Derivatives of hinoklidina or their pharmaceutically acceptable salts and pharmaceutical composition

 

(57) Abstract:

The essence of the invention: derivatives of hinoklidina formula 1, in which the P-methoxy group, P is a group selected from isopropyl, tert-butyl, methyl, ethyl and sec-butyl, or their pharmaceutically acceptable salts and pharmaceutical composition having antagonistically effect on substance P in a mammal, based on the compounds of formula 1. The structure of the compounds of formula 1:

< / BR>
2 S. and 3 C.p. f-crystals.

The invention relates to new derivatives of hinoklidina, pharmaceutical compositions containing such compounds and to the use of such compounds for the treatment and prevention of inflammatory disorders and disorders of the Central nervous system, as well as some other disorders. Pharmaceutically active compounds of the present invention are antagonists of the receptor substance P. This invention relates to new intermediate compounds used for the synthesis of such antagonists of substance P.

Substance P represents a naturally occurring undecapeptide belonging to tachykinins group of peptides, the latter so named because of its fast stimulating action on t is formed in the body of mammals (and was originally isolated from the intestines) and possesses a characteristic amino acid sequence, which is shown in D. F. Veber et al., U.S. patent N 460283. Wide involvement of substance P and other tachykinins to the pathophysiology of many diseases sufficiently demonstrated. For example, it was recently shown that substance P is involved in the migration of pain or migraine (see C. E. C. Sandbeog et al., Journal of Medical Chemistry, 25, 1009 (1982)), as well as disorders of the Central nervous system, such as fear and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, respectively, and in rheumatic diseases, such as fibrosis, and sacrament and gastrointestinal disorders and diseases LCD tract, such as ulcerative colitis and Crohn's disease, and so on (see D. Regoli "Treuols in Cluster Headache", edited by F. Sicutery et al., Elsevier Scieutific Publishens, Amsterdam, pp. 85-95 (1987)).

Recent efforts to provide antagonists of substance P and other tachykinins peptides, in order to more effectively treat various disorders and diseases listed above. There is a small number of these so far described antagonists, who, as a rule, are patentable substances in nature and, therefore, are too unstable from the point of view of metabolism, to serve as PA, on the other hand, does not have this disadvantage, being much more stable from the point of view of metabolism than the above-mentioned agents.

Derivatives of hinoklidina of the present invention relate to the type of connections in the application for the patent cooperation Treaty PCT/US 89/05338, filed November 20, 1989, and in the application for U.S. patent N 557442, filed July 23, 1990, both applications are fixed together with the present application. Other derivatives of hinoklidina, which show activity as receptor antagonists of substance P, refer to the connections in the application for the patent cooperation Treaty PCT/US 91/02853 under the heading "3-Amino-2-aryl-hioliday", filed April 25, 1991, and in the application for the patent cooperation Treaty PCT/US 92/03369, entitled "Derivatives of hinoklidina", and filed may 14, 1991. These applications are also fixed together with the present application.

Derivatives of piperidine derivatives and related heterocyclic nitrogen-containing compounds, which are used as antagonists of substance P, are mentioned in the patent applications U.S. N 619361, filed November 28, 1990, and N 590423, filed September 28, 1990, both applications are fixed together with the present application.

The present invention relates to compounds fo PY, consisting of isopropyl, tert-butyl, methyl, ethyl and sec-butyl; and to pharmaceutically acceptable salts of such compounds.

Typical examples of the compounds of the present invention are the following compounds:

(2S, 3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1 - azabicyclo[2.2.2]Octan-3-amine;

(2S, 3S)-N-(5-tert-butyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1 - azabicyclo[2.2.2]Octan-3-amine;

(2S, 3S)-N-(5-methyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1 - azabicyclo[2.2.2]Octan-3-amine;

(2S, 3S)-N-(5-ethyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1 - azabicyclo[2.2.2]Octan-3-amine;

(2S, 3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1 - azabicyclo[2.2.2]Octan-3-amine;

(2S, 3S)-N-(5-sec-butyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2- .2.2]octane-3-amine;

and pharmaceutically acceptable salts of such compounds.

