Derivatives of benzene or pyridine and a pharmaceutical composition based on them

 

(57) Abstract:

The invention relates to new derivatives of benzene or pyridine of the formula (I)

where R denotes H, C1-C7alkyl and halogen; R1denotes H or halogen, provided that in the 4th position R1not denotes bromine or iodine; R2denotes H or CF3; R3denotes N or C1-C7alkyl; R4denotes H, halogen, C1-C7alkyl and others; R5denotes N or C1-C7alkyl; X represents-C(O)N(R5)-, -N(R5)-C(O)- or-C(O)O-; Y represents -(CH2)n-, -O-, -S-, -SO2-, -C(O)- or N(R5’)-; R5’means (ness.)alkyl; Z represents =N-, -CH= or-C(C1)=; n denotes a number from 0 to 4; and their pharmaceutically acceptable salts. The compounds of formula (I) exhibit antagonistic activity against receptor neirokinina-1 and can find application in medicine. 2 N. and 6 C.p. f-crystals.

The present invention relates to compounds of General formula

in which

R denotes hydrogen atom, lower alkyl, respectively (ness.)alkyl, (ness.)alkoxy, halogen atom or trifluoromethyl;

R1denotes a hydrogen atom or halogen; or

R and RR3each independently of one another denotes a hydrogen atom, (ness.)alkyl or they may form cycloalkyl group;

R4denotes a hydrogen atom or halogen, (ness.)alkyl, (ness.)alkoxy,

-N(R5)2, -N(R5)S(O)2-(ness.)alkyl, -N(R5)C(O)R5or a cyclic tertiary amine groups

R5each independently of one another denotes a hydrogen atom, a C3-C6cycloalkyl, benzyl or (ness.)alkyl;

R6denotes a hydrogen atom, hydroxyl, (ness.)alkyl, -N(R5) (Ness.)-alkyl, hydroxy(ness.)alkyl, cyano, -Cho or a 5 - or 6-membered heterocyclic group, optionally linked through alkalinous groups;

X denotes-C(O)N(R5)-, -(CH2)mO-, -(CH2)mN(R5)-, -N(R5)C(O)-,

-C(O)O -, or-N(R5)(CH2)m-;

Y represents -(CH2)n-, -O-, -S-, -SO2-, -C(O)- or N(R5)-;

Z represents =N-, -CH= or-C(CL)=;

n denotes a number from 0 to 4; and

m denotes 1 or 2;

and their pharmaceutically acceptable acid additive salts.

The compounds of formula I and their salts otlichayutsa the present invention are antagonists of the receptor neirokinina (NK-1, substance P). Substance P is a naturally occurring undecapeptide belonging to the peptides of the family of tachykinins, the latter so called because of their rapid contractile action on extravascular tissue of smooth muscles. The receptor for substance P is a member of the superfamily-related G protein receptors.

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

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

Data about the possibility of using ant is ssennoga sclerosis, attenuation syndrome waiver of morphine, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial Hyper-reactivity and other respiratory diseases including allergic rhinitis, inflammatory bowel disease, including ulcerative colitis and Crohn's disease, eye injury and ocular inflammatory diseases, summarized in the article "Tachykinin Receptor and Tachykinin Receptor Antagonists". J. Auton. Pharmacol., 13, 23-93, 1993.

In addition, antagonists of the receptor neirokinina-1 developed for the treatment of numerous physiological disorders associated with an excess or imbalance of tachykinins, especially substance P. Examples of conditions that are associated with substance P, include disorders of the Central nervous system such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798).

Antagonists of the receptor neirokinina-1, in addition, can be used to treat a condition of sickness and induced drug vomiting.

In addition, in the journal The New England Journal of Medicine, volume 34, No. 3, 190-195, 1999 described the reduction of cisplatin-induced vomiting, using the election as the who or psychosomatic disorders by introducing receptor antagonist tachykinin, such as receptor NK-1.

Objects of the present invention are the compounds of formula I and their pharmaceutically acceptable salts, receiving the aforementioned compounds, drugs containing these compounds, and their production, as well as the use of the above compounds for the treatment or prevention of illnesses, especially of illnesses and disorders of the previously mentioned types, or for the manufacture of the drugs.

The most preferred indications in accordance with the present invention are indications, which include diseases of the Central nervous system or vomiting, for example the treatment or prevention of certain depressive disorders by introducing an antagonist of the receptor NK-1. It is established that serious bout of depression lasts for at least two weeks, during which during the greater part of the day and almost every day there is depressed mood or loss of interest in all or pleasure in all, or almost complete loss of activity.

Presented below is a General notion in the present description used the following values regardless of whether they meet individually or in the Naya alkyl group, containing from 1 to 7 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.

Preferred (ness.)alkyl groups are groups containing from 1 to 4 carbon atoms.

The term "(ness.)alkoxy" denotes the group where the alkyl residue is a residue that described above and which is attached via an oxygen atom.

The term "halogen" denotes an atom of chlorine, iodine, fluorine or bromine.

The concept of "cycloalkyl" denotes a saturated carbocyclic group containing from 3 to 6 carbon atoms.

The term "cyclic tertiary amine" refers to, for example, pyrrol-1-yl, imidazol-1-yl, piperidine-1-yl, piperazine-1-yl, morpholine-4-yl, thiomorpholine-4-yl, 1-Osotimehin-4-yl or 1,1-diocletianopolis-4-yl.

The term "5 - or 6-membered heterocyclic group" denotes, for example, pyridinyl, pyrimidinyl, oxadiazolyl, triazolyl, tetrazolyl, thiazolyl, thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolin, piperazinil or piperidyl.

The term "pharmaceutically acceptable acid additive salts" embraces salts with mineral and organic acids, such as hydrochloric acid, nitric key is acid, acetic acid, succinic acid, tartaric acid, methanesulfonate acid, p-toluensulfonate etc.

Preferred examples are compounds in which Y represents-C(O)-, a R4denotes 4-methylpiperazine, in particular the following compounds:

N-[2-benzoyl-4-(4-methylpiperazin-1-yl)phenyl]-2-(3,5-bis-triptime-ylphenyl)isobutyramide,

4-benzoyl-N-(3,5-bis-trifloromethyl)-N-methyl-6-(4-methylpiperazin-1-yl)nicotinamide and

N-(3,5-bis-trifloromethyl)-4-(2-chlorobenzoyl)-N-methyl-6-(4-methylpiperazin-1-yl)nicotinamide.

Even more preferred compounds in which Y denotes-O-, and R4denotes a hydrogen atom, morpholinyl or 4-methylpiperazine. Examples of such compounds are:

2-(3,5-bis-triptoreline)-N-methyl-N-(2-phenoxyphenyl)isobutyramide,

2-(3,5-bis-triptoreline)-N-methyl-N-(2-o-tolylacetic)isobutyramide,

2-(3,5-bis-triptoreline)-N-[2(2,4-dichlorophenoxy)phenyl]-N-methylisoleucine,

N-(3,5-bis-trifloromethyl)-N-methyl-6-morpholine-4-yl-4-phenoxyimine,

N-(3,5-bis-trifloromethyl)-4-(2-chlorophenoxy)-N-methyl-6-morpholine-4-iniatiated,

N-(3,5-bis-trifloromethyl)-4-(2-chlorophenoxy)-N-methyl-6-(4-mailpipe the CLASS="ptx2">Most preferred are compounds in which Y represents-N(CH3)-, a R4denotes a hydrogen atom, in particular the following compounds:

2-(3,5-bis-triptoreline)-N-methyl-N-[2-(methylpentylamino)phenyl]propionamide,

2-(3,5-bis-triptoreline)-N-methyl-N-[2-(methylpentylamino)phenyl]isobutyramide,

2-(3,5-bis-triptoreline)-N-[2(methylpentylamino)phenyl]ndimethylacetamide and

2-(3,5-bis-triptoreline)-N-methyl-N-[2-(methylpentylamino)phenyl]ndimethylacetamide.

