Ortho-substituted aniline derivative and antioxidant medicinal agent

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound or its salt of formula 1: , where A, E, D, R0, R1-R4 and a assume values given in the formula of invention. The invention also relates to an antioxidant medicinal agent.

EFFECT: effectiveness during treatment of ischemic diseases of organs, during treatment of diseases caused by oxidation cell disorders and when inhibiting disorders of the retina.

4 cl, 1 tbl, 6 ex

 

The technical field

The present invention relates to a new ortho-substituted aniline derivative and antioxidant drugs, in which this compound is used as the active ingredient.

The claimed priority under the patent application of Japan No. 2005-321612 dated November 4, 2005, the contents of which are incorporated here by reference.

The level of technology

In recent years it has become clear thatin vivoperechislenie lipids and related radical reactions have various adverse effects on a living organism as the result of damage to the membranes, cell damage and such. As a consequence, conduct various tests on the use of antioxidant drugs and substances that inhibit perechislenie lipids as potential drugs. However, despite the fact that the investigated many antioxidant medicines, all of them suffer from many problems, such as low activity or the presence of side effects, and they are not very satisfactory in terms of prospects for practical application.

Examples of compounds that exhibit antioxidant activity and have a structure similar to the structure of the compounds of the present invention include compounds represented below formula is:

[Formula 1]

where each radical R1-R4independently represents a hydrogen atom or

C1-C6alkyl group, and n represents an integer of 1 or 2. A typical compound is a compound represented by the formula below (see reference patent 1).

[Formula 2]

However, due to the fact that this compound shows a low concentration in the blood after injection and do not necessarily have satisfactory immigration characteristics, it does not provide adequate medical effect when used as a drug for oral administration.

[Patent document 1]

Description of international patent application No. 2004/092153.

Disclosure of invention

The applicants of the present invention assume that the reason for the poor efficiency of existing antioxidant drugs when administered orally is that drugs do not reach our planned destination, or lose their activity before reaching the planned destination. Thus, the aim of the present invention is the provision of antioxidant drugs, which demonstrates favorable migration characteristics in body is, in particular, easily passes through the blood-brain barrier or genitorurinary barrier even when administered orally, after the introduction provides a high concentration in the blood and satisfactory migration characteristics.

As a result of intensive research aimed at achieving the above objectives, the applicants of the present invention have focused their attention on the aminomethyl group in position 4 typical compounds disclosed in the reference patent 1, and found that if you enter the function group, for example an aromatic hydrocarbon group or heterocyclic group via a spacer of a particular type, then the compound obtained shows excellentin vivoantioxidant effect even after oral administration, and therefore, they were able to perform the present invention.

Thus, the first aspect of the present invention relates to compounds represented by formula (1)or its salt.

[Formula 3]

{In the formula (1), a is 1 or 2,

R0denotes unsubstituted or substituted by an amino group,

each of the radicals R1-R4independently denotes a hydrogen atom or alkyl group

E denotes unsubstituted or substituted alkylenes chain,

D represents a simple bond, oxygen atom is and, unsubstituted or substituted nitrogen atom, sulfur atom, sulfinyl group, sulfonyloxy group, carbonyl group, carbonylation or aminocarbonyl group, and

A denotes an unsubstituted or substituted aromatic hydrocarbon group, unsubstituted or substituted heterocyclic group, unsubstituted or substituted aracelio group or unsubstituted or substituted heteroalkyl group.}

The second aspect of the present invention relates to antioxidant medicines, which includes as an active ingredient, at least one substance selected from the group consisting of compounds represented by formula (1), and their salts.

The compound of the present invention represented by the above formula (1)or its salt shows an effective antioxidant in the treatment of ischemic disorders of organs, such as arteriosclerosis, myocardial infarction and infarction of the brain, and in the treatment of diseases caused by oxidative damage cells, such as kidney disease.

In addition, the compound or salt can also effectively inhibit retinal lesions caused by oxidation under the action of light, or the like. In addition, the antioxidant drug of the present invention can also be used as the inhibitor of oxidative lesions with minimal side effects, the lipoxygenase inhibitor, an inhibitor of 20-HETE synthase, medicines to treat kidney disease, cerebral-vascular disease or cardiovascular disease, and drugs for treatment of heart attack, brain and the like.

The best way of carrying out the invention

The following is a more detailed description of the present invention.

1) Compounds represented by the formula (1), and their salts

In the compound represented by the above formula (1), R0denotes unsubstituted or substituted by an amino group, and an unsubstituted amino group is preferred.

Specific examples of the substituents for R0include acyl groups such as formyl group, acetyl group or benzoline group; alkoxycarbonyl groups, such as methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, sec-butoxycarbonyl group, solutionline group or tert-butoxycarbonyl group; alkyl groups such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, sec-bucilina group, isobutylene group, tert-bucilina group, n-pencilina group or n-exilda group; aromatic the ski hydrocarbon group, such as phenyl group, 1-naftalina group, 2-naftalina group, 1-antanella group, 2-antanella group or 9-antanella group; and kalkilya groups such as benzyl group, 1-phenylethylene group, 2-phenylethylene group, 1-methylnaphthalene group, 2-methylnaphthalene group, 1-ethylnaphthalene group or 2-ethylnaphthalene group. Functional groups that are capable of dissociate or decompose atin vivometabolism, are preferred.

Each of the radicals R1-R4denotes a hydrogen atom or alkyl group, and an alkyl group is preferred.

Specific examples of the alkyl groups of R1-R4include the same groups as listed above as specific examples of alkyl groups which may be substituents for the amino group, R0and C1-C6alkyl groups are preferred.

E denotes unsubstituted or substituted alkylenes chain, preferably denotes unsubstituted alkylenes chain and preferably represents -(CH2)n- (where n is an integer from 1 to 6).

Specific examples of substituents in the composition alkalinous chain include the following: a hydroxyl group; Tolna group; halogen atoms such as fluorine atom, chlorine atom, bromine atom or iodine atom; C is anagraph; the nitro-group; formyl group; unsubstituted or substituted amino, for example amino group, methylaminopropyl, benzylamino, belinograph, dimethylaminopropyl, diethylaminopropyl or phenylethylamine; alkyl groups such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, sec-bucilina group, isobutylene group, tert-bucilina group, n-pencilina group or n-exilda group; alkeneamine group such as vinyl group or allyl group; alkyline group, for example etinilnoy group, 1-proponila group or propargyl group; alkoxygroup, such as a methoxy group ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, second-butoxypropan, isobutoxy or tert-butoxypropan; alkenylacyl, such as vinyloxy or alliancegroup; alkyloxy, such as atenololviagrawp or propargyloxy; alloctype, such as fenoxaprop; halogenoalkane group, for example chloromethylene group, permetrina group, brometalia group, dichloromethylene group, deformational group, dibromoethylene group, trichlorethylene group, triptorelin group, bromodifluoromethyl group, 1,1,1-triptorelin group, 1-chlorethylene group, 2-chloraniline group, 1-bromacil the Naya group or panafcortelone group; halogenlampe, such as formationtype, chlorethoxyfos, bromatologia, dipterocarp, dichloromethoxy, dibromochloro, tripterocarpa, trichlormethiazide, tribromomethane, triftoratsetata, pentaceratops or pendaftar-n-propoxylate; alkylthiomethyl group, for example petitiononline group, ethyldiethanolamine group, n-proportionably group, isopropylaminocarbonyl group, n-butyldiethanolamine group, isobutylthiazole group, sec-butyldiethanolamine group or tert-butyldiethanolamine group; alkylcarboxylic, such as methylcobalamine, ethylcarbodiimide, n-propylnitrosamine or isopropylcarbodiimide; alkoxycarbonylmethyl, such as methoxycarbonylamino, ethoxycarbonylmethyl, n-propoxycarbonyl or isopropoxycarbonyl; alkoxycarbonyl group, for example methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group or tert-butoxycarbonyl group; aromatic hydrocarbon groups such as phenyl group, 1-naftalina group or 2-naftalina group; unsaturated 5-membered heterocyclic GRU is dust, for example furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isooctanol-3-yl, isooctanol-4-yl, isooctanol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, 1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazole-2-yl, 1,2,3-triazole-4-yl, 1,2,4-triazole-3-yl or 1,2,4-triazole-5-yl; unsaturated 6-membered heterocyclic group such as pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl, 1,3,5-triazine-2-yl or 1,2,4-triazine-3-yl; a saturated heterocyclic group, for example tetrahydrofuran-2-yl, tetrahydrofuran-4-yl, piperidine-3-yl, pyrrolidin-2-yl, morpholinopropan or piperidino; allylthiourea, such as methylthiourea ethylthiourea or tert-butylthiourea; alkylsulfonyl group, for example methylsulfonyl group, ethylsulfonyl group or tert-butylsulfonyl group; alkanesulfonyl group, for example arylsulfonyl group; alkylsulfonyl group, for example propargylglycine group; and arylsulfonyl group, for example phenylsulfonyl group.

D represents a simple bond, oxygen atom, unsubstituted or substituted nitrogen atom, sulfur atom, sulfonylurea, sulfonyloxy group, carbonyl group, carbonylation or aminocarbonyl group.

Specific examples of the substituents at the nitrogen atom of the fragment D include the same groups that are listed in the parts list specific substituents for alkalinous chain E.

A denotes an unsubstituted or substituted aromatic hydrocarbon group, unsubstituted or substituted heterocyclic group, unsubstituted or substituted aracelio group or unsubstituted or substituted heteroalkyl group.

Specific examples of aromatic hydrocarbons include A same group, which are listed in the parts list specific substituents for alkalinous chain E.

