Derivatives of pyrimidine and pharmaceutical composition

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrimidine of the general formula (I) and their pharmaceutically acceptable acid-additive salts possessing properties of neurokinin-1 (NK) receptors antagonists. In the general formula (I): R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)n-N(R)2, -N(R)2 or cyclic tertiary amine as a group of the formula: R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)-N(R)2, -N(R)2 or cyclic tertiary amine of the formula: that can comprise additional heteroatom chosen from atoms N, O or S, and wherein this group can be bound with pyrimidine ring by bridge -O-(CH2)n-; R2 means hydrogen atom, lower alkyl, lower alkoxyl, halogen atom or trifluoromethyl group; R3/R3' mean independently of one another hydrogen atom or lower alkyl; R4 means independently of one another halogen atom, trifluoromethyl group or lower alkoxyl; R means hydrogen atom or lower alkyl; R means independently of one another hydrogen atom or lower alkyl; X means -C(OH)N(R)- or -N(R)C(O)-; Y means -O-; n = 1, 2, 3 or 4; m means 0, 1 or 2. Also, invention relates to a pharmaceutical composition comprising one or some compounds by any claim among claims 1-19 and pharmaceutically acceptable excipients. Proposed compounds can be used in treatment, for example, inflammatory diseases, rheumatic arthritis, asthma, benign prostate hyperplasia, Alzheimer's diseases and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 1 tbl, 76 ex

 

The present invention relates to compounds of General formula

where R1means lower alkyl, lower alkoxy, pyridinyl, pyrimidinyl, phenyl, -S-(ness.)alkyl, -S(O)2-(ness.)alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH2)n-N(R)2, -N(R)2or a cyclic tertiary amine in the form of group

which may contain one additional heteroatom selected from N, O or S, and where this group can be linked to the pyrimidine ring bridge-O(CH2)n-;

R2means hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl;

R3/R3'mean independently from each other hydrogen or lower alkyl;

R4means, regardless of any other halogen, trifluoromethyl or lower alkoxy;

R5means hydrogen or lower alkyl;

R means, regardless of any other hydrogen or lower alkyl;

X is-C(O)N(R) -, or-N(R)C(O)-;

Y represents-O-;

n denotes 1, 2, 3 or 4 and

m means 0, 1 or 2,

and farmacevtichesky acceptable acid additive salts.

The compounds of formula I and their salts are characterized by valuable therapeutic properties. It has been unexpectedly found that the compounds of the present invention are antagonists of the receptor neirokinina-1 (NK-1, substance P). Substance P is found in nature undecapeptide related to theminimum family of peptides, the latter so called because of their rapid contractile effects on tissue extravascular smooth muscles. The receptor for substance P is a member of versamento associated with G-protein receptors.

Neuropeptide receptor for substance P (NK-1) is widely distributed throughout the nervous system of mammals (especially in the brain and spinal ganglia), the circulatory system and in peripheral tissues (especially in the duodenum and jejunum) and are involved in the regulation of various biological processes.

Central and peripheral actions thickening substance P mammals associated with numerous inflammatory conditions, including migraine, rheumatoid arthritis, asthma and inflammatory bowel disease, as well as mediation in gag reflex and modulation of disorders of the Central nervous system (CNS), such as Parkinson's disease (Neurosci. Res., 1996, 7, 187-214), anxiety (Can. J. Phys., 1997, 75, 612-621) and depression (Science, 1998, 281, 1640-1645).

Evidence of the usefulness of receptor antagonists tachykinin for pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of withdrawal syndrome of morphine, cardiovascular changes, oedema is, as, for example, oedema caused by thermal burn, chronic inflammatory diseases, such as rheumatoid arthritis, asthma/increased bronchial reactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn's disease, when eye damage and inflammatory eye diseases discussed in the article "Receptor tachykinin and antagonists of the receptor tachykinin", J. Auton. Pharmacol, 13, 23-93, 1993.

In addition, antagonists of the receptor neirokinina-1 are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance tachykinin, in particular substance P. the Examples of States are involved in substance P, include disorders of the Central nervous system, such as anxiety, depression and psychosis (international patent applications WO 95/16679, WO 95/18124, WO 95/23798).

Antagonists of the receptor neirokinina-1 further useful for the treatment of motion sickness and treatment-induced vomiting.

In addition, in the magazine "The New England Journal of Medicine, volume 340, No. 3, pp. 190-195, 1999, describes the attenuation caused by cisplatin vomiting using selective receptor antagonist neirokinina-1.

Further in U.S. patent US 5972938 describes a method of treating psychoimmunological or psychosomatic disorders in the introduction antagonist is a receptor tachykinin, as, for example, the antagonist of the receptor NK-1.

The suitability of receptor antagonists neirokinina-1 for the treatment of some forms of urinary incontinence is also described in the journal "Neuropeptides", 32(1), 1-49 (1998), "Eur. J. Pharmacol.", 383(3), 297-303 (1999).

In the journal "Life Sci" (2000), 67(9), 985-10001, describes that astrocytes Express functional receptors for many neurotransmitters, including substance P, which is an important stimulus for reactive astrocytes in the development of the Central nervous system, infections and injuries. In the case of brain tumors malignant neuroglial cells originating from astrocytes, initiated by tachykinins with receptors of NK-1 in order to release soluble mediators and increase their rate of proliferation. Therefore, selective antagonists of the receptor NK-1 may be useful as a therapeutic approach to the treatment of malignant gliomas in the treatment of cancer.

In the journal "Nature" (London) (2000), 405(6783), 180-183, describes that mice with a genetic disorder receptor NK-1 detect the loss of useful properties of morphine. Accordingly, antagonists of the receptor NK-1 may be useful in the treatment of withdrawal symptoms of drugs, which have developed addictive as, for example, opiates and nicotine, and to reduce abuse/addiction to him.

It is shown that antagonists of the receptor NK-1 also have a beneficial effect in tirap and traumatic brain injury (personal communication Professor Nimmo at the International conference on tachykinin in 2000 in La Grande Motta, France, 17-20 October 2000, entitled "Antagonists of the receptor neirokinina-1 (NK-1) improves neurological outcome after traumatic brain injury" (authors: A.J.Nimmo, C.J.Benett, X.Hu, I.Cernak, R.Vink).

Compounds of the present invention is also suitable for the treatment of benign prostatic hyperplasia (national Department of standardization), a disease that is widespread in elderly men. National Department of standardization can be progressive and lead to urine retention, infections, stones in the bladder and kidney failure. About the indications reported in the European patent EP 01109853.0.

The compounds of formula I can also be used in the form of their prodrugs, for example, in the form of their N-oxides. Prodrugs can add to the advantages of the presented compounds of advantages in absorption, pharmacokinetics in the distribution and transport to the brain.

Objects of the present invention are the compounds of formula I and their pharmaceutically acceptable salts, obtaining the above-mentioned compounds containing their medicines and their preparation and the use of the above compounds for disease control or prevention of illnesses, especially of illnesses and disorders of this type, referred to earlier, or for the preparation of the drugs.

The term "lower ALK is l", as used in this context, means a saturated alkyl group with straight or branched chain, containing from 1 to 7 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl and the like. Preferred represent lower alkyl groups are groups with 1-4 carbon atoms.

The term "halogen" means chlorine, iodine, fluorine and bromine.

The term "lower alkoxy" means a group in which the alkyl residue is as described above, and which is attached via an oxygen atom.

The term "cyclic tertiary amine" means a five - or six-membered heterocycle in which one nitrogen atom is always connected with the pyrimidine ring and which may optionally contain nitrogen atoms, oxygen or sulfur, such as pyrrolidinyl, imidazolidinyl, pyrazolidine, piperidine, piperazinil, morpholinyl, thiomorpholine, thiomorpholine-1,1-dioxo or thiomorpholine-1-oxo.

The term "pharmaceutically acceptable acid additive salts" embraces salts with inorganic or organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate, p-toluensulfonate and they like the haunted.

The most preferred indications in accordance with the present invention are those which include disorders of the Central nervous system, for example, the treatment or prevention of certain depressive disorders or vomiting by introducing antagonists of the receptor NK-1. Serious bout of depression is defined as a period of at least two weeks, during which time most days and almost every day has taken place or depressed mood, or loss of interest in everything, sick of nothing finds pleasure or lose interest in any activity.

Preferred compounds of formula I where X is-C(O)N(CH3)- and Y represents-O-. Examples of preferred compounds in this group are those in which R1is a cyclic tertiary amine, for example the following compounds:

(3,5-bis(trifluoromethyl)benzyl)methylamide 2-(4-methylpiperazin-1-yl)-4-o-collectibility-5-carboxylic acid,

(3,5-bis(trifluoromethyl)benzyl)methylamide 2-piperazine-1-yl-4-o-collectibility-5-carboxylic acid, or

(3,5-bis(trifluoromethyl)benzyl)methylamide 4-(2-chlorophenoxy)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid.

Other preferred compounds of the above group are those in which R1means-O-(CH2)n-cyclic tertiary amine or a group-O-(CH2)-NR2

(3,5-bis(trifluoromethyl)benzyl)methylamide 2-(2-morpholine-4-ylethoxy)-4-o-collectibility-5-carboxylic acid, or

(3,5-bis(trifluoromethyl)benzyl)methylamide 2-(2-dimethylaminoethoxy)-4-o-collectibility-5-carboxylic acid.

Further preferred compounds of formula I in which X is-N(CH3)C(O)- and Y represents-O-. Examples of preferred compounds in this group are those in which R1means-S-(lower)alkyl, for example the following compounds:

2-(3,5-bis(trifluoromethyl)phenyl)-N-methyl-N-(2-methylsulfanyl-4-o-collectibility-5-yl)isobutyramide,

2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-methylsulfonylamino-5-yl]-N-methylisoleucine or

2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-methylsulfonylamino-5-yl]-N-methylisoleucine.

Other preferred compounds of the above group are those in which R1means a cyclic tertiary amine, for example the following compounds:

2-(3,5-bis(trifluoromethyl)phenyl)-N-methyl-N-(2-morpholine-4-yl-4-o-collectibility-5-yl)isobutyramide,

2-(3,5-bis(trifluoromethyl)phenyl)-N-methyl-N-[2-(4-methylpiperazin-1-yl)-4-o-collectibility-5-yl]isobutyramide,

2-(3,5-bis(trifluoromethyl)phenyl)-N-methyl-N-(2-piperazine-1-yl-4-o-collectibility-5-yl)isobutyramide,

2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(4-fluoro what enocsi)-2-(4-methylpiperazin-1-yl)pyrimidine-5-yl]-N-methylisoleucine,

2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-piperazine-1-Yeremey-5-yl]-N-methylisoleucine,

2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-morpholine-4-Yeremey-5-yl]-N-methylisoleucine,

2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-(4-methylpiperazin-1-yl)pyrimidine-5-yl]-N-methylisoleucine or

2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-piperazine-1-Yeremey-5-yl]-N-methylisoleucine.

The preferred compounds of this group are, in addition, those in which R1means-N(R)(CH2)nNR2for example the following compounds:

2-(3,5-bis(trifluoromethyl)phenyl)-N-[2-(2-diethylaminoethylamine)-4-o-collectibility-5-yl]-N-methylisoleucine or

2-(3,5-bis(trifluoromethyl)phenyl)-N-[2-(2-diethylaminoethylamine)-4-(4-pertenece)pyrimidine-5-yl]-N-methylisoleucine.

Further preferred compounds of this group are those in which R1means-O(CH2)n-cyclic tertiary amine or a group-O(CH2)nNR2for example the following compounds:

2-(3,5-bis(trifluoromethyl)phenyl)-N-methyl-N-[2-(2-morpholine-4-ylethoxy)-4-o-collectibility-5-yl]isobutyramide,

2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-(2-morpholine-4-ylethoxy)-pyrimidine-5-yl]-N-methylisoleucine,

2-(3,5-bis(trifluoromethyl)phenyl)-N-[2-(2-dimethylaminoethoxy)-4-o-collectibility-5-yl]-N-meth is isobutyramide,

2-(3,5-bis(trifluoromethyl)phenyl)-N-[2-(3-dimethylaminopropoxy)-4-o-collectibility-5-yl]-N-methylisoleucine,

2-(3,5-bis(trifluoromethyl)phenyl)-N-[2-(2-dimethylaminoethoxy)-4-(4-pertenece)pyrimidine-5-yl]-N-methylisoleucine,

2-(3,5-bis(trifluoromethyl)phenyl)-N-[2-(3-dimethylaminopropoxy)-4-(4-pertenece)pyrimidine-5-yl]-N-methylisoleucine,

2-(3,5-bis(trifluoromethyl)phenyl)-N-[2-(2-dimethylaminoethoxy)-4-(2-chlorophenoxy)pyrimidine-5-yl]-N-methylisoleucine or

2-(3,5-bis(trifluoromethyl)phenyl)-N-[2-(3-dimethylaminopropoxy)-4-(2-chlorophenoxy)pyrimidine-5-yl]-N-methylisoleucine.

