Piperazine indoles as oxytocin receptor antagonists

FIELD: chemistry.

SUBSTANCE: described are piperazine indoles of general formula , in which R1 represents 2-indanyl, R2 represents 1-methylpropyl, R3 and R4 together with nitrogen atoms to which they are bonded represent a morpholino group, and pharmaceutically acceptable salts thereof. Also described is a pharmaceutical composition based on formula (I) compound.

EFFECT: compounds have antagonistic effect on oxytocin receptor.

6 cl, 1 tbl, 6 ex

 

The invention relates to new derivatives of diketopiperazine, with a strong and selective antagonistic effect on the oxytocin receptor, methods for their preparation, pharmaceutical compositions containing these compounds, and their use in medicine.

The hormone oxytocin is a potent tool for reducing the uterus and is used to stimulate or enhance delivery. Also the density of uterine oxytocin receptors increases significantly more than 100 times during pregnancy and takes the maximum value at the time of birth (premature and timely).

Premature birth/birth (between 24 and 37 weeks) are the cause of about 60% mortality/morbidity among newborns and thus a compound that inhibits contractions of the uterus under the influence of oxytocin, for example antagonists of oxytocin should be useful for the prevention or management of preterm labor.

International patent application WO 99/47549 describes derivatives of diketopiperazine, including derivatives of 3-benzyl-2,5-diketopiperazine, as inhibitors of fructose 1,6-phosphate (FBPase).

International patent application WO 03/053443 describes the class of the derivatives of diketopiperazine, which shows, in particular, a significant level of activity as antagonists of the voter is th effect on the oxytocin receptor. A preferred class of compounds described in the patent application, represent formula (A)

These compounds include those in which inter alia R1means 2 indanyl, R2means3-4alkyl, R3means 5 - or 6-membered heteroaryl group associated with the rest of the molecule through a carbon atom in the ring, R4represents a group NR5R6in which R5and R6each represents alkyl, for example methyl, or R5and R6together with the nitrogen atom to which they are attached, form a 3-7-membered saturated heterocyclic ring, the heterocycle may contain an additional heteroatom selected from oxygen.

International patent application WO 2005/000840 describes derivatives of diketopiperazine formula (In)

in which R1means 2 indanyl, R2mean 1-methylpropyl, R3means 2-methyl-1,3-oxazol-4-yl, and R4and R5together with the nitrogen atom to which they are attached, represent morpholinopropan.

Currently, the authors of a patent application discovered by a group of antagonists selective oxytocin receptor that exhibit particularly advantageous pharmacokinetic profile.

The present invention thus relates to, cu is ina least one chemical compound selected from compounds of formula (I)

in which R1means 2 indanyl, R2mean 1-methylpropyl, R3is a group selected from 2,6-dimethyl-3-pyridyl or 4,6-dimethyl-3-pyridyl, R4denotes methyl and R5denotes hydrogen or methyl, or R4and R5together with the nitrogen atom to which they are attached, represent morpholinopropan, and its pharmaceutically acceptable derivatives.

It should be understood that the compounds of formula (I) have the absolute stereochemistry shown at the asymmetric carbon atom carrying the group R1, R2and R3i.e. the stereochemistry at these positions is always (R). However, it should also be understood that although such compounds are essentially free from (S-epimer whenever R1, R2and R3each epimer may be present in small amounts, for example, may be 1% or less (S-epimer.

You should also understand that the group R2contains an asymmetric carbon atom and that the invention includes both of them (R-epimer and (S-epimer.

In one embodiment of the present invention R2means (1S)-1-methylpropyl. In another embodiment, the present invention R2means (1R)-1-IU is improper.

One embodiment of the present invention are compounds which, in particular, is described in examples 1-3 and 6. Another embodiment of the present invention are compounds which, in particular, is described in examples 1-3. Another embodiment of the present invention are compounds which, in particular, is described in examples 3 and 6. In addition, another embodiment of the present invention are compounds which, in particular, described in example 3. Another embodiment of the present invention are compounds which, in particular, described in example 1.

In one aspect, the chemical compounds of the present invention can be at least one chemical compound selected from the

(2R)-2-{(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinil}-2-(2,6-dimethyl-3-pyridinyl)-N-methylethanamine;

(2R)-2-{(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinil}-2-(2,6-dimethyl-3-pyridinyl)-N,N-dimethylethanamine;

(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinone;

(2R)-2-{(3R,6R/i> )-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinil}-2-(4,6-dimethyl-3-pyridinyl)-N,N-dimethylethanamine;

(2R)-2-{(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinil}-2-(4,6-dimethyl-3-pyridinyl)-N-methylethanamine;

(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(4,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinone, and their pharmaceutically acceptable derivatives.

Used in the description, the term "pharmaceutically acceptable" means a compound that can be used for pharmaceutical purposes. Salt and solvate of the compounds of the present invention, which is suitable for use in medicine are those compounds in which the counterion or associated solvent is pharmaceutically acceptable. However, salt and a solvate with non-pharmaceutical acceptable counterions or associated solvents are included in the scope of the present invention, for example, for use as intermediates in obtaining other compounds of the present invention and their pharmaceutically acceptable salts and solvate.

Used in the description, the term "pharmaceutically acceptable derivative" means any pharmaceutically acceptable salt, MES or prodrug, is for example a complex ester compounds of the present invention, which in the appointment of the recipient is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite or residue. Such derivatives are recognized experts in this field without the need for experimentation. However, reference is made to study Burger''s Medical Chemistry and Drug Discovery, 5thEdition, Vol.1: Principles and Practice, which is included in this patent application by reference to an in-depth study of such derivatives. In one aspect, the pharmaceutically acceptable derivatives are salts, solvate, esters, carbamates and phosphates esters. In another aspect, the pharmaceutically acceptable derivatives are salts, solvate, ester. In the following aspect, pharmaceutically acceptable derivatives are salts and solvate. In another aspect, the pharmaceutically acceptable derivatives are physiologically acceptable salt.

Valid physiologically acceptable salts of the compounds of the present invention include acid additive salts formed with physiologically acceptable inorganic acids or organic acids. Examples of such acids include hydrochloric acid, Hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, sulfonic acid, for example methanesulfonate, econsultancy, benzosulfimide the p-toluensulfonate, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, succinic acid, fumaric acid and maleic acid.

The present invention also relates to the solvate of the compounds of formula (I), for example hydrates, or the solvate with pharmaceutically acceptable solvents. Non-limiting examples of solvents include alcohols, for example ethanol, isopropanol, acetone, ethers, esters, such as ethyl acetate.

Compounds of the present invention can also be used in combination with other therapeutic agents. Thus, the present invention relates, on the other hand, the combination containing the compound of the present invention, or its pharmaceutically acceptable derivative, together with another therapeutic agent.

When using the compounds of the present invention or its pharmaceutically acceptable derivative in combination with a second therapeutic agent active against this disease, the dose of each compound may differ from the dose when used only connection. The appropriate dose is easy to find experts in this field. It should be understood that the number of compounds of the present invention, required for the treatment will vary depending on the nature, against the TA and the patient's condition and will remain at the discretion of the attending physician or veterinarian. Compounds of the present invention can be used in combination with drugs that reduce generic activities (tokoliticheskoe) or preventive agents. Non-limiting examples include beta-agonists, such as terbutaline and ritodrin, calcium channel blockers, such as nifedipine, non-steroidal anti-inflammatory drugs such as indomethacin, magnesium salts such as magnesium sulfate, other antagonists of oxytocin, such as atosiban, and agonists of the progesterone and recipes. In addition, the compounds of the present invention can be used in combination with antenatal steroids, including, but without limitation, betamethasone and dexamethasone, prenatal vitamins, especially folate supplements, antibiotics, including, but not limited to, ampicillin, amoxicillin/clavulanate, metronidazole, clindamycin, and anxiolytic drugs (tranquilizers).

Combinations referenced above, can be conveniently represented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations containing a combination as defined above together with a pharmaceutically acceptable carrier or excipient are as aspect of the present invention. Individual components of such combinations can be entered either follow the consequently, or simultaneously in separate or combined pharmaceutical formulations using any convenient method.

The sequential introduction of either the compound of the present invention or the second therapeutic agent can be applied first. With the simultaneous introduction of combination can be applied either in the same or in different pharmaceutical compositions.

When combined in the same formulation should be understood that the two compounds must be stable and compatible with each other and other components of the formulation. When the formulation separately they can be presented in any suitable formulations are known for these compounds in this field.

The compounds of formula (I) have a greater affinity with oxytocin receptors in the uterus of rats and humans, and this may determine the use of traditional procedures. For example, the affinity of oxytocin receptors in the uterus of rats can be determined using the procedure Pettibone et al., Drug Development Research 30, 129-142 (1993). Compounds of the present invention also exhibit a greater affinity with rekomendovannym receptor oxytocin person in Cho cells, and it can usually be demonstrated by using the procedure described by Wyatt et al., Bioorganic & Medical Letters, 2001 (11), p.1301-1305.

