Derivatives of diphenyl and drug

 

(57) Abstract:

The invention relates to new compounds of General formula

which have the properties of receptor antagonists neirokinina-1(NK-1). In the General formula (I), R denotes a hydrogen atom, a C1-C7alkyl, C1-C7alkoxy, halogen atom, amino group, -N(R6)2or trifluoromethyl; R1denotes a hydrogen atom, a C1-C7alkoxy or halogen atom; or R and R1may together form-CH=CH-CH=CH-; R2denotes a halogen atom, a C1-C7alkyl or trifluoromethyl; R3denotes a hydrogen atom or a C1-C7alkyl; R4denotes a hydrogen atom or a saturated cyclic tertiary amine containing 5 to 6 atoms in the cycle, possibly substituted C1-C7by alkyl; R5denotes a hydrogen atom, nitro, amino or-N(R6)2; R6denotes a hydrogen atom or a C1-C7alkyl; X represents-C(O)N(R6)-, -(CH2)nO-, -(CH2)nN(R6)-, -N(R6)C(O) -, or-N(R6)(CH2)n-; n represents 1 or 2; and their pharmaceutically acceptable acid additive salts, with the exception of N-[(4-were)methyl]hydrochloride (1,1’-di is also applies to a medicinal product on the basis of the claimed compounds. 2 N. and 7 C.p. f-crystals.

The invention relates to compounds of General formula

in which R denotes hydrogen atom, lower alkyl, respectively (ness.)alkyl, (ness.)alkoxy, halogen atom, amino group, -N(R6)2or trifluoromethyl;

R1denotes a hydrogen atom, (ness.)alkoxy or halogen atom; or

R and R1may together form-CH=CH-CH=CH-;

R2denotes a halogen atom, (ness.)alkyl or trifluoromethyl;

R3denotes a hydrogen atom or (ness.)alkyl;

R4denotes a hydrogen atom or a cyclic tertiary amine, optionally substituted (ness.)by alkyl;

R5denotes a hydrogen atom, nitro, amino or-N(R6)2;

R6denotes a hydrogen atom or (ness.)alkyl;

X denotes-C(O)N(R6)-, -(CH2)nO-, -(CH2)nN(R6)-, -N(R6)C(O)- or N(R6)(CH2)n-;

n denotes 1 or 2;

and their pharmaceutically acceptable acid additive salts, except for the following compounds:

N-[(4-were)methyl]hydrochloride (1,1’-diphenyl)-2-methanamine and

N-{[4-(1,1-dimethylethyl)phenyl]methyl}-N-metalhydroxide (1,1’-given is the boost of the invention unexpectedly, it was found, the compounds of the present invention are antagonists of the receptor neirokinina 1 (NK-1, substance P). Substance P is a naturally occurring undecapeptide belonging to the peptides of the family of tachykinins, which got its name due to their rapid contractile action on extravascular tissue of smooth muscles.

The receptor for substance P is a member of the superfamily of receptors that are associated with protein G.

Neuropeptide receptors substance P (NK-1) are widely distributed in the nervous system of mammals (primarily in the brain and spinal ganglia), the circulatory system and peripheral tissues (primarily in the duodenum and jejunum) and 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, and their role as a mediator gag reflex and modulator of disorders of the Central nervous system (CNS), such as Parkinson's disease (Neurosci. Res. 7, 187-nenia receptor antagonists tachykinin for the treatment of pain, headache, especially migraine, Alzheimer's disease, multiple 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 I 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 Inna-1.

In the patent US 5972938 also described is a method of treatment psychoimmunological 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, for example, the treatment or prevention of certain depressive disorders or vomiting by introducing antagonists of the receptor NK-1. It is established that the main attack 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.

PR is t, do they individually or in combination.

The term "(ness.)alkyl" in the present description are marked pravarasena or branched 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 a group in which 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. Preferred pieperazinove group.

The term "pharmaceutically acceptable acid additive salts" embraces salts with mineral and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric to the traveler acid, tartaric acid, methanesulfonate acid, p-toluensulfonate etc.

Preferred examples are compounds in which X represents-C(O)N(R6)-, where R6denotes methyl, in particular the following compounds:

(3,5-bistrifluormethylbenzene)methylamide 2’-methylbiphenyl-2-carboxylic acid,

(3,5-bistrifluormethylbenzene)methylamide 2’-methyl-5-(4-methylpiperazin-1-yl)diphenyl-2-carboxylic acid and

(3,5-bistrifluormethylbenzene)methylamide 2’-chloro-5-(4-methylpiperazin-1-yl)diphenyl-2-carboxylic acid.

More preferred compounds in which X represents-N(R6)C(O)-, where R6denotes methyl.

