Derivatives of 4-(phenylpiperazinylmethyl)-benzamide, method for their preparing and pharmaceutical composition based on thereof

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

SUBSTANCE: invention relates to derivatives of 4-(phenylpiperazinylmethyl)-benzamide of the general formula (I): or their salt, or separate enantiomers and their salts wherein R1 means phenyl, pyridinyl, thienyl, furanyl, imidazolyl that can be substituted possibly; R2 means ethyl and isopropyl; R3 means hydrogen, fluorine atom; R4 means -NH2, -NHSO2R5 wherein R5 means (C1-C6)-alkyl. Compounds are useful in therapy, in particular, in treatment of pain. Also, invention describes methods for synthesis of compounds of the formula (I) and a pharmaceutical composition based on thereof.

EFFECT: improved method of synthesis, valuable medicinal property of compounds and pharmaceutical composition.

12 cl, 1 tbl, 11 ex

 

The scope of the invention

The present invention relates to new compounds, to a method of production thereof, their use and pharmaceutical compositions containing these new compounds. These new compounds are useful in therapy, in particular for the treatment of pain, anxiety, and functional gastrointestinal disorders.

Prior art

δ-Receptor identified as a receptor that plays a role in many body functions, such as cardiovascular and lymphatic and bollapragada system. Therefore, ligands for δ-receptor can find potential use as analgesics and/or anti-hypertensive agents. It is also shown that ligands for δ-receptor possess immunomodulatory activity.

Identify at least three different groups of opioid receptors (μ, δ and K) now clearly established, and it is obvious that all three are located in both Central and peripheral nervous systems of many species, including humans. Analgesia was observed in various animal models when the activation of one or more than one of these receptors.

With rare exception, currently available selective δ-opioid ligands are peptidic in nature and are not suitable for injection through a system PU is her. One example ones δ-agonist SNC80 is (E.J. Bilsky et al., Journal of Pharmacology and Experimental Therapeutics, 273 (1) pp.359-366 (1995)). However, there is still a need for selective δ-agonists, possessing not only high selectivity, but also improved side effect profile.

Thus, the problem underlying the present invention was to search for new analgesics with improved analgesic effects, and with an improved side effect profile compared to today μ-agonists, as well as with improved system efficiency.

Analgesics, which have been identified and are available in the prior art have many disadvantages, namely that they have poor pharmacokinetics and not have analgesic actions for introduction through a system of paths. Also documented that the preferred connection δagonists described in this prior art, have a strong convulsive effects upon systemic administration.

The inventors have now discovered some compounds that exhibit unexpectedly superior properties, among other things, improved δ-agonistic efficacy, efficacy in vivo pharmacokinetics, bioavailability, stability in vitro and/or Bo is its low toxicity.

Summary of the invention

The new compounds of the present invention are defined by formula I

where

R1selected from any one of

(1) phenyl

(2) pyridinyl

(3) teenie

(4) furanyl

(5) imidazolyl

(6) triazolyl

(7) pyrrolyl

(8) thiazolyl

(9) pyridyl-N-oxide

where each heteroaromatic ring R1it may be possible, and independently optionally substituted by 1, 2 or 3 substituents selected from straight and branched C1-C6of alkyl, halogenated C1-C6of alkyl, NO2, CF3C1-C6alkoxy, chloro, fluorescent, bromo and iodide,

R2independently selected from ethyl and isopropyl;

R3independently selected from hydrogen, fluorescent;

R4independently selected from-OH, -NH2and-NHSO2R5; and

R5independently selected from hydrogen, -CF3and C1-C6of alkyl,

provided that when R2represents ethyl, and R3p is ecstasy a hydrogen, then R4can't be a HE.

Substitution on the heteroaromatic ring may be in any position on these ring systems.

When the phenyl ring of R1and heteroaromatic(s) ring(a) R1substituted, preferred substituents selected from any of: CF3, bromide, iodide, bromo, fluorescent and chloro, of which the most preferred methyl.

Another embodiment of the present invention, therefore, is a compound of formula I, where R1is the same as defined above, and each phenyl ring of R1and heteroaromatic ring R1may be independently optionally substituted methyl group.

Another embodiment of the present invention is a compound of formula I, where R1represents phenyl, pyrrolyl, furanyl, thienyl or imidazolyl: R2represents ethyl or isopropyl; R3represents hydrogen or fluorescent; R4represents-NH2or-NHSO2R5; and R5represents a C1-C6the alkyl may have 1 or 2 of the preferred substituents on the phenyl ring of R1or heteroaromatic ring R1.

An additional embodiment of the present invention is a compound of formula I, where R1represents phenyl, pyrrolyl, f is wounded, thienyl or imidazolyl; R2represents ethyl or isopropyl; R3represents hydrogen; R4represents-NHSO2R5; and R5represents a C1-C6the alkyl may have 1 or 2 of the preferred substituents on the phenyl ring of R1or heteroaromatic ring R1.

Other embodiments of the present invention are the compounds of formula I, where (a) R1represents phenyl, pyrrolyl or furanyl; R2represents ethyl or isopropyl; R3represents hydrogen or fluorescent; and R4represents-NH2b) R1is thienyl or imidazolyl: R2represents ethyl or isopropyl; R3represents hydrogen or fluorescent, and R4represents-NH2;) R1represents phenyl, pyrrolyl, furanyl, thienyl or imidazolyl; R2represents ethyl or isopropyl; R3represents hydrogen or fluorescent; R4represents-NHSO2R5; and R5represents a C1-C6alkyl; and g) R1represents phenyl, pyrrolyl, furanyl, thienyl or imidazolyl; R2represents ethyl or isopropyl; R3represents hydrogen or fluorescent; R4represents-NHSO2R5; and R5 represents a C1-C6alkyl, where everything embodiment a)-d) can be substituted by 1 or 2 of the preferred substituents on the phenyl ring of R1or heteroaromatic ring R1.

In the scope of the present invention also includes the individual enantiomers and the salts of compounds of formula I, including salts of enantiomers. Also in the scope of the present invention includes mixtures of the individual enantiomers, such as racemic mixture or salt mixtures of the individual enantiomers.

The separation of racemic mixtures, individual enantiomers is well known in the art and may be implemented, for example, by separation on a suitable chiral chromatographic column.

Obtaining salts is well known in the art and may be implemented, for example, by mixing the compounds of formula I in a suitable solvent with the desired proton acid and allocation methods standard in the art. Salts of compounds of formula I include pharmaceutically acceptable salts, and pharmaceutically unacceptable salt.

The new compounds of the present invention are useful in therapy, especially for the treatment of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid what tricom, migraine, visceral pain, and so forth. This list, however, should not be interpreted as exhaustive.

Compounds of the present invention are useful as immunomodulators, especially in autoimmune diseases, such as arthritis, skin grafts, transplants of organs and similar surgical needs, when collagenoses, various allergies, for use as antitumor agents, and antiviral agents.

Compounds of the present invention are useful in disease States in which there is degeneration or dysfunction of opioid receptors, either degeneration or dysfunction of opioid receptors involved in the process. In diagnostic techniques and applications related to imaging, such as positron emission tomography (PET), may be also involved the use of labeled isotopes are variants of the compounds of the present invention.

Compounds of the present invention are useful for the treatment of diarrhea, depression, anxiety, and disorders associated with stress, such as disorders associated with post traumatic stress disorder, panic disorder, generalized anxiety disorder, social phobia and obsessive-compulsive disorder; incontinence of urine, various mental Zabol the requirements, cough, pulmonary edema, various gastro-intestinal disorders, e.g. constipation, functional gastrointestinal disorders such as irritable bowel syndrome and functional dyspepsia, Parkinson's disease and other movement disorders, traumatic brain injury, stroke, cardioprotection after myocardial infarction, spinal cord injury and addiction to the excessive use of drugs, including the treatment of abuse of alcohol, nicotine, opioids and other drugs, as well as to treat disorders of the sympathetic nervous system, such as hypertension.

Compounds of the present invention are useful as an analgesic agent for use during General anesthesia and controlled adjustments of anesthesia. Combinations of agents with different properties are often used to balance the effects required to maintain the state of anesthesia (e.g., amnesia, analgesia, muscle relaxation and sedation). In this combination enabled inhalation anesthetics, sleeping pills, anxiolytics, neuromuscular blockers and opioids.

In the scope of the present invention also includes the use of any of the compounds of formula I, above, for the production of drugs for the treatment of any of the conditions discussed above.

The next aspect of the present invention is a method of treatment of a subject suffering from any of the conditions discussed above, whereby a patient in need of such treatment is administered an effective amount of the compounds of formula I, above.

Ways to get

Compounds of the present invention can be obtained using the following General method.