The proposed compounds of formula I and their pharmaceutically acceptable salts can be obtained by methods which are in this area known in the art, for example by the methods described below, which include the

a) reaction of compounds of formula

with the compound of the formula

obtaining the compounds of formula

in which R1-R5, R, Y, Z and n have the meanings stated above, or

b) reaction of the compound of the formula

with the compound of the formula

obtaining the compounds of formula

in which R1-R5, R, Z, Y and n have the meanings stated above, or

C) the restoration of the compounds of formula

before joining f is of the formula

with the compound of the formula

obtaining the compounds of formula

in which the substituents have the meanings mentioned above, or

d) the reaction of the compound of the formula

with the compound of the formula

obtaining the compounds of formula

in which the substituents have the meanings mentioned above, or

e) recovery of the compounds of formula

to compounds of the formula

in which the substituents have the meanings mentioned above, or

g) reaction of compounds of formula

with the compound of the formula

obtaining the compounds of formula

in which the substituents have the meanings mentioned above, or

C) the reaction of the compound of the formula

with the compound of the formula

obtaining the compounds of formula

in which the substituents have the meanings mentioned above, or

and the reaction of the compound of the formula

with the compound of the formula

obtaining the compounds of formula

in which the substituents have the meanings mentioned above, or

K) the modification of one or more replaces the th compound in pharmaceutically acceptable acid additive salt.

In accordance with process variant a) compound of formula II, for example 3-amino-4-benzoylpyridine, cooled in an ice bath and added a compound of the formula III, for example 2-(3,5-bis-triptoreline)-2-methylpropionitrile, in the presence of DIPEA (N-ethyldiethanolamine) in dichloromethane, and the mixture is then stirred at room temperature. After cleaning with a good yield of product is obtained target compound of the formula I-1.

Process variant b) involves the reaction of the compounds of formula IV with a compound of formula V to obtain the compounds of formula I-2. The reaction is carried out in the usual way, for example in a solvent such as a mixture of toluene with triethylamine. The mixture is refluxed for about 1 h

In accordance with process variant C) a compound of formula I-2 to restore the compounds of formula I-4. This reaction is carried out with a reducing agent, such as LiAlH4or NR3THF, in the usual way.

Process variant d) involves the reaction of the compounds of formula VI with the compound of the formula VII to obtain the compounds of formula I-2. This reaction is carried out by deprotonation of compounds of formula VI hexamethyldisilazide potassium (GMDSS) and subsequent interconnection seeuthere.

In accordance with process variant d) receive compound of formula I-5. This reaction is carried out by deprotonation of compounds of formula VIII NaH and subsequent merger of the compounds of formula VII. This reaction is carried out in the usual way.

Process variant (e) is another method of obtaining the compounds of formula I. the Compound of formula I-1 to restore the compounds of formula 1-3 in the usual way, such as LiAlH4or NR3THF.

In process variant f) the compound of formula IX activate DCC (N,N’-dicyclohexylcarbodiimide), DMAP (4-N,N-dimethylaminopyridine). In the subsequent addition of the compounds of formula X have the compound of formula I-6.

In accordance with process variant C), the compound of formula IX activate the OED (1,1’-carbonyldiimidazole) and the subsequent addition of the compounds of formula V have the compound of formula I-2.

Technological option and includes the process of obtaining the compounds of formula I-1, during which the compound of formula XII activate the OED and the subsequent addition of the compounds of formula II have the compound of the formula I-13.

The process of obtaining salt was performed at room those who Noah engineering. Have in mind not only salts with mineral acids, but also salts with organic acids. Examples of such salts are hydrochloride, hydrobromide, sulfates, nitrates, citrates, acetates, maleate, succinate, methanesulfonate, p-toluensulfonate etc.

Methods for obtaining compounds of formula I in more detail, illustrated in the following schemes 1 to 7. Starting materials of formula IX, X, XI, II, III, XII, XIII, XV, XVII, XVIII, XX, XXII, XXIV and XXV are compounds that are known or can be obtained in accordance with methods in the art known.

These charts use the following abbreviations.

DCC N,N’-dicyclohexylcarbodiimide

DMAP 4-(N,N-dimethylamino)pyridine

The OED 1,1’-carbonyldiimidazole

GMDSS hexamethyldisilazide potassium

DIPEA N-ethyldiethanolamine

Beer-CL pualeilani

Scheme 1

Values of the substituents listed above.

Scheme 2

Values of the substituents listed above.

Scheme 3

Values of the substituents listed above.

Scheme 4

Values of the substituents listed above.

Scheme 5

Values of the substituents listed above.

Shil)-N’-ethylcarbodiimide)

R, R1, R2, R3and R5have the values specified above.

As noted previously, the compounds of formula I and their pharmaceutically acceptable acid additive salts have valuable pharmacological properties. It is established that the compound of the present invention is an antagonist of the receptor neirokinina 1 (NK-1, substance P).

The compound of the formula I were investigated using the following tests.

The affinity of the compounds of formula I to the NK1 receptor was evaluated using human NK1 receptors in Cho cells infected with the human NK1 receptor (using the expression system of the virus Semliki), and in the presence of radioactiveman with [3N]-substance P (final concentration of 0.6 nm). Experiments on the binding was performed in HEPES-buffer (50 mm, pH 7.4) containing BSA (bovine serum albumin) (0,04%), leupeptin (8 µg/ml), MnCl2(3 mm) and phosphoramidon (2 μm). In experiments on the binding used 250 μl of the suspension membrane (1,25 105cells/tube for analysis), a 0.125 µl of buffer, including the replacement agent, and 125 μl of [3N]-substance P. To obtain the curves of substitution used at least 7 concentrations of compounds. Tubes for analysis incubated EES filters type GF/C, which previously within 60 min, soaked PEI (0,3%) 2 leaching, each of which used 2 ml of HEPES buffer (50 mm, pH 7.4). The radioactivity remaining on the filters was assessed using the acquired scintillation counter. All experiments were performed in triplicate in at least 2 different experiments.

The affinity to the receptor NK-1, expressed in terms of the PKifor the preferred compounds of EUR 7.50-9,00. Examples of such compounds are

The compounds of formula I and their pharmaceutically acceptable acid salt additive can be used as medicines, for example, in the form of pharmaceutical compositions. The pharmaceutical compositions can be administered orally, for example in the form of tablets, filmtabletten, pills, gelatin capsules, soft or hard surface solutions, emulsions or suspensions. However, the introduction can also be carried out rectally, for example in the form of suppositories, or parenterally, for example in the form of injectable solutions.

The compounds of formula I and their pharmaceutically acceptable acid additive salts can be processed with pharmaceutically inert inorganic or organic is as such excipients for preparation, for example, tablets, coated tablets and gelatin capsules with solid floor can be used lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. Acceptable excipients for preparation of gelatin capsules with a soft coating are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc.

Acceptable excipients for preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

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

Acceptable excipients for suppositories are, for example, natural or hydrogenated oils, waxes, fats, semi-solid or liquid polyols.

In addition, the pharmaceutical compositions can contain preservatives, soljubilizatory, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, corrigentov, salts for modifying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically valuable substances.