Compounds of the present invention demonstrate a time favorable the fair pharmacokinetic profile, including good bioactivity, interconnected with good solubility in water. In one aspect, compounds of the present invention show high activity and low self-clearance. In another aspect, compounds of the present invention show low self-clearance.

Consequently, the compounds of the present invention have been successfully used in the treatment or prevention of diseases and/or conditions caused by the action of oxytocin. Examples of such diseases and/or conditions include premature labor, dysmenorrhoea, endometriosis and benign prostatic hyperplasia.

Connections can also be successfully used for retaining childbirth before the recommended caesarean section or transfer the patient in a tertiary medical center, treatment of sexual dysfunction (men and women), particularly in premature ejaculation, obesity, eating disorders, acute heart failure, arterial hypertension, liver cirrhosis, renal or ophthalmic hypertension, obsessive-compulsive disorder and neuropsychiatric disorders. Compounds of the present invention can also be successfully used to improve the odds of fertility in animals, such as livestock.

In view of the above on toadie the invention relates to at least one chemical compound, selected from the compounds of formula (I) and/or its pharmaceutically acceptable derivative for use in therapy, in particular for use in therapy and veterinary medicine, and, in particular, the use as a drug to counteract the effects of oxytocin on the oxytocin receptor.

The invention also relates to the use of at least one chemical compound selected from the group of compounds of formula (I) and/or its pharmaceutically acceptable derivatives to obtain drugs to counter the impact of oxytocin on the oxytocin receptor.

In accordance with the following aspect of the invention also leads to a way to counter the influence of oxytocin on the oxytocin receptor, which consists in the introduction to a patient in need of such treatment, an antagonistic amount of at least one chemical compound selected from the group of compounds of formula (I) and/or its pharmaceutically acceptable derivatives.

Professionals it is clear that the reference herein to treatment extends to prophylaxis as well as treatment of established diseases or syndromes.

Further it should be understood that the number of compounds of the present invention, required for the treatment will vary depending on the nature of the disease, the way in which edenia, age and condition of the patient and will be installed, in the end, at the discretion of the attending physician or veterinarian. In General, however, doses used for the treatment of adult patients will be in the range from 2 to 1000 mg per day, depending on the method of administration.

Thus, parenteral application of the daily dose will typically range from 2 to 50 mg, preferably from 5 to 25 mg per day. For oral use daily dose will typically be in the range of from 10 to 1000 mg, e.g. 50 to 500 mg per day.

The desired quantity of a drug can usually be represented as a single dose or as divided doses, as appropriate intervals, for example, as two, three, four or more subds a day.

Although it is possible that when therapeutic use of the compound of the present invention could be introduced in the form of the raw chemical product, at the same time, it is preferable to present the active ingredient as a pharmaceutical composition.

Thus, the invention further relates to pharmaceutical compositions containing a compound of the formula (I) and/or its pharmaceutically acceptable derivatives, together with one or more of their pharmaceutically acceptable carriers and, possibly, other therapeutic and/or prophylactic ingredien the AMI. The carrier(s) must be "acceptable" in the sense of compatibility with other ingredients of the formulation and not dangerous to their recipients.

These compositions of the present invention include compositions that have a form specially prepared for oral, buccal, parenteral, inhalation or insufflation (blowing), implant, vaginal or rectal application.

Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, gum Arabic, gelatin, sorbitol, tragakant, the adhesive starch or polyvinylpyrrolidone; fillers, for example lactose, sugar, microcrystalline cellulose, maize starch, calcium phosphate or sorbitol; lubricants, for example magnesium stearate, stearic acid, talc, polyethylene glycol or silica; agents, disintegrant, for example, potato starch or sodium starch glycolate, or wetting agents such as sodium lauryl sulfate. Tablets can be coated film in accordance with methods known in this field. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product, which is diluted with water or another suitable solvent is m before use. Such liquid preparations may contain conventional additives such as suspendresume agents, for example sorbitol syrup, glucose syrup/sugar, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, gel, aluminum stearate or hydrogenated edible fats; emulsifying agents, for example lecithin, monooleate sorbitol or gum Arabic; anhydrous solvents (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; soljubilizatory, such as surface-active substances such as Polysorbate or other agents, such as cyclodextrins; and preservatives, for example methyl - or propyl p-hydroxybenzoate or ascorbic acid. The composition may also be in the form of suppositories, e.g. containing conventional suppozitornoj bases, such as coconut oil or other glycerides.

For buccal administration of composition may be in the form of tablets or pellets obtained by the traditional method.

The composition in accordance with the present invention may have a shape suitable for parenteral administration by injection or continuous infusion. Compositions for injection can be prepared in the form of a single dose ampoules or in multi-dose containers with an added preservative. Composers the AI may take such form, as suspensions, solutions or emulsions in oily or aqueous solvent, and may contain a composite agents, such as suspendida, stabilizing and/or dispersing agents. Alternative active ingredient may be in powder form which can be diluted with a suitable solvent, such as sterile, pyrogen-free water before use.

Compositions in accordance with the present invention may contain from 0.1 to 99% of active ingredient, traditionally from 1 to 50% for tablets and capsules and 3-50% for liquid medicines.

Effective pharmacokinetic profile of the compounds of the present invention is easy to demonstrate, using the usual procedure for measuring the pharmacokinetic properties of biologically active compounds.

Compounds of the present invention and their pharmaceutically acceptable derivatives can be obtained using the methods described below, the above methods form another aspect of the present invention. In the following description of the group, as defined above, consist of compounds of the present invention, if there is no other approval.

The compounds of formula (I) can be obtained by the reaction of carboxylic acids (II)in which R1, R2and R3have the meanings defined in formula (I), and chirality R3is libo> RorSor their mixture

or an activated derivative with the amine HNR4R5in which R4and R5have the meanings defined in formula (I), under standard conditions of obtaining the amides of the carboxylic acid or activated derivative and amine.

It should be remembered that the mixture of diastereomers of compounds of formula (I)obtained by the above reaction, can be separated using standard techniques for the separation of the products that are well known in this field, such as column chromatography.

Thus, the amide of formula (I) can be obtained by treatment of carboxylic acid of the formula (I) as an activating agent, such as a THIEF (hexaphosphate benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium), TBTU (tetrafluoroborate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium), BOP-Cl (acid chloride bis(2-oxo-3-oxazolidinyl)phosphinic acid), oxalicacid or 1,1'-carbonyldiimidazole in an aprotic solvent such as dichloromethane, optionally in the presence of a Quaternary amine, such as triethylamine, followed by reaction of the product thus formed, for example, an activated derivative of a compound of formula (II)with the amine HNR4R5.

Alternative amide of the formula (I) can be obtained by the interaction of the mixed anhydride, poluchennogo is of the carboxylic acid (II), in which R1, R2and R3have the meanings defined in formula (I) with an amine HNR4R5in an aprotic solvent such as tetrahydrofuran. It is convenient to conduct the reaction at low temperatures, for example, from 25 to -90°C, conveniently at about -78°C.

Mixed anhydride conveniently be obtained by interaction of the carboxylic acid (II) with a suitable acid chloride such as revalorisation, in an aprotic solvent, such as ethyl acetate in the presence of a Quaternary organic bases, such as trialkylamine, such as triethylamine, and at low temperatures, for example from 25 to -90°C, conveniently at about -78°C.

The compounds of formula (I) can also be obtained by reacting the compounds of formula (III)

in which R1, R2and R3have the meanings defined in formula (I), and R6denotes 2-hydroxyphenyl, with 1,1'-carbonyl diimidazol or 1,1'-thiocarbonyldiimidazole in an appropriate solvent, such as dichloromethane and subsequent reaction products formed thereby, with the amine HNR4R5.

The compounds of formula (II) can also be obtained from compounds of formula (III)in which R6denotes 2-hydroxyphenyl, through reaction with 1,1'-carbonyl diimidazol or 1,1'-thiocarbonyldiimidazole in appropriate rest retele, such as dichloromethane and subsequent reaction of the product formed thereby with an aqueous solution of acetone.

The compounds of formula (III)in which R6denotes 2-hydroxyphenyl, can be obtained from corresponding compounds of formula (III)in which R6denotes 2-benzyloxyphenyl by hydrogenolysis using hydrogen and a palladium catalyst.

Alternative compounds of formula (III)in which R6denotes 2-hydroxyphenyl, can be obtained from compounds of formula (IV)

in which R1, R2and R3have the meanings defined in formula (I), R6denotes 2-benzyloxyphenyl, R7denotes benzyloxycarbonyl and R8represents C1-6alkyl, by reaction with hydrogen in the presence of a catalyst of palladium-on-coal and acetic acid. This reaction was successfully carried out in a solvent such as ethanol, triptorelin or mixtures thereof.

The compounds of formula (IV) can be obtained by reacting the hydrochloride of complex aminoether (V)

in which R1has the meaning given in formula (I), and R8represents C1-6alkyl,with aldehyde R3CHO (VI)in which R3has the meaning given in formula (I), in the presence of triethylamine and in a solvent such as triptolide the ol, and then the interaction of the resulting product with the compound of the formula (VII)

in which R1has the meaning given in formula (I), and R7denotes tert-butyloxycarbonyl or benzyloxycarbonyl, and isocyanides CNR6(VIII)in which R6denotes 2-benzyloxyphenyl group, in a solvent such as triptorelin.

