Substituted 2-hydroxy-3-[1-(1h-imidazol-4-yl)-alkyl] - benzoperoxide, their optical isomers, racemic mixture, or their non-toxic, ophthalmologist acceptable salt accession acids.

 

(57) Abstract:

Offered these compounds of General formula I ,where R1is a hydrogen atom or an alkyl radical with 1 to 4 C-atoms; R2is a hydrogen atom, hydroxyl group, amino group or alkyl radical with 1 to 4 C-atoms; R3is a hydrogen atom, or R1and R2together form the group-CH2-CH2- and their non-toxic, ophthalmologist acceptable salt accession acids. A method of producing compounds of the formula I, which lies in the interaction of the compounds of formula II, where R1has the above significance, with alkanols with 1 to 4 C-atoms, in the presence of gaseous hydrogen chloride; the product of formula III, where a value of R1above and alk represents an alkyl radical with 1 to 4 C-atoms, enter into interaction with one of the enantiomers of methylbenzylamine; the thus obtained 2-hydroxy-3-[1-(1H-imidazol-4-yl)-alkyl]-N--methylbenzyl-benzene-carboxamide formula IV, where R1has the specified value, enter in interaction with nitrogen-containing compound of the formula R2NH2(Y) in which R2denotes a hydrogen atom, hydroxyl group, amino group or alkyl radical with 1 to 4 C-the UB>2-CH2group; and if you want to obtain the compound of formula I in the form of optical isomers, the pre-shared N--methylbenzylamine diastereoisomer formula IV in which R1denotes an alkyl radical with 1 to 4 C-atoms; and if you want to obtain the compound of formula I, where R2and R3means hydrogen, split diastereoisomers remove alpha methylbenzyl group by hydrolysis with concentrated hydrochloric acid at a temperature of 80 - 110oC, and, if necessary, the target product was transferred to an additive salt with acid. The proposed pharmaceutical composition for lowering intraocular pressure, containing the active principle, one or more 2-hydroxy-3-[1-(1H-imidazol-4-yl)-alkyl]-benzoperoxide formula I or their non-toxic, ophthalmologist acceptable salt accession acids in an amount of 0.01 wt.%. 5 C. and 10 C.p. f-crystals, 4 PL.

The present invention relates to new substituted 2-hydroxy-3-[3-1-(1H-imidazol-4-yl)alkyl] -benzoperoxide, their non-toxic, ophthalmologist acceptable salts accession acids, processes for their preparation and their use in pharmaceutical compositions.

In European patent application N XI-3-[1-(1H-imidazol-4-yl)-alkyl]-benzoimidazole. These 1H-imidazoles have anti-ischemic properties of the heart, brain and tissues.

In the European patent N 341231, also on behalf of the applicant, describes substituted [1-(1H-imidazol-4-yl)-alkyl]-benzamide have not only an antiischemic properties of the heart, brain and tissues, but also agonistic properties2- adrenergic receptors.

These latter properties allow their use in the treatment of pathologies caused by or resulting from abnormal increase the content of catecholamines, such as, for example, heart, blood, disease Raynand or spasms of the coronary arteries.

On the same basis, these compounds also find use in the treatment of disorders associated with gastric or intestinal hypersecretion, as well as in the treatment of the syndrome associated with discontinuation of drug addicts. These compounds, in addition, have some diuretic activity.

Further research in this area, the applicant synthesized new substituted 2-hydroxy-3-[1-(1H-imidazol-4-yl)-alkyl] -benzoperoxide who are strong agonists 2- adrenergenic or peripheral origin. As a consequence, these compounds preferably can be used to reduce intraocular pressure and preferably for the prophylaxis and treatment of glaucoma.

Glaucoma is an eye disease characterized by increased intraocular pressure that causes hardening of the eyeball, atropia the optic nerve with a characteristic failure of the papilla (hillock), narrowing of the field of view and more or less marked decrease in visual acuity. End-stage glaucoma (or absolute glaucoma) followed by the complete blindness of the patient.

Emergency treatment of glaucoma usually involves topical introduction cholinergic agents such as pilocarpine; agonistic or antagonistic - or - adrenergic agents, such as clonidine, timolol, or epinephrine, or inhibitors of carbonic anhydrase system path.

Finally, as a last resort, it is sometimes necessary to perform surgical intervention.

However, currently available at the disposal of the various traditional methods of treatment of glaucoma are accompanied by side effects, the nature and severity of which is very variable.

So, vipiana in the eyes of kholinergicheskaya, tears, salivation, etc. On the same eye level you can see a reduction in the papilla (miosis) ciliary muscles exactly the same as the dilation of blood vessels of the iris and conjunctiva.

