Derivatives of 4-phenylpyridine n-oxides, medicinal agent comprising thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of 4-phenylpyridine N-oxides of the general formula (I) and their pharmaceutically acceptable acid-additive salts wherein R means hydrogen atom, lower alkyl or halogen atom; R1 means hydrogen atom; R2 and R2' mean independently of one another hydrogen, halogen atom, trifluoromethyl group, (lower)-alkoxy-group; or R2 and R2' can mean in common the group -CH=CH-CH=CH- optionally substituted with one or two substitutes taken among lower alkyl or (lower)-alkoxy-group; R3 and R3' mean independently of one another hydrogen atom, lower alkyl; R4 and R4' mean independently of one another -(CH2)mOR6 or lower alkyl; or R4 and R4' form in common with N-atom to which they are bound substituted R5-cyclic tertiary amine representing pyrrolidine-1-yl, piperidine-1-yl, piperazine-1-yl, morpholine-4-yl or 1,1-dioxomorpholine-4-yl; R5 means hydrogen atom, hydroxyl, -COOR3, -N(R3)CO-lower alkyl or -C(O)R3; R6 means hydrogen atom, lower alkyl; X means -C(O)N(R6)-, -N(R6)C(O)-; n = 0, 1, 2, 3 or 4; m = 1, 2 or 3. Also, invention describes a medicinal agent comprising these compounds. Compounds can be used as drugs in treatment or prophylaxis of diseases associated with antagonists of NK-1 receptor.

EFFECT: valuable medicinal properties of agent.

6 cl, 32 ex

 

The present invention relates to N-oxides of compounds of General formula

where R is hydrogen, lower alkyl, (ness.)alkoxygroup, halogen or trifluoromethyl;

R1means a hydrogen or halogen or

R and R1may together with the carbon atoms of the ring to which they are attached, be-CH=CH-CH=CH-;

R2and R2'mean independently from each other hydrogen, halogen, trifluoromethyl, (ness.)alkoxy - or langroup or

R2and R2'may together denote-CH=CH-CH=CH-, optionally substituted with one or two substituents selected from lower alkyl or (ness.)alkoxygroup;

R3, R3'mean independently from each other hydrogen, lower alkyl or cycloalkyl;

R4, R4'mean independently from each other -(CH2)mOR6or lower alkyl, or

R4and R4'form together with the nitrogen atom to which they are connected, a cyclic tertiary amine in the form of group

R5means hydrogen, hydroxyl, lower alkyl, -(ness.)alkoxygroup, -(CH2)m-OH, -COOR3, -CON(R3)2, -N(R3)CO-lower alkyl or-C(O)R3;

R6means hydrogen, lower alkyl or phenyl;

X is-C(O)N(R6)-, -N(R6)C(O)-, -(CH2)mO - or-O(CH2) -;

n means 0, 1, 2, 3 or 4 and

m denotes 1, 2 or 3,

and their pharmaceutically acceptable acid additive salts.

It was found that these N-oxide of the present invention exhibit in vitro activity against receptor NK-1 and/or can be used as prodrugs of compounds of the formula

which are antagonists of the receptor neirokinina 1 (NK-1, substance P).

However, the advantage of prodrugs lies in its physical properties, such as increased water solubility for parenteral administration compared to the original drug, or it increases the absorption from the digestive tract, or it can increase the stability of drugs during long-term storage. The compounds of formula II are of limited solubility in water, not allowing bolus injection. Therefore, it was useful to find derivatives of compounds of formula II, to make such compounds are suitable for parenteral or intramuscular use. It was shown that the N-oxide compounds of the formula I meet all the requirements of good prodrugs.

The prodrug in most cases is a pharmacologically inactive derivative of a molecule of the original drug that requires spontaneous or fer is entatives transformations in the body in order to release the active drug, and it improves associated with the delivery of the medicinal product properties compared to the original molecule drugs. It was shown that a molecule with optimal structural configuration and the optimal physico-chemical properties for the manifestation of the desired therapeutic response in the target area do not necessarily have the best of molecular shape and properties for its delivery to the point of its maximum activity. Usually only a small part of the injected dose reaches the target area, and because most tools also interacts with non-target areas, inefficient delivery may result in undesirable side effects. It's a fact of differences in transport and in situ effective properties of many molecules of drugs is the main reason why boonratana chemical derivatization of drugs, i.e. the formation of prodrugs, is a tool, which can be often achieved a significant improvement in the overall efficiency of medicines. Prodrugs are designed to overcome related to pharmacy and pharmacokinetics of the problems associated with a molecule of the original drug, which would otherwise limit the clinical usefulness of medicinal environments is TBA.

In recent years, several types bioapatite derivatives was applied for be used to create prodrugs. The most popular use of ester-type prodrug for medicines containing carboxyl or hydroxyl function. Later, the well-known proletarienne derived peptides, 4-imidazolidinone and the like, described in "Drugs of the Future", 1991, 16(5), 443-458, or N-oxide, as described, for example, in U.S. patent No. 5691336.

As mentioned earlier, the compounds of formula II are antagonists of the receptor neirokinina. Central and peripheral actions thickening substance P in a mammal associated with numerous inflammatory conditions, including migraine, rheumatoid arthritis, asthma and inflammatory bowel disease, and induction of gag reflex and modulation of disorders of the Central nervous system (CNS), such as Parkinson's disease (Neurosci. Res., 1996, 7, 187-214), anxiety (Can. J. Phys., 1977, 75, 612-621) and depression (Science, 1998, 281, 1640-1645).

Evidence of the usefulness of receptor antagonists tachykinin for pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of withdrawal syndrome of morphine, cardiovascular changes, oedema, such as oedema caused by thermal burn, chronic vospitatel what's diseases, as, for example, rheumatoid ariat, asthma/ increased bronchial reactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn's disease, damaged eye and ocular inflammatory diseases is given in the review "Thekennady receptor and antagonists thickening receptor", J. Auton. Pharmacol., 13, 23-93, 1993.

In addition, antagonists of the receptor neirokinina 1 are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance tachykinin, in particular substance P. the Examples of States are involved in substance P, include disorders of the Central nervous system, such as anxiety, depression and psychosis (international patent applications WO 95/16679, WO 95/18124 and WO 95/23798).

Antagonists of the receptor neirokinina 1 further suitable for the treatment of motion sickness and to treat induced vomiting.

In addition, in "The New England Journal of Medicine, volume 340, No. 3, 190-195, 1999, describes the attenuation caused by cisplatin vomiting using selective receptor antagonist neirokinina 1.

The suitability of receptor antagonists neirokinina 1 for the treatment of some forms of urinary incontinence is described below in "Neuropeptides", 32(1), 1-49, (1998), "Eur. J. Pharmacol"., 383(3), 297-303, (1999).

In addition, U.S. patent No. 5972938 describes a method of treatment psychoimmunology the ski or psychosomatic disorders by introducing receptor antagonist tachykinin, as, for example, an antagonist of the receptor NK-1.

Objects of the present invention are the compounds of formula I and their pharmaceutically acceptable salts, obtaining the above-mentioned compounds containing their drugs and their preparation and the use of the above compounds for the control and prevention of illnesses, especially of illnesses and disorders of this type, referred to earlier, or upon receipt of relevant medicines.

The most preferred indications in accordance with the present invention are those which include disorders of the Central nervous system, for example the treatment or prevention of certain depressive disorders or vomiting by introducing antagonists of the receptor NK-1. A long period of depression is considered to be a period of at least two weeks, during which time most days and almost every day there is either depressed mood or loss of interest or pleasure in all or almost all activities.

The following notation is conventional terms used in this description, apply regardless of mentioned if the terms separately or in combination. Used herein, the term "lower alkyl" means alkyl group with straight or branched chain, containing from 1 to 7 atoms, the angle of the ode, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like.

Preferred lower alkyl groups are groups with 1-4 carbon atoms.

The term "(ness.)alkoxygroup" means a group where the alkyl residues are as described above, and which is attached via an oxygen atom.

The term "halogen" means chlorine, iodine, fluorine and bromine.

The term "cycloalkyl" means a saturated carbocyclic group containing 3-6 carbon atoms.

The term "cyclic tertiary amine" means, for example, pyrrolidin-1-yl, piperidine-1-yl, piperazine-1-yl, morpholine-4-yl or 1,1-diocletianopolis-4-yl.