The compounds of formula (III)in which R6denotes 2-benzyloxyphenyl group, can be obtained from the compounds of formula (IV)in which R1, R2and R3have the meanings defined in formula (I), and R6denotes 2-benzyloxyphenyl, and R7denotes tert-butyloxycarbonyl by reaction with hydrogen chloride in dioxane, followed by interaction with triethylamine in a solvent such as dichloromethane.

The compound of formula (IV)in which R7denotes tert-butyloxycarbonyl, can be obtained using the method described above in the text of the patent application using the connection formula (VII)in which R7denotes tert-butyloxycarbonyl.

Deputy R2is a 1-methylpropyloxy group, and the compound of formula (I)in which R2denotes 1-methylpropyloxy group having (S)- or (R)-configuration can be obtained by starting the reaction with hydrochloride complicated AMI is ofira (V), in which R2the group has a (S)- or (R)-configuration.

Hydrochloride complex aminoether (V)in which R1has the meaning given in formula (I) and R8stands With1-6alkyl, can be obtained from the corresponding commercially available amino acids, D-alliteration or D-isoleucine, using the method described by Schmidt, U.; Kroner, M.; Griesser, H. Synthesis (1989), (11), 832-5.

Aldehydes R3CHO (VI)in which R3has the meaning given in formula (I)are either commercially available or can be obtained using the methods described in the literature (Comins, Daniel L.; Weglarz, Michael A.; J. Org. Chem.; 53, 19, 1988; 4437-4442).

Amino acid derivative (VII)in which R1has the meaning given in formula (I) and R7denotes tert-butyloxycarbonyl, is commercially available; the derived amino acid (VII)in which R1has the meaning given in formula (I) and R7denotes benzyloxycarbonyl, can be obtained from the corresponding commercially available amino acids (R)-R1CH(NH2)CO2H (IX)in which R1has the meaning given in formula (I), by reacting with N-(benzyloxycarbonyloxy)succinimide and triethylamine in a solvent such as dioxane in water.

Isocyanic CNR6(VIII) can be obtained in accordance with the methods described in the literature (brecht, Roland; Herrmann, Rudolf; Ugi, Ivar,Synthesis, 1985, 4, 400-402).

Acid additive salts of the compounds of formula (I) can be obtained by conventional methods, for example, by treatment of a solution of the compound in a suitable solvent such as dichloromethane or acetone, with a suitable solution of the corresponding inorganic or organic acid.

The following non-limiting examples illustrate embodiments of the present invention.

EXPERIMENTAL PART

Nomenclature

All intermediate and examples are named using ACD Name Pro 6.02 in ISIS Draw.

Abbreviation

CV: the column Volume. One column volume is defined as volume filled with a sorbent in a Packed column. It can be estimated from the mass and density of certain of the used sorbent (1CV=mass divided by density).

The main methods of purification and analysis

Analytical liquid chromatography HPLC was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm × 4.6 mm ID)by elution with 0.1% HCO2H and 0.01 M ammonium acetate in water (solvent A)and 0.05% HCO2H and 5% water in acetonitrile (solvent B), using either a gradient elution 1, 0-0,7 min 0%B, 0.7 to 4.2V min 0-100%B, 4,2-5,3 min 100%B, 5,3-5,5 min 0%, or gradient elution 2, 0-0,7 min 0%B, 0.7 to 4.2V min 0-100%B, 4,2-4,6 min 100%B, 4,6-4,8 min 0%at a flow rate of 3 ml/min Time what I retention (Rt) given in minutes. Mass spectra (MS) were recorded on a Waters ZQ 2000 mass spectrometer, using electrospray positive [ES+to get MH+and M(NH4)+molecular ions] or electrospray negative [ES-to get M-H-molecular ion] types.1H NMR spectra were recorded using a spectrometer Bruker DPX 400 MHz, using tetramethylsilane was used as the external standard.

Purification using a silica gel cartridge concerns chromatography performed using Combiflash® CompanionTMwith Redisep® cartridge supplied Presearch. Hydrophobic Frit belong to the filtration tube set Whatman. SPE (solid phase extraction) relates to the use of cartridges, supplied by International Sorbent Technology Ltd. TLC (thin layer chromatography) relates to the use of plates for thin-layer chromatography, supplied by Merck, coated with silica gel 60 F254.

The intermediate connection 1

MethylN-[(2R)-2-(2,3-dihydro-1N-inden-2-yl)-2-({[(phenylmethyl)oxy]carbonyl}amino)acetyl]-N-[1-(2,6-dimethyl-3-pyridinyl)-2-oxo-2-({2-[(phenylmethyl)oxy]phenyl}amino)ethyl]-D-allowisolation

2,6-Dimethylpyridin-3-carboxaldehyde (Aurora Feinchemie GmbH) (2.00 g, 16,1 mmol) and (D)-alliteration methyl ester hydrochloride (2,93 g, 16,1 mmol) in methanol (50 ml) and 2,2,2-triptoreline (50 ml) clicks sativali by triethylamine (2,24 ml, at 16.1 mmol) and the mixture was stirred in nitrogen atmosphere at room temperature for 20 hours.

(2R)-2,3-dihydro-1N-inden-2-yl-({[(phenylmethyl)oxy]carbonyl}amino)acetic acid (5,24 g, 16,1 mmol) and 2-benzyloxybenzoate (3,37 g, 16,1 mmol) was added and the mixture was stirred in nitrogen atmosphere at room temperature for 4 days. The mixture was concentrated under reduced pressure, then was divided between ethyl acetate (150 ml) and water (150 ml) and saturated aqueous sodium bicarbonate (6 ml). The aqueous phase was back extracted with ethyl acetate (50 ml) and the combined organic extracts successfully washed polysystem aqueous solutions of sodium bicarbonate, ammonium chloride and sodium chloride (100 ml each), dried over anhydrous magnesium sulfate and evaporated under vacuum to obtain the crude product (12,01 g). This product was purified on a Redisep silikagelevye column (330 g)was suirable 20-50% ethyl acetate in cyclohexane to obtain 7,46 g specified in the connection header as a pair of diastereomers.

HPLC Rt=3,88 vs. 3.96 min (gradient 1); m/z [M+H]+=797

Intermediate compound 2

2-{(3R,6R)-3-(2,3-dihydro-1N-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinil}-2-(2,6-dimethyl-3-pyridinyl)-N-(2-hydroxyphenyl)ndimethylacetamide

The crude methylN-[(2R)-2-(2,3-di is Idro-1 N-inden-2-yl)-2-({[(phenylmethyl)oxy]carbonyl}amino)acetyl]-N-[1-(2,6-dimethyl-3-pyridinyl)-2-oxo-2-({2-[(phenylmethyl)oxy]phenyl}amino)ethyl]-D-allowisolation (intermediate compound 1) (7,46 g) was dissolved in ethanol (150 ml) and acetic acid (10 ml), the mixture was first made at 1 atmosphere of H2over 10% palladium-on-coal (Degussa type) (1.8 g moistened with water 1:1 wt./mass.) within 18 hours. The reaction mixture was evaporated under vacuum and the residue was separated between ethyl acetate and water, with saturated aqueous sodium bicarbonate added until the aqueous phase was basic (pH 8). The aqueous phase was extracted with ethyl acetate and the combined organic extracts were washed with saturated aqueous sodium bicarbonate and water in the ratio 3:1 (100 ml), then saturated saline solution before drying over anhydrous magnesium sulfate and evaporation under vacuum. The crude product was purified on a Redisep silikagelevye column (120 g)was suirable 0-10% methanol in ethyl acetate to obtain specified in the connection header as a pair of diastereomers (2,94 g).

HPLC Rt=2,75 and of 2.81 min (gradient 2); m/z [M+H]+=541

Intermediate compound 3

2-{(3R,6R)-3-(2,3-dihydro-1N-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinil}-2-(4,6-dimethyl-3-pyridinyl)-N-{2-[(phenylmethyl)oxy]phenyl}ndimethylacetamide

4,6-Dimethyl-3-pyridine bandaged 1(2,52 g) and methyl-D-alliteration hydrochloride (3.4 g) was dissolved in 2,2,2-triptoreline (50 ml). To this mixture was added triethylamine (2,61 ml) and the reaction mixture was left to stand for 18 hours. (2R)-2,3-dihydro-1N-inden-2-yl({[(1,1-dimethylethyl)oxy]carbonyl}amino)acetic acid (5,44 g) and 2-[(phenylmethyl)oxy]phenylisocyanate (4,18 g) with methanol (10 ml) was added to the reaction mixture and the solution was stirred at room temperature for 3 days. The solvent was removedin vacuoand the residue was separated between dichloromethane and water. The organic phase was passed through a hydrophobic Frits and evaporated in vacuum. The residue was dissolved in 4N hydrogen chloride in dioxane (50 ml) and the reaction mixture was left to stand for 4 hours. The solvent was removedin vacuoand the residue was dissolved in dichloromethane (200 ml). To it was added triethylamine (20 ml) and the reaction mixture was left to stand for 20 hours. The reaction mixture was separated between dichloromethane and water. The organic phase was passed through a hydrophobic Frits and evaporatedin vacuo. The precipitate was sent in 4×90 g Biotage column and suirable cyclohexane/ethyl acetate (1:1, 1:2 vol./about.) and ethyl acetate. The required fractions were combined and evaporatedin vacuoto obtain 2-{(3R,6R)-3-(2,3-dihydro-1N-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinil}-2-(4,6-dimethyl-3-pyridinyl)- -{2-[(phenylmethyl)oxy]phenyl}ndimethylacetamide (of 5.55 g, 47%) as a yellow-brown foam.