The invention also relates to pharmaceutical compositions for the treatment or prevention of a condition selected from the group consisting of inflammatory diseases (such as arthritis, psoriasis, asthma and inflammatory intestinal diseases), fear, depression or discomycete disorders, colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive digitalin is to angina, migraine and Raynaud's disease (Reynaud), fibrous and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder syndrome, nakasalalay, such as alcoholism, family stress, somatic disorders, peripheral nervous system diseases, neuralgia, neurotic diseases disorders such as Alzheimer's disease, AIDS dementia, diabetic neuropathy and multiple sclerosis, disorders related to the strengthening and weakening of the immune system, such as systemic lupus erythematosus, and rheumatic diseases such as fibrositis, in mammals, including humans, contains a number of compounds of the formula I, or its pharmaceutically acceptable salts, are effective for treating or preventing such condition, and a pharmaceutically acceptable carrier.

The invention also relates to a method of treating or preventing a condition selected from the group comprising inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory intestinal disease), anxiety, depressive or distamine disorders, colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive as angina, migraine and Raynaud's disease, fibrous and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder syndrome, nakasalalay, such as alcoholism, family stress, somatic disorders, peripheral nervous system diseases, neuralgia, neurotic diseases disorders such as Alzheimer's disease, AIDS dementia, diabetic neuropathy and multiple sclerosis, disorders related to strengthening or weakening of the immune system, such as systemic lupus erythematosus, and rheumatic diseases such as fibrosis, in mammals, including humans, which consists in introducing said mammal amounts of compounds of formula I, or its pharmaceutically acceptable salt, is effective for treating or preventing such condition.

The invention also relates to pharmaceutical compositions with an antagonistic effect on substance P in a mammal, including humans, contain a compound of the formula I, or its pharmaceutically acceptable salt in an amount providing an antagonistic effect on substance P and a pharmaceutically acceptable carrier.

The invention that is mentioned in the introduction to the mammal the compounds of formula I, or its pharmaceutically acceptable salt in an amount providing an antagonistic action on substance P.

The invention also relates to pharmaceutical compositions for treating or preventing disorders in a mammal, including man, caused by an excess of substance P-containing compound of the formula I, or its pharmaceutically acceptable salt in an amount providing an antagonistic effect on substance P, and a pharmaceutically acceptable carrier.

The invention also relates to a method of treating or preventing disorders in a mammal, including man, caused by an excess of substance P, which consists in the introduction referred to the mammal the compounds of formula I, or its pharmaceutically acceptable salt in an amount providing an antagonistic action on substance P.

The invention also relates to pharmaceutical compositions for the treatment or prevention of a condition selected their group, which includes inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory bowel disease), anxiety, depressive or distamine disorders, colitis, psychosis, pain, allergies such to the Zia, vasospastic diseases such as angina, migraine and Raynaud's disease, fibrous and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder syndrome, nakasalalay, such as alcoholism, family stress, somatic disorders, peripheral nervous system diseases, neuralgia, neurotic diseases disorders such as Alzheimer's disease, AIDS dementia, diabetic neuropathy and multiple sclerosis, disorders related to strengthening or weakening of the immune system, such as systemic lupus erythematosus, and rheumatic diseases such as fibrositis, mammal, including humans, contains a number of compounds of formula I, or its pharmaceutically acceptable salt that is effective to provide antagonistic action on substance P in the location of its receptor, and a pharmaceutically acceptable carrier.

The invention also relates to a method of treating or preventing a condition selected from the group comprising inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory bowel disease), anxiety, depressive or discemi the ways, allergies such as poison ivy, hypertension, vasospastic diseases such as angina, migraine and Raynaud's disease, fibrous and collagen diseases such as scleroderma and eosinophillia fascioliasis, reflex sympathetic dystrophy such as shoulder syndrome, nakasalalay, such as alcoholism, family stress, somatic disorders, diseases of the peripheral nervous system, neuralgia, neurotic diseases disorders such as Alzheimer's disease, AIDS dementia, diabetic neuropathy and multiple sclerosis, disorders related to strengthening or weakening of the immune system, such as systemic lupus erythematosus, and rheumatic diseases, such as fibrositis, mammal, including man, which consists in introducing said mammal amounts of compounds of formula I, or its pharmaceutically acceptable salt that is effective to provide antagonistic action on substance P in the location of its receptor.

