Bicyclic derivatives of amidine, the method of production thereof, pharmaceutical composition and method synthetase inhibition of nitric oxide

 

(57) Abstract:

Describes bicyclic derivatives of amidine formula I, where D represents a five-membered heterocyclic aromatic ring containing 1 to 4 heteroatoms selected from O, N or S, optionally substituted on the carbon atom by halogen, trifluoromethyl, alkyl (C1-6, nitro or cyano, and which is connected with the rest of the compounds of formula I through a carbon atom; a represents N(X) or CH (-(CH2)m-NXY), U represents NH, O, or CH2; V is CH2)a; W represents (CH2)b; a, b, m, X and Y are specified in the value formula, as well as methods for their preparation and the pharmaceutical composition. The compounds of formula I are inhibitors synthetase nitrogen oxide and suitable for use in therapy. 5 c. and 15 C.p. f-crystals.

The present invention relates to bicyclic derivatives of amidine, to methods for their preparation, to their containing compositions and to their use in therapy. Described the use of certain derivatives of amidine for therapeutic purposes. The use of derivatives of N - phenylaniline for the treatment of diabetes has been described in U.S. patent N 3669974 (USV Pharmaceutical Corp.) in the patent lucidogen conditions described in international patent application WO 92/04054 (University of Oregon). Some amidino and symmetric bisamidines as analgesics in the treatment of inflammation and in the treatment of hypertension are disclosed in Belgium patent N 71740 and the United Kingdom patent N 1180629 (both Delalande). Use of derivatives of amidine as herbicides has been disclosed in a patent application Germany DE-OS-2321330 (Bayer).

Applying synthetase inhibitors of nitric oxide in the treatment of diseases was also described, for example, in international patent applications WO 94/12163 (Abbott), WO 93/13066 and WO 94/12165 (both Wellcome) and in European patent applications 446699 (Merrell Dow), 547558 and 558468 (both from the University of Washington). Inhibitors synthetase nitrogen oxides disclosed in WO 95/00505, WO 95/09619, WO 95/09621 (all welcome), WO 95/10266 (Otsuka), WO 95/11231 and WO 95/11014 (both Searle).

Previously, the applicant has disclosed the use of derivatives of guanidine and derivatives of amidine that are synthetase inhibitors of nitric oxide in the treatment, along with other neurodegenerative diseases (WO 094/21621, WO 95/05363).

Currently, the authors discovered a new group of bicyclic derivatives of amidine, which have useful pharmaceutical activity.

In accordance with the first aspect of the present invention proposed coetsee from 1 to 4 heteroatoms, selected from O, N or S, optionally substituted on the carbon atom by halogen, trifluoromethyl, alkyl (C1-6, nitro or cyano, and which is connected with the rest of the compounds of formula I through a carbon atom;

A represents N(X) or CH(-(CH2)m-NXY);

U represents NH, O, or CH2;

V represents (CH2)a;

W represents (CH2)b;

a and b independently represent an integer from 0 to 3, provided that a+b ranges from 1 to 3;

X and Y independently represent hydrogen, alkyl (C1-6or a group -(CH2)nQ or-NXY is piperidinyl, pyrrolidinyl, morpholinyl or tetrahydroisoquinoline;

Q represents a biphenyl or phenyl, optionally substituted by one or more groups selected from alkyl (C1-6anoxi C1-6, perfluoroalkyl C1-6, halogen, nitro or cyano,

m represents an integer from 0 to 5;

n represents an integer from 0 to 6;

or chain U-V-A-W has the previously indicated values, except for the ability to be unsaturated, or chain U-V-A-W can represent-NH-CH2-CH2-O-, substituted on the carbon atom by a group -(CH2)m-NXY, where m, X and Y have the previously indicated meanings, and its pharmaceutical preparations>/BR>< / BR>
where T represents C3-5saturated or unsaturated alkylenes chain, substituted -(CH2)m-NXY; -O- (CH2)2-NH-substituted -(CH2)m-NXY; or-U-(CH2)a-N(X)-(CH2)b-;

X and Y independently represent hydrogen, alkyl (C1-6or a group - (CH2)nQ, or NXY is piperidinyl, pyrrolidinyl, morpholinyl or tetrahydroisoquinoline;

Q is phenyl, optionally substituted alkyl (C1-6, alkoxy, C1-6, trifluoromethyl, halogen, nitro or cyano;

a U, m, n, b and D have the above values, except that if T is-U-(CH2)a-N(X)- (CH22)b- and X is -(CH2)nQ, n represents an integer from 0 to 5, and its pharmaceutically acceptable salts.

It is preferable that D was represented by five-membered heterocyclic aromatic ring containing one heteroatom selected from O, N or S, optionally substituted on the carbon atom by halogen. Particularly preferably, D is represented thienyl, furyl or pyrrolyl, especially thienyl or furyl, more preferably thienyl, most preferred 2-thienyl.

It is preferable that T was C3-5military alkylenes chain, substituted - (CH2)m-NXY, and especially, C3-5rich alkylenes chain, substituted -(CH2)m-NXY.

If T represents C3-5saturated or unsaturated alkylenes chain, substituted -(CH2)m-NXY; or-O- (CH2)2-Substituted NH -(CH2)m-NXY, it is preferable that X and Y are independently represented by hydrogen, alkyl (C1-6or a group -(CH2)nQ. Particularly preferably, X and Y independently represented by hydrogen, methyl, ethyl or the group - (CH2)nQ most preferably, one of X or Y would represent hydrogen and the other represents hydrogen or the group -(CH2)nQ.

Preferably, m is 0 or 1, especially 0;

If T is-U-(CH2)a-N(X)- (CH2)b-, preferably U was CH2,

If T is-U-(CH2)a-N(X)- (CH2)b-, preferably a+b was 1 or 2;

If T is-U-(CH2)a-N(X)-(CH2)bis, preferably, X is represented by hydrogen, alkyl (C1-6or a group -(CH2)nQ.

If X and/or Y represents -(CH2)nQ, it is preferable that n was 0, 1 UB> or halogen, although the most preferred Q represents unsubstituted phenyl.

In accordance with the invention proposed a further method of preparing compounds of formula I and their pharmaceutically acceptable salts, which includes:

(a) obtaining the compounds of formula I by reacting the corresponding compounds of formula II:

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where U, V, A and W have the above meanings, with a compound of formula III:

< / BR>
where D is above said value, a L is tsepliaeva group;

(b) obtaining the compounds of formula I by reacting the corresponding compounds of formula IV:

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where U, V, A and W have the above values, and HA represents an acid, with a compound of formula V:

< / BR>
where D has the above meanings;

(c) obtaining the compounds of formula I in which a represents N(X), and X represents alkyl, C1-6or a group -(CH2)nQ, by reacting the corresponding compounds of formula I in which X represents hydrogen, with a compound of formula VI:

R9-L

where R9represents C1-6or a group - (CH2)nQ and L represents tsepliaeva group;

(d) obtaining the compounds of formula I, where A represents CH(-(CH2
(e) obtaining the compounds of formula I, where A represents CH(-(CH2)m-NXY), a m is an integer from 1 to 5, the recovery of the corresponding compounds of formula VII

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where U, V, W, X, Y and D have the above meanings;

(f) obtaining the compounds of formula I, where A represents CH(-(CH2)m-NXY), and both X and Y represent hydrogen, the recovery of the corresponding compounds of formula VIII:

< / BR>
where U, V, W, n and D have the above values

(g) obtaining the compounds of formula I, where A represents CH(-(CH2)m-NXY), X represents hydrogen, a m is an integer from 1 to 5, the recovery of the corresponding compounds of formula IX:

< / BR>
where U, V, W, D and Y have the previously indicated meanings;

(h) obtaining the compounds of formula I, where A represents CH(-(CH2)m-NXY), one of X and Y represents hydrogen and the other represents -(CH2)nQ, where n is an integer from 1 to 6, due to the recovery of the corresponding compounds of formula X:

< / BR>
where Q, m, U, V, W and D have the above values.

(i) obtaining the compounds of formula I, where A represents CH(-(CH2)m-NXY), one of the X formation of compounds of formula XI

< / BR>
where Q, m, U,V, W and D have the above values, or

(j) obtaining the compounds of formula I, where A represents CH(-NXY), and X represents hydrogen, the recovery of the corresponding compounds of formula XII

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where U, V, W, D and Y have the previously indicated meanings; and where, if desired or if necessary, transform the obtained compound of formula I or other salt, pharmaceutically acceptable salt it or Vice versa.

In method (a) the reaction is carried out at a stirring mixture of the reactants in a suitable solvent, for example, in this lower alkanol as ethanol, isopropanol or tert. - butanol, at a temperature in the range from room temperature to the boiling point of the solvent under reflux. Reaction time (along with others) depends on the solvent and the nature tsepliaeva group, and may be up to 48 hours, however, it usually takes from 1 to 5 hours. A suitable present tsepliaeva group L may be thioalkyl, sulfonyl, triftoruranmetilidina, halogen, alkilany and arrowy alcohols, and tselnye group; others are listed in "Advanced Organic Chemistry", J. March (1985) 3 Ed., McGraw - Hill, pp 315, and is well known to specialists.

In method (b) the reaction is preferably carried out at the appropriate solvent, due to which the reaction temperature is high enough to easily happened condensation, but not high enough to cause decomposition of forming amidine. The reaction temperature may vary from room temperature to about 250oC, although it is preferable to conduct the reaction at a temperature of from about 100oC to 200oC. Found that the most suitable solvent is o-dichlorobenzene, and that it is useful to add as a catalyst 4-dimethylaminopyridine. Upon cooling, two layers are formed, the solvent can be decanted and the reaction mixture is treated by adding an aqueous base. In another embodiment, if the reagents are dissolved in a solvent, the solvent can evaporate in vacuum and the reaction mixture was treated by adding water. Acid HA can be organic or inorganic acid, e.g. hydrochloric, Hydrobromic, uudistoodetena, sulphuric, nitric, phosphoric, acetic, lactic, succinic, fumaric, malic, maleic, tartaric, citric, benzoic or methansulfonate acid.

In method (c) the reaction is carried out under standard conditions, for example, when the interaction between the two compounds in an inert solvent in sabrebiade Amin NaOH before as interact with the compound of the formula VI. It is preferable that L was represented by halogen, especially bromine.

Method (d) can be performed under conditions similar to those described previously for the method (c).

In method (e) recovery can be accomplished by treatment with DIBORANE in an inert solvent, for example, THF. Alternatively, although less preferred reagents that can be used include sociallyengaged and reagents for catalytic hydrogenation, for example, H2on Pd/C. details of the reaction conditions when using these reactions are described in the reference J. March "Advanced Organic Chemistry" on page 1099, including quoted your link here.

In method (f) response recovery can be performed in various conditions, for example, those described in J. March "Advanced Organic Chemistry" on pages 1103-1104. These include catalytic hydrogenation, using Zn, Sn or Fe metals, AlH3-AlCl3, sulfides, etc. it is Preferable to conduct the reaction of hydrogenation at atmospheric pressure for a period of 3-6 hours in the presence of a catalyst of palladium on coal.

In the methods (g), (i) and (j), recovery can be accomplished by processing the connection with sodium borohydride or lanborghini conditions, previously described for the method (e).

