Dipeptide nitrile inhibitors of cathepsin k

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to biologically active compounds. Invention represents dipeptide nitrile inhibitors of cathepsin K, their pharmaceutically acceptable salts or their esters of the general formula:

wherein X means -CH or nitrogen atom (N); R means (C1-C7)-(lower)-alkyl, (C1-C7)-(lower)-alkoxy-(C1-C7)-(lower)-alkyl, (C5-C10)-aryl-(C1-C7)-(lower)-alkyl or (C3-C8)-cycloalkyl.

EFFECT: valuable biochemical properties of compounds.

6 cl, 12 ex

 

This invention relates to inhibitors of cysteine proteases, in particular to dipeptidyl inhibitors of cathepsin K, and to their pharmaceutical use in the treatment or prevention of diseases or pathological States involving cathepsin K.

Cathepsin It is a member of a family of cysteine Katasonov enzymes of the lysosomes, such as cathepsins B, K, L and S, which are involved in various disorders, including inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, tumors (especially in invasion and metastasis of cancers, coronary heart disease, atherosclerosis (including the destruction of atherosclerotic plaques and destabilization), autoimmune diseases, respiratory diseases, infectious diseases and mediated immunological disease status (including transplant rejection).

Coming from applicants simultaneously considering an application for an international patent WO 99/24460 describes dipeptidase, which are inhibitors of cysteine cathepsins and their use for treating diseases and pathological States dependent of cysteine cathepsins. Currently received new dipeptidyl derivatives, which are inhibitors of cathepsin K and which have the required properties for pharmaceutical applications.

Accordingly what about the present invention provides a compound of formula I or its pharmaceutically acceptable salt, or its ester

where R1and R2mean independently from each other H or (C1-C7)(ness.)alkyl, or R1and R2together with the carbon atom to which they are attached, form a (C3-C8)cycloalkyl ring and

Het denotes optionally substituted nitrogen-containing heterocyclic Deputy, provided that Het is not meant 4-pyrrol-1-yl.

Deputy Het may be in position 2 or 3 of the phenyl ring, although preferably it is in position 4.

In the present description, the term "nitrogen-containing heterocycle" means heterocyclic system containing at least one nitrogen atom, 2-10, preferably 3 to 7, most preferably 4 or 5 carbon atoms and optionally one or more additional heteroatoms selected from O, S or N. preferably

Deputy Het may include unsaturated, for example aromatic, nitrogen-containing heterocycle, although preferably includes a saturated nitrogen-containing heterocycle. Particularly preferred nitrogen-containing heterocycles are piperazinil, preferably piperazine-1-yl, or piperidinyl, preferably piperidine-4-yl.

Het may be substituted by one or more substituents, for example, up to 5 substituents, independently from each other selected is h, halogen, hydroxy, amino, nitro, optionally substituted (C1-C4)alkyl (such as alkyl, substituted hydroxy, alkyloxy, amino, optionally substituted, alkylamino, optionally substituted, dialkylamino, aryl or heterocyclyl), (C1-C4)alkoxy.

Preferably Het substituted on the nitrogen atom, most preferably monogamist on the nitrogen atom.

Preferred substituents for Het are (C1-C7)(ness.)alkyl, (C1-C7)(ness.)alkoxy(C1-C7)(ness.)alkyl, (C5-C10)aryl(C1-C7)(ness.)alkyl or (C3-C8)cycloalkyl.

R1and R2as (C1-C7)(ness.)alkyl preferably are the same, such as stands, or R1and R2together with the carbon atom to which they are attached, preferably form a (C3-C8)cycloalkyl ring, for example cyclopropyl ring. It is most preferable as R1and R2mean N.

Thus, in particularly preferred embodiments of embodiment of the invention provides a compound of formula II or its pharmaceutically acceptable salt, or ester

where X denotes CH or N, and

R is H, (C1-C7)(ness.)alkyl, (C1-C7)(ness.)alkoxy(C1-C7 )(ness.)alkyl, (C5-C10)aryl(C1-C7)(ness.)alkyl or (C3-C8)cycloalkyl.

Thus, specific examples of R as (C1-C7)(ness.)of alkyl are methyl, ethyl, n-propyl or isopropyl.

Specific examples of R as (C1-C7)(ness.)alkoxy(C1-C7)(NISS,)alkyl is methoxyethyl.

Specific examples of R as (C5-C10)aryl(C1-C7)(ness.)the alkyl is benzyl.

Specific examples of R as (C3-C8)cycloalkyl is cyclopentyl.

Examples of specific compounds of formula II are

N-[1-(cyanomethylene)cyclohexyl]-4-(piperazine-1-yl)benzamide;

N-[1-(cyanomethylene)cyclohexyl]-4-(4-methylpiperazin-1-yl)benzamide;

N-[1-(cyanomethylene)cyclohexyl]-4-(4-ethylpiperazin-1-yl)benzamide;

N-[1-(cyanomethylene)cyclohexyl]-4-[4-(1-propyl)piperazine-1-yl]benzamide;

N-[1-(cyanomethylene)cyclohexyl]-4-(4-isopropylpiperazine-1-yl)benzamide;

N-[1-(cyanomethylene)cyclohexyl]-4-(4-benzylpiperazine-1-yl)benzamide;

N-[1-(cyanomethylene)cyclohexyl]-4-[4-(2-methoxyethyl)piperazine-1-yl]benzamide;

N-[1-(cyanomethylene)cyclohexyl]-4-(1-propylpiperidine-4-yl)benzamide;

N-[1-(cyanomethylene)cyclohexyl]-4-[1-(2-methoxyethyl)piperidine-4-yl]benzamide;

N-[1-(cyanomethylene)cyclohexyl]-4-(1-isopropylpiperazine-4-the l)benzamid;

N-[1-(cyanomethylene)cyclohexyl]-4-(1-cyclopentenopyridine-4-yl)benzamide;

N-[1-(cyanomethylene)cyclohexyl]-4-(1-methylpiperidin-4-yl)benzamide and

N-[1-(cyanomethylene)cyclohexyl]-4-(piperidine-4-yl)benzamide.

Compounds of formulas I and II and the specific compounds listed above, henceforth referred to as compounds according to the invention.

Compounds according to the invention can be obtained by condensation of the corresponding Het-substituted derivative of benzoic acid with cyanomethylation 1-aminocyclohexanecarboxylic acid. For example, a derivative of benzoic acid, preferably in the form of hydrochloride, is mixed with cyanomethylation 1-aminocyclohexanecarboxylic acid, for example, in the presence of NEWT (1-hydroxybenzotriazole), water soluble carbodiimide (WSCD) and triethylamine in solution, for example in DMF, and stirred, for example, over night at room temperature. The product can be obtained, for example, by evaporation of the solvent, followed by washing with an aqueous solution of sodium carbonate, preferably in slightly alkaline conditions, followed by extraction with a solvent, for example ethyl acetate, drying of the extract, for example, with sodium sulfate, evaporation of the solvent and filtration. Can be used with alternative reagents and methods, for example, as described below in the examples.

Therefore clicks the zoom, in a further aspect the invention provides a method for producing compounds of formula I which comprises condensing the corresponding Het-substituted derivative of benzoic acid of formula III

with cyanomethylation 1-aminocyclohexanecarboxylic acid.

Cyanomethylene 1-aminocyclohexanecarboxylic acid can be obtained by condensation of 1-aminocyclohexanecarboxylic acid, as a rule, with appropriate protection for the amino group, such as FMOC (9-fluorenylmethoxycarbonyl)-1-aminocyclohexanecarboxylic acid, 2-aminoacetonitrile. For example, FMOC-1-aminocyclohexanecarboxylic acid, for example, with NOWT and WSCD added to a solution of 2-aminoacetonitrile and triethylamine in DMF, the mixture was stirred at 25°With during the night. Cyanomethylene 1-aminocyclohexanecarboxylic acid can be selected, as described in the examples. FMOC-1-aminocyclohexanecarboxylic acid may be obtained as described in the examples.

Compounds according to the invention or get in free form or in salt form, if present soleobrazutaya group.

Compounds according to the invention, containing basic groups can be converted into acid additive salts, especially pharmaceutically acceptable salts. They are formed, for example, with inorganic acids, so the mi, as mineral acids, e.g. sulfuric acid, phosphoric or halomonadaceae acid, or with organic carboxylic acids such as (C1-C5)alcancarao acids, for example, are unsubstituted or substituted by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, succinic, maleic or fumaric acid, such as hydroxycarbonate acids, for example glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid, or with organic sulfonic acids, such as (C1-C4)alkylsulfonate acid (for example, methanesulfonate acid) or arylsulfonic acids which are unsubstituted or substituted (e.g., halogen). Preferred are the salts formed with hydrochloric acid, methanesulfonic acid and malic acid.