Obtaining phenols. Examples 1-3

The compounds of formula I, where R4is a HE, is produced by the interactions of the compounds of General formula II

where R2and R3are as defined in formula I, a R4represents OMe, BOC-piperazine in acetonitrile in the presence of triethylamine under standard conditions, followed by removal of the protective group BOC under standard conditions to obtain the compounds of formula III

which is then subjected to alkylation in the reducing conditions of a compound of formula R1-CHO with subsequent splitting of the methyl ester using BBr3in dichloromethane to obtain the compounds of formula I, where R4is a HE.

Getting anilines. Examples 4-6

The compounds of formula I, where R4represents-NH2receive by implementing wsimages is via compounds of General formula IV

where R2and R3are as defined in formula I, a R4represents NO2with BOC-piperazine in acetonitrile in the presence of triethylamine under standard conditions, followed by removal of the protective group BOC under standard conditions to obtain the compounds of formula V

which is then subjected to alkylation in the reducing conditions of a compound of formula R1CHO and subsequent reduction of the nitro group using hydrogen and palladium on coal with obtaining the compounds of formula I, where R4represents-NH2.

Getting methylsulfonylamino. Examples 7-8

The compound of formula I, where R4represents-NHSO2R5produced by the interactions of the compounds of General formula VI

where R2and R3are as defined in claim 1, a R4represents NO2with BOC-piperazine in acetonitrile in the presence of triethylamine under standard conditions, followed by reduction of the nitro group by hydrogenolysis using palladium on coal as a catalyst, methysulfonylmethane using methanesulfonanilide in dichloromethane in presence of triethylamine, and then UDA is the group of protective group BOC under standard conditions to obtain the compounds of formula VII

which is then subjected to alkylation in the reducing conditions of a compound of formula R1CHO and subsequent reduction of the nitro group using hydrogen and palladium on coal with obtaining the compounds of formula I, where R4represents-NHSO2R5.

In the scope of the present invention also includes the individual enantiomers and the salts of compounds of formula I, including salts of enantiomers. The compounds of formula I are chiral compounds with diarylpyrimidine group as a chiral center, see formula I* below.

The following embodiment of the present invention, therefore, is (-)-enantiomer of compounds of formula I, as well as salt specified connection.

Another embodiment of the present invention, therefore, is (+)-enantiomer of compounds of formula I, as well as salt specified connection.

EXAMPLES

Hereinafter the invention will be described in more detail using the following Examples, which should not be construed as limiting the invention.

Scheme 1: Getting tortenelem. Examples 1-3

Intermediate compound 1: 4-[(4-Fluoro-3-methoxyphenyl)(hydroxy)-methyl]-N,N-aminobutiramida benzamid

N,N-Aminobutiramida 4-itbased (6.0 g, 18 mmol) restore and in THF (200 ml) and cooled to -78° C in nitrogen atmosphere. N-BuLi (14 ml, 1.3 M solution in hexane, 18 mmol) was added dropwise over 10 min at a temperature of from -65°C to -78°C. was Added dropwise 4-fluoro-3-methoxybenzaldehyde (2.8 g, 18 mmol)dissolved in THF (5 ml). After 30 min was added NH4Cl (aq.). The residue after concentration in vacuo, extraction with EtOAc/water, drying (MgSO4) and evaporation of the organic phase was purified by chromatography on silica (0-75% EtOAc/heptane) to give the desired product (3.9 g, 60%).1H NMR (CDCl3) δ 1.0-1.6 (m, 12H), 2.65 (d, J=4 Hz, 1H), 3.4-3.9 (m, 2H), 3.80 (s, 3H), 6.10 (d, J=4 Hz, 1H), 6.76 (m, 1H), 6.95 (m, 1H), 7.04 (m, 1H), 6.76 (m, 1H), 7.25, 7.40 (2d, J=7.5 Hz, 4H).

Intermediate compound 2: 4-(4-Fluoro-3-methoxyphenyl)(1-piperazinil)methyl]-N,N-aminobutiramida benzamid.

Intermediate compound 1 (3.9 g, 11 mmol) was dissolved in anhydrous CH2Cl2(50 ml) and treated SOBr2(from 0.88 ml, 11 mmol) at a temperature of from 0 to 25°within 30 minutes After neutralization of knso4(aq.) and drying (K2CO4) the organic phase, the solvent is evaporated in vacuum. Balance and Et3N (1.8 ml, 13 mmol) was dissolved in MeCN (50 ml) and was stirred with BOC-piperazine (2.1 g, 11 mmol) at 25°within 12 hours After concentration in vacuo and chromatography on silica (0 to 50% EtOAc in heptane) received a 4.6, 1.6 g were treated TFU in CH2Cl2(1:1), conc the Wali in vacuum, was extracted with CH2Cl2/K2CO4(aq.), dried (K2CO4) and was evaporated in vacuum to obtain intermediate compound 2 (1.3 g, 81% from intermediate compound 1). MS (ER; elektrorazpredelenie) 428,21 (MH+).

Example 1: 4-[1-(4-Benzyl-piperazine-1-yl)-1-(4-fluoro-3-hydroxy-phenyl)-methyl]-N,N-aminobutiramida benzamid

Intermediate compound 2 (0,41 g, 0.96 mmol) and triethylamine (of 0.20 ml, 1.4 mmol) was dissolved in MeCN (10 ml). Benzylbromide (of 0.14 ml, 1.1 mmol) was added under stirring at 25°C. After 12 h the solution was concentrated and purified by chromatography with reversed phase (LiChroprep RP-18, 10-80% MeCN in water, 0.1% of TFU). Received of 0.53 g of the free base after extraction of CH2Cl2/K2CO4(aq.), drying (K2CO4) and evaporation in vacuum. After processing tribromide boron (4 EQ., 1 M solution in CH2Cl2in CH2Cl2at -78°With the addition of water, concentration in vacuo and chromatography with reversed phase obtained compound of Example 1 in the form of triptoreline (0.35 g, 50%). MS (ER) 504.22 (MH+). IR (NaCl) 3222, 1677, 1592, 1454, 1346, 1201, 1135 (cm-1).1H NMR (CD3OD) δ=1.1, 1.5 (m, 12H), 2.3 (m, 3H), 2.9-3.8 (m, 7H), 4.33 (s, 2H), 4.75 (s, 1H), 6.60 (m, 1H), 6.83 (m, 1H), 6.94 (m, 1H), 7.24 (d, J=8 Hz, 2H), 7.47 (m, 7H). Analytically calculated for C31H38FN3O2×0,8S4H2F6O4FROM: 59,87, N.: OF 5.82, N: 6,12. Found: C:60,06, N: OF 5.83, N: TO 6.19.

Example 2: 4-[1-(4-Fluoro-3-hydroxy-phenyl)-1-(4-thiophene-3-ylmethyl-piperazine-1-yl)-methyl]-N,N-aminobutiramida benzamid

Intermediate compound 2 (of 0.43 g, 1.0 mmol) was dissolved in Meon (5 ml) with 3-thiophene-carboxaldehyde (of 0.11 ml, 1.2 mmol) and the SPLA (57 μl, 1.0 mmol) and was stirred for 1 hour Cyanoborohydride sodium (63 mg, 1.0 mmol) was added in portions over 6 h, and the reaction mixture was stirred at 25°C for an additional 12 h, and then subjected to processing by concentration in vacuo and extraction (CH2Cl2/K2CO4(aq.)). After purification by chromatography with reversed phase, as for Example 1, was obtained 0.32 g (of 0.62 mmol) in the form of free base. After processing tribromide boron, as for Example 1, and chromatography obtained compound of Example 2 (0.20 g, 26%) as trifenatate. MS (ER) 510,17 (MH+). IR (NaCl) 3281, 1674, 1606, 1454, 1346, 1200, 1135 (cm-1).1H NMR (CD3OD) δ=1.1, 1.5 (m, 12H), 2.30 (m, 2H), 2.9-3.7 (m, 10H), 4.37 (s, 2H), 4.75 (s, 1H), 6.60 (m, 1H), 6.84 (m, 1H), 6.94 (m, 1H), 7.18 (m, 1H), 7.25, 7.48 (2d, J=8 Hz, 4H), 7.55 (m, 1H), 7.65 (m, 1H). Analytically calculated for C29H36FN3O2S×0,8S4H2F6O4FROM: 55,16, N: 5,55, N: 5,99. Found: C: 55,12, H: 5.39, N: 6.07.