HPLC Rt=3,43, of 3.45 min (gradient 1); m/z [M+H]+=631

Link:

1Comins, Daniel L.; Weglarz, Michael A.; J. Org. Chem.; 53; 19; 1988; 4437-4442.

Intermediate compound 4

2-{(3R,6R)-3-(2,3-dihydro-1N-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinil}-2-(4,6-dimethyl-3-pyridinyl)-N-(2-hydroxyphenyl)ndimethylacetamide

2-{(3R,6R)-3-(2,3-dihydro-1N-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinil}-2-(4,6-dimethyl-3-pyridinyl)-N-{2-[(phenylmethyl)oxy]phenyl}ndimethylacetamide (intermediate compound 3) (3,30 g) was dissolved in ethanol (75 ml) and was first made over palladium-on-coal (moistened with 10% Pd, 0.50 g) for 20 hours. The catalyst was removed by filtration and washed with dichloromethane. The combined filtrate and washings evaporatedin vacuo.The precipitate was sent to 90 g Biotage column and suirable with ethyl acetate. The required fractions were combined and evaporated toin vacuoto obtain 2-{(3R,6R)-3-(2,3-dihydro-1N-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinil}-2-(4,6-dimethyl-3-pyridinyl)-N-(2-hydroxyphenyl)ndimethylacetamide (2,43 g, 87%) as a pale yellow solid.

HPLC Rt=2,86 min (gradient 1); m/z [M+H]+=541.

The intermediate compound 5

Hydrochloride {(3R,6R)-3-(2,3-dihydro-1N-inden-2-yl)-6-[(1 )-1-methylpropyl]-2,5-dioxo-1-piperazinil}(2,6-dimethyl-3-pyridinyl)acetic acid

2-{(3R,6R)-3-(2,3-dihydro-1N-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinil}-2-(4,6-dimethyl-3-pyridinyl)-N-(2-hydroxyphenyl)ndimethylacetamide (24,25 g, 45 mmol) (intermediate compound 2) and 1,1'-carbonyldiimidazole (11,7 g, 72 mmol) was dissolved in dry dichloromethane (200 ml) and left to stand in an atmosphere of nitrogen for 20 hours. The solvent was removedin vacuoand the residue was dissolved in acetone (200 ml) and 2N hydrochloric acid (20 ml). After stirring for 20 h the solvent was removedin vacuoand the residue was dissolved in methanol (50 ml). The solution was applied on aminopropionic cartridge (2×70 g) and suirable methanol (250 ml)and then 10% acetic acid in methanol (250 ml). The required fractions were combined and evaporatedin vacuo.The residue was treated with 2N hydrochloric acid and the resulting solution evaporatedin vacuoobtaining specified in the title compound hydrochloride {(3R,6R)-3-(2,3-dihydro-1N-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinil}(2,6-dimethyl-3-pyridinyl)acetic acid as a yellow-brown solid (12,21 g, 56%).

HPLC Rt=2,48 min (gradient 2); m/z [M+H]+=450.

The intermediate compound 6

(2R)-2,3-dihydro-1N-inden-2-and the({[(phenylmethyl)oxy]carbonyl}amino)acetic acid

(2R)-amino(2,3-dihydro-1N-inden-2-yl)acetic acid (1,91 g, 10 mmol) suspended in dioxane (10 ml) and water (10 ml). To this mixture was added triethylamine (1.7 ml) and N-(benzyloxycarbonyloxy)succinimide (2,54 g), the reaction mixture was rapidly stirred at room temperature for 2 days. The reaction mixture was poured into water (50 ml) and was extracted with chloroform (100 ml). The organic phase is washed with 1N hydrochloric acid (50 ml) and water (50 ml). Next was dried over magnesium sulfate, the solvent was removedin vacuoobtaining specified in the connection header (of 3.06 g, 94%):

1H NMR (CDCl3) δ 7,40-7,29 (m, 5H), 7,21-7,11 (m, 4H), 5,28 (d, 1H, J=8.6 Hz), 5,11 (s, 2H), 4,57 (m, 1H), 3,14-and 2.79 (m, 5H); LCMS m/z 326 (MH+), Rt at 3.35 min (gradient 2).

Example 1

(2R)-2-{(3R,6R)-3-(2,3-dihydro-1N-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinil}-2-(2,6-dimethyl-3-pyridinyl)-N-methylethanamine

2-{(3R,6R)-3-(2,3-dihydro-1N-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinil}-2-(4,6-dimethyl-3-pyridinyl)-N-(2-hydroxyphenyl)ndimethylacetamide (intermediate compound 2) (0.400 g, of 0.74 mmol) and 1,1'-carbonyldiimidazole (0,192 g, 1.18 mmol) in dry dichloromethane (10 ml) was stirred at room temperature in an atmosphere of N2within 7 hours. The mixture was treated with a 2M solution of methylamine in tetrahydrofuran (UAH 1,849 ml, 3,70 IMO is) and left to stand overnight at room temperature. The solvent was removed by blowing in an atmosphere of N2and the residue was purified on Redicep silikagelevye column (35 g)was suirable 0-10% methanol in ethyl acetate, followed by purification on a Kromasil KR100-10-C18 column, reverse phase sequence, elyuirovaniya water acetonitrile (20-45% MeCN)containing 0.1% formic acid. This gives specified in the title compound as a white lyophilisate (30%) after freeze-drying of 1,4-dioxane.

HPLC Rt=2,44 min (gradient 1); m/z [M+H]+=463

1H NMR (CDCl3) δ 7,63 (d, 1H), 7,25-to 7.15 (m, 4H), 7,05 (d, 1H), 6,79 (d, 1H), 5,96 (square, 1H), 5,35 (s, 1H), 4,07 (DD, 1H), 3,88 (d, 1H), 3,19-is 2.88 (m, 4H), 2,85 (d, 3H), 2,81-by 2.73 (m, 1H), has 2.56 (s, 3H), by 2.55 (s, 3H), 1,82-to 1.67 (m, 2H), 1,20-1,08 (m, 1H), 0,99 (d, 3H), of 0.90 (t, 3H).

Similarly prepared from intermediate 2 and dimethylamine (2.0m in tetrahydrofuran):

Example 2

(2R)-2-{(3R,6R)-3-(2,3-dihydro-1N-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinil}-2-(2,6-dimethyl-3-pyridinyl)-N,N-dimethylethanamine

as a white lyophilisate (33%) after freeze-drying of 1,4-dioxane.

HPLC Rt=2,69 min (gradient 1); m/z [M+H]+=477

1H NMR (CDCl3) δ 7,49 (d, 1H), 7,27-to 7.15 (m, 4H), was 7.08 (d, 1H), 6,66 (s, 1H), 6.30-in (d, 1H), 4,10 (DD, 1H), 4,05 (d, 1H), 3,22-is 3.08 (m, 3H), 2,99-2,84 (m, 4H), 2,80-2,70 (m, 4H), 2.63 in (s, 3H), 2,58 (s, 3H), 1,65-of 1.53 (m, 1H), 0,97-0,78 (m, 2H), of 0.71 (t, 3H), and 0.46 (d, 3H).

Similarly prepared from intermediate joint is 2 and research (3.7 mmol):

Example 3 (Method A)

(3R,6R)-3-(2,3-dihydro-1N-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinyl

as a white lyophilisate (88 mg, 23%) after freeze-drying of 1,4-dioxane.

HPLC Rt=2,70 min (gradient 2); m/z [M+H]+=519

1H NMR (CDCl3) δ 7,49 (d, 1H), 7,27-to 7.15 (m, 4H), 7,10 (d, 1H), of 6.68 (s, 1H), 6,40 (d, 1H), 4,10 (DD, 1H), 4,01 (d, 1H), 3,74-to 3.52 (m, 5H), 3,28-of 3.07 (m, 5H), 2,97-2,84 (m, 2H), 2,79-a 2.71 (m, 1H), 2,62 (s, 3H), 2,59 (s, 3H), 1,65-of 1.53 (m, 1H), 0,98 is 0.80 (m, 2H), 0,70 (t, 3H), 0,45 (d, 3H).