Preferred examples are compounds in which X is-C(O)N(R6)-, where R6means methyl, for example, the following connections:

tert-butyl ether 4-{5-[(3,5-bis-trifloromethyl)methylcarbamoyl]-4-o-tailpiece-2-yl}-4-oxopiperidin-1-carboxylic acid,

ethyl ester 5'-[(3,5-bis-trifloromethyl)methylcarbamoyl]-4'-o-tolyl-1-hydroxy-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid,

(RS)-6-[3-(acetylecholine)-1-oxopyrrolidin-1-yl]-N-(3,5-bis-trifloromethyl)-N-methyl-4-o-callincoming,

N-(3,5-bis-trifloromethyl)-N-methyl-6-(4-Oxymorphone-4-yl)-4-o-callincoming,

N-(3,5-bis-trifloromethyl)-6-(1,1-dioxo-1λ6-4-occationaly--yl)-N-methyl-4-o-callincoming,

N-(3,5-bis-trifloromethyl)-6-(4-formyl-1-oxopiperidin-1-yl)-N-methyl-4-o-callincoming,

N-methyl-N-(2-methylnaphthalene-1-ylmethyl)-6-(4-Oxymorphone-4-yl)-4-o-callincoming,

N-methyl-6-(4-Oxymorphone-4-yl)-N-naphthalene-1-ylmethyl-4-o-callincoming,

N-(2-methoxynaphthalene-1-ylmethyl)-N-methyl-6-(4-Oxymorphone-4-yl)-4-o-callincoming,

N-(2-methoxybenzyl)-N-methyl-6-(4-Oxymorphone-4-yl)-4-o-callincoming,

N-(5-chloro-2-methoxybenzyl)-N-methyl-6-(4-Oxymorphone-4-yl)-4-o-callincoming,

N-(2-chloro-5-methoxybenzyl)-N-methyl-6-morpholine-4-yl-4-o-callincoming,

N-methyl-6-(4-Oxymorphone-4-yl)-N-pantothenicacid-4-o-callincoming,

N-methyl-6-(4-Oxymorphone-4-yl)-N-naphthalene-2-ylmethyl-4-o-callincoming,

N-[2-methoxy-5-(5-cryptomaterial-1-yl)benzyl]-N-methyl-6-(4-Oxymorphone-4-yl)-4-o-callincoming,

N-(1,4-dimethoxyaniline-2-ylmethyl)-N-methyl-6-(4-Oxymorphone-4-yl)-4-o-callincoming or

5'-[(3,5-bis-trifloromethyl)methylcarbamoyl]-4'-o-tolyl-1-hydroxy-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid.

Further preferred compounds in which X is-N(R6)-CO-, where R6means hydrogen or methyl.

Examples of such compounds are:

2-(3,5-bis-triptoreline)-N-methyl-N-[6-(4-Oxymorphone-4-yl)-4-o-tailpiece-3-yl]isobutyramide,

2-(3,5-bis-triptoreline)-N-[4-(2-chlorophenyl)-6-(4-ACS is morpholine-4-yl)pyridine-3-yl]-N-methylisoleucine,

2-(3,5-bis-triptoreline)-N-[6-(4-Oxymorphone-4-yl)-4-o-tailpiece-3-yl]isobutyramide,

2-(3,5-bis-triptoreline)-N-[4'-(2-chlorophenyl)-1-hydroxy-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5 yl]-N-methylisoleucine,

2-(3,5-bis-triptoreline)-N-(6-oxydiethylene-4-o-tailpiece-3-yl)-N-methylisoleucine,

2-(3,5-bis-triptoreline)-N-[4-(2-chlorophenyl)-6-oxydiethylene-3-yl]isobutyramide,

2-(3,5-bis-triptoreline)-N-1-(4-hydroxy-1-hydroxy-4'-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5 yl)-N-methylisoleucine,

2-(3,5-bis-triptoreline)-N-{6-[(2-hydroxyethyl)-1-oxymethylene]-4-o-tailpiece-3-yl}-N-methylisoleucine,

(R)-2-(3,5-bis-triptoreline)-N-[6-(3-hydroxy-1-oxopyrrolidin-1-yl)-4-o-tailpiece-3-yl]-N-methylisoleucine,

2-(3,5-bis-triptoreline)-N-methyl-N-[6-(4-Oxymorphone-4-yl)-4-o-tailpiece-3-yl]acetamide", she

2-(3,5-acid)-N-methyl-N-[6-(4-Oxymorphone-4-yl)-4-o-tailpiece-3-yl]ndimethylacetamide or

2-(3-fluoro-5-triptoreline)-N-methyl-N-[6-(4-Oxymorphone-4-yl)-4-o-tailpiece-3-yl]ndimethylacetamide.

Presents the compounds of formula I and their pharmaceutically acceptable salts may be obtained using methods known in this field, for example the methods described below, such a method includes

a) oxidation of compounds of formula

using a suitable oxidizing agent with the education of the compounds of formula

where the substituents have the above values, and if desired, converting the compounds obtained into pharmaceutically acceptable acid additive salt.

In accordance with this method, the compound of the formula I can be obtained, for example, as follows. To a solution of 10 mmol of compounds of General formula II in 50 ml of a suitable solvent, such as dichloromethane, added with ice cooling a solution of 10 mmol of a suitable oxidizing reagent, such as, for example, 3-chlormadinone acid, 50 ml of a suitable solvent, such as dichloromethane. Stirring is continued within a reasonable time (usually from 1 to 24 h) at 0°and over the course of the reaction can be monitored using thin-layer chromatography. In cases where the formation of the product is too slow, the reaction mixture is stirred at room temperature. After evaporation of the solvent, the products of General formula I can be isolated using flash chromatography with a yield of 15 to 85%. Further purification of the crystalline products can be achieved by recrystallization from a suitable solvent.

This transformation can be applied to other oxidizing reagents instead of 3-chlormadinone acid. These oxidizing reagents familiar to anyone skilled in the Anna area, as, for example, dimethyldioxirane in acetone, hydrogen peroxide in acetic acid or potassium salt mononational acid in a suitable solvent, such as water.

The salt formation occurs at room temperature according to methods known in themselves and which are familiar to any person skilled in the art. Discusses not only salts with inorganic acids, but also salts with organic acids. Examples of such salts are hydrochloride, hydrobromide, sulfates, nitrates, citrates, acetates, maleate, salts of succinic acid, salts of methanesulfonate, p-toluenesulfonic acid and the like.

The following schemes 1-8 describe how to obtain compounds of formula I in more detail. Source materials are known compounds and can be obtained according to known in the field methods, for example, in accordance with the methods described in EP 99103504.9.

The diagrams use the following abbreviations:

PivClthe acid chloride trimethylhexanoic acid
THFtetrahydrofuran
TMEDAN,N,N',N'-tetramethylethylenediamine
DIPEAN-ethyldiethanolamine
KHMDShexamethyldisilazide potassium

p>

The designation of the substituents is given above.

The designation of the substituents is given above.

Z=Cl, Br, I or OS(O)2With6H4CH3and the designation of other substituents is given above.

The designation of the substituents is given above.

Z denotes Cl, Br, I or-OS(O)2With6H4CH3and the designation of other substituents is given above.

Z denotes Cl, Br, I or-OS(O)2With6H4CH3and the designation of other substituents is given above.

R5'means the group-C(O)R3and the designation of the remaining substituents is given above.

The designation of the substituents is given above.

As mentioned earlier, the compounds of formula I and their use in pharmacy salt additive can be used as prodrugs of the parent compounds of formula II, which have valuable pharmacological properties. These compounds are antagonists of the receptor neirokinina 1 (NK-1, substance P).

In addition, some of the N-oxide of the formula I possess a good affinity to the receptor NK-1. For some is that the preferred compounds of the values PK ilie in the range from 8.3 to 8.7.

These compounds were tested according to the tests below.

The analysis of binding (in vitro)

The affinity of these compounds to the receptor NK-1 was evaluated on the receptors of the human NK-1 in the ovary cells Chinese hamster infected with the human receptor NK-1 (using viral expression of Semliki) and radioactively labeled with [3N]substance P (final concentration of 0.6 nm). Experiments on the binding was performed in HEPES buffer (50 mm, pH 7.4)containing bovine serum albumin (0,04%), leupeptin (8 µg/ml), MnCl2(3 mm) and phosphoramidon (2 μm). Experiments on binding consisted of 250 μl of membrane suspension (1,25×105cells in vitro for experience), a 0.125 ál of buffer replacement of tools and 125 μl of [H3]substance P. the Curves of substitution was determined when at least seven concentrations of the compounds. Test tubes with samples were incubated for 60 min at room temperature after which time the contents of the tubes were rapidly filtered under vacuum through filters GF/C, pre-soaked for 60 minutes using polyethylenimine (PEI) (0,3%), with leaching 2×2 ml of HEPES buffer (50 mm, pH 7.4). Held on the filters and radioactivity was measured using scintillation counting. All analyses were repeated three times in at least two separate experiments.

Witness the creation, the compounds of formula I can be used as prodrugs their parent compounds of formula II, submitted in accordance with the following description.

The conversion of the prodrugs in the form of N-oxides to the corresponding parent compound occurs on the appropriate recovery mechanism and known from the literature some evidence that such reactions occur in vivo and may kataliziruetsa hemoglobin, so it was decided to study the stability and plasma, and blood. The presence of the oxidizing agent in the processing solution should help to prevent the recovery of N-oxides.

The transformation in plasma: added 10 μl of a solution of the prodrug at a concentration of 100 μg/ml in dimethyl sulfoxide (DMSO) to 1 ml of plasma to achieve a final concentration of 1 µg/ml Incubation was carried out at 37°and selected 8 of the aliquot at various time points within 30 minutes. These aliquots was treated with three volumes of cold methyl alcohol, hydrogen peroxide (final concentration 10% vol./vol.), and centrifuged at 3500 g for 20 minutes at 10°C. Directly used the supernatant for determination of levels of drugs using liquid chromatography and detection using tandem mass spectrometry (HPLC on a column of the reversed-phase X-Terra MS 18 3.5 µm 2,1× 30 mm Waters at 40°C, the gradient polarity Meon/HCOOH 1% 20/80/Meon; the time course of 3.0 min; injection volume 10 μl; the expiration of 0.2 µl/min and detection using tandem mass spectrometry spectrometer (PE Sciex API 2000 MS/MS; ion source - torbarina; mode ionization - electrospray, positive ionization).