Example 3: 4-{1-(4-Fluoro-3-hydroxy-phenyl)-1-[4-(1H-imidazol-2-ylmethyl)-piperazine-1-yl]-methyl}-N,N-aminobutiramida benzamid

Using the same procedure as for Example 2, were is deystviya with 2-imidazole-carboxaldehyde (0.10 g, 1.1 mmol), followed by processing tribromide boron (6 EQ.) received the compound of Example 3 (0.18 g, 25%) as trifenatate. MS (ER) 494,23 (MH+). IR (NaCl) 3123, 1673, 1592, 1454, 1350, 1201, 1135 (cm-1).1H NMR (CD3OD) δ=1.1, 1.5 (m, 12H), 2.7-3.8 (m, 10H), 3.95 (s, 2H), 5.20 (m, 1H), 6.70 (m, 1H), 6.94 (m, 1H), 7.02 (m, 1H), 7.32, 7.58 (2d, J=8.0 Hz, 4H), 7.46 (s, 1H). Analytically calculated for C28H36FN5O2×1,2C4H2F6O4×0,7N2O: 50,51, N: 5,14, N: 8,98. Found: C: 50,44, N: 5,18, N: 9,11.

Scheme 2: Getting anilines. Examples 4-6

Intermediate compound 3: 4-[Hydroxy(3-nitrophenyl)methyl]-N,N-aminobutiramida benzamid

Method as for intermediate 1, but after adding n-BuLi solution was Coulibaly in a solution of 3-nitrobenzaldehyde (2.7 g, 18 mmol) in toluene/THF (1:1, 100 ml) at -78°C. Processing and chromatography obtained intermediate compound 3 (2.4 g, 37%).1H NMR (CDCl3) δ 1.1-1.7 (m, N), 3.90 (d, J=3.5 Hz, 1H), 3.4-3.9 (m, 2H), 5.91 (s, J=3.5 Hz, 1H), 7.27, 7.35 (2d, J=8 Hz, 4H), 7.51 (m, 1H), 7.71 (m, 1H), 8.13 (m, 1H), 8.30 (s, 1H).

Intermediate compound 4: N,N-Aminobutiramida 4-[(3-nitrophenyl)(1-piperazinil)methyl]benzamide

Using the same method as for intermediate 2, intermediate 3 (2.4 g, 6.7 mmol) received the BOC-protected intermediate compound 4 (2.83 g, 81%). As a result of processing TFU share of the public received intermediate compound 4, MS (ER) 425,23 (MH+).

Example 4: 441-(3-Amino-phenyl)-1-(4-benzyl-piperazine-1-yl)-methyl]-N,N-aminobutiramida benzamid

After the reaction 7 (0.40 g, were 0.94 mmol) with benzylbromide, as for Example 1, was carried out by hydrogenation (H2, 40 pounds/square inch (275,79 kPa)) with 10% Pd/C (50 mg) in EtOH (25 ml) and 2 N. HCl (1.2 ml, 2.4 mmol) for 2 h Purification by chromatography with reversed phase, using the same conditions as for Example 1, the obtained compound of Example 4 (0.20 g, 30%) as trifenatate. MS (ER) 485.40 (MH+). IR (NaO) 3414, 1673, 1605, 1455, 1345, 1201, 1134 (cm-1).1H NMR (CD3OD) δ=1.1, 1.5 (m, 12H), 2.3 (m, 2H), 2.9-3.8 (m, 8H). 4.31 (s, 2H), 4.47 (s, 1H), 7.02 (m, 1H), 7.21-7.52 (m, 12H). Analytically calculated for C31H40N4O×1,2C4H2F6O4×0,5H2O: 56,04, N: 5,70, N: 7,30. Found: C: 56,06, N: 5,67, N: 7,41.

Example 5: 4-[1-(3-Amino-phenyl)-1-(4-thiophene-3-ylmethyl-piperazine-1-yl)-methyl]-N,N-aminobutiramida benzamid

After the reaction intermediate compound 4 (0.40 g, were 0.94 mmol) with 3-thiophene-carboxaldehyde, as for Example 2, was carried out by hydrogenation (H2, 30 psi (206.84 kPa)) with 10% Pd/C (50 mg) in EtOH (25 ml) and 2 N. HCl (1.0 ml, 2.0 mmol) within 12 h of Purification by chromatography with reversed phase, using the same conditions as for Example 1, the obtained compound of Example 5 (of 0.13 g, 20%) as DATEFORMAT. MS (ER) 491,28 (MH+). IR (NaCl) 3408, 1673, 1605, 1455, 1345, 1201, 1134 (cm-1).1H NMR (CD3OD) δ=1.1, 1.5 (m, 12H, 2.3 (m, 2H), 2.9-3.8 (m, 8H), 4.35 (s, 2H), 4.44 (s, 1H), 6.98 (m, 1H), 7.16-7.32 (m. 6H), 7.49 (d, J=8 Hz, 2H), 7.55 (m, 1H), 7.64 (m, 1H). Analytically calculated for C29H38N4OS×1,3C4H2F6O4×0,6N2O: 51,48, N: 5,28, N: 7,02. Found: C: 51,51, N: 5,20, N: 7,01.

Example 6, 4-{1-(3-Amino-phenyl)-1-[4-(1H-imidazol-2-ylmethyl)-piperazine-1-yl]-methyl}-N,N-aminobutiramida benzamid

Using the same procedure as for Example 2, through the implementation of the interaction of intermediate compound 4 with 2-imidazole-carboxaldehyde (0.10 g, 1.1 mmol) followed by hydrogenation of the obtained compound of Example 6 (45 mg, 7%) as a salt of DATEFORMAT. MS (ER) 475,30 (MH+). PC (htfu, NaCl) 3351, 1674, 1621, 1455, 1349, 1202, 1134 (cm-1).1H NMR (htfu, CD3OD) δ=1.1, 1.5 (m, 12H), 2.9-3.8 (m, 8H), 4.35 (s, 2H), 4.44 (s, 1H), 6.98 (m, 1H), 7.16-7.32 (m, 6H), 7.49 (d, J=8 Hz, 2H), 7.55 (m, 1H), 7.64 (m, 1H). Analytically calculated for C28H38N6O×1,6 C4H2F6O4×0,8H2O: 48,39, N.: OF 5.05, N: 9,84. Found: C: 48,43, N: 5,06, N: 9,85.

Scheme 3: Getting methylsulfonylamino. Examples 7-8

The intermediate compound 5: N,N-Aminobutiramida 4-[{3-[(methylsulphonyl)-amino]phenyl}(1-piperazinil)methyl]benzamide

From the intermediate compound 3 was obtained BOC-protected intermediate compound 4 as described above for intermediate 4. The BOC-protected intermediate compound 4 (1.1 g, 2.3 mmol) was first made in an atmosphere of H2at 30 psi (206,84 kPa) with 10% Pd/C (150 mg) in Asón (25 ml) within 12 hours After evaporation in vacuo and extraction of the CH2Cl2/K2CO4(aq.) obtained 1.1 g (2.3 mmol) of the intermediate aniline, which was dissolved in MeCN/CH2Cl2(1:1, 10 ml). Et3N (of 0.48 ml, 3.4 mmol), then methanesulfonamide (0,41 g, 2.4 mmol) was added at 0°C. After warming to room temperature, this reaction mixture was treated by extraction of CH2Cl2/brine. Purification by chromatography on silica (0-5% MeOH/CH2Cl2) received the BOC-protected intermediate compound 5 (1.3 g, 97%). Processing TFU in CH2Cl2quantitatively obtained intermediate compound 5. MS (ER) 473,16 (MH+).

Example 7: N,N-Aminobutiramida 4-[1-(3-methanesulfonamido-phenyl)-1-(4-thiophene-3-ylmethyl-piperazine-1-yl)-methyl]-benzamide

The methodology of restorative amination, as for Example 2 from intermediate 5 (0.20 g, 0.43 mmol) was obtained the compound of Example 7 (90 mg, 26%) as a salt of DATEFORMAT. Salt is the dihydrochloride was obtained after extraction of the free base of CH2Cl2/KzCO4(aq.) and processing 2 EQ. HCl (aq.). MS (ER) 569,21 (MH+). PC (free base, NaCl) 1604, 1455, 1340, 1151 (cm-1).1H NMR (free base. CDCl3) δ=0.9-1.7 (m, N), 2.5 (m, 8H), 2.85 (s, 3H), 3.55 (s, 2H), 3. (m, 2H), 4.22 (s, 1H), 7.00-7.40 (m, N). Analytically calculated for C30H40N4O3S2×2,6 HCl With: 54,30, N: 6,47, N: 8.44. Found: C: 54,33, N: 6,20, N: 8,32.