Example 3 (Method B)

(3R,6R)-3-(2,3-dihydro-1N-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinyl

The suspension of the hydrochloride {(3R,6R)-3-(2,3-dihydro-1N-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinil}(2,6-dimethyl-3-pyridinyl)acetic acid (5.0 g, or 10.3 mmol) (intermediate compound 5) in dry dichloromethane (50 ml) was treated with 1,1-carbonyl diimidazol (2.6 g, 16 mmol) and the reaction mixture was stirred in nitrogen atmosphere for 18 hours. Morpholine (4.8 ml, 55 mmol) was added and the resulting solution was left to stand in an atmosphere of nitrogen for 18 hours. The solvent was removedin vacuoand the residue was separated between ethyl acetate and water. The organic phase is washed the Li salt solution and dried over anhydrous magnesium sulfate. The solvent was removedin vacuoand the residue was dissolved in dichloromethane. The resulting mixture was applied on the basic cartridge from aluminum oxide (240 g) and suirable using gradient 0-7,5% methanol in diethyl ether (9CV), 7.5 to 10% methanol in diethyl ether (1CV) and 10% methanol in diethyl ether (1V). The required fractions were combined and evaporatedin vacuoobtaining (3R,6R)-3-(2,3-dihydro-1N-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinone in the form of a white solid (2.4 g, 45%).

HPLC Rt=2,72 min (gradient 2); m/z [M+H]+=519.

Example 4

(2R)-2-{(3R,6R)-3-(2,3-dihydro-1N-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinil}-2-(4,6-dimethyl-3-pyridinyl)-N,N-dimethylethanamine

2-{(3R,6R)-3-(2,3-dihydro-1N-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinil}-2-(4,6-dimethyl-3-pyridinyl)-N-(2-hydroxyphenyl)ndimethylacetamide (intermediate compound 4) (0,700 g) and 1,1'-carbonyldiimidazole (0,324 g) was dissolved in dry dichloromethane (20 ml) and left to stand for 20 hours. One half of this solution (10 ml) was added 2.0 M solution of dimethylamine in tetrahydrofuran (5 ml) and the reaction mixture was left to stand for 3 days. The reaction mixture was separated between dichloromethane and saturated water is the first sodium bicarbonate solution. The organic phase was passed through a hydrophobic Frits and evaporated in vacuum.The residue was applied onto a silica gel cartridge (10 g) and suirable with ethyl acetate and then 5% methanol in ethyl acetate. The required fractions were evaporated toin vacuoand the residue was purified using Mass Directed AutoPrep. This gives (2R)-2-{(3R,6R)-3-(2,3-dihydro-1N-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinil}-2-(4,6-dimethyl-3-pyridinyl)-N,N-dimethylethanamine (0.10 g, 32%) as a white foam.

HPLC Rt=2,82 min (gradient 1); m/z [M+H]+=477

1H NMR (CDCl3) δ 8,32 (s, 1H), 7,26-to 7.15 (m, 4H), was 7.08 (s, 1H), of 6.71 (s, 1H), 6,16 (d, 1H), 4,17 (d, 1H), 4,10 (DD, 1H), 3,22-of 3.06 (m, 3H), 2,98 (s, 3H), 2.91 in (m, 1H), 2,74 (DD, 1H), to 2.67 (s, 3H), 2.57 m (s, 3H), 2,39 (, 3H), and 1.56 (m, 1H), 0,93 (m, 1H), 0,85 (m, 1H), of 0.68 (t, 3H), 0,45 (d, 3H).

Similarly prepared from intermediate 4 and methylamine:

Example 5

(2R)-2-{(3R,6R)-3-(2,3-dihydro-1N-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinil}-2-(4,6-dimethyl-3-pyridinyl)-N-methylethanamine

HPLC Rt=2,60 min (gradient 1); m/z [M+H]+=463

1H NMR (CDCl3) δ 8,48 (s, 1H), 7,25-7,14 (m, 4H),? 7.04 baby mortality (s, 1H), 6,72 (d, 1H), 6,07 (square, 1H), the 5.45 (s, 1H), 4,07 (DD, 1H), 3,90 (d, 1H), 3,17 totaling 3.04 (m, 3H), of 2.92 (m, 1H), 2,86 (d, 3H), was 2.76 (DD, 1H), 2,53 (s, 3H), 2,33 (, 3H), of 1.70 (m, 2H), 1,12 (m, 1H), were 0.94 (d, 3H), of 0.87 (t, 3H).

Similarly prepared from intermediate 4 and of the research:

Example 6

(3R,6R)-3-(2,3-dihydro-1N-inden-2-yl)-1-[(1R)-1-(4,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinyl

HPLC Rt=2,94 min (gradient 2); m/z [M+H]+=519

1H NMR (CDCl3) δ a 8.34 (s, 1H), 7,25-to 7.15 (m, 4H), to 7.09 (s, 1H), of 6.71 (s, 1H), 6,21 (d, 1H), 4,14-4,07 (m, 2H), of 3.73-3,47 (m, 5H), 3,23 was 3.05 (m, 5H), 2.95 and-and 2.83 (m, 2H), 2,74 (DD, 1H), 2,58 (s, 3H), of 2.38 (s, 3H), and 1.56 (m, 1H), 0,94 (m, 1H), 0,86 (m, 1H), of 0.68 (t, 3H), 0,44 (d, 3H).

Biological activity

Examples 1-6 of the present invention was tested in all biological tests described below. The results for each compound are presented in the table below. For comparison, the table also includes the connection X.

Biological test 1

The definition of antagonistic affinity of receptors for oxytocin-1 person using FLIPR

Cell culture

Adhesive cells Chinese hamster ovary (CHO)stably expressing the recombinant receptor oxytocin-1 man (hOT), maintained in culture in DMEM:F12 (Sigma, cat. No D6421), was added 10% warm inactivated amniotic calf serum (Gibco/Invitrogen, cat. No. 01000-147), 2 mm L-glutamine (Gibco/Invitrogen, cat. No. 25030-024) and 0.2 mg/ml G418 (Gibco/Invitrogen, cat. No. 10131-027). Cells were grown as monolayers in an atmosphere of air:CO2in the ratio of 95%:5% at a temperature of 37°C and perseval every 3-4 days using TrypLETMExpress (Gibco/nvitrogen, cat. No. 12604-013).

Measurement of [Ca2+] using FLIPRTM

CHO-hOT cells were sown framed in black 384-well plates (Nunc) with a transparent basis at a density of 10,000 cells per well in culture medium, as described above, and kept overnight (95%:5%air:CO2at 37°C). After removal of culture medium, the cells were incubated for 1 hour at 37°C in Tyrode medium (NaCl, 145 mm; KCl, 2.5 mm; HEPES, 10 mm; glucose, 10 mm; MgCl2, 1.2 mm; CaCl21.5 mm)containing probenecid (0.7 mg/ml), the cytoplasmic calcium indicator, Fluo-4 (4 μm; Teflabs, USA) and a quenching agent, Brilliant Black (black Diamond) (250 μm; Molecular Devices, UK). Then cells were incubated for an additional 30 min at 37°C either with buffer or with buffer containing antagonist, prior to placing the cells in the FLIPRTM(Molecular Devices, UK) to monitor cell fluorescence (λex=488 nm, λEM=540 nm) before or after addition of a submaximal concentration of oxytocin (ES).

Data analysis

Functional response using FLIPR were analyzed using Activity Base Version 5.0.10.

Biological test 2

Analysis of the binding of oxytocin

Drugs

Membranes were prepared from Cho cells expressing recombinant receptors oxytocin person. The membrane preparation was frozen in aliquot at -70°C until used for the output.

Protocol analysis of binding

Membrane (~50 µg) were incubated in 200 ál analytical buffer (50 mm Tris, 10 mm MgCl2and 0.1% bovine serum albumin, pH 7.5)containing ~2,4 nm [3H]-oxytocin in the absence (total binding) or presence (without specific binding) of 1 μm unlabelled oxytocin and elevated concentrations of the compounds of examples 1-6 and comparative compounds. Incubation was performed at room temperature for 60 minutes the Reaction was stopped by 3 ml of ice-cold buffer and filtered through Whatman GF/C filter paper pre-soaked in 0.3% polyethylenimine. The filters were washed 4 times with 3 ml of buffer, using the cell header Brandela. The filters consisted of 3 ml of Ready Safe scintillation fluid (Beckman).

Specific binding was approximately 90% of total binding.

Data analysis

IC50values determined from competitive binding experiments using the analysis of nonlinear regression (GraphPad), and converted to Ki using the method of Cheng and Prusoff, 1974. Data are presented as mean values.

Biological test 3

Determination of in vitro own clearance in microsomes

NADP regeneration buffer for use in the incubations was freshly prepared on the day of analysis. It contained 7.8 mg glucose-6-FOSFA is (monosodium salt), 1.7 mg NADP and 6 units of glucose-6-phosphate dehydrogenase in 1 ml of 2% sodium bicarbonate. Microsome assay (human, female; macaques-Griboedov, females, dogs, bitches; rats, females), prepared in pH 7.4 phosphate buffer, containing 0.625 mg of protein/ml

Unless otherwise noted, all subsequent steps were performed using the Tecan Genesis RSP 150/8. 1.25 mm stock solution of the compounds were prepared in a mixture of acetonitrile/water (1:1). 25 μl of 1.25 mm stock solution was added to 600 μl of a mixture of acetonitrile/water (1:1) to obtain a 50 μm solution. For each sample, 50 μm solutions (10 ál) was added to the microsomes (790 μl) in a microplate (Porvair, 96 wells, square).