Often related to vision complications, such as akomodasi spasm, myopia or decreased visual acuity.

Treatment sympathomimetic agent such as dipicolylamine, as you know, often causes a burning sensation or irritation. In addition, significant side effect of such agents is the appearance of cardiac disorders, such as palpitations, tachycardia, arrhythmia, etc.

Clonidine, known as agonist2- adrenergic receptors causes mydriasis (pupil dilation), as well as the initial phase of hypertension eye (two-phase effect). In addition, despite the topical product introduction, see significant systemic effects, such as bradycardia and hypotension.

Using - blocking agents also entails significant systemic effects resulting from the lack of "first-pass"effect at the time of their introduction into the eye. Timolol, for example, causes bradycardia or hypotension. I stop the treatment. In connection with the introduction of these drugs, in some cases causing suicide, depression, hallucinations, nightmares or psychosis, causing the need for hospitalization.

Moreover, these compounds should be used with extreme caution in patients exposed to functional regarding heart and lung disorders. This type of patients, among other things, include cases of arrhythmia, cardiac arrest, asthma, shortness of breath and spasm of the bronchi.

Treatment simpatricheskimi agent, as guanethidine, conjunctive causes the redness and irritation, in addition to the fact that these agents have only a weak tendency to decrease intraocular pressure.

Finally, in the treatment of glaucoma by carbonic anhydrase inhibitors such as acetazolamide or methazolamide, there are serious secondary systemic effects, such as depression of the Central nervous system, weight loss and mainly hyperfunctioning bone marrow.

Therefore, the use of classical gipotenzivnyj agents for the treatment of glaucoma is accompanied by significant risks. Known methods of treatment are not particularly well adapted for the local treatment, and the secondary system and in some cases they can have severe consequences.

The purpose of the invention is to develop new tools that can effectively reduce intraocular pressure, and which can eliminate the above-mentioned secondary systemic effects, especially when it comes to the treatment of the so-called " patients "at risk", such as heart patients and asthmatics.

This goal is achieved by using the new substituted 2-hydroxy-3-[1-(1H-imidazol-4-yl)-alkyl]-benzoperoxide of the present invention.

These compounds are strong presynaptic agonists2- adrenergic receptors. Moreover, these compounds are devoid of secondary systemic effects of Central or peripheral origin. In fact, at doses at which these compounds are effective to reduce intraocular pressure did not watch either hypotension or bradycardia, or mydriasis.

In addition, these compounds do not cause hookworm treated eyes, and not see the secondary contralateral effect of untreated eyes during treatment of the eye by topical administration, it clearly shows the lack of action as a relay, or due to the circulation of the blood, either by neuronal system.

Risks associated with ispolzovaniya which substituted 2-hydroxy-3-[1-(1H-imidazol-4-yl)-alkyl] -benzoperoxide, according to the present invention is particularly well applied for the treatment of intraocular hypertension and particularly glaucoma.

More specifically, the present invention relates to new substituted 2-hydroxy-3-[1-(1H-imidazol-4-yl)-alkyl] -benzoperoxide responsible of General formula I

< / BR>
in which R1denotes a hydrogen atom or an alkyl radical with 1-4 C-atoms;

R2denotes a hydrogen atom, hydroxyl group, amino group or alkyl radical with 1-4 C-atoms;

R3denotes a hydrogen atom, or

R2and R3together represent a group-CH2-CH2-;

as well as to their non-toxic, ophthalmologist acceptable salts accession acids.

When the molecule contains an asymmetric carbon atom, the compounds of formula I can be either in the form of a racemic mixture or in the form of one or the other enantiomer. These different forms are also included in the scope of the present invention.

The present invention also relates to non-toxic, ophthalmologist acceptable salts accession acids substituted 2-hydroxy-3-[-(1H-imidazol-4-yl)-alkyl]-benzoperoxide formula I. you Can use any salt, connected the lot indicated at C. 2 Journal of Pharm. Sciences 66(1), January 1977; by the way, you can specify phosphoric, maleic, boric, carbonic acid.

Preferred compounds according to the invention, are:

-2-hydroxy-3-(1H-imidazol-4-yl-methyl)-benzoperoxide;

-N,2-dihydroxy-3-(1H-imidazol-4-yl-methyl)- benzoperoxide;

-2-hydroxy-3-(1H-imidazol-4-yl-methyl)-N-methyl - benzoperoxide;

-2-hydroxy-3-(1H-imidazol-4-yl-methyl)-N-(1-methyl-ethyl) benzoperoxide;

-hydrazide-2-hydroxy-3-(1H-imidazol-4-yl-methyl)- benzonorbornadiene;

-(+)-2-hydroxy-3-[1-(1H-imidazol-4-yl)-ethyl]- benzoperoxide and

-(-)-2-hydroxy-3-[1-(1H-imidazol-4-yl)-ethyl]- benzoperoxide.