Given the close relationship between the compounds in free form and compounds in the form of their salts, whenever mentioned the connection in this context, a corresponding salt is also implied, provided such is possible or appropriate under the circumstances.

The compounds, including their salts, can that is to be received in the form of their hydrates or include other solvents, used for crystallization.

Compounds according to the invention have valuable pharmacological properties when applied in mammals and is particularly useful as inhibitors of cathepsin K.

Inhibitory properties of the compounds according to the invention in respect of cathepsin K may be demonstrated in vitro by measuring the inhibition of, for example, recombinant human cathepsin K.

The in vitro assays carried out as follows. For cathepsin K: the analysis is performed in 96-well tablets for micrometrology at ambient temperature, using recombinant human cathepsin K. Inhibition of cathepsin To analyze at constant concentrations of the enzyme (0.16 nm) and substrate (54 mm Z(N-carbobenzoxy)-Phe-Arg-AMCA(7-amino-4-methoxycoumarin-3-acetic acid)), Peptide Institute Inc., Osaka, Japan) in 100 mm phosphate buffer, pH 7.0, containing 2 mm dithiotreitol, 20 mm tween-80 and 1 mm EDTA (ethylenediaminetetraacetic acid). Catepsin To have preincubated with hibitory for 30 min, the reaction was started by addition of substrate. After 30 min incubation the reaction was stopped by the addition of E-64 (TRANS-epoxyamine-L-leucinamide-(4-guanidino)butane) (2 mm) and the fluorescence intensity was read apparatus for reading advance tablets at the wavelengths of excitation and radiation of 360 and 460 nm, respectively. Connection from which retenue usually have K i(inhibition constant) human cathepsin less than about 5 nm, preferably about 5 nm or less, for example about 1 nm.

Whereas their activity as inhibitors of cathepsin K, the compounds according to the invention are particularly useful in mammals as agents for treatment and prevention of diseases and medical conditions, including elevated levels of cathepsin K. Such diseases include diseases, including infection with organisms such as Pneumocystis carinii, Trypsanoma cruzi, Trypsanoma brucei, Crithidia fusiculata, and parasitic diseases such as schistosomiasis and malaria, tumor invasion of tumors and metastatic tumors, and other diseases such as metachromatic leukodystrophy, muscular dystrophy, atrophy of muscle tissue and similar diseases.

Cathepsin involved in diseases associated with excessive bone loss, and therefore, the compounds according to the invention may be applicable for the treatment and prevention of such diseases, including osteoporosis, gum disease such as gingivitis and periodontitis, Paget's disease, hypercalcemia in malignant tumors, i.e. tumor induced hypercalcemia and metabolic disease of bone. Compounds according to the invention can also be used for the treatment and prevention of diseases caused the excessive degradation of cartilage or skeletal including osteoarthritis and rheumatoid arthritis, as well as some tumor diseases that cause the expression of high levels of proteolytic enzymes and degradation of the skeleton.

Compounds according to the invention is also indicated for the prevention or treatment of coronary heart disease, atherosclerosis (including the destruction of atherosclerotic plaques and destabilization), autoimmune diseases, respiratory diseases, infectious diseases and mediated immunological status of diseases including graft rejection).

Compounds according to the invention is particularly indicated for the prevention or treatment of osteoporosis of various Genesis (for example, emerged in adolescence, menopause, postmenopausal caused by old age or corticosteroid therapy or inactivity).

Favorable impacts evaluated in pharmacological tests in vitro and in vivo, are known, as a rule, specialists and presented in context as an illustration.

The above-mentioned properties are demonstrated in tests in vitro and in vivo with a predominant use of mammals such as rats, mice, dogs, rabbits, monkeys, or isolated organs and tissues, as well as enzyme preparations mammals or natural, or obtained, for example, recombinantly the way. Compounds according to the invention can be applied in vitro in the form of solutions, e.g. preferably aqueous solutions or suspensions, or in vivo, or interline, or parenteral, mostly orally, for example, in suspension or in aqueous solution or in the form of hard capsules, or tablets. The dosage in vitro may change in the concentration range between about 10-5and 10-9mol. Dosing in vivo depending on the route of administration may vary in the range 0.1-100 mg/kg

In accordance with the present invention it was found that the compounds according to the invention have good bioavailability, in particular good oral bioavailability. So, for example, selected compounds according to the invention have an absolute oral bioavailability of 50% or higher, such as 80% or more.

Anti-arthritis the efficacy of the compounds according to the invention for the treatment of rheumatoid arthritis can be determined using the model, the same or a similar rat model induced arthritis, which is described previously (R.E.Esser etc., J. Rheumatology, 1993, 20, 1176).

The effectiveness of the compounds according to the invention in the treatment of osteoarthritis can be defined using the model, the same or a similar rabbit model of partial lateral meniscectomy described previously (Colombo and others, Arth. Rheum. 1993 26, 875-886). Now the TB connections on the model can be quantified using methods histological indicators as described previously (O Byrne and others, Inflamm. Res. 1995, 44, 117-118).

The effectiveness of the compounds according to the invention in the treatment of osteoporosis can be determined using animal models such as rat with remote ovaries, or other similar species, such as rabbit or monkey, in experience, in which the compounds enter the animal and the presence of markers of bone resorption measured in urine or serum (e.g., as described in Osteoporos. Int. (1997) 7: 539-543).

In accordance with further aspects the invention provides

the connection according to the invention for use as a pharmaceutical;

pharmaceutical composition comprising the compound according to the invention as an active ingredient;

the method of treatment of a patient suffering from a disease or morbid condition or susceptible to a disease or morbid condition, which involved catepsin To, including the introduction to the patient an effective amount of the compounds according to the invention, and

the use of compounds according to the invention to obtain drugs for therapeutic or prophylactic treatment of diseases or conditions involving cathepsin K.

The present invention relates to methods of using compounds according to the invention and their pharmaceutically acceptable salts or the x pharmaceutically acceptable compositions for the inhibition of cathepsin K in mammals and treatment-dependent cathepsin K States, such as is described in the context of, for example, inflammation, osteoporosis, rheumatoid arthritis and osteoarthritis.

In particular, the present invention relates to a method of selective inhibition of the activity of cathepsin K in mammals, which includes an introduction to the needy in the mammal an effective ingibiruyushchego catepsin To the number of compounds according to the invention.

More specifically, this connection with the method of treatment of osteoporosis, rheumatoid arthritis and inflammation (and other diseases, as described above) in a mammal includes an introduction to the needy in the mammal, respectively, the effective amount of the compounds according to the invention.

Assume that the following examples illustrate the invention and should not be construed as limiting it. Temperature is given in °C. Unless otherwise noted, all evaporation was carried out under reduced pressure, preferably between about 15 and 100 mm Hg (=20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical techniques, for example by microanalysis and spectroscopic characteristics (e.g., MS, IR, NMR). The used abbreviations are commonly used in this technical field.

Examples

A. FMOC-1-aminocyclohexanecarboxylic acid

The title compounds is tion was obtained by well-known methods from 1-aminocyclohexanecarboxylic acid (700 mmol), FMOC-chloride (770 mmol), diisopropylethylamine (770 mmol) and 770 ml of 1 n sodium hydroxide in 950 ml of dioxane. tPL180-182°S; Rf=0,21 (CH2Cl2/MeOH, 95:5).

As the solvent instead of dioxane can be used acetonitrile.

B. Cyanomethylene FMOC-1-aminocyclohexanecarboxylic acid

Hydrochloride of 2-aminoacetonitrile (564 mmole) and triethylamine (564 mmole) was dissolved in DMF (1700 ml). Was added FMOC-1-aminocyclohexanecarboxylic acid (564 mmole), HOBt (564 mmole) and WSCD (564 mmole), the mixture was stirred at 25°With during the night. After evaporation of the solvent the residue was dissolved in a mixture of water and sodium carbonate (to ensure weakly basic conditions) and was extracted three times with ethyl acetate. The extract was washed with water, 10% citric acid, saturated salt solution, dried over magnesium sulfate and evaporated. The residue is suspended in diethyl ether, the solid was separated by filtration and dried (vacuum). Received white powder with tPL167-169°, Rf=0,27 (n-hexane:ethyl acetate =1:1).

As an alternative, the condensation reaction can be used THF as solvent and 1-chloro-3,5-dimethoxytrityl (CDMT) as activator, along with N-methylmorpholine (NMM); in this case, the product can be isolated by adding isopropylacetate and water, separating the organic phase, subsequent premiani the m with a saturated solution of salt, partial evaporation of the solvent, separation of the crystalline product by filtration and drying.