Salts of the compounds of formula I can be obtained by interaction of a free base or a salt, enantiomer, tautomer or protected derivative, with one or more equivalents of the appropriate acid. The reaction can be conducted in a solvent or medium in which the salt is insoluble, or in such a solvent, in which this salt is soluble, for example, water, dioxane, ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents that can be removed under vacuum or by freeze-drying. This reaction can be exchange process, or it can lead to ion-exchange resin.

The compounds of formula II can be obtained by recovering the corresponding compounds of formula XIII:

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where U, V, A and W have the above values.

The reduction can be conducted in conditions similar to the conditions described for process (f).

Some compounds of formula II are either known or can be obtained by conventional means, known per se. Other compounds of formula II can be obtained from known compounds with more than a simple replacement groups in accordance with the methods described wound is that the compounds of formula XIII, where A represents CH(-NXY), and X represents hydrogen, due to the recovery of the corresponding imine formed in the reaction of compounds of formula NH2Y nitrified bicyclic ketone.

The compounds of formula IV can be obtained by methods similar to those described for preparing compounds of formula II. The compounds of formula IV can be converted into the corresponding compounds of formula II, their processing base. The compounds of formula II can be converted into the corresponding compounds of formula IV, treating the proton acid HA, for example, one of those that have been listed previously.

The compounds of formula III are either known compounds or they can be obtained by known methods. For example, the compounds of formula II in which L represents thioalkyl, you may receive the processing result teamed formula XIV

< / BR>
where D is above said value, alkylation.

Compounds of formulas VII, VIII, IX, X, XI and XII can be obtained by methods similar to the methods described for preparing compounds of formula I. Such compounds can easily be obtained from compounds with a simpler surrogate groups by conventional means, for example, using the formation of the amide (VII, X) and by reaction of the amine with the aldehyde.

Compounds of formulas V, VI, XIII and XIV are either known compounds or they can be obtained in the usual way per se.

Professionals should be understood that it may be desirable to protect the amine or other reactive group, using a protective group, as described in the standard text "Protecting groups in Organic Synthesis", and 2nd Ed. (1991) by Greene and Wuts. You can mention such amine protecting groups, as alkoxycarbonyl C2-7for example, tert.-butoxycarbonyl, generalconditions C8-13for example, benzyloxycarbonyl, or, preferably, triptorelin. Remove protection usually at the expense of processing water base, acid, or treating with hydrogen.

Compounds of the present invention and intermediate compounds can be isolated from reaction mixtures by conventional means.

The term "alkyl (C1-6" includes branched and non-branched chain, saturated, unsaturated, aliphatic and cyclic alkyl groups containing from 1 to 6 carbon atoms.

The compounds of formula I may exist in tautomeric, enantiomeric or diastereoisomeric forms, and they are all included in the scope of the present invention. Various optical isomers can be vitalitatii or by HPLC. In another embodiment, the single enantiomers can be obtained by reaction of the appropriate optically active starting materials under such reaction conditions that will not cause racemization.

Intermediate compounds may exist in enantiomeric forms, and can be used as purified enantiomers, diastereoisomers, racemates or mixtures.

The compounds of formula I possess useful pharmacological activity in animals. In particular, they are useful in inhibiting the synthetase of nitric oxide activity, and it is expected that they can be useful in the treatment or prophylaxis of human diseases or conditions in which synthesis or excessive synthesis of nitric oxide contributes; an example is hypoxia, for example in cases of cardiac arrest or shock, neurodegenerative diseases, including degeneration of the nerves and/or necrosis of nerves for diseases such as hypoxia, hypoglycemia, epilepsy, and in external wounds (such as damage to the spine or head), hyperbaric oxygen convulsions and toxicity, dementia, for example, senile dementia, Alzheimer's disease and dementia associated with AIDS, chorea Sydenham, boletellus, associated with cerebral blood vessels, sleep disorders, schizophrenia, depression, autism, seasonal disorders, disorder of the normal circadian rhythm, depression and other symptoms associated with adult syndrome (PMS), anxiety and septic shock. The compounds of formula I are expected to demonstrate the activity for the prevention and treatment based on drugs, relieving pain and in the treatment of migraines and other headaches of vascular origin. Compounds of the present invention can also show immunosuppressive activity, to be useful in the treatment or prevention of inflammation, neurogenic inflammation, diseases, leading to the blockade of the respiratory tract, including asthma and respiratory distress syndrome in adults (ARDS), in the treatment of motility disorders of the gastrointestinal tract, cancer, promote delivery, to reduce the secretion of gastric acid and to increase the force of contraction of skeletal muscles.

Compounds of the present invention of formula I are of particular interest in the treatment of neurodegenerative diseases, migraines, or for the prevention or treatment of tolerance to opiates and benzodiazepines, or to treat zavisimosti with the following aspect of the invention proposed compound of formula I or its pharmaceutically acceptable salt for use in the pharmaceutical industry.

In accordance with the following distinctive feature of the invention it is proposed to use the compounds of formula I or its pharmaceutically acceptable salt in obtaining medications for treatment or prophylaxis of the aforementioned diseases or conditions.

Also we propose a method for the treatment or prevention of one of the above diseases or conditions, which includes the introduction of therapeutically effective amounts of compounds of formula I or its pharmaceutically acceptable salt to a patient suffering from or susceptible to such disease or condition.

For the above therapeutic indications injected dose will naturally vary depending on the compounds used, the method of introduction and needed treatment. However, generally, satisfactory results are achieved in cases when these compounds are administered to humans in a daily dose of from 1 mg to 2000 mg (measurement for solid forms).

The compounds of formula I and their pharmaceutically acceptable salts can be used alone or in the form of relevant medical preparations for enteral or parenteral administration.

In accordance with the present invention proposed by the geography of formula I or its pharmaceutically acceptable salt, in a mixture with a pharmaceutically acceptable diluent or carrier.

Examples of diluents and carriers that can be used are well known to the specialists.

Enzyme synthase-nitric oxide has several isoforms, and the compounds of formula I or their pharmaceutically acceptable salts can be skanirovat activity against synthetase of nitric oxide by methods based on the methods Bredt and Snyder "Proc. Natl. Acad. Sci. (1990) 87, 682- 685, and Forstermann et.al. , Eur. J. Pharm. (1992) 225, 161 to 165. Synthase-nitric oxide makes 3H-L-arginine in3H-L - citrulline, which can be distinguished by using cation-exchange chromatography, and quantified using a scintillation counter.

An example of A screening

(A) Screening for the activity of the synthetase nitrogen oxides

The enzyme isolated from the hippocampus or cerebellum of rats. The hippocampus or cerebellum in rats strain Spraque-Dawley (250-275 g) is removed after anestesiologia animals CO2and beheadings. The supernatant of the cerebellum or hippocampus receive as a result of homogenization in 50 mm Tris-HCl with 1 mm EDTA buffer (pH of 7.2 at 25oC) and centrifugation for 15 minutes at 20000 g. The residual L-arginine is removed from the supernatant liquid resulting from khromatograficheskaya at 1000 g for 30 seconds.

For analysis, 25 μl of the final supernatant is added to each of the 12 test vials containing 25 μl of a solution of L-arginine (at a concentration of 18 μm1H-L-arginine, 96 nm3H-L - arginine), and either 25 μl of analytical buffer (50 mm HEPES, 1 mm EDTA, 1.5 mm CaCl2pH 7,4), or test compound in the buffer at 22oC. In each test vial add 75 ál of complete analytical buffer (50 mm HEPES, 1 mm EDTA, 1.5 mm CaCl2, 1 mm DTT, 10 μm NADPH, 10 μg/ml calmodulin, pH of 7.4) to initiate the reaction, and the reaction is stopped after 10 minutes by adding 2 ml of stop buffer (20 mm HEPES, 2 mm EDTA, pH 5.5).

Labeled L-citrulline is separated from the labeled L-arginine in the chromatographic treatment on Dowex AG-50W-X8 200 - 400 mesh column. 1 ml of each of the stopped reaction mixtures administered in separate 1 ml column, and eluent combine with two washes in 1 ml of distilled water and 16 ml of scintillation "cocktail". Then the number of L-citrulline determined using a scintillation counter.

In a typical experiment with the supernatant liquid of the cerebellum main activity increased by 20,000 disintegrations per minute/ml compared with the control, the activity of which is 7000 dissolved, and the ICI nitrogen, at a concentration of 1 μm testing in the analysis to control for the procedure.

Example of screening B

(B) screening the activity of the synthetase of nitric oxide by macrophages

Enzyme prepared after induction from cultured cells of the mouse macrophage line J774A-1 (obtained from the laboratories of the Imperial Cancer Research Fund). J774A-1 cells cultured in Dulbecco-modified environment, the Needle (DMEM), supplemented with 10% serum, fetal calf, 4 mm L-glutamine and antibiotics (100 u/ml penicillin G, 100 μg/ml streptomycin and 0.25 μg/ml amphotericin b). Cells grown in the usual way in 225 cm2flasks containing 35 ml medium, maintained at 37oC in a humid atmosphere containing 5% CO2.

Synthase-nitric oxide is produced by cells in response to interferon- (IFN ) and lipopolysaccharide (LPS). The medium from confluent culture flasks are removed and replaced with 25 ml (flask) with fresh medium containing 1 μg/ml LPS and 10 units/ml IFN . After 17-20 hours in culture, the collection of cells is carried out, removing the layer of cells from the surface of the flask in culture medium. Cells are harvested by centrifugation (1000 g for 10 minutes), and prepare the lysate by adding cellular precipitate in a solution containing Il protease inhibitors, containing leupeptin (2 μg/ml), trypsin inhibitor soybean (10 μg/ml), Aprotinin (5 μg/ml) and phenylmethylsulfonyl (50 µg/ml).

For the analysis of 25 µg cocktail substrate (50 mm Tris-HCl (pH 7.5 at 20oC), 400 μm NADPH, 20 μm flavinadeninnukleotid, 20 μm playmonopolyonline, 4 μm tetrahydrobiopterin, 12 μm L-arginine and 0.025 MX L-[3H] arginine) is added to the cell filter plate with 96 cells (0.45 µm cell size) containing 25 μl of a solution of test compound in 50 mm Tris-HCl. The reaction is initiated by adding 50 μl of cell lysate (obtained as described previously), and, after incubation for 1 hour at room temperature the reaction is complete, adding 50 μl of an aqueous solution of 3 mm nitroarginine and 21 mm EDTA.

Labeled L-citrulline is separated from the labeled L-arginine using Dowex AG-50W. 150 μl of 25% aqueous suspension of Dowex 50W (Na+form) add in the analyzed composition which is filtered in a plate with 96 wells. Selected samples of the filtrate at 70 ál and add to plate with 96 cells containing solid scintillation agent. After the sample is allowed to dry, the amount of L-citrulline determined using a scintillation counter.

In typical experiments the RTS for reagent controls. Aminoguanidine, which gives IR50(50% inhibitory concentration) in 10 mm test as the standard for test procedures.