The invention also relates to pharmaceutical compositions for treating or preventing disorders in a mammal, including a human, the treatment or prevention of which is effected or the pharmaceutically acceptable salt, in amounts effective to provide antagonistic action on substance P in the location of its receptor, and a pharmaceutically acceptable carrier.

The invention also relates to a method of treating or preventing disorders in a mammal, including humans, treatment and prevention of which is effected or facilitated by reducing the intermediate transmission of substance P, which consists in introducing said mammal amounts of compounds of formula I, or its pharmaceutically acceptable salt that is effective to provide antagonistic action on substance P in the location of its receptor.

The invention relates also to pharmaceutical compositions for treating or preventing disorders in a mammal, including a human, the treatment or prevention of which is effected or facilitated by reducing the intermediate transmission of substance P containing the amount of the compounds of formula I, or its pharmaceutically acceptable salts, are effective for treating or preventing such disorder, and a pharmaceutically acceptable carrier.

The invention also relates to a method of treating or preventing disorders in mlec is of intermediate transmission of substance P, which consists in introducing said mammal amounts of compounds of formula I, or its pharmaceutically acceptable salt that is effective to treat or prevent such disorders.

Compounds of the invention have chiral centers and therefore exist in different enantiomeric forms. The invention relates to all optical isomers and all stereoisomers of compounds of the formula I and their mixtures.

Compounds of the invention include compounds that are identical to the compounds described above, and compounds in which one or more hydrogen atoms, nitrogen or carbon replace their isotopes (isotopes such as tritium or carbon-14). Such compounds are useful as research and diagnostic tool in the study of pharmokinetic metabolism and assess the links. Specific research applications include the method of labeled atoms with radioactive ligand to determine the relationships used in autoradiographically studies and research links in vivo, while the typical application in diagnostic areas include studies of substance P receptor in the brain in vivo - in connection with the performance communications disorders in the intestine, etc.

Compounds of the invention can be obtained when the compound of formula II

< / BR>
having the same stereochemistry, which is desirable for the compounds of formula I, is subjected to hydrolytic removal methoxybenzyloxy group to obtain the corresponding compound of formula III

< / BR>
having the same stereochemistry, and then injected into the reaction of the compound of formula III, which is thus obtained, with an aldehyde of the formula IV

< / BR>
in the presence of a reducing agent.

Hydrolytic cleavage (delete) methoxybenzyloxy groups are, as a rule, using a strong mineral acid, such as hydrochloric, Hydrobromic or itestosterone acid, at a temperature of from room temperature to the boiling point of the acid reflux. It is preferable to conduct the reaction in Hydrobromic acid at the boiling temperature under reflux. This reaction is usually performed for 23 PM

On the other hand, hydrolytic cleavage methoxybenzyloxy group on the above methodology can be replaced by gidrodinamicheskoe the removal of such groups. Gidrodinamicheskoe removal is usually performed using vadodar in relatively inert reaction solvent, such as acetic acid or a lower alcohol, at a temperature of from 0oC to 50oC. Methoxybenzyl group can also be split, alternatively, by treating the compounds of formula II dissolved metal, such as lithium or sodium in ammonia at a temperature of from -30oC 78oC, or a salt of formic acid in the presence of palladium or cyclohexane in the presence of palladium.

It is preferable to split methoxybenzyloxy group by treating the compounds of formula II with hydrogen in the presence of palladium hydroxide-on-coal in methanol containing hydrochloric acid, at 25oC.

The resulting compound of the formula III can be converted into the desired compound of formula IV in the presence of a reducing agent. The reaction is usually performed using a reducing agent such as cyanoborohydride sodium, triacetoxyborohydride sodium, borohydride sodium, hydrogen and a metal catalyst, zinc and hydrochloric acid, of dimethyl sulfide borane or formic acid, at a temperature of from -60oC to 50oC. Suitable inert solvents for this reaction include lower alcohols (e.g. methanol, ethanol and isopropanol), acetic acid, methylene chloride and Tetra is as reductant.