Presents the compounds of formula I and their pharmaceutically acceptable salts can be obtained by methods known in this field, for example by the methods described below, such a method includes

a) interaction of the compounds of formula

with the compound of the formula

to obtain the compounds of formula

where Y, R1, R2, R3, R3', R4, R and m have the above significance, or

b) interaction of the compounds of formula

with the compound of the formula

to obtain the compounds of formula

where Y, R1, R2, R3, R' , R4, R and m have the above significance, or

C) Simocatta the compounds of formula

with the compound of the formula

to obtain the compounds of formula

where hal denotes Cl, Br or I and Y, R1, R2, R3, R3', R4, R and m have the above significance, or

d) Simocatta the compounds of formula

with the compound of the formula

to obtain the compounds of formula

where Y, R1, R2, R3, R3', R4, R and m have the above significance, or

d) alkylation of the compounds of formula

or

in the compound of the formula

or

where Y, R1, R2, R3, R3', R4, R and m have the above significance, or

e) the conversion of compounds of formula

in the compound of the formula

where X, Y, R1, R2, R3, R3', R4and m have the above significance, or

g) the interaction of the compounds of formula

p> with the appropriate cyclic or cyclic amine to obtain the compounds of formula

or with the appropriate alcohol to obtain the compounds of formula

where Y, X, R1, R2, R3, R3', R4and m have the above meanings, And means-N(R)-(CH2)n-N(R)2, -N(R)2or a cyclic tertiary amine of the formula

In the mean lowest alkoxyl, -O-(CH2)n-N(R)2or

and R5is such as described above, or

C) modifying one or more substituents R1, R2, R3, R3', R4or R under the above notation, and

if desired, the conversion of the compounds obtained into pharmaceutically acceptable acid additive salt.

In accordance with variant a) method was added N-ethyldiethanolamine (DIPEA) to a mixture of the compounds of formula II and compounds of formula III in dichloromethane and the mixture is stirred at a temperature in the range of 25-40°C. the Desired compound of formula Ia emit after cleaning with high yields.

In variant b) method describes the reaction of the compound of formula IV with a compound of formula V to obtain the compounds of formula Ib. The reaction is carried out conventional method is m, for example, in a solvent such as toluene, in the presence of triethylamine. The mixture is refluxed for about 1 hour.

In accordance with variant b) method are compound of formula Ib. This reaction is carried out with N-ethyldiethanolamine, which added to the mixture of compounds of formula VI and a compound of formula VII in dichloromethane.

Another method of obtaining the compounds of formula Ib is described in version d) method. The compound of formula VIII is treated with an accepted way compound of the formula V in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) and hydrate of 1-hydroxybenzotriazole (NOVT), and triethylamine.

Compounds of formula Ia or Ib can be obtained by alkylation-NH-binding groups corresponding lower alkyllithium the usual way in the presence of sodium hydride in dimethylformamide (DMF) under option d) method.

Under option e) of the method the compound of formula I-1 is treated with m-chlormadinone acid (m-SRV) in dichloromethane to obtain the compounds of formula I-2. In addition, this compound can then be treated cyclic amine, such as morpholine, piperazine or methylpiperazine, to obtain the corresponding compounds of formula I-3, or the corresponding alcohol, such as 2-dimethylaminoethanol, or N-(2-hydroxyethyl)morpholine, to obtain the value of the corresponding compounds of formula I-4 under option g) method.

The formation of salts is carried out at room temperature in accordance with methods known in themselves and which are familiar to any person skilled in the art. Discusses not only salts with inorganic acids, but also salts with organic acids. Examples of such salts are hydrochloride, hydrobromide, sulfates, nitrates, citrates, acetates, maleate, salts of succinic acid, salts of methanesulfonate, p-toluenesulfonic acid and the like.

The following schemes 1-4 describe how to obtain compounds of formula I in more detail. The starting substances are known compounds or they can be obtained according to known in this field.

The charts use the following abbreviations:

DIPEAN-ethyldiethanolamine

EDCI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

NOT-hydrate of 1-hydroxybenzotriazole

DMF-dimethylformamide (DMF)

m-SRVA-m-chlormadinone acid

DPPA-diphenylphosphinite

R1, R2, R3, R3'and R4have the above meanings and R is lower alkyl.

R1, R2, R3, R3', R4andY have the above meanings and R is lower alkyl.

R2 , R3, R3', R4X, Y and m have the above meanings, And means-N(R)-(CH2)n-N(R)2, -N(R)2or a cyclic tertiary amine of the formula

In the mean lowest alkoxyl, -O-(CH2)n-N(R)2or

and R5is the same as described above.

R, R1, R2, R3, R3', R4, Y and m have the above values.

As mentioned previously, the compounds of formula I and their pharmaceutically used additive salts have valuable pharmacological properties. It was found that the compounds of the present invention are antagonists of the receptor neirokinina-1 (NK-1, substance P).

Compounds were subjected to research in accordance with the following tests.

The affinity of these compounds to the receptor NK-1 was evaluated on the receptors of the human NK-1 in the ovary cells Chinese hamster infected with the human receptor NK-1 (when using the expression system of the virus Semliki) and radioactively labeled with [3N]substance P (final concentration of 0.6 nm). Experiments on the binding was performed in HEPES buffer (N-2-hydroxyethylpiperazine-N'-2-econsultancy acid) (50 mm, pH 7.4)containing bovine serum albumin (BSA) (0,04%), leupeptin (8 m is g/ml), MnCI2(3 mm) and phosphoramidon (2 μm). Samples for studying the binding consisted of 250 μl of aspasie membrane (1,25×105cells/vial for analysis), a 0.125 ál of buffer replacement agent and 125 μl of [3H]substance P. the Curves replacement built at least seven concentrations of the compounds. Test tubes with samples were incubated 60 minutes at room temperature, after which the contents of the tubes were rapidly filtered under vacuum through GF/C filters pre-soaked for 60 minutes with polyethylenimine (0,3%) leaching (2x2 ml), HEPES buffer (50 mm, pH 7.4). Kept on filters and radioactivity was measured using a scintillation counter. All three analyses were repeated in at least two different experiments.

The affinity to the receptor NK-1, expressed as PKi(the negative logarithm of the inhibition constants), is described for compounds in the range of 6.00-9,38.

Examples of values pKifor these compounds are given in the table.

tr>
Example No.pKi
17,38
48,54
78,33
116,77
15at 7.55
19of 6.71
237,01
296,50
397,79
447.70
499,04
529,10
638,02
737,49

The compounds of formula I and their pharmaceutically acceptable acid additive salts can be used as medicines, for example, in the form of pharmaceutical preparations. The pharmaceutical preparations can be used orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. Medications may be, however, carried out through the rectum, for example, in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

The compounds of formula I and their pharmaceutically acceptable acid additive salts can be processed with pharmaceutically inert inorganic or organic excipients for the preparation of tablets, coated tablets, dragées and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients, for example, tablets, coated tablets and hard gelatin capsules.

Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols etc

Suitable fillers for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils etc.

Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc

Moreover, the pharmaceutical preparations can contain preservatives, soljubilizatory, stabilizers, wetting means, emulsifiers, sweeteners, colorants, corrigentov, salts for modifying the osmotic pressure, buffers, masking means or antioxid antes. They can also contain other therapeutically valuable substances.

The dosage may vary within wide limits and will, of course, satisfy the individual requirements in each particular case. Usually in the case of oral administration a daily dose of about 10 to 1000 mg per person of compounds of General formula I should be appropriate, although, if necessary, the upper limit can also be exceeded.

The following examples illustrate h the present invention, not limiting it. All temperatures are given in degrees Celsius.

Example 1

(3,5-Bis(trifluoromethyl)benzyl)methylamide 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid

a) Ethyl ester of 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid

To a solution of 5.40 g (23,31 mmole) of ethyl ether 4-chloro-2-methylsulfonylamino-5-carboxylic acid in 150 ml of acetonitrile was added 3,26 g (30,17 mmol) of o-cresol and 30.25 g (92,83 mmole) Cs2CO3and the reaction mixture was stirred 14 hours at room temperature. The suspension was poured into a mixture of ice and water and twice was extracted with methylene chloride. The combined organic phases were dried (sodium sulfate), filtered and evaporated, was obtained 7.0 g (99%) of ethyl ester of 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid, which is directly used in the next stage.

b) 2-Methylsulfanyl-4-o-collectibility-5-karanova acid

To a solution of 7.0 g (23,0 mmole) ethyl ester 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid in 50 ml of ethanol was added a solution of 1.37 g (34,50 mmole) of sodium hydroxide in 30 ml of water and the resulting mixture was stirred for 1 hour at room temperature. Brought the pH of the solution to 1 with 25%hydrochloric acid. The mixture was twice extracted with methylene chloride. United organizes the s phase was dried (sodium sulfate), filtered and evaporated. The resulting solid was twice washed with 10 ml of diisopropyl ether, filtered and dried, received 3.00 g (47%) 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid as a colourless solid, mass spectrum (MS) ionization by electron spray with the formation of negative ions (ISN): 257,1 (M-N)-.

in) (3,5-Bis(trifluoromethyl)benzyl)methylamide 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid

To a solution of 1.0 g (3,62 mmole) 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid in 60 ml of methylene chloride was added 1.0 ml (7,24 mmol) of triethylamine, 0,554 g (3,62 mmole) of 1-hydroxybenzotriazole and 0.69 g (3,62 mmole) of the hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, 1,11 g (4,34 mmole) of (3,5-bis(trifluoromethyl)benzyl)methylamine. The reaction mixture was stirred 16 hours. The reaction mixture was diluted with 20 ml of methylene chloride, washed with 50 ml of 0.5 N. hydrochloric acid and 50 ml of water. The aqueous layers were subjected to reverse extraction with 50 ml of methylene chloride. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/MeOH 40:1), were of 1.80 g (96%) of (3,5-bis(trifluoromethyl)benzyl)methylamine 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid as colorless, pinoo the different substances MS ionization by electron impact (EI): 515 (M+).

Example 2

(3,5-Bis(trifluoromethyl)benzyl)methylamide 2-methanesulfonyl-4-o-collectibility-5-carboxylic acid

To a solution of 1.70 g (3,30 mmole) of (3,5-bis(trifluoromethyl)benzyl)methylamine 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid in 70 ml of methylene chloride was added at 5°From 2.03 g (8,24 mmol) 3-chlormadinone acid (70%) and the reaction mixture was stirred 2 hours at room temperature. After addition of 150 ml of saturated sodium bicarbonate solution, the layers were separated, the organic phase is washed with saturated sodium bicarbonate solution, dried (sodium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/ethyl acetate 9:1)were 1.50 g (83%) of (3,5-bis(trifluoromethyl)benzyl)methylamine 2-methanesulfonyl-4-o-collectibility-5-carboxylic acid as a colourless solid, MS with ionization by electron spray with the formation of positive ions (ISP): 548,1 (M+N)+.

Example 3

(3,5-Bis(trifluoromethyl)benzyl)methylamide 2-morpholine-4-yl-4-o-collectibility-5-carboxylic acid

To a solution of 0.2 g (0.37 mmole) of (3,5-bis(trifluoromethyl)benzyl)methylamine 2-methanesulfonyl-4-o-collectibility-5-carboxylic acid in 10 ml of dioxane was added 0.08 ml (of 0.91 mmole) of the research. The reaction mixture is stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of methylene chloride and 50 ml of water. The aqueous layer was extracted with 50 ml of methylene chloride, the combined organic layers were dried (magnesium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/MeOH 40:1), was obtained 0.18 g (88%) of (3,5-bis(trifluoromethyl)benzyl)methylamine 2-morpholine-4-yl-4-o-collectibility-5-carboxylic acid as colorless oil, MS (ISP): 555,2 (M+N)+.

Example 4

(3,5-Bis(trifluoromethyl)benzyl)methylamide 2-(4-methylpiperazin-1-yl)-4-o-collectibility-5-carboxylic acid

To a solution of 0.25 g (0,46 mmole) of (3,5-bis(trifluoromethyl)benzyl)methylamine 2-methanesulfonyl-4-o-collectibility-5-carboxylic acid in 10 ml of dioxane was added to 0.12 ml (1,14 mmole) of 1-methylpiperazine. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of methylene chloride and 50 ml of water. The aqueous layer was extracted with 50 ml of methylene chloride, the combined organic layers were dried (magnesium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/Meon/NH4HE 140:10:1), was obtained 0.2 g (77%) of (3,5-bis(trifluoromethyl)benzyl)methylamine 2-(4-methylpiperazin-1-yl)-4-o-collectibility-5-carboxylic acid as a colourless foam, washes the VA, MS (ISP): 563,3 (M+N)+.

Example 5

(3,5-Bis(trifluoromethyl)benzyl)methylamide 2-piperazine-1-yl-4-o-collectibility-5-carboxylic acid

To a solution of 0.32 g (of 0.58 mmole) of (3,5-bis(trifluoromethyl)benzyl)methylamine 2-methanesulfonyl-4-o-collectibility-5-carboxylic acid in 10 ml of dioxane was added 0.125 g (of 1.46 mmole) piperazine. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of methylene chloride and 50 ml of water. The aqueous layer was extracted with 50 ml of methylene chloride, the combined organic layers were dried (magnesium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/MeOH/NH4OH 110:10:1), was obtained 0.25 g (77%) of (3,5-bis(trifluoromethyl)benzyl)methylamine 2-piperazine-1-yl-4-o-collectibility-5-carboxylic acid as colorless foamy substance, MS (ISP): 554,2 (M+N)+.

Example 6

(3,5-Bis(trifluoromethyl)benzyl)methylamide 2-(2-diethylaminoethylamine)-4-o-collectibility-5-carboxylic acid

To a solution of 0.25 g (0,46 mmole) of (3,5-bis(trifluoromethyl)benzyl)methylamine 2-methanesulfonyl-4-o-collectibility-5-carboxylic acid in 10 ml of dioxane was added 0,125 ml (1,14 mmole) of 2-diethylaminoethylamine. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of methylene chloride and 0 ml of water. The aqueous layer was extracted with 50 ml of methylene chloride, the combined organic layers were dried (magnesium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/Meon/NH4HE 140:10:1), was obtained 0.15 g (59%) (3,5-bis(trifluoromethyl)benzyl)methylamine 2-(2-diethylaminoethylamine)-4-o-collectibility-5-carboxylic acid as colorless foamy substance, MS (ISP): 556,2 (M+N)+.