Examples of such compounds are:

2-(3,5-bistrifluormethylbenzene)-N-methyl-N-(2’-methyl-4-nitrobiphenyl-2-yl) isobutyramide,

N-(4-amino-2’-methylbiphenyl-2-yl)-2-(3,5-bistrifluormethylbenzene)-N-methylisoleucine,

2-(3,5-bistrifluormethylbenzene)-N-methyl-N-(2’-methyl-4-methylamino-phenyl-2-yl)isobutyramide,

2-(3,5-bistrifluormethylbenzene)-N-methyl-N-(2’-methylbiphenyl-2-yl)out-of butyramide and

N-(2’-aminobiphenyl-2-yl)-2-(3,5-bistrifluormethylbenzene)-N-metriso-butyramide.

The proposed compounds of formula I and their pharmaceutically acceptable salts can be p clucalc

a) reaction of compounds of formula

with the compound of the formula

obtaining the compounds of formula

in which R1-R6, R 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-R6R and n have the meanings stated above, or

C) the restoration 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

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

C) methylation of the compounds of formula

to compounds of the 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 of the substituents R1-R6and R within them above values and, if necessary, converting the compounds obtained into pharmaceutically acceptable acid additive salt.

In accordance with process variant a) to the cooled solution of the compound of formula II, for example 2’-methyl-4-nitrobiphenyl-2-amine, and DIPEA (N-ethyldiethanolamine) introducing a solution of the compounds of formula III, for example 2-(3,5-bistrifluormethylbenzene)-2-methylpropionitrile, in dichloromethane and the mixture is stirred at a temperature in the range from 35 to 40 C. After purification 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 usually what dildocam 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 of the compounds of formula VII. Acceptable solvent is tetrahydrofuran. The reaction is carried out at room temperature.

In accordance with process variant d) receive compound of formula I-5. This reaction is carried out by deprotonation of compounds of formula VIII with 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 I-3 in the usual way, for example Lil4or NR3THF.

In accordance with process variant g) conducting the reaction of the compound of formula XII with the compound of the formula XIII with getting the connection Ferrante C) carry out methylation of the compounds of formula I-41 formalin and NaBH4to the compounds of formula I-42.

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

The process of obtaining salt is carried out at room temperature in accordance with methods that are well known and which are familiar to any person skilled in the art. 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 5. Starting materials of formulas II, III, IX, X, XI, XII, XIII, XIV and XV are compounds that are known or can be obtained in accordance with methods known in the art.

These charts use the following abbreviations.

DI-CL hydrochloride N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide

HOBT 1-hydroxybenzotriazole

DMF dimethylformamide

The OED isolated potassium

NaBH4sodium borohydride

NaCNBH4cyanoborohydride sodium

TFK triperoxonane acid

DIEA N,N-diisopropylethylamine

As mentioned above, the compounds of formula I and their acceptable for use with pharmaceutical purposes 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 studied using the following tests.

The affinity of test compounds to NK1the receptor was evaluated using the human NK1receptors in Cho-cells infected by human NK1receptor (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), nl2(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 Mecenate connection. Tubes for analysis were incubated for 60 min at room temperature, after which the contents of the tubes were rapidly filtered under vacuum through a filter 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 separate experiments.

The affinity to the receptor NK-1, expressed as pKi, for 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, e.g. in the form of injectable solutions.

The compounds of formula I and automatic inert inorganic or organic excipients for the preparation of tablets, filmtabletten, tablets and gelatin capsules with a hard surface. As such excipients for preparation of, 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 antioxi the wide range and, of course, should be chosen depending on the individual requirements in each particular case. 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. The temperature in all cases specified in degrees Celsius.

Example 1

(3.5-bistrifluormethylbenzene)methylamide diphenyl-2-carboxylic acid

a) 3,5-bistrifluormethylbenzene diphenyl-2-carboxylic acid

In a solution of 0.79 g (4 mmole) of diphenyl-2-carboxylic acid in 30 ml of CH2Cl2was introduced to 1.12 ml (8 mmol) of triethylamine, 0,60 g (4 mmole) of 1-hydroxybenzotriazole, 0,76 g (4 mmole) of the hydrochloride of N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide and 1,167 g (4 mmole) of 3,5-bistrifluormethylbenzene. The reaction mixture was stirred for 16 hours the Reaction mixture was diluted with 20 ml of CH2Cl2off , washed with 50 ml of 0.5 N. Hcl and 50 ml of N2O. the Aqueous layers were subjected to back extraction with 50 ml of CH2CL2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO73%) 3.5-bistrifluormethylbenzene diphenyl-2-carboxylic acid, tPL:86-87 .

b) (3,5-bistrifluormethylbenzene)methylamide diphenyl-2-carboxylic acid

In the solution to 0.63 g (1.50 mmole) of 3,5-bistrifluormethylbenzene diphenyl-2-carboxylic acid in 10 ml of N,N-dimethylformamide was introduced 0.08 g (1.98 mmole) of sodium hydride (60% dispersion in mineral oil) and the reaction mixture was stirred for 1 h After adding 0 0.15 ml (2.4 mmole) under the conditions of the reaction mixture was stirred for 3 h at RT. The reaction mixture was distributed between 50 ml of N2About 50 ml of brine and 50 ml of CH2Cl2. The phases were separated and the aqueous layer was twice washed with 50 ml of CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, ethyl acetate/CH2CL2in the ratio 15:1) to give a colourless solid 0.50 g (yield: 76%) of (3,5-bistrifluormethylbenzene)methylamide diphenyl-2-carboxylic acid tPL:97-98 .