Example 8: 4-([4-(3-Furylmethyl)-1-piperazinil]{3-[(methylsulphonyl)-amino]phenyl}-N,N-aminobutiramida benzamid

Using the same method as for intermediate 7, of intermediate compound 5 (0.21 g, 0.45 mmol) was obtained the compound of Example 8 (80 mg, 32%) as the free base. MS (ER) 553,23 (MH+). IR (free base, NaCl) 1604, 1455, 1340, 1151 (cm-1).1H NMR (free base, CDCl3) δ=1.0-2.6 (m, 20H), 2.91 (s, 3H), 3.40 (s, 2H), 4.22 (s, 1H), 6.39 (s, 1H), 7.06-7.42 (m, 11H). Analytically calculated for C30H40N4O4S×2,8HCl With: 55,03, N: 6,59, N: 8,56. Found: C: 54.93, N.; 5,93, N: 8,49.

Scheme 4: formation of compounds of Examples 9-11

Example 9: 4-{(3-AMINOPHENYL)[4-(3-thienylmethyl)-1-piperazinil]methyl}-N,N-diethylbenzamide. N,N-Diethyl-4-{(3-nitrophenyl)(1-piperazinil)methyl]benzamide (obtained similarly to the intermediate compound (4) in Scheme 2) of 0.85 g, 2.1 mmol) was dissolved in MeOH (5 ml) with 3-thiophenecarboxaldehyde (and 0.40 ml, 4.3 mmol) and HOAc (60 μl, 1.0 mmol) and was stirred for 1 hour Cyanoborohydride sodium (135 mg, 2.1 mmol) was added in portions over 6 h, and the reaction mixture was stirred at 25°C for an additional 12 h, and then subjected to processing, concentration is the key in vacuum and extraction (CH 2Cl2/K2CO4(aq.)). After purification by chromatography on silica get 3-thienylmethyl derived (0.45 g, 43%). After hydrogenation of this product is 0.30 g, 0.61 mmol) and chromatography with reversed phase received the connection specified in the header (0.17 g, 35%) in Tris-trifenatate. MS (ER) 463,34 (MH+). IR (NaCl) 3418, 1673, 1600, 1461, 1200, 1135 (cm-1).1H NMR (CD3OD) δ=1.17, 1.31 (m, 6H), 2.45 (m, 2H), 3.11 (m, 2H), 3.24-3.66 (m, 10H), 4.47 (s, 2H), 4.62 (s, 1H), 7.21 (m, 1H), 7.31 (m, 1H), 7.39-7.56 (m, 5H), 7.61-7.68 (m, 3H), 7.77 (m, 1H).

Example 10: 4-[(3-AMINOPHENYL)(4-benzyl-1-piperazinil)methyl]-N,N-diethylbenzamide.

N,N-Diethyl-4-[(3-nitrophenyl)(1-piperazinil)methyl]-benzamide (1.7 g, 4.3 mmol) and triethylamine (1.2 ml, 8.6 mmol) was dissolved in MeCN (10 ml). Benzylbromide high (0.56 ml, 4.7 mmol) was added under stirring at 25°C. After 12 h the solution was concentrated in vacuum. After extraction (CH2Cl2/K2CO4(aq.)) and purification by chromatography on silica obtained Antilibanus product (1.4 g, 2.9 mmol). After hydrogenation (H2, 40 pounds/square inch (275,79 kPa)) with 10% Pd/C (100 mg) in EtOH (25 ml) and 2 N. HCl (2.5 ml, 5 mmol) for 4 h followed by concentration in vacuo and chromatography with reversed phase received the connection specified in the header, in the form of Tris-trifenatate (0.9 g, 26%). MS (ER) 457,26 (MH+). IR (NaCl) 3422, 1672, 1603, 1458, 1209, 1133 (cm-1).1H NMR (CD3OD) δ=11, 1.2 (m, 6H), 2.3 (m, 2H), 2.9-3.6 (m, 10H), 4.33 (s, 2H), 4.49 (s, 1H), 5.48 (s, 2H), 7.01 (m, 1H), 7.24-7.34 (m, 5H), 7.47 (m, 5H), 7.52 (d, J=7.5 Hz, 2H).

Example 11: 4-((4-Benzyl-1-piperazinil){3-[(methylsulphonyl)amino-phenyl}methyl)-N,N-diethylbenzamide. The product of Example 10 (0.35 g, from 0.76 mmol) and triethylamine (of 0.12 ml, 0.84 mmol) was dissolved in MeCN (10 ml) and added methanesulfonyl anhydride (0.14 g, 0.84 mmol) at 0°C. After stirring for 10 min at 25°this solution was concentrated in vacuo and purified by chromatography with reversed phase with obtaining the connection specified in the header, in the form of bis-trifenatate (0,23 g, 40%). MS (ER) 535,21 (MH+). IR(NaCl) 3479, 1673, 1604, 1458, 1337, 1200, 1150 (cm-1).1H NMR (CD3OD) δ=1.18, 1.31 (m, 6H), 2.41 (m, 2H), 2.98 (s, 3H), 3.13 (m, 2H), 3.28-3.65 (m, 8H), 4.44 (s, 2H), 4.57 (s, 1H), 5.57 (d, J=2 Hz, 2H), 7.15 (m, 1H), 7.30 (m, 1H), 7.37 (m, 1H), 7.42 (m, 2H), 7.54-7.60 (m, 6H), 7.63 (m, 2H).

The pharmaceutical composition

The new compounds according to the present invention can be administered orally, intramuscularly, subcutaneously, by local, intranasally, intraperitoneally, intraorale, intravenously, epidurally, vnutriobolochechnoe, intracerebroventricularly and by injection into the joints.

The preferred route of administration is oral, intravenous or intramuscular.

The dosage will depend on the route of administration, severity of disease, age and weight of the patient, and other factors normally considered by the attending physician when the definition is of an individual mode and dose level as the most appropriate for a particular patient.

For the manufacture of pharmaceutical compositions of the compounds according to this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Drugs in solid dosage forms include powders, tablets, dispersible granules, capsules, starch capsules and suppositories.

A solid carrier can be one or more than one of the substances which may also act as diluents, corrective agents, solubilizing agents, lubricating agents, suspendida agents, binding agents or loosening agents for tablets; it can also be an encapsulating material.

In powders, the carrier is a finely ground solid material, which is mixed with finely ground active ingredient. In tablets, the active ingredient is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape desired size.

For the manufacture of compositions in the form of suppositories first melted low-melting wax such as a mixture of glycerides of fatty acids and cocoa butter, and an active ingredient dispersed therein, for example, by stirring. Then, this molten homogeneous mixture is poured into forms convenient size and is allowed to cool and harden.

Podhodyaschaya are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragakant, methylcellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter and the like.

Salts include, but are not limited to, pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts within the scope of the present invention include: acetate, bansilalpet, benzoate, bicarbonate, bitartrate, bromide, calcium acetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, Eilat, fumarate, gluceptate, gluconate, glutamate, picolylamine, hexylresorcinol, geranamine, hydrobromide, hydrochloride, hydroxynaphthoate, isetionate, lactate, lactobionate, malate, maleate, mandelate, mesilate, bromide, methylnitrate, methyl sulfate, mukat, napsylate, nitrate, pamoate (embonate), Pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannat, tartrate, teoclate, triethiodide, benzathine salt, chloroprocaine, choline, diethanolamine, Ethylenediamine, meglumine, procaine, aluminum salts, calcium, lithium, magnesium, potassium, sodium and zinc. Examples of pharmaceutically unacceptable salts within the scope of the present invention include: hydroiodic, perchlorate and tetrafluoroborate. Pharmaceutically unacceptable salts can be used in connection with their pre-emptive Phi is practical and/or chemical properties, such as crystallinity.

Preferred pharmaceutically acceptable salts are hydrochloride, sulfates and bitartrate. Especially preferred salts are hydrochloride and sulfates.

The term "compositions should include the preparation of the active ingredient with encapsulating material as a carrier, forming a capsule in which the active component (with other carriers or without them) is surrounded by carrier, which is thus associated with him. In this way enabled starch capsules.

Tablets, powders, starch capsules and the capsules can be used as solid dosage forms suitable for oral administration.

Compositions in the form of liquid forms include solutions, suspensions and emulsions. Solutions of the active compounds in sterile water or water-propylene glycol can be mentioned as examples of liquid preparations suitable for parenteral administration. Liquid compositions can also make a solution of the drug in the aqueous solution of polyethylene glycol.

Aqueous solutions for oral administration can be produced by dissolving the active component in water and adding suitable colorants, corrigentov, stabilizers, and thickening agents as desired. Aqueous suspensions for oral administration can be produced by the dispergirovanija finely ground active component in water with viscous material, such as natural and synthetic resins, gums, methylcellulose, sodium carboxymethyl cellulose and other suspendresume agents known in the field of pharmaceutical preparations.

Preferably the pharmaceutical compositions are in a standard dosage form. In this form, the composition is divided into standard doses containing appropriate quantities of the active component. Standard dosage form can be a packaged preparation, the package contains a discrete number of drugs, such as packaged tablets, capsules, and powders in vials or ampoules. Standard dosage form may be a capsule, a starch capsule or tablet itself, or it may be a suitable number of any of these packaged forms.