On the other hand, the reaction of the compound of formula III with the compound of the formula IV can be carried out in the presence of a desiccant or when using equipment that allows azeotrope to remove water formed to receive Imin formula V

< / BR>
which is then injected into the reaction with the reducing agent, as described above, preferably with triacetoxyborohydride sodium at room temperature. Getting imine, as a rule, is carried out in an inert solvent, such as benzene, xylene or toluene, preferably toluene, at a temperature of 25oC to 110oC, preferably at the boiling temperature of the solvent under reflux. Suitable systems are "drier-solvent" include "the titanium tetrachloride - dichloromethane, isopropoxide titanium - dichloromethane and molecular sieve - THF". The preferred system the titanium tetrachloride - dichloromethane".

The compounds of formula III can be converted into compounds of formula I, having the same stereochemistry, by reaction with the appropriate compound of formula VI

< / BR>
in which L represents tsepliaeva group (for example, chlorine-, bromine-, iodine or mesilate). This reaction is usually performed in an inert restorativejusticela - at 25oC.

The compounds of formula III can also be converted into compounds of formula I, having the same stereochemistry, by reacting these compounds with an appropriate compound of formula VII

< / BR>
in which L has the foregoing values, or represents an imidazole, and subsequent reduction of the resulting amide. This reaction is usually performed in an inert solvent, such as THF or dichloromethane at a temperature from -20oC to 60oC, preferably in dichloromethane at 0oC. Recovering the resulting amide is accomplished by processing the restoration, such as complex disulfide with borane, alumoweld lithium or hydride diisobutylaluminum, in an inert solvent, such as ethyl ether or THF. The reaction temperature may be in the range of 0oC to the boiling point of the solvent under reflux. Preferably, the recovery is performed using the complex of dimethyl sulfide with DIBORANE in THF at 60oC.

The new compounds of formula I and their pharmaceutically acceptable salts are suitable as antagonists of substance P, i.e., they have the ability to have antagonistic task therapeutic agent for the treatment of the aforementioned disorders and diseases in sick mammal.

Compounds of the invention, which are, by nature, bases capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts for the introduction of animals should be pharmaceutically acceptable, in practice it is often desirable to first isolate the compounds of formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter free base by treatment with an alkaline reagent, and then to turn the latter free base in a pharmaceutically acceptable salt accession acid. Salt accession acids are the major compounds of the invention are easily obtained by processing the primary connection essentially equivalent amount of the chosen mineral or organic acid in an aqueous solvent or in a suitable organic solvent, such as methanol or ethanol. After careful evaporation of the solvent easily get the desired salt.

Those compounds of formula I that are acidic nature, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include salts of alkali metals is as reagents for producing pharmaceutically acceptable basic salts of the present invention, are bases which form non-toxic salts of the base with the acidic compounds of formulas I, II and III. Such non-toxic basic salts include salts formed from such pharmacologically acceptable cations such as the cations of sodium, potassium, calcium and magnesium, etc., Such salts can be easily obtained by treating the corresponding acid compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and subsequent evaporation to dryness the resulting solution, preferably under reduced pressure. On the other hand, they can also be obtained by mixing solutions of the acidic compounds in the lower alcohols and the desired alkali metal alkoxide, and subsequent evaporation to dryness the resulting solution in the same way as in the previous case. In any case, it is preferable to use stoichiometric amounts of reactants in order to ensure completeness of reaction and maximum yield of the desired final product.