There are no particular restrictions on the heterocyclic group A, provided that it has a cyclic structure at least one heteroatom such as oxygen atom, nitrogen atom or sulfur atom, and specific examples include unsaturated heterocyclic groups such as a furan-2-yl, furan-3-yl, thiophene-2-yl, thiophene-3-yl, pyrrol-2-yl, pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, the thiazole-2-yl, thiazol-4-yl, thiazol-5-yl, isooctanol-3-yl, isooctanol-4-yl, isooctanol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, pyrazole-3-yl, pyrazole-4-yl, pyrazole-5-yl, 1,3,4-oxadiazol-2-yl, 1,3,4-the thiadiazole-2-yl, 1,2,triazol-4-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-5-yl, 5-phenyl-5-triftoratsetilatsetonom-3-yl, 2-furfurylamine group, 3-thienylmethyl group, 1-methyl-3-personalily group, pyridine-2-yl, pyridin-3-yl, pyridine-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl, pyrimidine-2-yl, pyrimidine-4-yl, pyrimidine-5-yl, 1,3,5-triazine-2-yl or 1,2,4-triazine-3-yl; and saturated heterocyclic groups such as a tetrahydrofuran-2-yl, tetrahydrofuran-4-yl, piperidine-3-yl, pyrrolidin-2-yl, morpholinopropan or piperidino.

Specific examples aranceles group include A benzyl group and fenetylline group.

Specific examples heteroalkyl group include A 3-thienylmethyl group, 2-pyridylmethyl group, 3-pyridylmethyl group and 2-pyrimidinemethanol group.

Specific examples of substituents in the aromatic hydrocarbon group, heterocyclic group, aranceles group or heteroalkyl A group include the same groups that are listed in the parts list specific substituents for alkalinous chain E.

R5denotes a hydroxyl group, a halogen atom or an unsubstituted or substituted organic group.

Specific examples of the halogen atom, R5include fluorine atom, chlorine atom, bromine atom and iodine atom.

The organic group R5represents all the functionality of the groups, including atom(s) of carbon, and specific examples include the same groups that are listed in the parts list specific substituents for groups E, such as cyano, alkyl group, formyl group, amino group, alkeline group, alkyline group, alkoxygroup, alkenylacyl, alkyloxy, alloctype, alkylthiomethyl group, alkylcarboxylic, alkoxycarbonylmethyl, alkoxycarbonyl group, aromatic hydrocarbon group, heterocyclic group, allylthiourea, alkylsulfonyl group, alkanesulfonyl group, alkylsulfonyl group and arylsulfonyl group, and provided chemical assumptions, these groups can also enable the Deputy of the atom, which is the functional group. Specific examples of these substituents include the same groups that are listed in the list of specific substituents for alkalinous chain E.

If the parameter values from e to i, which is described below, is equal to 2 or more groups from a variety of R5groups may be the same or different. In addition, R5groups can also be linked together with the formation of a cyclic structure.

The nitrogen atoms in (A-1), (A-3), (A-4) and (A-5) can be attached directly to the group D, or, if not attached directly to the group D, it can be concerned with a hydrogen atom or a group R 5assuming that this relationship is chemically acceptable.

A preferably represents a group represented by the formula (A-1) to (A-5) in the formula of the invention, and specific examples include groups shown below.

2) the Way to obtain

The compound (1) can be obtained, for example, by using the following method.

[Formula 10]

(where, R0, R1-R4, E, D, A and A such as defined above).

In other words, the nitro-group of compounds represented by formula (2) (hereafter also referred to as "compound (2)"), or subjected to hydrogenation in the presence of a hydrogenation catalyst, or restore, using a reducing agent, with the formation of compounds of the present invention, represented by formula (1-1) (hereafter also referred to as "compound (1-1)").

There are no particular restrictions on the hydrogenation catalyst used in the hydrogenation reaction of the compound (2), and you can use the usual hydrogenation catalysts, such as palladium on charcoal, palladium hydroxide, platinum oxide and Raney Nickel.

This hydrogenation reaction can be carried out in a suitable solvent. There are no special restrictions p is used the solvent provided the solvent is inert in relation to the reaction mixture. Examples include alcohols such as methanol and ethanol; ethers, such as diethyl ether, tetrahydrofuran (hereafter also abbreviated as "THF") and 1,4-dioxane; hydrocarbons such as benzene, toluene, xylene and cyclohexane; amides such as N,N-dimethylformamide (hereafter also abbreviated as "DMF"); organic acids, for example formic acid and acetic acid; esters such as ethyl acetate; and mixed solvents containing two or more solvents.

Examples of ways in which use of the reducing agent with compound (2)include, for example, the way in which carry out the restoration, using hydrochloric acid and tin chloride (II) in an alcohol solvent such as methanol or ethanol; a way in which to carry out the restoration, using acetic acid and iron in a mixed solvent comprising water and a ketone, for example acetone or methyl ethyl ketone; and the way in which carry out the restoration, using ammonium chloride, ammonium acetate, ammonium formate or acetic acid and zinc in ethanol or a mixed solvent containing alcohol and water.

In any of the above methods, the reaction temperature is a value in the range from 0°C to the boiling temperature used dissolve the I.

Converting the amino group of the obtained compound (1-1) in group R0in the usual way, for example by alkylation of aniline, it is possible to obtain the compound (1) according to the present invention.

The intermediate product (2) this way you can get the typical interactions, as described below.

[Formula 11]

(where, R1-R4, E, D, A and A such as defined above).

In other words, the compound represented by formula (3), subjected to formirovanie under the action of the oxidizing agent, thus obtaining the compound (4).

More specifically, this interaction can be made by adding the base, including amine, such as triethylamine, pyridine or DBU, or inorganic base, for example sodium bicarbonate, sodium carbonate, potassium carbonate or sodium hydroxide at room temperature to a solution of compound (3) in alcohol, such as tert-butanol, then adding to the mixture a saturated hydrocarbon, e.g. n-hexane and water, also adding an oxidant such as potassium permanganate and boric acid, and then stirring the whole mixture at a temperature in the range from -20°C to +50°C and preferably from -10°C to +10°C.

In those cases, when D represents a simple bond, the compound (2) can be obtained, for example, by alkenylamine connection (4) using the Wittig reaction and then extending alkylene the eighth circuit, applying typical recovery.

In addition, in cases where D denotes an oxygen atom, unsubstituted or substituted nitrogen atom, sulfur atom, sulfinyl group, sulfonyloxy group or carbylamines, the compound (2) can be obtained by reaction of compound (4) with a reducing agent to obtain a hydroxyl group, the introduction of the leaving group, if necessary, and subsequent reaction of the combination or similar.

In addition, in cases where D denotes a carbonyl group or aminocarbonyl group, the compound (2) can be obtained by converting compound (4) to carboxylic acid using a typical oxidizer, conversion of the acid into galoyanized acid and subsequent carrying out of the typical reactions of a combination or similar.

Structure of the obtained compounds can be identified and confirm, through IR, NMR and MS spectral definition.

The compound (1) may include optical isomers or tautomers, but all of these isomeric forms are included within the scope of the present invention.

There are no particular restrictions on salt of compound (1) if it is the salt of the compound represented by formula (1), although pharmacologically acceptable salts are preferred. Examples of such salts include salts of inorganic acids, such as Alana acid, sulfuric acid, nitric acid and phosphoric acid; and salts of organic acids such as acetic acid, propionic acid, lactic acid, succinic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, nicotinic acid and galagluhova acid. These salts can easily be obtained using conventional methods of chemical synthesis.

3) Antioxidant drug

Antioxidant drug of the present invention includes as an active ingredient, at least one substance selected from the group consisting of compounds represented by the above formula (1) and their pharmacologically acceptable salts (hereafter referred to as "compound of the present invention").

The compound of the present invention demonstrate excellent antioxidant activity and preventing oxidative degeneration of low density lipoprotein (hereafter also abbreviated as "LDL"), able to inhibit the emergence and development of arteriosclerotic defeat, and, therefore, can be used as a drug for the treatment of arteriosclerosis. In addition, it is also suitable as a therapeutic drug for various diseases caused by oxidation, the key age state of dementia, heart disease, cancer, diabetes, digestive disorders, burns, eye disease and kidney disease. In addition, in the case of ischemic diseases such as cerebral stroke or myocardial infarction, reperfusion of ischemic foci generated various active oxygen atoms, which can exacerbate tissue damage through the destruction of cell membranes as a result of reactions perechisleniya lipids, but the connection of the present invention is capable of removing various types of active oxygen and plots of lipid peroxides due to its antioxidant activity and, therefore, can be used as a drug for the treatment of ischemic diseases, preventing tissue damage in ischemic lesions.

In addition, the compounds of the present invention also include compounds that have an inhibitory effect on lipoxygenase or inhibitory effect of 20-HETE synthase and, therefore, can be used to inhibit the conversion of arachidonic acid in hydroperoxidation acid (HPETE) by inhibiting the action of lipoxygenase, or to suppress the production of 20-HETE by inhibiting the action of 20-HETE synthase.

In addition, the compounds of the present invention also include compounds for which the inhibition of visual the statement of dopamine is minimal, reducing the likelihood of side effects in the treatment of Parkinson's disease and the like.

In addition, the compound of the present invention can also be used for the prevention and treatment of (a) diseases caused by oxidative lesions of the retina, (b) diabetes (c) high blood pressure, (d), arteriosclerosis, (e) anemia, (f) leukemia, (g) connective tissue diseases such as systemic lupus erythematosus and scleroderma, (h) vascular disorders, inflammation or degenerative lesions of the retina as a result of systemic diseases, including congenital metabolic disorders, such as disease, and Tay-Sachs or disease Vogt-Spielmeyer, (i) vascular disorders of the retina, such as retinopathy in premature infants, retinal vein occlusion, occlusion of retinal artery and periferic retina, (j) inflammation or degeneration of the retina in the detachment or external damage to the retina, (k) degenerative disorders of the retina during aging, such as age-related macular degeneration, and (l) of localized retinal diseases, such as congenital degenerative diseases of the retina, and this compound is particularly useful as a drug for such violations, as age-related macular degeneration, caused by photoinduced oxidative lesions.