Century Cyanomethylene 1-aminocyclohexanecarboxylic acid

Dissolved cyanomethylene FMOC-1-aminocyclohexanecarboxylic acid (248 mmol) in DMF (200 ml)was added piperidine (248 ml), the mixture was stirred at room temperature for 2 hours, the Reaction mixture was poured into water (3000 ml) and was stirred for 30 minutes, the Suspension was filtered, the filtrate was acidified 4 N. hydrochloric acid and then was extracted with ethyl acetate. Was added 1 n sodium hydroxide to make the aqueous phase alkaline, and three times was extracted with a mixture of ethyl acetate. The organic fraction was dried over sodium sulfate, the solvent was evaporated. The residue was dried (vacuum)to give a pale yellow oil. Rf=0,26 (CH2Cl2:MeOH=95:5).

1H-NMR (d6-DMSO): 1,05 and 1.80 (m, 10H); 4,0 (ush. s, 2H); NH (very broad signal).

Alternative at the stage of removal of the FMOC protective group can be used THF instead of DMF and diethylamine instead of piperidine.

Example 1: synthesis of N-[1-(cyanomethylene)cyclohexyl]-4-piperazine-1-ilasamaja

A. Methyl ester 4-piperazine-1-eventing acid

Was dissolved 1-(4-cyanophenyl)piperazine (11 mmol) in 15 ml of a mixture of concentrated sulfonic acid and methanol (5 BC) and was stirred in a sealed tube at 110°in ECENA 3 hours After evaporation of the solvent the residue was dissolved in water and was extracted with ethyl acetate. The addition of sodium carbonate to the aqueous phase to pH 9 resulted in precipitation of a white solid substance was separated by filtration and dried (vacuum). Received white powder with Rf=0,59 (CH2Cl2:MeOH(+3 N. NH3)=9:1).

B. Hydrochloride 4-piperazine-1-eventing acid

Dissolved methyl ester 4-piperazine-1-eventing acid (17 mmol) in 6 N. hydrochloric acid (25 ml) and heated at boiling for 3 hours the Mixture was cooled in a bath of ice to 0-4°With the formed solid substance was separated by filtration, washed with acetone and dried (vacuum). Received white powder with tPL>240°C.

Century 4-(4-FMOC-piperazine-1-yl)benzoic acid

Dissolved hydrochloride 4-piperazine-1-eventing acid (10.5 mmole) in 15 ml of dioxane and 11.6 ml of sodium hydroxide (2 BC) and was cooled to 0°C. were Simultaneously added dropwise FMOC-chloride (to 11.6 mmole) in dioxane (5 ml) and diisopropylethylamine (to 11.6 mmole) in dioxane (5 ml) for 20 min at 0°C, the mixture was stirred for 15 min, then was allowed to warm to room temperature and was stirred overnight. The mixture was diluted with water (50 ml) and was extracted twice with diethyl ether. The aqueous phase was acidified aqueous hydrochloric acid (4 BC) at 0-4°formed of solid substances is the primary objective was separated by filtration, washed with water and dried (vacuum). Received white powder with Rf=0,2 (CH2Cl2:MeOH=95:5).

G. of N-[1-(Cyanomethylene)cyclohexyl]-4-(4-FMOC-piperazine-1-yl)benzamid

Dissolved cyanomethylene 1-aminocyclohexanecarboxylic acid (8.3 mmole), 4-(4-FMOC-piperazine-1-yl)benzoic acid (8.3 mmole), NOT (8.3 mmole) and WSCD (8.3 mmole) in DMF (20 ml) and was stirred over night at room temperature. After evaporation of the solvent the residue was dissolved in a mixture of water and sodium carbonate (to create a weakly basic conditions) and was extracted three times with ethyl acetate. The combined extract was dried over sodium sulfate and evaporated. The residue was purified flash chromatography on silica gel with a mixture of ethyl acetate/hexane (4:1) as mobile phase. The fractions containing the product were combined and evaporated. The residue is suspended in diethyl ether, the solid was separated by filtration and dried (vacuum). Received white powder with tPL192-194°, Rf=0,26 (CH2Cl2:MeOH=95:5).

D. N-[1-Cyanomethylene)cyclohexyl]-4-(piperazin-1-yl)benzamid

Was dissolved N-[1-(cyanomethylene)cyclohexyl]-4-(4-FMOC-piperazine-1-yl)benzamide (4.4 mmole) in DMF (15 ml)was added piperidine (4.4 mmole), the mixture was stirred at room temperature for 4 h was Added 4 more drops of piperidine and the mixture was stirred the night. The reaction mixture was poured into a mixture of water and ethyl acetate, the suspension was filtered, the filtrate was acidified 4 N. hydrochloric acid, then was extracted with ethyl acetate. Was added a saturated solution of sodium carbonate to make the aqueous phase is basic, the mixture was extracted three times with ethyl acetate. The aqueous phase was saturated with sodium chloride and again were extracted three times with ethyl acetate. The organic fraction was dried over sodium sulfate, the solvent was evaporated. The residue was purified flash chromatography on silica gel with a mixture of CH2Cl2:Meon(+3 N. NH3)=95:5 as mobile phase. The fractions containing the product were combined and evaporated. The residue is suspended in diethyl ether, the solid was separated by filtration and dried (vacuum). Received white powder with tPL206-210°, Rf=0,28 (CH2Cl2:MeOH(+3 N. NH3)=9:1).

1H-NMR (d6-DMSO): 1,15-1,35 (m, 1H); is 1.4-1.6 (m, 5H); of 1.65 to 1.8 (m, 2H); 2,05-of 2.15 (m, 2H); 2,8 (m, 4H); 3.15 in (m, 4H); 4.0 a (d, 2H), 6,95 (d, 2H); the 7.65 (s, 1H); of 7.75 (d, 2H), 8,15 (m, 1H).

Example 2: synthesis of N-[1-(cyanomethylene)cyclohexyl]-4-(methylpiperazin-1-yl)benzamide

A. Methyl ester of 4-(4-methylpiperazin-1-yl)benzoic acid

Methyl ester of 4-fermenting acid (34 mmole), 1-methylpiperazine (75 mmol) and potassium carbonate (34 mmole) suspended in acetonitrile (30 ml) and stirred at boiling for three days. After upari the project of the solvent the residue was dissolved in water and was extracted three times with ethyl acetate. The extract was dried over sodium sulfate and evaporated. The residue was purified flash chromatography on silica gel with a mixture of CH2Cl2:MeOH=95:5 as mobile phase. The fractions containing the product were combined and evaporated. The residue is suspended in a mixture of diethyl ether/pentane, the solid substance was separated by filtration and dried (vacuum). Received powder pale yellow color with tPL117-119°, Rf=0,20 (CH2Cl2:MeOH=95:5).

B. Hydrochloride 4-(4-methylpiperazin-1-yl)benzoic acid

Dissolved methyl ester of 4-(4-methylpiperazin-1-yl)benzoic acid (8.5 mmole) in 4 N. hydrochloric acid (15 ml) and heated at boiling for 8 hours the Mixture was cooled in a bath of ice to 0-4°C, diluted with 5 ml of acetone, the solid was separated by filtration, washed with acetone and dried (vacuum). Received white powder with tPL>270°, Rf=0,11 (CH2Cl2:MeOH=9:1).

C. N-[1-(Cyanomethylene)cyclohexyl]-4-(4-methylpiperazin-1-yl)benzamid

Cyanomethylene 1-aminocyclohexanecarboxylic acid (1,38 mmole)of the hydrochloride of 4-(4-methylpiperazin-1-yl)benzoic acid (1,38 mmole), NOT (1,38 mmole), WSCD (1,38 mmole) and triethylamine (1,38 mmole) was dissolved in DMF (5 ml) and was stirred over night at room temperature. After evaporation of the solvent the residue was dissolved in a mixture of water and sodium carbonate (to provide with obosnovanie conditions) and was extracted three times with ethyl acetate. The combined extract was dried over sodium sulfate and evaporated. The residue is suspended in diethyl ether, the solid was separated by filtration and dried (vacuum). Received whitish powder with tPL218-220°, Rf=0,19 (CH2Cl2:MeOH=9:1).

1H-NMR (d6-DMSO): 1,15-1,35 (m, 1H); is 1.4-1.6 (m, 5H); of 1.65 to 1.8 (m, 2H); 2,05-of 2.15 (m, 2H); 2,2 (s, 3H); 2,4 (m, 4H); 3,2 (m, 4H); 4.0 a (d, 2H), 6,95 (d, 2H); the 7.65 (s, 1H); 7.75 (d, 2H), 8,15 (m, 1H).