The dose can vary within wide prelude. In General, in the case of oral administration, the daily dose may be approximately 10-1000 mg of the compounds of General formula I to the patient, however, if necessary, the upper limit may be exceeded.

Below the invention is illustrated in the examples, not limiting its scope. All temperatures are in degrees Celsius.

Below the invention is illustrated in the examples, not limiting its scope. The temperature in all cases specified in degrees Celsius.

Example 1

N-(4-benzoylpyridine-3-yl)-2-(3,5-bis-triptoreline)-N-methylisoleucine

a) N-(4-benzoylpyridine-3-yl)-2-(3,5-bis-triptoreline)isobutyramide

A solution of 397 mg (2 mmole) 3-amino-4-benzoylpyridine and 517 mg (4 mmole) of N-ethyldiethanolamine in 8 ml dichloromethane was cooled in an ice bath and added dropwise injected with a solution 765 mg (2.4 mmole) of 2-(3,5-bis-triptoreline)-2-methylpropionitrile in 8 ml dichloromethane. The reaction mixture was heated to room temperature and was stirred overnight. Added 5 ml of water and separated the organic layer. The aqueous phase was extracted with dichloromethane. The combined organic layers were dried (over magnesium sulfate) and evaporated. The residue was purified Express chromatography with getting in ASS="ptx2">b) N-(2-benzoyl-4-chlorophenyl)-2-(3,5-bis-triptoreline)-N-methylisoleucine

In a solution of 96 mg (0.2 mmole) of N-(4-benzoylpyridine-3-yl)-2-(3,5-bis-triptoreline)isobutyramide in 1.2 ml of dimethylformamide at 0 C was introduced to 0.22 ml of 1 M solution hexamethyldisilazide potassium. After 30 min was added 57 mg (0.4 mmole) under the conditions and at room temperature the reaction mixture was stirred over night. The solvent is evaporated and to the residue was added water and dichloromethane, the organic layer was separated and dried over magnesium sulfate. After evaporation of the solvent the product was purified Express chromatography to produce in the form of a yellow oil, 12 mg (yield: 12%) specified in the title compound.

MS m/e (%): 495,2 (M+N+, 100).

Example 2

N-(2-benzoyl-4-chlorophenyl)-2-(3,5-bis-triptoreline)-N-methylisoleucine

a) N-(2-benzoyl-4-chlorophenyl)-2-(3,5-bis-triptoreline)isobutyramide

In a solution of 233 mg (1 mmol) 2-amino-5-chlorobenzophenone in 2 ml of 1,2-dichloroethane was introduced 360 mg (1.2 mmole) of 2-(3,5-bis-triptoreline)-2-methylpropionic acid at 80 the reaction mixture was shaken for 1 h was Added 194 mg (1.2 mmole) of dicyclohexylcarbodiimide and at the same temperature, stirring was continued over night. Ried im Innkreis yellow oil 298 mg (yield: 58%) specified in the title compound.

MS m/e (%): 514,2 (M+N+, 100);

b) N-(2-benzoyl-4-chlorophenyl)-2-(3,5-bis-triptoreline)-N-methylisoleucine

To a solution of 154 mg (0.3 mmole) of N-(2-benzoyl-4-chlorophenyl)-2-(3,5-bis-triptoreline) isobutyramide in 1 ml of dimethylformamide were introduced 26 mg (0.6 mmole) of sodium hydride (55% suspension in mineral oil). After 30 minutes stirring at room temperature was added 85 mg (0.6 mmole) under the conditions and at 80 the reaction mixture was stirred over night. Under reduced pressure, the solvent evaporated and the residue was purified Express chromatography to produce in the form of white crystals 51 mg (yield: 32%) specified in the title compound; tPL: 89-91 C.

MS m/e (%): 528,1 (M+N+, 100).

Example 3

N-(2-benzoyl-5-chlorophenyl)-2-(3,5-bis-triptoreline)-N-methylisoleucine

Specified in the title compound as a yellow oil was obtained with comparable output values in accordance with the above-described method of obtaining N-(2-benzoyl-4-chlorophenyl)-2-(3,5-bis-triptoreline)-N-methylisobutyl, using 2-amino-4-chlorobenzophenone instead of 2-amino-5-chlorobenzophenone.

MS m/e (%): 528,1 (M+N+, 100).

Example 4

N-(2-benzoyl-3-chlorophenyl)-2-(3,5-bis-triptoreline)-N-metricname output in accordance with the above-described method of obtaining N-(2-benzoyl-4-chlorophenyl)-2-(3,5-bis-triptoreline)-N-methylisobutyl, using 2-amino-6-chlorobenzophenone instead of 2-amino-5-chlorobenzophenone.

MS m/e (%): 528,1 (M+H+, 100).

Example 5

2-(3,5-bis-triptoreline)-N-[2-(3-chlorobenzoyl)phenyl]-N-methyl-isobutyramide

Specified in the title compound as a yellow oil was obtained with comparable output values in accordance with the above-described method of obtaining N-(2-benzoyl-4-chlorophenyl)-2-(3,5-bis-triptoreline)-N-methylisobutyl, using 2-(3-chlorobenzoyl)aniline instead of 2-amino-5-chlorobenzophenone.

MS m/e (%): 528,1 (M+N+, 100).

Example 6

N-(2-benzoyl-6-methoxyphenyl)-2-(3,5-bis-triptoreline)-N-methylisoleucine

Specified in the title compound as a yellow oil was obtained with comparable output values in accordance with the above-described method of obtaining N-(2-benzoyl-4-chlorophenyl)-2-(3,5-bis-triptoreline)-N-methylisobutyl, using 2-amino-3-methoxybenzophenone instead of 2-amino-5-chlorobenzophenone.

MS m/e (%): 523,5 (M+N+, 100).

Example 7

N-(2-benzoyl-4-methoxyphenyl)-2-(3,5-bis-triptoreline)-N-methylisoleucine

Specified in the title compound as a yellow oil was obtained with comparable output values in accordance with the above-methoxybenzophenone instead of 2-amino-5-chlorobenzophenone.

MS m/e (%): 523,5 (M+N+, 100).

Example 8

(RS)-2-(3,5-bis-triptoreline)-N-[4-chloro-2-(2-chlorophenylsulfonyl)phenyl]-N-methylpropionamide

To a solution of 142 mg (0.5 mmole) of 1-chloro-4-methylamino-3-(2-chlorophenylsulfonyl) benzene in 2 ml of 1,2-dichloroethane was administered to 172 mg (0.6 mmole) 2(3,5-bis-triptoreline) propionic acid and at 80 the reaction mixture was shaken for 1 h was Added 97 mg (0.6 mmole) of DICYCLOHEXYL-carbodiimide and at the same temperature, stirring was continued over night. The solvent is evaporated and the obtained residue was purified by column chromatography on silica gel to produce in the form of a light yellow oil, 56 mg (yield: 20%) specified in the title compound.

MS m/e (%): 551,9 (M+N+, 100), 553,9 (M+N+, 90).

Example 9

(RS)-N-[2-benzoyl-4-chlorophenyl)-2-(3,5-bis-triptoreline)-N-methylpropionamide

Specified in the title compound as a yellow oil was obtained with comparable output values in accordance with the method described above to obtain (RS)-2-(3,5-bis-triptoreline)-N-[4-chloro-2(2-chlorophenyl-sulfonyl)phenyl]-N-methylpropionamide using 2-methylamino-5-chlorobenzophenone instead of 1-chloro-4-methylamino-3-(2-chlorophenylsulfonyl)benzene.