For antioxidantes the medicinal product according to the present invention a therapeutically effective dose of a compound of the present invention varies depending on the individual and subject to the treatment status of the disease. Usually you can assign a therapeutically effective daily dose per kg body weight in the range from 0.14 to 14.3 mg/day of the compound represented by formula (1) or its pharmacologically acceptable salt, a preferred dose per kg of body weight is a value in the range from 0.7 to 10 mg/day, and particularly preferred dose per kg body weight ranges from 1.4 to 7.2 mg/day. For example, in the case of the introduction of man with a mass of 70 kg, the dosage range for the compounds represented by formula (1), or its pharmacologically acceptable salt is from 10 mg to 1.0 g per day, preferably from 50 to 700 mg per day and even more preferably from 100 to 500 mg per day, although you can use a dose outside this range depending on the subject to the treatment status of the disease.

Antioxidant drug of the present invention can be used in the form of a composition which, besides the compounds of the present invention, which operates as an active ingredient, may also include a conventional pharmaceutical carriers or excipients and other drugs or adjuvants, provided that they do not interact with other components. This composition can be in accordance with the method so that it contains from 1 to 99 wt.%. the active ingredient and from 99 to 1% wt. suitable pharmaceutical N. the bearers or fillers, and preferably contain from 5 to 75 wt.%. the active ingredient, and the rest is suitable pharmaceutical carriers or excipients.

Examples of fillers that can be used in antioxidant medicinal product according to the present invention include all known fillers, such as pharmaceutical mannitol, lactose, starch, gelatinising starch, magnesium stearate, sodium saccharin, talc, simple ester derivatives of cellulose, glucose, gelatin, sucrose, citrate and propylgallate. In addition, in the case of antioxidant drugs for oral administration, it may include diluents, for example lactose, sucrose and dicalcium phosphate, leavening agents, for example sodium, croscarmellose or its derivatives, a binder such as magnesium stearate and lubricants, for example starch, Arabic gum, polyvinylpyrrolidone, gelatin and simple ester derivatives of cellulose.

Antioxidant drug of the present invention can be introduced in the form of a pharmaceutical for the treatment of the above diseases using all variants of systems administration.

For example, the drug can be administered orally, through the nose, parenterally, locally, transdermal or rectal, and the drug may be in the form of solids, polute the Dogo substances, liofilizirovannogo powder or liquid, which take, for example, in the form of tablets, suppositories, pills, soft or hard capsules, medical powder, liquid drug, a drug for injection, suspensions, aerosols or product with a slow release of the active ingredient. Preferably choose a form that allows precise introduction of the necessary dose of a simple way of introduction.

These types of medicinal products can be obtained by using conventional methods, for example methods disclosed in Remington's Pharmaceutical Sciences, 18th edition, Mack publishing Publishing Company, Easton, Pennsylvania, 1990.

Preparations for injection may include aseptic aqueous or non-aqueous solvents, suspendresume agents or emulsifiers. Specific examples of aqueous solvents and thinners for suspensions include distilled water for injection and the solution of salt. Specific examples of nonaqueous solvents and thinners for suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and Polysorbate (trade mark). These compositions may also include other additives, such as agents regulation toychest, preservatives, moisturizing agents, emulsifiers, dispersing agents (e.g., lactose) and dissolving agents and agents that facilitate the solution of the Oia. These supplements can be obtained in the form of decontaminated solid composition by filtration through a filter that retains bacteria, and then dissolved in aseptic water or aseptic solvent for injection before use.

In those cases, when the antioxidant drug of the present invention is prepared in the form of a suppository, then use a medium that dissolves thein vivogradually,for example polyoxyethyleneglycol or polyethylene glycol (hereafter also abbreviated as "PEG"), or, more specifically, PEG1000 (96%) or PEG4000 (4%), and is dispersed in the carrier is from 0.5 to 50% wt. the compounds of formula (1) or its pharmacologically acceptable salt.

In those cases, when the antioxidant drug of the present invention is prepared in the form of liquid preparation, preferably used as a carrier salt solution, aqueous dextrose, glycerol, ethanol or the like, and the media, together with 0.5 to 50% wt. the compounds of formula (1) or its pharmacologically acceptable salt with any suitable adjuvant process with the aim of dissolution or dispersion with the formation of a solution or suspension.

The compound of the present invention is particularly suited for inhibition of photoinduced oxidative damage of the retina. As a system for the introduction of Lech the only means form input medicines and input dose you can use the same system for the introduction, forms and input dose, as described above for antioxidant drugs. In addition, you can include the same components of the drug, carriers, adjuvants and the like, as the materials described above for antioxidant medicines, you can add one or more fillers, disintegrating agents, binders or other inhibitors of oxidative damage of the retina, which do not interact with the active ingredient, can also include other components having different pharmaceutical effects. Examples of forms in which you can enter the drug, include the same dosage form as described above for antioxidant treatment, such as eye drops and eye ointments.

In cases where the medicinal product for inhibition of photoinduced oxidative lesions of the retina produced according to the present invention in the form of eye drops, then add to the typical main solvent is one or more compounds of the present invention, receiving an aqueous solution or suspension, and then bring the pH to a value in the range from 4 to 10 and preferably from 5 to 9. To ensure aseptic product eye capl is preferably subjected to processing for sterilization, this sterilization can be performed at any stage of the retrieval process.

The concentration of the compounds of the present invention in eye drops is usually from 0.001 to 3% (wt./about.) and preferably from 0.01 to 1% (wt./vol.), and enter the dose can be set in several drops from 1 to 4 times a day depending on various factors such as the severity of the symptoms and the patient's state of health. The above dose is only recommended, and you can also enter a dose in excess of the above range.

Eye drops may also include suitable amounts of various additives such as buffering agents, agents to adjust toychest, preservatives, pH regulators, thickeners, chelating agents, and agents that promote dissolution, provided that they do not interact with the compound of the present invention.

Examples of buffering agents include citrate buffers, minocycline buffers, acetate buffers and amino acids, whereas examples of agents adjust toychest include sugars, such as sorbitol, glucose and mannitol, polyhydric alcohols such as glycerin, polyethylene glycol and propylene glycol, and salts, such as sodium chloride. Examples of preservatives include esters of peroxybenzoate, such as methylparahydroxybenzoate and metilparagidroksibenzoat, benzyl alcohol, Venetia the initial alcohol and sorbic acid and its salts, while examples of the pH regulators include phosphoric acid and sodium hydroxide. Examples of thickeners include hydroxyethyl cellulose, hydroxypropylcellulose, methylcellulose, hypromellose, carboxymethyl cellulose and their salts, examples of chelating agents include edetate sodium, sodium citrate and condensed sodium phosphate, and examples of agents that promote dissolution include ethanol and castor oil, utverjdenie a polyoxyethylene.

In cases where the medicinal product for inhibition of photoinduced oxidative damage of the retina produced according to the present invention in the form of eye ointment, you can mix one or more compounds of the present invention with a typical basis for eye ointment, such as purified lanolin, white petrolatum, macrogol, plastibase (mineral oil containing dispersed polyethylene) or liquid paraffin, and to ensure aseptic product ointment preferably subjected to processing for sterilization.

The concentration of the compounds of the present invention is usually from 0.001 to 3% (wt./about.) and preferably from 0.01 to 1% (wt./vol.), and enter the dose can be taken 1 to 4 times a day depending on various factors such as the severity of the symptoms and the patient's state of health. The above dose is what I just recommended, and you can also enter a dose in excess of the above range.

So as a drug for the inhibition of photoinduced oxidative damage of the retina of the present invention demonstrate excellent antioxidant effect, it is effective, for example, for the prevention and treatment of degenerative disorders of the retina that accompany aging, such as age-related macular degeneration.

EXAMPLES

The following is a more detailed description of the present invention on the basis of a number of examples, although the scope of the present invention is in no way limited to the following examples.

(Example 1) Obtaining 2,2,6,7-tetramethyl-4-phenylethyl-5-aminocephalosporanic

Stage 1: getting 2,2,6,7-tetramethyl-5-retrodigitization-4-aldehyde

[Formula 12]

0.4 g of 60% sodium hydride is added to 50 ml of tert-butanol and the mixture is stirred for 10 min at room temperature. To this mixture add a solution of 0.80 g of 2,2,6,7-tetramethyl-4-nitro methyl-5-retrodigitization dissolved in 80 ml of tert-butanol, and the mixture was stirred for 20 min at room temperature.

To the resulting solution was added a solution containing 0,80 g of potassium permanganate and 0.63 g of boric acid dissolved in 1200 ml of n-hexane and 50 ml of the odes, and the entire solution is stirred for 10 min at room temperature. Then added to the reaction solution of sodium thiosulfate and continue mixing until until the reaction liquid becomes colorless. Thus obtained reaction liquid, extracted with n-hexane, washed with saturated salt solution and dried over anhydrous magnesium sulfate, and then remove the solvent by evaporation under reduced pressure, getting 0.71 g of the crude target compound.

Stage 2: getting 2,2,6,7-tetramethyl-4-styryl-5-retrodigitization

[Formula 13]

2.1 g determenirovana added to 38 ml of THF, add 30 mg of 60% sodium hydride, and the whole mixture is stirred for 30 min at room temperature. Then add 1,9 g 2,2,6,7-tetramethyl-5-retrodigitization-4-aldehyde, and the whole mixture is stirred over night at room temperature. Then pour the reaction liquid into ice water and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and then remove the solvent by evaporation under reduced pressure. The residue is purified by chromatography on silica gel (eluent: benzene/n-hexane=1/1 (volume ratio))to give 1.4 g of the target compound.

Stage 3: getting 2,2,6,7-tetramethyl-4-phenylethyl-5-aminoderivatives the

[Formula 14]

0,70 g 2,2,6,7-tetramethyl-4-styryl-5-retrodigitization dissolved in 20 ml of methanol, add 0.3 g of 10% palladium on coal and stirred the whole mixture for 3 h at 70°C under hydrogen pressure of 1 MPa. Then the reaction liquid is filtered through celite and concentrate the filtrate under reduced pressure, receiving 0.75 g of the target compound.