Example 7

(3,5-Bis(trifluoromethyl)benzyl)methylamide 2-(2-morpholine-4-ylethoxy)-4-o-collectibility-5-carboxylic acid

To a solution of 0.2 g (0.37 mmole) of (3,5-bis(trifluoromethyl)benzyl)methylamine 2-methanesulfonyl-4-o-collectibility-5-carboxylic acid in 10 ml of acetonitrile was added of 0.066 ml (0.55 mmole) of N-(2-hydroxyethyl)the research and 0,595 g (1,83 mmole) Cs2CO3. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of methylene chloride and 50 ml of water. The aqueous layer was extracted with 50 ml of methylene chloride, the combined organic layers were dried (magnesium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/MeOH/NH4OH 140:10:1), was obtained 0.12 g (54%) of (3,5-bis(trifluoromethyl)benzyl)methylamine 2-(2-morpholine-4-ylethoxy)-4-o-collectibility-5-carboxylic acid as colorless foamy substance, the (ISP): 599,1 (M+N) +.

Example 8

(3,5-Bis(trifluoromethyl)benzyl)methylamide 2-(2-dimethylaminoethoxy)-4-o-collectibility-5-carboxylic acid

To a solution of 0.25 g (0,46 mmole) of (3,5-bis(trifluoromethyl)benzyl)methylamine 2-methanesulfonyl-4-o-collectibility-5-carboxylic acid in 10 ml of acetonitrile was added 0,069 ml (0.68 mmole) of 2-dimethylaminoethanol and 0,743 g (2,28 mmole) Cs2CO3. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of methylene chloride and 50 ml of water. The aqueous layer was extracted with 50 ml of methylene chloride, the combined organic layers were dried (magnesium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/MeOH/NH4OH 140:10:1), was obtained 0.15 g (59%) (3,5-bis(trifluoromethyl)benzyl)methylamine 2-(2-dimethylaminoethoxy)-4-o-collectibility-5-carboxylic acid in the form of oil is light yellow in color, MS (ISP): 557,3 (M+N)+.

Example 9

(3,5-Dimethoxybenzyl)methylamide 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid

By the way, is similar to that described in example 1B), from 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid and (3,5-dimethoxybenzyl)of methylamine were obtained (3,5-dimethoxybenzyl)methylamide 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid as colorless oil, MS (EI): 439,1 (M+).

PR is measures 10

(3,5-Dimethoxybenzyl)methylamide 2-methanesulfonyl-4-o-collectibility-5-carboxylic acid

By the way, is similar to that described in example 2, from (3,5-dimethoxybenzyl)methylamide 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid and 3-chlormadinone acid was obtained (3,5-dimethoxybenzyl)methylamide 2-methanesulfonyl-4-o-collectibility-5-carboxylic acid as colorless foamy substance, MS (ISP): 472,1 (M+H)+.

Example 11

(3,5-Dimethoxybenzyl)methylamide 2-(4-methylpiperazin-1-yl)-4-o-collectibility-5-carboxylic acid

By the way, is similar to that described in example 4, from (3,5-dimethoxybenzyl)methylamide 2-methanesulfonyl-4-o-collectibility-5-carboxylic acid and 1-methylpiperazine received (3,5-dimethoxybenzyl)methylamide 2-(4-methylpiperazin-1-yl)-4-o-collectibility-5-carboxylic acid as colorless foamy substance, MS (ISP): 492,3 (M+N)+.

Example 12

(3,5-Dimethoxybenzyl)methylamide 2-(2-dimethylaminoethoxy)-4-o-collectibility-5-carboxylic acid

By the way, is similar to that described in example 8 from (3,5-dimethoxybenzyl)methylamide 2-methanesulfonyl-4-o-collectibility-5-carboxylic acid and 2-dimethylaminoethanol received (3,5-dimethoxybenzyl)methylamide 2-(2-dimethylaminoethoxy)-4-o-collectibility-5-carboxylic acid as colorless oil, MS (ISP): 481,4 (M+H) +.

Example 13

(3,5-Dimethylbenzyl)methylamide 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid

By the way, is similar to that described in example 1B), from 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid and (3,5-dimethylbenzyl)of methylamine were obtained (3,5-dimethylbenzyl)methylamide 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid as colorless oil, MS (ISP): 408,3 (M+N)+.

Example 14

(3,5-Dimethylbenzyl)methylamide 2-methanesulfonyl-4-o-collectibility-5-carboxylic acid

By the way, is similar to that described in example 2, from (3,5-dimethylbenzyl)methylamide 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid and 3-chlormadinone acid was obtained (3,5-dimethylbenzyl)methylamide 2-methanesulfonyl-4-o-collectibility-5-carboxylic acid as colorless foamy substance, MS (ISP): 440,4 (M+N)+.

Example 15

(3,5-Dimethylbenzyl)methylamide 2-(4-methylpiperazin-1-yl)-4-o-collectibility-5-carboxylic acid

By the way, is similar to that described in example 4, from (3,5-dimethylbenzyl)methylamide 2-methanesulfonyl-4-o-collectibility-5-carboxylic acid and 1-methylpiperazine received (3,5-dimethylbenzyl)methylamide 2-(4-methylpiperazin-1-yl)-4-o-collectibility-5-carboxylic acid in the form of a foamy substance white, MS (ISP): 460,5 (M+N)+.

Example 16

(3,5-Dim is tenbensel)methylamide 2-(2-dimethylaminoethoxy)-4-o-collectibility-5-carboxylic acid

By the way, is similar to that described in example 8 from (3,5-dimethylbenzyl)methylamide 2-methanesulfonyl-4-o-collectibility-5-carboxylic acid and 2-dimethylaminoethanol received (3,5-dimethylbenzyl)methylamide 2-(2-dimethylaminoethoxy)-4-o-collectibility-5-carboxylic acid as colorless oil, MS (ISP): 449,5 (M+N)+.

Example 17

3,5-Dichloraniline 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid

By the way, is similar to that described in example 1B), from 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid and 3,5-dichloraniline received a 3.5-dichlorbenzene 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid in the form of oil is light yellow; MS (EI): 433 (M+).

Example 18

3,5-Dichloraniline 2-methanesulfonyl-4-o-collectibility-5-carboxylic acid

By the way, is similar to that described in example 2 of the 3.5-dichlorobenzamide 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid and 3-chlormadinone acid was obtained 3,5-dichloraniline 2-methanesulfonyl-4-o-collectibility-5-carboxylic acid as colorless solid, MS (ISP): 466,2 (M+N)+.

Example 19

3,5-Dichloraniline 2-(4-methylpiperazin-1-yl)-4-o-collectibility-5-carboxylic acid

By the way, is similar to that described in example 4 of the 3.5-dichlorobenzamide 2-methanesulfonyl-4-o-whether oxopyrimidine-5-carboxylic acid and 1-methylpiperazine received a 3.5-dichlorbenzene 2-(4-methylpiperazin-1-yl)-4-o-collectibility-5-carboxylic acid as a colourless solid, MS (ISP): 486,3 (M+N)+.

Example 20

(3,5-Dichlorobenzyl)methylamide 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid

To a solution of 0.6 g (1.8 mmole) of 3,5-dichlorobenzamide 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid in 20 ml of N,N-dimethylformamide was added 0,096 g (2.4 mmole) of sodium hydride (60%dispersion in mineral oil) and the mixture was stirred for 1 hour. After the addition of 0.18 ml (2.9 mmole) iodotope bromide at 0°the reaction mixture was stirred 3 hours at room temperature. The reaction mixture was distributed between 50 ml water, 50 ml brine and 50 ml of methylene chloride. The phases were separated and the aqueous layer was twice extracted with 50 ml methylene chloride. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/ethyl acetate 19:1), was obtained 0.5 g (61%) of (3,5-dichlorobenzyl)methylamide 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid in the form of oil is light yellow; MS (EI): 447,1 (M+).

Example 21

(3,5-Dichlorobenzyl)methylamide 2-methanesulfonyl-4-o-collectibility-5-carboxylic acid

By the way, is similar to that described in example 2, from (3,5-dichlorobenzyl)methylamide 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid and 3-chlormadinone acid was obtained (3,5-dichlorobenzyl)methylamide 2-meta is sulfonyl-4-o-collectibility-5-carboxylic acid as colorless foamy substance, MS (ISP): of 480.2 (M+H)+.

Example 22

(3,5-Dichlorobenzyl)methylamide 2-(4-methylpiperazin-1-yl)-4-o-collectibility-5-carboxylic acid

By the way, is similar to that described in example 4, from (3,5-dichlorobenzyl)methylamide 2-methanesulfonyl-4-o-collectibility-5-carboxylic acid and 1-methylpiperazine received (3,5-dichlorobenzyl)methylamide 2-(4-methylpiperazin-1-yl)-4-o-collectibility-5-carboxylic acid as colorless foamy substance, MS (ISP): 500,2 (M+H)+.

Example 23

(3,5-Bis(trifluoromethyl)benzyl)methylamide 2-methylsulfanyl-4-phenoxypyridine-5-carboxylic acid

By the way, is similar to that described in example 1 (a), from ethyl ether 4-chloro-2-methylsulfonylamino-5-carboxylic acid and phenol were obtained ethyl ester 2-methylsulfanyl-4-phenoxypyridine-5-carboxylic acid, which omilami as described in example 1 b), and subjected to reaction with (3,5-bis(trifluoromethyl)benzyl)methylamine for the receipt, as described in example 1), (3,5-bis(trifluoromethyl)benzyl)methylamine 2-methylsulfanyl-4-phenoxypyridine-5-carboxylic acid as a colourless solid, MS ionization thermoreception with the formation of positive ions (TSP): 501 (M+).

Example 24

(3,5-Bis(trifluoromethyl)benzyl)methylamide 2-methanesulfonyl-4-phenoxypyridine-5-carboxylic acid

By the way, is similar to that described in the ore 2, from (3,5-bis(trifluoromethyl)benzyl)methylamine 2-methylsulfanyl-4-phenoxypyridine-5-carboxylic acid and 3-chlormadinone acid was obtained (3,5-bis(trifluoromethyl)benzyl)methylamide 2-methanesulfonyl-4-phenoxypyridine-5-carboxylic acid as colorless solid, MS (TSP): 533 (M+).

Example 25

(3,5-Bis(trifluoromethyl)benzyl)methylamide 2-(4-methylpiperazin-1-yl)-4-phenoxypyridine-5-carboxylic acid

By the way, is similar to that described in example 4, from (3,5-bis(trifluoromethyl)benzyl)methylamine 2-methanesulfonyl-4-phenoxypyridine-5-carboxylic acid and 1-methylpiperazine received (3,5-bis(trifluoromethyl)benzyl)methylamide 2-(4-methylpiperazin-1-yl)-4-phenoxypyridine-5-carboxylic acid as colorless solid, MS (ISP): 554,2 (M+H)+.

Example 26

(3,5-Bis(trifluoromethyl)benzyl)methylamide 4-(2-chlorophenoxy)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid

By the way, is similar to that described in example 1 (a), from ethyl ether 4-chloro-2-methylsulfonylamino-5-carboxylic acid and 2-chlorophenol was obtained ethyl ester 4-(2-chlorophenoxy)-2-methylsulfonylamino-5-carboxylic acid, which omilami as described in example 1 b), and subjected to reaction with (3,5-bis(trifluoromethyl)benzyl)methylamino to obtain, as described in example 1), (3,5-bis(trifluoromethyl)benzyl)methylamide 4-(2-chlorophenoxy)-2-(4-methylpiperid the Jn-1-yl)pyrimidine-5-carboxylic acid as a colourless solid, MS (ISP): 536,2 (M+N)+.

Example 27

(3,5-Bis(trifluoromethyl)benzyl)methylamide 4-(2-chlorophenoxy)-2-methanesulfonamido-5-carboxylic acid

By the way, is similar to that described in example 2, from (3,5-bis(trifluoromethyl)benzyl)methylamide 4-(2-chlorophenoxy)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid and 3-chlormadinone acid was obtained (3,5-bis(trifluoromethyl)benzyl)methylamide 4-(2-chlorophenoxy)-2-methanesulfonamido-5-carboxylic acid as colorless solid, MS (ISP): 560, 0m (M+N)+.

Example 28

(3,5-Bis(trifluoromethyl)benzyl)methylamide 4-(2-chlorophenoxy)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid

By the way, is similar to that described in example 4, from (3,5-bis(trifluoromethyl)benzyl)methylamide 4-(2-chlorophenoxy)-2-methanesulfonamido-5-carboxylic acid and 1-methylpiperazine received (3,5-bis(trifluoromethyl)benzyl)methylamide 4-(2-chlorophenoxy)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid as colorless solid, MS (ISP): 588,2 (M+N)+.

Example 29

(3,5-Bis(trifluoromethyl)benzyl)methylamide 4-(2-methoxyphenoxy)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid

By the way, is similar to that described in example 1 (a), from ethyl ether 4-chloro-2-methylsulfonylamino-5-carboxylic acid and 2-methoxyphenol received ethyl ester 4-(2-methoxyphenoxy)-2-methylsulfanyl the one-5-carboxylic acid, which omilami as described in example 1 b), and subjected to reaction with (3,5-bis(trifluoromethyl)benzyl)methylamine, prepared as described in example 1), (3,5-bis(trifluoromethyl)benzyl)methylamide 4-(2-methoxyphenoxy)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid as colorless solid, MS (ISP): 532,1 (M+N)+.