Example 3: synthesis of N-[1-(cyanomethylene)cyclohexyl]-4-(4-ethylpiperazin-1-yl)benzamide

A. Methyl ester of 4-(4-ethylpiperazin-1-yl)benzoic acid

Methyl ester of 4-fermenting acid (53 mmole), 1-ethylpiperazine (44 mmole) and potassium carbonate (44 mmole) suspended in dimethylacetamide (50 ml) and stirred at boiling during the night. After evaporation of the solvent the residue was dissolved in water and was extracted three times with ethyl acetate. The extract was dried over sodium sulfate and evaporated. The residue is suspended in a mixture of diethyl ether/pentane, the solid substance was separated by filtration and dried (vacuum). Received brownish powder with tPL102-104°C, Rf=0,22 (CH2Cl2:MeOH=95:5).

B. Hydrochloride 4-(4-ethylpiperazin-1-yl)benzoic acid

Methyl ester of 4-(4-ethylpiperazin-1-yl)benzoic acid (15 mmol) was dissolved in 4 N. hydrochloric acid (35 ml) and heated at boiling for 8 hours the Mixture was cooled in a bath of ice to 04° With the formed solid substance was separated by filtration, washed with acetone and dried (vacuum). Got the gray powder with tPL>270°, Rf=0,08 (CH2Cl2:Meon=9:1).

C. N-[1-(Cyanomethylene)cyclohexyl]-4-(4-ethylpiperazin-1-yl)benzamid

Cyanomethylene 1-aminocyclohexanecarboxylic acid (0.9 mmole)of the hydrochloride of 4-(4-ethylpiperazin-1-yl)benzoic acid (0.9 mmole), NOT (0.9 mmole), WSCD (0.9 mmole) and triethylamine (0.9 mmole) was dissolved in DMF (5 ml) and was stirred over night at room temperature. After evaporation of the solvent the residue was dissolved in a mixture of water and sodium carbonate (to ensure weakly basic conditions) and was extracted three times with ethyl acetate. The combined extract was dried over sodium sulfate and evaporated. The residue was purified flash chromatography on silica gel with a mixture of CH2Cl2:MeOH(+3 N. NH3)=93:7 as the mobile phase. The fractions containing the product were combined and evaporated. The residue is suspended in diethyl ether, the solid was separated by filtration and dried (vacuum). Received white powder.

1H-NMR (d6-DMSO): 1,0 (t, 3H), 1,15-1,35 (m, 1H); is 1.4-1.6 (m, 5H); of 1.65 to 1.8 (m, 2H); 2,05-of 2.15 (m, 2H); 2,35 (q, 2H); of 2.45 (m, 4H); 3,2 (m, 4H); 4.0 a (d, 2H), 6,95 (d, 2H); the 7.65 (s, 1H); of 7.75 (d, 2H), 8,15 (m, 1H).

Example 4: synthesis of N-[1-(cyanomethylene)cyclohexyl]-4-[4-(1-propyl)piperazine-1-yl]benzamide

A. Marked the initial ester 4-[4-(1-propyl)piperazine-1-yl]benzoic acid

Methyl ester of 4-fermenting acid (165 mmol), dihydrobromide 1-(1-propyl)piperazine (138 mmol) and potassium carbonate (690 mmol) suspended in dimethylacetamide (320 ml) and stirred at boiling during the night. After evaporation of the solvent the residue was dissolved in water and was extracted three times with ethyl acetate. The extract was dried over sodium sulfate and evaporated. The residue is suspended in a mixture of diethyl ether/pentane, the solid substance was separated by filtration and dried (vacuum). Received brownish powder with tPL99-101°C, Rf=0,23 (CH2Cl2:MeOH=95:5).

In the above method instead of potassium carbonate can be used cesium carbonate.

B. Hydrochloride 4-[4-(1-propyl)piperazine-1-yl]benzoic acid

Methyl ester of 4-[4-(1-propyl)piperazine-1-yl]benzoic acid (38 mmol) was dissolved in 4 N. hydrochloric acid (60 ml) and heated at boiling for 7 hours the Mixture was cooled in a bath of ice to 0-4°With the formed solid substance was separated by filtration, washed with cold water and dried (vacuum). Received whitish powder with tPL>270°, Rf=0,19 (CH2Cl2:MeOH=9:1).

Alternative 4-[4-(1-propyl)piperazine-1-yl]benzoic acid can be obtained in the form of an internal salt with acetic acid. For example, the methyl ester of 4-[4-(1-propyl)piperazine-1-yl]benzoic acid are suspended in the mixture is water/methanol at 70° With and hydrolyzed by adding 1 EQ. sodium hydroxide; the solution was osvetleni by filtration, the product is precipitated with addition of 1 EQ. acetic acid, separated by filtration and dried.

C. N-[1-(Cyanomethylene)cyclohexyl]-4-[4-(1-propyl)piperazine-1-yl)benzamid

Cyanomethylene 1-aminocyclohexanecarboxylic acid (22 mmole), hydrochloride 4-[4-(1-propyl)piperazine-1-yl]benzoic acid (22 mmole), NOT (22 mmole), WSCD (22 mmole) and triethylamine (22 mmole) was dissolved in DMF (50 ml) and was stirred over night at room temperature. After evaporation of the solvent the residue was dissolved in a mixture of water and sodium carbonate (to ensure weakly basic conditions) and was extracted three times with ethyl acetate. The combined extract was dried over sodium sulfate and evaporated. The residue was purified flash chromatography on silica gel with a mixture of (CH2Cl2:MeOH=9:1) as mobile phase. The fractions containing the product were combined and evaporated. The residue is suspended in diethyl ether, the solid was separated by filtration and dried (vacuum). Received white powder with tPL216-218°C, Rf=0,34 (CH2Cl2:MeOH=9:1).

1H-NMR (d6-DMSO): of 0.85 (t, 3H), 1,2-1,3 (m, 1H); is 1.4-1.6 (m, 7H); of 1.65 to 1.8 (m, 2H); 2,05-of 2.15 (m, 2H); of 2.25 (t, 2H); of 2.45 (m, 4H); 3,2 (m, 4H); 4.0 a (d, 2H), 6,95 (d, 2H); the 7.65 (s, 1H); of 7.75 (d, 2H), 8,15 (m, 1H).

Alternative methods of internal salt of acetic acid is 4-[4-(1-propyl)piperazine-1-yl)benzoic acid in acetonitrile was treated with NOWT, NMM (nitrosomethylurea) and diisopropylcarbodiimide (DICI), after stirring for 1 h at 40°C was added a solution of cyanoethylated 1-aminocyclohexanecarboxylic acid in acetonitrile. Upon completion of the reaction product is precipitated with addition of water to the reaction mixture, was filtered and the subsequent sopariwala with ethanol final dried product.

Example 5: synthesis of N-[1-(cyanomethylene)cyclohexyl]-4-(4-isopropylpiperazine-1-yl)benzamide

A. Methyl ester 4-[4-isopropylpiperazine-1-yl]benzoic acid

Tris(dibenzylideneacetone)dipalladium (0.05 mmole), (2'-dicyclohexylphosphino-2-yl)dimethylamine (0.1 mmole) and potassium carbonate (4.6 mmole) suspended in 1,2-dimethoxyethane (10 ml) in an atmosphere of N2that does not contain oxygen. Was added methyl ether 4-bromobenzoyl acid (3.3 mmole) and 1-isopropylpiperazine (3.9 mmole), stir the mixture was heated at boiling within 28 hours After cooling, the solvent was evaporated, to the residue was added water, then was extracted three times with ethyl acetate. The combined extract was dried over sodium sulfate and evaporated. The residue was purified flash chromatography on silica gel with a mixture of CH2Cl2:MeOH=95:5 as mobile phase. The fractions containing the product were combined and evaporated. The residue is suspended in a mixture of diethyl ether/pentane, the solid is about delali by filtration and dried (vacuum). Received powder pale brown with Rf=0,23 (CH2Cl2:MeOH=95:5).

B. Hydrochloride 4-(4-isopropylpiperazine-1-yl)benzoic acid

Methyl ester of 4-(4-isopropylpiperazine-1-yl)benzoic acid (0.9 mmole) was dissolved in 4 N. hydrochloric acid (2 ml) and heated at boiling for 7 hours the Mixture was cooled in a bath of ice to 0-4°and added acetone. The formed solid substance was separated by filtration, washed with cold acetone and dried (vacuum). Received powder pale brown with tPL>270°, Rf=0,08 (CH2Cl2:MeOH=9:1).