Example 2

(3,5-dichlorobenzyl)methylamide diphenyl-2-carboxylic acid

Analogously to example 1 (a) of diphenyl-2-carboxylic acid and 3,5-dichlorobenzenesulfonyl-2-carboxylic acid as a colourless solid was obtained 3,5-dichloraniline with tPL152-153 , which metamod diphenyl-2-carboxylic acid withPL126-128 .

Example 3

Methyl-(3-methyl-5-trifloromethyl)amide diphenyl-2-carboxylic acid

Analogously to example 1 (a) of diphenyl-2-carboxylic acid and 3-methyl-5-triphtalocyaninine in the form of a colorless solid was obtained 3-methyl-5-triptoreline diphenyl-2-carboxylic acid with tPLa 126.7-127,1 , which has metilirovanie as described in example 1 b), receiving in the form of a colorless oil of methyl-(3-methyl-5-trifloromethyl)humidifier-2-carboxylic acid, MS (EI): 383 (M+).

Example 4

3,5-bistrifluormethylbenzene 2’-bromodiphenyl-2-carboxylic acid

Analogously to example 1 a) from 2’-bromodiphenyl-2-carboxylic acid and 3,5-bistrifluormethylbenzene in the form of a colorless solid was obtained 3,5-bistrifluormethylbenzene 2’-bromodiphenyl-2-carboxylic acid, MS (EI):502 (M+).

Example 5

3,5-dichloraniline 2’-bromodiphenyl-2-carboxylic acid

Analogously to example 1 a) from 2’-bromodiphenyl-2-carboxylic acid and 3,5-dichloroaniline in the form of a colorless solid was obtained 3,5-dichloraniline 2’-bromodiphenyl-2-carboxylic acid, tPL: 122,5-of 123.2 .

Example 6

(3,5-bistrifluormethylbenzene)methylamide 2’-bradfordians)of methylamine in the form of a colorless solid was obtained (3,5-bistrifluormethylbenzene) methylamide 2’-bromodiphenyl-2-carboxylic acid, MS (EI): 514 (M-H+).

Example 7

N-(3,5-bistrifluormethylbenzene)-N-methyl-2-naphthalene-1-ylbenzene

Analogously to example 1 (a) of 2-naphthalene-1-eventing acid and (3,5-bistrifluormethylbenzene)of methylamine in the form of a colorless solid was obtained N-(3,5-bistrifluormethylbenzene)-N-methyl-2-naphthalene-1-ylbenzene, MS (EI): 514 (M-H+).

Example 8

(3,5-bistrifluormethylbenzene) methylamide 2’-methoxybiphenyl-2-carboxylic acid

Analogously to example 1 a) from 2’-methoxybiphenyl-2-carboxylic acid and (3,5-bistrifluormethylbenzene) of methylamine in the form of a colorless oil was obtained (3,5-bistrifluormethylbenzene)methylamide 2’-methoxybiphenyl-2-carboxylic acid, MS (ISP): 468,2 (M+N)+.

Example 9

(3,5-bistrifluormethylbenzene)methylamide 2’-methoxybiphenyl-2-carboxylic acid

Analogously to example 1 (a) of the 3’-methoxybiphenyl-2-carboxylic acid and (3,5-bistrifluormethylbenzene)of methylamine in the form of a colorless oil was obtained (3,5-bistrifluormethylbenzene)methylamide 3’ methoxydiphenyl 2 carboxylic acid, MS (ISP): 468,1 (M+N)+.

Example 10

(3,5-bistrifluormethylbenzene)methylamide 2’-methylbiphenyl-2-carboxylic acid

Analogously to example 1 a) from 2’-methylbiphenyl-2-carboxylic sour the MFA 2’-methylbiphenyl-2-carboxylic acid, MS (EI): 450 (M+N)+.