Example 30

(3,5-Bis(trifluoromethyl)benzyl)methylamide 4-(2-methoxyphenoxy)-2-methanesulfonamido-5-carboxylic acid

By the way, is similar to that described in example 2, from (3,5-bis(trifluoromethyl)benzyl)methylamide 4-(2-methoxyphenoxy)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid and 3-chlormadinone acid was obtained (3,5-bis(trifluoromethyl)benzyl)methylamide 4-(2-methoxyphenoxy)-2-methanesulfonamido-5-carboxylic acid as colorless solid, MS (ISP): 564,2 (M+N)+.

Example 31

(3,5-Bis(trifluoromethyl)benzyl)methylamide 4-(2-methoxyphenoxy)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid

By the way, is similar to that described in example 4, from (3,5-bis(trifluoromethyl)benzyl)methylamide 4-(2-methoxyphenoxy)-2-methanesulfonamido-5-carboxylic acid and 1-methylpiperazine received (3,5-bis(trifluoromethyl)benzyl)methylamide 4-(2-methoxyphenoxy)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid as colorless solid, MS (ISP): 584,1 (M+H)+.

Example 32

(3,5-Bis(t is iformity)benzyl)methylamide 2-(2-diethylaminoethylamine)-4-(2-methoxyphenoxy)pyrimidine-5-carboxylic acid

By the way, is similar to that described in example 6 from (3,5-bis(trifluoromethyl)benzyl)methylamide 4-(2-methoxyphenoxy)-2-methanesulfonamido-5-carboxylic acid and 2-diethylaminoethylamine received (3,5-bis(trifluoromethyl)benzyl)methylamide 2-(2-diethylaminoethylamine)-4-(2-methoxyphenoxy)pyrimidine-5-carboxylic acid as colorless solid, MS (ISP): 572,1 (M+N)+.

Example 33

(3,5-Bis(trifluoromethyl)benzyl)methylamide 4-(4-pertenece)-2-methanesulfonamido-5-carboxylic acid

By the way, is similar to that described in example 1 (a), from ethyl ether 4-chloro-2-methylsulfonylamino-5-carboxylic acid and 4-terfenol received ethyl ester of 4-(4-pertenece)-2-methylsulfonylamino-5-carboxylic acid, which omilami as described in example 1 b), and subjected to reaction with (3,5-bis(trifluoromethyl)benzyl)methylamine, prepared as described in example 1), (3,5-bis(trifluoromethyl)benzyl)methylamide 4-(4-fervency)-2-methanesulfonamido-5-carboxylic acid as colorless solid, MS (ISP): 520,1 (M+N)+.

Example 34

(3,5-Bis(trifluoromethyl)benzyl)methylamide 4-(4-pertenece)-2-methanesulfonamido-5-carboxylic acid

By the way, is similar to that described in example 2, from (3,5-bis(trifluoromethyl)benzyl)methylamide 4-(4-pertenece)-2-methylsulfonylamino-5-carboxylic acid and 3-chlormadinone key is lots received (3,5-bis(trifluoromethyl)benzyl)methylamide 4-(4-pertenece)-2-methanesulfonamido-5-carboxylic acid as a colourless solid, MS (ISP): 552,0 (M+N)+.

Example 35

(3,5-Bis(trifluoromethyl)benzyl)methylamide 4-(4-pertenece)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid

By the way, is similar to that described in example 4, from (3,5-bis(trifluoromethyl)benzyl)methylamide 4-(4-pertenece)-2-methanesulfonamido-5-carboxylic acid and 1-methylpiperazine received (3,5-bis(trifluoromethyl)benzyl)methylamide 4-(4-pertenece)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid in the form of a foamy substance white, MS (EI): 571 (M+).

Example 36

(3,5-Bis(trifluoromethyl)benzyl)methylamide-(4-pertenece)-2-piperazine-1-Yeremey-5-carboxylic acid

By the way, is similar to that described in example 5, from (3,5-bis(trifluoromethyl)benzyl)methylamide 4-(4-pertenece)-2-methanesulfonamido-5-carboxylic acid and piperazine was obtained (3,5-bis(trifluoromethyl)benzyl)methylamide 4-(4-pertenece)-2-piperazine-1-Yeremey-5-carboxylic acid as colorless foamy substance, MS (ISP): 558,2 (M+N)+.

Example 37

(3,5-Bis(trifluoromethyl)benzyl)methylamide 2-(2-diethylaminoethylamine)-4-(4-pertenece)pyrimidine-5-carboxylic acid

By the way, is similar to that described in example 6 from (3,5-bis(trifluoromethyl)benzyl)methylamide 4-(4-pertenece)-2-methanesulfonamido-5-carboxylic acid and diethylaminoethylamine received (3,5-bis(trifluoromethyl)benzyl)noted the ID 2-(2-diethylaminoethylamine)-4-(4-pertenece)pyrimidine-5-carboxylic acid as colorless foamy substance, MS (ISP): 560,2 (M+N)+.

Example 38

(3,5-Bis(trifluoromethyl)benzyl)methylamide 2-(2-dimethylaminoethoxy)-4-(4-pertenece)pyrimidine-5-Karanovo acid

By the way, is similar to that described in example 8 from (3,5-bis(trifluoromethyl)benzyl)methylamide 4-(4-pertenece)-2-methanesulfonamido-5-carboxylic acid and 2-dimethylaminoethanol received (3,5-bis(trifluoromethyl)benzyl)methylamide 2-(2-dimethylaminoethoxy)-4-(4-pertenece)pyrimidine-5-carboxylic acid as colorless foamy substance, MS (ISP): 561,3 (M+N)+.

Example 39

(3,5-Bis(trifluoromethyl)benzyl)methylamide 2-pyridin-4-yl-4-o-collectibility-5-carboxylic acid

a) Ethyl ester of 4-chloro-2-pyridine-4-Yeremey-5-carboxylic acid

Suspension 4,78 g (19.5 mmol) of the ethyl ester of 4-hydroxy-2-pyridine-4-Yeremey-5-carboxylic acid in 20 ml of phosphorus oxychloride was heated under reflux for 1 hour. The solution was cooled to room temperature and poured into 100 ml of a mixture of ice water. Brought the pH of the solution to 8 with saturated sodium bicarbonate solution. The aqueous phase three times was extracted with 80 ml methylene chloride. The combined organic phases were dried (magnesium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/MeOH 40:1), received 4,34 g (84%) of ethyl ether 4-chloro-2-pyridine-4-Yeremey-karbonovoi acid in a solid yellow color, MS (EI): 263,1 (M+).

b) Ethyl ester of 2-pyridine-4-yl-4-o-collectibility-5-carboxylic acid

A suspension of 0.6 g (2,28 mmole) of ethyl ether 4-chloro-2-pyridine-4-Yeremey-5-carboxylic acid, 0.27 g (2.50 mmole) of o-cresol and of 2.97 g (9,10 mmol) Cs2CO3in 15 ml of acetonitrile was stirred 17 hours at room temperature. The suspension was poured into 150 ml of water and was extracted three times with 90 ml of ethyl acetate. The combined organic phases were dried (magnesium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2, ethyl acetate/Meon 100:1)were 0.74 g (97%) of ethyl ester of 2-pyridine-4-yl-4-o-collectibility-5-carboxylic acid in a solid yellow color, MS (EI): 335,1 (M+).

a) 2-Pyridin-4-yl-4-o-collectibility-5-carboxylic acid

To a solution 0,70 g (of 2.08 mmole) ethyl ester 2-pyridin-4-yl-4-o-collectibility-5-carboxylic acid in 20 ml of ethanol was added a solution of 0.12 g (3,12 mmole) of sodium hydroxide in 10 ml of water and the resulting mixture was stirred 2 hours at room temperature. Brought the pH of the solution to 3 with 25%hydrochloric acid. The mixture was twice extracted with methylene chloride. The combined organic phases were dried (sodium sulfate), filtered and evaporated. The resulting solid residue was twice washed with 10 ml of ethanol was filtered and sushi and, received 0,60 g (94%) of 2-pyridin-4-yl-4-o-collectibility-5-carboxylic acid as colorless solid, MS (EI): to 307.1 (M+).

g) (3,5-Bis(trifluoromethyl)benzyl)methylamide 2-pyridin-4-yl-4-o-collectibility-5-carboxylic acid

To a solution of 0.35 g (1,14 mmole) 2-pyridin-4-yl-4-o-collectibility-5-carboxylic acid in 20 ml of methylene chloride was added of 0.32 ml (2,28 mmole) of triethylamine, 0.15 g (1,14 mmole) of 1-hydroxybenzotriazole and 0.22 g (1,14 mmole) of the hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, 0.33 g (of 1.37 mmole) of (3,5-bis(trifluoromethyl)benzyl)methylamine. The reaction mixture was stirred 16 hours. The reaction mixture was diluted with 20 ml of methylene chloride and washed with 50 ml water. The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/Meon 19:1), was obtained 0.33 g (53%) of (3,5-bis(trifluoromethyl)benzyl)methylamine 2-pyridin-4-yl-4-o-collectibility-5-carboxylic acid as colorless foamy substance, MS (ISP): 547,1 (M+N)+.

Example 40

(3,5-Bis(trifluoromethyl)benzyl)methylamide 4-(4-pertenece)-2-pyridine-4-Yeremey-5-carboxylic acid

By the way, is similar to that described in example 39 (b), from ethyl ether 4-chloro-2-pyridine-4-Yeremey-5-carboxylic acid and 4-terfenol received ethyl ester of 4-(4-pertenece)-2-pyridine-4-Yeremey-5-carbon is Oh acid, which omilami as described in example 39), and subjected to reaction with (3,5-bis(trifluoromethyl)benzyl)methylamine, prepared as described in example 39 g), (3,5-bis(trifluoromethyl)benzyl)methylamide 4-(4-pertenece)-2-pyridine-4-Yeremey-5-carboxylic acid as colorless foamy substance, MS (ISP): 551,0 (M+N)+.

Example 41

(3,5-Bis(trifluoromethyl)benzyl)methylamide 2-methyl-4-o-collectibility-5-carboxylic acid

Similar to that described in example 39B) of the ethyl ester of 4-chloro-2-methylpyrimidin-5-carboxylic acid and o-cresol was obtained ethyl ester of 2-methyl-4-o-collectibility-5-carboxylic acid, which omilami as described in example 39), and subjected to reaction with (3,5-bis(trifluoromethyl)benzyl)methylamine, prepared as described in example 39 g), (3,5-bis(trifluoromethyl)benzyl)methylamide 2-methyl-4-o-collectibility-5-carboxylic acid as colorless foamy substance, MS (EI): 483 (M+).

Example 42

(3,5-Bis(trifluoromethyl)benzyl)methylamide 2-phenyl-4-o-collectibility-5-carboxylic acid

Similar to that described in example 39 (b) of the ethyl ester of 4-chloro-2-phenylpyrimidine-5-carboxylic acid and o-cresol was obtained ethyl ester of 2-phenyl-4-o-collectibility-5-carboxylic acid, which omilami as described in example 39), and subjected to reaction with (3,5-bis(trifluoromethyl)benzyl)METI is an amine, received as described in example 39 g), (3,5-bis(trifluoromethyl)benzyl)methylamide 2-phenyl-4-o-collectibility-5-carboxylic acid as colorless foamy substance, MS (ISP): 546,1 (M+H)+.

Example 43

(3,5-Bis(trifluoromethyl)benzyl)methylamide 4-o-tolyloxy[2,2']bipyridinyl-5-carboxylic acid

a) Ethyl ester of 4-hydroxy[2,2']bipyridinyl-5-carboxylic acid

To a freshly prepared solution of ateleta sodium in ethanol (obtained from 0,44 g (18,92 mmol) of sodium in 20 ml of ethanol) was added 1.50 g (9,46 mmol) of the hydrochloride pyrimidine-2-carboxamidine. After 10 minutes, was added 1.89 ml (9,46 mmol) of diethyl ether ethoxymethylenemalonic acid at 0°and the resulting suspension was stirred for 12 hours. After addition of 20 ml water, the pH was brought to 5 and the aqueous phase was extracted three times with methylene chloride. The combined organic phases were dried (sodium sulfate), filtered and evaporated. The residue is triturated with 5 ml of diisopropyl ether, filtered and dried, received of 1.62 g (70%) of ethyl ester of 4-hydroxy[2,2']bipyridinyl-5-carboxylic acid as light yellow colour powder, MS (EI): 246,1 (M+).

b) Ethyl ester of 4-chloro[2,2']bipyridinyl-5-carboxylic acid

A suspension of 1.62 g (6.5 mmol) of the ethyl ester of 4-hydroxy[2,2']bipyridinyl-5-carboxylic acid in 16 ml of phosphorus oxychloride was heated with about atnam the refrigerator for 1 hour. The solution was cooled to room temperature and poured into 100 ml of a mixture of ice water. Using a saturated solution of sodium bicarbonate was placed in a solution of pH 8. The aqueous phase three times was extracted with 80 ml methylene chloride. The combined organic phases were dried (sodium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/Meon 95:5), received 1,43 g (82%) of ethyl ether 4-chloro[2,2']bipyridinyl-5-carboxylic acid in the form of solids, light brown, MS (EI): 264,1 (M+).

b) Ethyl ester of 4-o-tolyloxy[2,2']bipyridinyl-5-carboxylic acid

To a solution of 1.43 g (5.4 mmol) of ethyl ether 4-chloro[2,2']bipyridinyl-5-carboxylic acid in 35 ml of acetonitrile was added 0.5 g (7.0 mmol) of o-cresol and 7.0 g (21.6 mmole) Cs2CO3and the reaction mixture was stirred 14 hours at room temperature. The suspension was poured into ice water and was extracted two times with methylene chloride. The combined organic phases were dried (sodium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/MeOH 19:1), was obtained 0.96 g (53%) of ethyl ester of 4-o-tolyloxy[2,2']bipyridinyl-5-carboxylic acid in the form of a solid of light yellow color, MS (ISP): 337,2 (M+N)+.

g) 4-o-Tolyloxy[2,2']bipyridinyl-5-carboxylic acids of the Sabbath.