C. N-[1-(Cyanomethylene)cyclohexyl]-4-(4-isopropylpiperazine-1-yl)benzamid

Cyanomethylene 1-aminocyclohexanecarboxylic acid (0.6 mmole)of the hydrochloride of 4-(4-isopropylpiperazine-1-yl)benzoic acid (0.6 mmole), NAWT (0.6 mmole), WSCD (0.6 mmole) and triethylamine (0.6 mmole) was dissolved in DMF (2 ml) and was stirred over night at room temperature. After evaporation of the solvent the residue was dissolved in a mixture of water and sodium carbonate (to ensure weakly basic conditions) and was extracted three times with ethyl acetate. The combined extract was dried over sodium sulfate and evaporated. The residue is suspended in a mixture of ethyl acetate/diethyl ether, the solid was separated by filtration and dried (vacuum). Received white powder with tPL218-220°C Rsub> f=0,28 (CH2Cl2:MeOH=9:1).

1H-NMR (d6-DMSO): 1,0 (d, 6N), 1,2-1,3 (m, 1H); is 1.4-1.6 (m, 5H); of 1.65 to 1.8 (m, 2H); 2,05-of 2.15 (m, 2H); of 2.45 (m, 4H); to 2.65 (m, 1H); 3,2 (m, 4H); 4.0 a (d, 2H), 6,95 (d, 2H); the 7.65 (s, 1H); of 7.75 (d, 2H), 8,15 (m, 1H).

Example 6: synthesis of N-[1-(cyanomethylene)cyclohexyl]-4-(4-benzylpiperazine-1-yl)benzamide

A. Methyl ester 4-[4-benzylpiperazine-1-yl)benzoic acid

Suspended Tris(dibenzylideneacetone)dipalladium (0.03 mmole), (2'-dicyclohexylphosphino-2-yl)dimethylamine (0.9 mmole) and tert-butyl sodium (6.5 mmole) in toluene (20 ml) in an atmosphere without oxygen (N2). Was added methyl ether 4-bromobenzoyl acid (4,65 mmole) and 1-(benzyl)piperazine (5.6 mmole), stir the mixture was heated at boiling for 4 hours, After cooling, was added a mixture of ethyl acetate and diethyl ether, the mixture was filtered. Then the solvent was evaporated, the residue suspended in diethyl ether, the solid was separated by filtration and dried (vacuum). Received whitish powder with tPL105-107°C, Rf=0,67 (CH2Cl2:Meon=95:5).

B. Hydrochloride 4-(4-benzylpiperazine-1-yl)benzoic acid

Methyl ester of 4-(4-benzylpiperazine-1-yl)benzoic acid (from 0.84 mmole) was dissolved in 4 N. hydrochloric acid (2 ml) and heated at boiling for 8 hours the Mixture was cooled in a bath of ice to 0-4°With the formed solid substance was separated by filtration, washed and cold acetone and dried (vacuum). Got the gray powder with tPL>270°, Rf=0,18 (CH2Cl2:MeOH=95:5).

C. N-[1-(Cyanomethylene)cyclohexyl]-4-(4-benzylpiperazine-1-yl)benzamid

Cyanomethylene 1-aminocyclohexanecarboxylic acid (from 0.84 mmole), hydrochloride 4-[4-(2-propyl)piperazine-1-yl]benzoic acid (from 0.84 mmole), NOT (from 0.84 mmole), WSCD (from 0.84 mmole) and triethylamine (from 0.84 mmole) was dissolved in DMF (2 ml) and was stirred over night at room temperature. After evaporation of the solvent the residue was dissolved in a mixture of water and sodium carbonate (to ensure weakly basic conditions) and was extracted three times with ethyl acetate. The combined extract was dried over sodium sulfate and evaporated. The residue is suspended in methanol, the solid was separated by filtration and dried (vacuum). Received whitish powder with tPL210-212°, Rf=0,20 (CH2Cl2:MeOH=95:5).

1H-NMR (d6-DMSO): 1,15-1,35 (m, 1H); is 1.4-1.6 (m, 5H); of 1.65 to 1.8 (m, 2H); 2,05-of 2.15 (m, 2H); of 2.45 (m, 4H); 3,2 (m, 4H); 3,5 (s, 2H); 4.0 a (d, 2H), 6,9 (d, 2H); of 7.2 to 7.4 (m, 5H), the 7.65 (s, 1H); of 7.75 (d, 2H), 8,15 (m, 1H).

Example 7: synthesis of N-[1-(cyanomethylene)cyclohexyl]-4-[4-(2-methoxyethyl)piperazine-1-yl]benzamide

A. Methyl ester of 4-(4-benzylpiperazine-1-yl)benzoic acid

Methyl ester of 4-fermenting acid (200 mmol), 1-benzylpiperazine (300 mmol) and potassium carbonate (300 mmol) suspended in acetonitrile (400 ml) and stirred pricitanie for 6 days. After evaporation of the solvent the residue was dissolved in water and was extracted three times with diethyl ether. The extract was dried over sodium sulfate and evaporated. The residue was purified flash chromatography on silica gel (CH2Cl2first, then CH2Cl2:MeOH=15:1) as mobile phase. The fractions containing the product were combined and evaporated. The residue is suspended in a mixture of diethyl ether/pentane, the solid substance was separated by filtration and dried (vacuum). Received powder with tPL105-107°C.

B. Methyl ester 4-(piperazine-1-yl)benzoic acid

Methyl ester of 4-(4-benzylpiperazine-1-yl)benzoic acid (to 19.4 mmole) was dissolved in methanol (150 ml) was added Pd/C (0.6 g). The mixture was stirred in hydrogen atmosphere until it ceases to absorb. The catalyst was removed by filtration, the filtrate was evaporated. The residue is suspended in a mixture of diethyl ether/pentane, the solid substance was separated by filtration and dried (vacuum). Received powder with tPL95-97°C.

Century Methyl ester [4-(2-methoxyethyl)piperazine-1-yl]benzoic acid

Methyl ester of 4-(piperazine-1-yl)benzoic acid (19 mmol), 2-bromatology ether (21 mmol) and potassium carbonate suspended in acetonitrile (950 ml) and stirred at 80°within 8 hours After evaporation of the solvent the residue was dissolved in water and was extracted three times Meiling what oredom. The extract was dried over sodium sulfate and evaporated. The residue is suspended in a mixture of diethyl ether/pentane, the solid substance was separated by filtration and dried (vacuum). Received powder with tPL103-105°C.

He Hydrochloride [4-(2-methoxyethyl)piperazine-1-yl]benzoic acid

Methyl ester [4-(2-methoxyethyl)piperazine-1-yl]benzoic acid (17 mmol) was dissolved in 4 N. hydrochloric acid and heated at boiling for 5 hours After cooling, the solvent was evaporated, the residue suspended in ethanol, the solid was separated by filtration, washed with diethyl ether and dried (vacuum). Received powder with tPL>270°, Rf=0,35 (CH2Cl2:MeOH=9:1).

D. N-[1-(Cyanomethylene)cyclohexyl]-4-[4-(2-methoxyethyl)piperazine-1-yl]benzamide

Cyanomethylene 1-aminocyclohexanecarboxylic acid (1.0 mmol), hydrochloride [4-(2-methoxyethyl)piperazine-1-yl]benzoic acid (1.0 mmol), NAWT (1.0 mmol), WSCD (1.0 mmol) and triethylamine (1.0 mmol) was dissolved in DMF (4 ml) and was stirred over night at room temperature. After evaporation of the solvent the residue was dissolved in a mixture of water and sodium carbonate (to ensure weakly basic conditions) and was extracted three times with ethyl acetate. The combined extract was dried over sodium sulfate and evaporated. The residue was purified flash chromatography on silica gel with a mixture of CH2 Cl2/MeOH (92,5:7,5) as a mobile phase. The fractions containing the product were combined and evaporated. The residue is suspended in diethyl ether, the solid was separated by filtration and dried (vacuum). Received whitish powder with tPL166-168°, Rf=0,37 (CH2Cl2:MeOH=9:1).

1H-NMR (d6-DMSO): 1,15-1,35 (m, 1H); is 1.4-1.6 (m, 5H); of 1.65 to 1.8 (m, 2H); 2,05-of 2.15 (m, 2H); of 2.45 (m, 6H); 3,2 (m, 7H); of 3.45 (t, 2H); 4.0 (d, 2H), 6,95 (d, 2H); the 7.65 (s, 1H); of 7.75 (d, 2H), 8,15 (m, 1H).

Example 8: synthesis of N-[1-(cyanomethylene)cyclohexyl]-4-(1-propylpiperidine-4-yl)benzamid

A. 1-(4-Phenylpiperazin-1-yl)alanon

Dissolved 4-phenylpiperidine (87 mmol) and pyridine (96 mmol) in anhydrous methylene chloride (100 ml) and stir the solution was added dropwise at 10°With acetylchloride (96 mmol) in methylene chloride (40 ml). The reaction mixture was stirred for 1 h at room temperature. The mixture was extracted three times with water, the aqueous phase was again extracted with methylene chloride. The combined organic phases were dried over sodium sulfate and evaporated. Got a pale-brown oil with Rf=0,13 (ethyl acetate/hexane, 1:1).