Example 11

2-(3,5-bistrifluormethylbenzene)diphenyl

In a solution of 1.53 g (6,26 mmole) of (3,5-bistrifluormethylbenzene) methanol in 15 ml of N,N-dimethylformamide was introduced to 0.30 g (7,52 mole) of sodium hydride (60% dispersion in mineral oil) and the reaction mixture was stirred for 1 h After adding 0 1.27 g (6,26 mmole) of 2-chloromethylpyridine in 5 ml of N,N-dimethylformamide, the reaction mixture was stirred at RT for 3 h the Reaction mixture was distributed between 50 ml of N2About 50 ml of brine and 50 ml of CH2CL2. The phases were separated, the aqueous layer was twice washed with 50 ml of CH2CL2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, hexane/ethyl acetate in a ratio of 40:1) to give a colourless oil of 1.25 g (yield: 47%) of 2-(3,5-bistrifluormethylbenzene)diphenyl, MS (EI): 410 (M+).

Example 12

(3,5-bistrifluormethylbenzene)-(2’-methoxybiphenyl-2-ylmethyl)AMI

In a solution of 0.55 g (2.3 mmole) of 3,5-bistrifluormethylbenzene in 15 ml of methanol was introduced 0.50 g (2,34 mmole) of (2’-methoxybiphenyl-2-yl)methylamine and the reaction mixture was stirred for 1 h After addition of 0.13 g (3.45 mmole) NaBH4reaction 60 ml of CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2with getting in the form of a colorless oil of 0.82 g (yield: 81%) of (3,5-bistrifluormethylbenzene)-(2’-methoxybiphenyl-2-ylmethyl)amine, MS (ISP): 440,3 (M+N)+.

Example 13

(3,5-bistrifluormethylbenzene)-(2’-methoxybiphenyl-2-ylmethyl) methylamine

To a solution of 0.40 g (of 0.91 mmole) of 3,5-bistrifluormethylbenzene)-(2’-methoxybiphenyl-2-ylmethyl)amine in 5 ml of acetonitrile and 0.35 ml (4,55 mmole) of formaldehyde (36% in water) in small portions was introduced 0,091 g (of 1.46 mmole) of laborgerate sodium. The reaction mixture was stirred for 45 min and then poured into water. The aqueous phase three times was extracted with 60 ml of CH2CL2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2CH2CL2with getting in the form of a colorless oil, 0.33 g (yield: 80%) (3,5-bistrifluormethylbenzene)-(2’-methoxybiphenyl-2-ylmethyl) methylamine, MS (ISP): 454,4 (M+N)+.

Example 14

N-diphenyl-2-yl-2-(3,5-bistrifluormethylbenzene)-N-methylacetamide

To a solution of 272 mg (1.0 mmole) of 3,5-bis(trifluoromethyl)phenylacetic acid in 1 ml tetali for 2 h at room temperature and was added 147 mg (0.8 mmole) of diphenyl-2-ylmethylamino. At room temperature, stirring was continued for 3 days. The reaction mixture is evaporated and the residue was purified by chromatography (SiO2, hexane/ethyl acetate in the ratio 3:1) to obtain white crystals of 160 mg (yield: 46%) of N-diphenyl-2-yl-2-(3,5-bistri-formationl)-N-methylacetamide, MS (ISP): 438,2 (M+N)+.

Example 15

(R,S)-N-diphenyl-2-yl-2-(3,5-bistrifluormethylbenzene)-N-methylprop-aramid

a) N-diphenyl-2-yl-2(3,5-bestresveratrol)ndimethylacetamide

Analogously to example 14 from 2-aminodiphenyl and 3,5-bis(trifluoromethyl)phenylacetic acid in the form of white crystals was obtained N-diphenyl-2-yl-2-(3,5-bistrifluormethylbenzene)ndimethylacetamide, MS (ISP): 424,2 (M+N)+.

b) (R,S)-N-diphenyl-2-yl-2-(3,5-bistrifluormethylbenzene)-N-methylpropionamide

To a solution of 288 mg (0.68 mmole) of N-diphenyl-2-yl-2-(3,5-bistritei-phenyl)ndimethylacetamide in 0.5 ml of N,N-dimethylformamide in an argon atmosphere at 0 was administered to 204 mg (1,02 mmole) hexamethyldisilazide potassium. Stirring was continued at room temperature for 1 h and the reaction mixture was again cooled to 0 . At this temperature was added 160 mg (1,07 mmole) under the conditions. After stirring for 3 h at room temperature was added ethyl acetate and the organic layer washed is wearing 4:1) to obtain white crystals of 200 mg (yield: 65%) of N-diphenyl-2-yl-2-(3,5-bistrifluormethylbenzene)-N-methyl-propanamide, MS (ISP): 452,2 (M+N)+.

Example 16

2-(3,5-bistrifluormethylbenzene)-N-(2’-methyl-4-nitrobiphenyl-2-yl)out-of butyramide

a) 2’-methyl-4-nitrobiphenyl-2-ylamine

A mixture of 1.0 g (4.6 mmole) of 2-bromo-5-nitroaniline, 20 ml of benzene, 10 ml of 2 n sodium carbonate solution, 159 mg (about 0.14 mmole) tetrakis(triphenylphosphine)PAL-lady(0) and 725 mg (5,07 mmole) of tolylboronic acid was kept in an argon atmosphere at 60 for 20 hours After cooling to room temperature the aqueous phase was separated and washed twice with toluene.