The compounds of formula I and their pharmaceutically acceptable salts show activity receptor binding substance P, and, therefore, are valuable for the treatment and prevention of a wide range erotichnoe transmission of substance P. Such conditions include inflammatory diseases (such as arthritis, psoriasis, asthma and inflammatory bowel disease), anxiety, depressive or distamine disorders, colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstruction of the respiratory tract, allergies such as poison ivy, hypertension, vasospastic diseases such as angina, migraine and Raynaud's disease, fibrous and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder syndrome, nakasalalay, such as alcoholism, family stress, somatic disorders, diseases of the peripheral nervous system, neuralgia, neurotic diseases disorders such as Alzheimer's disease, AIDS dementia, diabetic neuropathy and multiple sclerosis, disorders related to strengthening or weakening of the immune system, such as systemic lupus erythematosus, and rheumatic diseases such as fibrositis. Therefore, these compounds are readily adapted to therapeutic use as antagonists of substance P for regulation and/or treatment of any of the above clinical conditions in milk is sterile oral, parenteral or local way. As a rule, these compounds are most preferably administered in doses, comprising from 0.5 mg to 500 mg per day, although if necessary, changes are possible, depending on the weight and condition of the subject to be treated and the particular route of administration. Changes may occur depending on the type of animal that is being treated and its individual response to the above mentioned medicine, and also on the type of pharmaceutical formulation, time and frequency with which this introduction perform. In some cases, more than adequate can be a dose below the lower limit of the above areas, although in other cases, significantly higher doses can be used without causing any harmful side effects, provided that such larger doses are first appointed to the introduction of several small doses throughout the day.

Compounds of the invention can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the three above methods, and such introduction can be performed in a single dose or as multiple doses. Specifically, new therapeutic tools nachname pharmaceutically acceptable inert carriers in the form of tablets, capsules, pellets, lozenges, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, etc. Such carriers include solid diluents or fillers, sterile aqueous medium and various non-toxic organic solvents, etc. moreover, the oral pharmaceutical compositions can be appropriately podkosheny and/or otdushina. In General, therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels lying in the range from 5.0 to 70 wt.%.

In oral introduction of tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various leavening agents, such as starch (and preferred corn, potato or tapioca starch), alginic acid and certain complex silicates, together with binding granules such as polyvinylpyrrolidone, sucrose, gelatin and Arabian gum. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulphate and talc of all the as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When oral administration is required aqueous suspensions and/or elixirs, the active ingredient may be combined with various sweetening agents or flavoring, coloring matter or dyes and, if desired, emulsifiers and/or suspendresume agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

For parenteral administration can be used solutions of therapeutic compounds of the present invention or in Kungaeva or peanut oil or in aqueous propylene glycol. In aqueous solutions must be entered buffer (preferably, pH exceeded 8) if necessary and the liquid diluent first make isotonic. These aqueous solutions are suitable for internal injection. The oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection. The preparation of these solutions under sterile conditions is easy to implement techniques standard pharmaceutical techniques, and these techniques are well known to specialists.

In addition, it is preferable to make use of creams, jellies, gels, pastes, ointments, etc., in accordance with conventional pharmaceutical practice.

The activity of compounds of the invention as antagonists of substance P is determined by their ability to inhibit the binding of substance P at the locations of its receptors in tissues of the tail of the cow, using radioactive ligands for visualization tachykinin receptors by autoradiography. The activity described here compounds as antagonists of substance P can be estimated using the standard assessment procedure (M. A. Cascieri et al., as reported in the Journal of Biological Chemistry, vol. 258, p. 5158, 1983). This method essentially involves determining the concentration of the individual compound required to reduce by 50% the number of labeled radioactive ligand substance P in the locations of its receptors in these isolated tissues of cows, whereby given the characteristic value of the IC50for each of the test compounds.

According to this method, the tissue of the cow's tail extract from the freezer, the temperature at which -70oC, and homogenized in 50 volumes (W/V) ice 50 mm Tris-cleaners containing hydrochloride buffer having a pH of 7.7 (Tris-trimethylamine, which predc after centrifugation again suspended in 50 volumes of Tris-buffer, again homogenized, and centrifuged again at 30,000 x G for 20 minutes the Precipitate then re-suspended in 40 volumes of ice in 50 mm Tris buffer (pH of 7.7) containing 2 mm calcium chloride, 2 mm magnesium chloride, 40 g/ml bacitracin (bacitracin), 4 μg/ml leupeptin (leupeptin), 2 μg of hemostasia and 20 g/ml bovine serum albumin. This stage completes the preparation of tissue preparations.

The procedure of linking radioligand then perform the following way, namely, by initiating the reaction by adding 100 ál of the test compound, brought to a concentration of 1 μm, by adding following this, 100 μl of the radioactive ligand, brought to a concentration of 0.5 mm, and then, finally, add 800 ál of the drug tissue, obtained as described above. The final volume is, thus, 1.0 ml, the reaction mixture was then stirred in a circular motion and incubated at room temperature (approximately 20 theoC) for 20 minutes the Contents of the test tubes are then filtered using the collector cells (cell harvester, and the filters glass fiber (Whatman GF/B), washed four times with 50 mm Tris buffer (pH of 7.7), with filters pre-soaked for two hours before the procedure is 50 calculated using standard statistical methods.