The transformation in fresh blood: the same technique was used to study the stability in blood, even if it was required much more careful after treatment with hydrogen peroxide.

Stability of the sample (plasma and blood): first preparing the final matrix (plasma or blood treated with 3 volumes of cold methanol containing hydrogen peroxide, 10% vol./about., and centrifuged at 3500 g for 20 min at 10° (C) and then incubated at 37°With two tubes; a prodrug or drug then incubated and finally determined their concentrations using liquid chromatography and detection using tandem mass spectrometry as described above.

It was found that the method used to terminate the reaction, both in plasma and in blood, reliable enough for research, at least when the analysis was carried out immediately after incubation.

Data about the time half-life obtained for the conversion of the Strait is the drugs in the drug in the plasma, in the following table (it was found that the preparation of plasma samples is crucial for the accurate determination of the values of t1/2).

t1/2(watch)
Example No.Plasma dogPlasma manPlasma rat
11884
218125
161662

Stability in the blood is much lower (t1/2<30 min) and it was impossible to determine the exact value of t1/2. However, it can be concluded that no significant model differences from the point of view of stability in the blood and prodrugs that are converted in the desired medicinal product with high yield (>90%).

In accordance with the test compounds of formula I can function as prodrugs their parent compounds of formula II.

The compounds of formula I and their pharmaceutically used acid additive salts can be used as medicines, for example, in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragées, hard the soft gelatin capsules, solutions, emulsions or suspensions. The introduction can be carried out, but also through the rectum, for example, in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

The compounds of formula I and their pharmaceutically used acid additive salts can be processed with pharmaceutically inert, inorganic or organic fillers to obtain tablets, coated tablets, dragées and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients, for example, tablets, coated tablets and hard gelatin capsules.

Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols etc

Suitable fillers for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

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

Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc

In addition, pharmaceutical preparations which s can contain preservatives, soljubilizatory, stabilizers, wetting means, emulsifiers, sweeteners, colorants, giving the fragrance substances, salts for modifying the osmotic pressure, buffers, masking means or antioxidants. They can also contain other therapeutically valuable substances.

The dose can vary within wide limits and can, of course, be selected to meet the specific requirements of each individual case. Usually in the case of oral administration a daily dose for a human, comprising from about 10 to 1000 mg of the compounds of General formula I, should be appropriate, although if necessary, the upper limit can also be exceeded.

The following examples illustrate the present invention without limiting it. All temperatures are given in degrees Celsius.

Obtaining compounds of formula I from compounds of formula II, represented in this description. This method of oxidation is always the last stage to obtain the N-oxides of compounds of formula I. a Detailed description of this last stage specifically described in the following examples 1, 2 and 13. Oxidation at the nitrogen atom of the other compounds from 3 to 12 and from 14 to 29 in the General form given in accordance with the above description.

Example 1

2-(3,5-Bis-triptoreline)-N-methyl-N-[6-(4-Oxymorphone-4-yl)-4-o-tailpiece the-3-yl]isobutyramide

a) 4-(5-Nitro-2-pyridyl)morpholine

To a solution of 20 g (126 mmol) of 2-chloro-5-nitropyridine in 150 ml of tetrahydrofuran was added dropwise 27 ml (315 mmol) of the research within 10 minutes. The reaction mixture is boiled under reflux for another 2 hours. After cooling to room temperature the solvent was removed in vacuo and the residue re-dissolved in 200 ml of ethyl acetate. The organic phase is washed with 200 ml of 1 n sodium bicarbonate solution, dried (magnesium sulfate) and was evaporated, got 27,3 g (quantitative yield) specified in the title compound in a solid yellow color. TPL142-143°C.

b) 2,2-Dimethyl-N-(6-morpholine-4-espiridion-3-yl)propionamide

To a solution of 27.3 g (126 mmol) of 4-(5-nitro-2-pyridyl)the research in 600 ml of methanol was added 2.5 g of 10% palladium on charcoal. The reaction mixture was first made (temperature from room temperature up to about 45°C, 1 bar) to the absorption of theoretical amount of hydrogen (about 3 hours). The catalyst was filtered and washed twice with methanol in portions of 100 ml. of the Filtrate was evaporated in vacuo, got 22,6 g butter purple color, which according to the analysis by thin-layer chromatography consisted of approximately 95% of the desired aniline derivative.

This product was dissolved in a mixture of 240 ml of tetrahydrofuran and 60 ml of diethyl ether. After cooling the 0° With added in one step 26 ml (189 mmol) of triethylamine. Stirring is continued at that time, as was dropwise added 23 g (189 mmol) of the acid chloride trimethylhexanoic acid for 10 minutes. Bath ice was removed and the reaction mixture was stirred 1 h at room temperature. Then the solvent was removed in vacuum and the residue suspended in 200 ml of 1 n sodium bicarbonate solution. The product was extracted three times with dichloromethane portions 200 ml), dried (sodium sulfate) and was evaporated. Recrystallization of the solid residue from ethyl acetate/hexane (1:8) resulted in 28.6 g (86%) specified in the title compound as white crystals.

Mass spectrum (MS) m/e (%): 264 (M+N+, 100).

C) N-(4-Iodine-6-morpholine-4-espiridion-3-yl)-2,2-dimethylpropanamide

A solution of 28.4 g (108 mmol) of 2,2-dimethyl-N-(6-morpholine-4-espiridion-3-yl)-propionamide and 49 ml (324 mmole) N,N,N',N'-tetramethylethylenediamine in 600 ml of tetrahydrofuran in an argon atmosphere was cooled in a bath of dry ice to -78°C. for 1 h was added dropwise 202 ml (324 mmole) of 1.6 n solution of n-utility in hexane. The reaction mixture was allowed to warm to -35°With during the night. After cooling again to -78°was added dropwise over 15 minutes a solution of 37 g (146 mmol) of iodine in 60 ml of tetrahydrofuran. Bath with dry ice was replaced by a bath of ice was added a solution of 90 g (363 mmole) pentahydrate tio is of Ulfat of sodium in 250 ml of water for 10 minutes, when the temperature of the reaction mixture reached 0°C. Then there was added 1000 ml of diethyl ether and the organic layer was separated. The aqueous layer was extracted twice with 500 ml of dichloromethane and the combined organic layers were dried (magnesium sulfate) and was evaporated. Flash chromatography resulted in 15.6 g (37%) specified in the title compound in the form of butter, light brown, which crystallized upon standing at room temperature.

MS m/e (%): 389 (M+, 71), 358 (25), 304 (43), 57 (100).

g) 2,2-Dimethyl-N-(6-morpholine-4-yl-4-o-tailpiece-3-yl)propionamide

A mixture of 3.50 g (9.0 mmol) of N-(4-iodine-6-morpholine-4-espiridion-3-yl)-2,2-dimethylpropanamide, 35 ml of toluene, 18 ml of 2 n sodium carbonate solution, 312 mg, or 0.27 mmole) tetrakis(triphenylphosphine)palladium(0) and 1.34 g (9.9 mmol) of o-tolylboronic acid was heated under argon at 80°within 12 hours After cooling to room temperature the aqueous phase was separated and washed twice with ethyl acetate. The combined organic layers were washed with 50 ml brine, dried (sodium sulfate) and was evaporated. Purification using flash chromatography led to 3,23 g (yield quantitative) specified in the title compound in the form of a white foam.

MS m/e (%): 354 (M+N+, 100).

d) 6-Morpholine-4-yl-4-o-tailpiece-3-ylamine

Suspension of 2.93 g (compared to 8.26 mmol) 2,2-dimethyl-N-(6-morpholine-4-yl-4-o-tailpiece-3-yl)propionamide in 0 ml 3 N. hydrochloric acid and 5 ml of 1-propanol was heated at 90-95°With during the night. The reaction mixture was cooled to room temperature, washed with three portions of 20 ml of diethyl ether and filtered through celite. The filtrate was diluted with 20 ml water and set pH 7-8 by addition of 28%aqueous sodium hydroxide solution while cooling with ice. The product was extracted with four portions of dichloromethane, 100 ml each. The combined organic layers were washed with 50 ml brine, dried (magnesium sulfate) and was evaporated, got 2,31 g (quantitative yield) specified in the title compound in the form of a white foam.

MS m/e (%): 269 (M+, 100).

e) Methyl(6-morpholine-4-yl-4-o-tailpiece-3-yl)Amin

A solution of 2.24 g (8.3 mmol) of 6-morpholine-4-yl-4-o-tailpiece-3-ylamine in 17 ml trimethylboron ether orthomorphisms acid with 3 drops of triperoxonane acid was heated for 2 h at 130°C. the Reaction mixture was evaporated and dried in vacuum for 30 minutes. The remainder in the form of oil was dissolved in 5 ml of tetrahydrofuran was added dropwise under ice cooling to 630 mg (16,6 mmole) of lithium aluminum hydride in 20 ml of tetrahydrofuran. The reaction mixture was stirred 1 h at room temperature, again cooled to 0°and acidified (pH 1-2) with the addition of 28%aqueous hydrochloric acid solution. After stirring for 5 minutes was added 28%is actor of sodium hydroxide to bring the pH to 10. The solution was filtered through celite, evaporated and purified using flash chromatography, obtained 1.56 g (66%) specified in the title compound as a white foam.

MS m/e (%): 283 (M+, 100).