The combined organic layers were washed with brine, dried (Na2SO4) and evaporated. The residue was purified by chromatography (SiO2CH2CL2/hexane in the ratio 2:1) to obtain in the form of a pale yellow oil 950 mg (yield: 91%) of 2’-methyl-4-nitrobiphenyl-2-ylamine, MS (EI): 228 (M+).

b) 2-(3,5-bistrifluormethylbenzene)-N-(2’-methyl-4-nitrobiphenyl-2-yl)isobutyramide

A solution of 925 mg (of 4.05 mmole) of 2’-methyl-4-nitrobiphenyl-2-ylamine and 1.03 ml (between 6.08 mmole) of N-ethyldiethanolamine in 9 ml of CH2Cl2was cooled in an ice bath and added dropwise injected with a solution of 1.42 g (4,46 mmole) 2-(3,5-bistrifluormethylbenzene)-2-methylpropionitrile in 1 ml of CH2Cl2. The reaction mixture was stirred at room temperature is the Hcl er, dried (MgSO4) and evaporated to produce in the form of yellow crystals of 1.84 g (yield: 89%) of 2-(3,5-bistrifluormethylbenzene)-N-(2’-methyl-4-nitrobiphenyl-2-yl)isobutyramide, MS (ISP): 511,3 (M+N)+.

Example 17

2-(3,5-bistrifluormethylbenzene)-N-methyl-N-(2’-methyl-4-nitrobiphenyl-2-yl)isobutyramide

In a solution of 1.75 g (3,43 mmole) 2-(3,5-bistrifluormethylbenzene)-N-(2’-methyl-4-nitrobiphenyl-2-yl)isobutyramide in 11 ml of N,N-dimethylformamide in an argon atmosphere at 0 dropwise introduced with 4.1 ml (4.1 mmole) of 1 M solution hexamethyldisilazide potassium in tetrahydrofuran. Stirring was continued at room temperature for 1 h and the reaction mixture was again cooled to 0 . At this temperature was added of 0.32 ml (5,14 mmole) under the conditions. After stirring for 3 h at room temperature was added ethyl acetate and the organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was purified by chromatography (SiO2, ethyl acetate/hexane in the ratio 1:1) to obtain in the form of yellow crystals 1.0 g (yield: 56%) of 2-(3,5-bistrifluormethylbenzene)-N-methyl-N-(2’-methyl-4-nitrobiphenyl-2-yl)isobutyramide, MS (EI): 524 (M+).

Example 18

N-(4-amino-2’-methylbiphenyl-2-yl)-2-(3,5-bistrifluormethylbenzene)-N-methylisoleucine

To a solution of furan and 3 ml of water was injected 608 mg (10,87 mmole) of iron powder and 3 drops triperoxonane acid. After aging at 85 for 3 h, the reaction mixture was cooled to room temperature and evaporated. The residue was purified by chromatography (SiO2, hexane/ethyl acetate in the ratio 1:4) to obtain in the form of pale yellow crystals 890 mg (yield: 99%) of N-(4-amino-2’-methylbiphenyl-2-yl)-2-(3,5-bistrifluormethylbenzene)-N-methylisobutyl, MS (ISP): 495,2 (M+N)+.

Example 19

2-(3,5-bistrifluormethylbenzene)-N-(4-dimethylamino-2’-methylbiphenyl-2-yl)-N-methylisoleucine

Into a solution of 300 mg (0,61 mmole) of N-(4-amino-2’-methylbiphenyl-2-yl)-2-(3,5-bistrifluormethylbenzene)-N-methylisobutyl in 3 ml of acetone was injected 420 mg (3,03 mmole)2CO3and 0,057 ml of 0.91 mmole) under the conditions. Stirring was continued at room temperature overnight. The reaction mixture was filtered and the filtrate evaporated. The residue was purified by chromatography (SiO2, hexane/ethyl acetate in the ratio 1:4) to obtain in the form of a pale yellow oil, 96 mg (yield: 30%) 2-(3,5-bistrifluormethylbenzene)-N-(4-dimethylamino-2’-methylbiphenyl-2-yl)-N-methylisobutyl, MS (ISP): 532,2 (M+N)+.

Example 20

2-(3,5-bistrifluormethylbenzene)-N-methyl-N-(2’-methyl-4-methylamino-phenyl-2-yl)isobutyramide

Specified in the title compound was isolated as a yellow oil, MS (ISP): 509-N-methylisobutyl.