Antipsychotic activity of the compounds of the present invention as adjunct tools for regulation of various psychotic disorders determined mainly by studying their ability to inhibit induced by substance P or agonist-induced substance P, hypermotility in Guinea pigs. This study carried out by introducing first Guinea pigs of the control connection or the appropriate test connection, and then injecting Guinea pigs substance P or agonist substance P intracerebrally the introduction of the cannula, and measuring their individual locomotor response to the above stimuli.

Example 1. Salt of (2S, 3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2 - diphenylmethyl-1-azabicyclo [2.2.2]Octan-3-amine and methanesulfonic acid.

A. (2S, 3S)-2-(2-diphenylmethyl-1-azabicyclo[2.2.2]Octan-3-amine.

Hydronaut (2S, 3S)-N-(2-methoxyphenyl)methyl-1-azabicyclo[2.2.2] Octan-3-amine (4.12 g, 10 mmol) at room temperature in a mixture of methanol (MeOH) (40 ml) with 6N hydrochloric acid HCl (10 ml) using 20% palladium hydroxide-on-coal (0.2 g) under hydrogen pressure of 2.5 kg/cm2within 60 hours Reaktsionnoj">

B. salt of (2S, 3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2 - diphenylmethyl-1-azabicyclo[2.2.2]Octan-3-amine and methanesulfonic acid.

To a solution of 5-isopropyl-2-methoxybenzaldehyde (748 mg, 4.2 mmol) and (2S, 3S)-2-diphenylmethyl-1-azabicyclo[2.2.2] Octan-3-amine (4 mmol) in methylene chloride CH2Cl2(40 ml) is added parts of triacetoxyborohydride (933 mg, 4.4 mmol). The mixture is stirred until then, until there is no longer Amin. The solution is carefully neutralized chilled with ice, saturated solution of sodium bicarbonate (NaHCO3). The organic layer was washed with water, dried over magnesium sulfate (MgSO4), and concentrated to obtain the product (1,82 g). To a solution of the product in acetone add an equivalent amount of methanesulfonic acid. Then besieged mesilate salt harvested and dried in vacuum.

Compounds named in the titles of examples 2-15, get a procedure similar to the procedure in example 1.

Example 2. Salt of (2S, 3S)-N-(5-methyl-2-methoxyphenyl)methyl-2 - diphenylmethyl-1-azabicyclo[2.2.2]Octan-3-amine and methanesulfonic acid.

So pl. 240oC.

X (KBr) cm-1: 3410, 2980, 1640, 1500, 1455, 1200, 1060, 710.

1H NMR (CDCl3) : of 7.5 to 7.2 (10H, m), 7,10 (1H, m), 8,40 (1H, sh.C.), 6,63 (1H, d , J = 8 Hz), 6P> Example 3. Salt of (2S, 3S)-N-(5-ethyl-2-methoxyphenyl)methyl-2 - diphenylmethyl-1-azabicyclo[2.2.2]Octan-3-amine and methanesulfonic acid.

So pl. 151oC.

X (KBr) cm-1: 3420, 2970, 1640, 1510, 1460, 1195, 1060, 785.

1H NMR (CDCl3): 10,9 (1H, sh), 8,18 (1H, sh), the 7.85 - 7,15 (11N, m), 6,86 (1H, m), of 6.68 (1H, d, J = 8,8 Hz), to 5.57 (1H, sh), the 5.45 (1H, m), of 5.05 (1H, d, J = 13,2 Hz), 4,24-the 3.65 (5H, m), of 3.48 (3H, s), 3,50-to 3.35 (3H, m ), of 2.92 (1H, m), 2,61 (6N, S.), 2,8-2,2 (6N, m), of 2.54 (2H, m), 2,30 and 1.80 (2H, m), 1,21 (3H, m).