W) 2-(3,5-Bis-triptoreline)-N-methyl-N-(6-morpholine-4-yl-4-o-tailpiece-3-yl)isobutyramide

A solution of 1.46 g (5.15 mmol) of methyl(6-morpholine-4-yl-4-o-tailpiece-3-yl)amine and of 1.32 ml (7,73 mmol) of N-ethyldiethanolamine in 15 ml dichloromethane was cooled in a bath of ice and dropwise added 1.8 g (5,67 mmol) of acid chloride of 2-(3,5-bis-triptoreline)-2-methylpropionic acid. The reaction mixture was heated at 35-40°C for 3 h, cooled again to room temperature and was stirred with 25 ml saturated sodium bicarbonate solution. The organic layer was separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate) and was evaporated. The residue was purified using flash chromatography, was obtained 2.9 g (quantitative yield) specified in the title compound as white crystals. TPL131-132°C.

C) 2-(3,5-Bis-triptoreline)-N-methyl-N-[6-(4-Oxymorphone-4-yl)-4-o-tailpiece-3-yl]isobutyramide

To a solution of 5.0 g (8,84 mmol) of 2-(3,5-bis-triptoreline)-N-methyl-N-(6-morpholine-4-yl-4-o-tailpiece-3-yl)isobutyramide in 50 ml of dichloromethane were added under ice cooling a solution of 2.18 g (8,84 mmol) 3-horned what antinoi acid (about 70%) in 35 ml of dichloromethane. After stirring 1 h at 0°slowly added 2.6 g (25.7 mmol) of triethylamine. The reaction mixture was concentrated to a total volume of 10 ml and the residue was purified using flash chromatography. Technical product suspended in 20 ml of diethyl ether, filtered and dried in vacuum, received 4,2 g (82%) specified in the title compound as white crystals. TPL149-151 (partial decomposition).

MS m/e (%): 582 (M+N+, 100).

Example 2

2-(3,5-Bis-triptoreline)-N-[4-(2-chlorophenyl)-6-(4-Oxymorphone-4-yl)pyridine-3-yl]-N-methylisoleucine

Specified in the title compound was obtained as white crystals with comparable outputs according to the procedures described above for example 1, using 2-chloraniline acid instead of o-tolylboronic acid in stage g). TPL141-143°With (partial decomposition).

MS m/e (%): 602 (M+N+, 100), 624 (M+Na+, 10).

Example 3

2-(3,5-Bis-triptoreline)-N-[6-(4-Oxymorphone-4-yl)-4-o-tailpiece-3-yl]isobutyramide

The original compound was obtained as white powder with comparable outputs according to the procedures described above to obtain compounds of example 1 at the stages a) to f). Stage e) missed.

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

N-Oxide was obtained according to stage C) of example 1.

Example 4

2-(3,5-Bis-triptoreline)-N-[4'-(2-chlorophenyl)-1-the XI-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-yl]-N-methylisoleucine

The original compound was obtained as white powder with comparable outputs in accordance with the techniques described above to obtain compounds of example 1 at stages from a) to g)using piperidine instead of the research in stage a) and using 2-chloraniline acid instead of o-tolylboronic acid in stage d).

MS m/e (%): 583 (M+, 20), 296 (78), 255 (100).

N-Oxide was obtained according to stage C) of example 1.

Example 5

2-(3,5-Bis-triptoreline)-N-(6-oxydiethylene-4-o-tailpiece-3-yl)-N-methylisoleucine

The original connection was received in the form of a solid white color with comparable outputs according to the procedures described above to obtain compounds of example 1, stage a) to g)using dimethylamine hydrochloride instead of the research in stage a). TPL174-175°C.

MS m/e (%): 524 (M+N+, 100).

N-Oxide was obtained according to stage C) of example 1.

Example 6

2-(3,5-Bis-triptoreline)-N-[4-(2-chlorophenyl)-6-oxydiethylene-3-yl]isobutyramide

The original connection was received in the form of a solid white color with comparable outputs according to the procedures described above to obtain compounds of example 1 at stages from a) to g)using dimethylamine hydrochloride instead of the research in stage a) and using 2-chloraniline acid instead of o-tolylboronic acid in stage g). T PL162-163°C.

MS m/e (%): 544 (M+N+, 100).

N-Oxide was obtained according to stage C) of example 1.

Example 7

2-(3,5-Bis-triptoreline)-N-1-(4-hydroxy-1-hydroxy-4'-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5 yl)-N-methylisoleucine

The original compound was obtained as white foam with comparable outputs according to the procedures described above to obtain compounds of example 1 at stages from a) to g)using 4-hydroxypiperidine instead of the research in stage a).

MS m/e (%): 580 (M+N+, 100).

N-Oxide was obtained according to stage C) of example 1.

Example 8

2-(3,5-Bis-triptoreline)-N-{6-[(2-hydroxyethyl)-1-oxymethylene]-4-o-tailpiece-3-yl}-N-methylisoleucine

The original compound was obtained as white foam with comparable outputs according to the procedures described above to obtain compounds of example 1 at stages from a) to g)using N-methylethanolamine instead of the research in stage a).

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

N-Oxide was obtained according to stage C) of example 1.

Example 9

(R)-2-(3,5-Bis-triptoreline)-N-[6-(3-hydroxy-1-oxopyrrolidin-1-yl)-4-o-tailpiece-3-yl]-N-methylisoleucine

The original compound was obtained as white foam with comparable outputs according to the procedures described above to obtain compounds of example 1 at the stages a) to f), using (R)-3-hydroxyprop the Dean instead of the research in stage a).

MS m/e (%): 566 (M+N+, 100).

N-Oxide was obtained according to stage C) of example 1.

Example 10

2-(3,5-Bis-triptoreline)-N-methyl-N-[6-(4-Oxymorphone-4-yl)-4-o-tailpiece-3-yl]ndimethylacetamide

To a solution of 300 mg (1.1 mmole) of 3,5-bis-triftormetilfullerenov acid in 7 ml of N,N-dimethylformamide was added 185 mg (1,14 mmole) of 1,1'-carbonyldiimidazole and the solution was stirred for 30 minutes at room temperature. After addition of 283 mg (1 mmol) of methyl(6-morpholine-4-yl-4-tailpiece-3-yl)amine (as described in stage e) for obtaining the compounds of example 1), the reaction mixture was heated overnight at 90°C. After cooling to room temperature the solvent was removed in vacuo and the residue re-dissolved in 30 ml of ethyl acetate. The organic phase is washed with water (2×30 ml), with brine, dried (magnesium sulfate) and was evaporated. After flash chromatography received 506 mg (94%) of starting compound in the form of foam light brown color.

MS m/e (%): 538 (M+N+, 100).

N-Oxide was obtained according to stage C) of example 1.

Example 11

2-(3,5-Acid)-N-methyl-N-[6-(4-Oxymorphone-4-yl)-4-o-tailpiece-3-yl]ndimethylacetamide

To a solution of 226 mg (1.15 mmole) of 3,5-dimethoxyphenylacetic acid in 7 ml of N,N-dimethylformamide was added 244 mg (1.5 mmole) of 1,1'-carbonyldiimidazole and the solution was stirred for 30 minutes at room temperature. After addition of 283 mg (1) - Rev. mol) of methyl(6-morpholine-4-yl-4-tailpiece-3-yl)amine (as described in stage e) for obtaining the compounds of example 1, the reaction mixture was heated for 7 hours at 70° C. After cooling to room temperature the solvent was removed in vacuo and the residue re-dissolved in 30 ml of ethyl acetate. The organic phase is washed with water (2×30 ml), with brine, dried (magnesium sulfate) and was evaporated. After flash chromatography got 347 mg (75%) of the compounds in the form of a white foam.

MS m/e (%): 462 (M+N+, 100).

N-Oxide was obtained according to stage C) of example 1.

Example 12

2-(3-Fluoro-5-triptoreline)-N-methyl-N-[6-(4-Oxymorphone-4-yl)-4-o-tailpiece-3-yl]ndimethylacetamide

To a solution of 266 mg (1.2 mmole) H-fluoro-5-triftormetilfullerenov acid in 7 ml of N,N-dimethylformamide was added 195 mg (1.2 mmole) of 1,1'-carbonyldiimidazole and the solution was stirred for 30 minutes at room temperature. After addition of 283 mg (1 mmol) of methyl(6-morpholine-4-yl-4-tailpiece-3-yl)amine (as described in stage e) upon receipt of the compounds from example 1), the reaction mixture was heated for 6 hours at 90°C. After cooling to room temperature the solvent was removed in vacuo and the residue re-dissolved in 30 ml of ethyl acetate. The organic phase is washed with water (2×30 ml), with brine, dried (magnesium sulfate) and was evaporated. After flash chromatography got 432 mg (88%) of starting compound in the form of foam a light yellow color.

MS m/e (%): 488 (M+H+, 100).

N-Oxide was obtained according to stage C) of example 1.