Example 21

2-(3,5-bistrifluormethylbenzene)-N-(2’-methoxybiphenyl-2-yl)-N-methyl-isobutyramide

A solution of 53 mg (0.25 mmole) of (2’-methoxybiphenyl-2-yl)methylamine and 0,064 ml (0,375 mmole) of N-ethyldiethanolamine in 4 ml of CH2Cl2was cooled in an ice bath and added dropwise injected with a solution of 88 mg (0,275 mmole) 2-(3,5-bistrifluormethylbenzene)-2-methylpropionitrile in 1 ml of CH2Cl2. The reaction mixture was stirred at room temperature overnight. Added ethyl acetate and the organic layer was washed with saturated solution of Na2CO3, 1 N. Hcl solution, dried (MgSO4) and evaporated. The residue was purified by chromatography (SiO2, hexane/ethyl acetate in the ratio 4:1) to obtain in the form of orange crystals 107 mg (yield: 87%) of 2-(3,5-bistrifluormethylbenzene)-N-(2’-methoxybiphenyl-2-yl)-N-methylisobutyl, MS (ISP): 496,1 (M+N)+.

Example 22

2-(3,5-bistrifluormethylbenzene)-N-methyl-N-(2’-methylbiphenyl-2-yl)-isobutyramide

Analogously to example 21 from (2’-methylbiphenyl-2-yl)methylamine and 2-(3,5-bistrifluormethylbenzene)-2-methylpropionitrile in the form of white crystals was obtained 2-(3,5-bistrifluormethylbenzene)-N-methyl-N-(2’-methylbiphenyl-2-yl)isobutyramide, MS (ISP): of 480.2 (M+N)+.

Example 23

2-(3,5-bistrifluormethylbenzene 2-(3,5-bistrifluormethylbenzene)-2-methylpropionitrile in the form of white crystals was obtained 2-(3,5-bistrifluormethylbenzene)-N-(2’-chlorodiphenyl-2-yl)-N-methyl-isobutyramide, MS (ISP): 502,2 (M+N)+

Example 24

N-(2’-aminobiphenyl-2-yl)-2-(3,5-bistrifluormethylbenzene)isobutyramide

Analogously to example 16 from 2,2’-diaminodiphenyl and 2-(3,5-bistrifluormethylbenzene)-2-methylpropionitrile in the form of white crystals was obtained N-(2’-aminobiphenyl-2-yl)-2-(3,5-bistrifluormethylbenzene)isobutyramide, MS (ISP): 467,2 (M+N)+

Example 25

N-(2’-aminobiphenyl-2-yl)-2-(3,5-bistrifluormethylbenzene)-N-methyl-isobutyramide

To a solution of 151 mg (0,32 mmole) of N-(2’-aminobiphenyl-2-yl)-2-(3,5-bis-triptoreline)isobutyramide in 1 ml N,N-dimethylformamide in an argon atmosphere at 0 was introduced 130 mg (0.65 mmole) hexamethyldisilazide potassium. Stirring was continued at room temperature for 1 h and the reaction mixture was again cooled to 0 . At this temperature was added 115 mg (0,81 mmole) under the conditions. After stirring for 3 h at room temperature was added ethyl acetate and the organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was purified by chromatography (SiO2, ethyl acetate/CH2Cl2in the ratio 1:1) to give a colourless oil, 56 mg (yield: 36%) of N-(2’-aminobiphenyl-2-yl)-2-(3,5-bistrifluormethylbenzene)-N-methylisobutyl, MS (ISP): 481,1 (M+N)+.

P is glavie compound was isolated as white crystals, MS (ISP): 495,2 (M+N)+, (14 mg, yield: 9%) during purification N-(2’-aminobiphenyl-2-yl)-2-(3,5-bistrifluormethylbenzene)-N-methylisobutyl.

Example 27

(3,5-bistrifluormethylbenzene)methylamide 2’-methyl-5-(4-methylpiperazin-1-yl)diphenyl-2-carboxylic acid

a) 2-chloro-4-fluoro-N-methylbenzamide

To 1.00 g (5,73 mmole) of 2-chloro-4-fermenting acid at 0 was added to 4.16 ml (57,3 mmole) of thionyl chloride and 3 drops of DMF. After boiling the mixture under reflux during the night by distillation remove excess thionyl chloride. The oily brown residue was dissolved in 5 ml of CH2CL2. The solution at 0 was treated with gaseous methylamine until then, until he noted the termination of the exothermic reaction. The resulting suspension was diluted with 20 ml of CH2Cl2/H2O. the Layers were separated and the aqueous layer was extracted with 3 10-ml portions of CH2CL2. In the drying of the organic layer (Na2SO4) and evaporation in the form of a light yellow solid substance was obtained 1.07 g (yield: 99.6 percent) of 2-chloro-4-fluoro-N-methylbenzamide, MS (EI): 187 (M+).