Refractive index: nD20,51,5467

1H NMR (CDC13that δ is ppm): 1,3 (s, 6H), 2,1 (s, 6H), 2,7-2,9 (m, 4H), 3,2 (Shir, 2H),a 7.1 to 7.3 (m, 5H).

(Example 2) to Obtain 4-(5-amino-2,2,6,7-tetramethylcyclobutane-4-ylmethyl)-1-[(4-imidazol-1-yl)phenylmethyl]piperazine

Stage 1: obtain 4-(5-nitro-2,2,6,7-tetramethylcyclobutane-4-ylmethyl)-1-[(4-imidazol-1-yl)phenylmethyl]piperazine

[Formula 15]

of 0.54 g of 1-[(4-imidazol-1-yl)phenylmethyl]piperazine and 0.50 g 2,2,6,7-tetramethyl-5-retrodigitization-4-aldehyde are dissolved in 17 ml of methylene chloride. To the resulting solution was added 0.25 ml of acetic acid and stirred the mixture for one hour at room temperature. Add to the reaction liquid of 0.85 g of triacetoxyborohydride sodium and stirred the whole mixture for one day at room temperature. Then the reaction liquid was poured into water, neutralized with an aqueous solution of sodium hydroxide and then ex is reginout chloroform. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate, then the solvent is evaporated under reduced pressure. The residue is purified by chromatography on silica gel (eluent: chloroform/ethyl acetate=9/1→ chloroform/methanol=20/1 (volume ratio))to give 0.51 g of the target compound.

Stage 2: obtain 4-(5-amino-2,2,6,7-tetramethylcyclobutane-4-ylmethyl)-1-[(4-imidazol-1-yl)phenylmethyl]piperazine

0.51 g of 4-(5-nitro-2,2,6,7-tetramethylcyclobutane-4-ylmethyl)-1-[(4-imidazol-1-yl)phenylmethyl]piperazine and 2.3 g of ammonium chloride is added to a mixed solvent containing 45 ml of ethanol and 12 ml of water, then add 3.5 g of powdered zinc and stirred the whole mixture for 30 min at room temperature. Upon completion of the interaction of the reaction liquid is filtered and removed solvent from the filtrate by evaporation under reduced pressure. To the thus obtained residue add chloroform, the resulting solution was washed sequentially with saturated aqueous sodium bicarbonate solution and saturated salt solution, and after drying over anhydrous magnesium sulfate the solution is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (eluent: chloroform/methanol=20/1 (volume ratio))to give 0.40 g of Clevo what about the connection.

Melting point: 187-190°C.

(Example 3) Obtain 5-(4-(5-amino-2,2,6,7-tetramethylcyclobutane-4-ylmethyl)AMINOPHENYL)pyrazole

Stage 1: obtain 5-(4-(5-nitro-2,2,6,7-tetramethylcyclobutane-4-ylmethyl)AMINOPHENYL)pyrazole

4,80 g of 5-(4-AMINOPHENYL)pyrazole and of 5.00 g 2,2,6,7-tetramethyl-5-retrodigitization-4-aldehyde are dissolved in 180 ml of methylene chloride. To the resulting solution was added to 21.4 ml of acetic acid and the whole mixture is refluxed for 15 hours. After cooling the reaction liquid to room temperature, add tetrahydrofuran to dissolve the insoluble substances, the resulting solution was sequentially washed with saturated aqueous sodium bicarbonate and saturated salt solution, and after drying over anhydrous magnesium sulfate the solvent is removed by evaporation under reduced pressure. The residue is dissolved in a mixed solvent containing 80 ml of methanol and 50 ml of tetrahydrofuran, add 3.04 from g tetrahydroborate sodium and the whole mixture is stirred for 4 hours at room temperature. Add to the resulting reaction liquid saturated salt solution and the mixture is extracted 3 times with chloroform. The extract is washed successively 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated salt solution and Polessky over anhydrous magnesium sulfate to remove the solvent by evaporation under reduced pressure. The residue is purified by chromatography on silica gel (eluent: chloroform/methanol=20/1 (volume ratio)), receiving of 5.92 g of target compound.

Stage 2: obtain 5-(4-(5-amino-2,2,6,7-tetramethylcyclobutane-4-ylmethyl)AMINOPHENYL)pyrazole

0.66 g of 5-(4-(5-nitro-2,2,6,7-tetramethylcyclobutane-4-ylmethyl)AMINOPHENYL)pyrazole was dissolved in 29 ml of acetic acid and gradually add 2.9 g of powder of zinc upon cooling of the solution in a bath with ice. At the end add the whole mixture is stirred for 15 min at room temperature. Upon completion of the interaction of the reaction liquid is filtered, and after washing the solids with methanol, the solvent is removed from the filtrate by evaporation under reduced pressure. Added to the thus obtained residue chloroform, the resulting solution was washed successively 1N aqueous sodium hydroxide solution and saturated salt solution, and after drying over anhydrous magnesium sulfate the solution is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (eluent: chloroform/methanol=20/1 (volume ratio)), receiving of 0.44 g of the target compound.

Melting point: 166-169°C.

(Example 4) to Obtain 5-(4-(5-amino-2,2,6,7-tetramethylcyclobutane-4-ylmethyl)-N-acetylaminophenol)pyrazole

Stage 1: the doctrine 5-(4-(5-nitro-2,2,6,7-tetramethylcyclobutane-4-ylmethyl)AMINOPHENYL)-1-(tetrahydropyran-2-yl)pyrazole

2,87 g of 5-(4-(5-nitro-2,2,6,7-tetramethylcyclobutane-4-ylmethyl)AMINOPHENYL)pyrazole and 0.06 g of hydrate pair-toluensulfonate acid was dissolved in 20 ml of tetrahydrofuran and the whole mixture is heated to 50°C. Then the reaction solution was added dropwise over 30 min a solution containing 0,92 g of 3,4-dihydro-2H-Piran, dissolved in 20 ml of tetrahydrofuran, and then the resulting mixture is stirred for a 19.5 hour at 55°C. during this period add additional samples of 3,4-dihydro-2H-Piran 2 ml after 5 hours and after 7.5 h, respectively. After cooling, the reaction liquid was washed with 19 ml of 3N ammonia water and then the organic layer is washed with water to pH 7. The organic layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue is purified by chromatography on silica gel (eluent: hexane/ethyl acetate=2/1 (volume ratio)), getting 3,10 g of target compound.

Stage 2: obtain 5-(4-(5-nitro-2,2,6,7-tetramethylcyclobutane-4-ylmethyl)-N-acetylaminophenol)-1-(tetrahydropyran-2-yl)pyrazole

of 0.90 g of 5-(4-(5-nitro-2,2,6,7-tetramethylcyclobutane-4-ylmethyl)AMINOPHENYL)-1-(tetrahydropyran-2-yl)pyrazole was dissolved in 5 ml of methylene chloride. To the resulting solution was added to 0.23 g of triethylamine and 0.18 g of acetylchloride and the whole mixture AC who're asked for 1.5 hour at room temperature. Then the reaction liquid is successively washed with saturated aqueous sodium bicarbonate and saturated salt solution, and after drying over anhydrous magnesium sulfate the solvent is removed by evaporation under reduced pressure. The residue is purified by chromatography on silica gel (eluent: chloroform/ethyl acetate=9/1 (volume ratio)), getting to 0.72 g of the target compound.

Stage 3: obtain 5-(4-(5-amino-2,2,6,7-tetramethylcyclobutane-4-ylmethyl)-N-acetylaminophenol)pyrazole

to 0.72 g of 5-(4-(5-nitro-2,2,6,7-tetramethylcyclobutane-4-ylmethyl)-N-acetylaminophenol)-1-(tetrahydropyran-2-yl)pyrazole was dissolved in 22 ml of methanol. To the resulting solution was added 11 ml of 6N hydrochloric acid and then the whole mixture is stirred for 2.5 hours at room temperature. The reaction liquid is neutralized with an aqueous solution of sodium hydroxide and then twice extracted with chloroform. The organic layer was washed with saturated salt solution, and after drying over anhydrous magnesium sulfate the solvent is removed by evaporation under reduced pressure. The residue is dissolved in 24 ml of acetic acid and gradually add 0,91 g powder zinc cooling solution in a bath with ice. At the end add the whole mixture is stirred for 15 min at room temperature. At the end of the interaction is the major reaction liquid is filtered, and after washing solids with chloroform, the solvent is removed from the filtrate by evaporation under reduced pressure. To the thus treated residue add chloroform, the resulting solution was successively washed with 1N aqueous sodium hydroxide solution and saturated salt solution, and after drying over anhydrous magnesium sulfate the solution is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (eluent: chloroform/methanol=20/1 (volume ratio))to give 0.15 g of the target compound.

Melting point: 196 to 199°C.

(Example 5) Obtain 5-(4-(5-amino-2,2,6,7-tetramethylcyclobutane-4-ylethoxy)phenyl)pyrazole

Stage 1: getting 2,2,6,7-tetramethyl-5-retrodigitization-2-ylmethylphosphonate

2,00 g 2,2,6,7-tetramethyl-4-hydroxymethyl-5-retrodigitization dissolved in 33 ml of toluene. To the resulting solution was added to 1.61 g of triethylamine and a solution containing 0.96 g of methanesulfonamide dissolved in 5 ml of toluene, and then the whole mixture is stirred for 4 hours at room temperature. Then the reaction liquid is filtered, the solid washed with toluene and removing the solvent by evaporation under reduced pressure, obtaining a 3.06 g of the target compound.