MS m/e (%): 514,2 (M+N+, 100).

a) 2,2-dimethyl-N-[4-(4-methylpiperazin-1-yl)phenyl]propionamide

The solution to 5.58 g (29 mmol) of 1-(4-AMINOPHENYL)-4-methylpiperazine and 3.77 g (29 mmol) of N-ethyldiethanolamine in 30 ml of tetrahydrofuran was cooled in an ice bath and was added dropwise 3,518 g (29 mmol) of pivaloate. The suspension was stirred for 18 h at room temperature. Added 30 ml of water and 50 ml of dichloromethane and separated the organic layer. The aqueous phase is re-extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate) and evaporated to obtain white solids. As a result of washing with a mixture of hexane with ethyl acetate in a ratio of 4/1 received 6,69 g (yield: 83%) of a white crystalline substance.

MS m/e (%): 276,3 (M+N+, 100);

b) N-[2-benzoyl-4-(4-methylpiperazin-1-yl)phenyl]-2,2-dimethylpropanamide

The solution 1,375 g (5 mmol) of 2,2-dimethyl-N-[4-(4-methylpiperazin-1-yl)-phenyl] propionamide was dissolved in 25 ml of tetrahydrofuran and the solution was cooled to -70 C. In an argon atmosphere at this temperature, was slowly added to 7.8 ml (12.5 mmole) of 1.6 M solution of n-utility in hexane. The cooling bath was removed and the mixture was stirred for 3 h at room temperature. The reaction mixture was again cooled to -70 C and slowly dollardays bath was removed and stirring continued at room temperature for 1 h Order to suppress the reaction was added to 50 ml of water and the mixture was extracted with diethyl ether (three times 50 ml). The organic layer was dried with magnesium sulfate and evaporated, receiving in the form of a brown oil product, which was purified Express chromatography using dichloromethane/methanol, to obtain 315 mg (yield: 17%) of product as a light orange solid.

MS m/e (%): 380,4 (M+N+, 100);

C) [2-amino-5-(4-methylpiperazin-1-yl)phenyl]phenylmethanone

A solution of 0.3 g (0.8 mmole) of N-[2-benzoyl-4-(4-methylpiperazin-1-yl)phenyl]-2,2-dimethylpropanamide in 10 ml of 3h. aqueous hydrochloric acid was stirred for 20 h at room temperature. The reaction mixture was extracted once with ethyl acetate, the aqueous layer was podslushivaet concentrated sodium hydroxide solution and four times was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate and evaporated to obtain 245 mg of the product (quantitative yield) as a pale yellow oil.

MS m/e (%): usd296.4 (M+N+, 100);

g) of the hydrochloride of N-[2-benzoyl-4-(4-methylpiperazin-1-yl)phenyl]-2-(3,5-bis-triptoreline)isobutyramide

A solution of 200 mg (0.68 mmole) of [2-amino-5-(4-methylpiperazin-1-yl)phenyl]phenylmethanone and 219 mg (1,69 mmole the I) 2-(3,5-bis-triptoreline)-2-methylpropionitrile in 2 ml of dichloromethane. The reaction mixture was heated to room temperature and was stirred for 3 hours was Added 5 ml of water and the layers were separated. The aqueous phase is re-extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate) and evaporated to obtain 50 mg of the product as oil. This residue was dissolved in 2 ml of ethyl acetate was added 0,018 ml of 4.75 n solution of hydrochloric acid in ethanol. After adding 1 ml of diethyl ether, the suspension was stirred for 15 min, the solid material was filtered and dried to obtain a white solid of 24 mg (yield: 6%) specified in the title compound.

MS m/e (%): 578,1 (M+N+, 100).

Example 11

Hydrochloride 4-benzoyl-N-(3,5-bis-trifloromethyl)-N-methyl-6-(4-methylpiperazin-1-yl)nicotinamide (1:1)

a) hydrochloride of 2-chloro-5-(4,4-dimethyl-4,5-dihydrooxazolo-2-yl)pyridine

10 g (63.47 per mmole) 2-chloropyridin-5-carboxylic acid were introduced 60 g (507 mmol) of thionyl chloride and the mixture is boiled under reflux for 3 hours, the Excess thionyl chloride drove, was added 50 ml of diethyl ether and evaporated to remove traces of thionyl chloride. The residue was dissolved in 30 ml dichloromethane and at 0 C was added dropwise a solution of 11,88 g (of 0.133 mmole) of 2-amino-2-Metalli 30 ml of water. The layers were separated and the aqueous phase was again extracted with dichloromethane. The combined organic layers were dried with magnesium sulfate and evaporated to obtain an oily liquid. To this residue at 0 C was added and 22.6 g (190 mmol) of thionyl chloride and the mixture was stirred for 30 minutes was Added ethyl acetate, and the mixture was stirred for further 30 minutes and the crystals were washed with ethyl acetate and diethyl ether, receiving 14 g (yield: 89%) of a white solid.

MS m/e (%): 210 (M+N+, 10);

b) 1-[5-(4,4-dimethyl-4,5-dihydrooxazolo-2-yl)pyridine-2-yl]-4-methylpiperazin

Hydrochloride of 2-chloro-5-(4,4-dimethyl-4,5-dihydrooxazolo-2-yl) pyridine was converted to its free base by dissolving 8.0 g (32 mmol) of a substance in a saturated solution of sodium bicarbonate and extraction Foundation dichloromethane. The solvent is evaporated and the residue was dissolved in toluene. After adding 11,35 g (113 mmol) of N-methylpiperazine the mixture was boiled under reflux for 36 hours After cooling to room temperature was added 50 ml of water and 150 ml ethyl acetate and the aqueous layer was extracted with 150 ml of ethyl acetate. The combined organic layers two times were extracted 1H. hydrochloric acid, the acidic aqueous layer was podslushivaet 28% solution gidrostatom was led from ethyl acetate/hexane to obtain 6.0 g (yield: 67%) of a white crystalline substance.

MS m/e (%): 274,1 (M+N+, 100);

C) [5-(4,4-dimethyl-4,5-dihydrooxazolo-2-yl)-2-(4-methylpiperazin-1-yl)pyridine-4-yl]phenylmethanone

0,932 g (6.6 mmole) of 2,2,6,6-tetramethylpiperidine was loaded into the three-neck flask. In an argon atmosphere was added 10 ml of hexane, the solution was cooled to 0 C and slowly added n-utility (1.6 M solution in hexane). After stirring the yellow suspension for 10 min at 0 C was added 767 mg (6.6 mmole) of N,N,N’,N’-tetramethylethylenediamine. Dropwise at -78 the mixture was introduced into a suspension of 1.65 g (6 mmol) of 1-[5-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)pyridine-2-yl]-4-methylpiperazine in 20 ml of hexane. After stirring yellow solution for 30 min at this temperature and for 45 min at 0 C was slowly added at 0 To a solution of 1.19 g (7.2 mmole) of N-methoxy-N-methylbenzamide in 2 ml of hexane/2 ml of tetrahydrofuran.

After 30 min the cooling bath was removed and stirring continued at room temperature overnight. Added water and the mixture was extracted with ethyl acetate. The organic layer was dried (magnesium sulfate) and evaporated to produce in the form of a brown oil product, which was purified Express chromatography using dichloromethane/methanol, with the receipt of 1.16 g (yield: 51%) of product as a yellow TV is piperazin-1-yl) nicotinic acid

In a solution of 1.13 mg (3 mmole) of [5-(4,4-dimethyl-4,5-dihydrooxazolo-2-yl)2-(4-methylpiperazin-1-yl)pyridine-4-yl]phenylmethanone in 30 ml of tetrahydrofuran was injected 3 ml of 2n. aqueous hydrochloric acid and the reaction mixture is kept at 50 for 18 hours After cooling to room temperature, with the aim to bring the pH to 11 was added 1N. the sodium hydroxide solution and the mixture was extracted with ethyl acetate. The organic layer was dried (magnesium sulfate) and evaporated to produce in the form of a yellow oil, 1.18 g (quantitative yield) of product.