Example of screening C

(C) Screening for the activity of the synthetase of nitric oxide endothelium

The enzyme can be isolated from endothelial cells of the umbilical vein of a person (HUVECs) by the method based on the method of Pollock et.al (1991), Proc. Nat. Acad. Sci. , 88, 10480-10484. HUVECs purchased from Clonetics Corp. (San Diego, CA, USA) and cultured until confluence. Cells can be maintained up to 35-40 passages without noticeable loss of output synthetase nitric oxide. When cells are merged, they are again suspended in Dulbecco phosphate bateriafina saline solution, centrifuged at 8000 rpm for 10 minutes, the cell sediment homogenized in ice-cold 50 mm Tris-HCl, 1 mm EDTA, 10% glycerol, 1 mm phenylmethylsulfonyl, 2 μm leupeptin at a pH of 4.2. After centrifugation at 34000 rpm for 60 minutes to precipitate solubilizer in homogenizing buffer containing 20 mm CHAPS. After 30 minutes incubation on ice, the suspension is centrifuged at 34000 rpm for 30 minutes. The obtained supernatant stored at -80oto use.

For analysis, 25 μl of the obtained supernatant to the on, 64 nm3H-L-arginine) and either 25 μl of analytical buffer (50 nm HEPES, 1 mm EDTA, 1.5 mm CaCl2, a pH of 7.4) or 25 μl of test compound in the buffer at 22oC. In each test vial add a full analytical buffer (50 mm HEPES, 1 mm EDTA, 1.5 mm CaCl2, 1 mm DTT, 100 μm NADPH, 10 μg/ml calmodulin, 12 μm tetrahydrobiopterin, pH of 7.4) to initiate the reaction, and the reaction is stopped after 10 minutes by adding 2 ml of stop buffer (20 mm HEPES, 2 mm EDTA, pH 5.5).

Labeled L-citrulline is separated from the labeled L-arginine in the chromatographic treatment on Dowex AG-50W-X8 200 - 400 mesh column. 1 ml of each stopped reaction solution injected in separate 1 ml column, and each eluent, together with two washes in 1 ml of distilled water and 16 ml of scintillation cocktail. Then the number of L-citrulline determined using a scintillation counter.

In a typical experiment the main activity increases by 5000 disintegrations per minute/ml for sample compared to the reagent control, the activity of which is 1500 disintegrations per minute/ml of a Comparative standard, N-nitro-L-arginine, which gives 70-90% synthetase inhibition of nitric oxide at a concentration of 1 μm, is tested in the analysis for the penetration into the brain.

Example of screening D

(D) Ex-vivo assay for determining the activity of the synthetase of nitric oxide neurons

The male rats of the strain Spraque-Dawley (250-275 g) was injected intravenously at 10 mg/kg of the test compounds, dissolved in 0.9% saline solution or a saline solution as a control. At the specified time (usually 2-24 hours) after treatment, animals kill, remove the cerebellum, and the supernatant prepared and examined for the synthetase activity of nitric oxide, as described in example A. screening

As a further confirmatory test, fraction cerebellar supernatant is injected into the column 2'-5'-ADP Sepharose (which connects synthase nitric oxide) and then elute at the expense of NADPH. Eluent test for the synthetase activity of nitric oxide by the method of example A. screening

Compounds that penetrate into the brain of rats and inhibit the synthetase of nitric oxide neurons, leading to decreased activity of the synthetase of nitric oxide in the preparations of the supernatant liquid, and eluent from the column 2'-5'-ADP Sepharose.

In the examples of the screening activity of the synthetase inhibition of nitric oxide activity of the compounds is expressed as IRwhat I IR50for test compounds first estimate of the activity of inhibition of 1,10 and 100 μm solutions of compounds. Compounds that inhibit the enzyme, at least 50% at a concentration of 10 µm, re-test, using the appropriate concentrations to estimate IR50.

In the example of A screening (screening for activity against neural synthetase isoforms of nitric oxide), connection the following example 1 gives IR50less than 10 μm, which indicates that we can expect a satisfactory therapeutic activity. In examples B and C screening (screening for activity against mikrofalowe and endothelial synthetase isoforms of nitric oxide) compound of example 1 shows IR50values that are more than 10 times higher than obtained in the example of A screening value, demonstrating the desired activity.

The compounds of examples 2 to 9, 10(a)-(f), 11-13 and 19-24 testing in the example of A screening, and they also demonstrate the value IR50less than 10 microns. Thus, it can also be expected that these compounds will have a satisfactory therapeutic effect.

The compounds of formula I and their pharmaceutically p which are stated over a long action, have a broader spectrum of activity and more effective, cause fewer side effects, are more easily absorbed or have other useful pharmacological properties compared to previously known compounds, and are used in the previously mentioned areas of therapy.

The compounds of formula 1 and their pharmaceutically acceptable salts may also have the advantage that they are more selective in relation to neural isoforms of the enzyme synthetase nitrogen oxides, and therefore we can expect a satisfactory therapeutic activity while reducing side effects associated with inhibition of other isoforms.

Further, the present invention is illustrated by the following examples.

Example 1

N-((2-(phenylmethyl)amino)indan-5-yl)-2-thiofanox - midmedical

(a) 5-nitro-2-indanol

This connection get in the way Heusler, Schief-fer Ber., (1899) 32, 33.

(b) 5-nitro-2-(phenylmethyl)aminoindan

5-nitro-2-indanol (1.48 g, at 8.36 mmole), benzylamine (4,40 ml, 41.8 mmole), acetic acid (15.0 ml), 4 A molecular sieves (20 ml), THF (15 ml), and MeOH (15 ml) are loaded into a flask and cooled to 0oC. Then added in several portions of cyanoborohydride sodium (1,05 g, 16.7 mmole) in 5 minutes. Recip is alkalinized 2n. NaOH and extracted with ether (3 x 50 ml). The combined extracts washed with water, dried over magnesium sulfate, filtered, concentrated and the chromatographic process on silica gel (3% methanol/methylene chloride) to obtain 5-nitro-2-(phenyl-methyl) aminoindane: (1.18 g, 53%).

Mass spectrum: (M+N)+= 269.

(c) 2-(5-nitroindole)-N-(phenylmethyl)triptorelin

To a stirred solution of 5-nitro-2-(phenylmethyl)-aminoindane (1.18 g, 4.40 mmol) and triethylamine (and 0.61 ml, and 4.40 mmole) in 50 ml of methylene chloride add triperoxonane anhydride (0.63 ml, 4.40 mmol) dropwise. After stirring for 1 minutes the solution is poured into water and extracted with methylene chloride (3 x 20 ml). The combined extracts washed with water, dried over magnesium sulfate and filtered through a short plug of silica gel (20% ethyl acetate/hexane) to obtain 2-(5-nitroindole)-N- (phenylmethyl)trifurcated: (1,17 g, 73%).

Mass spectrum (M+N)+=365.

(d) 2-(5-aminoindane)-N-(phenylmethyl)triptorelin

To a stirred solution of 2-(5-nitroindole)-N- (phenylmethyl)trifurcated (1,17 g is 3.21 mmole) in THF/MeOH (100 ml, 1:1) is added a catalytic amount of 10% Pd/C. the resulting mixture hydronaut at 50 psi (3,515 kg/cm2within 1 hour, Phil the TLC data is homogeneous, and used immediately at the stage (f).

(e) 3-methyl-2-theoreticalmethodological

A solution of 2-thiophenecarboxylate (Maybridge Chemical) (11.1 g) in 60 ml of acetone is treated with iodomethane (13,4 g). After 6 hours at 22oC obtained solid yellow is collected by filtration, washed with acetone (2 x 25 ml) and dried to obtain of 18.45 g of S-methyl-2-theoreticalmethodological.

So melting 195oC (decomposition).

(f) N-((2-(phenylmethyl)amino)indan-5-yl)-2-thiophene - carboxymethyloxime

To a solution of 2-(5-aminoindane)-N-(phenylmethyl)-trifurcated (1.0 g, 3.0 mmole) in isopropanol (6 ml)/DMF (0.5 ml) is added 3-methyl-2-theoreticalmethodological of 0.85 g, 3.0 mmole). The resulting mixture is stirred for 14 hours, diluted with methanol (6 ml) and 2n. NaOH (6 ml) and heated to 50oC for 0.5 hours. The resulting mixture was poured into water and extracted with ethyl acetate (3 x 30 ml). The combined extracts washed with water, dried over magnesium sulfate, filtered and process chromatography on silica gel (20% methanol/methylene chloride) to obtain specified in the title

connection in the form of free base. After processing IPA/oxalic acid to obtain N-((2-(phenylmethyl)-amino) the effect 130-135oC.

Example 2

N-((2-(phenylmethyl)amino)-1,2,3,4-tetrahydronaphtyl-7-yl)- 2-thiophencarboxylic

(a) 7-nitro-3,4-dihydro-2(1H)-naphtalene

This connection receive according to the method of J. Med. Chem. (1989) 32, 2128.

(b) 7-nitro-2-((phenylmethyl)amino)-1,2,3,4-tetrahydronaphthalen

7-nitro-3,4-dihydro-2(1H)-naphtalene (1.50 g, a 7.85 mmole), benzylamine (4,30 ml, 39,3 mmole), acetic acid (8.0 ml), 4 a molecular sieves (20 ml), THF (15 ml) and MeOH (15 ml) are loaded into a flask and cooled to 0oC. Then added in several portions of cyanoborohydride sodium (0,99 g, 15.7 mmole) in 5 minutes. The resulting mixture is stirred for 14 hours, filtered through celite and concentrated to syrup. The resulting mixture is alkalinized 2n. NaOH and extracted with ether (3 x 50 ml). The combined extracts washed with water, dried over magnesium sulfate, filtered, concentrated and chromatographic on silica gel (3% methanol/methylene chloride) to obtain 7-nitro-2- ((phenylmethyl)amino)-1,2,3,4-tetrahydronaphthalene: (2, 10 g, 95%).

Mass spectrum (M+N)+283.

(C) 2-(7-nitro-(1,2,3,4-tetrahydronaphthyl))-N-(phenylmethyl) triptorelin

To a stirred solution of 7-nitro-2-((phenylmethyl)amino)-1, 2,3,4-tetrahydronaphthalene (2.10 g, 7,45 mmole) and triethylamine (1.07 ml, 7,45 mmole) in 50 ml matilta solution is poured into water and extracted with methylene chloride (3 x 20 ml). The combined extracts washed with water, dried over magnesium sulfate and filtered through a short plug of silica gel (20% ethyl acetate/hexane) to obtain 2-(7-nitro-(1, 2,3,4-tetrahydronaphthyl))-N-(phenylmethyl)trifurcated: (2.55 g, 90%).

Mass spectrum (M+N)+= 379

(d) 2-(7-amino-(1,2,3,4-tetrahydronaphthyl)-N-(phenylmethyl) trifurcated

To a stirred solution of 2-(7-nitro-(1,2,3,4 - tetrahydronaphthyl)-N-(phenylmethyl)trifurcated (2.55 g, of 6.75 mmole) in THF/MeOH (100 ml, 1:1) is added a catalytic amount of 10% Pd/C. the resulting mixture hydronaut at 50 psi (3,515 kg/cm2) for 1 hour, filtered through celite and concentrated to obtain 2-(7-amino-(1,2,3,4-tetrahydronaphthyl))-N-(phenylmethyl)- trifurcated, which according to TLC is homogeneous, and immediately used in the next stage.