400 μl of microsomal solution containing the compound was transferred to a microplate (Porvair, 96 well, round) and pre-washed at 37°C for 5 min before initiating the incubation. All incubation was initiated by adding 100 ál of NADP regeneration system to a pre-washed the microsomes. The mixture was incubated at 37°C in Techne heating unit. Following 0, 3, 6, 12 and 30 min incubation took 20 ál aliquots and added to 100 μl of acetonitrile containing internal standard.

To determine the speed of metabolism incubation was performed at the concentration of the compound of 0.5 μm and a protein concentration of 0.5 mg/ml concentration of the solvent during the incubation was 0.5%.

Concentrations tested with the of dinani were determined using LC/MC/MC; the results are presented as the ratio of the analyzed substance:the peak area of the internal standard.

The rate of disappearance was calculated by adjusting a single exponential decay curve based concentration - time using Excel, and own clearance was calculated using the following formula:

Results

Examples 1-6 of the present invention and comparative compound X=(2R)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazinyl-1-yl]-N,N-dimethyl-2-(6-methylpyridin-3-yl)ethanamide (example 209 in WO 03/053443) tested in the above assays.

Comparative compound X when tested in biological tests 1 and 2 showed activity similar to that demonstrated a connection 1-6 of the present invention, in fact, each of these compounds demonstrated fpKi between an 8.1 and 9.2 (Biological test 1) and pKi between an 8.8 and 10.5 (Biological test 2).

However, compounds of the present invention showed remarkable improvementin vitroown clearance in microsomes (biological test 3) in comparison with the comparative compound X.

Biological test 3Microsomal Cl (m) - Rev./min/g)
RatDogMacaque-havingPeople
Comparative compound X++++++++
Example 1++++
Example 2++++,++++,+
Example 3++++
Example 4+,++,+++++,++++++,+
Example 5++++++
Example 6++++++

The key to that is the person:

+matches 1-8 ml/min/mg;

++corresponds 9-15 ml/min/mg;

+++match 16-20 ml/min/mg;

++++corresponds 21-30 ml/min/mg;

+++++match>31 ml/min/mg.

1. Piperazinone General formula (I)

in which R1means 2 indanyl, R2mean 1-methylpropyl, R3means 2,6-dimethyl-3-pyridyl, R4and R5together with the nitrogen atom to which they are attached, represent morpholinopropan, and its pharmaceutically acceptable salt accession acid in which the acid is selected from hydrochloric acid, Hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, econsultancy acid, benzosulfimide and p-toluensulfonate acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, succinic acid, fumaric acid and maleic acid.

2. The compound according to claim 1, which represents the (3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinyl bansilalpet.

3. The compound according to claim 1, which represents the (3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinyl.

4. Pharmaceutical composition having antagonist of the economic effect on the oxytocin receptor, comprising the compound according to claim 1 in an effective amount and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition according to claim 4, comprising the compound according to claim 2 and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition according to claim 4, comprising the compound according to claim 3 and a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) and their pharmaceutically acceptable salts as chemokine receptor CCR3 activity modulators, a pharmaceutical composition based on the said compounds, to synthesis method and use thereof. Said compounds can be used for treating and preventing diseases mediated by chemokine receptor CCR3 activity, such as inflammatory and allergic diseases etc. In general formula , R1 represents phenyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo [5,4-b]pyridinyl, benzothiazolyl, benzoxazolyl, pyridinyl, where each of the said phenyl or heterocycles can be substituted with one, two or three radicals R2; R2 each independently represents (C1-C6)halogenalkyl, halogen, COOR3; CONR3R4; R3 represents H or (C1-C6)alkyl; R4 represents H or (C1-C6)alkyl, R5 represents (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl; R6 each independently represents (C1-C6)alkoxy, (C1-C6)halogenalkyl, halogen, OR3, CN, CONR3R4; A represents C(CH3)2-CH2-CH2-, CH2-CH2-CH2- or B represents phenyl; D-E represents CH-CH2- or C=CH-, X-W-V represents N-C=CR7 or C=C-NR7; R7 represents H or (C1-C6)alkyl; Y represents NR4, O, S(O)n; i, j, m each equals 1, n equals 0 or 2.

EFFECT: increased effectiveness of using said compounds.

13 cl, 37 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula I and their pharmaceutically acceptable salts which have inhibitory properties towards mGluR5. In formula I , P represents phenyl; R1 is bonded to P through a carbon atom on ring P and is selected from a group consisting of halogen, C1-6alkylhalogen, OC1-6alkylhalogen, C1-6alkyl, OC1-6alkyl and C0-6alkylcyano; X1 is selected from a group consisting of N, NR4 and CR4; X2 is selected from a group consisting of C and N; X3 is selected from a group consisting of N and O; X4 is selected from a group consisting of N and O; X5 is selected from a group consisting of a bond, CR4R4', NR4, O, S, SO, SO2; X6 represents N; X7 is selected from a group consisting of C and N; Q represents triazolyl.

EFFECT: invention also relates to a pharmaceutical composition containing a therapeutically effective amount of the disclosed compound as an active ingredient, use of the compound in making a medicinal agent for treating disorders mediated by mGluR5 and to a method of inhibiting activation of mGluR5 receptors.

25 cl, 82 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a morpholine type cinnamide derivative with general formula I or its pharmacologically acceptable salt, where (a) R1, R2 , R3 and R4 are identical or different and each represents a hydrogen atom or C1-6alkyl group; X1 represents a C1-6alkylene group, where the C1-6alkylene group can be substituted with 1-3 hydroxyl groups or C1-6alkyl groups, or a C3-8cycloalkyl group formed by two C1-6alkyl groups all bonded to the same carbon atom of the C1-6alkylene group; Xa represents a methoxy group or a fluorine atom; Xb represents an oxygen atom or a methylene group, under the condition that Xb represents only an oxygen atom when Xa represents a methoxy group; and Ar1 is an aryl group, pyridinyl group which can be substituted with 1-3 substitutes selected from A1 group of substitutes; (b) Ar1-X1- represents a C5-7cycloalkyl group condensed with a benzene ring, where one methylene group in the C5-7cycloalkyl group can be substituted with an oxygen atom, the C5-7cycloalkyl group can be substituted with 1-3 hydroxyl groups and/or C1-6alkyl groups, and R1, R2, R3, R4, Xa and Xb assume values given in (a); (d) Ar1-X1- and R4 together with the nitrogen atom bonded to the Ar1-X1- group and the carbon atom bonded to the R4 group form a 5-7-member nitrogen-containing heterocyclic group which is substituted with an aryl group or a pyridinyl group, where one methylene group in the 5-7-member nitrogen-containing heterocyclic group can be substituted with an oxygen atom, and the aryl or pyridinyl group can be substituted with 1-3 substitutes selected from A1 group of substitutes, Xb is an oxygen atom, and R1, R2, R3 and Xa assume values given in (a) and (b); group A1 of substitutes: (1) halogen atom. The invention also relates to a pharmaceutical composition containing a formula I compound, which is useful in treating Alzheimer's disease, senile dementia, Down syndrome or amyloidosis.

EFFECT: obtaining novel morpholine type cinnamide derivatives with inhibitory effect on amyloid-β production.

17 cl, 9 tbl, 113 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of formula (I) or to salts thereof: , where R1 is a hydrogen atom, amino group, R11-NH-, where R11 is a C1-6alkyl group, hydroxy-C1-6alkyl group, C1-6alkoxycarbonyl-C1-6alkyl group, R12-(CO)-NH-, where R12 is a C1-6alkyl group or C1-6alkoxy-C1-6alkyl group, C1-6alkyl group, hydroxy-C1-6-alkyl group, C1-6alkoxy group or C1-6alkoxy-C1-6alkyl group; R2 is a hydrogen atom, C1-6alkyl group, amino group or di-C1-6alkylamino group; one of X and Y represents a nitrogen atom, while the other represents a nitrogen or oxygen atom; ring A is a 5- or 6-member heteroaryl ring or benzene ring which can have 1 or 2 halogen atoms; Z is a single bond, methylene group, ethylene group, oxygen atom, sulphur atom, -CH2O-, -OCH2-, -NH-, -CH2NH-, -NHCH2-, -CH2S- or -SCH2-; R3 is hydrogen or a halogen atom, or C1-6alkyl group, C3-8cycloalkyl group, C6-10aryl group, 5- or 6-member heteroaryl group, where these groups can have 1 or 2 substitutes selected from a group of α substitutes: and [group of α substitutes] group of α substitutes is a group consisting of a halogen atom, cyano group, C1-6alkyl group, C1-6alkoxy group, C1-6alkoxycarbonyl group, C3-8cycloalkyl group, C1-6alkenyl group and C1-6alkynyl group; R4 is a hydrogen atom or halogen atom; except compounds in which all of R1, R2 and R4 represent a hydrogen atom while Z represents a single bond or R3 is a hydrogen atom; as well as a pharmaceutical composition and a medicinal agent with antifungal activity, based on these compounds, to an antifungal agent and use of formula I compounds for preparing an antifungal agent.