MS m/e (%): 481,4 (M+N+, 100);

d) 4-benzoyl-6-(4-methylpiperazin-1-yl) nicotinic acid

In a solution of 1.15 g (2.9 mmole) of 2-amino-2-methylpropionic ether 4-benzoyl-6-(4-methylpiperazin-1-yl)nicotinic acid in 20 ml of tetrahydrofuran at 0 dropwise introduced 367 mg (3,05 mmole) of pivaloate. After stirring the light yellow suspension at the same temperature for 1 h was added 1 M aqueous hydrochloric acid. Dichloromethane was extracted with excess pualeilani, the aqueous layer was podslushivaet 28% sodium hydroxide solution and twice was extracted with dichloromethane. The organic layer was dried (magnesium sulfate) and evaporated. The residue was dissolved in methanol at 0 was slowly added 1 M aqueous solution of g is. actuarial evaporated from obtaining contaminated with sodium chloride product, which was used in the next stage without additional purification.

e) of the hydrochloride of 4-benzoyl-N-(3,5-bis-trifloromethyl)-N-methyl-6-(4-methylpiperazin-1-yl)nicotinamide (1:1)

A mixture of 1.5 mmole 4-benzoyl-6-(4-methylpiperazin-1-yl)nicotinic acid with the last stage and 3 ml of thionyl chloride was heated to 110 C for 1 h, the Excess thionyl chloride are evaporated, the obtained product in the form of a brown oil was again dissolved in diethyl ether and again evaporated to remove traces of thionyl chloride. The residue was dissolved in 2 ml acetone and added to 1.16 g (4.5 mmole) of (3,5-bis-trifloromethyl) methylamine. The mixture was stirred for 1.5 h at room temperature. The solvent is evaporated, was added dichloromethane and water and 28% sodium hydroxide solution was podslushivaet water layer. The organic layer was dried (magnesium sulfate), evaporated and purified Express chromatography, receiving in the form of oil 202 mg of the product. This compound was dissolved in 5 ml of diethyl ether was added 0.075 ml of 4.75 n solution of hydrochloric acid in ethanol. After stirring for 15 min, the suspension is evaporated to dryness, the residue is again suspended in 10 ml of diethyl eavie product with tPL: 105 C (With decomposition).

MS m/e (%): 565,2 (M+N+, 100).

Example 12

The hydrochloride of N-(3,5-bis-trifloromethyl)-4-(2-chlorobenzoyl)-N-methyl-6-(4-methylpiperazin-1-yl)nicotinamide (1:1)

Specified in the title compound as white crystals was obtained with comparable output values in accordance with the above-described method of obtaining hydrochloride 4-benzoyl-N-(3,5-bis-trifloromethyl)-N-methyl-6-(4-methylpiperazin-1-yl)nicotinamide (1:1) using on stage) N-methoxy-N-methyl-2-chlorobenzamide instead of N-methoxy-N-methylbenzamide. tPL: 145 C (With decomposition).

MS m/e (%): 599,1 (M+N+, 100).

Example 13

3,5-bis-cryptomaterial ether 2-phenoxybenzoic acid

To a solution of 118 mg (0.55 mmole) of 2-phenoxybenzoic acid and 122 mg (0,50 mmole) of 3,5-bis(trifluoromethyl)benzyl alcohol in 1.5 ml dichloromethane at 0 were injected With a solution of 124 mg (0.60 mmole) of 1,3-dicyclohexylcarbodiimide and 7 mg (0.06 mmole) of 4-dimethylaminopyridine in 1 ml dichloromethane. The ice bath was removed and stirring continued at room temperature overnight. Under vacuum solvent was removed and the residue was again dissolved in diethyl ether, filtered and evaporated. The residue was purified Express-chromatography+, 51), 347 (39), 227 (36), 197 (100).

Example 14

2-benzyl-N-(3,5-bis-trifloromethyl) benzamid

To a solution of 255 mg (1.2 mmole) 2-benzoylbenzene acid in 1.5 ml of tetrahydrofuran at 0 was administered to 195 mg (1.2 mmole) of 1,1’-carbonyldiimidazole. After stirring for 2.5 h at room temperature was added a solution of 243 mg (1.0 mmole) of 3,5-bis(trifluoromethyl)benzylamine in 0.5 ml of tetrahydrofuran and stirring continued over night. Under vacuum solvent was removed and the residue was purified Express chromatography to produce in the form of white crystals 210 mg (yield: 49%) specified in the title compound.

MS m/e (%): 438 (M+N+, 100).

Example 15

2-benzyl-N-(3,5-bis-trifloromethyl)-N-methylbenzamide

In a solution of 100 mg (0,23 mmole) of 2-benzyl-N-(3,5-bis-trifloromethyl)-benzamide in 1 ml N,N-dimethylformamide at 0 were injected With 50 mg (0.25 mmole) hexamethyldisilazide potassium. Stirring at this temperature was continued for 1 h and added to 0.016 ml (0.25 mmole) under the conditions. After stirring for 3 h at room temperature was added ethyl acetate. The mixture was washed with brine, dried (magnesium sulfate) and evaporated. Under vacuum solvent was removed and the residue was purified Express chromatography with SUP>, 100).

Example 16

N-(3,5-bis-trifloromethyl)-N-methyl-2-(methylpentylamino)benzamid

a) N-(3,5-bis-trifloromethyl)-2-phenyliminomethyl

Specified in the title compound as white crystals was obtained with comparable output values in accordance with the above method of obtaining 2-benzyl-N-(3,5-bis-trifloromethyl) benzamide.

MS m/e (%): 477 (M+K+, 24), 461 (M+Na+, 40), 439 (M+H+, 100);

b) 2-benzyl-N-(3,5-bis-trifloromethyl)-N-methylbenzamide

Specified in the title compound as a colourless oil was obtained with a comparable output in accordance with the above method of obtaining 2-benzyl-N-(3,5-bis-trifloromethyl)-N-methylbenzamide.

MS m/e (%): 505 (M+K+, 12), 489 (M+Na+, 19), 467 (M+N+, 100).

Example 17

N-(2-benzosulfimide)-2-(3,5-bis-triptoreline)-N-methylisoleucine

a) N-(2-benzosulfimide)-2-(3,5-bis-triptoreline)isobutyramide

A solution of 233 mg (1.0 mmole) 2-aminobenzylpenicillin and 0.25 ml (1.5 mmole) of N-ethyldiethanolamine in 2 ml of dichloromethane was cooled in an ice bath and was added dropwise a solution of 350 mg (1.1 mmole) of 2-(3,5-bis-triptime-terphenyl)-2-methylpropionitrile in 1 ml dichloromethane. Rea-chromatography with obtaining in the form of a pale yellow oil 490 mg (yield: 95%) specified in the title compound.

MS m/e (%): 533 (M+NH+4, 60), 516 (M+N+, 100);

b) N-(2-benzosulfimide)-2-(3,5-bis-triptoreline)-N-methylisoleucine

Specified in the title compound as a colourless oil was obtained with a comparable output in accordance with the above method of obtaining 2-benzyl-N-(3,5-bis-trifloromethyl)-N-methylbenzamide.