(e) N-((2-(phenylmethyl)amino)-1,2,3,4-tetrahydronaphtyl - 7-yl)-2-thiophencarboxylic

To a solution of 2-(7-amino-(1,2,3,4-tetrahydronaphthyl))-N-(phenylmethyl) trifurcated (2,11 g, 6,07 mmole) in 10 ml isopropanol added 3-methyl-2-theoreticalmethodological (1,72 g, 6,07 mmole). The resulting mixture is stirred for 14 hours, diluted with methanol (6 ml) and 2 N. NaOH (6 ml), and heated to 50oC for 0.5 hours. Received smglta magnesium, filtered and concentrated to a solid, which is recrystallized (methylene chloride/hexane) to obtain N-((2-(phenylmethyl)amino)-1,2,3,4-tetrahydronaphtyl-7-yl)-2 - thiophenecarboxaldehyde in the form of a white solid (0.66 g, 30%).

So melting point 119-120oC.

Example 3

N-((2-amino)-1,2,3,4-tetrahydronaphtyl-7-yl)-2 - thiophenecarboxaldehyde

(a) 7-nitro-2-amino-1,2,3,4-tetrahydronaphthalene

7-nitro-1-tetralone (1.50 g, a 7.85 mmole), ammonium acetate (6,05 ml, 78.5 per mmole), acetic acid (8.0 ml), 4 a molecular sieves (20 ml), THF (15 ml) and MeOH (15 ml) are loaded into a flask and cooled to 0oC. Then add cyanoborohydride sodium (0,99 g, 15.7 mmole) in portions over 5 minutes. The resulting mixture was stirred for 1 hour, filtered through celite and concentrated to syrup. The resulting mixture is alkalinized 2n. NaOH and extracted with ether (3 x 50 ml). The combined extracts washed with water, dried over magnesium sulfate, filtered and concentrated to obtain oil. This compound is isolated in the form of a salt of hydrochloric acid: 7-nitro-2-amino - 1,2,3,4-tetrahydronaphthalene (1,00 g, 56%).

The melting point of more than 300oC.

(b) 2-(7-nitro-(1,2,3,4-tetrahydronaphthyl))-N-Cryptor-ndimethylacetamide

the (1,22 ml, 8,77 mmole) in 50 ml of methylene chloride add triperoxonane anhydride (0,62 ml, 4,39 mmole) dropwise. After stirring for 1 minute, the solution was poured into water and extracted with methylene chloride (3 x 20 ml). The combined extracts washed with water, dried over anhydrous magnesium sulfate and filtered through a short plug of silica gel (20% ethyl acetate/hexane) to obtain 2-(7-nitro-(1,2,3,4-tetrahydronaphthyl))-N-trifurcated (0,78 g, 62%).

Mass spectrum (M+H)+= 289.

(c) 2-(7-amino-(1,2,3,4-tetrahydronaphthyl))-N-triptorelin

To a stirred solution of 2-(7-nitro-(1,2,3,4-tetrahydronaphthyl))- N-trifurcated (0,76 g, 2.21 mmole) in THF/MeOH (100 ml, 1:1) is added a catalytic amount of 10% Pd/C. the resulting mixture hydronaut at 50 psi (3,515 kg/cm2) for 1 hour, filtered through celite and concentrated to obtain 2-(7-amino(1,2,3,4 - tetrahydronaphthyl))-N-trifurcated, which according to TLC is homogeneous, and used immediately in the next reaction.

(d) N-((2-amino)-1,2,3,4-tetrahydronaphtyl-7-yl)-2 - thiophenecarboxaldehyde

To a solution of 2-(7-amino-(1,2,3,4-tetrahydronaphthyl)-N-trifurcated (0,70 g, a 2.71 mmole) in 10 ml isopropanol added 3-methyl-2 - theoreticalmethodological (0,77 g, 2,71 the 50oC for 0.5 hours. The resulting mixture was poured into water and extracted with ethyl acetate (3 x 30 ml). The combined extracts washed with water, dried over magnesium sulfate, filtered, concentrated and process chromatography on silica gel (20% methanol/methylene chloride) to obtain the oil, which is converted into dihydrobromide: N-((2-amino)- 1,2,3,4-tetrahydronaphtyl-7-yl)-2-thiophenecarboxaldehyde: (0,37 g, 32%).

So melting over 210oC (decomposition).

Example 4

N-((1-amino)-1,2,3,4-tetrahydronaphtyl-7-yl)-2 - thiophenecarboxaldehyde

(a) 7-nitro-1-amino-1,2,3,4-tetrahydronaphthalen

7-Nitro-1-amino-1,2,3,4-tetrahydronaphthalen get like 7-nitro-2-amino-1,2,3,4-tetrahydronaphthalen. The compound is isolated in the form of salt-hydrochloride (0,30 g, 12%).

So melting more than 300oC.

(b) 1-(7-nitro-(1,2,3,4-tetrahydronaphthyl))-N-Cryptor-ndimethylacetamide

1-(7-nitro-(1,2,3,4-tetrahydronaphthyl))-N-triptorelin get like 2-(7-nitro-(1,2,3,4-tetrahydronaphthyl))-N-triptorelin (0.35 g, 95%).

Mass spectrum (M+H)+= 289

(c) 1-(7-amino-(1,2,3,4-tetrahydronaphthyl))-N-triptorelin

1-(7-amino-(1,2,3,4-tetrahydronaphthyl))-N-triptorelin get like 2-(7-amino-(1,2,3,4-tetrahedronal-7-yl)-2 - thiophenecarboxaldehyde

N-((1-amino)-1,2,3,4-tetrahydronaphtyl-7-yl)-2 - thiophenecarboxaldehyde get as N-((2-amino) -1,2,3,4-tetrahydronaphtyl-7-yl)-2-thiophenecarboxaldehyde except that it is isolated in the form of dioxalate (0.18 g, 33%).

Melting point 155oC with decomposition.

Example 5

N-((2-amino)indan-5-yl)-2-thiophenecarboxaldehyde

(a) 5-nitro-2-aminoethanethiol

2-aminoethanethiol (19,11 g, 0,112 mol) at 0oC add sulfuric acid (60 ml), then potassium nitrate (11,84 g, 0,117 mol). The resulting mixture was left to warm to room temperature, stirred for further 2 hours, then poured into a mixture of ice/50% NaOH (total 500 ml). The resulting mixture was extracted with ether (3 x 200 ml) and the combined extracts washed with water, dried over magnesium sulfate, filtered and concentrated to an oil, which turned into salt is hydrochloride. After recrystallization from a mixture of isopropanol/methanol to obtain 5-nitro-2-aminoethanethiol (14,58 g, 60%).

The melting point of more than 300oC.

(b) 2-(5-nitroindole)-N-triptorelin

To a stirred solution of 5-nitro-2-aminoethanethiol (1,00 g of 5.89 mmole) and triethylamine (0,82 ml of 5.89 mmole) in 50 ml of minuty solution was poured into water and extracted with methylene chloride (3 x 20 ml). The combined extracts washed with water, dried over magnesium sulfate and filtered through a short plug of silica gel (20% ethyl acetate/hexane) to obtain 2-(5-nitroindole)-N-trifurcated (1.51 g, 93%).

So melting point 153-154oC.

(c) 2-(5-aminoindane)-N-triptorelin

To a stirred solution of 2-(5-nitroindole)-N-trifurcated (0,58 g, 2.25 mmole) in THF/MeOH (100 ml, 1:1) is added a catalytic amount of 10% Pd/C. the resulting mixture hydronaut at 50 psi (3,515 kg/cm2), filtered through celite and concentrated to obtain 2-(5-aminoindane)-N-trifurcated, which is homogeneous according to TLC and used immediately in the next stage.

(d) N-((2-amino)indan-5-yl)-2-thiophenecarboxaldehyde

To a solution of 2-(5-aminoindane)-N-trifurcated (0.52 g, 2.25 mmole) in isopropanol (6 ml) and DMF (0.5 ml) is added S-methyl-2-theoreticalmethodological (0.64 g, of 2.23 mmole). The resulting mixture is stirred for 14 hours, diluted with methanol (6 ml) and 2n. NaOH (6 ml) and heated to 50oC for 0.5 hours. The resulting mixture was poured into water and extracted with ethyl acetate (3 x 30 ml). The combined extracts washed with water, dried over magnesium sulfate, filtered and process khromatograficheskaya. After processing IPA/oxalic acid to obtain N-((2-amino)indan-5-yl)-2-thiophenecarboxaldehyde in a solid white color (0,60 g, 50%).

So melting 70oC, with decomposition.

Example 6

N-((2-(methyl)(phenylmethyl)amino)indan-5-yl)-2 - thiophenecarboxaldehyde

(a) 5-nitro-2-(phenylmethyl)aminoethanethiol

To 5-nitro-2-aminoethanethiol (3.00 g, 14,00 mmol) in 60 ml DMF added triethylamine (4,07 ml, 29,40 mmole), and then benzylbromide (1,74 ml, 14,68 mmole). The resulting mixture was warmed to room temperature, stirred for 1 hour, poured into water (200 ml) and extracted with ethyl acetate (3 x 50 ml). The combined extracts washed with water, dried over magnesium sulfate, filtered through a small layer of silica gel and evaporated to syrup. Specified in pozegnanie connection is isolated in the form of cleaners containing hydrochloride salt (to 2.29 g, 54%).

So melting with decomposition 266oC.

(b) 5-nitro-2-(methyl)(phenylmethyl)aminoethanethiol

To 5-nitro-2-(phenylmethyl)aminoethanethiol (to 2.29 g, 7,52 mmole) in 100 ml DMF added potassium carbonate (2,60 g, 18,80 mmole), and then methyliodide (of 0.47 ml, 7,52 mmole). The resulting mixture was warmed to room temperature, stirred during the th, dried over magnesium sulfate, filtered through a small layer of silica gel and evaporated to syrup. Specified in the title compound is isolated in the form of salt-hydrochloride (1.08 g, 45%).

So melting 280oC (decomposition).

(c) 5-amino-2-(methyl)(phenylmethyl)aminobenzimidazole

To 5-nitro-2-(methyl)(phenylmethyl)aminoethanethiol (1.08 g, 3,39 mmole) in 85% acetic acid/water, add the powdered zinc (3.0 g). The resulting mixture was stirred for 1 min, filtered through celite and concentrated. The resulting concentrate is neutralized 2n. NaOH and extracted with ethyl acetate (3 x 50 ml). The combined extracts washed with water, dried over magnesium sulfate and evaporated to a syrup. The oil obtained is treated with IPA/HCl, concentrated and used immediately in the next stage.

(d) N-((2-(methyl)(phenylmethyl)amino)indan-5-yl)-2 - thiophenecarboxaldehyde

To 5-amino-2-(methyl) (phenylmethyl)aminobenzenesulfonamide in DMF (10 ml) is added 3-methyl-2-theoreticalmethodological (0,98 g, 3.45 mmole) and pyridine (0,27 ml, 3,29 mmole). The resulting mixture is stirred for 14 hours, then poured into a mixture of water/2n. NaOH and extracted with ethyl acetate (3 x 50 ml). The combined extracts washed with water, dried over alsahlawi connection in the form of free base. As a result of processing IPA/HBr receive N-((2-(methyl) (phenylmethyl)-amino)indan-5-yl)-2-thiophenecarboxaldehyde in a solid white color (0,43 g, 25%).