Stage 2: obtain 4'-(5-nitro-2,2,6,7-tetramethylcyclobutane-4-ylethoxy)of acetophenone

0.50 g of 4'-hydroxyacetophenone dissolved in 5 ml of N,N-DIMET formamide. The resulting solution was cooled to 0°C, added 0.16 g of 60% sodium hydride and the whole mixture is stirred for 30 min at 0°C. Then added to the reaction mixture solution containing 1,00 g 2,2,6,7-tetramethyl-5-retrodigitization-2-ylmethylphosphonate dissolved in 5 ml of N,N-dimethylformamide, and the whole mixture is stirred for 30 min at 0°C and then 7 hours at room temperature. Then the reaction liquid was poured into ice water and extracted three times with ether. The organic layer is washed three times with water and dried over anhydrous magnesium sulfate and then remove the solvent by evaporation under reduced pressure, obtaining of 1.00 g of the target compound.

Stage 3: obtain 5-(4-(5-nitro-2,2,6,7-tetramethylcyclobutane-4-ylethoxy)phenyl)pyrazole

[Formula 24]

to 1.00 g of 4'-(5-nitro-2,2,6,7-tetramethylcyclobutane-4-ylethoxy)of acetophenone are dissolved in 6 ml N,N-dimethylformamide. To the resulting solution was added 6 ml of dimethylacetal N,N-dimethylformamide and the whole mixture is heated at the boil under reflux for 14 hours. Upon completion of the interaction between the solvent is removed by evaporation under reduced pressure. The residue is dissolved in 12 ml of ethanol, add 0.20 g of hydrate pair-toluensulfonate acid and 1.6 ml of hydrazine hydrate is added, the entire mixture is heated at the boil with a reflux is m for 2.5 hours. Upon completion of the interaction between the solvent is removed by evaporation under reduced pressure. To the thus obtained residue add chloroform, the resulting solution was successively washed with 1N aqueous sodium hydroxide solution and saturated salt solution, and after drying over anhydrous magnesium sulfate the solvent is removed by evaporation under reduced pressure. The residue is purified by chromatography on silica gel (eluent: chloroform/ethyl acetate=4/1 (volume ratio))to give 0.95 g of the target compound.

Stage 4: obtain 5-(4-(5-amino-2,2,6,7-tetramethylcyclobutane-4-ylethoxy)phenyl)pyrazole

[Formula 25]

0.95 g of 5-(4-(5-nitro-2,2,6,7-tetramethylcyclobutane-4-ylethoxy)phenyl)pyrazole was dissolved in 41 ml of acetic acid and gradually add 1,58 g powder zinc cooling solution in a bath with ice. At the end add the whole mixture is stirred for 30 min at room temperature. Upon completion of the interaction of the reaction liquid is filtered, and after washing the solids chloroform is removed from the filtrate the solvent by evaporation under reduced pressure. To the thus obtained residue add chloroform, the resulting solution was washed successively 1N aqueous sodium hydroxide solution and saturated salt solution and after su the key over anhydrous magnesium sulfate the solution is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (eluent: chloroform/methanol=20/1 (volume ratio)) and remove the solvent by evaporation under reduced pressure. Add to the residue 1N hydrochloric acid, the mixture is washed 3 times with chloroform, is added to the aqueous phase of 1N sodium hydroxide and the product extracted with chloroform and washed with a saturated solution of salt. The organic phase is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, obtaining of 0.30 g of the target compound.

Melting point: 131-135°C.

(Example 6) to Obtain 1-(1-(5-amino-2,2,6,7-tetramethylcyclobutane-4-ylmethyl)piperidine-4-yl)-3-phenylpyrazole

Stage 1: obtain 1-tert-butoxycarbonylamino-4-ylmethanone

5,42 g of 1-tert-butoxycarbonyl-4-hydroxypiperidine dissolved in 54 ml of toluene. To the resulting solution was added 5,44 g of triethylamine and 3,24 g methanesulfonanilide and the whole mixture is stirred for one hour at room temperature. Then the reaction liquid is filtered, and after washing the solids with toluene, the solvent is removed from the filtrate by evaporation under reduced pressure, obtaining the rate of 7.54 g of target compound.

Stage 2: obtain 1-(1-tert-butoxycarbonylamino-4-yl)-3-phenylpyrazole

of 1.57 g phenylpyrazole dissolved in 11 ml of N,N-dimethylformamide. To the resulting solution was added 0.50 g of 60% sodium hydride and the whole mixture is stirred for 1.5 hours at room temperature. To this mixture is added a solution containing 2,90 g of 1-tert-butoxycarbonylamino-4-ylmethanone dissolved in 2 ml N,N-dimethylformamide, and the whole mixture is stirred for two hours at 50°C, one hour at 70°C and then for 3.5 hours at 100°C. Then the reaction liquid was poured into water and extracted twice with ether. The organic layer is washed three times with water and dried over anhydrous magnesium sulfate and then remove the solvent by evaporation under reduced pressure. The residue is purified by chromatography on silica gel (eluent: hexane/ethyl acetate=4/1 (volume ratio))to give 1.54 g of the target compound.

Stage 3: obtain 1-(piperidine-4-yl)-3-phenylpyrazole

To 1.54 g of 1-(1-tert-butoxycarbonylamino-4-yl)-3-phenylpyrazole add 15 ml of 35% hydrochloric acid and then the whole mixture is stirred for 9 h at room temperature. Upon completion of the interaction add aqueous sodium hydroxide solution to neutralize the reaction liquid and three times extracted with a mixed solvent mixture consisting of chloroform and methanol. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and then remove the solvent, liparian who eat under reduced pressure, getting 1,09 g of target compound.

Stage 4: obtain 1-(1-(5-nitro-2,2,6,7-tetramethylcyclobutane-4-ylmethyl)piperidine-4-yl)-3-phenylpyrazole

0,92 g 2,2,6,7-tetramethyl-5-retrodigitization-2-ylmethylphosphonate and of 0.58 g of 1-(piperidine-4-yl)-3-phenylpyrazole dissolved in 9 ml of acetonitrile. To the resulting solution was added to 0.30 g of sodium carbonate and then the whole mixture is refluxed under heating for 13 hours. After the interaction, the solvent is removed by evaporation under reduced pressure, add chloroform, the resulting solution was sequentially washed with water and saturated salt solution, then dried over anhydrous magnesium sulfate and then remove the solvent by evaporation under reduced pressure. The residue is purified by chromatography on silica gel (eluent: hexane/ethyl acetate=4/1 (volume ratio)), getting to 1.00 g of the target compound.

Stage 5: obtain 1-(1-(5-amino-2,2,6,7-tetramethylcyclobutane-4-ylmethyl)piperidine-4-yl)-3-phenylpyrazole

to 1.00 g of 1-(1-(5-nitro-2,2,6,7-tetramethylcyclobutane-4-ylmethyl)piperidine-4-yl)-3-phenylpyrazole dissolved in 37 ml of acetic acid and gradually add 1.42 g of powder of zinc upon cooling of the solution in a bath with ice. At the end add the whole mixture is stirred for 30 mi is at room temperature. Upon completion of the interaction of the reaction liquid is filtered, and after washing the solids with chloroform, the solvent is removed from the filtrate by evaporation under reduced pressure. To the obtained residue is added chloroform, the resulting solution was washed successively 1N aqueous sodium hydroxide solution and saturated salt solution, and after drying over anhydrous magnesium sulfate the solution is concentrated under reduced pressure. The residue is purified by chromatography on silica gel (eluent: chloroform/ethyl acetate=3/2 (volume ratio))to give 0.65 g of the target compound.

Melting point: 134-136°C.

Examples of the compound (1)obtained as described above are shown below in table 1.

For those compounds for which the column entitled "physical constants", includes the expression and NMR", the table below shows the NMR data.

In addition, the expression "nD20,81,5852" means that the refractive index at a temperature of 20.8°C is equal to 1,5852 (it is also used for similar expressions).

Used in the table of abbreviations represent the following groups :

Me: methyl group, Et: ethyl group, iPr: isopropyl group, nBu: normal bucilina group, tBu: tertiary bucilina group, Ph: phenyl group, Ac: acetyl group and Bn: benzyl group.

That is person 1

1H-NMR (CDCl3, δ ppm)

Compound 16: to 1.5 (s, 6H), 1,6-1,9 (m, 4H), of 2.05 (m, 2H), 2,1 (s, 3H), 2,2 (s, 3H), 2,5 (m, 1H), 2,9 (s, 2H), 3.0 (d, 2H), and 3.5 (s, 2H), and 6.5 (d, 1H), and 7.3 (d, 2H), and 7.6 (d, 1H), 7.7 (d, 2H).

Compound 25: 1,5 (m, 8H), 2,1 (s, 3H), 2,2 (s, 3H), 2,5 (width, 2H), and 2.7 (m, 2H), 3.0 a (s, 2H), 3,2 (m, 2H), and 3.5 (s, 2H), 6,1 (m, 1H), 6,5 (m, 1H), 7.5 (d, 2H), 7,65 (d, 2H), of 7.75 (d, 1H), 7,9 (d, 1H), and 8.8 (s, 1H).

Compound 73: 1,4 (s, 6H), 2,0-2,1 (m, 2H), 2,09 (s, 3H), 2.13 and (s, 3H), and 2.6 (t, 2H), 2,9 (s, 2H), 3,1 (width, 2H), and 3.7 (s, 2H), 4,2 (t, 2H), and 6.5 (d, 1H), 7,25 (d, 1H), 7,22-7,30 (m, 1H), 7,35-7,41 (m, 2H), and 7.8 (d, 2H).

Compound 83: 1,3 (s, 6H), 2,1 (s, 6H), 2,7-2,9 (m, 4H), 3,2 (width, 2H), a 7.1 to 7.3 (m, 5H).

Compound 86: 1,4 (s, 6H), 1,76 is 1.86 (m, 2H), 2.06 to (s, 3H), 2,12 (s, 3H), 2,63 of 2.68 (m, 4H), 2,9 (s, 2H), and 3.7 (s, 2H), 7,13-7,21 (m, 3H), 7,28 (m, 2H).

Compound 87: 1,4 (s, 6H), 1,49-of 1.56 (m, 6H), was 2.05 (s, 3H), 2,12 (s, 3H), 2,4 (width, 4H), 2,9 (s, 2H), 3,3 (s, 2H), 4,4 (broad, 2H).