BIOLOGICAL ASSESSMENT

Model in vitro

Cell culture

A. the 293S Cells expressing the cloned μ-, δ- and K-receptors of man and resistance to neomycin, were grown in suspension at 37°C and 5% CO2in katalozhnyh flasks containing free calcium modified Dulbecco Wednesday Needle (DMEM), 10% FBS, 5% BCS, 0.1% pluronic (Pluronic F-68 and 600 μg/ml of geneticin.

B. the brain of mice and rats were weighed and washed in chilled on ice in phosphate-buffered solution (PBS) (the soda is containing 2.5 mm EDTA, pH 7.4). Brains are homogenized by the homogenizer transmitter station in 15 seconds (mouse) or 30 (rat) in chilled on ice buffer (50 mm Tris, pH 7.0, 2.5 mm EDTA with phenylmethylsulfonyl added immediately prior to use up to 0.5 mm from 0.5 M initial solution in a mixture of DMSO : ethanol).

The preparation of membranes

Cells were besieged and resuspendable in the buffer for lysis (50 mm Tris, pH 7.0, 2.5 mm EDTA with phenylmethylsulfonyl (PMSF)added immediately prior to use up to 0.1 mm 0.1 M initial solution in ethanol), incubated on ice for 15 min, then homogenized using Potytron, within 30 C. the Suspension was centrifuged at 1000 g (max) for 10 min at 4°C. the Supernatant was kept on ice, and precipitation resuspendable and centrifuged as described above. Supernatant from both zentrifugenbau were combined and centrifuged at 46000 g (max) for 30 minutes Precipitation resuspendable in cold Tris buffer (50 mm Tris/Cl, pH 7.0) and centrifuged. The final precipitation resuspendable in the buffer to membranes (50 mm Tris, Of 0.32 M sucrose, pH 7.0). Aliquots (1 ml) in polypropylene tubes were frozen in a dry ice/ethanol and stored at -70°s to use. Protein concentration was determined by the modified analysis by Lowry with sodium dodecyl sulfate (SDS).

Analyses linking

Memb the Ana were subjected to thawing at 37° C, cooled on ice, passed 3 times through a needle of the 25 size and was diluted in binding buffer (50 mm Tris, 3 mm MgCl21 mg/ml bovine serum albumin (BSA) (Sigma A-7888), pH 7.4, which was stored at 4°after filtration through a 0.22 m filter, and to which was added a freshly prepared 5 mg/ml Aprotinin, 10 μm of bestatin, 10 μm diprolene And (without DTT). Aliquots of 100 µl were added to chilled on ice polypropylene tubes 12×75 mm containing 100 μl of each radioactive ligand and 100 μl of test compounds at various concentrations. Overall (OS) and nonspecific (NS) binding was determined in the absence and presence of 10 μm naloxone, respectively. The tubes were shaken and incubated at 25°for 60-75 min, and after this time the contents were rapidly filtered under vacuum and washed with approximately 12 ml/tube chilled on ice buffer for washing (50 mm Tris, pH 7.0, 3 mm MgCl2through filters GF/B (Whatman), pre-soaked for at least 2 h in 0.1% polyethylenimine. Radioactivity (disintegrations per minute, dpm), remaining on the filters was measured using a beta counter after soaking the filters for at least 12 hours in mini-vials containing 6-7 ml of scintillation fluid. If the analysis were placed in 96-well tablets with deep holes, filtrowanie is carried through the 96-well standard filters, soaked in PEI, which was washed 3×1 ml buffer for washing and dried in an oven at 55°C for 2 h Filter plates were counted in a TopCount (Packard) after adding 50 μl of scintillation fluid MS-20 per well.

Functional tests

Agonistic activity of the compounds was measured on the basis of determining the degree to which complex compounds with the receptor activates the binding of GTP to G-proteins involved in these receptors. In the analysis of binding GTP GTP[γ]35S combined with the tested compounds and membranes from cells HEK-293S, expressing the cloned opioid receptors of the man, or from homogenized brain of the rat and mouse. Agonists stimulate the binding of GTP[γ]35S with these membranes. Values EU50and Emaxcompounds determined on the basis of the curves dose-response. The curve shifts the dose-response right Delta-agonist by naltrindole used to confirm the fact that agonistic activity mediated by Delta-receptors.

Method for GTP brain rats

Membranes of rats brain was thawed at 37°C, passed 3 times through a needle with a blunt end 25 size and was diluted in GTPγS binding buffer (50 mm HEPES, 20 mm NaOH, 100 mm NaCl, 1 mm EDTA, 5 mm MgCl2, a pH of 7.4, was added a freshly prepared 1 mm DTT, 0.1% BSA). On the once, the dilutions membranes were added to 120 μm GDF. Values EU50and Emaxcompounds were evaluated on the basis of the curves of the dose-response for 10 points, built for 300 μl with the appropriate amount of membrane protein (20 μg/well) and 100000-130000 dpm (disintegrations per minute) GTPγ35S per well (0,11-0,14 nm). Basal and maximally stimulated binding was determined in the absence and presence of 3 μm SNC-80.

Data analysis

Specific binding (SS) was calculated as OS-NS and SS in the presence of various test compounds was expressed as percent of the control of the SS. The values of the IC50and hill coefficient (Hill) (nHfor ligand substitution specific bound radioactive ligand was calculated on the basis of the graphs in logarithmic scale or programs to draw the curve by points, such as Ligand, GraphPad Prism, SigmaPlot or ReceptorFit. Values of Kiwas calculated based on the equation of Cheng-Prussoff. Values are mean ± mean square error (RMSE) IC50, Kiand nHpresented for the tested ligands in at least three curves replacement. The biological activity of the compounds of the present invention are presented in the Table.

Table
Biological data.
P the emer no HDELTA (nm)The RAT BRAIN (nm)The MOUSE BRAIN (nm)
IC50EU50%EmaxEU50%EmaxEU50%Emax
1-110,50-130,32-10494-1062,9-867125-1594,9-1441126-154

Experiments on saturation of the receptor

Values of Kδ radioactive ligands were determined by analysis of the binding on cell membranes with the appropriate radioactive ligands at concentrations in the range from 0.2 to 5-fold from an estimated K valuesδ (up to 10-fold, if necessary quantities of radioactive ligand available). Specific binding of the radioactive ligand was expressed in pmol/mg of membrane protein. Values of Kδ andmaxfrom individual experiments obtained on the basis of nonlinear mappings specific bound (SS) vs. nm free (C) radioactive ligand from the individual experiment according to the constitutive model.

Determination of the mechanical allodynia using test Von Frey

Testing was carried out between 08:00 and 16:00 h, using a method that is written Chapian et al. (1994). Rats were placed in Plexiglas cages on the upper surface of the bottom of the wire mesh, which provided access to the foot, and left for addiction 10-15 minutes the Test area was the middle of the sole of the left hind legs, avoiding less sensitive pads of the foot. The paw was affected by a series of 8 hairs Von Frey logarithmically incremental stiffness(0,41, 0,69, 1,20, 2,04, 3,63, 5,50, 8,51 and 15,14 g; Stoelting, III, USA). Hair Von Frey was applied from below the mesh floor perpendicular to the surface of the sole with sufficient force to cause slight bending against the legs, and held for about 6-8 seconds. A positive response was noted when the paw was sharply jerk away. Wince immediately after removal of the hair is also considered a positive response. The movement was considered uncertain answer, and in such cases, the stimulus was repeated.

The testing Protocol

Animals were tested on the 1st day after the operation for the group treated with FCA. 50%threshold otdergivanija was determined using the direct method of Dixon (1980). Testing started from 2.04 g of hair, in the middle of the series. Incentives always gave consistent manner, either ascending or descending. In the absence of a response in the form of otdergivanija paws on the source selected hair gave a stronger incentive; if otdergivanija paws were chosen following the more weak stimulus. To calculate the optimal threshold values this way, you need 6 responses in the immediate vicinity of the 50%threshold, and counting these 6 answers began when he appeared the first change of the response, that is, when the threshold is first crossed. In cases where the threshold value was outside the range of incentives, respectively, were established values 15,14 (normal sensitivity) or 0,41 (maximum allodynia). The resulting picture of positive and negative responses were made to the table using legend: X = no otdergivanija; O = OTDELENIE, and 50%threshold otdergivanija was interpolable, using the formula:

50% g threshold =10(Xf+kδ)/10000

where Xf = the value of the last used hair Von Frey (logarithmic units); k = - valued (from Chapman et al. (1994)) for pictures of positive/negative responses; and δ = value of the difference between stimuli (logarithmic units). Here δ = 0,224.