Example 4. Salt of (2S, 3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2 - diphenylmethyl-1-azabicyclo[2.2.2]Octan-3-amine and methanesulfonic acid.

So pl. 221oC.

X (KBr) cm-1: 3430, 2960, 1600, 1500, 1455, 1245, 1160, 1040, 710.

1H NMR (CDCl3) : to 8.40 (1H, sh), of 7.5 to 7.2 (10H, m), 7,06 (1H, m), to 6.67 (1H, d, J = 8,4 Hz), 6,56 (1H, sh.C.), 4,58 (1H, m), 4,24 (1H, m), 3,6-3,3 (5H, m), 3,53 (3H, s), 3,24 (1H, m), up 3.22 (1H, m), 2,78 (1H, sec., J = 7 Hz), 2,48 (4H, s), 2,42 (1H, m), and 2.27 (1H, m), 1,99 (2H, m), of 1.76 (1H, m), 1,20 (6N, D. D., J = 2,9 Hz, 7 Hz).

Example 5. Salt of (2S, 3S)-N-(5-fluoro-butyl-2-methoxyphenyl)methyl-diphenylmethyl-1-azabicyclo[2- .2.2]octane-3-amine and methanesulfonic acid.

So pl. 224oC.

X (KBr) cm-1: 3440, 2960, 1610, 1500, 1455, 1220, 1160, 1035, 755, 710, 560.

1H NMR (CDCl3) : to 8.41 (1H, sh), of 7.5 to 7.2 (10H, m), 7,00 (1H, m), to 6.67 (1H, WHOM (1H, m), 2.00 in to 1.60 (3H, m), of 1.52 (2H, m), of 1.18 (2H, m), of 0.82 (3H, m).

1. Derivatives of hinoklidina General formula I

< / BR>
where R1the methoxy group;

R2group selected from isopropyl, tert.butyl, methyl, ethyl and Deut. butyl,

or their pharmaceutically acceptable salts.

2. Connection on p. 1, selected from the group comprising (2S, 3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]Octan-3-amine, (2S, 3S)-N-(5-ethyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]Octan-3-amine, (2S, 3S)-N-(5-methyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2] Octan-3-amine, (2S, 3S)-N-(5-tert.butyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2] Octan-3-amine, (2S, 3S)-N-(5-Deut. butyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2] Octan-3-amine and pharmaceutically acceptable salt of these compounds.

3. Methanesulfonate (2S, 3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]Octan-3-amine under item 1.

4. Pharmaceutical composition having an antagonistic effect on substance P in a mammal, comprising as active ingredient an effective amount of a derivative of hinoklidina and a pharmaceutically acceptable carrier, characterized in that cachestate-additive salt.

5. The dihydrochloride (2S, 3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]Octan-3-amine under item 1.

 

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The invention relates to compounds of the formula

(I)

where R1represents hydrogen, lower alkyl, lower alkenyl, lower quinil, aryl lower alkyl, cycloalkyl lower alkyl, lower alkoxy lower alkyl, hydroxy lower alkyl, amino lower alkyl, mono - or di-lower alkyl, amino lower alkyl, formyl, lower alkylsulphonyl, amino lower alkylsulphonyl, lower alkoxycarbonyl, mono - or di-aryl-substituted lower alkyl, arylcarbamoyl lower alkyl, aryloxy lower alkyl, or lower alkylene

< / BR>
X represents O or S;

W represents hydrogen, halogen, hydroxy, lower alkoxy, aryl lower alkoxy, nitro, trifluoromethyl or

< / BR>
where R3represents hydrogen, lower alkyl or aryl lower alkyl, and R4represents lower alkyl or aryl lower alkyl; or alternatively the groupas a whole represents the

< / BR>
R5is hydrogen, lower alkyl, aryl or aryl lower alkyl; and

Z predepression

Eye ointment // 2082434
The invention relates to medicine, in particular to ophthalmology, and can be used in the treatment of traumatic keratitis, chemical burns, conjunctivitis, corneal, and especially when wound infection

The invention relates to new derivatives of diazepinone having valuable properties, in particular derivatives of diazepinone General formula (I)

< / BR>
where B is one of the divalent residues and) g)

< / BR>
and

X, l, m, n and R1R7have the following meanings:

X Gruppen or, if B denotes the divalent residue (a), a nitrogen atom,

l integer 1, 2 or 3,

m is an integer 1 or 2,

n is an integer of 1 to 4,

R1a hydrogen atom or an unbranched or branched alkyl with 1 to 6 carbon atoms,

R2a hydrogen atom, an unbranched or branched alkyl with 1 to 8 carbon atoms, unbranched or branched alkenyl with 4 to 6 carbon atoms, cycloalkyl with 3 to 7 carbon atoms, unsubstituted or substituted by alkyl with 1 to 3 carbon atoms, substituted, phenyl, unsubstituted or substituted by one or two methyl groups or methoxypropane or one halogen atom, or phenylalkyl with 1 to 3 carbon atoms in the alkyl part, unsubstituted or substituted at the fragrance stands or methoxy group or a halogen atom,

R3and R4the same or the difference is,

R5a hydrogen atom or a chlorine or methyl,

R6and R7the same or different and denote hydrogen atoms or alkali with 1 to 3 carbon atoms, and, in addition, R7may also indicate a halogen atom,

mixtures of their isomers or their individual isomers and their salts, mainly their physiologically tolerated acid additive salts, in particular with pharmacological action
The invention relates to medicine and veterinary medicine, namely to the new immune modulating drug on the basis of N-metrocable-9-acridone and physiologically active monosaccharides, various buildings

The invention relates to medicine, namely to the production of medicines on the basis of [N-methyl-N-/D-glyukopiranozil/ammonium-2-/acridin-9-one-10-Il/acetate] -cycloferon, and can be used for the treatment of acquired immunodeficiency syndromes (AIDS), including HIV-related

FIELD: medicine, phthisiology.

SUBSTANCE: one should lymphotropically introduce the mixture of 5.0 ml 0.25%-novocaine solution and 2.0 ml 1%-dioxidine solution or the mixture of 5.0 ml 0.25%-novocaine solution and 0.5 g cefazoline subcutaneously into jugular cavity and deeply behind xiphoid process, successively 1 point once daily, 5-7 injections/course. After injection the site of injection should be treated either with heparin ointment or ultrasound (1-3 MHz, PPM 0.2 W/sq. cm, for 2 min, through Vaseline oil) followed by evaluating roentgenological dynamics of the process 10-14 d later.

EFFECT: higher efficiency of differential diagnostics.

3 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, medicine, pharmacy.

SUBSTANCE: invention describes diazepane derivative of the general formula (I)

or its pharmaceutically acceptable salt wherein ring B means phenyl; ring A means pyridyl substituted with halogen atom optionally, or phenyl substituted optionally with lower alkyl, lower alkoxy-group or halogen atom; X1 represents -C(=O)-NR2- or -NR2-C(=O)- wherein R2 means hydrogen atom; X2 represents -C(=O)-NR3- or NR3-C(=O)- wherein R3 means hydrogen atom; R represents hydrogen atom or halogen atom; R1 means lower alkyl. Also, invention relates to a pharmaceutical composition and inhibitor of blood coagulation activated factor X that can be used for prophylaxis and treatment of patients suffering with thrombosis or embolism.

EFFECT: valuable medicinal properties of compound.

5 cl, 5 tbl, 6 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to a new pentacyclic compound derivative of taxane represented by the formula:

wherein R1 represents dimethylaminomethyl group or morpholinomethyl group; R2 represents halogen atom or alkoxy-group comprising from 1 to 6 carbon atoms, or its salt eliciting an antitumor effect, and to a medicine agent based on its. Invention provides preparing new derivatives of taxane eliciting the valuable biological effect.

EFFECT: valuable medicinal properties of compound.

13 cl, 1 dwg, 4 tbl, 16 ex

FIELD: organic chemistry, cardiology, pharmacy.

SUBSTANCE: invention describes compounds of the formula (I)

wherein R1, R2, R3 and Ra-Rh have values given in the description. Proposed compounds are useful in prophylaxis and treatment of arrhythmia, in particular, atrial and ventricular arrhythmia, Also, the invention relates to methods for preparing compounds of the formula (I) and intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

41 cl, 1 tbl, 8 ex

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