Substituted 2-hydroxy-3-[1-(1H-imidazol-4-yl)-alkyl] -benzoperoxide formula I can be obtained by the General method, which includes the following stages:

(1) 2-hydroxy-3-[1-(1H-imidazol-4-yl)-alkyl] -benzonitrile formula II is administered in cooperation with alkanols with 1-4 C-atoms in the presence of gaseous hydrogen chloride according to the equation:

< / BR>
This reaction is usually carried out at a temperature from -45oC to +15oC;

(2) next, the thus obtained alkyl-2-hydroxy-3-[1-(1H-imidazol-4-yl)-alkyl] - the equation:

< / BR>
(3) finally, the obtained 2-hydroxy-3-[1-(1H-imidazol-4-yl)-alkyl]-N -- methylbenzyl-benzoperoxide formula IV is administered in cooperation with a nitrogen-containing compound of the formula R2-NH2V, in which R2denotes a hydrogen atom, hydroxyl group, amino group, or an alkyl radical with 1-4 C-atoms, when R3denotes hydrogen; or with Ethylenediamine of the formula IV, where R2and R3together represent a group-CH2-CH2- according to the equation:

< / BR>
and in all these formulas, R1have the above significance and alk denotes an alkyl radical with 1-4 C-atoms.

To obtain the compounds of General formula I, in the form of optical isomers, pre-shared diastereoisomers N -- methylbenzylamine derivatives of the formula IV in which R1denotes an alkyl radical with 1-4 C-atoms before the reaction of aminolysis at the stage (3).

According to this method, thus receive the compounds of General formula I, either in racemic form or in the form of optical isomers, when R1denotes an alkyl radical with 1-4 C atoms, or in the optically inactive form when the molecule contains no asymmetric carbon atom (R12-NH2V, in which R2denotes a hydrogen atom, hydroxyl group, amino group or alkyl radical with 1-4 C-atoms, if R3denotes hydrogen, or with Ethylenediamine formula, if R2and R3together represent a group-CH2-CH2.

According to a variant used to obtain 2-hydroxy-3-[1-(1H-imidazol-4-yl)-alkyl] -benzoperoxide responsible of General formula I, in which R2denotes a hydroxyl group, and R3denotes a hydrogen atom, hydroxylamine enter into interaction with 2-hydroxy-3-[1-(1H-imidazol-4-yl)-alkyl]-benzonitrile formula II in which R1have the above meaning.

In the particular case of obtaining 2-hydroxy-3-[1-(1H-imidazol-4-yl)-alkyl]-benzoperoxide responsible of General formula I, in which R1denotes an alkyl radical with 1-4 C-atoms, and R2and R3both represent a hydrogen atom, formcommand formula IV, carrying only the stage (1) and (2) of the method described above, the share received diasteroisomers N -- methylbenzylamine derivatives of the formula IV, and then from each of the thus obtained diastereoisomer remove - methylbenzyl group by hydrolysis with concentrated hydrochloric acid at a temperature of 80 - 110oC.

Non-toxic, ophthalmologist acceptable salt accession acids can be obtained from 2-hydroxy-3-[1-(1H-imidazol-4-yl)-alkyl]-benzoperoxide formula I itself known methods.

2-Hydroxy-3-[1-(1H-imidazol-4-yl)-alkyl]-benzonitrile formula II used as starting product can be obtained by the method described in the European patent N 341231.

As mentioned above, the substituted 2-hydroxy-3-[1-(1H-imidazol-4-yl)-alkyl] -benzoperoxide formula I, as well as their non-toxic, ophthalmologist acceptable salt accession acids have agonistic properties presynaptic2- adrenergic receptors, they are able to reduce intraocular pressure and lack significant secondary effects.

The following pharmacological tests emphasize these Raia:

- 2-hydroxy-3-[1H-imidazol-4-yl-methyl]-benzoperoxide (compound A obtained in example 2.1);

- 2-hydroxy-3-[1H-imidazol-4-yl-methyl] -II-methyl-benzoperoxide (compound B obtained according to example 2.2);

- N, 2-dihydroxy-3-(1H-imidazol-4-yl-methyl)- benzoperoxide (compound C obtained in example 3);

- (+)-2-hydroxy-3-[1-(1H-imidazol-4-yl)-ethyl)- benzoperoxide (compound D obtained in example 4);

- (-)-2-hydroxy-3-[1-(1H-imidazol-4-yl)-ethyl)- benzoperoxide (compound E obtained in example 4);

- 2-hydroxy-3-[1H-imidazol-4-yl-methyl)-N-(1-methylethyl)- benzoperoxide (compound F obtained in example 5.2);

- hydrazide-2-hydroxy-3-[1H-imidazol-4-yl-methyl)- benzonorbornadiene (compound G obtained in example 2.6).