Threshold Von Frey translated into a percentage of the maximum possible response (% MBO) according Chaptan et al., 1994. For computing % MBO used the following equation:

% MBO = Threshold drug treatment (g) - threshold-allodynia (g) × 100 Control threshold (g) - threshold alladine the (g)

The introduction of the test substance

Before testing for Von Frey rats were injected with (subcutaneously, intraperitoneally, intravenously or orally) the test substance, the time between the introduction of the test compounds and test Von Frey depended on the nature of the tested compounds.

The Writhing test

Acetic acid when administered to mice intraperitoneally will cause contraction of the abdomen. Then their body would be a typical way to stretch. When injected painkillers, described the movement see less often, and this medication is chosen as a potential good candidate.

The Writhing reflex is considered complete and typical only when the following items are included animal is not in motion; lower back slightly lowered; visible plantar side of both legs. This analysis demonstrated that the compounds of the present invention significantly inhibit the Writhing reflex after oral dosing 1-100 µmol/kg

(1) Preparation of solutions

Acetic acid (Asón): 120 µl of acetic acid is added to a fall of 19.88 ml of distilled water to obtain a final volume of 20 ml at a final concentration of 0.6% of the Asón. Then this solution is stirred (to shake), and it is ready for injection.

Connection (medicine): Each connection and get dissolved in the most appropriate is ositelu according to standard methods.

(2) infusion

Compound (drug) administered orally, intraperitoneally (R), subcutaneously (s.c.) or intravenously (i.v.) in the dose of 10 ml/kg (given an average body weight of mice) for 20, 30 or 40 minutes (respectively, the class of compound and its characteristics) before testing. When the connection takes Central: intraventricular (i.c.v.) or vnutriobolochechnoe (i.t.), injected volume of 5 ál.

Asón injected intraperitoneally (I.P. Pavlova.) in two places in the dose of 10 ml/kg (given an average body weight of mice) directly before testing.

(3) Testing

Animal (mouse) is followed over a period of 20 minutes and at the end of the experiment celebrate and compile the number of cases (Writhing reflex). Mice kept in individual cages "Shoe box" with contact bedding. Usually see only 4 mice at the same time: one control and three doses of the medication.

Efficacy in anxiety symptoms and such anxiety has set in conflict test Geller-Seifter in rats.

Efficiency in the symptoms of functional gastrointestinal disorders can be set in the analysis described Coutinho SV, et al, in the American Journal of discrimination - Gastrointestinal &Liver discrimination, 282 (2): G307-16, 2002 Feb, in rats.

1. The compound of the formula

where R1selected from any of:

(1) phenyl

(2) pyridinyl

(3) teenie

(4) furanyl

(5) imidazolyl

where each phenyl or heteroaromatic ring R1it may be possible, and independently optionally substituted by 1, 2 or 3 substituents selected from CF3, stands, chloro, fluorescent, bromo and iodide;

R2independently selected from ethyl and isopropyl;

R3independently selected from hydrogen, fluorescent;

R4independently selected from-NH2and-NHSO2R5;

R5independently represents a C1-C6alkyl, or salts thereof, or individual enantiomers and their salts.

2. The compound according to claim 1, where R1represents phenyl, furanyl, thienyl or imidazolyl; R2represents ethyl or isopropyl; R3represents hydrogen or fluorescent; R4represents-NH2or-NHSO2R5; R5represents a C1-C6alkyl.

3. The compound according to claim 1, where R1represents phenyl, furanyl, thienyl or imidazolyl; R2represents ethyl or isopropyl; R3represents hydrogen; R4represents-NHSO2R5; R5before the hat is 1-C6alkyl.

4. The compound according to claim 1, where the heteroaromatic(s) ring(a) substituted(s) CF3, stands, iodine, bromine, fluorescent or chloro.

5. The compound according to claim 1, where the heteroaromatic(s) ring(a) substituted(s) stands.

6. The compound according to claim 1, selected from any of:

4-[1-(3-amino-phenyl)-1-(4-benzyl-piperazine-1-yl)-methyl]-N,N-aminobutiramida benzamide;

4-[1-(3-amino-phenyl)-1-(4-thiophene-3-ylmethyl-piperazine-1-yl)-methyl]-N,N-aminobutiramida benzamide;

4-{1-(3-amino-phenyl)-1-[4-(1H-imidazol-2-ylmethyl)-piperazine-1-yl]-methyl}-N,N-aminobutiramida benzamide;

N,N-aminobutiramida 4-[1-(3-methanesulfonamido-phenyl)-1-(4-thiophene-3-ylmethyl-piperazine-1-yl)-methyl]-benzamide;

4-([4-(3-furylmethyl)-1-piperazinil]{3-[methylsulphonyl)amino]phenyl}-N,N-aminobutiramida benzamide;

4-{(3-AMINOPHENYL)[4-(3-thienylmethyl)-1-piperazinil]methyl}-N,N-diethylbenzamide;

4-[(3-AMINOPHENYL)(4-benzyl-1-piperazinil)methyl]-N,N-diethylbenzamide and

4-((4-benzyl-1-piperazinil){3-[(methylsulphonyl)amino]phenyl}methyl)-N,N-diethylbenzamide.

7. The compound according to any one of claims 1 to 6 in the form of its salts, hydrochloride, dihydrochloride, or DATEFORMAT.

8. The method of obtaining the compounds of formula I, where R4represents-NH2, wherein the compound of General formula

where R2and R3are the same and, as defined in claim 1, a R4represents NO2, is subjected to the interaction with SOBr2in CH2Cl2subsequent interaction with BOC-piperazine in acetonitrile in the presence of triethylamine under standard conditions, followed by removal of the protective group BOC under standard conditions to obtain the compounds of formula V

which is then subjected to alkylation in the reducing conditions of a compound of formula R1CHO and subsequent reduction of the nitro group using hydrogen and palladium on coal with obtaining the compounds of formula I, where R4represents-NH2.

9. The method of obtaining the compounds of formula I, where R4represents-NHSO2CH3, wherein the compound of General formula

where R2and R3are as defined in claim 1, a R4represents NO2, is subjected to the interaction with SOBr2in CH2Cl2subsequent interaction with BOC-piperazine in acetonitrile in the presence of triethylamine under standard conditions, followed by reduction of the nitro group by hydrogenolysis using palladium on coal as a catalyst, methysulfonylmethane using methanesulfonanilide dichloromethane in presence of triethylamine, and then removing the protective group BOC under standard conditions to obtain the compounds of formula VII

which is then subjected to alkylation in the reducing conditions of a compound of formula R1-SNO obtaining the compounds of formula I, where R4represents-NHSO2CH3.

10. The compound according to any one of claims 1 to 7, manifesting δ-agonistic properties.

11. The use of the compounds of formula 1 according to claim 1 for the production of medicines for use in the treatment of pain.

12. The pharmaceutical composition exhibiting δ-agonistic properties, containing as active ingredient a compound of the formula I according to claim 1 together with a pharmacologically and pharmaceutically acceptable carrier.

Priority points and features:

18.05.2001 - claims 1 to 5, 8, 9, 11 and 12, p.6 compounds 1-5, partially to claims 7 and 10;

15.11.2001 - p.6 compounds 6-8, partially to claims 7 and 10.



 

Same patents:

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

SUBSTANCE: invention relates to novel isoquinoline compounds of the general formula (I): wherein R1 represents hydrogen atom, halogen atom or alkyl; Y is absent or represents alkylene chain comprising from 1 to 8 carbon atoms wherein arbitrary carbon atom can comprise hydroxyl group as a substitute; R represents the following formula (II): wherein X represents -CH or nitrogen atom under condition that if Y absent in the formula (I) then X must represent -CH; W represents -CH or nitrogen atom under condition that if X represents -CH then W must represents nitrogen atom; s represents a whole number from 1 to 3; t represents a whole number from 1 to 3; if R3 represents hydrogen atom or alkyl then R2 represents hydrogen atom, alkyl, hydroxyl group or hydroxyalkyl, and R2' represents hydroxyl group or hydroxyalkyl, and if R3 represents hydroxyalkyl then R2 and R2' represent hydrogen atom. Also, invention relates to their optically active forms, pharmaceutically acceptable salts, aqueous adducts, hydrates and solvates. Compounds of the formula (I) elicit inhibitory effect on activity of poly-(ADP-ribose)-polymerase and can be used in prophylaxis of diseases associated with cerebral infarction.