So melting point: 196-200oC.

Example 7

N-((1-amino)indan-6-yl)-2-thiophenecarboxaldehyde

(a) 6-nitro-1-aminoethanethiol

1-aminoindan (10.0 g, 75,08 mmole) is added to concentrated sulfuric acid (40 ml) at 0oC. the resulting mixture was warmed to room temperature, to aid dissolution, then cooled to 0oC. Then portioned add potassium nitrate (7,60 g, 75,08 mmole) and the resulting mixture is left under stirring at room temperature for 1 hour before pouring into a mixture of ice/50% NaOH. The aqueous solution is extracted with chloroform (3 x 100 ml). The combined extracts washed with water, discolor charcoal, dried over magnesium sulfate, filtered and concentrated to oil. As a result of processing IPA/HCl receive specified in pozegnanie connection (6,90 g, 43%).

So melting 280oC (decomposition).

(b) 6-amino-1-aminoethanethiol

To a solution of 6-nitro-1-aminoethanethiol (1,00 g 4,66 mmole) in MeOH (100 ml) is added a catalytic amount of 10% Pd/C. is to obtain 6-amino-1-aminoethanethiol, which according to TLC is homogeneous, and used immediately in the next stage.

(c) N-((1-amino)indan-6-yl)-2-thiophenecarboxaldehyde

To 6-amino-1-aminoethanethiol (0.74 g, 4,01 mmole) in DMF/IPA (4 ml, 1: 1) add 3-methyl-2-theoreticalmethodological (1.26 g, to 4.41 mmole). The resulting mixture was heated to 50oC, stirred for 16 hours, poured into a mixture of water/2n. NaOH and extracted with ethyl acetate (3 x 50 ml). The combined extracts washed with water, dried over magnesium sulfate, filtered and concentrated to oil. As a result of processing IPA/HCl get N-((1-amino)-indan-6-yl)-2-thiophenecarboxaldehyde in a solid white color (0,79 g, 60%).

So melting 200oC with decomposition.

Example 8

N-((1-(phenylmethyl)amino)indan-6-yl)-2-thiophenecarboxaldehyde

(a) 6-nitro-1-(phenylmethyl)aminoethanethiol

6-nitro-1-aminoethanethiol (1.90 g, 8.85 mmole) in 30 ml DMF added triethylamine (2,50 ml, 18,06 mmole), and then benzylbromide (1.07 ml, 9,03 mmole). The resulting mixture was warmed to room temperature, stirred for 3 hours, poured into water (100 ml) and extracted three times with ethyl acetate portions 70 ml. of the United EXT is to syrup. Specified in the title compound is isolated in the form of salt-hydrochloride (1,34 g, 50%).

So melting 234-235oC.

(b) 6-Amino-1-(phenylmethyl)aminoethanethiol

6-nitro-1-(phenylmethyl) aminoethanethiol (1,34 g, and 4.40 mol) in 100 ml MeOH added catalytic amount of 10% Pd/C. the resulting mixture hydronaut at 50 psi (3,515 kg/cm) for 1 hour, filtered through celite and concentrated to obtain 6-amino-1- (phenylmethyl)aminoethanethiol, which according to TLC is homogeneous and is used immediately in the next stage.

(C) N-((1-(phenylmethyl)amino)indan-6-yl)-2 - thiophenecarboxaldehyde

To 6-amino-1-(phenylmethyl)aminoethanethiol (1,21 g, 4.40 mmol) in 20 ml DMF) add 8-methyl-2-theoreticalmethodological (1,38 g, 4,84 mmole). The resulting mixture was heated to 50oC for 16 hours, then poured into a mixture of water and 2n. NaOH and extracted with ethyl acetate (3 x 50 ml). The combined extracts washed with water, dried over magnesium sulfate, filtered and concentrated to oil. As a result of processing IPA/oxalic acid to obtain N-((1-(phenylmethyl)amino)indan-6-yl)-2 - thiophenecarboxaldehyde in a solid white color (1.06 g, 46%).

So melting bol is midin

(a) 2-((3-Chlorophenyl)carbonyl)amino-6-nitrogen

To 2-amino-6-nitroindazole (1.5 g, 7.0 mmole) in 50 ml of methylene chloride at 0oC add triethylamine (2.1 ml of 15.0 mmole), and then 3-chlorobenzylchloride (1.0 ml, 7.5 mmole). The resulting mixture was immediately poured into water and the layers separated. The aqueous layer was extracted with methylene chloride (2 x 20 ml) and the combined extracts washed with water, dried over magnesium sulfate, filtered and concentrated to an oil, which according to TLC is homogeneous, and it is used immediately in the next stage.

Mass spectrum (M+N)+= 317.

(b) 2-((3-chlorophenyl)methyl)amino-6-nitrogen

To 2-((3-chlorophenyl)carbonyl)amino-6-nitroindole (2.2 g, 7.0 mmole) in 75 ml THF add BH3THF (1.0 M, 35 ml, 35 mmol) dropwise. The resulting mixture was refluxed for 12 hours, cooled to 0oC, quenched with 4n. HCl (60 ml) and refluxed for 1 hour. The resulting solution is evaporated to oil, alkalinized 50% NaOH and extracted with methylene chloride three times with portions of 20 ml combined extracts washed with water, dried over magnesium sulfate, filtered and concentrated to oil. As a result of processing IPA/HCl get 2-((3-chlorophenyl)methyl)amino-6-nor-6-aminoindan

To 2-((3-chlorophenyl)methyl)amino-6-nitroindazole (2.1 g, 6.13 mmol) in 40 ml of a mixture of 85% AcOH/H2O add metallic zinc (1.6 g, 24.5 mmole). The resulting mixture was stirred for 5 minutes, filtered through celite and evaporated to an oil. The resulting oil was poured into alkaline water and extracted with chloroform (3 x 20 ml). The combined extracts washed with water, dried over magnesium sulfate, filtered and concentrated to oil. As a result of processing IPA/HCl get 2-((3-chlorophenyl)methyl)amino-6-aminoindan (1.5 g, 70%).

So melting over 270oC

(d) N-((2-((3-chlorophenyl)methyl)amino)indan-5-yl)-2 - thiophencarboxylic

2-((3-chlorophenyl)methyl)amino-6-aminobenzimidazole (1.5 g, 4.2 mmole), 3-methyl-2-theoreticalmethodological (1.3 g, 4.6 mmole) and pyridine (of 0.34 ml, 4.2 mmole) in 10 ml of DMF is stirred for 24 hours. The resulting mixture was poured into water, alkalinized 2n. NaOH and extracted with ethyl acetate (3 x 50 ml). The combined extracts washed with water, dried over magnesium sulfate, filtered, concentrated and process chromatography on silica gel (12% MeOH/methylene chloride) to obtain a colorless oil. As a result of processing IPA/HCl get N-((2-((3-chlorophenyl)methyl)amino) indan-5-yl)-2-thiophenecarboxylate (0.75 g, is unity:

(a) N-((2-((2-were)methyl)amino)indan-5-yl)-2 - thiophenecarboxylate;

So melting 183oC.

(b) N-((2-((3-were)methyl)amino)indan-5-yl) thiophencarboxylic;

So melting 195oC.

(C) N-((2-((4-(were)methyl)amino)indan-5-yl)-2 - thiophenecarboxylate;

So melting 182oC.

(d) N-((2-(ethyl)amino)indan-5-yl)-2-thiophencarboxylic

So melting 236-238oC.

(o) N-((2-(((4-phenyl)phenyl)methyl)amino)indan-5-yl)- 2-thiophenecarboxylate;

So melting 182oC.

(f) N-((2-(((4-hexyl)phenyl)methyl)amino)indan-5-yl)-2 - thiophenecarboxylate;

So melting 125oC.

(g) N-((2-((3-bromophenyl)methyl)amino)indan-5-yl)-2 - thiophenecarboxylate;

So melting 182oC.

Example 11

N-((2-(((3-Chlorophenyl)methyl)amino)-1,2,3,4-tetrahydronaphtyl-7-yl)- 2-thiophencarboxylic

(a) 7-nitro-2-(((3-chlorophenyl)methyl)amino)-1,2,3,4-tetrahydronaphthalen

7-Nitro-3,4-dihydro-2(1H)-naphtalene (1.50 g, a 7.85 mmole), 3-chlorobenzylamino (4,70 ml, 39,3 mmole), acetic acid (6.0 ml), 4 a molecular sieves (20 ml), TTF (15 ml) and MeOH (15 ml) are loaded into a flask and cooled to 0oC. Portions add cyanoborohydride sodium (0,99 g, 15.7 mmole) in 5 minutes. The resulting mixture is stirred is tracerout ether (3 x 50 ml). The combined extracts washed with water, dried over magnesium sulfate, filtered, concentrated and chromatographic on silica gel (3% methanol/methylene chloride). As a result of processing oils IPA/HCl get 7-nitro-2- (((3-chlorophenyl)methyl)amino)-1,2,3,4-tetrahydronaphthalene (1,34 g, 50%).

Mass spectrum (M+N)+= 317.

(b) 7-Amino-2-(((3-chlorophenyl)methyl)amino)-1,2,3,4 - tetrahydronaphthalen

To 7-nitro-2-(((3-chlorophenyl)methyl)amino)-1,2,3,4 - tetrahydronaphthalene (1,34 g of 3.80 mmol) in AcOH 85/H2O (75 ml) is added metallic zinc (2,48 g, 38,0 mmole). The resulting mixture was stirred for 5 minutes, filtered through celite and evaporated to an oil. The resulting oil was poured into alkaline water and extracted with chloroform (3 x 20 ml). The combined extracts washed with water, dried over magnesium sulfate, filtered and concentrated to oil. As a result of processing IPA/HCl get 7-amino-2-(((3-chlorophenyl)methyl)amino)-1,2,3,4-tetrahydronaphthalen (1.4 g, 99%).

Mass spectrum (M+H)+= 288.

(c) N-((2-((3-chlorophenyl)methyl)amino)-1,2,3,4-tetrahydronaphtyl - 7-yl)-2-thiophencarboxylic

7-Amino-2-(((3-chlorophenyl)methyl)amino)-1,2,3,4 - tetrahydronaphthalene (1,32 g, 3.70 mmol), 3-methyl-2-theoreticalmethodological the ode, alkalinized 2n. NaOH and extracted with ethyl acetate (3 x 50 ml). The combined extracts washed with water, dried over magnesium sulfate, filtered and concentrated to oil. As a result of processing IPA/oxalic acid to obtain N-((2-((3-chlorophenyl)methyl)amino)-1,2,3,4 - tetrahydronaphtyl-7-yl)-2-thiophenecarboxaldehyde (0.71 g, 33%).

So melting more than 100oC with decomposition.

