstatin A, 10 μg/ml leupeptin and 0.1 μm p-amidinotransferase. After centrifugation for 30 min at 1000g supernatant further centrifuged for 30 min at 100000g. The precipitate in the test tube suspended in buffer A and recentrifuged for 30 min at 100000g. The precipitate is suspended in buffer A and the suspension stored at -80oC.

The analysis of binding125I-endothelin-1:

Thus obtained membrane sample (1 µl) was incubated together with125I-endothelin-1 (2 of 10-11M) and connections used in different concentrations for 2 h at 25oC in 250 ál total volume 50 mm buffer Tris-HCl (pH 7,4) containing 0.5% bovine serum albumin. Incubated the mixture is filtered using filters HVPP (pore size 0.45 μm, product Milipore). The filters are washed with cold buffer And four times and measure the count of gamma-rays (Aroka Autowell Gamina System ARC-251).

Obtaining the crude membrane samples of the receptor (ETB) from rat brain and analysis125I-endothelin-1:

The brain tissue is which is used in the above case, the porcine thoracic aorta. In addition, the analysis125I-endothelin-1 is conducted in the same manner as described above.

The results thus conducted experiment on inhibition of binding of endothelin to each of the two receptors is given in table 3.

Additional Example 1

Synthesis of sodium salt of the compound of Example 2

N-(2-isopropylphenyl)-3-[6-(4-tert-butylphenylphosphine)-5-(2 - methoxyphenoxy)-2-morpholino-4-pyrimidinone] propionamide (76 g) dissolved in ethyl acetate and washed with saturated aqueous NaHCO3and then saturated aqueous NaCl. This mixture is dried over anhydrous sodium sulfate, concentrated under reduced pressure and recrystallized from methanol-ether, the result is the sodium salt of N-(2-isopropylphenyl)-3-[6-(4-tert - butylphenylphosphine)-5-(2-methoxyphenoxy)-2-morpholino-4 - pyrimidinone]propionamide (53 g) as colorless powder.

Additional Example 2

Synthesis of sodium salt of the compound of Example 3

N-(2-pyridyl)-3-[6-(4-tert-butylphenylphosphine)-5-(2 - methoxyphenoxy)-2-morpholino-4-pyrimidinone]propionamide (14 g) is dissolved in a solvent mixture of dichloromethane-methanol, then to the resulting solution at re completion of the reaction the mixture was concentrated under reduced pressure, recrystallized from diethyl ether, followed by heating and suspendirovanie in ethyl acetate. The result is the sodium salt of N-(2-pyridyl)-3-[6-(4-tert-butylphenylphosphine)-5-(2 - methoxyphenoxy)-2-morpholino-4-pyrimidinone]propionamide (10 g) as colorless powder.

Additional Example 3

The compound of Example 3 (60 g), lactose (3084 g), nitrosamino hydroxypropylcellulose (360 g) and hydroxypropylcellulose (60 g) are mixed using a high speed apparatus for mixing and granulating, kneaded with water, dried in a vacuum dryer to obtain granules. The obtained granules were milled until homogeneous particles and then mixed with magnesium stearate (36 g), using a V-shaped mixer, and then crush them into powder. The powder was processed using tabletiruemogo apparatus, which receives the tablets with a diameter of 7.0 mm (weighing 2 mg each).

Additional test data

The test was performed using a model of renal disease in rats caused by abnormal proliferation mesangial region (mesangial cells and substrates), known as a key factor that plays an important role in n the project for the effectiveness of this compound. The result of this experiment it was found that the compound is highly effective suppressor of proliferation mesangial area, as well as suppressor in relation to the high content of peptides in urine.

Industrial applicability

New pyrimidine derivatives (1) according to the present invention possess a strong inhibitory binding activity against endothelin, having a very strong vasoconstrictor action. Therefore, these compounds are effective as medicines for various associated with endothelin diseases, including heart disease, such as ischemic heart attack, congestive heart failure, arrhythmia, unstable angina; diseases of the respiratory tract, such as asthma; hypertension, such as pulmonary hypertension and renal hypertension; hypofunction of the authorities, which may occur in connection with their operation or transplantation, subarachnoid hemorrhage; re-narrowing of the blood vessels after RTSA; disease, flowing with blood circulation, such as vasospasm; kidney diseases such as acute and chronic renal failure; diseases that are accompanied by vascular damage, liver; gastrointestinal disorders, such as disorders of the mucous membrane of the stomach; bone disease; prostatic hypertrophy and urinary disorders.

1. Derivatives of pyrimidine of the General formula I or the salts of these derivatives

< / BR>
where R1represents a hydroxyl group, a lower CNS group, phenyl-lower CNS group, benzyloxy or NR2R3;

X represents an oxygen atom or N-R4;

m is 2 or 3;

n is 1 or 2;

R2represents hydrogen;

R3represents a lower alkyl group, phenylethylene group, phenyl group which may be substituted by lower alkyl or lower alkoxyl, or pyridyl;

R4represents a lower alkyl group, phenyl group, formyl group or a lower alkoxycarbonyl group.

2. Derivatives of pyrimidine under item 1 for medicines.

3. Derivatives of pyrimidine under item 1 to obtain medications under item 2 for the prevention or treatment of diseases induced by endothelin.

4. Derivatives of pyrimidine under item 1 to obtain drugs for the treatment of diseases induced by endothelin under item 3, the cat is m inhibitor of binding of endothelin, containing pyrimidine derivative under item 1 or a salt of the specified derivative and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition according to p. 5, suitable for the prevention or treatment of diseases caused by endothelin.

7. The pharmaceutical composition according to p. 6 for the treatment of the disease, occurring with circulatory disorders.