To a solution of 0.33 g (0,98 mmole) ethyl ester of 4-o-tolyloxy[2,2']bipyridinyl-5-carboxylic acid in 15 ml of ethanol was added 3,68 ml of 0.4 N. of sodium hydroxide and the resulting solution was stirred 2 hours at room temperature. With 1 N. hydrochloric acid in the solution was set pH 4. The aqueous solution was extracted three times with methylene chloride. The combined organic phases were dried (sodium sulfate), filtered and evaporated. The resulting solid residue was twice washed with diethyl ether, filtered and dried, was obtained 0.26 g (85%) 4-o-tolyloxy[2,2']bipyridinyl-5-carboxylic acid in the form of a solid of light yellow color, MS (ISN): 307,3 (M-N)-.

d) (3,5-Bis(trifluoromethyl)benzyl)methylamide 4-o-tolyloxy[2,2']bipyridinyl-5-Carbo new acid

To a solution of 0.25 g of 4-o-tolyloxy[2,2']bipyridinyl-5-carboxylic acid in 15 ml of methylene chloride was added to 0.23 ml (1.6 mmole) of triethylamine, 0,13 g (0,83 mmole) of 1-hydroxybenzotriazole, 0.16 g (0,83 mmole) of the hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide and 0.25 g (1 mmol) (3,5-bis(trifluoromethyl)benzyl)methylamine. The reaction mixture was stirred 16 hours. The reaction mixture was diluted with 20 ml of methylene chloride, washed with 50 ml of 0.5 N. hydrochloric acid and 50 ml of methylene chloride. The combined organic layers were dried (magnesium sulfate), filtered and UPA is ivali. The residue was purified by chromatography (SiO2CH2Cl2/MeOH 19:1)were 0.39 g (86%) of (3,5-bis(trifluoromethyl)benzyl)methylamide 4-o-tolyloxy[2,2']bipyridinyl-5-karbonovoi acid as a pale yellow foamy substance, MS (ISP): 548,1 (M+N)+.

Example 44

(3,5-Bis(trifluoromethyl)benzyl)methylamide 2-thiomorpholine-4-yl-4-o-collectibility-5-carboxylic acid

To a solution of 0.79 g (1.44 mmole) of (3,5-bis(trifluoromethyl)benzyl)methylamine 2-methanesulfonyl-4-o-collectibility-5-carboxylic acid in 40 ml of dioxane was added to 0.34 ml (3.6 mmole) thiomorpholine. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of methylene chloride and 50 ml of water. The aqueous layer was extracted with 50 ml of methylene chloride, the combined organic layers were dried (magnesium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/MeOH 40:1), were of 0.48 g (59%) (3,5-bis(trifluoromethyl)benzyl)methylamine 2-thiomorpholine-4-yl-4-o-collectibility-5-carboxylic acid as colorless solid, MS (ISP): 571,1 (M+N)+.

Example 45

(3,5-Bis(trifluoromethyl)benzyl)methylamide 2-(1,1-dioxo-1λ6-thiomorpholine-4-yl)-4-o-collectibility-5-carboxylic acid

To a solution of 0.44 g (0.77 mmole) of (3,5-bis(trifluoromethyl)benzyl)methylamine 2-thiomorpholine-4-yl-4-o-relaxability-5-carboxylic acid in 25 ml of methylene chloride was added to 0.48 g (1,93 mmole) 3-chlormadinone acid (70%) at 5° C and the reaction mixture was stirred for 1 hour at room temperature. After addition of 50 ml of saturated sodium bicarbonate solution, the layers were separated, the organic phase is washed with sodium bicarbonate solution, dried (sodium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/ethyl acetate 4:1), received 0,42 g (91%) of (3,5-bis(trifluoromethyl)benzyl)methylamine 2-(1,1-dioxo-1λ6-thiomorpholine-4-yl)-4-o-collectibility-5-carboxylic acid as colorless solid, MS (ISP): 602,9 (M+N)+.

Example 46

2-(3,5-Bis(trifluoromethyl)phenyl)-N-methyl-N-(2-methylsulfanyl-4-o-collectibility-5-yl)isobutyramide

a) tert-Butyl ether (2-methylsulfanyl-4-o-collectibility-5-yl)-carbamino acid

To a solution of 1.90 g (6,88 mmol) 2-methylsulfanyl-4-o-collectibility-5-carboxylic acid, 0.95 ml of triethylamine (6,88 mmol) and 1.29 ml (1,37 mmole) of tert-butanol in 25 ml of tetrahydrofuran was added to 1.47 ml (6,88 mmol) diphenylphosphinite and the resulting solution was boiled under reflux for 12 hours. After evaporation of the solvent the residue was distributed between methylene chloride and water. The aqueous phase was extracted twice with 80 ml methylene chloride. The combined organic layers were dried (sodium sulfate), filtered and evaporated. The residue was purified through the Yu chromatography (SiO 2CH2Cl2the ethyl acetate 40:1)were 1.70 g (71%) of tert-butyl methyl ether (2-methylsulfanyl-4-o-collectibility-5-yl)carbamino acid as colorless solid, MS (ISP): 348,2 (M+N)+.

b) tert-Butyl methyl ether(2-methylsulfanyl-4-o-collectibility-5-yl)carbamino acid

To a solution of 1.60 g (br4.61 mmole) of tert-butyl methyl ether (2-methylsulfanyl-4-o-collectibility-5-yl)carbamino acid in 20 ml of N,N-dimethylformamide was added 0.25 g (6.4 mmole) of sodium hydride (60%dispersion in mineral oil) and the reaction mixture was stirred for 1 hour. After addition of 0.48 ml (7.83 mmol) iodotope bromide at 0°C the reaction mixture was stirred for 3 hours. The reaction mixture was poured into 100 ml of a mixture of ice water and three times was extracted with 80 ml methylene chloride. The combined organic layers were dried (sodium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/ethyl acetate 19:1), received 1,60 g (98%) of tert-butyl methyl ether(2-methylsulfanyl-4-o-collectibility-5-yl)carbamino acid in the form of a colorless oil, MS (EI): 361 (M+).

b) Methyl(2-methylsulfanyl-4-o-collectibility-5-yl)Amin

To a solution of 1.60 g (4,43 mmole) of tert-butyl methyl ether(2-methylsulfanyl-4-o-collectibility-5-yl)carbamino acid in 20 ml of methylene chloride PR is balali 2 ml triperoxonane acid and the reaction mixture was stirred 2 hours at 40° C. the Reaction mixture was poured into a mixture of ice water and with 1 n sodium hydroxide solution were placed in a solution of pH 10. The aqueous phase three times was extracted with 80 ml methylene chloride. The combined organic layers were dried (sodium sulfate), filtered and evaporated, got 1.10 g (95%) of methyl(2-methylsulfanyl-4-o-collectibility-5-yl)amine in the form of solid white, MS (EI): 261 (M+).

g) 2-(3,5-Bis(trifluoromethyl)phenyl)-N-methyl-N-(2-methylsulfanyl-4-o-collectibility-5-yl)isobutyramide

To a solution of 1.10 g (4,21 mmole) of methyl(2-methylsulfanyl-4-o-collectibility-5-yl)amine and 1.44 ml (8,42 mmol) of N-ethyldiethanolamine in 30 ml of methylene chloride was added a solution of 1.87 g (of 5.89 mmol) of 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionitrile in 5 ml of methylene chloride and the reaction mixture was stirred 12 hours at room temperature. The reaction mixture was poured into 50 ml of 0.5 n sodium hydroxide solution. The phases were separated and the aqueous phase three times was extracted with 80 ml methylene chloride. The combined organic layers were dried (sodium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2, hexane/ethyl acetate 2:1), received 2,10 g (92%) of 2-(3,5-bis(trifluoromethyl)phenyl)-N-methyl-N-(2-methylsulfanyl-4-o-collectibility-5-yl)isobutyramide in the form of a foamy substance white, MS (ISP): 544,2 (M+N) +.

Example 47

2-(3,5-Bis(trifluoromethyl)phenyl)-N-(2-methanesulfonyl-4-o-collectibility-5-yl)-N-methylisoleucine

To a solution of 2.00 g (3,68 mmole) of 2-(3,5-bis(trifluoromethyl)phenyl)-N-methyl-N-(2-methylsulfanyl-4-o-collectibility-5-yl)isobutyramide in 80 ml of methylene chloride at 5°With added of 2.26 g (9,20 mmol) 3-chlormadinone acid (70%) and the reaction mixture was stirred 2 hours at room temperature. After addition of 150 ml of saturated sodium bicarbonate solution, the layers were separated, the organic phase is washed with saturated sodium bicarbonate solution, dried (sodium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/ethyl acetate 19:1), received 1,90 g (83%) of 2-(3,5-bis(trifluoromethyl)phenyl)-N-(2-methanesulfonyl-4-o-collectibility-5-yl)-N-methylisobutyl in the form of a foamy substance white, MS (EI): 575 (M+).

Example 48

2-(3,5-Bis(trifluoromethyl)phenyl)-N-methyl-N-(2-morpholine-4-yl-4-o-collectibility-5-yl)isobutyramide

To a solution of 0.2 g (0.35 mmole) of 2-(3,5-bis(trifluoromethyl)phenyl)-N-(2-methanesulfonyl-4-o-collectibility-5-yl)-N-methylisobutyl in 10 ml of dioxane was added 0,076 ml of 0.87 mmole) of the research. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of methylene chloride and 50 ml of a saturated solution of bi is carbonate sodium. The aqueous layer was extracted with 50 ml of methylene chloride, the combined organic layers were dried (magnesium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/methanol 50:1), was obtained 0.17 g (84%) of 2-(3,5-bis(trifluoromethyl)phenyl)-N-methyl-N-(2-morpholine-4-yl-4-o-collectibility-5-yl)isobutyramide in the form of a foamy substance white, MS (ISP): 583,2 (M+H)+.

Example 49

2-(3,5-Bis(trifluoromethyl)phenyl)-N-methyl-N-[2-(4-methylpiperazin-1-yl)-4-o-collectibility-5-yl)isobutyramide

To a solution 0,22 g (range 0.38 mmole) of 2-(3,5-bis(trifluoromethyl)phenyl)-N-(2-methanesulfonyl-4-o-collectibility-5-yl)-N-methylisobutyl in 10 ml of dioxane was added 0,106 ml (0.96 mmole) of 1-methylpiperazine. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of methylene chloride and 50 ml of saturated sodium bicarbonate solution. The aqueous layer was extracted with 50 ml of methylene chloride, the combined organic layers were dried (magnesium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/MeOH/NH4OH 110:10:1), was obtained 0.11 g (48%) of 2-(3,5-bis(trifluoromethyl)phenyl)-N-methyl-N-[2-(4-methylpiperazin-1-yl)-4-o-collectibility-5-yl)isobutyramide in the form of a foamy substance white, MS (ISP): 596,2 (M+N)+.

Example 50

2-(3,5-Bis(three is tormentil)phenyl)-N-methyl-N-(2-piperazine-1-yl-4-o-collectibility-5-yl)isobutyramide

To a solution of 0.30 g (0,52 mmole) of 2-(3,5-bis(trifluoromethyl)phenyl)-N-(2-methanesulfonyl-4-o-collectibility-5-yl)-N-methylisobutyl in 10 ml of dioxane was added 0,112 g (1.3 mmole) piperazine. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of methylene chloride and 50 ml of saturated sodium bicarbonate solution. The aqueous layer was extracted with 50 ml of methylene chloride, the combined organic layers were dried (magnesium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/MeOH/NH4OH 140:10:1), was obtained 0.20 g (66%) of 2-(3,5-bis(trifluoromethyl)phenyl)-N-methyl-N-(2-piperazine-1-yl-4-o-collectibility-5-yl)isobutyramide in the form of a foamy substance white, MS (ISP): 582,2 (M+N)+.

Example 51

2-(3,5-Bis(trifluoromethyl)phenyl)-N-[2-(2-diethylaminoethylamine)-4-o-collectibility-5-yl]-N-methylisoleucine

To a solution of 0.25 g (0.43 mmole) of 2-(3,5-bis(trifluoromethyl)phenyl)-N-(2-methanesulfonyl-4-o-collectibility-5-yl)-N-methylisobutyl in 10 ml of dioxane was added 0,119 ml (1.09 mmole) of 2-diethylaminoethylamine. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of methylene chloride and 50 ml of saturated sodium bicarbonate solution. The aqueous layer was extracted with 50 ml of methylene chloride, the combined organization is organic layers were dried (magnesium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/MeOH/NH4OH 140:10:1), was obtained 0.20 g (79%) of 2-(3,5-bis(trifluoromethyl)phenyl)-N-[2-(2-diethylaminoethylamine)-4-o-collectibility-5-yl]-N-methylisobutyl in the form of a foamy substance white, MS (ISP): 584,2 (M+N)+.

Example 52

2-(3,5-Bis(trifluoromethyl)phenyl)-N-methyl-N-[2-(2-morpholine-4-ylethoxy)-4-o-collectibility-5-yl]isobutyramide

To a solution of 0.4 g (0.7 mmole) of 2-(3,5-bis(trifluoromethyl)phenyl)-N-(2-methanesulfonyl-4-o-collectibility-5-yl)-N-methylisobutyl in 20 ml of acetonitrile was added 0,126 ml (1.04 million mmole) of N-(2-hydroxyethyl)the research and 1.13 g (3,48 mmole) Cs2CO3. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of methylene chloride and 50 ml of water. The aqueous layer was extracted with 50 ml of methylene chloride, the combined organic layers were dried (magnesium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/MeOH 40:1), received 0,30 g (69%) of 2-(3,5-bis(trifluoromethyl)phenyl)-N-methyl-N-[2-(2-morpholine-4-ylethoxy)-4-o-collectibility-5-yl]isobutyramide in the form of a colorless foamy substance, MS (ISP): 627,2 (M+H)+.