MS m/e (%): 552 (M+Na+, 40), 530 (M+N+, 100).

Example 18

2-(3,5-bis-triptoreline)-N-methyl-N-(2-phenoxyphenyl)isobutyramide

Specified in the title compound as a colourless oil was obtained with a comparable output in accordance with the above-described method of obtaining N-(2-benzosulfimide)-2-(3,5-bis-triptoreline)-N-methylisobutyl using 2-phenoxyimino instead of 2-aminobenzylpenicillin.

MS m/e (%): 482 (M+N+, 100).

Example 19

N-(2-benzoylphenyl)-2-(3,5-bis-triptoreline)-N-methylisoleucine

Specified in the title compound as a colourless oil was obtained with a comparable output in accordance with the above-described method of obtaining N-(2-benzosulfimide)-2-(3,5-bis-triptoreline)-N-methylisobutyl using 2-benzylaniline instead of 2-aminobenzylpenicillin.

MS m/aramid

Specified in the title compound as pale yellow crystals were obtained with a comparable output in accordance with the above-described method of obtaining N-(2-benzosulfimide)-1-(3,5-bis-triptoreline)-N-methylisobutyl using 2-(o-tolyloxy) aniline instead of 2-aminobenzylpenicillin.

MS m/e (%): 496 (M+N+, 100).

Example 21

N-(2-benzoylphenyl)-2-(3,5-bis-triptoreline)-N-methylisoleucine

Specified in the title compound as a pale yellow oil was obtained with a comparable output in accordance with the above-described method of obtaining N-(2-benzosulfimide)-2-(3,5-bis-triptoreline)-N-methylisobutyl using 2-aminobenzophenone instead of 2-aminophenethyl-sulfone.

MC m/e (%): 516 (M+Na+, 55), 494 (M+H+, 100).

Example 22

2-(3,5-bis-triptoreline)-N-[2-(2,4-dichlorophenoxy)phenyl]-N-methylisoleucine

Specified in the title compound as a colorless foam was obtained with a comparable output in accordance with the above-described method of obtaining N-(2-benzosulfimide)-2-(3,5-bis-triptoreline)-N-methylisobutyl using 2-(2,4-dichlorophenoxy)aniline instead of 2-aminobenzylpenicillin.

MS m/e (%): 549 (M+H+, 4ptx2">Specified in the title compound as a pale yellow oil was obtained with a comparable output in accordance with the above-described method of obtaining N-(2-benzosulfimide)-2-(3,5-bis-triptoreline)-N-methylisobutyl using 2-aminobenzylpenicillin instead of 2-aminobenzylpenicillin. Stage b) is not carried out.

MC m/e (%): 484 (M+N+, 100).

Example 24

2-(3,5-bis-triptoreline)-N-methyl-N-[2-(methylpentylamino)phenyl]propionamide

a) 2-(3,5-bis-triptoreline)-N-(2-phenylaminopropyl)ndimethylacetamide

In a solution of 545 mg (2.0 mmole) of 3,5-bis(trifluoromethyl)phenylacetic acid in 2 ml of tetrahydrofuran at 0 was introduced 325 mg (2.0 mmole) of 1,1’-carbonyldiimidazole. After stirring for 2.5 h at room temperature was added 305 mg (of 1.66 mmole) 2-aminodiphenylamine and stirring continued at 60 C for 8 h, the Solvent was removed under vacuum and the residue was purified Express chromatography to produce in the form of white crystals 480 mg (yield: 66%) specified in the title compound.

MS m/e (%): 439 (M+N+, 35), 142 (100);

b) 2-(3,5-bis-triptoreline)-N-methyl-N-[2-(methylpentylamino)-phenyl]propionamide

In a solution of 389 mg (0,89 mmole) of 2-(3,5-bis-triptoreline)-N-(2-phenylaminopropyl)and the round stirring was continued for 1 h and added 510 mg (2,66 mmole) under the conditions. After stirring for 3 h at room temperature was added ethyl acetate. The mixture was washed with brine, dried (magnesium sulfate) and evaporated. Under vacuum solvent was removed and the residue was purified Express chromatography to produce in the form of white crystals 110 mg (yield: 25%) specified in the title compound.

MS m/e (%): 480 (M+, 76), 239 (100).

Example 25

2-(3,5-bis-triptoreline)-N-methyl-N-[2(methylpentylamino)phenyl]isobutyramide

To a solution of 52 mg (0.11 mmole) of 2-(3,5-bis-triptoreline)-N-methyl-N-[2-(methylpentylamino)phenyl]propionamide in 0.5 ml of N,N-dimethylformamide at 0 C was administered 32 mg (0.16 mmole) hexamethyldisilazide potassium. At this temperature, the stirring was continued for 1 h and was added 30 mg (0.16 mmole) under the conditions. After stirring for 3 h at room temperature was added ethyl acetate. The mixture was washed with brine, dried (magnesium sulfate) and evaporated. Under vacuum solvent was removed and the residue was purified Express chromatography to produce in the form of a colourless oil, 54 mg (quantitative yield) specified in the title compound.

MS m/e (%): 494 (M+, 87), 195 (100).

Example 26

2-(3,5-bis-triptoreline)-N-[2-(methylpentylamino)phenyl]ndimethylacetamide

the toboggan above method of obtaining 2-(3,5-bis-triptoreline)-N-methyl-N-[2-(methylpentylamino)phenyl]propionamide using N-methyl-N-phenylbenzo-1,2-diamine instead of 2-aminodiphenylamine. Stage b) is not carried out.

MS m/e (%): 453 (M+N+, 100).

Example 27

2-(3,5-bis-triptoreline)N-methyl-N-[2-(methylpentylamino)phenyl]ndimethylacetamide

Specified in the title compound as a colourless oil was obtained with a comparable output in accordance with the above-described method of obtaining 2-(3,5-bis-triptoreline)-N-methyl-N-[2-(methylpentylamino)phenyl]propionamide using N,N’-dimethyl-N-phenylbenzo-1,2-diamine instead of 2-aminodiphenylamine. Stage b) is not carried out.

MS m/e (%): 467 (M+N+, 100).

Example 28

N-(3,5-bis-trifloromethyl)-N-methyl-6-morpholine-4-yl-4-phenoxyimine

a) ethyl ester of 6-chloro-4-phenoxyimino acid

To a solution of 196 mg (approximately 4 mmole) of a dispersion of sodium hydride in mineral oil (about 50%) in 15 ml of N,N-dimethylformamide at room temperature in an argon atmosphere was dropwise introduced a solution of 385 mg (4.09 to mmole) of phenol in 10 ml of N,N-dimethylformamide. After 15 min the solution by means of a hollow needle at room temperature was slowly added to a solution of ethyl ester of 4,6-dichloronicotinic acid in 20 ml of N,N-dimethylformamide. After 2 h the reaction was suppressed 20 ml of water. The mixture was extracted with 3 50-ml on what the loud under high vacuum at 50 C and Express chromatography column in the form of a white solid substance was obtained 800 mg (yield: 70.4% of) specified in the title compounds. As a side product was isolated 130 mg (yield: 11.4%) of ethyl ether 4-chloro-6-phenoxyimino acid.