b) 2-chloro-N-methyl-4-(4-methylpiperazin-1-yl)benzamid

A mixture of 316 mg (1.68 mmole) of 2-chloro-4-fluoro-N-methylbenzamide and 0.94 ml (8.4 mmole) of 1-methylpiperazine withstood 50 /0.5 mbar remove excess 1-methylpiperazine. The residue was divided between 25 ml of CH2CL2/2 n NaOH solution. The layers were separated and the aqueous layer was extracted with 3 15-ml portions of dichloromethane. The combined organic extracts were dried (Na2SO4) and evaporated. The result chromatography (SiO2CH2CL2/methanol in the ratio 19:1) as a light yellow solid substance was obtained 236 mg (yield: 52%) of 2-chloro-N-methyl-4-(4-methylpiperazin-1-yl)benzamide, MS (EI): 267 (M+).

in) Methylamide 2’-methyl-5-(4-methylpiperazin-1-yl)diphenyl-2-carboxylic acid

In a solution of 125 mg (0,467 mmole) of 2-chloro-N-methyl-4-(4-methylpiperazin-1-yl)benzamide and 0.22 ml (1.5 mmole) of N,N,N’,N ' - tetramethylethylenediamine in 2 ml of THF at -78 dropwise injected with a solution of o-taillite prepared by adding at -78 2.5 ml (3.8 mmole) of 1.5 M solution of tert-utility in pentane into a solution of 0.23 ml (1.9 mmole) of 2-bromthymol in 2 ml of diethyl ether. The reaction mixture was allowed to warm for 2 h to -25 C. After quenching the reaction with 1 ml of water at -25 the mixture was heated to room temperature, followed by diluting 10 ml of ethyl acetate and washing with 10 ml 1 n NaOH solution. The layers were separated and the aqueous layer was extracted with 2 10-ml portions of ethyl acetate. The combined organic layers were dried (Na19:1) as a colourless oil was obtained 55 mg (yield: 36%) methylamide 2’-methyl-5-(4-methylpiperazin-1-yl)diphenyl-2-carboxylic acid, MS (EI): 324 (M+).

g) (3,5-bistrifluormethylbenzene)methylamide-2’-methyl-5-(4-methylpiperazin-1-yl)diphenyl-2-carboxylic acid

In a solution of 50 mg (0.15 mmole) methylamide 2’-methyl-5-(4-methylpiperazin-1-yl)diphenyl-2-carboxylic acid in 2 ml of THF at 0 was injected with 0.2 ml of 1 M solution (0.2 mmole) hexamethyldisilazide potassium in THF. After 20 min the resulting suspension was added dropwise 0,028 ml (0.15 mmole) of 3,5-bis(trifluoromethyl)benzylbromide. After 1.5 h the reaction extinguished with water. The mixture was diluted with 5 ml of 2 n NaOH solution and was extracted with 3 5-ml portions of ethyl acetate. The combined organic extracts were dried (PA2SO4) and evaporated. The result chromatography (SiO2CH2Cl2/methanol in the ratio 19:1) received 25 mg (yield: 29%) (3,5-bistrifluormethylbenzene)methylamide 2’-methyl-5-(4 methylpiperazin-1-yl)diphenyl-2-carboxylic acid, MS (ISP): 550,5 (M+N)+.

Example 28

(3,5-bistrifluormethylbenzene)methylamide 2’-chloro-5-(4-methylpiperazin-1-yl)diphenyl-2-carboxylic acid

(3,5-bistrifluormethylbenzene)methylamide 2’-chloro-5-(4-methylpiperazin-1-yl)diphenyl-2-carboxylic acid [MS 570 (M+N)+] was obtained analogously to the method get (3,5-bistrifluormethylbenzene)methylamide 2’-methyl-5-(4-hundred on-bromthymol.

Example 29

(3,5-bistrifluormethylbenzene)methylamide 4’-fluoro-2’-methylbiphenyl-2-carboxylic acid

Analogously to example 1A) from 4’-fluoro-2’-methylbiphenyl-2-carboxylic acid and (3,5-bistritei)methylbenzylamine in the form of a colorless oil was obtained (3,5-bistrifluormethylbenzene)methylamide 4’-fluoro-2’-methylbiphenyl-2-carboxylic acid, MS (EI): 468 (M-N)+.