Example 53

2-(3,5-Bis(trifluoromethyl)phenyl)-N-[2-(2-dimethylaminoethoxy)-4-o-collectibility-5-yl]-N-methylisoleucine

It is astory 0.25 g (0.43 mmole) of 2-(3,5-bis(trifluoromethyl)phenyl)-N-(2-methanesulfonyl-4-o-collectibility-5-yl)-N-methylisobutyl in 10 ml of acetonitrile was added of 0.066 ml (0.65 mmole) of 2-dimethylaminoethanol and 0.70 g (2,14 mmole) Cs 2CO3. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of methylene chloride and 50 ml of water. The aqueous layer was extracted with 50 ml of methylene chloride, the combined organic layers were dried (magnesium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/MeOH/NH4OH 110:10:1), was obtained 0.18 g (71%) of 2-(3,5-bis(trifluoromethyl)phenyl)-N-[2-(2-dimethylaminoethoxy)-4-o-collectibility-5-yl]-N-methylisobutyl in the form of a colorless foamy substance, MS (ISP): 585,2 (M+N)+.

Example 54

2-(3,5-Bis(trifluoromethyl)phenyl)-N-[2-(3-dimethylaminopropoxy)-4-o-collectibility-5-yl]-N-methylisoleucine

To a solution of 0.30 g (0,52 mmole) of 2-(3,5-bis(trifluoromethyl)phenyl)-N-(2-methanesulfonyl-4-o-collectibility-5-yl)-N-methylisobutyl in 20 ml of acetonitrile was added 0,061 ml (0,78 mmole) 3-dimethylaminopropanol and 0.85 grams (2,61 mmole) Cs2CO3. The reaction mixture was stirred 16 hours. After evaporation of the solvent the residue was distributed between 50 ml of methylene chloride and 50 ml of water. The aqueous layer was extracted with 50 ml of methylene chloride, the combined organic layers were dried (magnesium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/MeOH/NH4OH 140:10:1), was obtained 0.20 g (64%) of 2-(3,5-bis(trifter ethyl)phenyl)-N-[2-(3-dimethylaminopropoxy)-4-o-collectibility-5-yl]-N-methylisobutyl in the form of a colorless oil, MS (ISP): 599,2 (M+N)+.

Example 55

2-(3,5-Bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-methylsulfonylamino-5-yl]-N-methylisoleucine

By the way, is similar to that described in example 46 (a), from 4-(4-pertenece)-2-methylsulfonylamino-5-carboxylic acid, diphenylphosphinite and tert-butanol was obtained tert-butyl ester [4-(4-pertenece)-2-methylsulfonylamino-5-yl]carbamino acid, which has metilirovanie using iodotope bromide, and then filmed protection with trifluoroacetic acid according to example 43 (b)). The resulting [4-(4-pertenece)-2-methylsulfonylamino-5-yl]methylamine was treated with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionamide as described in example 43 d), was obtained 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-methylsulfonylamino-5-yl]-N-methylisoleucine in the form of a colorless foamy substance, MS (EI): 547 (M+).

Example 56

2-(3,5-Bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-methanesulfonamido-5-yl] -N-methylisoleucine

Similar to that described in example 47 by way of 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-methylsulfonylamino-5-yl]-N-methylisobutyl and 3-chlormadinone acid was obtained 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-methanesulfonamido-5-yl]-N-methylisoleucine in the form of a foamy substance of white color is the MS (ISP): 580,2 (M+N)+.

Example 57

2-(3,5-Bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-morpholine-4-Yeremey-5-yl]-N-methylisoleucine

Similar to that described in example 48 by way of 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-methanesulfonamido-5-yl-N-methylisobutyl and the research was obtained 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-morpholine-4-Yeremey-5-yl]-N-methylisoleucine in the form of a colorless foamy substance, MS (ISP): 587,2 (M+N)+.

Example 58

2-(3,5-Bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-(4-methylpiperazin-1-yl)pyrimidine-5-yl]-N-methylisoleucine

Similar to that described in example 49 by way of 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-methanesulfonamido-5-yl]-N-methylisobutyl and 1-methylpiperazine received 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-(4-methylpiperazin-1-yl)pyrimidine-5-yl]-N-methylisoleucine in the form of a colorless foamy substance, MS (ISP): 600,1 (M+N)+.

Example 59

2-(3,5-Bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-piperazine-1-Yeremey-5-yl]-N-methylisoleucine

Similar to that described in example 50 by way of 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-methanesulfonamido-5-yl]-N-methylisobutyl and piperazine was obtained 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-piperazine-1-Yeremey-5-yl]-N-methylisoleucine the form of a colorless foamy substance, MS (ISP): 586,2 (M+N)+.

Example 60

2-(3,5-Bis(trifluoromethyl)phenyl)-N-[2-(2-diethylaminoethylamine)-4-(4-pertenece)pyrimidine-5-yl]-N-methylisoleucine

Similar to that described in example 51 by way of 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-methanesulfonamido-5-yl]-N-methylisobutyl and 2-diethylaminoethylamine received 2-(3,5-bis(trifluoromethyl)phenyl)-N-[2-(2-diethylaminoethylamine)-4-(4-pertenece)pyrimidine-5-yl]-N-methylisoleucine in the form of a colorless foamy substance, MS (ISP): 588,3 (M+N)+.

Example 61

2-(3,5-Bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-(2-morpholine-4-ylethoxy)pyrimidine-5-yl]-N-methylisoleucine

Similar to that described in example 52 by way of 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-methanesulfonamido-5-yl]-N-methylisobutyl and N-(2-hydroxyethyl)the research was obtained 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-(2-morpholine-4-ylethoxy)pyrimidine-5-yl]-N-methylisoleucine in the form of a colorless foamy substances, MS (ISP): 631,1 (M+N)+.

Example 62

2-(3,5-Bis(trifluoromethyl)phenyl)-N-[2-(2-dimethylaminoethoxy)-4-(4-pertenece)pyrimidine-5-yl]-N-methylisoleucine

Similar to that described in example 53 by way of 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-methanesulfonamido-5-yl]-N-methylisobutyl and 2-dimethylaminoethanol received 2-(3,5-bis(trifluoromethyl)FeNi is)-N-[2-(2-dimethylaminoethoxy)-4-(4-pertenece)pyrimidine-5-yl]-N-methylisoleucine in the form of a colorless foamy substance, MS (ISP): 589,2 (M+N)+.

Example 63

2-(3,5-Bis(trifluoromethyl)phenyl)-N-[2-(3-dimethylaminopropoxy)-4-(4-pertenece)pyrimidine-5-yl]-N-methylisoleucine

Similar to that described in example 54 by way of 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-methanesulfonamido-5-yl]-N-methylisobutyl and 3-dimethylaminopropanol received 2-(3,5-bis(trifluoromethyl)phenyl)-N-[2-(3-dimethylaminopropoxy)-4-(4-pertenece)pyrimidine-5-yl]-N-methylisoleucine in the form of a colorless foamy substance, MS (ISP): 603,1 (M+N)+.

Example 64

2-(3,5-Bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-methylsulfonylamino-5-yl]-N-methylisoleucine

Similar to that described in example 46 (a) by way of 4-(2-chlorophenoxy)-2-methylsulfonylamino-5-carboxylic acid, diphenylphosphinite and tert-butanol was obtained tert-butyl ester [4-(2-chlorophenoxy)-2-methylsulfonylamino-5-yl]carbamino acid, which has metilirovanie using iodotope bromide, and then filmed protection with trifluoroacetic acid according to example 43 (b)). The resulting [4-(2-chlorophenoxy)-2-methylsulfonylamino-5-yl]methylamine was treated with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionamide as described in example 43 d), was obtained 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-methylsulfonylamino-5-yl]-N-methylisoleucine in the form of foam ve is esta white, MS (ISP): 564,2 (M+N)+.

Example 65

2-(3,5-Bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-methanesulfonamido-5-yl]-N-methylisoleucine

Similar to that described in example 47 by way of 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-methylsulfonylamino-5-yl]-N-methylisobutyl and 3-chlormadinone acid was obtained 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-methanesulfonamido-5-yl]-N-methylisoleucine in the form of a foamy substance white, MS (ISP): 596,1 (M+N)+.

Example 66

2-(3,5-Bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-morpholine-4-Yeremey-5-yl]-N-methylisoleucine

Similar to that described in example 48 by way of 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-methanesulfonamido-5-yl]-N-methylisobutyl and the research was obtained 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-morpholine-4-Yeremey-5-yl]-N-methylisoleucine in the form of a colorless foamy substance, MS (ISP): 603,0 (M+H)+.

Example 67

2-(3,5-Bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-(4-methylpiperazin-1-yl)pyrimidine-5-yl]-N-methylisoleucine

Similar to that described in example 49 by way of 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-methanesulfonamido-5-yl]-N-methylisobutyl and 1-methylpiperazine received 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-(4-methylpiperazin-1-yl)pyrimidine-5-yl]--methylisobutyl in the form of a colorless foamy substance, MS (ISP): 616,1 (M+N)+.

Example 68

2-(3,5-Bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-piperazine-1-Yeremey-5-yl]-N-methylisoleucine

Similar to that described in example 50 by way of 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-methanesulfonamido-5-yl]-N-methylisobutyl and piperazine was obtained 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-piperazine-1-Yeremey-5-yl]-N-methylisoleucine in the form of a colorless foamy substance, MS (ISP): 602,1 (M+N)+.

Example 69

2-(3,5-Bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-(2-morpholine-4-ylethoxy)pyrimidine-5-yl]-N-methylisoleucine

Similar to that described in example 52 by way of 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-methanesulfonamido-5-yl]-N-methylisobutyl and N-(2-hydroxyethyl)the research was obtained 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-(2-morpholine-4-ylethoxy)pyrimidine-5-yl]-N-methylisoleucine in the form of a colorless foamy substances, MS (ISP): 647,1 (M+N)+.

Example 70

2-(3,5-Bis(trifluoromethyl)phenyl)-N-[2-(2-dimethylaminoethoxy)-4-(2-chlorophenoxy)pyrimidine-5-yl]-N-methylisoleucine

Similar to that described in example 53 by way of 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-methanesulfonamido-5-yl]-N-methylisobutyl and 2-dimethylaminoethanol received 2-(3,5-bis(trifluoromethyl)phenyl)-N-[2-(2-dimethylaminoethoxy)-4-(2-harfe the oxy)pyrimidine-5-yl]-N-methylisoleucine in the form of a colorless foamy substance, MS (ISP): 605,0 (M+N)+.

Example 71

2-(3,5-Bis(trifluoromethyl)phenyl)-N-[2-(3-dimethylaminopropoxy)-4-(2-chlorophenoxy)pyrimidine-5-yl]-N-methylisoleucine

Similar to that described in example 54 by way of 2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-methanesulfonamido-5-yl]-N-methylisobutyl and 3-dimethylaminopropanol received 2-(3,5-bis(trifluoromethyl)phenyl)-N-[2-(3-dimethylaminopropoxy)-4-(2-chlorophenoxy)pyrimidine-5-yl]-N-methylisoleucine in the form of a colorless foamy substance, MS (ISP): 619,1 (M+N)+.

Example 72

2-(3,5-Bis(trifluoromethyl)phenyl)-N-methyl-N-(2-methyl-4-o-collectibility-5-yl)isobutyramide

a) tert-Butyl ether (2-methyl-4-o-collectibility-5-yl)carbamino acid

To a solution of 2.50 g (10,24 mmole) of 2-methyl-4-o-collectibility-5-carboxylic acid, 1,43 ml of triethylamine (10,24 mmol) and 1.9 ml (20.4 mmol) of tert-butanol in 50 ml of tetrahydrofuran was added 2.2 ml (10,24 mmol) diphenylphosphinite and the resulting solution was boiled under reflux for 12 hours. After evaporation of the solvent the residue was distributed between methylene chloride and water. The aqueous phase was extracted twice with 80 ml methylene chloride. The combined organic layers were dried (sodium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/Meon 40:1), received 1,83 g (56% tert-butyl ether (2-methyl-4-o-collectibility-5-yl)carbamino acid as a colourless solid, MS (ISP): 316,3 (M+H).

b) tert-Butyl methyl ether(2-methyl-4-o-collectibility-5-yl)carbamino acid

To a solution of 1.83 g (5.8 mmol) of tert-butyl methyl ether (2-methyl-4-o-collectibility-5-yl)carbamino acid in 25 ml of N,N-dimethylformamide was added 0.35 g (68.7 mmol) of sodium hydride (60%dispersion in mineral oil) and the reaction mixture was stirred for 1 hour. After addition of 0.65 ml (10.4 mmol) iodotope bromide at 0°C the reaction mixture was stirred for 2 hours. The reaction mixture was poured into 100 ml of a mixture of ice water and three times was extracted with 80 ml methylene chloride. The combined organic layers were dried (sodium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/ethyl acetate 40:1), received 1,90 g (99%) of tert-butyl methyl ether(2-methyl-4-o-collectibility-5-yl)carbamino acid in the form of a colorless oil, MS (ISP): 330,4 (M+N)+.

b) Methyl(2-methyl-4-o-collectibility-5-yl)Amin

To a solution of 1.90 g (5,77 mmol) of tert-butyl methyl ether(2-methyl-4-o-collectibility-5-yl)carbamino acid in 25 ml of methylene chloride was added 2 ml triperoxonane acid and the reaction mixture was stirred 2 hours at 40°C. the Reaction mixture was poured into a mixture of ice water and with 1 n sodium hydroxide solution were placed in a solution of pH 10. The aqueous phase three was ratexchhaireani 80 ml of methylene chloride. The combined organic layers were dried (sodium sulfate), filtered and evaporated, was obtained 0.95 g (72%) of methyl(2-methyl-4-o-collectibility-5-yl)amine in the form of a solid of light yellow color, MS (EI): 229,2 (M+).

g) 2-(3,5-Bis(trifluoromethyl)phenyl)-N-methyl-N-(2-methyl-4-o-collectibility-5-yl)isobutyramide

To a solution of 0.4 g (1,74 mmole) of methyl(2-methyl-4-o-collectibility-5-yl)amine and 0.6 ml (3,49 mmole) of N-ethyldiethanolamine in 15 ml of methylene chloride was added a solution 0,78 g (2,44 mmole) of 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionitrile in 5 ml of methylene chloride and the reaction mixture was stirred 12 hours at room temperature. The reaction mixture was poured into 50 ml of 0.5 n sodium hydroxide solution. The phases were separated and the aqueous phase three times was extracted with 80 ml methylene chloride. The combined organic layers were dried (sodium sulfate), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/Meon 40:1), received 0,82 g (94%) of 2-(3,5-bis(trifluoromethyl)phenyl)-N-methyl-N-(2-methyl-4-o-collectibility-5-yl)isobutyramide in the form of a foamy substance white, MS (ISP): 511,1 (M+N)+.