EFFECT: novel compounds with excellent antifungal effect are obtained and described.

36 cl, 228 ex, 8 tbl

FIELD: medicine.

SUBSTANCE: invention refers to compounds of formula I or formula II, to their pharmaceutically acceptable salts, enantiomers and diastereoisomers as metalloprotease inhibitors, and also to a pharmaceutical composition based thereon and to versions of application thereof. Said compounds can find application in treatment of the diseases mediated by activity of metalloproteases, Her-2 SHEDDASE, ADAM-10 and ADAM-17, such as arthritis, cancer, cardiovascular disorders, skin diseases, inflammatory and allergic conditions, etc. In general formula I or II: A represents CWNHOH; B represents CH2; G represents CH2; D represents oxygen; X represents CH2NRb; Y represents CH2; M represents C; U is absent or represents NRb; V is absent or represents phenyl, or 4-10-members heterocyclyl containing 1-2 heteroatoms chosen from N and S, substituted with 0-5 groups Re; U' is absent or represents C1-10alkylene, O or combinations thereof; V' represents H, C1-8alkyl, NRbRc, C6-10carbocyclyl substituted with 0-3 groups Re, or 5-14-members heterocyclyl containing 1-3 heteroatoms chosen from N, O and C substituted with 0-4 groups Re; Ra and Re, independently represents H, T, C1-8alkylene-T, C(O)NRa'(CRb'Rc')r-T, (CRb'Rc')r-O-(CRb'Rc')r-T, OH, Cl, F, CN, NO2, NRIRII, COORIV, ORIV, CONRIRII, C1-8halogenalkyl, C3-13carbocyclyl; Rb and Rc independently represents H, T, C1-6alkylene-T, C(O)O(CRb'Rc')r-T, C(O)(CRb'Rc')r-T, S(O)p(CRb'Rc')r-T; T represents H, C1-10alkyl substituted with 0-1 groups Rb'; C3-6carbocyclyl, 5-6-members heterocyclyl containing one oxygen atom; Ra' Rb' and Rc' independently represents H, ORIV or phenyl; R1 represents hydrogen; R2 represents hydrogen; R3 represents: (i) C1-10alkyl; (ii) 4-14-members heterocyclyl containing 1-3 nitrogen atoms optionally substituted with one or two substitutes chosen from C1-6alkyl, OR13, 5-10-members heterocyclyl containing 1-3 heteroatoms chosen from N O and C, or phenyl; (iii) NR16R17; R4 represents H; R4' represents H; R5' represents H; W represents oxygen; R13 represents C1-C6alkyl; R16 and R17 independently represents C1-C10alkyl or phenyl where each is optionally substituted with one C1-4alkyl; RI and RIIindependently represents H or C1-6alkyl; RIV represents C1-6alkyl; i is equal to 0; p is equal to 1 or 2 and r is equal to 0, 1 or 2; provided that a) a spiro ring represents a stable chemical base unit and b) NR8 and NRb do not contain neither N-N, nor N-O bonds.

EFFECT: higher efficiency of the composition and method of treatment.

54 cl, 1 tbl, 9 dwg, 284 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives (indole-3-yl)heterocyclic compounds of formula 1: , where: A represents 5-member aromatic heterocyclic ring, where X1, X2 and X3 are independently selected from N, O, S, CR; R means H, (C1-4)alkyl; or R, when it is available in X2 or X3, may form 5-8-member ring together with R3; R1 means 5-8-member saturated carbocyclic ring, which unnecessarily contains heteroatom O; R2 means H; or R2 is connected to R7 with creation of 6-member ring, which unnecessarily contains heteroatom O, or where mentioned heteroatom is connected to position 7 of indole ring; R3 and R4 independently mean H, (C1-6)alkyl, which is unnecessarily substituted with OH, (C1-4)alkyloxy; or R3 together with R4 and N, with which they are connected, creates 4-8-member ring, which unnecessarily contains additional heteroatom, selected from O and S, and unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy or (C1-4)alkyloxy-(C1-4)alkyl; or R3 together with R5 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; or R3 together with R, when present in X2 or X3, creates 5-8-member ring; R5 means H; or R5 together with R3 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; R5' means H; R6 means one substituent selected from H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; R7 means H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; or R7 is connected to R2 with creation of 6-member ring, which unnecessarily contains additional heteroatom O, and where heteroatom is connected to position 7 of indole ring; or its pharmaceutically acceptable salt. Compounds of formula I display activity of agonists to cannabinoid receptor CB1.

EFFECT: possibility to use them for treatment of pains of various nature.

10 cl, 1 tbl, 42 ex

FIELD: medicine.

SUBSTANCE: invention is related to compounds with common formulae I , III , IV and V , value of radicals such as given in formula of invention. Also suggested invention is related to pharmaceutical composition in the basis of above-mentioned compounds, to their use, and also to method of frequent urination treatment, enuresis and increased activity of urinary bladder.

EFFECT: increased efficiency of diseases treatment, in particular for treatment of frequent urination and enuresis, increased activity of urinary bladder and pain.

16 cl, 406 ex, 73 tbl

V:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (ZP) , in which U is a CH group, V is an oxygen atom, W is a hydroxyl-substituted heterocycloalkylene group which contains 5 to 7 atoms in the ring, including an N atom as a heteroatom, X is an oxygen atom, Y is , Z is C1-C6-alkylene group. Invention also relates to use of invented compounds to produce compounds of formula (I) , in which A is a nitrogen atom or CH group.

EFFECT: wider field of use of compounds.

6 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I), compounds, , their pharmacologically acceptable salt, solvate and hydrate, where A is an alkylene group, alkenyl group, alkynyl group, heteroalkylene group, cycloalkylene group, heterocylcoalkylene group, arylene group or heteroarylene group, where each of the said groups can be substituted, Q is CR4, X is CR7 or N, Y is CR6 or N, n equals 1, 2 or 3, m equals 1, 2 or 3, R1 is H, F, Cl, Br, I, OH, NH2, alkyl group or heteroalkyl group, R is H, F or Cl, R3 is H, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, alkylaryl group or heteroarylalkyl group, where each of the said groups can be substituted with one, two or more halogen atoms or amino groups, R4 is hydroxy, a group with formula OPO3R92 or OSO3R10 or a heteroalkyl group, containing at least one OH, NH2, SO3R10, PO3R92 or COOH group or ester group of natural amino acid or its derivative, where R9 groups independently represent H, alkyl, cycloalkyl, aryl or aralkyl, and R10 is H, alkyl, cycloalkyl, aryl or aralkyl, and further values of R5, R6, R7 and R8 are given in the formula of invention. The invention also relates to pharmaceutical compositions with antibacterial activity, containing compounds described above, as well as to use of formula (I) compounds and a pharmaceutical composition for treating bacterial infection.

EFFECT: new compounds are obtained and described, which can be used as antibacterial agents and which are effective against multi-drug resistant bacteria.

18 cl, 32 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns compounds of the formula and other compounds listed in cl. 1 of invention claim, and pharmaceutical composition based on them, as well as method of mGluR5 receptor activity inhibition involving claimed compounds.

EFFECT: application in treatment and prevention of diseases mediated by mGluR5 receptor activity.

4 cl, 18 dwg, 1009 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula I and their pharmaceutically acceptable salts which have inhibitory properties towards mGluR5. In formula I , P represents phenyl; R1 is bonded to P through a carbon atom on ring P and is selected from a group consisting of halogen, C1-6alkylhalogen, OC1-6alkylhalogen, C1-6alkyl, OC1-6alkyl and C0-6alkylcyano; X1 is selected from a group consisting of N, NR4 and CR4; X2 is selected from a group consisting of C and N; X3 is selected from a group consisting of N and O; X4 is selected from a group consisting of N and O; X5 is selected from a group consisting of a bond, CR4R4', NR4, O, S, SO, SO2; X6 represents N; X7 is selected from a group consisting of C and N; Q represents triazolyl.

EFFECT: invention also relates to a pharmaceutical composition containing a therapeutically effective amount of the disclosed compound as an active ingredient, use of the compound in making a medicinal agent for treating disorders mediated by mGluR5 and to a method of inhibiting activation of mGluR5 receptors.

25 cl, 82 ex

Pyrazoles // 2381217

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), where one of R1 and R2 is hydrogen or alkyl, and the other is (CH2)PY, where p=0 or 1, Y is a saturated mono-, bi- or tricyclic 5-10-member cycloalkyl ring optionally substituted with alkyl, or R1 and R2 together with N form a 7-10-member saturated bicyclic ring Z, optionally substituted with halogen, or a 5-7-member monocyclic ring Z, optionally substituted with alkyl, phenyl, phenylalkyl or pyridinyl; R3 is [2,2']bithiophenyl, 1-methylindole, 2,3-dihydrobenzo[1,4]dioxin, benzo[1,3]dioxole, benzothiophene, dibenzofuran, furan, naphthalene, quinoline, thianthrene, thiophene or pyrrole, or biphenyl substituted with halogen, or phenyl optionally substituted with one or more amino, cyano, formyls, halogens, hydroxyl, hydroxymethyls, acyls, acylamino, alkoxy, nitro, trifluoromethoxy, trifluoromethyls, phenoxy or benzyloxy, or R3 is a group, where Ar is phenyl substituted with halogen; and R4 is alkyl; and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition with inhibitory activity towards the 11β-hydroxysteroid dehydrogenase1 (11(β-HSD1) enzyme.