Used as source material 4’-fluoro-2’-methylbiphenyl-2-carboxylic acid was prepared as follows.

a) (4’-fluoro-2’-methylbiphenyl-2-ylmethylene)Isopropylamine

The solution of 14.57 g (81 mmol) of N-(2-methoxybenzylidene)Isopropylamine in 50 ml of THF was added dropwise to the Grignard reagent derived from to 18.01 g (90 mmol) of 2-bromo-5-Tortolla and 2,19 g (90 mmol) of magnesium turnings in 50 ml of THF. The mixture was boiled under reflux for 12 hours Under vigorous stirring the mixture was poured into 25% aqueous solution of NH4Cl and was stirred for 1 h resulting from the extraction of CH2Cl2drying (Na2SO4) and evaporation in the form of pale yellow oil was obtained 20,83 g (yield: 98%) of (4’-fluoro-2 methylbiphenyl-2-ylmethylene)Isopropylamine.

b) 4’-fluoro-2’-methylbiphenyl-2-carbaldehyde

The solution 20,36 g (79,8 mmole) of (4’-fluoro-cenie 6 o'clock After cooling to CT the solution was extracted twice with 150 ml of CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2CH2CL2/hexane in the ratio 1:1) to give 4’-fluoro-2’-methylbiphenyl-2-carbaldehyde as a pale yellow oil.

C) 4’-fluoro-2’-methylbiphenyl-2-carboxylic acid

In a solution of 2.70 g (12.6 mmole) of 4’-fluoro-2’-methylbiphenyl-2-carbaldehyde in 75 ml of acetone and 25 ml of N2About introduced to 3.38 g (21,4 mmole) KMPO4and the mixture was stirred for 20 hours the Solution is evaporated, the residue was treated with 100 ml of N2About 100 ml of CH2CL2and concentrated H2SO4the pH of the aqueous phase was brought to 1. After filtration through product Hyflo, the phases were separated and the aqueous phase is twice washed with 100 ml of CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (SiO2CH2Cl2/MeOH in a ratio of 19:1) to give 4’-fluoro-2’-methylbiphenyl-2-carboxylic acid as colorless solid, MS (EI): 230 (M+).

The active ingredient, lactose and corn starch are mixed first in smesitel is up. Mechanically mix fill hard gelatin capsules.

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 forms appropriate size for suppositories, leave to cool, and then suppositories extract form and is Packed in an individual package of waxed paper or metal foil.

1. Compounds of General formula

in which R denotes a hydrogen atom, a C1-C7alkyl, C1-C7alkoxy, halogen atom, amino group, -N(R6)2or trifluoromethyl;

R1denotes a hydrogen atom, a C1-C7alkoxy or halogen atom;

R and R1may together form-CH=CH-CH=CH-;

R2denotes a halogen atom, a C1-C7alkyl or trifluoromethyl;

R3denotes a hydrogen atom or a C1-C7alkyl;

R4denotes a hydrogen atom or a saturated cyclic tertiary amine containing 5 to 6 atoms in the cycle, applicatio-N(R6)2;

R6denotes a hydrogen atom or a C1-C7alkyl;

X denotes-C(O)N(R6)-, -(CH2)nO-, -(CH2)nN(R6)-, -N(R6)C(O) -, or-N(R6)(CH2)n-;

n = 1 or 2

and their pharmaceutically acceptable acid additive salts with the exception of the following compounds: N-[(4-were)methyl]hydrochloride (1,1’-diphenyl)-2-methanamine and N-{[4-(1,1-dimethylethyl)phenyl]methyl}-N-metalhydroxide (1,1’-diphenyl)-2-methanamine.

2. Connection on p. 1, where X denotes-C(O)N(R6)-, and R6denotes methyl.

3. Connection on p. 2, which is a

(3,5-bistrifluormethylbenzene)methylamide 2’-methylbiphenyl-2-carboxylic acid,

(3,5-bistrifluormethylbenzene)methylamide 2’-methyl-5-(4-methylpiperazin-1-yl)diphenyl-2-carboxylic acid, or

(3,5-bistrifluormethylbenzene)methylamide 2’-chloro-5-(4-methylpiperazin-1-yl)diphenyl-2-carboxylic acid.

4. Connection on p. 1, where X represents-N(R6)C(O)-, a R6denotes methyl.

5. Connection on p. 4, which is a

2-(3,5-bistrifluormethylbenzene)-N-methyl-N-(2’-methyl-4-nitrobiphenyl-2-yl)isobutyramide,

N-(4-amino-2’-methylbiphenyl-2-yl)-2-(3,5-beschriften)isobutyramide,

2-(3,5-bistrifluormethylbenzene)-N-methyl-N-(2’-methylbiphenyl-2-yl)isobutyramide or

N-(2’-aminobiphenyl-2-yl)-2-(3,5-bistrifluormethylbenzene)-N-methylisoleucine.

6. A drug that has affinity for the receptor neirokinina I (NK-1), comprising one or more compounds according to any one of paragraphs.1-5 and a pharmaceutically acceptable fillers.

7. Drug under item 6 for the treatment of diseases associated with receptor antagonists (NK-1.

8. The compounds of formula I according to any one of paragraphs.1-5 for the treatment of diseases, oposredstvovanii receptor NK-1.

9. The compounds of formula I according to any one of paragraphs.1-5 for the preparation of drugs that includes one or more compounds of formula I in the treatment of diseases associated with receptor NK-1.

 

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