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

40 cl, 4 tbl, 55 ex

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EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 2 tbl, 538 ex

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52 cl, 2 tbl, 505 ex

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19 cl, 90 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a compound of the formula (I): or its pharmaceutically acceptable salt wherein X is chosen from the group consisting of carbon (C), oxygen (O), nitrogen (N) and sulfur (S) atoms; Z represents nitrogen atom (N); Y is chosen from the group consisting of =O, =S or their tautomers; SPU means a spacer element providing distance d between Z and N atom wherein -SPU- represents bi-radical -(CR6R7)n- wherein n means 1, 2, 3, 4 or 5; N atom in common with R1 and R2 forms heterocyclic ring wherein indicated heterocyclic ring is chosen from the group consisting of piperidine and 8-azabicyclo[3.2.1]octane and wherein heterocyclic ring is substituted with one or more substitutes R4 chosen from the group consisting of hydrogen atom, (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C1-C8)-alkoxy-group, (C1-C8)-alkylidene, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkyloxyimino-group each of them is substituted optionally with a substitute R5 and wherein at least with one of indicated substitutes R4 is represented by R4' chosen from the group consisting of (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C1-C8)-alkoxy-group and (C1-C8)-alkylidene wherein each of them is substituted optionally with a substitute R5 wherein R5 is chosen from the group consisting of hydrogen, halogen atom, hydroxy-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, (C3-C8)-cycloalkyl, (C2-C8)-alkenyl and (C2-C8)-alkynyl; RX can absent or can be chosen from the group consisting of hydrogen atom and optionally substituted (C1-C8)-alkyl; R3 can be represented in 0-4-fold range and chosen from the group consisting of halogen atom, optionally substituted (C1-C8)-alkyl and (C1-C8)-alkoxy-group; each R6 and R7 is chosen optionally and independently among the group consisting of hydrogen atom, hydroxy-group and optionally substituted (C-C8)-alkyl. Also, invention relates to a pharmaceutical composition possessing the selective activity with respect to M and/or M4-subtypes of muscarinic receptors and antagonism with respect to D2-dopamine receptors and comprising compound of the formula (I) by claim 1 in common with pharmaceutically acceptable carriers or excipients. Also, invention relates to a method for enhancing activity of cholinergic receptor comprising interaction of cholinergic receptor and system comprising cholinergic receptor with the effective amount of at least one compound of the formula (I) by claim 1. Also, invention relates to using the compound according to any claim among 1-11 or its pharmaceutically acceptable salt, or pharmaceutical composition containing any base for preparing a medicinal preparation used in prophylaxis aim or treatment of psychosis or for attenuation of symptoms associated with psychosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

27 cl, 3 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to derivative of pyridine of the general formula (I): wherein each symbol has the following values: R1 and R2 mean hydrogen, halogen atoms, lower alkyl, lower alkoxy-group; R3 and R4 mean hydrogen atom, lower alkyl, halogen atom; R5 means hydrogen atom, lower alkyl; n = 0 or 1, or its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition based on compounds of the formula (I) and intermediates substances used in synthesis. Compounds possess inhibitory effect on activity of phosphodiesterase of type 4.

EFFECT: valuable medicinal and biochemical properties of derivatives.

9 cl, 13 tbl, 147 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

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

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): in free form or as a salt wherein Ar1 means phenyl substituted with one or some halogen atoms; Ar2 means phenyl or naphthyl that can be unsubstituted or substituted with one or some substitutes chosen from the group comprising halogen atom, cyano-, hydroxy-, nitro-group, (C1-C8)-alkyl, (C1-C8)-halogenalkyl, (C1-C8)-alkoxy-group or (C1-C8)-alkoxycarbonyl; R1 means hydrogen atom or (C1-C8)-alkyl optionally substituted with hydroxy-,(C1-C8)-alkoxy-, acyloxy-group, -N(R2)R3, halogen atom, carboxy-group, (C1-C8)-alkoxycarbonyl, -CON(R4)R5 or monovalence cyclic organic group; each among R2 and R3 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R2 means hydrogen atom and R3 means acyl or -SO2R6, or R and R3 in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; each among R4 and R5 and independently of one another means hydrogen atom or (C1-C8)-alkyl, or R4 and R in common with nitrogen atom to which they are bound form 5- or 6-membered heterocyclic group; R6 means (C1-C8)-alkyl, (C1-C8)-halogenalkyl or phenyl optionally substituted with (C1-C8)-alkyl; n means 1, 2, 3 or 4 under condition that when Ar1 means para-chlorophenyl and R1 means hydrogen atom then Ar2 doesn't mean phenyl or para-nitrophenyl. Compounds of the formula (I) possess the inhibitory CCR-3 activity and can be used in medicine.

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

7 cl, 47 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indole of the formula (1): and their pharmaceutically acceptable salts wherein represents a double bond; Z1 represents nitrogen atom (N), -CR5 wherein R5 represents hydrogen atom (H), (C1-C6)-alkyl, hydroxy-group (OH),(C1-C6)-alkoxy-group or halogen atom; Z2 at position 2 represents CR1 and at position it represents CA wherein each R1 means independently (C1-C6)-alkyl; A represents -Wi-COXjY wherein Y means -COR2 wherein R2 means -OR, -NR2, -NRNR2 or -NROR wherein each R represents independently hydrogen atom (H), (C1-C6)-alkyl, or (C5-C6)-heteroaryl comprising one or two heteroatoms in ring chosen from atoms N, O and S wherein each of them is substituted with one or some groups chosen from -NR'2, -OR', -COOR', (C1-C6)-alkyl, -CN, =O, and -SR' wherein each R' represents hydrogen atom (H) or (C1-C6)-alkyl and wherein two R or R' jointed to the same nitrogen atom (N) can form 3-8-membered ring chosen from the group comprising piperazine ring, morpholine ring, thiazolidine ring, oxazolidine ring, pyrrolidine ring, piperidine ring, azacyclopropane ring, azacyclobutane ring and azacyclooctane ring and wherein indicated ring can be substituted additionally with (C1-C6)-alkyl or -COO-(C1-C6)-alkyl; X represents unsubstituted (C1-C6)-alkylene, or Y means imidazole substituted with methyl group; i = 0; j = 0 or 1; R7 means hydrogen atom (H) or (C1-C6)-alkyl, -SOR, -SO2R, -RCO, -COOR, (C1-C6)-alkyl-COR, -CONR2, -SO2NR2,-CN, -OR, (C1-C6)-alkyl-SR, (C1-C6)-alkyl-OCOR, (C1-C6)-alkyl-COOR, (C1-C6)-alkyl-CN, or (C1-C6)-alkyl-CONR2 wherein each R represent independently hydrogen atom (H), (C1-C6)-alkyl or aryl that is substituted optionally with halogen atom, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; or R7 represents methoxymethyl, methoxyethyl, ethoxymethyl, benzyloxymethyl or 2-methoxyethyloxymethyl; each R3 represent independently halogen atom, (C1-C6)-alkyl, -OR, -SR or -NR2 wherein R represents hydrogen atom (H) or (C1-C6)-alkyl; n = 0-3; L1 means -CO; L2 means (C1-C4)-alkylene optionally substituted with one or two groups of (C1-C4)-alkyl; each R4 is chosen independently from the group comprising (C1-C6)-alkyl, halogen atom, -OR, -NR2, -SR, -SOR, -SO2R, -RCO, -COOR, -CONR2, -SO2NR2 wherein each R represents independently hydrogen atom (H) or (C1-C6)-alkyl; or R4 represents =O; m = 0-4; Ar means aryl group substituted with from 0 to 5 substitutes chosen from the group comprising (C1-C6)-alkyl, halogen atom, -OR, -NR2, -SR, -SOR, -SO2R, -RCO, -COOR, -CONR2 and -SO2NR2 wherein each R represents independently hydrogen atom (H) or (C1-C6)-alkyl. Compounds of the formula (I) possess the inhibitory activity with respect to p38-α kinase that allows their using as components of the pharmaceutical composition.

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

63 cl, 3 tbl, 9 sch, 16 ex

FIELD: pharmaceutical industry.

SUBSTANCE: invention relates to composition containing at least two active ingredients, opioid analgesic, and opioid agonist in non-swelling diffusive matrix. Releasing characteristics are defined by matrix made of ethylcellulose and at least one fatty alcohol. Also disclosed is pharmaceutical preparation containing 10-150 mg of oxycodone and 1-50 mg of naloxone in standard dose.

EFFECT: composition of long storage time with prolonged invariant and independent releasing of substances.

17 cl, 14 dwg, 16 ex, 19 tbl

FIELD: medicine.

SUBSTANCE: preparation has pharmaceutical composition containing Oxycodon, Naloxon enclosed into matrix with ethyl cellulose, and the like pharmaceutical composition enclosed into matrix with ethyl cellulose and fatty alcohols being used.

EFFECT: prolonged active ingredients release; high storage stability.