EFFECT: pyrazole composition is disclosed.

22 cl, 1 tbl, 116 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new indolylmaleimide derivatives with formula I , where: Ra is H; C1-C4alkyl; one of Rb, Rc, Rd and Re is C1-C4alkyl, and the others are H; or Rb, Re, Rd and Re are all H; and R is a radical with formula (a), (b) and (c), presented in the claim.

EFFECT: compounds inhibit protein kinase C (PKC), which allows for their use in making a medicinal agent for treating or preventing diseases or disorders mediated by T lymphocytes and/or PKC, particularly during transplantation.

8 cl, 11 tbl, 47 ex

FIELD: chemistry.

SUBSTANCE: new 5-sulphanyl-4H-1,2,4-triazole derivatives of general formula I (meaning of radicals R1-R3 are indicated in the description of the invention), methods of their preparation by liquid-phase parallel synthesis and pharmaceutical composition are claimed.

EFFECT: claimed compounds display high affinity to some subtypes of somostatin receptors of the SST2 and SST5 subtypes and possibility of their usage for treatment of pathological states or diseases involving one or more of the given somostatin receptors

9 cl, 708 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new pyrimidine derivatives with general formula (I), their tautomeric or stereoisomeric form, in free form, in form of pharmaceutically acceptable salt or C1-6alkyl ester which are effective antagonists of CRTH2 (G-protein-associated chemoattractant receptor, ex prone on Th2 cells) and can be used for preventing and treating diseases related to CRTH2 activity, particularly in treatment of allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, diseases related to eosinophil. In formula (I) R1 is hydrogen, or in which n is an integer from 0 to 6; -Q1- is -NH-, -N(C1-6alkyl)- or -O; Y is hydrogen, C1-6alkyl, C3-6cycloalkyl, optionally substituted with C1-6alkyl, C3-6cycloalkyl, condensed with a benzene ring, phenyl, naphthyl or 5-6-member heteroaryl, possibly condensed with a benzene ring, and containing at least one heteroatom, chosen from a group consisting of oxygen and nitrogen, where the said phenyl, naphthyl or heteroaryl are optionally substituted on the displaceable position with one or several substitutes, chosen from a group consisting of cyano, halogen, nitro, guanidine, pyrroyl, sulfamoyl, phenyloxy, phenyl, di(C1-6)alkylamino, C1-6alkanoylamino, C1-6alkyl, optionally mono-, di- or tri-substituted with halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen and C1-6alkylthio, optionally mono-, di- or tri-substituted with halogen; or phenyl, condensed with 1,3-dioxolane; R2 is hydrogen or C1-6alkyl; R3 is a halogen, C1-6alkoxy, optionally mono-, di- or tri-substituted with halogen, or , R3a and R3b are independently C3-8cycloalkyl or C1-6alkyl, this C1-6alkyl is optionally substituted with hydroxyl, carboxy, C3-6cycloalkylcarbamoyl, C5-6heterocyclocarbonyl containing a heteroatom in form of nitrogen, or C1-6alkoxy, q is an integer from 1 to 3; R3c is hydrogen, hydroxyl or carboxy; Xa is -O-; R4 is hydrogen, halogen, di(C1-6alkyl) amino or C1-6alkyl, optionally substituted C1-6alkoxy or mono- , di- or tri-substituted with halogen; R5 is hydrogen or C1-6alkyl; and R6 is carboxy, carboxamide, nitrile or tetrazolyl.

EFFECT: wider field of use of compounds.

32 cl, 9 tbl, 13 ex

FIELD: chemistry, medicine.

SUBSTANCE: invention refers to the triheterocylic compounds of formula (Ia) and their pharmaceutically acceptable salts used as growth inhibitors of the cancer or tumor cells, to the preparation method and pharmaceutical compositions thereof, to the treatment method used aforesaid compounds as well as to the intermediates of formula (II) the to the method of its preparation. In general formulas (Ia) and

, Q1 is -N(R1)-; Q2 is -C(R3)-; Q3 is -C(R5)-; Q4 is -C(R9)-; R1 is -Ym(Ra), where -Ra is -H, -OH, -C(O)R14, -O-C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OS(O)2ONa-; R2 is -H; R3, R4 and R5 independently are -Ym(Rb), where Rb is -H, halogen, -C1-C8 alkyl, -O-(C1-C8 alkyl) or -OR14, -at condition that if value m of radical Ym(Rb) is equal 0, then R5 is not H; R6 is -H; R7 is -Ym-(RC), where -RC is -O-(C1-C8 alkyl) or -NH(phenyl), R8 is -Ym(Rd), where - Rd is -H, -OH, R9, R10, R11, R12 and R13 independently are -Ym(Re), where Re is -H, halogen, 5-6-membered heterocycle containing 2 heteroatoms selected from N or O, -OR14, or -O-C(O)OR14; every R14 independently is -H, -C1-C8 alkyl, -phenyl, 5-6-membered heterocycle containing one heteroatom being S; every Y independently is -C1-C8 alkylene-; every m independently is equal 0 or 1.

EFFECT: claimed compounds can find application for treatment of different cancer species.

41 cl, 4 tbl, 4 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: compounds under the present invention are characterised by properties of aurora-kinase-A and/or aurora-kinase-B inhibitor. In general formula (I) : A represents 5-merous heteroaryl containing two nitrogen atoms; X represents NR14; m represents 0, 1, 2 or 3; Z represents the group chosen from -NR1R2, and 4-7-merous saturated ring connected by carbon atom containing nitrogen atom and substituted at nitrogen atom with C1-C4alkyl substituted by phosphonoxy; R1 represents C1-C6-alkyl substituted by phosphonoxy; R2 represents the group chosen from hydrogen, C1-C6-alkyl where C1-C6-alkyl is optionally substituted with 1, 2 or 3 halogen or C1-C4-alkoxy groups, or R2 represents the group chosen from C2-C6-alkenyl, C2-C6-alkinyl, C3-C6-cycloalkyl and C3-C6-cycloalkyl-C1-C4alkyl; or R1 and R2 together with nitrogen atom whereto attached form 4-7-merous saturated ring substituted at carbon or nitrogen atom by the group chosen from phosphonoxy and C1-C4-alkyl where C1-C4alkyl is substituted by phosphonoxy; R3 represents the group chosen from hydrogen, halogen, C1-C6-alkoxy; R4 represents phenyl substituted with 1-2 halogens; R5, R6, R7 and R14 represent hydrogen. In addition, the invention concerns the pharmaceutical composition containing therapeutically active amount of the compound under the invention, to application of the compound for preparation of a medical product applied in therapy of disease wherefore inhibition of one or more aurora-kinases is efficient, to method treatment, as well as production of the compounds under the invention.

EFFECT: high-yield end product.

26 cl, 5 tbl, 50 ex

FIELD: chemistry.

SUBSTANCE: there are disclosed 1-(2-aminobenzol)piperazine derivatives of formula (I) and pharmaceutically acceptable acid-additive salts with radical values specified in patent claim. The compounds are characterised with inhibiting effect on glycine I carrier. There is also disclosed medical product based on the compounds of formula (I).

EFFECT: compound can be used for treatment of the diseases associated with glycine uptake inhibition.

12 cl, 5 tbl, 396 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) and their pharmaceutically acceptable salts as chemokine receptor CCR3 activity modulators, a pharmaceutical composition based on the said compounds, to synthesis method and use thereof. Said compounds can be used for treating and preventing diseases mediated by chemokine receptor CCR3 activity, such as inflammatory and allergic diseases etc. In general formula , R1 represents phenyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo [5,4-b]pyridinyl, benzothiazolyl, benzoxazolyl, pyridinyl, where each of the said phenyl or heterocycles can be substituted with one, two or three radicals R2; R2 each independently represents (C1-C6)halogenalkyl, halogen, COOR3; CONR3R4; R3 represents H or (C1-C6)alkyl; R4 represents H or (C1-C6)alkyl, R5 represents (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl; R6 each independently represents (C1-C6)alkoxy, (C1-C6)halogenalkyl, halogen, OR3, CN, CONR3R4; A represents C(CH3)2-CH2-CH2-, CH2-CH2-CH2- or B represents phenyl; D-E represents CH-CH2- or C=CH-, X-W-V represents N-C=CR7 or C=C-NR7; R7 represents H or (C1-C6)alkyl; Y represents NR4, O, S(O)n; i, j, m each equals 1, n equals 0 or 2.

EFFECT: increased effectiveness of using said compounds.

13 cl, 37 ex

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