B. 4-piperidine-4-Albertina acid

Was dissolved 1-(4-phenylpiperazin-1-yl)alanon (84 mmole) in methylene chloride (250 ml) and was added dropwise oxalicacid (336 mmol) at a temperature of from -20 to -10°C. After adding oxalicacid added portions of trahal rusty aluminum (260 mmol) at -10° C. the Mixture was stirred at -10°C for 3 hours the Cooling bath was removed and the mixture was stirred over night at room temperature. The reaction mass was poured into a mixture of ice/water (600 ml) and was extracted three times with methylene chloride. The combined organic phases are washed with water, dried over sodium sulfate and evaporated. The residue was dissolved in aqueous sodium hydroxide solution (2 N., 250 ml) was added at 0°6 N. hydrochloric acid to acidify the solution. The precipitate was separated by filtration and washed with water. The solid is suspended in 6 N. hydrochloric acid, the mixture was heated at boiling for 18 hours After cooling to room temperature the solvent was removed, the residue is suspended in ethanol. A solid substance was separated by filtration and dried. Got brown powder with tPL>270°C.

C. Methyl ether 4-piperidine-4-eventing acid

Dissolved 4-piperidine-4-eventing acid (47 mmol) in methanol (300 ml) was added 1 ml of concentrated sulfonic acid. The mixture was heated at boiling during the night. After evaporation of the solvent the residue was dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and was extracted three times with ethyl acetate. The combined extract was dried over sodium sulfate and evaporated. Got the powder brown is Board with R f=0,18 (CH2Cl2:MeOH=9:1).

, Methyl ester 4-(1-propylpiperidine-4-yl)benzoic acid

Methyl ester of 4-piperidine-4-eventing acid (28 mmol), ethylisopropylamine (31 mmol) and 1-iodopropane (42 mmole) was dissolved in 1,2-dimethoxyethane (100 ml) and the mixture was heated at 70°With during the night. After evaporation of the solvent the residue was dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and was extracted three times with ethyl acetate. The combined extract was dried over sodium sulfate and evaporated. The residue was purified flash chromatography on silica gel with CH2Cl2:MeOH=9:1 as mobile phase. The fractions containing the product were combined and evaporated. The residue is suspended in diethyl ether, the solid was separated by filtration and dried (vacuum). Received powder pale brown with Rf=0,35 (CH2Cl2:MeOH=9:1).

D. Hydrochloride 4-(1-propylpiperidine-4-yl)benzoic acid

Methyl ester of 4-(1-propylpiperidine-4-yl)benzoic acid (32 mmole) was dissolved in 4 N. hydrochloric acid (45 ml) and heated at boiling for 7 hours the Mixture was cooled in a bath of ice to 0-4°With the formed solid substance was separated by filtration, washed with cold acetone and dried (vacuum). Got brown powder with tPL>270°C, Rf=0,08 (CH2Cl2:MeOH=9:1).

E. N-[1-(t is animationname)cyclohexyl]-4-(1-propylpiperidine-4-yl)-benzamide

Cyanomethylene 1-aminocyclohexanecarboxylic acid (23 mmole)of the hydrochloride of 4-(1-propylpiperidine-4-yl)benzoic acid (23 mmole), NOT (23 mmole), WSCD (23 mmole) and triethylamine (23 mmole) was dissolved in DMF (50 ml) and was stirred over night at room temperature. After evaporation of the solvent the residue was dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and was extracted three times with ethyl acetate. The combined extract was dried over sodium sulfate and evaporated. The residue is suspended in a mixture of diethyl ether/pentane, the solid substance was separated by filtration and dried (vacuum). Received whitish powder with tPL198-200°, Rf=0,34 (CH2Cl2:MeOH=9:1).

1H-NMR (d6-DMSO): of 0.85 (t, 3H); 1,2-1,3 (m, 1H); is 1.4-1.6 (m, 7H); of 1.6-1.8 (m, 6N); 1,9-2,0 (m, 2H); 2,05-of 2.15 (m, 2H); of 2.25 (t, 2H); to 2.55 (m, 1H); 2.95 and (d, 2H); 4.0 a (d, 2H), 7,35 (d, 2H); 7,8 (d, 2H), 7,9 (s, 1H); 8,15 (m, 1H).

Example 9: synthesis of N-[1-(cyanomethylene)cyclohexyl]-4-[1-(2-methoxyethyl)piperidine-4-yl]benzamide

A. Methyl ester 4-carboxyaniline acid

Dissolved 4-carboxyphenylazo acid (300 mmol) in methanol (400 ml) and stir the solution was added 1.5 ml of concentrated hydrochloric acid. The reaction mixture was heated at boiling for 30 hours the Solvent was evaporated, the resulting residue is suspended in diethyl ether, the solid was separated, filtered the eating and dried (vacuum). Received whitish powder with tPL201-205°, Rf=0,28 (CH2Cl2:MeOH=95:5). This powder is a mixture of the methyl ester 4-carboxyaniline acid and dimeric anhydride methyl ester 4-carboxyaniline acid was used without further purification.

B. Methyl ester 4-pyridin-4-eventing acid

Methyl ester of 4-carboxybenzeneboronic acid (248 mmol) of section a, 4-bromopyridin (248 mmol), tetrakis(triphenylphosphine)palladium (2.5 mmole) and potassium carbonate (744 mmole) suspended in 1,2-dimethoxyethane (1100 ml). Stir the mixture was heated at boiling for 8 hours After cooling, the solvent was evaporated, to the residue was added water and then was extracted three times with ethyl acetate. The combined extract was dried over sodium sulfate and evaporated. The residue is suspended in diethyl ether, the solid was separated by filtration and dried (vacuum). Got the powder is light brown with tPL99-101°C, Rf=0,39 (CH2Cl2:Meon=95:5).

Century 4-(4-Ethoxycarbonylphenyl)-1-(2-methoxyethyl)pyridineboronic

Methyl ester 4-pyridin-4-eventing acid (70 mmol) and 2-bromatology ether (28 ml) was heated for 1 h at 110°C. After cooling, the reaction mixture is suspended in acetone, the solid was separated by filtration and dried (vacuum). Received powder is to pale brown with t PL170-171°, Rf=0,22 (CH2Cl2:MeOH=9:1).

, Methyl ester 4-[1-(2-methoxyethyl)piperidine-4-yl]benzoic acid

Suspended 4-(4-ethoxycarbonylphenyl)-1-(2-methoxyethyl)pyridineboronic (67 mmol) in methanol (250 ml) was added platinum oxide (1.2 g). The mixture was stirred in hydrogen atmosphere at normal pressure until the cessation of hydrogen absorption. The catalyst was removed by filtration, the filtrate was evaporated. The residue was dissolved in methylene chloride and was extracted with an aqueous solution of sodium carbonate. The organic phase was dried over sodium sulfate and evaporated. The residue was purified flash chromatography on silica gel with a mixture of CH2Cl2:MeOH=9:1 as mobile phase. The fractions containing the product were combined and evaporated. Got the oil is pale yellow in color with Rf=0,22 (CH2Cl2:MeOH=95:5).

D. Hydrochloride 4-[1-(2-methoxyethyl)piperidine-4-yl]benzoic acid

Methyl ester of 4-[1-(2-methoxyethyl)piperidine-4-yl]benzoic acid (47 mmol) was dissolved in 4 N. hydrochloric acid (80 ml) and heated at boiling for 12 hours After cooling, the solvent was evaporated, the residue is suspended in acetone, the solid was separated by filtration, washed with acetone and dried (vacuum). Received white powder with tPL>270°C.

E. N-[1-(Cyanomethylene)cyclohexyl]-4-[1-(2-methoxyethyl)piperid is n-4-yl]benzamide

Cyanomethylene 1-aminocyclohexanecarboxylic acid (107 mmol), hydrochloride 4-[1-(2-methoxyacridine-4-yl]benzoic acid (107 mmol), NOT (107 mmol), WSCD (107 mmol) and triethylamine (107 mmol) was dissolved in DMF (250 ml) and was stirred over night at room temperature. After evaporation of the solvent the residue was dissolved in a mixture of water and sodium carbonate (to ensure weakly basic conditions) and was extracted three times with ethyl acetate. The combined extract was dried over sodium sulfate and evaporated. The residue was purified flash chromatography on silica gel with a mixture of CH2Cl2:MeOH(2 N. NH3)=9:1 as mobile phase. The fractions containing the product were combined and evaporated. The residue is suspended in a mixture of diethyl ether/ethyl acetate, the solid was separated by filtration and dried (vacuum). Received whitish powder with tPL160-162°C, Rf=0,42 (CH2Cl2:MeOH(3 N. NH3)=9:1).