Example 12

N-((2-(phenylmethyl)(methyl)amino)-1,2,3,4-tetrahydronaphtyl-7-yl)-2 - thiophencarboxylic

(a) 7-Nitro-2((phenylmethyl)(methyl)amino)-1,2,3,4-tetrahydronaphthalen

To a stirred solution of 7-nitro-2-((phenylmethyl)amino)-1, 2,3,4-tetrahydronaphthalene (1.5 g, 5.4 mmole) in 30 ml DMF added potassium carbonate (1.5 g, 10.8 mmole) and methyliodide (0,36 ml, 5.8 mmole). The resulting mixture is stirred for 24 hours, poured into water and extracted with ethyl acetate (3 x 50 ml). The combined extracts washed with water, dried over magnesium sulfate, filtered and concentrated to oil. As a result of processing IPA/HCl get 7-nitro-2-((phenylmethyl)(methyl) amino)-1,2,3,4-tetrahydronaphthalene (0,89 g, 50%).

Mass spectrum (M+N)+=297.

b) 7-Amino-2-((phenylmethyl)(methyl)amino)-1,2,3,4 - tetrahydronaphthalen

To 7-nitro-2-((phenylmethyl)(methyl)amino)-1,2,3,4 is Olya). The resulting mixture was stirred for 5 minutes, filtered through celite and evaporated to an oil. The resulting oil was poured into alkaline water and extracted with chloroform (3 x 20 ml). The combined extracts washed with water, dried over magnesium sulfate, filtered and concentrated to oil. As a result of processing IPA/HCl get 7-amino-2-((phenyl)methyl)(methyl)amino)-1,2,3,4-tetrahydronaphthalen (0,81 g, 88%).

Mass spectrum (M+N)+= 267

(c) N-((2-(phenylmethyl)(methyl)amino)-1,2,3,4-tetrahydronaphtyl-7 - yl)-2-thiophencarboxylic

7-Amino-2-((phenylmethyl)(methyl)amino)-1,2,3,4 - tetrahydronaphthalene (0,81 g, 2.4 mmole), S-methyl-

2-theoreticalmethodological (0.74 g, 2.6 mmole) and pyridine (to 0.19 ml, 2.4 mmole) in 15 ml DMF is stirred for 24 hours. The resulting mixture was poured into water, alkalinized 2n. NaOH and extracted with ethyl acetate (3 x 50 ml). The combined extracts washed with water, dried over magnesium sulfate, concentrated and chromatographic on silica gel (% MeOH/methylene chloride). In the concentration faction get a solid, which after recrystallization from a mixture of ethyl acetate/hexane gives N-((2-(phenylmethyl)(methyl)amino)-1,2,3,4-tetrahydronaphtyl-7 - yl)-2-thiophenecarboxaldehyde (0.14 g,16%).

Mass spectrum (M+N)+= 283.

(b) 1-(7-Nitro-(1,2,3,4-tetrahydronaphthyl))-N-(phenylmethyl) triptorelin

To a stirred solution of 7-nitro-1-((phenylmethyl)amino)- 1,2,3,4-tetrahydronaphthalene (2,96 g, 10.5 mmole) and triethylamine (1,46 ml, 10,50 mmole) in 50 ml of methylene chloride add triperoxonane anhydride (1,46 ml, 10,50 mmole) dropwise. After stirring for 1 minute, the solution was poured into water and extracted with methylene chloride (3 x 20 ml). The combined extracts washed with water, dried over magnesium sulfate and filtered through a small layer of silica gel (20% ethyl acetate/hexane) to obtain 1-(7-nitro-(1,2,3,4-tetrahydronaphthyl))- N-(phenylmethyl)trifurcated (1.90 g, 48%, two stages).

Mass spectrum (M+N)+2) for 1 hour, filtered through celite and concentrated to obtain 1-(7-amino-(1, 2,3,4-tetrahydronaphthyl))-N-(phenylmethyl)trifurcated, which according to TLC is homogeneous, and immediately used in the next stage.

(d) N-((1-(Phenylmethyl)amino)-1,2,3,4-tetrahydronaphtyl-7-yl)- 2-thiophencarboxylic

To a solution of 1-(7-amino-(1,2,3,4-tetrahydronaphthyl))-N- (phenylmethyl)trifurcated (1,76 g of 5.05 mmole) in 10 ml isopropanol added S-methyl-2-theoreticalmethodological (1.44 g, of 5.05 mmole). The resulting mixture is stirred for 14 hours, diluted with methanol (6 ml) and 2n. NaOH (6 ml) and heated to 50oC for 0.5 hours. The resulting mixture was poured into water and extracted with ethyl acetate (3 x 30 ml). The combined extracts washed with water, dried over magnesium sulfate, filtered and concentrated to oil. As a result of processing IPA/HBr receive N-((2-phenylethyl)amino)-1,2,3,4-tetrahydronaphtyl-7-yl)-2 - thiophenecarboxaldehyde in a solid white color (0,53 g, 20%).

So melting 260-262oC.

Example 14

N-((1-(Phenylmethyl)amino)indan-5-yl)-N-typenormal is(3.1 ml, of 27.9 mmole) and isopropoxide titanium (10,2 ml, 34.5 mmole) are combined and stirred for 1 hour. The resulting mixture was diluted with absolute ethanol (30 ml), treated with cyanoborohydride sodium (1.2 g, and 19.3 mmole) and allowed to mix for 20 hours. The hard part is filtered off and washed with ethanol. The ethanol is concentrated and the remaining oil is dissolved in ethyl acetate and extracted with 1N. HCl (3 x 50 ml). The water layer is neutralized 2n. NaOH and extracted with ethyl acetate (3 x 100 ml). The combined extracts washed with water, dried over magnesium sulfate, filtered and concentrated to an oil which is used without further purification in the next stage.

(b) 6-Amino-(1-((phenyl)methyl)amino)indan

6-Acetamido-(1-((phenyl)methyl)amino)indan refluxed in 4n. HCl (50 ml) for 20 minutes, cooled and extracted with ethyl acetate (3 x 50 ml). The water layer is neutralized 2n. NaOH and extracted with ethyl acetate (3 x 100 ml). The combined extracts washed with water, dried over magnesium sulfate, filtered and concentrated to oil. The oil obtained is dissolved in IPA and treated with IPA/HCl, resulting in a gain of salt-dihydrochloride (2.0 g, 24%, two stages).

So melting over 250oC (decomposition).

oC for 20 hours, poured into podslashennoyi water and extracted with ethyl acetate (3 x 100 ml). The combined extracts washed with water, dried over magnesium sulfate, filtered, concentrated and chromatographic on silica gel (6% methanol/methylene chloride). The extract is concentrated to an oil, which was dissolved in methanol, treated with IPA/HCl and triturated with ether. The hard part is filtered off and washed with ether (1.1 g, 40%).

The melting point of more than 180oC (decomposition).

Example 15

The following connection receive by way of example 14:

N-((2-(phenylmethyl)amino)-1,2,3,4-tetrahydronaphtyl-6-yl)-2 - thiophencarboxylic

So melting more than 200oC (decomposition).

Example 16

N-((2-(phenylmethyl)amino)-1,2,3,4-tetrahydronaphtyl-7-yl)- 2-furancarboxylic

(a) 2-((Phenyl)carbonyl)amino-7-nitrotyrosine

To 2-amino-7-nitrotyrosine (2.8 g, 14.5 mmole) in 50 ml of THF and 10% K2CO3(100 ml) was added benzoyl chloride (1.7 ml, 15.3 mmole). After adding the resulting mixture was dilute with water to volume">

So melting 194-198oC.

(b) 2-((Phenyl)methyl)amino-7-nitrotyrosination

To 2-((phenyl)carbonyl)amino-7-nitrotyrosine (4,2 g, a 14.1 mmole) in anhydrous THF (100 ml) was added borane-THF (49,3 ml, 1M THF, 49,3 mmole). The resulting mixture was refluxed for 5 hours, cooled to 0oC, and quenched, prokopeva 4h. HCl. The resulting mixture is again brought to a boil under reflux for 1 hour, concentrated in vacuo and the solid is filtered (washed with water) and dried in vacuum (3.5 g, 78%).

So melting more than 300oC.

(c) 2-((Phenyl)methyl)amino-7-aminotetrahydrofuran

To a stirred solution of 2-((phenyl)methyl)amino-7 - nitrotyrosine (2.0 g, 6.3 mmole) in MeOH (100 ml) is added a catalytic amount of 10% Pd/C. the resulting mixture hydronaut at 50 psi (3,515 kg/cm) for 1 hour, filtered through celite and concentrated to obtain oil, which according to TLC is homogeneous, and used immediately in the next stage.

(d) N-((2-Phenylethyl)amino)-1,2,3,4-tetrahydronaphtyl-7-yl)-2 - furancarboxylic

To 2-((phenyl)methyl)amino-7-aminotetrahydrofuran (1.8 g, 6.3 mmole) in 20 ml DMF added S-methyl-2-furandicarboxylic (2.0 g, 7.5 for irout with ethyl acetate (3 x 100 ml). The combined extracts washed with water, dried over magnesium sulfate, filtered and concentrated to oil. This oil is dissolved in methanol, treated with IPA/HCl and triturated with ether. The solid is filtered off and washed with ether (2.2 g, 84%).

The melting point of more than 195oC (decomposition).

Obtaining chiral intermediates for examples 17 and 18

Division 2-amino-7-nitrotyrosine

2-Amino-7-nitrotyrosine (30 g, 156 mmole) is dissolved in 200 ml of acetone, add to Dibenzoyl-D-tartaric acid (58,7 g, 164 mmole), dissolved in 200 ml of acetone. A thick paste was filtered and washed with acetone. This paste is refluxed in 3 l of a mixture of water/ethanol/acetonitrile (1: 1: 1), then filtered while hot. The solid is collected by filtration, recrystallized from the mixture (3); get (5,25 g, 6%) of one isomer (according to chiral capillary zone electrophoresis).

So melting 240-242oC.

Similarly, Dibenzoyl-L-tartaric acid can be used for the separation of opposite enantiomers, using the same solvent system, as described earlier: (5,3 g, 6%) of one isomer get (it is SUP>C.

Example 17

(+)-N-((2-((phenyl)methyl)amino)-1,2,3,4-tetrahydronaphtyl-7-yl)-2 - thiophencarboxylic

(a) (+)-2-((phenyl)carbonyl)amino-1-nitrotyrosine

To 2-amino-7-nitrotyrosine (1.8 g, 9,39 mmole, obtained from Dibenzoyl-D-tartaric acid) in THF (50 ml) and 10% K2CO3(100 ml) was added benzoyl chloride (1.2 ml, 10.1 mmole). After complete addition, the mixture is diluted with water to a volume of 250 ml. of Precipitated precipitated solid is collected by filtration, washed with water and dried in vacuum (2.8 g, 100%).

So melting point 208-209oC,

[]D+21,9oC (c 0,33, DMSO).

(b) (+)-2-((phenyl)methyl)amino-2-nitrotyrosination

To the (+)-2-((phenyl)carbonyl)amino-7-nitrotyrosine (2.8 g, 9.4 mmole) in anhydrous THF (100 ml) was added borane-THF (32,8 ml, 1M THF, 32,8 mmole). The resulting mixture was refluxed for 5 hours, cooled to 0oC, and quenched, prokopeva 4h. HCl. The resulting mixture is brought to a boil under reflux for 1 hour, concentrated in vacuo and the solid part is filtered (washed with water) and dried in vacuum (2.8 g, 94%).