When is EP 13

tert-Butyl ether 4-{5-[(3,5-bis-trifloromethyl)methylcarbamoyl]-4-o-tailpiece-2-yl}-4-oxopiperidin-1-carboxylic acid

a) 6-Chloro-N-methyl-4-o-callincoming

To a solution 3,41 g (20.0 mmol) of 6-chloro-N-nicotine amide in 80 ml of tetrahydrofuran was added dropwise at 0°With 50 ml (50 mmol) of 1 M solution of o-wellmanicured in tetrahydrofuran. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours. The mixture was again cooled to 0°With, then was added dropwise to 5.7 ml (100 mmol) of acetic acid and a solution of 5.1 g (22 mmole) of 2,3-dichloro-5,6-dicyan-1,4-benzoquinone in 18 ml of tetrahydrofuran. After the addition, the reaction mixture was allowed to warm to room temperature and was stirred for 15 minutes was Added 30 ml of 2 N. aqueous solution of sodium hydroxide and then diluted with 1 l of ethyl acetate and 200 ml of water. The layers were separated and the organic layer was washed (4×250 ml) 2 N. aqueous solution of sodium hydroxide. The combined aqueous layers were extracted 3 times with ethyl acetate portions of 500 ml the combined organic extracts were washed with saturated aqueous solution of sodium chloride and dried with sodium sulfate. After concentration was received 5,44 g butter brown-red color. Flash chromatography led to 2.15 g (41,3%) specified in the title compound in the form of solid substances the ETS light yellow color.

MS m/e (%): 260 (M+, 11). TPL91-93°C.

b) tert-Butyl ester 4-(5-methylcarbamoyl-4-o-tailpiece-2-yl)piperazine-1-carboxylic acid

The mixture 8,31 g (31.9 per mmole) of 6-chloro-N-methyl-4-o-telinekataja, 6,53 g (35,0 mmol) 1-tert-butoxycarbonylamino, and 16.7 ml (95.6 mmol) of N-ethyl-Diisopropylamine and catalytic amounts of 4-(N,N-dimethylamino)pyridine were heated under reflux overnight. After cooling to room temperature the mixture was dissolved in dichloromethane and washed with two portions of 0.1 G. of an aqueous solution of hydrochloric acid. After drying with sodium sulfate and concentration was obtained 10.7 g of a technical product. Flash chromatography resulted in 6,28 g (48.0 per cent) specified in the title compound in the form of a solid not quite white matter.

MC m/e (%): 411 (M+H+, 100).

C) tert-Butyl ether 4-{5-[(3,5-bis-trifloromethyl)methylcarbamoyl]-4-o-tailpiece-2-yl}piperazine-1-carboxylic acid

To a solution 6,28 g (15.3 mmol) of tert-butyl ester 4-(5-methylcarbamoyl-4-o-tailpiece-2-yl)piperazine-1-carboxylic acid in 250 ml of tetrahydrofuran was added at 0°With 20 ml of 1 M solution (20 mmol) hexamethyldisilazide potassium in tetrahydrofuran. After 30 minutes, was added dropwise 2,81 ml (15.3 mmol) of methyl 3,5-bis-cryptomelane. The reaction mixture was allowed to warm to room temperature over night. P is imously water and 1 M aqueous solution of sodium hydroxide, then was extracted with three portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. Column flash chromatography resulted in 6,89 g (70,8%) of starting compound in a solid white color.

MC m/e (%): 637 (M+N+, 100).

N-Oxide was obtained according to stage C) of example 1.

Example 14

Ethyl ester 5'-[(3,5-bis-trifloromethyl)methylcarbamoyl]-4'-o-tolyl-1-hydroxy-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid

The original compound was obtained as a solid white color with comparable outputs according to the procedures described above to obtain tert-butyl ester 4-{5-[(3,5-bis-trifloromethyl)methylcarbamoyl]-4-o-tailpiece-2-yl}piperazine-1-carboxylic acid (example 13), when using isonipecotate instead of 1-tert-butoxycarbonylamino at the stage b) and using ethyl ester 5'-methylcarbamoyl-4'-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid instead of the tert-butyl ester 4-(5-methylcarbamoyl-4-o-tailpiece-2-yl)piperazine-1-carboxylic acid stage).

MC m/e (%): 608 (M+N+, 100).

N-Oxide was obtained according to stage C) of example 1.

Example 15

(RS)-6-[3-(Acetylecholine)-1-oxopyrrolidin-1-yl]-N-(3,5-bis(trifluoromethyl)benzyl)-N-methyl-4-o-callincoming

The original connection was received in the form of TV is Gogo substances light yellow color with comparable outputs according to the procedures described above, to obtain tert-butyl ester 4-{5-[(3,5-bis-trifloromethyl)methylcarbamoyl]-4-o-tailpiece-2-yl}piperazine-1-carboxylic acid (example 13)using (RS)-3-(acetylecholine)pyrrolidine instead of 1-tert-butoxycarbonylamino at the stage b) and using (RS)-6-[3-(acetylecholine)pyrrolidin-1-yl]-N-methyl-4-o-callincoming instead of tert-butyl ester of 4-(5-methylcarbamoyl-4-o-tailpiece-2-yl)piperazine-1-carboxylic acid stage).

MS m/e (%): 593 (M+H+, 100).

N-Oxide was obtained according to stage C) of example 1.

Example 16

N-(3,5-Bis-trifloromethyl)-N-methyl-6-(4-Oxymorphone-4-yl)-4-o-callincoming, monohydrate

a) 6-Chloro-N-nicotine amide

To 50 g (317 mmol) of 2-chloronicotinic acid was added 230 ml (3,16 mole) chloride tiomila at 0°C. After boiling the mixture under reflux for 2 hours, the excess chloride tiomila was removed by distillation. The oily brown residue was dissolved in 250 ml of dichloromethane. The solution was treated with methylamine gas at 0°up until more was not observed exothermic reaction. The resulting suspension was diluted with 1000 ml of dichloromethane/water. The layers were separated and the aqueous layer was extracted with dichloromethane, the three portions of 300 ml After drying the combined organic layers with sodium sulfate and kontsentrirovanie who received a 53.2 g (98%) specified in the title compound in the form of a solid of light yellow color.

MS m/e (%): 171 (M+N+, 15).

b) 6-Chloro-N-methyl-4-o-callincoming

To a solution 3,41 g (20.0 mmol) of 6-chloro-N-nicotine amide in 80 ml of tetrahydrofuran was added dropwise at 0°With 50 ml (50 mmol) of 1 M solution of o-wellmanicured in tetrahydrofuran. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours. The mixture was again cooled to 0°then dropwise added 5.7 ml (100 mmol) of acetic acid and a solution of 5.1 g (22 mmole) of 2,3-dichloro-5,6-dicyan-1,4-benzoquinone in 18 ml of tetrahydrofuran. After the addition, the reaction mixture was allowed to warm to room temperature and was stirred for 15 minutes was Added 30 ml of 2 N. aqueous sodium hydroxide solution, then diluted with 1 l of ethyl acetate and 200 ml of water. The layers were separated and the organic layer was washed with 4 portions of 250 ml of 2 N. aqueous solution of sodium hydroxide. The combined aqueous layers were extracted with ethyl acetate three times with portions of 500 ml the combined organic extracts were washed with saturated aqueous solution of sodium chloride and dried with sodium sulfate. After concentration was received 5,44 g butter brown-red color. Column flash chromatography led to 2.15 g (41,3%) specified in the title compound in the form of a solid of light yellow color. TPL91-93°C.

MS m/e (%): 260 (M+, 11).

C) N-6-morpholine-4-yl-4-o-callincoming

A mixture of 1.00 g (of 3.84 mmole) of 6-chloro-N-methyl-4-o-telinekataja, and 0.37 ml (4,22 mmole) of the research, 2.0 ml (12 mmol) of N-ethyldiethanolamine and catalytic amounts of 4-(N,N-dimethylamino)pyridine was heated at 100°With during the night. After cooling to room temperature the mixture was dissolved in ethyl acetate and washed with two portions of water. The combined aqueous layers were extracted with three portions of dichloromethane. Drying with sodium sulfate and concentration resulted of 1.23 g of a technical product. Column flash chromatography led to a 1.11 g (92,9%) specified in the title compound in the form of not-quite-white solid. TPL156-158°C.

MS m/e (%): 311 (M+, 64).

g) N-(3,5-Bis-trifloromethyl)-N-methyl-6-morpholine-4-yl-4-o-callincoming

To a solution of 0.27 g (of 0.87 mmole) of N-methyl-6-morpholine-4-yl-4-o-telinekataja in 15 ml of tetrahydrofuran was added to 1.12 ml of 1 M solution of (1.12 mmole) hexamethyldisilazide potassium in tetrahydrofuran at 0°C. After 30 minutes, was added dropwise 0.16 ml (of 0.87 mmole) of methyl 3,5-bis-cryptomelane and the reaction mixture was allowed to warm to room temperature over night. Mixed with water and then was extracted with ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography led to 0.20 g (44%) indicated in the title of the link is in the form of a solid white color.

MS m/e (%): 538 (M+N+, 100).

d) N-(3,5-Bis-trifloromethyl)-N-methyl-6-(4-Oxymorphone-4-yl)-4-o-callincoming, monohydrate

To a solution of 0.40 g (0,74 mmole) of N-(3,5-bis-trifloromethyl)-N-methyl-6-morpholine-4-yl-4-o-telinekataja in 4 ml dichloromethane was added at 0°0.17 g of 3-chlormadinone acid (70%; of 0.71 mmole). After 4 hours the reaction mixture was diluted with dichloromethane and washed with three portions of saturated sodium carbonate solution. The combined aqueous layers were extracted with dichloromethane. The combined organic extracts were washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated. After chromatography on a column was obtained 0.31 g (73%) specified in the title compound in the form of a solid white color.

MS m/e (%): 534 (M+N+, 100).

Crystallization of a sample of 100 mg of a mixture of simple (tert-butyl)methyl ether and cyclohexane resulted in 90 mg specified in the title compound as white crystals. TPL116-117°C.