{Obtaining a medicinal product}

Pharmaceutical preparation containing a compound of the present invention, is prepared using the following method.

Example 1 drug: getting medicines for oral administration (tablets 10 mg active ingredient):

the compound of the present invention: 10 mg;

lacto is a: 81,4 mg;

corn starch: 20 mg;

hydroxypropylcellulose: 4 mg;

calcium carboxymethylcellulose: 4 mg;

magnesium stearate: 0,6 mg

Total: 120 mg

To compile the above composition 50 g of compound of the present invention, 407 g of lactose and 100 g of corn starch are homogeneously mixed, using the device for ink-jet irrigation (manufactured by Okawara Corporation). Then sprayed over the mixture of 200 g of a 10% aqueous solution of hydroxypropylcellulose, receiving granules. After drying, the granules pass through a sieve of 20 mesh, add 20 g of carboxymethylcellulose calcium and 3 g of magnesium stearate and use the machine for making tablets (manufactured by Hata Iron Works Co., Ltd.) with pestle 7 mm × 8,4R and get a tablet weight of 120 mg per pill.

(Test to assessin vitroinhibition of perechisleniya lipids)

Assessmentin vitroinhibition of perechisleniya lipid compound of the present invention is conducted by way opened Malvy and others (Malvy, C., and others, Biochemical and Biophysical Research Communications, 1980, vol.95, pp.734-737).

As the body uses retina isolated from the eyeballs of pigs and then stored at -80°C. During use add 5-fold excess of the salt solution with phosphate buffer (pH 7,4) and the mixture is homogenized using micropolarization (PHYSCOTRON, NITI-ON).

To this homogenate of porcine retinal add 0,5M KCl, the compound of the present invention, 500 μm cysteine and 5 μm FeSO4and next incubated the mixture for 30 min at 37°C.

Define malonic dialdehyde generated during the decomposition of lipid peroxide, applying method using thiobarbituric acid. On the basis of measured values determine the concentration of the compound of the present invention, required for 50% inhibition (hereafter also denoted "IC50").

The results are shown in the table below.

It is evident that the compound of the present invention showsin vitroinhibition of perechisleniya lipids.

Table 2
Connection # In vitroinhibition of perechisleniya lipids (concentration 50%
inhibition IC50: mkm)
10,36
70,37
160,34
260,27
270,29
280,30
29 0,36
300,27
310,30
320,28
390,31
400,33
430,30
470,31
480,27
490,26
570,33
590,30
600,32
610,28
620,33
630,30
640,30
650,31
660,35
680,30
690,31
700,25
730,33
740,29
830,26
840,25
850,33
860,31
R-10,30

(Test to assess distribution in the tissue)

Properties of the distribution in the tissue of the compounds of the present invention evaluated by measuringex vivoinhibition of perechisleniya lipids.

The compound of the present invention dissolved in DMSO (final concentration: 20%) and then dissolved or suspended in salt solution with 0,1N hydrochloric acid or dry 1% polyethylene castor oil (NIKOL HCO-60, manufacturing, Nikko Chemicals Co., Ltd.).

This solution was administered orally at the dose of 30 mg/kg each animal in a group of three male SD rats (Japan SLC, age 6 weeks), which were not fed within 24 hours, or in a group of three male SD rats (Japan SLC, age 6 weeks), which were not deprived of food. One hour after injection and after anesthesia remove the brain and eyeballs. Using the method disclosed above in the section relating to "esto to assess in vitroinhibition of perechisleniya lipids", homogenize the brain and retina isolated from the eyeballs, and determine the amount of lipid peroxides in each tissue homogenate.

The degree of inhibition for the compounds of the present invention is determined in each tissue sample based on the number of lipid peroxides generated in the control group (20% DMSO-salt solution with 0,1N hydrochloric acid/utverjdenie 1% polyethylene castor oil) and in the group of animals who enter the compound of the present invention. The results are shown in the table below. From the following table it is evident that the compound of the present invention shows a high degree distribution in the tissue of the retina and brain.

Table 3
Connection
No.
Ex vivoinhibition of perechisleniya lipids. Quantity for 50% inhibition
(ID50: mg/kg)
Ex vivoinhibition of perechisleniya lipids. The degree of inhibition (%)
Retin-aThe brain
2960 (with feeding the) -
4024 (breastfeeding)-
8367 (with feeding)96 (fasting)
R-172 (breastfeeding)-

(Test to assess absorption after oral administration)

The absorbance of the compounds of the present invention after oral administration evaluated in rats.

The compound of the present invention dissolved in DMSO (final concentration: 20%) and then dissolved or suspended in salt solution with 0,1N hydrochloric acid or dry 1% polyethylene castor oil (NIKOL HCO-60, manufacturing, Nikko Chemicals Co., Ltd.).

This solution is administered orally at a dose of 30 mg/kg animals in a group of three male SD rats (Japan SLC, age 6 weeks). One hour after injection and after anesthesia away the blood from the abdominal Vena cava in a plastic test tube for blood collection, containing the agent to separate the serum. A blood sample is left to stand for about one hour and after coagulation receive the serum, making separation by centrifugation at 3000 rpm./min for 10 min To 0.3 ml serum sample add 0.9 ml of acetonitrile, after mixing, the mixture C is stripperwhat for 10 min at 12000 rpm./min, and the resulting phase supernatant filtered (chromatodisc 13P). Using high-performance liquid chromatography (HPLC) under the following conditions to determine the number of compounds of the present invention, which remains in the filtered solution. The filtered solution for HPLC analysis stored at -20°C until determination.

The filtered solution for HPLC, as described in the previous paragraph, determine, using the following typical conditions:

HPLC: HPLC system from JASCO Corporation;

column: Inertsil ODS-3 (manufactured by GL Sciences Inc.);

mobile phase: acetonitrile/10 mm phosphate buffer pH 6,8=70/30;

flow rate: 1 ml/min;

wavelength measurement: 254 nm.

To calculate the concentration in the blood within one hour after oral administration to rats use pre-obtained calibration curve for the compound of the present invention. The results are shown in the table below. From the following table it is evident that the compound of the present invention demonstrates a high level of absorption by oral administration.

Table 4
Connection # Test to assess absorption after oral administration:
the serum concentration (µm)
292,4
R-1Below the detection limit (

In each of these tests as the control connection is used (R-1) of the following formula, disclosed in the pamphlet of international patent publication No. 2004/092153.

Industrial applicability

The compound of the present invention represented by the above formula (1)or its salt demonstrates effective antioxidant activity in the treatment of ischemic disorders of organs, such as arteriosclerosis, myocardial infarction and infarction of the brain, and in the treatment of diseases caused by oxidative damage cells, such as kidney disease.

Thus, this compound or salt can effectively inhibit retinal lesions caused by oxidation under the action of light, or the like, giving the possibility of obtaining excellent antioxidant medicines containing ortho-substituted aniline derivative of the present invention. In addition, the antioxidant drug of the present invention can also be used as an inhibitor of oxidative lesions with minimal side effects, lipoxygenase inhibitor, inhibitor HETE synthase, medicines to treat kidney disease, C is rapalino-vascular disease or cardiovascular disease and drugs for the treatment of heart attack, brain and the like.

1. The compound represented by formula (1)or its salt:

{where in the formula (1):
and is 1 or 2,
R0represents the unsubstituted amino group,
each of the radicals R1-R4independently represents an alkyl group,
E represents an unsubstituted or substituted alkylenes chain,
D represents a simple bond, oxygen atom, or unsubstituted or substituted nitrogen atom, and
Rather it represents a benzyl group or a group represented by one of the following formulas:


(where in the above formulas (a-1), (a-2), (a-4) and (A-5):
R5represents a hydroxyl group, a halogen atom, unsubstituted or substituted phenyl group, unsubstituted or substituted benzyl group, unsubstituted or substituted imidazol-1-ilen group, unsubstituted or substituted imidazol-2-ilen group, unsubstituted or substituted pyrazole-1-ilen group, unsubstituted or substituted pyrazole-3-ilen group, unsubstituted or substituted indole-3-ilen group or unsubstituted or substituted benzisoxazol-3-ilen group, and when e is 2 or 3, or if f, h or i is equal to 2, then group R5may be identical or different, or can be joined together to form a cyclic structure is at,
b is 1 or 2,
e is an integer from 0 to 3,
f is an integer from 0 to 2,
h is an integer from 0 to 2,
i is an integer from 0 to 2,
X and Y each independently represents a carbon atom or a nitrogen atom, provided that X and Y both are not carbon atoms at the same time,
the dashed line in the formula (a-1) represents a simple bond or a double bond when X represents a carbon atom, and the two dashed lines cannot signify a double bond; or a represents a simple bond, if X denotes a nitrogen atom, and
* indicates the location of the connection)}.

2. Antioxidant drug containing as an active ingredient, at least one substance selected from the group including compounds represented by formula (1), and their salts:

{where in the formula (1):
and is 1 or 2,
R0represents the unsubstituted amino group,
each of the radicals R1-R4independently represents an alkyl group,
E represents an unsubstituted or substituted alkylenes chain,
D represents a simple bond, oxygen atom, or unsubstituted or substituted nitrogen atom, and
Rather it represents a benzyl group or a group represented by one of the following formulas:


(where in the above formulas (a-1), (a-2), (a-4) and (A-5):
R5represents a hydroxyl group, a halogen atom, unsubstituted or substituted phenyl group, unsubstituted or substituted benzyl group, unsubstituted or substituted imidazol-1-ilen group, unsubstituted or substituted imidazol-2-ilen group, unsubstituted or substituted pyrazole-1-ilen group, unsubstituted or substituted pyrazole-3-ilen group, unsubstituted or substituted indole-3-ilen group or unsubstituted or substituted benzisoxazol-3-ilen group, and when e is 2 or 3, or if f, h or i is equal to 2, then group R5may be identical or different, or can be joined together to form a cyclic structure,
b is 1 or 2,
e is an integer from 0 to 3,
f is an integer from 0 to 2,
h is an integer from 0 to 2,
i is an integer from 0 to 2,
X and Y each independently represents a carbon atom or a nitrogen atom, provided that X and Y both are not carbon atoms at the same time,
the dashed line in the formula (a-1) represents a simple bond or a double bond when X represents a carbon atom, and each dotted line may not indicate a double bond at the same time; or is prostokvasha, if X denotes a nitrogen atom, and
* indicates the location of the connection)}.