8. Method of prevention and treatment of diseases induced by endothelin, wherein introducing an effective amount of the compounds under item 1 or a salt of the compounds.

9. Method of prevention and treatment of disease on p. 8, wherein the disease induced by endothelin is a disease, occurring with circulatory disorders.

 

Same patents:

The invention relates to 2-[1',2',4'-triazole-3'-roximation] anilides formula I

< / BR>
in which the index and the substituents have the following meanings:

n means 0, 1, 2, 3 or 4, where the substituents R1may be different if n is greater than 1;

X represents a direct bond, O, or NRa;

Rameans hydrogen, alkyl, alkenyl, quinil, cycloalkyl or cycloalkenyl;

R1means nitro, cyano, halogen, optionally substituted alkyl, alkenyl, quinil, alkoxy, alkenylacyl, alkyloxy or

if n is 2, additionally represents associated with two adjacent ring atoms optionally substituted by a bridge containing three or four members from the group containing 3 or 4 carbon atoms, 1-3 carbon atoms and 1 or 2 nitrogen atom, oxygen and/or sulphur, and this bridge together with the ring to which it is linked, may form a partially unsaturated or aromatic radical;

R2means hydrogen, nitro, cyano, halogen, C1-C4alkyl, C1-C4halogenated, C1-C4alkoxy, C1-C4alkylthio or C1-C4alkoxycarbonyl; R3means optionally substituted is which, together with the carbon atoms may contain one to three heteroatoms as members of a cycle of the following: oxygen, sulfur and nitrogen, or an optionally substituted single or dual core aromatic radical, which together with the carbon atoms may contain as members of the cycle from one to four nitrogen atoms or one or two nitrogen atom and one oxygen atom or sulfur or one oxygen atom or sulfur;

R4means hydrogen, optionally substituted alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, alkylaryl or alkoxycarbonyl;

R5means alkyl, alkenyl, quinil, cycloalkyl or cycloalkenyl or if X is NRaadditionally represents a hydrogen
The invention relates to pharmaceutical industry, and in particular to a method for producing an antiemetic - ondansetron

The invention relates to pharmaceutical industry

The invention relates to a new derivative of 4-oxo-1,4-dihydropyrimidin, specifically: 2,6-diethyl-5-phenyl-1(5,6-dimethylbenzimidazolyl-1)-4-oxo-1,4-dihydropyrimidine (I) having immunosuppressive activity, which can find application in medicine

The invention relates to derivatives of hydroxamic acids of formula I where X is-CH2-, -NR5-, -C(O); Y represents-CH2-, -NR5provided that if X is-NR5-, Y represents-CH2-; R1means H, C1-C20alkyl, -(CH2)jaryl, -(CH2)jcycloalkyl and others; R2means H, C1-C20-alkyl, -(CH2)j-R8, -(CH2)j-NR6R7, -(CH2)j-NR5-; -C(O)R5and others; R3means H, C1-C6alkyl, -(CH2)j-aryl, -(CH2)j- C3-6-cycloalkyl etc., R5means H, C1-C6alkyl, possibly substituted by 1 to 3 Halogens, etc.; R6and R7identical or different, represent H, C1-C6alkyl and the other, R8means-S-R8and others, R9-halogen, C1-C6alkyl and the other, R10- H; aryl is phenyl, possibly substituted, Het is pyridinyl, thienyl and others, i - 1 - 6, j - 0 - 4

The invention relates to new derivatives of piperidine F.-ly (I), where R1- aryl, heterocyclyl, R2is phenyl, naphthyl, acenaphthyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl, oxopyridine, diazines, triazoles, thienyl, oxazolyl, oxadiazolyl, thiazolyl, pyrrolyl or furyl which may be substituted with halogen, hydroxy, cyano, CF3, alkyl, R3-H, hydroxy, alkoxy, alkenylacyl, R4-H, alkyl, alkenyl, alkoxy, benzyl, oxo, Q is ethylene or absent, X is a bond, oxygen, sulfur, W is oxygen or sulfur, Z - alkylen, albaniles, -Oh, -S; n = 1, m = 0 or 1

The invention relates to disubstituted polycyclic compounds, their derivatives, pharmaceutical preparations and methods of use in treating mammals disorders mental and/or neurological dysfunction and/or depressions such as diseases associated with degeneration of the nervous system, and not only their

The invention relates to 1-phenylalanine - new ligands of 5-HT4receptors of formula I, where R1- halogen; R2- H, C1-C4alkoxy; R3- C1-C4alkoxy, phenyl C1-C4alkoxy, where phenyl optionally substituted by 1-3 substituents, independently selected from C1-C4of alkyl, C1-C4alkyloxy, 3,4-methylendioxy; R2and R3together represent methylenedioxy, Ethylenedioxy; R4denotes a group of formula (a) or (b), where n = 3, 4, 5; p = 0; q = 1 or 2; R5and R6each C1-C4alkyl or together are - (CH2)4- , - (CH2)6-, - (CH2)2O(CH2)2-,

-CHR8CH2CR9R10CHR11CH2- where R8and R11each H or together are - (CH2)t- where t =1; R9- H, HE, C1-C8alkyl, C1-C4alkyloxy; R10- H, C1-C8alkyl, phenyl, - (CH2)xR12where x = 0, 1, 2, 3; R12HE, C1-C4alkyloxy, - C(O)NR13R14, - NR13C(O)OR14, -SO2NR13R14, -NR13SO2R14, -NR13SO2NR14R15, -NR13C(O)NR14R15; R13, R14, R15- independently - H, C1-C4e is phenyl optionally substituted C1-C4alkyloxy, methylendioxy, Ethylenedioxy; or R7- (CH2)z- R12where z = 2, 3
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