So melting more than 300oC,

[]D+51,0oC (c 0,33 DMSO).

(c) (+)-2-(Phenyl)methyl)amino-7-aminotetraline ablaut catalytic amount of 10% Pd/C. The resulting mixture hydronaut at 50 psi (3,515 kg/cm2) for 1 hour, filtered through celite and concentrated to obtain a glassy solid, which according to TLC is homogeneous.

[]D+73,3oC (c 0,87 DMSO).

(d) (+)-N-((2-)Phenylmethyl)amino)-1,2,3,4-tetrahydronaphtyl-7-yl)- 2-thiophencarboxylic

To the (+)-2-((phenyl)methyl)amino-7-aminotetrahydrofuran (2.5 g, 8.7 mmole) in 20 ml DMF added S-methyl-2 - theoreticalmethodological (3.0 g, of 10.4 mmole). The resulting mixture is stirred for 4 hours at 45oC, poured into podslashennoyi water and extracted with ethyl acetate (3 x 100 ml). The combined extracts washed with water, dried over magnesium sulfate, filtered and concentrated to oil. This oil is dissolved in methanol, treated with IPA/HCl and triturated with ether. The solid is collected by filtration and washed with ether. After one recrystallization from IPA/MeOH/Et2O get a solid white product (2.5 g, 66%), so the melting point of more than 260oC (decomposition) []D+44,5oC (0,62 DMSO).

Example 18

(-)-N-((2-((Phenyl)methyl)amino)-1,2,3,4-tetrahydronaphtyl-7-yl)-2 - thiophencarboxylic

(a) (-)-2-(Phenyl)carbonyl)amino-7-nitrotyrosine

To 2-amino - add benzoyl chloride (1.2 ml, 10.1 mmole). After complete addition, the mixture is diluted with water to a volume of 250 ml. of Precipitated precipitate is collected by filtration, washed with water and dried in vacuum (2.8 g, 100%).

So melting point 208-209oC.

[]D-24,0oC (c 0,87 DMSO).

(b) (-)-2-((Phenyl)methyl)amino-7-nitrotyrosination

To the (-)-2-((phenyl)carbonyl)amino-7-nitrotyrosine (2.8 g, 9.4 mmole) in 100 ml anhydrous THF added borane-THF (32,8 ml, 1M THF, 32,8 mmole). The resulting mixture was refluxed for 5 hours,

cooled to 0oC and quenched, prokopeva 4h. HCl. The resulting mixture is again brought to a boil under reflux for 1 hour, concentrated in vacuo and the solid is filtered (washed with water) and dried in vacuum (2.8 g, 94%).

So melting more than 300oC,

[]D-59,4oC (from 0.39 DMSO).

(c) (-)-2-((Phenyl)methyl)amino-7-aminotetrahydrofuran

To a stirred solution of (-)-2-((phenyl)methyl)-amino-7 - nitrotyrosine (2.8 g, 8.7 mmole) in MeOH (100 ml) is added a catalytic amount of 10% Pd/C. the resulting mixture hydronaut at 50 psi (3,515 kg/cm2) for 1 hour, filtered through celite and concentrated to a glassy solid, which on residronate-7-yl)-2 - thiophencarboxylic

To the (-)-2-((phenyl)methyl)amino-7-aminotetrahydrofuran (2.5 g, 8.7 mmole) in 20 ml DMF added S-methyl-2-thiophenecarboxaldehyde (3.0 g, of 10.4 mmole). The resulting mixture is stirred for 4 hours at 45oC, poured into podslashennoyi water and extracted with ethyl acetate (3 x 100 ml). The combined extracts washed with water, dried over magnesium sulfate, filtered and concentrated to oil. This oil is dissolved in methanol, treated with IPA/HCl and triturated with ether. The solid is filtered off and washed with ether. After one recrystallization from IPA/MeOH/Et2O get a solid white color (2.7 g, 71%).

So the melting point of more than 260oC (decomposition).

[]D-44,5oC (from 0.57 DMSO).

Example 19

N-(2,3,4,5-Tetrahydro-1H-3-benzazepin-7-yl)thiophene-2-carboximidic

(a) 2,3,4,5-Tetrahydro-1H-3-benzazepin-7-aminonaphthalene

To a solution of 2,3,4,5-tetrahydro-7-nitro-1H-3-benzenedimethanamine (1.68 g, 7,35 mmole) in 100 ml of ethanol is added 5% palladium on coal (0.2 g) and the resulting solution was placed in the apparatus of Para for hydrogenation, pressure is brought to 45 psi (3,164 kg/cm2) hydrogen. After reaching the designed hydrogen absorption (2 hours) the catalyst is filtered off and Brooke evaporates all the water and does not form a solid product. The solid product is dissolved in hot ethanol (50 ml) and the product precipitated with ether (75 ml). The solid is collected and air-dried to obtain the product as off-white solids (2,43 g, 94%).

Melting point 288-91oC.

(h) N-(2,3,4,5-Tetrahydro-1H-3-benzazepin-7-yl)thiophene-2 - carboximidic

A suspension of 2,3,4,5-tetrahydro-1H-3-benzazepin-7 - aminomonosaccharide (of 0.60 g, 3.0 mmole) and 5-methyl-2 - thiophenecarboxaldehyde (1.1 g, 3.8 mmole) in 2.0 ml of dimethylformamide and 2.0 ml of isopropanol is stirred at room temperature for 20 hours. The solid reaction mixture is filtered and washed with isopropanol (5 ml) and ethyl acetate (15 ml). Air-dried, the solid weighs 1.18 g and is a mixed salt. It is dissolved in water, alkalinized and extracted with ethyl acetate. The solvent is dried over magnesium sulfate and concentrate to obtain the free base in the form of a solid yellow color. It is placed in 30 ml of isopropanol and acidified with hydrogen bromide in isopropanol until then, until the solution becomes acidic. The product precipitated 35 ml of ethyl acetate. This product is collected and dried to obtain the product as a salt - dihydrobromide-2-carboximidic

(a) 1,2,3,4-Tetrahydroisoquinoline-7-aminonaphthalene

It is produced by the method of example 19, stage (a). From 7-nitro - 1, 2, 3, 4-tetrahydroxyphenylchlorin (3, 00 g, 14,0 mmole) and 5% palladium on coal (0.3 g) in 150 ml of ethanol, to produce the product as a pale pink solid (2,43 g, 94%).

Melting point 232-4oC

(b) N-(-1,2,3,4-Tetrahydroisoquinoline-7-yl)thiophene-2-carboximidic

It is produced by the method of example 19, the stage (b). From 1,2,3,4-tetrahydroisoquinoline-7-aminomonosaccharide (0,46 g) and 3-methyl-2-theoreticalmethodological (0.95 g) in 2.0 ml of isopropanol and 2 ml of dimethylformamide, emit after processing the specified connection in the form of the free base (0,60 g, 94%). His turn in bisexuality salt in a solution of methanol/ethyl acetate to obtain the product as off-white solids (0,59 g, 54%).

Melting point 199-200oC (decomposition).

Example 21

N-(2-Benzyl-1,2,3,4-tetrahydroisoquinoline-7-yl-thiophene-2 - carboximidic

(a) 2-Benzyl-7-nitro-1,2,3,4-tetrahydroxyphenylchlorin

To a solution of 7-nitro-1,2,3,4-tetrahydrocannabinolicacid (2.50 g, of 11.6 mmole) and potassium carbonate (2.0 g) in 100 ml of acetonitrile add benzylbromide (2,22 g, 13,0 is education. The solvent is removed in vacuo to obtain a solid product, which is shared between methylene chloride and water. The dried (over magnesium sulfate) organic phase is concentrated and the resulting oil was placed in ethanol (50 ml). This solution is acidified with hydrochloric acid in ethanol. The precipitate, which formed, defend and add 150 ml ethanol and 50 ml of ether. The solid is collected and air dried to obtain 2-benzyl-7-nitro-1,2,3,4 - tetrahydroisoquinolinium as off-white solids (2,78 g, 79%).

Melting point 256-8oC (decomposition).

(b) 2-Benzyl-1,2,3,4-tetrahydroisoquinoline-7-aminogidrohlorid

This connection receive by way of example 19 (stage a). 2-benzyl-7-nitro-1,2,3,4-tetrahydroisoquinolinium (2.00 g, 6,56 mmole) and 5% Pd/C (0.2 g) in 100 ml of ethanol. The product is isolated in a solid yellow color (of 1.05 g, 78%).

So melting 257-9oC (decomposition).

(c) N-(2-Benzyl-1,2,3,4-tetrahydroisoquinoline-7-yl)thiophene-2 - carboximidic

It is produced by the method of example 19 (stage b). 2-benzyl-1,2,3,4-tetrahydroisoquinoline-7-aminomonosaccharide (0.50 g, 1.8 mmole) and 5-methyl-2-theoreticalmethodological (of 0.67 g, 2.3 mmole) in isopropanol (the TA (0,53 g, 84%). It turned into salt-oxalate in isopropanol. m/e = 348 (M+H).

Example 22

N-(1,2,3,4-tetrahydroisoquinoline-5-yl)thiophene-2-carboximidic, dioxalate salt

This compound is prepared as in the method described in example 20.

So melting 75oC (decomposition).

Example 23

N-(1,2,3, 4-Tetrahydroisoquinoline-6-yl) thiophene-2-carbox - imidated

(a) 1,2,3,4-Tetrahydroisoquinoline-6-aminonaphthalene

A solution of isoquinoline-6-amine (Manske, R. H. F., et.al., J. Am. Chem. Soc., 72, 4997 (1950)) (4,40 g, 30.5 mmole) and platinum oxide (300 mg) in acetic acid solution (85 ml) and 2.5 M hydrochloric acid (30 ml) is placed in the apparatus of Para and create a hydrogen pressure of 45 psi (3,164 kg/cm) for 16 hours. The solvent is removed in vacuo, and the resulting Sol divide between aqueous potassium carbonate and 20% isopropanol in methylene chloride. The dried (magnesium sulfate) organic phase is concentrated and the resulting oil chromatographic on silica gel, using as eluent 2% methanol in chloroform, to obtain is 3.08 g (93%) of product as a solid. This product is 3.08 g, 20.8 mmole) was placed in 200 ml of ethanol and add 1 equivalent of 0.10 M hydrochloric acid. The solvent is removed to obtain monohydrochloride in the form of a solid ve which It is produced according to the method of example 19 (stage b). 1, 2, 3, 4-tetrahydroquinolin-6-aminomonosaccharide (0, 90 g, 4.9 mmole) and 8-methyl-2-theoreticalmethodological (1.80 g, 6.2 mmole) in isopropanol (2.0 ml) and dimethylformamide (2.0 ml) was isolated after treatment and chromatographytandem on silica gel, the compound in the form of free base (0.74 g, 57%).

So melting 170-5oC.

Example 24

N-(Isoquinoline-7-yl)thiophene-2-carboximidic

(a) 7-Nitroisoquinoline

A solution of 7-nitro-3,4-dihydroisoquinoline (3.00 g, 17.0 mmole) and 5% palladium on coal (3.0 g) in 75 ml of decalin heated under reflux for 3 hours. After cooling the solution is filtered and the catalyst washed with chloroform (200 ml). The solvent is removed in vacuo to obtain 7-nitroisoquinoline (1.63 g) as a solid yellow-brown color.