3. Antioxidant drug according to claim 2, which is a therapeutic drug for the treatment of kidney disease, therapeutic drug for the treatment of cerebral-vascular diseases, therapeutic drug for the treatment of cardiovascular diseases, therapeutic drug for treatment of heart attack, brain or inhibitor of oxidative damage of the retina.

4. Antioxidant drug according to claim 3, where the specified inhibitor of oxidative damage of the retina is a therapeutic drug for treatment of age-related macular degeneration or therapeutic drug for the treatment of diabetic retinopathy.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: described is a compound selected from a group consisting of formula II formula III and formula IV , or its salt or ester, where G1 is selected from a group which includes - (CR1R2)n-, n equals 0 or 1; R1 and R2 are independently selected from a group which includes hydrogen; X1, X2 and X3 are independently selected from a group consisting of hydrogen, optionally substituted lower alkyl, halogen, optionally substituted lower alkoxy, G2 is a heterocycloalkyl linker optionally substituted with X4 and X5, where the heterocycloalkyl linker is selected from a group consisting of piperazinyl, 3,6-dihydro-2N-pyridinyl, [1,4]diazepanyl, 3,9-diazabicyclo[3,3,1]nonyl; X4 and X5 are independently selected from a group consisting of hydrogen and optionally substituted lower alkyl; CO2R; R is selected from a group consisting of optionally substituted lower alkyl and hydrogen; G3 is a bond; G4 is selected from a group consisting of hydrogen, aryl, selected from phenyl which is optionally substituted with a lower alkyl, halogen, lower haloalkyl or lower haloalkoxy; heteroaryl selected from pyridinyl which is optionally substituted with a halogen or lower haloalkyl; and optionally substituted cycloheteroalkyl selected from 1,3-benzodioxolyl. Described also are specific compounds and a pharmaceutical composition.

EFFECT: disclosed compounds are used as modulators of receptors activated by a peroxisomal proliferator.

5 cl, 2 tbl, 117 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 2,4-cis-8-anti-trialkyl-3-thia-1,5-diazabicyclo[3.2.1]octanes with general formula: The method involves reacting aliphatic aldehyde (acetic, propionic, butyric, valerianic, caproic) saturated with hydrogen sulphide with 1,2-diaminoethane in molar ratio diamine:aldehyde:hydrogen sulphide equal to 1:3:2, at 0°C for 3 hours. 2,4-cis-8-anti-trialkyl-3-thia-1,5-diazabicyclo[3.2.1]octanes can be used as selective sorbents and extraction agents of precious metals, as antibacterial, antiviral, fungicidal and acaricidal agents.

EFFECT: stereoselective synthesis of one conformationally pure 2,4-cis-8-anti-trialkyl-3-thia-1,5-diazabicyclo[3,2,1]octane isomer; the method is also distinguished by simplicity of carrying experiments and availability of initial reagents.

1 cl, 1 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: there described are diazabicyclic aryl derivatives of general formula I , their enantiomers or any mixture of those enantiomers, or their pharmaceutically acceptable salts, where radical values A, L, B and n are given in the description, and pharmaceutical composition containing the above diazabicyclic aryl derivatives.

EFFECT: new compounds represent cholinergic ligands of nicotinic receptors of acetylcholine and modulators of receptors and carrying agents of monoamines, and can be used for treatment of diseases and illnesses related to cholinergic system of central nervous system and periphery nervous system, which are related to activity of muscles, endocrine diseases, inflammatory diseases, and neurodegenerative diseases.

12 cl, 2 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: there are described new diazabicyclic aryl derivatives of general formula (I), where A', A", L and B, n possess the values as specified in the description which are cholinergic ligands to nicotinic acetylcholine receptors, as well as a based pharmaceutical composition. Owing to their pharmacological profile, the compound according to the invention, can be effective in treating such various diseases or disorders, as those associated with the cholinergic system of central nervous system (CNS), peripheral nervous system (PNS), as those associated with plain muscle contraction, endocrine diseases or disorders, neurodegenerative diseases or disorders, diseases or disorders involving inflammation, pain and abstinence symptoms caused by termination of abusing the chemical substances.

EFFECT: effective with regard to various diseases.

16 cl, 3 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to quinobenzoxazin analogues with general formula (1) where V represents H, halo-, or NR1R2; NH2, or NR1-(CR12)n-NR3R4; A represents H, fluoro-, or NR12; Z represents O, S, NR1 or CH2; U represents NR1R2; X represents NR1R2 or halo-; n=1-6; where in NR1R2, R1 and R2 can form 5-7-member heterocyclic ring which is optionally substituted and has 1-2 heteroatoms, selected from group consisting of N, O and S; R1 represents H or C1-6alkyl; R2 represents C1-10alkyl optionally including one or more non-adjacent heteroatoms N or O and is optionally substituted with if necessary substituted 3-6-member carbocyclic or 5-14-member heterocyclic ring; or R2 is 5-14-member heterocyclic ring, which has 1-2 heteroatoms, selected from group consisting of N, O or S, 6-member aryl or 5-7member heteroaryl ring, which contains 1-3 heteroatoms, selected from group consisting of N, O and S, each of which can be, if necessary, substituted; R3 represents H or C1-6alkyl; R4 represents H, C1-6alkyl, optionally substituted with 3-6 carbocyclic or 5-14-member heterocyclic ring, or 6-member aryl, R4 and R3, if necessary, can form optionally 5-7-member substituted heterocyclic ring, which contains 1-2 heteroatoms selected from N and O; W represents substituent, such as described in i.1 of invention formula, where Q, Q1, Q2, and Q3 represents independently CH or N; Y represents independently O or CH; R5 represents substituent in any position of closed ring in form of H or OR2; on condition that U is not morpholinyl or 2,4-difluoroaniline, when X represents F or pyrrolidinyl, A is F, Z represents O, and W represents phenylene; each obligatorily substituted fragment being substituted with one or more halogen, C1-6-alkoxy, amino, carbamate, C1-10alkyl, C2-10alkenyl, each of which is optionally substituted with halogen, =O, 6-member aryl or one or more heteroatom, selected from N and O; 6-member aryl, 3-6-member carbocyclic ring or 5-7-member heterocyclic ring containing 1-2 heteroatoms, selected from group, consisting of N and O; or its pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition based on formula (1) compound and to method of treatment of proliferative cell diseases using formula (1) compounds.

EFFECT: obtaining novel quinobenzoxazin analogues possessing useful biological properties.

48 cl, 3 tbl, 50 ex

FIELD: chemistry.

SUBSTANCE: invention claims compound of the general formula (I) , where R is hydrogen atom or vinyl group; n is 1, X is a group of the formula CH or nitrogen atom, R1 is either phenyl or naphthyl group, or cyclohexyl group, or heteroaryl group, R2 is either hydrogen atom or one or more substitutes selected out of halogen atoms and trifluoromethyl, alkyl, alkoxyl phenyloxy, hydroxyl groups or group of the general formula -NR4R5, SO2NR4R5, or group of the formula -OCF2O-, each of R4 and R5 groups is hydrogen atom or alkyl group; and method of obtaining compound of the general formula (I), medicine, pharmaceutical composition. Compounds display special effect as specific inhibitors of glycine GlyT1 and/or GlyT2 transmitters and thus are applied in treatment of various diseases.

EFFECT: obtaining compounds with high specific inhibition effect.

13 cl, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: derivatives of 7-aryl-3,9-diazabicyclo(3.3.1)non-6-ene of general formula I , general formula I, where X and W or both represent -CH-, or one of them represents -CH-, and the other -N. V represents -A-(CH2)s-, -(CH2)s-A-, -A-(CH2)v-B- or -CH2-A-(CH2)3-B-; A and B represent-O- U -phenyl, possibly 1-3 substituted with halogen, alkyl, alkoxy, CF3, CF3O - or alkylcarbonyl, or pyridyl, monosubstituted with cyanogroup. T represents -CONR1-, -(CH2)pOCO- or -(CH2)pN(R1)CO- Q-alkylene; M - hydrogen, phenyl, possibly substituted, benzo[1,3]dioxol, possibly substituted, or pyridyl; L represents -R3, -COR3, -COOR3, -CONR2R3 or -SO2R3; R1 - hydrogen, alkyl, C3-7 cycloalkyl, pyrrolidinyl, benzo[b]thienyl, chinoxalinyl, phenylalkyl, thienylalkyl or tetrazolylalkyl, possibly substituted. m=1, n=0 or m=0, n=1, p - integer 1-4, s - integer 2-5, v - integer 2-4, optically pure enantiomers, mixtures of enantiomers, pharmaceutically acceptable salts and complexes with solvents, possessing activity of phenin inhibitors.

EFFECT: efficient application in medicine for treatment of cardio-vascular diseases and renal failure.

8 cl, 743 ex

FIELD: chemistry.

SUBSTANCE: description is given of new diazabicyclic aryl derivatives, with general formula I: its enantiomers, or mixture of enantiomers, or its adjoining pharmaceutical salt, where X and Y independently represent CR2, CR3 or N, where R2 is hydrogen, C1-6alkyl or halogen; and R3 is hydrogen or halogen; and R1 is hydrogen or halogen, CF3, NO2 or phenyl, possibly substituted, group with formula phenyl-Z-(C1-6alkyl)m-, phenyl -C≡C- or pyridyl -Z-(C1-6alkyl)m-, where m equals 0 or 1; Z - O or S, where phenyl and pyridyl are possibly substituted, or R1 and R3 , together with carbon atoms to which they are bonded, form a benzocondensed aromatic carbocyclic ring, which can be substituted. The new compounds are cholinergic ligands of nicotinic acetylcholine receptors.