Example 73

2-(3,5-Bis(trifluoromethyl)phenyl)-N-methyl-N-(2-phenyl-4-o-collectibility-5-yl)isobutyramide

Similar to that described in example 72 (a) by way of 2-phenyl-4-o-collectibility-5-carboxylic acid diphenylphosphinite and tert-butanol was obtained tert-butyl ether (2-phenyl-4-o-collectibility-5-yl)carbamino acid, which metilirovanie using iodotope methyl, and then removed protection using triperoxonane acid according to example 72 (b)). The resulting methyl(2-phenyl-4-o-collectibility-5-yl)amine was treated with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropionamide as described in example 72 g)was obtained 2-(3,5-bis(trifluoromethyl)phenyl)-N-methyl-N-(2-phenyl-4-o-collectibility-5-yl)isobutyramide in the form of a foamy substance white, MS (ISP): 574,1 (M+N)+.

Example

Tablets of the following composition is prepared an accepted way:

mg tablet
The active ingredient5
Lactose45
Corn starch15
Microcrystalline cellulose34
Magnesium stearate1
Weight pills100

Example B

Prepare capsules of the following composition:

mg/capsule
The active ingredient10
Lactose155
Corn starch30
Talc5
Mass content is ICDO capsules 200

The active ingredient, lactose and corn starch are first mixed in a mixer and then in a machine for grinding. The mixture is returned to the mixer, it added to the talc and mix thoroughly. Mix using the appropriate device filled hard gelatin capsules.

The example In

Prepare suppositories of the following composition:

mg/suppository
The active ingredient15
Weight for suppository1285
Only1300

For a lot of suppository is melted in a glass or steel vessel, mix thoroughly and cooled to 45°C. then there are added powdered active substance is added and stirred until full dispersion. The mixture is then poured into molds for suppositories suitable size, leave to cool, suppositories then removed from the molds and wrap individually in waxed paper or metal foil.

1. Compounds of General formula:

where

R1means lower alkyl, lower alkoxy, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O)2-lower alkyl,

-N(R)-(CH2)n -N(R)2, -O-(CH2)n-N(R)2,

-N(R)2or a cyclic tertiary amine in the form of group

which may contain one additional heteroatom selected from N, O or S, and where this group can be linked to the pyrimidine ring bridge-O(CH2)n-;

R2means hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl;

R3/R3'mean independently from each other hydrogen or lower alkyl;

R4means, regardless of any other halogen, trifluoromethyl or lower alkoxy;

R5means hydrogen or lower alkyl;

R means, regardless of any other hydrogen or lower alkyl;

X is-C(O)N(R) -, or-N(R)C(O)-;

Y represents-O-;

n denotes 1, 2, 3 or 4; m is 0, 1 or 2;

and their pharmaceutically acceptable acid additive salt.

2. The compound of formula I according to claim 1, where X is-C(O)N(CH3)-.

3. The compound of formula I according to claim 2, where R1is a cyclic tertiary amine.

4. The compound of formula I according to claim 3, which means:

(3,5-bis(trifluoromethyl)benzyl)methylamide 2-(4-methylpiperazin-1-yl)-4-o-tolyloxy-pyrimidine-5-carboxylic acid,

(3,5-bis(trifluoromethyl)benzyl)methylamide 2-piperazine-1-yl-4-o-tolyloxy is kidin-5-carboxylic acid, or

(3,5-bis(trifluoromethyl)benzyl)methylamide 4-(2-chlorophenoxy)-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylic acid.

5. The compound of formula I according to claim 2, where R1means-O-(CH2)n-cyclic tertiary amine.

6. The compound of formula I according to claim 5, which is (3,5-bis(trifluoromethyl)benzyl)methylamino 2-(2-morpholine-4-ylethoxy)-4-o-collectibility-5-carboxylic acid.

7. The compound of formula I according to claim 2, where R1is a group-O-(CH2)-NR2.

8. The connection according to claim 7, which is

(3,5-bis(trifluoromethyl)benzyl)methylamino 2-(2-dimethylaminoethoxy)-4-o-collectibility-5-carboxylic acid.

9. The compound of formula I according to claim 1, where X is-N(CH3)C(O)-.

10. The compound of formula I according to claim 9, where R1means-S-lower alkyl.

11. The compound of formula I according to claim 9, which means

2-(3,5-bis(trifluoromethyl)phenyl)-N-methyl-N-(2-methylsulfanyl-4-o-tolyloxy-pyrimidine-5-yl)isobutyramide,

2-(3,5-bis(trifluoromethyl)phenyl)-N- [4-(4-pertenece)-2-methylsulfonylamino-5-yl]-N-methylisoleucine or

2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-methylsulfonylamino-5-yl]-N-methylisoleucine.

12. The compound of formula I according to claim 9, where R1is a cyclic tertiary amine.

13. The compound of formula I according to item 12, which means

2-(3,5-bis(trifluoromethyl)phenyl)-N-methyl-N-2-morpholine-4-yl-4-o-tolyloxy-pyrimidine-5-yl)isobutyramide,

2-(3,5-bis(trifluoromethyl)phenyl)-N-methyl-N-[2-(4-methylpiperazin-1-yl)-4-o-collectibility-5-yl] isobutyramide,

2-(3,5-bis(trifluoromethyl)phenyl)-N-methyl-N-(2-piperazine-1-yl-4-o-tolyloxy-pyrimidine-5-yl)isobutyramide,

2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-(4-methylpiperazin-1-yl)-pyrimidine-5-yl]-N-methylisoleucine,

2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(4-pertenece)-2-piperazine-1-Yeremey-5-yl]-N-methylisoleucine,

2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-morpholine-4-Yeremey-5-yl]-N-methylisoleucine,

2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-(4-methylpiperazin-1-yl)-pyrimidine-5-yl]-N-methylisoleucine or

2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-piperazine-1-Yeremey-5-yl]-N-methylisoleucine.

14. The compound of formula I according to claim 9, where R1means-N(R)(CH2)nNR2.

15. The compound of formula I to 14, which means 2-(3,5-bis(trifluoromethyl)phenyl)-N-[2-(2-diethylaminoethylamine)-4-o-tolyloxy-pyrimidine-5-yl]-N-methylisoleucine or

2-(3,5-bis(trifluoromethyl)phenyl)-N-[2-(2-diethylaminoethylamine)-4-(4-pertenece)-pyrimidine-5-yl]-N-methylisoleucine.

16. The compound of formula I according to claim 9, where R1means-O-(CH2)n-cyclic 5 tertiary amine.

17. The compound of formula I according to clause 16, which means

2-(3,5-bis(trifluoromethyl)Fe who yl)-N-methyl-N-[2-(2-morpholine-4-ylethoxy)-4-o-tolyl-oxopyrimidine-5-yl] isobutyramide,

2-(3,5-bis(trifluoromethyl)phenyl)-N-[4-(2-chlorophenoxy)-2-(2-morpholine-4-ylethoxy)-pyrimidine-5-yl]-N-methylisoleucine.

18. The compound of formula I according to claim 9, where R1means-O-(CH2)nNR2.

19. The compound of formula I according p, which means

2-(3,5-bis(trifluoromethyl)phenyl)-N-[2-(2-dimethylaminoethoxy)-4-o-tolyloxy-pyrimidine-5-yl]-N-methylisoleucine,

2-(3,5-bis(trifluoromethyl)phenyl)-N-[2-(3-dimethylaminopropoxy)-4-o-tolyloxy-pyrimidine-5-yl]-N-methylisoleucine,

2-(3,5-bis(trifluoromethyl)phenyl)-N-[2-(2-dimethylaminoethoxy)-4-(4-pertenece)-pyrimidine-5-yl]-N-methylisoleucine,

2-(3,5-bis(trifluoromethyl)phenyl)-N-[2-(3-dimethylaminopropoxy)-4-(4-pertenece)-pyrimidine-5-yl]-N-methylisoleucine,

2-(3,5-bis(trifluoromethyl)phenyl)-N-[2-(2-dimethylaminoethoxy)-4-(2-chlorophenoxy)-pyrimidine-5-yl]-N-methylisoleucine or

2-(3,5-bis(trifluoromethyl)phenyl)-N-[2-(3-dimethylaminopropoxy)-4-(2-chlorophenoxy)-pyrimidine-5-yl]-N-methylisoleucine.

20. Pharmaceutical composition having the properties of receptor antagonists neirokinina NK-1, containing one or more compounds according to any one of claims 1 to 19 and a pharmaceutically acceptable fillers.

21. The pharmaceutical composition according to claim 20, suitable for the treatment of diseases caused by infringement actions receptor neirokinina NK-1.



 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (IA) wherein X means -NH; R5a represents optionally substituted 5-membered heteroaromatic ring chosen from the group of the following formulae: (a) (b) (c) (d) (e) (f) (g) (h) (i) or (j) wherein * means the addition position to the group X in the formula (IA); R60 and R61 from group of the formula (k) wherein p and q mean independently 0 or 1; R1' and R1'' represent independently hydrogen atom, hydroxy-group wherein T represents C=O, sulfur atom (S), -C(=NOR)CO, -C(O)C(O) wherein R represents hydrogen atom, (C1-C6)-alkyl and phenyl; V represents independently hydrogen atom, hydroxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy-group, trifluoromethyl, phenyl optionally substituted with (C1-C6)-alkoxy- or (C1-C6)-alkanoyloxy-group or (C3-C7)-cycloalkyl; or V represents -N(R63)R64 wherein one of R63 and R64 is chosen independently from hydrogen atom, (C1-C10)-alkyl optionally substituted with hydroxy-group, (C1-C6)-alkoxycarbonyl and (C1-C6)-alkoxyl; and (C2-C6)-alkenyl and another represents (C1-C6)-alkyl optionally substituted 1 or 2 with (C1-C4)-alkoxyl, cyano-group, (C1-C4)-alkoxycarbonyl, (C2-C4)-alkanoyloxy- or hydroxy-group; heteroaryl-(C1-C6)-alkyl wherein heteroaryl represents 5-6-membered ring comprising 1-2 heteroatoms chosen from oxygen (O), sulfur (S) and nitrogen (N) atoms and optionally substituted with (C1-C6)-alkyl; phenyl or phenyl-(C1-C6)-alkyl optionally substituted with 1, 2 or 3 groups chosen from halogen atom, N,N-di-(C1-C6)-alkyl)-amino-, N-(C1-C6)-alkyl)-amino-, (C1-C6)-alkoxy-group, (C2-C6)-alkanoyl, trifluoromethyl, cyano-group, (C1-C6)-alkyl optionally substituted with hydroxy- or cyano-group, carbamoyl, hydroxy-, trifluoromethoxy-, nitro-, (C1-C6)-alkylthio-, amino-group, -O-(C1-C3)-alkyl-O- and (C1-C6)-alkylcarbonyl; heteroaryl chosen from pyridyl, furanyl and indolyl optionally substituted with 1 or 2 hydroxy-groups, halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl-(C1-C6)-alkyl optionally substituted with hydroxy-group; or R63 and R64 in common with nitrogen atom to which they are bound form 5-6-membered ring that can comprise additionally heteroatom N or O and can be optionally substituted with (C1-C6)-alkyl, hydroxy-group, hydroxy-(C1-C6)-alkyl or carbamoyl; R62 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl or carbamoyl; R1' represents hydrogen atom; R2' represents (C1-C5)-alkoxy-group; R3' represents -X1R9 wherein X1 represents -O- and R9 is chosen from the following groups: (1) (C1-C5)-alkyl; (2) (C1-C5)-alkyl-X3R20 wherein X3 represents -NR25- wherein R25 represents hydrogen atom or (C1-C3)-alkyl; R20 represents (C1-C3)-alkyl, cyclopentyl and (C1-C3)-alkyl group can comprise 1 or 2 substitutes chosen from oxo-, hydroxy-group, halogen atom and (C1-C4)-alkoxy-group; (3) represents (C1-C5)-X4-(C1-C5)-alkyl-X5R26 wherein each among X4 and X5 represents -NR31- wherein R31 represents hydrogen atom or (C1-C3)-alkyl; R26 represents hydrogen atom or (C1-C3)-alkyl; (4) (C1-C5)-alkyl-R32 wherein R32 represents 5-6-membered saturated heterocyclic group bound through carbon or nitrogen atom with 1-2 heteroatoms chosen independently from O and N and wherein heterocyclic group can comprise 1 or 2 substitutes chosen from hydroxy-group, (C1-C4)-alkyl and (C1-C4)-hydroxyalkyl; (5) (C1-C3)-alkyl-X9-(C1-C3)-alkyl-R32 wherein X9 represents -NR57- wherein R57 represents hydrogen atom or (C1-C3)-alkyl and R32 is given above; R4' represents hydrogen atom; or to its pharmaceutically acceptable salts. Compounds are inhibitors of kinase aurora 2 and can be used for preparing a medicinal agent used in treatment of proliferative diseases, in particular, in cancer treatment. Except for, invention relates to a pharmaceutical composition possessing the abovementioned activity and a method for preparing compounds of the formula (IA).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

14 cl, 30 tbl, 477 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

22 cl, 8 tbl, 453 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to series of new compounds that are inhibitors of enzyme dipeptidyl peptidase IV. Invention proposes a compound chosen from derivatives of the formula (1) its tautomers and stereomers and pharmaceutically acceptable salts of indicated derivatives, tautomers and isomers wherein R1 represents hydrogen atom (H) or -CN; X1 represents sulfur atom (S), oxygen atom (O), -SO2 or -CH2; X2 represents -CO, -CH2 or a covalent bond; Het represents nitrogen-containing heterocycle; n = 1-5. Invention proposes a pharmaceutical composition possessing properties of inhibitor of enzyme dipeptidyl peptidase IV, and a method for treatment of at least one diseases among diabetes mellitus type 2, reduced tolerance to glucose, growth hormone deficiency, polycystic ovary syndrome and autoimmune and inflammatory diseases. Invention provides preparing series of inhibitors of dipeptidyl peptidase IV showing the improved affinity to enzyme, preparing pharmaceutical compositions and their using in treatment of some human diseases including the reduced tolerance to glucose and diabetes mellitus of type 2.