Example 17

N-(3,5-Bis-trifloromethyl)-6-(1,1-dioxo-1λ6-4-occationaly-4-yl)-N-methyl-4-o-callincoming

a) N-(3,5-Bis-trifloromethyl)-N-methyl-6-thiomorpholine-4-yl-4-o-callincoming

Specified in the title compound was obtained in a solid white color with comparable outputs according to the procedures described is mentioned above, to obtain tert-butyl ester 4-{5-[(3,5-bis-trifloromethyl)methylcarbamoyl]-4-o-tailpiece-2-yl}piperazine-1-carboxylic acid, using thiomorpholine instead of 1-tert-butoxycarbonylamino at the stage b) and using N-methyl-6-thiomorpholine-4-yl-4-o-callincoming instead of the tert-butyl ester 4-(5-methylcarbamoyl-4-o-tailpiece-2-yl)piperazine-1-carboxylic acid at the stage b).

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

b) N-(3,5-Bis-trifloromethyl)-N-methyl-6-(1-oxo-1λ4-thiomorpholine-4-yl)-4-o-callincoming

To a solution of 1.24 g (2,24 mmole) of N-(3,5-bis-trifloromethyl)-N-methyl-6-thiomorpholine-4-yl-4-o-telinekataja (stage a)) in 25 ml of methanol was added 689 mg (1.12 mmole) Oksana®when 0°C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours. Was mixed with 5 ml of 40%aqueous solution of sodium bisulfite and then added 6 ml of 1 n sodium hydroxide solution to establish a pH of 7-8. The mixture was diluted with 50 ml water and was extracted with dichloromethane (3×150 ml). The combined extracts were dried with sodium sulfate and concentrated, obtained 1.20 g of a technical product. Flash chromatography led to 1,02 g (79,9%) specified in the title compound in the form of a solid white color.

MS m/e (%): 570 (M+N+, 100).

C) N-(3,5-Bis-trifloromethyl)-6-(1,1-dioxo-λ 6-thiomorpholine-4-yl)-N-methyl-4-o-callincoming

The original connection was received in the form of a solid white color with comparable outputs according to the method described above (stage b)), using N-(3,5-bis-trifloromethyl)-N-methyl-6-(1-oxo-1λ4-thiomorpholine-4-yl)-4-o-callincoming instead of N-(3,5-bis-trifloromethyl)-N-methyl-6-thiomorpholine-4-yl-4-o-telinekataja.

MS m/e (%): 586 (M+N+, 100).

N-Oxide was obtained according to stage C) of example 1.

Example 18

N-(3,5-Bis-trifloromethyl)-6-(4-formyl-1-oxopiperidin-1-yl)-N-methyl-4-o-callincoming

To the mixture 0,089 ml (1.1 mmole) of N,N-dimethylformamide and 38 mg high (0.56 mmole) of imidazole was added dropwise at room temperature 0,071 ml high (0.56 mmole) of trimethylchlorosilane. The reaction mixture was cooled to 0°and there was added 0.10 g (0,19 mmole) of N-(3,5-bis-trifloromethyl)-N-methyl-6-piperazine-1-yl-4-o-telinekataja. Bath with water and ice was removed and the mixture was stirred over night. To the reaction mixture were added a mixture of 2 ml of 1 N. aqueous solution of hydrochloric acid and 4 ml of water, the mixture was extracted with ethyl acetate. The combined extracts were dried with sodium sulfate and concentrated. Column flash chromatography led to 81 mg (82%) of starting compound in a solid white color.

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

Specified in the title compound was obtained from the according to stage C) of example 1.

Example 19

N-Methyl-N-(2-methylnaphthalene-1-ylmethyl)-6-(4-Oxymorphone-4-yl)-4-o-callincoming

a) N-Methyl-6-morpholine-4-yl-4-o-callincoming

Specified in the title compound was obtained as a solid substance not quite white with comparable outputs according to the method described above to obtain tert-butyl ester 4-{5-[(3,5-bis-trifloromethyl)methylcarbamoyl]-4-o-tailpiece-2-yl}piperazine-1-carboxylic acid (example 13, step b)using morpholine instead of 1-tert-butoxycarbonylamino.

MS m/e (%): 311 (M+, 63).

b) N-Methyl-N-(2-methylnaphthalene-1-ylmethyl)-6-morpholine-4-yl-4-o-callincoming

The original connection was received in the form of a solid white color with comparable outputs in accordance with the method described above to obtain N-(3,5-bis-trifloromethyl)-N-methyl-6-morpholine-4-yl-4-o-telinekataja (example 16, step d)using 1-chloromethyl-2-methylnaphthalene bromide instead of 3,5-bis-cryptomelane.

MS m/e (%): 466 (M+N+, 100).

N-Oxide was obtained according to stage C) of example 1.

Example 20

N-Methyl-6-(4-Oxymorphone-4-yl)-N-naphthalene-1-ylmethyl-4-o-callincoming

The original compound was obtained as a colorless viscous oil with comparable outputs according to the procedures described above, to obtain N-methyl-N-(2-methylnaphthalene-1-ylmethyl)-6-morpholine-4-yl-4-o-telinekataja (note the p 19), using 1-chloromethylation instead of 1-chloromethyl-2-methylnaphthalene at the stage b).

MS m/e (%): 452 (M+N+, 100).

N-Oxide was obtained according to stage C) of example 1.

Example 21

N-(2-Methoxynaphthalene-1-ylmethyl)-N-methyl-6-(4-Oxymorphone-4-yl)-4-o-callincoming

The original compound was obtained as a colorless viscous oil with comparable outputs according to the procedures described above, to obtain N-methyl-N-(2-methylnaphthalene-1-ylmethyl)-6-morpholine-4-yl-4-o-telinekataja (example 19)using 2-methoxynaphthalene-1-ymetray ester toluene-4-sulfonic instead of 1-chloromethyl-2-methylnaphthalene at the stage b).

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

N-Oxide was obtained according to stage C) of example 1.

Example 22

N-(2-Methoxybenzyl)-N-methyl-6-(4-Oxymorphone-4-yl)-4-o-callincoming

The original compound was obtained as a colorless viscous oil with comparable outputs according to the procedures described above to obtain N-methyl-N-(2-methylnaphthalene-1-ylmethyl)-6-morpholine-4-yl-4-o-telinekataja (example 19)using chloride 2-methoxybenzyl instead of 1-chloromethyl-2-methylnaphthalene at the stage b).

MS m/e (%): 432 (M+N+, 100).

N-Oxide was obtained according to stage C) of example 1.

Example 23

N-(5-Chloro-2-methoxybenzyl)-N-methyl-6-(4-Oxymorphone-4-yl)-4-o-callincoming

The original connection was received in the form of a solid white color with ravninyi outputs according to the procedures described above, to obtain N-methyl-N-(2-methylnaphthalene-1-ylmethyl)-6-morpholine-4-yl-4-o-telinekataja (example 19)using chloride 5-chloro-2-methoxybenzyl instead of 1-chloromethyl-2-methylnaphthalene at the stage b).

MS m/e (%): 466 (M+N+, 100).

N-Oxide was obtained according to stage C) of example 1.

Example 24

N-(2-Chloro-5-methoxybenzyl)-N-methyl-6-(4-Oxymorphone-4-yl)-4-o-callincoming

The original connection was received in the form of a solid white color with comparable outputs according to the procedures described above, to obtain N-methyl-N-(2-methylnaphthalene-1-ylmethyl)-6-morpholine-4-yl-4-o-telinekataja (example 19)using methyl 2-chloro-5-methoxybenzyl instead of 1-chloromethyl-2-methylnaphthalene at the stage b).

MS m/e (%): 466 (M+H+, 100).

N-Oxide was obtained according to stage C) of example 1.

Example 25

N-Methyl-6-(4-Oxymorphone-4-yl)-N-pantothenicacid-4-o-callincoming

The original connection was received in the form of a solid white color with comparable outputs according to the procedures described above, to obtain N-methyl-N-(2-methylnaphthalene-1-ylmethyl)-6-morpholine-4-yl-4-o-telinekataja (example 19)using methyl 2,3,4,5,6-pentafluorobenzyl instead of 1-chloromethyl-2-methylnaphthalene at the stage b).

MS m/e (%): 492 (M+N+, 100).

N-Oxide was obtained according to stage C) of example 1.

Example 26

N-Methyl-6-(4-Oxymorphone-4-yl)-N-Naftali is-2-ylmethyl-4-o-callincoming

The original connection was received in the form of a solid white color with comparable outputs according to the procedures described above, to obtain N-methyl-N-(2-methylnaphthalene-1-ylmethyl)-6-morpholine-4-yl-4-o-telinekataja (example 19)using 2-chloromethylation instead of 1-chloromethyl-2-methylnaphthalene at the stage b).

MC m/e (%): 452 (M+N+, 100).

N-Oxide was obtained according to stage C) of example 1.

Example 27

N-[2-Methoxy-5-(5-cryptomaterial-1-yl)benzyl]-N-methyl-6-(4-Oxymorphone-4-yl)-4-o-callincoming

The original connection was received in the form of a solid white color with comparable outputs according to the procedures described above, to obtain N-methyl-N-(2-methylnaphthalene-1-ylmethyl)-6-morpholine-4-yl-4-o-telinekataja (example 19)using [2-methoxy-5-(5-cryptomaterial-1-yl)phenyl]methyl ester toluene-4-sulfonic instead of 1-chloromethyl-2-methylnaphthalene at the stage b).