1H-NMR (d6-DMSO): 1,2-1,3 (m, 1H); is 1.4-1.6 (m, 5H); of 1.6-1.8 (m, 6H); of 2.0-2.2 (m, 4H); of 2.45 (m, 2H); to 2.55 (m, 1H); 2.95 and (ush. d, 2H); 3,2 (s, 3H); 3,4 (dd, 2H); 4.0 a (d, 2H); to 7.35 (d, 2H); 7,8 (d, 2H); and 7.9 (s, 1H); 8,15 (m, 1H).

Example 10: N-[1-(cyanomethylene)cyclohexyl]-4-(1-isopropylpiperazine-4-yl)benzamid

A. 1-Isopropyl-4-(4-ethoxycarbonylphenyl)pyridineboronic

Methyl ester 4-pyridin-4-eventing acid (2.3 mmole) and 2-iodopropane (1.0 ml) was heated for 24 h at 90°C. On the Les cooling, the solvent was evaporated, the residue is suspended in acetone, the solid was separated by filtration and dried (vacuum). Received powder pale yellow color with tPL187-189°, Rf=0,27 (CH2Cl2:MeOH=9:1).

B. Hydroiodide methyl ester 4-(1-isopropylpiperazine-4-yl)benzoic acid

Suspended 1-isopropyl-4-(4-ethoxycarbonylphenyl)pyridineboronic (1.9 mmole) in methanol (10 ml) was added platinum oxide (980 mg). The mixture was stirred in hydrogen atmosphere at normal pressure until the cessation of hydrogen absorption. The catalyst was removed by filtration, the filtrate was evaporated. The residue is suspended in a mixture of diethyl ether/pentane, the solid substance was separated by filtration and dried (vacuum). Received whitish powder with tPL219-224°C, Rf=0,41 (CH2Cl2:MeOH=9:1).

C. the Hydrochloride of 4-(1-isopropylpiperazine-4-yl)benzoic acid

Dissolved hydroiodide methyl ester 4-(1-isopropylpiperazine-4-yl)benzoic acid 4 N. hydrochloric acid (5 ml) and heated at boiling for 10 hours After cooling, the solvent was evaporated, the residue is suspended in acetone, the solid was separated by filtration, washed with acetone and dried (vacuum). Received powder gray-brown color with tPL>270°C.

G. of N-[1-(Cyanomethylene)cyclohexyl-4-(1-isopropylpiperazine-4-yl)benzamid

Cyanomethylene 1-aminocyclo hexacarbonyl acid (0.95 mmole), the hydrochloride of 4-(1-isopropylpiperazine-4-yl]benzoic acid (0.95 mmole), NOT (0.95 mmole), WSCD (0.95 mmole) and triethylamine (0.95 mmole) was dissolved in DMF (5 ml) and was stirred over night at room temperature. After evaporation of the solvent the residue was dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and was extracted three times with ethyl acetate. The combined extract was dried over sodium sulfate and evaporated. The residue is suspended in diethyl ether, the solid was separated by filtration and dried (vacuum). Received white powder with tPL214-216°, Rf=0,38 (CH2Cl2:MeOH(3 N. NH3)=9:1).

1H-NMR (d6-DMSO): 0,95 (d, 6N); 1,2-1,3 (m, 1H); 1,4-1,8 (m, 11H); 2,05 was 2.25 (m, 4H); to 2.55 (m, 1H); to 2.7 (m, 1H); 2,85 (d, 2H); 4.0 a (d, 2H), 7,35 (d, 2H); 7,8 (d, 2H), and 7.9 (s, 1H); 8,15 (m, 1H).

Example 11: N-[1-(cyanomethylene)cyclohexyl]-4-(1-cyclopentenopyridine-4-yl)benzamid

A. 1-Cyclopentyl-4-(4-ethoxycarbonylphenyl)pyridineboronic

Methyl ester 4-pyridin-4-eventing acid (2,35 mmole) and 1-itselemental (1.0 ml) was heated for 4 h at 110°C. were Added itselemental (0.5 ml) and the mixture was heated for a further 4 h at 120°C. After cooling, the solvent was evaporated, the residue is suspended in acetone, the solid was separated by filtration and dried (vacuum). The solid residue was purified flash chromatography on silica gel with cm is sue CH 2Cl2:MeOH=9:1 as mobile phase. The fractions containing the product were combined and evaporated. The residue is suspended in diethyl ether, the solid was separated by filtration and dried (vacuum). Received a yellow powder with tPL183-185°, Rf=0,35 (CH2Cl2:MeOH=9:1).

B. Hydroiodide methyl ester 4-(1-cyclopentenopyridine-4-yl)benzoic acid

Suspended 1-cyclopentyl-4-(4-ethoxycarbonylphenyl)pyridineboronic (1,27 mmole) in methanol (8 ml) was added platinum oxide (50 mg). The mixture was stirred in hydrogen atmosphere at normal pressure until the cessation of hydrogen absorption. The catalyst was removed by filtration, the filtrate was evaporated. The residue is suspended in a mixture of diethyl ether/pentane, the solid substance was separated by filtration and dried (vacuum). Received whitish powder with tPL204-210°, Rf=0,27 (CH2Cl2:Meon=95:5).

C. the Hydrochloride of 4-(1-cyclopentenopyridine-4-yl)benzoic acid

The hydrochloride of the methyl ester of 4-(1-cyclopentenopyridine-4-yl)benzoic acid (1,06 mmole) was dissolved in 4 N. hydrochloric acid (5 ml) and heated at boiling for 10 hours After cooling, the solvent was evaporated, the residue is suspended in acetone, the solid was separated by filtration, washed with acetone and dried (vacuum). Received powder gray-brown color with tPL >270°C.

G. of N-[1-(Cyanomethylene)cyclohexyl]-4-(1-cyclopentenopyridine-4-yl)benzamid

Cyanomethylene 1-aminocyclohexanecarboxylic acid (0,74 mmole)of the hydrochloride of 4-(1-cyclopentenopyridine-4-yl)benzoic acid (0,74 mmole), NOT (0,74 mmole), WSCD (0,74 mmole) and triethylamine (0,74 mmole) was dissolved in DMF (5 ml) and was stirred over night at room temperature. After evaporation of the solvent the residue was dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and was extracted three times with ethyl acetate. The combined extract was dried over sodium sulfate and evaporated. The residue is suspended in diethyl ether, the solid was separated by filtration and dried (vacuum). Received white powder with tPL233-234°C, Rf=0,34 (CH2Cl2:Meon(3 N. NH3)=9:1).

1H-NMR (d6-DMSO): 1,2-1,85 (m, 20H); 1,9-of 2.15 (m, 4H); 2.4 to a 2.6 (m, 2H); 3,05 (d, 2H); 4.0 a (d, 2H), 7,35 (d, 2H); 7,8 (d, 2H), and 7.9 (s, 1H); 8,15 (m, 1H).

Example 12: N-[1-(cyanomethylene)cyclohexyl]-4-(1-methylpiperidin-4-yl)benzamid

A. 4-Phenyl-1-methylpiperidin

Suspended 4-phenylpiperidine (12.4 mmole), paraformaldehyde (24.8 mmole) and tetraisopropoxide (12.4 mmole) in 1,2-dimethoxyethane (20 ml)was heated to 60°C for 30 min and stirred at room temperature for an additional 1 h Portions were added natrojarosite (12.4 mmole), the mixture peremeci the Ali at room temperature for 2 h and at 60° C for an additional 3 hours After cooling, the solvent was evaporated, the residue was dissolved in a mixture of aqueous ammonia (60 ml) and ethyl acetate and carefully filtered. The mixture was extracted three times with ethyl acetate, the combined organic phases were dried over sodium sulfate and evaporated. Got the oil is pale brown.

B. Methyl ester of 4-(1-methylpiperidin-4-yl)benzoic acid

Dissolved 4-phenyl-1-methylpiperidin (9,9 mmole) in methylene chloride (60 ml) and was added dropwise oxalicacid (39.6 mmole) at a temperature of from -20 to -10°C. After adding oxalicacid was added in portions at -10°With aluminum trichloride. The mixture was stirred at -10°for 1.5 hours Then the cooling bath was removed, and the mixture was stirred at room temperature for additional 2 hours, the Mixture was again cooled to 0°and dropwise added methanol (30 ml). Upon completion of the addition of methanol cooling bath was removed and the mixture was stirred at room temperature overnight. The reaction mass was poured into a mixture of aqueous sodium carbonate (to ensure basic conditions) and ethyl acetate, the suspension was carefully filtered. The filtrate was extracted three times with ethyl acetate, the combined extracts were dried over anhydrous sodium sulfate and evaporated. The residue was purified flash chromatography on silica gel with a mixture of CH2Cl2:MeH=9:1 as mobile phase. The fractions containing the product were combined and evaporated. Got the butter yellow with Rf=0,29 (CH2Cl2:MeOH=9:1).