EFFECT: valuable biochemical and medicinal properties of inhibitors.

14 cl, 6 tbl, 123 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds including all its enantiomeric and diastereomeric forms, and to their pharmaceutically acceptable salts wherein indicated compound corresponds to the formula: wherein A represents a conformationally limited ring system chosen from the group comprising the following formulae: (a) (d) and (e) wherein carbon atoms labeled by asterisks can be in any stereochemical configuration or their mixtures wherein Y has a formula: -(CH2)b-R15 wherein index b = 1-4, and R15 represents -OH, -NH2, guanidine-group, and Z has a formula: wherein R represents hydrogen atom; R9 represents naphthylmethyl; R10 represents -C(X)N(R16)2 wherein each R16 represents independently hydrogen atom or (C1-C10)-alkyl; X represents oxygen atom; or Z represents naphthylmethyl wherein W has a formula: wherein R represents phenyl substituted optionally with halogen atom of OH-group wherein fragment L is chosen from the group comprising: -NH- or -NHC(O)-; B represents hydrogen atom of fragment of the formula: wherein fragments R2, R3 and R4 are chosen independently among the group comprising hydrogen atom, -NHC(O)CH3, benzyl substituted optionally with hydroxy-group or halogen atom, imidazolylmethyl; or fragments R2, R3 and R represent in common naphthalinyl or isoquinolinyl; or one radical among R2, R3 and R4 represents hydrogen atom and two radical among R, R3 or R4 chosen in common form piperidine ring or tetrahydroisoquinoline ring substituted optionally with the group -C(O)CH3. Also, invention relates to a pharmaceutical composition possessing the agonistic activity with respect to MC-3/MC-4 receptors based on these compounds. Invention provides preparing new compounds and pharmaceutical compositions based on thereof for aims in treatment of disorders mediated by function of MC-3/MC-4 receptors.

EFFECT: valuable medicinal properties of compounds and compositions.

17 cl, 14 tbl, 12 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

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

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, medicinal virology, biochemistry, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrazole of the formula (I-A):

wherein R1 means (C1-C12)-alkyl that can be optionally substituted with 1-3 substitutes taken among fluorine, chlorine and bromine atoms, (C3-C8)-cycloalkyl, phenyl, pyridyl or (C1-C4)-alkyl substituted with phenyl; R2' means optionally substituted phenyl wherein phenyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano- and nitro-group; R3 means (C1-C12)-alkyl or (C1-C4)-alkoxy-(C1-C4)-alkyl; A' means (C1-C4)-alkyl optionally substituted with phenyl or optionally substituted with 4-pyridyl wherein phenyl or 4-pyridyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH2-U-heterocyclyl wherein U represents O, S or NR'' wherein R'' means hydrogen atom or (C1-C4)-alkyl and wherein heterocyclyl means pyridyl or pyrimidinyl that is optionally substituted with 1-2 substitutes taken among (C1-C4)-alkyl, fluorine, chlorine and bromine atoms, cyano-, nitro-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH(OH)-phenyl; or A' means the group CH=CHW wherein W means phenyl; X means S or O, and their pharmaceutically acceptable salts. These compounds are inhibitors of human immunodeficiency virus (HIV) reverse transcriptase and, therefore, can be used in treatment of HIV-mediated diseases. Also, invention relates to a pharmaceutical composition used in treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and composition.

11 cl, 5 tbl, 32 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes analgesic agent possessing the analgesic effect showing effectiveness against the pain by effect on nociceptors. As an active component the proposed analgesic agent comprises compound represented by the general formula (1) or its salt wherein X, Y, E, Q, A1, A2, R1, R3, R4, R5, R2A, R2C, R2D and R2B re determined in the invention claim.

EFFECT: valuable medicinal properties of agents.

3 tbl, 70 ex

FIELD: organic chemistry, chemical technology, herbicides, agriculture.

SUBSTANCE: invention relates to new sulfonamides of the formula (I):

and their salt wherein A represents substituted or unsubstituted benzene ring or 5-membered, or 6-membered substituted or unsubstituted heteroaromatic ring taken among the group comprising thienyl, pyrazolyl, imidazolyl, pyridyl wherein optional substitutes are taken among the group consisting of halogen atom, substituted or unsubstituted (C1-C4)-alkyl, unsubstituted or substituted (C1-C4)-alkoxy-group, nitro-group, phenyl, phenoxy-group, benzoyl and (C1-C4)-alkylcarboxylate when any alkyl fragment in the latter indicated substituted is substituted with one or some halogen atoms, (C1-C4)-alkoxy-groups, cyano-group and phenyl; Q represents -O-, -S- or group of the formula: -CXX' wherein X and X' can be similar or different and each represents hydrogen atom, halogen atom, cyano-group, alkyl comprising 1-8 carbon atoms, or the group -ORa, -SRa; or one of X and X' represents hydroxy-group and another has values determine above; Ra means (C1-C8)-alkyl, phenyl; Rb means (C1-C8)-alkyl, phenyl; Y means nitrogen atom or the group CR9; R1 means unsubstituted (C1-C8)-alkyl or that substituted with halogen atom, cyano-group, phenyl or (C1-C4)-alkoxycarbonylamino-group, or it represents phenyl; R2 means hydrogen atom (H), (C1-C4)-alkyl; R3 and R4 can be similar or different and each represents (C1-C4)-alkyl, (C1-C4)-alkoxy-group, halogen atom; R9 means hydrogen atom (H) under condition that when Q represents oxygen atom (O) or -S- then ring A represents 5-membered substituted or unsubstituted heteroaromatic ring and determined above. Compounds of the formula (I) possess the herbicide activity that allows their using for eradication of weeds. Also, invention describes a method for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable properties of compounds.

9 cl, 5 tbl, 18 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I)

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

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

24 cl, 3 sch, 166 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 1-91-methyl-2-(3,4-fullero[60]-pyrrolidinyl))-1H-1,2,4-triazole of the general formula (1): Method involves interaction of fullerene[60] with N-[(1,2,4-triazol-1-yl)methyl]-N,N-dimethylamine of the general formula: (R-CH2-N-(CH3)2 wherein R means taken in the mole ratio C60 : R-CH2-N-(CH3)2 = 0.01:(0.01-0.011) in the presence of Cp2TiCl2 as a catalyst taken in the amount 15-25 mole% relatively to fullerene[60], in argon atmosphere, in toluene medium as a solvent at temperature 140-160°C for 2-4 h. The end substance is prepared with the yield 78-86%. Compound of the formula (1) can be used as chelating agent, sorbent, biologically active compound and in the development of novel materials with required electronic, magnetic and optical properties.

EFFECT: improved method of synthesis.

1 tbl, 1 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: herbicides.

SUBSTANCE: invention relates to application of 2-diethylamino-6-methoxy-4-[(4'-ethoxycarnonyl-5'-methyl-1',2',3'-triazole)-1'yl]1,3,5,-triazine of formula as antidote against phytotoxic action of 2,4-dichlorophenoxyacetic acid herbicide onto germinated sunflower seeds.

EFFECT: more effective sunflower germ root length and hypocotyl elongation on background of phytotoxic 2,4-D herbicide action.

2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of N-heterocyclic compounds of the formula: , wherein n and m mean independently a whole number from 1 to 4; A means -C(O)OR1 or -C(O)N(R1)R2; W means -CH; R1 means hydrogen atom or (C1-C8)-alkyl; R means hydrogen atom, (C1-C8)-alkyl, heterocyclyl-(C1-C4)-alkyl chosen from the group comprising benzodioxolyl-, benzodioxanyl- or dihydrobenzofuranylalkyl or phenyl-(C1-C4)-alkyl substituted possibly with alkoxy-group; R4 means cyano-group or heterocyclyl chosen from the group comprising pyridinyl, morpholinyl, benzodioxolyl or benzodioxanyl-radical if m = 1; if m means from 2 to 4 then R4 can mean additionally hydroxy-group, -NR1R2 wherein R1 and R2 mean independently hydrogen atom, (C1-C8)-alkyl or benzyl-radical, -N(R1)-C(O)-R1, -N(R1)-C(O)-OR1, -N(R1)-S(O)t-R1 wherein R1 means hydrogen atom or (C1-C8)-alkyl, -N(R1)-C(O)-N(R1)2 wherein R1 means hydrogen atom; R5 means (C1-C8)-alkyl; t = 2, and their stereoisomers and pharmaceutically acceptable salts, pharmaceutical composition based on thereof and a method for treatment of diseases, in particular, rheumatic arthritis.

EFFECT: valuable medicinal properties of compounds and composition.

12 cl

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

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

11 cl, 2 tbl

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention describes using 4,6-bis-(diethylamino)-2-[(2'-tetrazol-(2'H)-5'yl]-1,3,5-triazine of the formula: as an antidote against phytotoxic effect of herbicide 2,4-dichlorophenoxyacetic acid on sunflower germinated seeds. The proposed substance shows the enhanced effectiveness in increasing roots and hypocotyls length of seedlings and to expand assortment of the known antidotes.

EFFECT: valuable properties of antidote.

2 cl, 2 tbl, 3 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

FIELD: organic chemistry, biochemistry, pharmacy.

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

eliciting inhibitory activity with respect to metalloproteinases and wherein R1 means phenoxy-group wherein phenyl residue can be substituted with one or some halogen atoms, hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkyl, cyano- or nitro-group; R2 means pyrimidine, pyrazine or its N-oxide or phenyl substituted with -SO2NR3R4 wherein R3 and R4 can be similar or different and mean hydrogen atom, direct-chain or branch-chain (C1-C6)-alkyl that can be substituted once or some times with the group OH, N(CH3)2, or it can be broken by oxygen atom, or it represents COR5 wherein R5 means (C1-C)-alkyl group that can be substituted with NH2. Also, invention relates to a pharmaceutical composition comprising above said compounds.

EFFECT: valuable biochemical properties of compounds and composition.

5 cl, 1 sch, 1 tbl, 10 ex

The invention relates to new imidazole compounds of the formula I:

where R1represents hydrogen, hydroxy, protected hydroxy, or aryl, optionally substituted with a suitable(and) substituent(s) selected from the group consisting of halogen(lower)alkyl, halogen, hydroxy, protected carboxy, carbamoyl, lower alkylenedioxy, lower alkoxy, optionally substituted aryl, and lower alkyl, optionally substituted by hydroxy or protected carboxy; R2represents hydrogen or lower alkyl; R3is hydroxy or protected hydroxy; R4represents cyano, (hydroxy)minamino(lower)alkyl, carboxy, protected carboxy, N-containing heterocyclic group, optionally substituted amino, or carbarnoyl, optionally substituted with a suitable(s) of the substituent(s) selected from the group consisting of amino, hydroxy, lower alkyl, lower alkylsulfonyl, amidoamine(lower)alkyl, optionally substituted by hydroxy; and-And - is-Q -, or-O-Q-, where Q is a single bond or lower alkylene, or its salt, provided when R2is the lowest Ala the substituent(s), the above, and also provided that the compound of formula I is not 1-(hydroxyethyl)-4-(etoxycarbonyl)imidazole or anilide 1-(2-hydroxyethyl)imidazole-4-carboxylic acid

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 2-[n-(1-adamantyl)benzyl]thio-6-methylpyrimidin-4(3H)-one of the formula: that can be used as a semiproduct in synthesis of medicinal preparations. Method involves dissolving 6-methyl-2-thiouracil in sodium hydroxide an aqueous solution in the mole ratio 6-methyl-2-thiouracil : sodium hydroxide = 1:1.1 to yield 6-methyl-2-thiouracil S-sodium salt that is subjected for interaction with n-(1-adamantyl)benzyl bromide in the mole ratio = 1:1.1, respectively, at temperature 30-50°C for 15-30 min in dioxane medium, Method provides preparing indicated compound with the high yield.

EFFECT: improved method of synthesis.

3 ex

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