EFFECT: compounds can be useful for treating such diseases or disorders related to the cholinergic system of the central nervous system, peripheral nervous system etc.

11 cl, 3 ex, 1 tbl

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to new crystalline form II of hydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride, including 2 moles water to 1 mole (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride, the form II content being equal 75% and more; the above form II of hydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3,3,1]non-4-yl)benzamide hydrochloride has one or more optional properties, as follows: a) form II infrared spectrum include characteristic peak at 835±1.5 cm-1; b) X-ray pattern obtained on the above form powder is essentially corresponds to image Fig. 21; and c) water content rates 8.3% to 9.8%. The invention relates also to the form II ofhydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride production methods, to the form II of hydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride, and the form II of hydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride identification method, as well as to pharmaceutical composition and treatment method for gastrointestinal motility impairment related disorders.

EFFECT: composition has improved properties for medical applications.

22 cl, 1 ex, 11 tbl, 22 dwg

FIELD: chemistry.

SUBSTANCE: invention concerns new derivatives of 1- and 7-[ω-(benzhydryl-4-piperazinyl-1)alkyl]-3-alkyloxantines of the general formulae I and II, including their pharmaceutically acceptable salts and/or salt hydrates, the derivatives showing antihistaminic and antiallergenic effect. In the general formulae I and II : R = H, Me, CH2Ph; R1 = Me, "н" - C4H9; n = 0-3; X = H, OH, OCOCH2CH2COOH; Y = Y1 = H, Cl, F; on the condition that R and R1 are not both methyl. Compounds of the invention feature high antihistaminic and antiallergenic activity. E.g., 7-[4-(benzhydryl-4-piperazinyl-1)butyl]-3-methyloxantine dihydrochloride surpasses most efficient antihistaminic and antiallergenic medications, such as cetirizine, loratadine and azelastine, in activity and lasting effect.

EFFECT: obtaining a compound with high antihistaminic and antiallergenic activity.

2 cl, 3 tbl, 8 ex

FIELD: biochemistry.

SUBSTANCE: invention relates to new compounds of formula wherein R1 represents linear or branched C1-C9-alkyl optionally substituted with C3-C8-cycloalkyl, C6-cycloalkyl, 2-furil; 3-furil, 2-thiazolyl, 2-thenyl, 3-thienyl, phenyl; X represents oxygen, NR4, wherein R4 is H, C1-C4-alkyl; Z represents H with the proviso, that when X and Y are oxygen, R1 is not methyl, ethyl, isopropyl, isobutyl or phenyl; and when X is oxygen, and Y is NR2, wherein R2 is hydrogen, methyl, isopropyl or tert-butyl R1 is not methyl. Compounds of present invention are useful as synthetic intermediates for bioactive substances.

EFFECT: new synthetic intermediates for bioactive substances.

8 cl, 28 dwg, 3 tbl, 38 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of aroylpiperazine of the formula (I):

wherein Y means lower alkylene; R1 means phenyl with 1 or 2 substitutes taken among group consisting of trihalogen-(lower)-alkyl, halogen atom, lower alkylamino-, di-(lower)-alkylamino- and nitro-group; R2 means phenyl or indolyl and each comprises 1 or 2 substitutes taken among group consisting of lower alkyl, trihalogen-(lower)-alkyl, lower alkylene dioxy-, hydroxy-group, hydroxy-(lower)-alkyl, lower alkoxy- lower alkylamino- and di-(lower)-alkylamino-group; R3 means hydrogen atom; R4 means morpholinyl-(lower)-alkyl comprising 1 or 2 substitutes taken among group consisting of ethyl, hydroxy-(lower)-alkyl, halogen-(lower)-alkyl and lower alkoxy-(lower)-alkyl, or morpholinyl-(lower)-alkynyl that can comprise 1 or 2 substitutes taken among group consisting of ethyl, propyl, isopropyl, isobutyl, spirocyclo-(lower)-alkyl, lower alkoxy-(lower)-alkyl, hydroxy-(lower)-alkyl, carboxy-(lower)-alkyl, di-(lower)-alkyl-carbamoyl, lower alkoxycarbonyl and halogen-(lower)-alkyl. Also, invention relates to a method for preparing, pharmaceutical composition based on these compounds and a method for treatment of tachykinine-mediated diseases, such as respiratory diseases, ophthalmic, cutaneous, inflammatory diseases, and as analgetic agents. Describes compounds are antagonists of tachykinine.

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

8 cl, 94 ex

FIELD: chemistry.

SUBSTANCE: novel compound is N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide or its pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition.

EFFECT: obtaining a novel biologically active compound with CFTR activity modulation properties.

2 cl, 485 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel 4-phenylpyrimidine-2-carbonitrile of formula

(values of R, R1, R2 are given in the formula of invention) or their pharmaceutically acceptable salts which have inhibition properties towards catepsin K and catepsin S. The invention also relates to use of derivatives of formula I for treating catepsin K and catepsin S related disorders, as well as to a pharmaceutical composition containing the said derivative.

EFFECT: improved properties of derivatives.

9 cl, 151 ex

FIELD: chemistry.

SUBSTANCE: invention proposes 5-member heterocyclic inhibitors of kinase p38, including kinase p38α and kinase p38β, based on pyrazoles and imidazoles, with the general formula given below , in which ring B is phenyl, and C is a pyrazole or imidazole ring, and the rest of the symbols assume values given in paragraph 1 of the formula of invention.

EFFECT: there are described pharmaceutical compositions containing said compounds, as well as methods of using the compounds and compositions, including a method of treating, preventing or suppressing one or more symptoms of diseases and conditions mediated by kinase p38 which include, but not limited to, inflammatory diseases and conditions.

31 cl, 6 tbl, 175 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds with general formula (I), where W is oxygen or sulphur; X1 and X3 are independently hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy and X4 is hydrogen, Y is in position (N2) or (N3); when Y is in position (N2), Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; when Y is in position (N3), Y is phenyl, pyridinyl or pyrimidinyl, where phenyl is optionally substituted with one or more atoms or groups selected from halogen, C1-C5 alkyl, C1-C6-alkoxy; the bond in position C4-C5 is a single or double bond; R1 and R2 each independently represent phenyl and C1-C6-alkyl, where at least one of R1 and R2 represents C1-C6-alkyl; or R1 and R2 together with the nitrogen atom to which they are bonded form a cyclic group containing from 4 to 7 links and a nitrogen atom and possibly another heteroatom, such as nitrogen or oxygen, possibly substituted with one or more C1-C6-alkyl groups; or to their pharmaceutically acceptable salts. The invention also relates to methods of producing the proposed compounds with formula (I), and specifically to compounds with formulae (Ia) and (Ib), in which X1, X3, X3, X4 and Y are as described in general formula (I). The invention also relates to intermediate compounds of synthesis of formula (I) compounds - compounds with formulae (Va) and (Vb). In formula (Va) X1, X3 and X4 represent hydrogen; X2 is hydrogen, halogen or C1-C6-alkoxy and Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; where phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. In formula (Vb) X1 and X3 represent hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy, X4 is hydrogen; Y is phenyl, pyridinyl or pyrmidinyl; phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. The invention also relates to a medicinal agent based on a formula (I) compound or its pharmaceutically acceptable salt for preventing and treating pathologies where peripheral type benzodiazepine receptors take part. The invention also relates to use of formula (I) compounds in preparing the said medicinal agent and to a pharmaceutical composition for preventing and treating pathologies in which peripheral type benzodiazepine receptors take part.

EFFECT: new compounds have useful biological activity.

11 cl, 3 tbl, 6 ex

.

FIELD: chemistry.

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

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

17 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula compounds, as well as their pharmaceutically acceptable salts, a pharmaceutical composition based on them, with inhibitory activity towards phosphorylation of protein Tau, and to methods of producing said compounds. In formula (I), R5 is aryl, aryl(C1-C6)alkyl; R6 is halogen; R3 is (C1-C6)alkyl, possibly substituted with substitutes selected from halogen, OH, NH2, azetidine; or monocyclic aryl or heteroaryl, such as thiophene or pyridine, possibly substituted with substitutes selected from NO2, CN, (C1-C6)alkoxy, (C1-C6)alkyl; or CONR1R2, SO2Ra, C(=NH)R1b, COOR1c; R1, R2 independently represent a hydrogen atom, possibly substituted with one halogen atom, (C1-C6)alkyl, moncyclic aryl or monocyclic 5- or 6-member heteroaryl containing 1 or 2 heteroatoms, such as S, O, N, possibly substituted with one or more substitutes selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxyl, trifluoromethyl, N(CH3)2; or R1 and R2 can form a 5- or 6-member ring which optionally contains a heteroatom such as N; R1a is aryl, possibly substituted with (C1-C6)alkoxy; R1b is (C1-C6)alkyl, possibly substituted aryl or 6-member heteroaryl, containing 1 or 2 N atoms, where the substitute is (C1-C6)alkoxyl; R1c is (C1-C6)alkyl, (C2-C6)alkenyl; and their pharmaceutically acceptable salts.

EFFECT: aminoindazole derivatives as kinase inhibitor.

8 cl, 44 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of benzoindazole of formula I , where radicals A1, A2, A3, R1, R2, R3, R4 and n have values mentioned in formula of invention, and their pharmaceutically acceptable salts, and also to application of these compounds for production of medicinal agent intended for modulation of α2-subsort of GABA receptor, and pharmaceutical composition that contains it.

EFFECT: application of compounds for preparation of medicinal agent intended for treatment of depression, disorder in the form of anxiety, psychic disorder, disturbed ability to learning and cognition, sleep disturbance, disorder in the form of cramps or fits or pain.

16 cl, 5 tbl, 40 ex

FIELD: medicine.

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

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

16 cl, 406 ex, 73 tbl

V:

Up!