MC m/e (%): 568 (M+N+, 100).

N-Oxide was obtained according to stage C) of example 1.

Example 28

N-(1,4-Dimethoxyaniline-2-ylmethyl)-N-methyl-6-(4-Oxymorphone-4-yl)-4-o-callincoming

The original compound was obtained as a colorless viscous oil with comparable outputs according to the procedures described above, to obtain N-methyl-N-(2-methylnaphthalene-1-ylmethyl)-6-morpholine-4-yl-4-o-telinekataja (example 19)using 2-chloromethyl-1,4-dimethoxyaniline in the seat 1-chloromethyl-2-methylnaphthalene at the stage b).

MC m/e (%): 512 (M+N+, 100).

N-Oxide was obtained according to stage C) of example 1.

Example 29

5'-[(3,5-Bis-trifloromethyl)methylcarbamoyl]-4'-o-tolyl-1-hydroxy-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid

A mixture of 200 mg (0,33 mmole) ethyl ester 5'-[(3,5-bis-trifloromethyl)methylcarbamoyl]-4'-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid (example 14), 10 ml of 1 N. aqueous solution of sodium hydroxide and 10 ml of methanol was stirred at room temperature overnight. After washing with two portions of ethyl acetate, the aqueous layer was acidified to pH 4 1 N. aqueous solution of hydrochloric acid. Extraction with dichloromethane, drying over sodium sulfate and column flash chromatography led to 81 mg (42%) of starting compound in a solid white color.

MS m/e (%): 580 (M+N+, 100).

N-Oxide was obtained according to stage C) of example 1.

Example a
Tablets of the following composition are produced in the usual way:
mg/per tablet
The prodrug5
Lactose45
Corn starch 15
Microcrystalline cellulose34
Magnesium stearate1
weight pills100
Example B
Capsules of the following composition is produced:
mg/capsule
The prodrug10
Lactose155
Corn starch30
Talc5
mass content capsules200

The active ingredient, lactose and corn starch are first mixed in a mixer and then into the chopping device. The mixture back into the blender, add it with talcum powder and mix thoroughly. With the help of a special device with a mixture of filled hard gelatin capsules.

The example In
Suppositories of the following composition is produced:
mg/suppository and
The prodrug15
Weight for suppository1285
total1300

For a lot of suppository is melted in a glass or steel vessel, thoroughly mixed and cooled to 45°C. Then it added to the active substance in the form of a fine powder and stirred until complete dispersion. The mixture is then poured into molds for suppositories suitable size, leave to cool, then suppositories are removed from the molds and wrap individually in waxed paper or metal foil.

1. N-oxide derivatives of 4-phenylpyridine General formula

where R is lower alkyl or halogen;

R1means hydrogen;

R2and R2'mean independently from each other hydrogen, halogen, trifluoromethyl or (ness.)alkoxygroup; or

R2and R2'may together denote-CH=CH-CH=CH-, optionally substituted with one or two substituents selected from lower alkyl or (ness.)alkoxygroup;

R3, R3'mean independently from each other hydrogen or lower alkyl;

R4, R4'mean independently from each other -(CH2)mOR6 or lower alkyl; or

R4and R4'form together with the nitrogen atom to which they are connected, a cyclic tertiary amine, as a group

which is pyrrolidin-1-yl, piperidine-1-yl, piperazine-1-yl, morpholine-4-yl or 1,1-diocletianopolis-4-yl;

R5means hydrogen, hydroxyl, -COOR3, -N(R3)CO-lower alkyl or-C(O)R3;

R6means hydrogen or lower alkyl;

X is-C(O)N(R6)- or-N(R6)C(O)-;

n means 0, 1, 2, 3 or 4;

m denotes 1, 2 or 3;

and their pharmaceutically acceptable acid additive salt.

2. The compound according to claim 1, where X is-C(O)N(R6)and R6means methyl.

3. The compound according to claim 2, which means

tributyl ether 4-{5-[(3,5-bis-trifloromethyl)methylcarbamoyl]-4-o-tailpiece-2-yl}-4-oxopiperidin-1-carboxylic acid,

ethyl ester 5'-[(3,5-bis-trifloromethyl)methylcarbamoyl]-4'-o-tolyl-1-hydroxy-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid,

(RS)-6-[3-(acetylecholine)-1-oxopyrrolidin-1-yl]-N-(3,5-bis-trifloromethyl)-N-methyl-4-o-callincoming,

N-(3,5-bis-trifloromethyl)-N-methyl-6-(4-Oxymorphone-4-yl)-4-o-callincoming monohydrate,

N-(3,5-bis-trifloromethyl)-6-(1,1-dioxo-1λsup> 6-4-occationaly-4-yl)-N-methyl-4-o-callincoming,

N-(3,5-bis-trifloromethyl)-6-(4-formyl-1-oxopiperidin-1-yl)-N-methyl-4-o-callincoming,

N-methyl-N-(2-methylnaphthalene-1-ylmethyl)-6-(4-Oxymorphone-4-yl)-4-o-callincoming,

N-methyl-6-(4-Oxymorphone-4-yl)-N-naphthalene-1-ylmethyl-4-o-callincoming,

N-(2-methoxynaphthalene-1-ylmethyl)-N-methyl-6-(4-Oxymorphone-4-yl)-4-o-callincoming,

N-(2-methoxybenzyl)-N-methyl-6-(4-Oxymorphone-4-yl)-4-o-callincoming,

N-(5-chloro-2-methoxybenzyl)-N-methyl-6-(4-Oxymorphone-4-yl)-4-o-callincoming,

N-(2-chloro-5-methoxybenzyl)-N-methyl-6-morpholine-4-yl-4-o-callincoming,

N-methyl-6-(4-Oxymorphone-4-yl)-N-pantothenicacid-4-o-callincoming,

N-methyl-6-(4-Oxymorphone-4-yl)-N-naphthalene-2-ylmethyl-4-o-callincoming,

N-[2-methoxy-5-(5-cryptomaterial-1-yl)benzyl]-N-methyl-6-(4-Oxymorphone-4-yl)-4-o-callincoming,

N-(1,4-dimethoxyaniline-2-ylmethyl)-N-methyl-6-(4-Oxymorphone-4-yl)-4-o-callincoming or

5'-[(3,5-bis-trifloromethyl)methylcarbamoyl]-4'-o-tolyl-1-hydroxy-3,4,5,6-tetrahydro-2H-[1,2'] bipyridinyl-4-carboxylic acid.

4. The compound according to claim 1, where X is-N(R6)C(O)- and R6means hydrogen or methyl.

5. The compound according to claim 4, which means

2-(3,5-bis-triptoreline)-N-methyl-N-[6-(4-OK is morpholin-4-yl)-4-o-tolyl-pyridin-3-yl]isobutyramide,

2-(3,5-bis-triptoreline)-N-[4-(2-chlorophenyl)-6-(4-Oxymorphone-4-yl)-pyridin-3-yl]-N-methylisoleucine,

2-(3,5-bis-triptoreline)-N-[6-(4-Oxymorphone-4-yl)-4-o-tailpiece-3-yl]-isobutyramide,

2-(3,5-bis-triptoreline)-N-[4'-(2-chlorophenyl)-1-hydroxy-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5 yl]-N-methylisoleucine,

2-(3,5-bis-triptoreline)-N-(6-oxydiethylene-4-o-tolyl-pyridin-3-yl)-N-methylisoleucine,

2-(3,5-bis-triptoreline)-N-[4-(2-chlorophenyl)-6-oxydemeton-aminopyridine-3-yl]isobutyramide,

2-(3,5-bis-triptoreline)-N-1-(4-hydroxy-1-hydroxy-4'-o-tolyl-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5 yl)-N-methylisoleucine,

2-(3,5-bis-triptoreline)-N-{6-[(2-hydroxyethyl)-1-oxymethylene]-4-o-tailpiece-3-yl}-N-methylisoleucine,

(R)-2-(3,5-bis-triptoreline)-N-[6-(3-hydroxy-1-oxopyrrolidin-1-yl)-4-o-tailpiece-3-yl]-N-methylisoleucine,

2-(3,5-bis-triptoreline)-N-methyl-N-[6-(4-Oxymorphone-4-yl)-4-o-tailpiece-3-yl]acetamide", she

2-(3,5-acid)-N-methyl-N-[6-(4-Oxymorphone-4-yl)-4-o-tailpiece-3-yl]ndimethylacetamide or

2-(3-fluoro-5-triptoreline)-N-methyl-N-[6-(4-Oxymorphone-4-yl)-4-o-tailpiece-3-yl]ndimethylacetamide.

6. Drug for the treatment of diseases associated with the antagonists of the receptor NK-1, containing one or more compounds of the formula I in I the th one of claims 1 to 5, and pharmaceutically acceptable excipients.



 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying compounds of the general formula (1):

as inhibitors of caspase-3 that allows their applying as "molecular tools" and as active medicinal substances inhibiting selectively the scheduling cellular death (apoptosis). Also, invention relates to pharmaceutical compositions based on compounds of the formula (1), to a method for their preparing and a method for treatment or prophylaxis of diseases associated with enhanced activation of apoptosis. Also, invention relates to new groups of compounds of the formula 91), in particular, to compounds of the formulae (1.1):

and (1.2):

. In indicated structural formulae R1 represents inert substitute; R2, R3 and R4 represent independently of one another hydrogen atom, fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J). CF3, inert substitute, nitro-group (NO2), CN, COOH, optionally substituted sulfamoyl group, optionally substituted carbamide group, optionally substituted carboxy-(C1-C6)-alkyl group; R5 represents oxygen atom or carbon atom included in optionally condensed, optionally substituted and optionally comprising one or some heteroatoms; R6 represents hydrogen atom or inert substitute; X represents sulfur atom or oxygen atom.