MS m/e (%): 277 (M+, 81), 232 ([M-OEt]+, 100).

b) Ethyl ester of 6-morpholine-4-yl-4-phenoxyimino acid Solution of 130 mg (0,468 mmole) ethyl ester of 6-chloro-4-phenoxyimino acid 0,040 ml (0,47 mmole) of the research and 0,065 ml (0,47 mmole) of triethylamine in 7 ml of tetrahydrofuran was boiled under reflux for 40 hours After cooling to room temperature the mixture was filtered, diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride. The organic layer was dried with sodium sulfate and concentrated. As a result, the rapid chromatography column in the form of a white solid substance was obtained 66 mg (yield: 43%) specified in the title compound.

MS m/e (%): 329 (M+N+, 100).

C) 6-morpholine-4-yl-4-phenoxyimino acid

A mixture of 66 mg (0,20 mmole) ethyl ester 6-morpholine-4-yl-4-phenoxyimino acid, 2 ml methanol and 2 ml of 1N. an aqueous solution of sodium hydroxide was stirred at room temperature for 1 h, the Reaction mixture was diluted with water and washed with tert-butylmethylamine ether. The aqueous layer was acidified to pH 4 to 5 kontsentrirovanija saturated aqueous sodium chloride and dried with sodium sulfate. The result of concentration in the form of a white solid substance was obtained 46 mg (yield: 77%) specified in the title compound.

MS m/e (%): 301 (M+N+, 100).

g) N-(3,5-bis-trifloromethyl)-N-methyl-6-morpholine-4-yl-4-phenoxyimine

A mixture of 46 mg (0.15 mmole) 6-morpholine-4-yl-4-phenoxyimino acid, 43 mg (0,17 mmole) of (3,5-bis-trifloromethyl) methylamine, 32 mg (0,17 mmole) of the hydrochloride of 1-(3-diaminopropan)-3-ethylcarbodiimide and a catalytically effective amount of 4-(N,N-dimethylamino) pyridine in 3 ml of dichloromethane was stirred overnight at room temperature. The reaction mixture was diluted with water, saturated aqueous ammonium chloride pH was brought to 6 and was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous solution of sodium chloride, dried with sodium sulfate and concentrated. As a result, the rapid chromatography column in the form of a white solid substance was obtained 68 mg (yield: 83%) specified in the title compound.

MS m/e (%): 540 (M+N+, 100).

Example 29

N-(3,5-bis-trifloromethyl)-4-(2-chlorophenoxy)-N-methyl-6-morpholine-4-yl-4-nicotinamide

Specified in the title compound as a white solid substance was obtained with copasetic-6-morpholine-4-yl-4-phenoxyimine (example 28) using on-stage and 2-chlorophenol instead of phenol.

MS m/e (%): 574 (M+N+, 100).

Example 30

N-(3,5-bis-trifloromethyl)-4-(2-chlorophenoxy)-N-methyl-6-(4-methylpiperazin-1-yl)nicotinamide

Specified in the title compound as a white solid substance was obtained with comparable output values in accordance with the above-described method of obtaining N-(3,5-bis-trifloromethyl)-N-methyl-6-morpholine-4-yl-4-phenoxyimine (example 28) using on-stage and 2-chlorophenol instead of phenol and at the stage b) 1-methylpiperazine instead of the research.

MC m/e (%): 587 (M+H+, 100).

Example 31

N-(3,5-bis-trifloromethyl)-N-methyl-6-morpholine-4-yl-4-o-tolylacetylene

Specified in the title compound as a white solid substance was obtained with comparable output values in accordance with the above-described method of obtaining N-(3,5-bis-trifloromethyl)-N-methyl-6-morpholine-4-yl-4-phenoxyimine (example 28) using in stage a) o-cresol instead of phenol.

MS m/e (%): 554 (M+N+, 100).

Example

By the usual method of manufacture of tablets of the following composition (mg/tablet:

Active substance 5

Lactose 45

Corn starch 15

Microcrystalline cellulose 34

ableto:

Active substance 10

Lactose 155

Corn starch 30

Talc 5

The weight of the contents of the capsules 200

The active ingredient, lactose and corn starch are mixed first in the mixer, and then grinding installation. The mixture back into the mixer, add the powder and thoroughly mix. Mechanically mix fill hard gelatin capsules.

Example

Prepare suppositories of the following composition (mg/suppository:

Active substance 15

The basis for the manufacture of suppositories 1285

Just 1300

The basis for the manufacture of suppositories is melted in a vessel made of glass or stainless steel, are thoroughly mixed and cooled to 45 C. After that it was added finely powdered active substance is added and stirred until full dispersion. The mixture is then poured into the form of suppositories appropriate size, leave to cool, and then suppositories extract form and is Packed in an individual package of waxed paper or metal foil.

1. Derivatives of benzene or pyridine of General formula

in which R denotes a hydrogen atom, a C1-C7is the situation R1not denotes a bromine atom, or iodine;

R2denotes a hydrogen atom or trifluoromethyl;

R3each independently of one another denotes hydrogen or C1-C7alkyl;

R4denotes a hydrogen atom or halogen, WITH1-C7alkyl, C1-C7alkoxy or cyclic tertiary amine selected from the group comprising piperazine-1-yl or morpholine-4-yl which may be substituted WITH1-C7by alkyl;

R5each independently of one another denotes hydrogen or C1-C7alkyl;

X denotes-C(O)N(R5)-, -N(R5)-C(O)- or-C(O)O-;

Y represents -(CH2)n-, -O-, -S-, -SO2-, -C(O)-or N(R5’)-;

R5’means (ness.)alkyl;

Z represents =N-, -CH= or-C(C1)=;

n denotes a number from 0 to 4,

and their pharmaceutically acceptable acid additive salt.

2. Connection on p. 1, in which Y represents-C(O)-, and R4denotes 4-methylpiperazine.

3. Connection on p. 2, which is a

N-[2-benzoyl-4-(4-methylpiperazin-1-yl)phenyl]-2-(3,5-bistriflate-terphenyl)isobutyramide,

4-benzoyl-N-(3,5-bistrifluormethylbenzene)-N-methyl-6-(4-methylpiperazine.

4. Connection on p. 1, in which Y denotes-O-, a R4denotes hydrogen, 4-methylpiperazine or morpholine.

5. Connection on p. 4, which is a

2-(3,5-bistrifluormethylbenzene)-N-methyl-N-(2-phenoxyphenyl)isobutyramide,

2-(3,5-bistrifluormethylbenzene)-N-methyl-N-(2-o-tolylacetic)isobutyramide,

2-(3,5-bistrifluormethylbenzene)-N-[2-(2,4-dichlorophenoxy)phenyl]-N-methylisoleucine,

N-(3,5-bistrifluormethylbenzene)-N-methyl-6-morpholine-4-yl-4-phenoxyimine,

N-(3,5-bistrifluormethylbenzene)-4-(2-chlorophenoxy)-N-methyl-6-morpholine-4-iniatiated,

N-(3,5-bistrifluormethylbenzene)-4-(2-chlorophenoxy)-N-methyl-6-(4-methylpiperazin-1-yl)nicotinamide or

N-(3,5-bistrifluormethylbenzene)-N-methyl-6-morpholine-4-yl-4-o-tolyl-oxycotine.

6. Connection on p. 1, in which Y represents-N(CH3)-, and R4denotes a hydrogen atom.

7. Connection on p. 6, which is a

2-(3,5-bistrifluormethylbenzene)-N-methyl-N-[2-(methylpentylamino)phenyl]propionamide,

2-(3,5-bistrifluormethylbenzene)-N-methyl-N-[2-(methylpentylamino)phenyl]isobutyramide,

2-(3,5-bistrifluormethylbenzene)-N-[2-(methylpentylamino)phenyl]ndimethylacetamide or

2-(3,5-bistrifluormethylbenzene)-N-methyl-N-[2-(methylphenylene receptor neirokinina-1 and comprising one or more compounds according to any one of paragraphs.1-7 and a pharmaceutically acceptable fillers.