25 cl, 7 dwg, 11 tbl

FIELD: medicine, pharmacy, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to a medicinal formulation of tramadol with delayed-release. Proposed medicinal formulation possesses the high effectiveness in treatment of pains of different etiology and can be used in treatment of diseases chosen from the following group: enuresis, cough, inflammatory processes and/or allergic responses, depression states, abuse and/or alcoholism, gastritis, diarrhea, cardiovascular diseases, diseases of respiratory ways, psychic diseases, epilepsy.

EFFECT: improved and valuable medicinal and pharmaceutical properties of formulation.

38 cl, 11 tbl, 4 dwg, 11 ex

FIELD: medicine, pharmacy, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to pharmaceutical salts of the biologically active substance tramadol and at least one sugar substitute chosen from a group comprising saccharin, cyclamate or acesulfam, and a medicament comprising these salts, and its using in treatment of enuresis and pains. The claimed tramadol pharmaceutical salt and sugar substitute possesses the delayed release that provides prolonged curative effect.

EFFECT: improved and valuable medicinal and pharmaceutical properties of salts.

12 cl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 2-pyridincyclohexane-1,4-diamine of the general formula (I): wherein R1, R2 and R3 mean independently of one another hydrogen atom (H), branched or linear (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R4 means H, branched or linear (C1-C8)-alkyl or -C(X)R7 wherein X means oxygen atom (O); R7 means branched or linear (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R5 means group -CHR11R12, -CHR11-CH2R12, -CHR11-CH-CH2R12, -CHR11CH2-CH2-CH2R12 wherein R11 means H, branched or linear (C1-C7)-alkyl or C(O)O-(C1-C6)-alkyl; R12 means H, (C3-C8)-cycloalkyl or five-membered nitrogen-containing heteroaryl optionally condensed with benzene ring as their racemates or pure stereoisomers being at first enantiomers or diastereomers, and as bases or physiologically compatible acid-additive salts. Compounds of the formula (I) elicit analgesic activity and can be used in medicine.

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

15 cl, 1 tbl, 9 ex

FIELD: organic chemistry, medicine, clinical pharmacology.

SUBSTANCE: invention relates to agents used in treatment of pain. Method involves administration to a patient the effective dose of enantiomer of compounds of the formula (Ib) or the formula (IIb) or their mixture. Method provides the antihyperanalgesic effect in acute and chronic pain.

EFFECT: valuable medicinal properties of derivatives.

5 cl, 1 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: invention represents a pharmaceutical tablet comprising a core and bound envelope wherein (a) core comprises solid particles of water-soluble dye dispersed in matrix, and (b) envelope comprises hellanic gum. Due to the presence of water-soluble dye in the tablet core it shows spotted shape that provides easy recognition of the tablet. The tablet is useful for peroral and intraoral administration.

EFFECT: improved and valuable properties of tablet.

30 cl, 6 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new biologically active compounds that are able to modulate the pharmacological response of one or some opioid receptors taken among ORL-1 and μ-receptors. Invention describes a compound of the formula (I): wherein W represents hydrogen atom, (C1-C10)-alkyl, (C1-C4)-alkyl-SO2N(V1)2, cyano-(C1-C10)-alkyl, (C1-C4)-alkyl-CON(V1)2, -NH2-SO2-(C1-C4)-alkyl-, (C1-C4)-alkyl-COOV1 wherein all V1 represent (C1-C6)-alkyl; Q represents a 6-membered aromatic group; n represents a whole number from 0 to 3; n' represents a whole number 0 or 1; A, B and C represent hydrogen atom; Z is taken among the group including a bond, linear or branched (C1-C6)-alkylene; R1 is taken among the group including hydrogen atom, (C1-C10)-alkyl, (C3-C12)-cycloalkyl, (C2-C10)-alkylene, (C3-C12)-cycloalkylamino-group, benzyl, (C3-C12)-cycloalkenyl, monocyclic, bicyclic or tricyclic aryl wherein indicated alkyl, cycloalkyl, alkenyl, (C3-C12)-cycloalkylamino-group or benzyl are optionally substituted with substitutes taken among the group including (C1-C10)-alkyl, phenyl, benzyl, benzyloxy-group wherein indicated phenyl, benzyl and benzyloxy-group are substituted optionally with (C1-C10)-alkyl and indicated (C3-C12)-cycloalkyl, (C3-C12)-cycloalkenyl, monocyclic, bicyclic or tricyclic aryl are substituted optionally with 1-3 substitutes taken among the group including (C1-C10)-alkyl and benzyl wherein indicated benzyl is substituted optionally with (C1-C10)-alkyl; R2 represents hydrogen atom and under condition that when n' = 0 then ZR1 doesn't means hydrogen atom (H), or to its pharmaceutically acceptable salt or solvate. Also, the invention describes a pharmaceutical composition based on thereof. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 5 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

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

EFFECT: valuable medicinal properties of agents.

3 tbl, 70 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted indole compounds of Mannich bases of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C10)-alkyl, unsubstituted phenyl or naphthyl bound through (C1-C2)-alkylene group or that monosubstituted at least with hydroxy group (-OH), halogen atom, -CF3, -CN, (C1-C6)-alkyl, (C1-C6)-alkoxy group; R2 means atoms H, F, Cl, Br, groups -CF3, -CN, -OR10, -CO(OR11), -CH2CO(OR12), -COR19, (C1-C10)-alkyl, unsubstituted phenyl or naphthyl, or that monosubstituted at least with -OH, halogen atom, -CF3, -CN, (C1-C6)-alkyl and (C1-C6)-alkoxy group; R3 means -CH(R13)N(R14)(R15); R4, R5, R6 and R7 can have similar or different values and mean atoms H, F, Cl, Br and groups -CF3, -CN, -NO2, -OR10 and others; R10 means H, -COR17, (C1-C6)-alkyl and others; R13 means unsubstituted phenyl or phenyl monosubstituted with at least (C1-C4)-alkyl, halogen atom, -CF3, -CN and -OH; R14 and R15 can have similar or different values and mean unbranched or branched (C1-C6)-alkyl, or R14 and R15 represent in common (CH2)n wherein n means a whole number from 3 to 6, or (CH2)O(CH2)2; R17 means (C1-C6)-alkyl; R19 means -NHR20, (C1-C6)-alkyl and others; R20 means H, (C1-C6)-alkyl and others, and/or their racemates, enantiomers, diastereomers and/or corresponding bases, and/or corresponding salts of physiologically acceptable acids with exception of racemates of some compounds given in claim 1. Also, invention describes method for their preparing and using as a medicinal agent possessing analgesic effect.

EFFECT: valuable medicinal properties of compounds.

42 cl, 2 dwg, 3 tbl, 103 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative compound of carboxylic acid represented by the formula (I): , wherein each X and Y represents independently (C1-C4)-alkylene; Z means -O-; each R1, R2, R3 and R4 means independently hydrogen atom or (C1-C8)-alkyl; R5 means (C2-C8)-alkenyl; A means -O- or -S-; D means D1, D2, D3, D4 or D5 wherein D1 means (C1-C8)-alkyl; D2 means compound of the formula: wherein ring 1 represents saturated 6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom chosen from oxygen, sulfur and nitrogen atoms; D3 means compound of the formula: wherein ring 2 represents (1) completely saturated (C3-C10)-monocarboxylic aryl, or (2) optionally saturated 5-membered monoheteroaryl comprising 3 atoms chosen from nitrogen and sulfur atoms, or completely saturated 6-membered monoheteroaryl comprising 1 heteroatom representing oxygen atom; D4 means compound of the formula: ; D5 means compound of the formula: ; R6 represents (1) hydrogen atom, (2) (C1-C8)-alkyl, (3) -NR7R8 wherein R7 or R8 represent hydrogen atom or (C1-C8)-alkyl, or R7 and R8 taken in common with nitrogen atom to which they are added form saturated 5-6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom representing oxygen atom; E means -CH or nitrogen atom; m means a whole number 1-3, or its nontoxic salt. Invention relates to a regulator activated by peroxisome proliferator receptor, agent used in prophylaxis and/or treatment of diseases associated with metabolism disorders, such as diabetes mellitus, obesity, syndrome X, hypercholesterolemia or hyperlipoproteinemia, hyperlipidemia, atherosclerosis, hypertension, diseases coursing with circulation disorder, overeating or heart ischemic disease, and to an agent that increases cholesterol level associated with HDL, reduces cholesterol level associated with LDL and/or VLDL, eliminates risk factor in development of diabetes mellitus and/or syndrome X and comprising a compound represented by the formula (I) or its nontoxic salt as an active component and a carrier, excipient or solvent optionally. Invention proposes derivative compounds of carboxylic acid possessing the modulating activity with respect to peroxisome proliferator receptor (PPAR).

EFFECT: valuable medicinal properties of compounds.

15 cl, 5 tbl, 48 ex

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