Mass spectrum 175 (M+H).

(b) Isoquinoline-7-amine

7-Nitroisoquinoline (1,62 g, a 9.25 mmole) in 150 ml of ethanol hydronaut in the office of Paara over 5% Pd/C (0.2 g) as a catalyst for 3 hours at 50 psi (3,515 kg/cm2). The reaction mixture is filtered and the solvent is removed under reduced pressure. After recrystallization of the solid from ethanol (3 ml) receive isoquinoline-7-amine (0,98 g) as a solid yellow-coric who,1H), 4,00 (width,2H).

(c) N-(Isoquinoline-7-yl)thiophene-2-carboximidic

A solution of isoquinoline-7-amine (0.96 g, 6.7 mmole) and S-methyl-2-titaniumoxide (2,42 g, at 8.36 mmole) in 4 ml of isopropanol and 4 ml of DMF is stirred for 18 hours. The solution is poured into dilute sodium hydroxide and extracted with methylene chloride. The obtained extract is dried over magnesium sulfate, and the solvent is evaporated to obtain an oil, which solidifies upon standing. This sample is purified on a chromatographic column with silica gel (5% methanol in chloroform saturated with gaseous ammonia) to obtain 1.31 g of a solid substance. This solid is recrystallized from ethyl acetate (25 ml) to obtain 1,05 g specified in the title compound in the form of a solid off-white color.

So melting 177,5-178,5oC.

1. Bicyclic derivatives of amidine formula I

< / BR>
where D represents a five-membered heterocyclic ring containing a heteroatom selected from O or S, and which is connected with the rest of the compound via a carbon atom;

A represents N(X) or CH (-(CH2)m-NXY);

U represents NH or CH2;

V represents (CH2)a;

W represents (CH2)b is about 3;

X and Y independently represent hydrogen, alkyl C1-6, or a group -(CH2)nQ;

Q represents a biphenyl or phenyl, optionally substituted by one or more groups selected from alkyl C1 to 6, halogen, nitro;

m represents an integer from 0 to 5;

n represents an integer from 0 to 6;

or chain U-V-A-W has the previously indicated meanings, except that she may not be rich,

and its pharmaceutically acceptable salts and enantiomers.

2. Connection on p. 1 of formula IA

< / BR>
where T represents a C3-5 saturated or unsaturated alkylenes chain, substituted (CH2a-NXV, or-U-(CH2)a-N(X)-(CH2)b-;

X and Y independently represent hydrogen, alkyl C1-6, or a group -(CH2)nQ;

Q is phenyl, optionally substituted by alkyl C1 to 6, halogen, nitro;

U, m, n, a, b, and D have the above values, except that if T is-U(-CH2)a-N(X)-(CH2)band X is -(CH2)nQ;

n represents an integer from 0 to 5,

and its pharmaceutically acceptable salts and enantiomers.

3. The compound of formula I on p. 2, where T represents C3-5saturated or unsaturated alkylenes chain, substituted (CH4. The compound of formula I under item 2 or 3, where T is C3-5 saturated or unsaturated alkylenes chain, substituted -(CH2)n-NXY.

5. The compound of formula I according to any one of items 1 to 4, where m is 0 or 1.

6. The compound of formula I on p. 2, where T is-U(-CH2)a-N(X)-(CH2)band X represents hydrogen, alkyl C1-6, or a group -(CH2)nQ-.

7. Connection on p. 2 or 6, where T is-U(-CH2)a-N(X)-(CH2)band U represents CH2.

8. Connection on p. 2, 6, or 7, where T is-U(-CH2)a-N(X)-(CH2)band a + b = 1 or 2.

9. The compound according to any one of the preceding paragraphs, where n is 0, 1 or 2, and X and/or Y represents -(CH2)nQ.

10. The compound according to any one of the preceding paragraphs, where X and/or Y represents -(CH2)nQ, Q is phenyl, optionally substituted by alkyl C1 to 6.

11. The compound of formula I according to any one of the preceding paragraphs, where D represents a five-membered heterocyclic ring containing one heteroatom selected from O or S.

12. The compound of formula I on p. 11, where D represents thienyl or furyl.

13. Connection formail)amino)indan-5-yl)-2-thiophenecarboxaldehyde;

N-((2-(phenylmethyl)amino)-1,2,3,4-tetrahydronaphtyl-7-yl)-2-thiophenecarboxaldehyde;

N-((2-amino)-1,2,3,4-tetrahydronaphtyl-7-yl)-2-thiophenecarboxaldehyde;

N-((1-amino)-1,2,3,4-tetrahydronaphtyl-7-yl)-2-thiophenecarboxaldehyde;

N-((2-amino)-indan-5-yl)-2-thiophenecarboxaldehyde;

N-((2-methyl)(phenylmethyl)amino)indan-5-yl)-2-thiophenecarboxaldehyde;

N-((2-amino)-indan-6-yl)-2-thiophenecarboxaldehyde;

N-((1-(phenylmethyl)amino)indan-6-yl)-2-thiophenecarboxaldehyde;

N-((2-((3-chlorophenyl)methyl)amino)indan-5-yl)-2-thiophenecarboxylate;

N-((2-((2-were)methyl)amino)indan-5-yl)-2-thiophenecarboxylate;

N-((2-((3-were)methyl)amino)indan-5-yl)-2-thiophenecarboxylate;

N-((2-((4-(were)methyl)amino)indan-5-yl)-2-thiophenecarboxylate;

N-((2-(ethyl)amino)indan-5-yl)-2-thiophenecarboxylate;

N-((2-(((4-phenyl)methyl)amino)indan-5-yl)-2-thiophenecarboxylate;

N-((2-(((4-hexyl)phenyl))methyl)amino)indan-5-yl)-2-thiophenecarboxylate;

N-((2-((3-bromophenyl)methyl)amino)indan-5-yl)-2-thiophenecarboxylate;

N-((2-((3-chlorophenyl)methyl)amino)-1,2,3,4-tetrahydronaphtyl-7-yl)-2-thiophenecarboxaldehyde;

N-((2-(phenylmethyl)(methyl)amino)-1,2,3,4-tetrahydronaphtyl-7-yl)-2-thiophenecarboxaldehyde;

N-((1-(phenylmethyl)amino)-amidon, N-((1-(phenylmethyl)amino)-1,2,3,4-tetrahydronaphtyl-6-yl)-2-thiophenecarboxaldehyde;

N-((2-(phenylmethyl)amino)-1,2,3,4-tetrahydronaphtyl-7-yl)-2-furancarboxaldehyde;

N-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)thiophene-2-carboxamidine;

N-(1,2,3,4-tetrahydroisoquinoline-7-yl)thiophene-2-carboxamidine;

N-(2-benzyl-1,2,3,4-tetrahydroisoquinoline-7-yl)thiophene-2-carboxamidine;

N-(1,2,3,4-tetrahydroisoquinoline-5-yl)thiophene-2-carboxamidine;

N-(1,2,3,4-tetrahydroisoquinoline-6-yl)thiophene-2-carboxamidine;

N-(isoquinoline-7-yl)thiophene-2-carboxamidine,

or their pharmaceutically acceptable salts or enantiomers.

15. The compound according to any one of the preceding paragraphs as a pharmaceutical agent.

16. Pharmaceutical composition having the property synthetase inhibitor of nitric oxide, including derivative of amidine in a mixture with a pharmaceutically acceptable diluent or carrier, wherein as derived amidine it contains a compound according to any one of FG1 - 14 in therapeutically effective amounts.

17. Bicyclic derivative of amidine formula I under item 1, with the property synthetase inhibitor of nitric oxide.

18. The way inhibion of amidine used therapeutically effective amount of the compounds of formula I according to any one of paragraphs.1 - 14.

19. A method of obtaining a bicyclic derivative of amidine formula I under item 1, characterized in that conduct the interaction of the compounds of formula II

< / BR>
with the compound of the formula III

< / BR>
where D is specified in paragraph 1 values;

L represents tsepliaeva group

and, if necessary, the obtained compound I, in which X is hydrogen, optionally subjected to interaction with the compound of the formula VI

R9-L

where R9represents alkyl Cl to 6, or a group -(CH2)nQ;

L represents tsepliaeva group

obtaining the compounds of formula I in which A represents a group-N(X), and X represents alkyl C1-6, or a group -(CH2)nQ or the obtained compound I, in which X and Y are hydrogen, then subjected to interaction with the compound of the formula VI

R9-L

where R9represents alkyl C1-6, or a group -(CH2)nQ;

L represents tsepliaeva group

obtaining the compounds of formula I in which A represents a group-CH-(CH2)m-NXY, and at least one of X and Y represents alkyl C1-6, or a group -(CH2)nQ.

20 a method of obtaining a bicyclic derivative of amidine formula I under item 1, the best of the treatment;

HA represents an acid,

with the compound of the formula V

< / BR>
where D is specified in paragraph 1 values

and, if necessary, the obtained compound I, in which X represents hydrogen, optionally subjected to interaction with the compound VI

R9-L

where R9represents alkyl C1-6, or a group -(CH2)nQ;

L represents tsepliaeva group

obtaining the compounds of formula I in which A represents a group-N(X), and X represents alkyl C1-6, or a group -(CH2)nQ or the obtained compound I, in which X and Y are hydrogen, then subjected to interaction with the compound of the formula VI

R9-L

where R9represents alkyl C1-6, or a group -(CH2)nQ;

L represents tsepliaeva group

obtaining the compounds of formula I in which A represents a group-CH-(CH2)m-NXY and at least one of X and Y represents alkyl C1-6, or a group -(CH2)nQ.

 

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< / BR>
in which the radicals R1and R2may be the same or different, represents hydrogen, C2-C6- alkyl, C3-C6-cycloalkyl, C3-C6alkenyl,

C2-C6-quinil, C1-C3-halogenated, benzoyloxy group containing substituents, benzoylamino, which can also contain one or two Deputy, C2-C6-alkanolamines, C3-C6-cycloalkylcarbonyl, benzyl group which may contain substituents, the phenyl group with possible alternates, and other substituents, provided that at the same time R1and R2are not hydrogen atoms, the second condition is that one of R1and R2is not unsubstituted phenyl group when the other one represents a hydrogen atom, and the third condition is one of R1and R2in anthopology is not an aniline ring, C2-C6-alkyl, C3-C6-cycloalkyl or C2-C6-alkoxygroup when the other one represents a hydrogen atom

The invention relates to new methods of obtaining salt orthocarbonate acids or alcoholate hem-triolo having the structural formula R-Me where R is phenyl, furyl, R1-CH= CH-, CH3-(CH= CH)2- CH= C-CH3; Me - Na, K; Rlis phenyl, furyl, used as an intermediate reagents in organic synthesis, as well as in the printing industry for the regeneration of aluminum plates

The invention relates to new derivatives of 1-[2-(substituted vinyl)]-3,4-dihydro-5H-2,3-benzodiazepine, method thereof, pharmaceutical composition, use of these benzodiazepine derivatives for the treatment of diseases and preparation of pharmaceutical compositions suitable for treatment of diseases
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