C. the Hydrochloride of 4-(1-methylpiperidin-4-yl)benzoic acid

Methyl ester of 4-(1-methylpiperidin-4-yl)benzoic acid (4,55 mmole) was dissolved in 4 N. hydrochloric acid (10 ml) and heated at boiling for 8 hours After cooling, the solvent was evaporated, the residue is suspended in acetone, the solid was separated by filtration, washed with acetone and dried (vacuum). Received powder pale brown with tPL>270°C.

G. of N-[1-(Cyanomethylene)cyclohexyl]-4-(1-methylpiperidin-4-yl)benzamid

Cyanomethylene 1-aminocyclohexanecarboxylic acid (0,98 mol), hydrochloride 4-(1-methylpiperidin-4-yl)benzoic acid (0,98 mmole), NOT (0,98 mmole), WSCD (0,98 mmole) and triethylamine (0,98 mmole) was dissolved in DMF (5 ml) and was stirred over night at room temperature. After evaporation of the solvent the residue was dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and was extracted three times with ethyl acetate. The combined extract was dried over sodium sulfate and evaporated. The residue is suspended in a mixture of diethyl ether/pentane, the solid substance was separated by filtration and dried (vacuum). Received white powder with tPL215-217°, Rf=0,34 (CH2Cl2:MeO is(3 N. NH3)=9:1).

1H-NMR (d6-DMSO): 1,2-1,3 (m, 1H); 1,4-1,8 (m, 11H); 1.85 to 2.0 a (m, 2H); 2,05-2,2 (m, 5H); to 2.55 (m, 1H); 2.95 and (d, 2H); 4.0 a (d, 2H), 7,35 (d, 2H); 7,8 (d, 2H), and 7.9 (s, 1H); 8,15 (m, 1H).

This image was obtained N-[1-(cyanomethylene)cyclohexyl]-4-(piperidine-4-yl)benzamid, essentially as described above in example 12, for example, excluding the stage and the initial synthetic methodology for the phase B, using 4-phenylpiperidine as the original substance.

1. The compound of formula II, or its pharmaceutically acceptable salt, or ester

where X denotes CH or N, and

R means (C1-C7)(ness.)alkyl, (C1-C7)(ness.)alkoxy(C1-C7)(ness.)alkyl, (C5-C10)aryl(C1-C7)(ness.)alkyl, or (C3-C8)cycloalkyl.

2. The compound according to claim 1, or its pharmaceutically acceptable salt, or ester selected from the

N-[1-(cyanomethylene)cyclohexyl]-4-(piperazine-1-yl)benzamide;

N-[1-(cyanomethylene)cyclohexyl]-4-(4-methylpiperazin-1-yl)benzamide;

N-[1-(cyanomethylene)cyclohexyl]-4-(4-ethylpiperazin-1-yl)benzamide;

N-[1-(cyanomethylene)cyclohexyl]-4-[4-(1-propyl)piperazine-1-yl]benzamide;

N-[1-(cyanomethylene)cyclohexyl]-4-(4-isopropylpiperazine-1-yl)benzamide;

N-[1-(cyanomethyl rebamol)cyclohexyl]-4-(4-benzylpiperazine-1-yl)benzamide;

N-[1-(cyanomethylene)cyclohexyl]-4-[4-(2-methoxyethyl)piperazine-1-yl]-benzamide;

N-[1-(cyanomethylene)cyclohexyl]-4-(1-propylpiperidine-4-yl)benzamide;

N-[1-(cyanomethylene)cyclohexyl]-4-[1-(2-methoxyethyl)piperidine-4-yl]-benzamide;

N-[1-(cyanomethylene)cyclohexyl]-4-(1-isopropylpiperazine-4-yl)benzamide;

N-[1-(cyanomethylene)cyclohexyl]-4-(1-cyclopentenopyridine-4-yl)benzamide;

N-[1-(cyanomethylene)cyclohexyl]-4-(1-methylpiperidin-4-yl)benzamide

and

N-[1-(cyanomethylene)cyclohexyl]-4-(piperidine-4-yl)benzamide.

3. N-[1-(Cyanomethylene)cyclohexyl]-4-[4-(1-propyl)piperazine-1-yl]benzamide, or its pharmaceutically acceptable salt, or ester.

4. The compound according to claim 1, having the ability to inhibit cathepsin To and intended for use as pharmaceuticals.

5. The pharmaceutical composition capable of inhibiting cathepsin To, including a connection according to claim 1 as an active ingredient.

6. The method of obtaining the compounds of formula II according to claims 1, 2 or 3, or its salt or a complex ester, which involves the condensation of the corresponding Het-substituted derivative of benzoic acid of formula III

in which Deputy Het denotes

< num="239">

R and X have the meanings indicated in claim 1,

with cyanomethylation 1-aminocyclohexanecarboxylic acid.



 

Same patents:

The invention relates to benzamide derivative of the formula I

< / BR>
where R3represents (1-6C)alkyl or halogen; Q is aryl or heteroaryl, which optionally carries 1, 2, 3, or 4 substituent selected from hydroxy, halogen, cyano, nitro, amino, carboxy, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-3C)alkylenedioxy, (1-6C)alkylamino and so on; R2- (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino or di-[(1-6C)alkyl]amino; p is 0, 1 or 2; q = 0, 1, 2, 3 or 4; R4- aryl, aryl-(1-6C)alkoxy, aryloxy, arylamino, cycloalkyl or heteroaryl and R4optionally carries 1, 2, 3, or 4 substituent selected from halogen, cyano, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino and so on, or its pharmaceutically acceptable salt, or cleaved in vivo ester

The invention relates to nitrogen-containing compounds that may constitute the active ingredient of the pharmaceutical composition active as an antagonist neirokinina, and more particularly to a derivative of arylpyrimidines and pharmaceutical compositions containing these compounds

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

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

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14 cl, 36 ex

The invention relates to new derivatives of 1,2,3,4-tetrahydronaphthalene formula (I) as (R)-enantiomers, (S)-enantiomers or racemates, in the form of free base or pharmaceutically acceptable salt or solvate, where X is N or CH; Y is NR2-CH2, NR2-CO or CO-NR2; R2represents N or C1-C6-alkyl; R1represents N or C1-C6-alkyl; R3represents phenyl which may be mono - or Disaese4; R4represents H, halogen, CN, CF3WITH1-C6-alkoxy, optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, or COR8; R8represents a heterocyclic ring containing one or two heteroatoms selected from N, O; R9is1-C6-alkyl, ОСНF2HE, halogen, C1-C6-alkoxy, C1-C6-alkoxy - C1-C6-alkyl

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18 cl, 1 tbl, 87 ex

FIELD: medicine; medical engineering.

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6 cl

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: improved control method, valuable medicinal properties of compounds.

9 cl, 5 sch, 36 tbl, 70 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted 2-aryl-3-(heteroaryl)imidazo[1,2-a]-pyrimidines of the formula (I):

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EFFECT: valuable medicinal properties of compounds and compositions.

40 cl, 1 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds and compositions.

40 cl, 1 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds.

FIELD: medicine, phytotherapy, pharmaceutical industry, pharmacy.

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EFFECT: valuable medicinal properties of extract.

4 cl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: improved method for inhibition, valuable medicinal properties of compounds.

33 cl, 7 tbl, 42 ex

FIELD: peptides, pharmacy.

SUBSTANCE: invention relates to low-molecular derivatives of peptides that are able to act as inhibitors in interaction between laminine and nidogen (interactions laminine/nidogen). Also, invention relates to a method for their preparing, pharmaceutical composition prepared on thereof and their using for preparing pharmaceutical agents, and for identification of inhibitors in interaction laminine/nidogen.

EFFECT: valuable properties of peptides.

5 cl, 12 dwg

FIELD: medicine, pharmacy.

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EFFECT: improved treatment method, enhanced and valuable properties of preparation.

5 cl, 7 ex

Antagonist npy y5 // 2264810

FIELD: medicine, pharmacology.

SUBSTANCE: the present innovation deals with applying pharmaceutical composition as an antagonist of NPY Y5 receptor that contains the compound of formula I

, moreover, it deals with compounds of formula I and method for treating obesity and suppressing food intake, as well.

EFFECT: higher efficiency of therapy.

18 cl, 13 ex, 6 tbl

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