EFFECT: improved preparing and applying methods, valuable medicinal and biochemical properties of compounds.

3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to biologically active compounds, in particular, to substituted 5R1,6R2-thiadiazine-2-amines and pharmaceutical compositions comprising thereof that can be used in medicine as potential pharmacologically active substances eliciting the unique combination of properties: expressed anticoagulant activity in combination with capacity to inhibit aggregation of platelets. Effect of these substances differ from preparations used in medicinal practice and they can be used therefore in treatment of such diseases as myocardium infarction, disturbance in cerebral circulation, rejection of transplanted organs and tissues and so on. Indicated compounds correspond to the formula (I):

wherein values of radicals R1, R2 and R3 are given in the invention claim.

EFFECT: valuable medicinal properties of compounds.

4 cl, 2 tbl, 7 dwg, 33 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepines of the general formula (I):

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

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

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

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

10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.

26 cl, 2 tbl, 253 ex

The invention relates to organic chemistry, in particular, optionally N-oxidized compounds represented by the formula:

in which R1represents a hydrogen atom, a C1-6alkyl group, phenyl group, optionally substituted by a halogen atom, a C1-6alkylthio or C1-6alkylsulfonyl, or amino group, optionally substituted (i) C1-6alkyl group, or (ii) acyl group(C=O)-R5where R5represents C1-6alkyl group, phenyl or pyridyl; R2is6-14aryl group, optionally substituted by a halogen atom or C1-6alkoxy, or 5 - or 6-membered aromatic heterocyclic group containing one sulfur atom or one nitrogen atom; R3represents a phenyl group, optionally substituted by one or two C1-6alkyl groups or C1-6alkoxy; X represents a sulfur atom; Y represents O, S, SO2or NR4where R4represents a hydrogen atom or a C1-6alkyl group; and Z represents a bond, C1-6alkylenes group, optional zameshannuu oxo or C1-6alkyl group

The invention relates to polycyclic, thiazolidin-2 - ildenafil amines and their physiologically acceptable salts and physiologically functional derivatives

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

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

The invention relates to novel polycyclic to dihydrothiazolo General formula (I), where Y is a simple bond; X is CH2; R1 is H, F, Cl, NO2, CN, COOH, (C1-C6)-alkyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, and alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine; (CH2)n-phenyl, SO2-(C1-C6)-alkyl, and n = 0 and the phenyl residue up to twice may be substituted by F, Cl, CF3, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; O-(CH2)n-phenyl, and n = 0 and phenyl cycle can be one - to twofold substituted by Cl, (C1-C6)-alkyl; 1 - or 2-naphthyl, 2 - or 3-thienyl; R1' is hydrogen; R2 is H, (C1-C6)-alkyl, R3 is hydrogen; R4 - (C1-C8)-alkyl, (C3-C7-cycloalkyl, (CH2)n-aryl, and n = 0-1, and aryl can be phenyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl, 2 - or 3-furyl, indol-3-yl, indol-5-yl, and aryl or heteroaryl residue up to twice may be substituted by F, Cl, HE, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, 2-, 3-, 4-pyridium, pyrrol-1-yl, with peregrinae ring may be substituted CF3; and their physio is

FIELD: agriculture, in particular method for controlling of specific insect pests.

SUBSTANCE: invention relates to method for controlling of lepidopterous, homopterous, hemipterans, coleopterous, and physopods by contacting of said pests or environment thereof with effective amount of compound of formula I SSS1, N-oxide or agriculturally acceptable salt thereof being effective against abovementioned insects, wherein A and B are independently O or S; R1, R2 represent H, C1-C6-alkyl; R3 represents H, optionally substituted C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, or C3-C6-cycloalkyl; R4 represents H, C1-C6-alkyl, C2-C6-alkinyl, C1-C6-haloalkyl, CN, halogen, C1-C4-alkoxy, C1-C4-haloalkoxy, NO2;. R5 represents H, C1-C6-alkyl, C1-C6-haloalkyl, C1-C4-hydroxyalkyl, CO2R11R12, halogen or C1-C4-alkoxy; R6 represents H, C1-C6-alkyl, C1-C6-haloalkyl; R7 represents H, C1-C6-alkyl, C2-C6-alkenyl, C1-C6-haloalkyl, phenyl ring, benzyl ring, or 5-6-membered heteroaromatic rind, naphthyl ring system, or 8-10-membered condensed heterodicyclic system. Also claimed are compound of formula I and benzoxazine derivative of formula 10 .

EFFECT: compounds effective against agriculture spineless depredators.

22 cl, 13 tbl, 1 dwg, 24 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of azole of the formula:

wherein R1 represents (1) halogen atom; (2) nitrogen-containing 5- or 6-membered heterocyclic group comprising from 1 to 4 nitrogen atoms as atoms of ring system in addition to carbon atoms, and group with condensed rings comprising nitrogen-containing 5- or 6-membered heterocyclic group comprising 1-2 nitrogen atoms as atoms of ring system in addition to carbon atoms, and benzene ring wherein nitrogen-containing 5- or 6-membered heterocyclic group and group with condensed rings can comprise optionally from 1 to 3 substituted taken among group consisting of: (i) aliphatic hydrocarbon group comprising from 1 to 15 carbon atoms; (ii) (C6-C14)-aryl group, and (iii) carboxy-group that can be in form of group of (C1-C6)-alkyl ester wherein above indicated substitutes (i)-(iii) can have from 1 to 3 substituted additionally taken among group consisting of: (a) carboxyl group and (b) hydroxy-group; (3) (C1-C10)-alkylsulfanyl group that can be substituted with hydroxy-group; (4) heteroarylsulfanyl group taken among pyridylsulfanyl, imidazolylsulfanyl and pyrimidinylsulfanyl, or (5) amino-group that can be mono- or di-substituted optionally with substitutes(substitutes) among group consisting of: (i) (C1-C10)-alkyl group that can be substituted with hydroxy-group, and (ii) (C7-C10)-aralkyl group; Ab represents aryloxy-group that is substituted with alkyl group and can be substituted with halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl group, hydroxy-group or (C1-C6)-alkylcarbonyloxy-group additionally; B represents (C6-C14)-aryl group or thienyl group each of that can has optionally from 1 to 4 substitutes taken among halogen atom, (C1-C6)-alkoxy-group and (C1-C6)-alkyl group that can has optionally from 1 to 3 halogen atoms; Y represents saturated aliphatic bivalent group with direct or branched chain and having from 1 to 7 carbon atoms, or to its salt. Also, invention relates to a pharmaceutical composition that elicits activity for promoting production/secretion of neurotrophine, and to methods for prophylaxis and treatment based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof used for prophylaxis and treatment of neuropathy.

EFFECT: improved and valuable medicinal properties of agent, improved methods for treatment.

19 cl, 1 dwg, 5 tbl, 122 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepines of the general formula (I):

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.

26 cl, 2 tbl, 253 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a new method for preparing 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxotetrahydropyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrol-3-carboxylic acid phenylamide that involves conversion of methylcyano acetate to the end compound for 8 or less stages. Also, invention relates to value intermediate compounds that are synthesized as result of realization of above indicated stages of the claimed method. 5-(4-Fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxotetrahydropyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrol-3-carboxylic acid phenylamide is a value intermediate compound used in synthesis of the drug atorvastatin calcium that is used as hypolipidemic and/or hypocholesterolemic agent. Proposed method allows avoiding usage of expensive chiral parent substances and to reduce the synthesis process time.

EFFECT: improved preparing method.

12 cl, 3 ex

The invention relates to the field of organic chemistry, namely to new individual compounds of class oxazino that exhibit fluorescent properties and can be used as starting products for the synthesis of new heterocyclic systems, as well as substances for sample labeling and additives for reflective paints

The invention relates to chemistry and agriculture, particularly to substituted 1,3,5-triazines as promoters prorostania seeds

The invention relates to novel alkyl-piperazinil benzoxazolinone and alkyl-piperidinyl benzoxazolinone derivative of the formula (I), where S1is hydrogen; Z is =C or N; R1, R2and R4independently represent hydrogen, Q is methyl, ethyl or cyclopropylmethyl, and their salts and prodrugs

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to derivatives of benzimidazole of general formulae (IV)

and

For compounds of the formula (IV): R represents hydrogen atom, (C1-C10)-alkyl and others; D represents phenyl or azaphenyl; n = 0; A, B and Q represent hydrogen atom, (C1-C10)-alkyl and others; Z represents a bond, (C1-C6)-alkylene or -CH2O-; R1 represents hydrogen atom, (C1-C10)-alkyl and others; R2 represents hydrogen atom. For compounds of the formula (IVA): n = 0; Z represents a bond, -CH2-, -CH2O-, -CH2CH2-; R represents hydrogen atom or (C1-C10)-alkyl; R1 represents hydrogen atom, (C3-C12)-cycloalkyl, benzyl and others; R2 represents hydrogen atom. Compounds of formulae (IV) and (IVA) possess affinity with respect to nociceptin and μ-receptors and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

18 cl, 5 tbl, 16 ex

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