 

Same patents:

The invention relates to new derivatives of 3-phenylpyridine formula (I)

in which R denotes hydrogen, C1-C7alkyl, C1-C7alkoxy, halogen or CF3, R1means H or halogen, or R and R1may together form-CH=CH-CH=CH-; R2means H, halogen, CF3, R3means H or C1-C7alkyl, R4means H or piperazine-1-yl; R5means H or C1-C7alkyl, X is-C(O)N(R5)-, -(CH2)mO-, -(CH2)mN(R5)-, -N(R5)C(O)- or N(R5)(CH2)m-; n is an integer from 0 to 4, m is 1 or 2, and their pharmaceutically acceptable acid additive salts

The invention relates to new nitrogen-containing aromatic 6-membered cyclic compounds of the formula (I) or their pharmaceutically acceptable salts, demonstrating excellent selective PDE V inhibitory activity

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group

The invention relates to derivatives of 6-sulfamoylbenzoic-4-carboxylic acid of formula (1), where R1, R2, R3and R4such as defined in the claims

The invention relates to new derivatives of 2-aminopyridine of General formula (I)

where And denotes the radical

in which R1, R2and R3mean hydrogen, halogen, HE, alkyl or alkoxy and the other,

or radical

in which R8means hydrogen, x is the radical -(CH2)m-Q, m is an integer from 0 to 6, Y represents alkyl, alkenylphenol or alkenylphenol chain or other, R10is hydrogen or alkyl, or their salts

The invention relates to new imidazolidine formulas (I) and (II) in which a is a =N-CR=CR-CR=, =CR-N=CR-CR=, =CR-CR=N=CR or = CR-CR= CR-N= ; B represents-NR-C(R)2-C(R)2-C(R)2C(R)2-NR-C(R)2-C(R)2, -C(R)2-C(R)2-NR-C(R)2or C(R)2-C(R)2-C(R)2-NR, where R is hydrogen, R1is hydrogen, unsubstituted or substituted C1-20-alkyl, C1-20-alkylene-NR3-Q-X-R4where Q represents-CO-or-SO2-, X is a simple bond, -O - or-NR3and R4- aryl, heteroaryl, heterocyclyl or1-20-alkyl or C2-20alkenyl

The invention relates to compounds of the formula I

< / BR>
where a is -(CH2)mm = 1 to 3;- (CH2)nn = from 1 to 3; x = from 0 to 2; R1selected from hydroxy, C1-C9-alkoxy, optionally substituted with halogen, C1-C9-cycloalkane where cycloalkyl group optionally substituted C1-C4-alkyl or halogen, and CNS group optionally substituted with halogen, Allakaket, where aryl group optionally substituted C1-C4-alkyl, C1-C3-alkoxy or halogen, and CNS group optionally substituted with halogen and C1-C9-alkylamino, where the alkyl group is optionally substituted with halogen; R2selected from hydrogen, alkyl, aryl, arylalkyl, cycloalkyl and cycloalkenyl, where the alkyl groups optionally substituted with halogen, and aryl groups are optionally substituted C1-C4-alkyl, C1-C4-alkoxy or halogen; R3is H, C1-C7-alkyl or benzyl, when-Y-Z-R2not attached to W; R3no, when-Y-Z-R2attached to W, W is nitrogen; X is-CH2-, -O - or-aetsa2-C10-alkylene, in which one of reconcavo carbon atom may be replaced by 0; and Z is

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
R5and R7independently selected from H, aryl(C1-C3)alkyl and cycloalkyl (C1-C3)alkyl, and optionally substituted with halogen, and Q is N or stands or Q is connected to R5or R7with the formation of five-membered ring, or Q is connected to R2with the formation of six-membered ring, provided that when Z is

< / BR>
at least one of R5and R7is aryl (C1-C3)alkyl or cycloalkyl (C1-C3)alkyl, optionally substituted with halogen; or pharmaceutically acceptable salts, and pharmaceutical compositions having the ability to bind with the receptors of N3histamine, which includes an effective amount of the compounds of General formula I

The invention relates to derivatives of 1-(N-phenyliminomethyl)piperazine of the formula I, where R is H, alkyl -, cycloalkyl-substituted cycloalkyl-WITH or monocyclic heteroaryl-CO; R1Is h or lower alkyl; R2- halogen, alkoxy, phenoxy, NO2, CN, acyl, NH2, NH(acyl), alkyl-SO2NH, alkoxycarbonyl, NH2WITH, (alkyl)NHCO (alkyl)2NCO, (acyl)NHCO, CF3or polyporaceae; benzyl or mono - or bicyclic aryl, or heteroaryl, all of which are optionally substituted

New ketoenamine // 2190599
The invention relates to new ketoenamine formula (1), where R1means phenyl, naphthyl, hinely, pyridyl, chinadoll, Minoxidil, benzothiazyl, isoquinoline, tetrahydroisoquinoline or tetrahydroquinolin, which may be unsubstituted or substituted, R2means hydrogen or alkyl, R3means alkyl, which may carry phenyl ring, X is a bond, -(CH2)m-, -(CH2)m-O-(CH2)0-, -(CH2)n-S-(CH2)m-, -CH= CH-, -CO-CH=CH-, -(CH2)m-NHCO-(CH2)0-, -(CH2)m-CONH-(CH2)0-, -(CH2)m-NHSO2-(CH2)0-, -(CH2)m-SO2NH-(CH2)0-; R4means group OR6, NR7R8; n is a number from 0 to 2

The invention relates to new derivatives benzoylpyridine General formula (I), where R1means alkyl with 1-8 carbon atoms, a represents a group represented by the formula of the invention, means (-CH2-)aor (-CO-)band means an integer of 0 to 8, preferably 1, 2, 3 or 4, b means of 0,1 or 2, preferably 1, R2means unsubstituted or substituted alkyl with 1-8 carbon atoms, unsubstituted phenyl, NR3R4or preferably the five-membered heterocycle represented in the claims, in which U, V, W, X and Z can mean CH, NH, O or S, R3and R4denote alkyl with 1-8 carbon atoms

The invention relates to new compounds of the formula I

Y-(CmH2m-CHR1)n-CO- (NH-CHR2CO)r-Z

where Y denotes

< / BR>
or

< / BR>
Z denotes

< / BR>
or if Y

< / BR>
also means

< / BR>
R1, R2and R7each means-CtH2t-R9,

R3means H or H2N-C(=NH)-,

R4and R6each means (H,H) or =O,

R5means H2N-C(=NH) -, or H2N-C(=NH)-NH,

R8means OH or OA,

R9denotes H or COOH,

A denotes alkyl with 1-4 C-atoms,

m and t each is 0, 1 or 2,

n and r each denotes 0 or 1 and

p is 0, 1 or 2,

and their salts

The invention relates to new derivatives of 3-phenylpyridine formula (I)

in which R denotes hydrogen, C1-C7alkyl, C1-C7alkoxy, halogen or CF3, R1means H or halogen, or R and R1may together form-CH=CH-CH=CH-; R2means H, halogen, CF3, R3means H or C1-C7alkyl, R4means H or piperazine-1-yl; R5means H or C1-C7alkyl, X is-C(O)N(R5)-, -(CH2)mO-, -(CH2)mN(R5)-, -N(R5)C(O)- or N(R5)(CH2)m-; n is an integer from 0 to 4, m is 1 or 2, and their pharmaceutically acceptable acid additive salts

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