The results were compared with those obtained with clonidine, an agonist2- adrenergic receptors, which, like some of its derivatives, are used for the treatment of glaucoma.

1. Presynaptic2- adrenergic agonistic property.

Stimulation of the ileum of the Guinea pig.

Presynaptic2- adrenergic agonistic property of the compounds of sevinci, caused by electrical stimulation.

Fragments of longitudinal muscles connected with the indicator isometric force, immersed in Tyrode solution and pull with a force of 1 g (G. M. DREW, Brit. J. Pharmacol. 64 (1978), 293 - 300; ANDREJAK M. and al. Naunyn-Schmiedeberg''s Arch. Pharmacol. 314 (1980), 83 - 87).

Electrical stimulation of parasympathetic nerves present in the fragments of the ileum causes contraction of the muscles. This reduction is reduced in the presence of presynaptic 2- agonist, and the reduction depends on the concentration used agonist. This effect antagonizers due to the simultaneous presence2- antagonistic compounds such as alpha-yohimbine.

The compounds are tested in increasing concentrations from 10-10up to 10-3mol/L. Determine the concentration (IC50in mol/l), which reduces by 50% the intensity of the muscle contraction.

Table 1 shows the concentration IC50(mol/l) obtained for compounds of the invention, except for the connection G, which indicates the concentration of the IC30.

These results indicate that these compounds are well active at very low concentrations.

2. Hypotonic intraocular act is the oliku (new Zealand white) by measuring the variation of intraocular pressure after unilateral injection of compounds into the left eye of the animal.

In three rabbits (weight of 2-2,5 kg) of either sex get subjects dose according to the Protocol of the experiment, in the form of "cross-permutatio" ("permutation-croisee"), in which each animal is also included in the control group.

The studied compounds, the same as clonidine, administered in the form of a solution, pre-aged at room temperature for 30 minutes, 30 Microlitre sterile distilled water (eye drops) at concentrations of 8 (standard) up to 0.5 (weight per volume). Measurement of intraocular pressure implement using pneumatometer BIORAD (DIGILAB CODULAR ONE) after local anesthesia using two drops of 0.4% (weight. on volume) oxybuprocaine-hydrochloride.

The following table 2 shows the observed pressure change during the dropping of the compounds of the invention and clonidine.

In this table: In the 1st column indicates the test compound; in the 2nd column indicates the concentration in percent (weight. volume); in the 3rd, 4th, 5th, 6th 7th columns indicate the change in intraocular pressure (P) expressed in percentage in relation to the animal treated with eye drops without test compounds, measured after 30 minutes, 1 hour, 2 hours, 3 hours or 6 hours, Noah hypotonic activity as opposed to clonidine, which initially causes hypertension treated eyes, the effect of which increases simultaneously with the concentration of the used product. This biphasic effect is not observed with the compounds according to the invention.

In addition, for compounds of the invention do not see simultaneous reduction of intraocular pressure in the other eye treated animals. In contrast, when using clonidine measure the following changes in intraocular pressure in the opposite eye:

- at a concentration of 0.01% P = -9,5% after 2 hours, and

to-9.2% after 6 hours;

- at a concentration of 0.1% P = -10,2% after 2 hours and

+2,6% after 6 hours;

- at a concentration of 0.5% P = -26,3% after 2 hours and

+15% after 6 hours.

This shows the lack of action as relay the compounds of the invention either by circulation or by natsonalnoi system.

In addition, these results show the difficulty of achieving reduction of intraocular pressure using clonidine because of its two-phase effect.

3. Impact on pupil diameter of the treated eye and the contralateral eye

The effect of the compounds of the invention on the diameter of the pupil demonstrates the living to the eye after topical administration of the compounds in the left eye of the animal.

The studied compounds, as well as clonidine, administered in the form of a solution, pre-aged at room temperature for 30 minutes in 30 μl of sterile distilled water (eye drops) with concentrations from 0 (standard) up to 0.5% (weight per volume). Pupil diameter was measured visually by the maximum vertical diameter using millimeter standard of metal.

Compounds of the invention do not cause or cause a small degree of appreciable modification of the diameter of the pupil in the doses in which they reduce eye pressure (table 2), whatever the observed eye (treated or the opposite). In fact, the maximum difference between the pupil diameter measured to the dropping of the test compounds, and the pupil diameter measured during the observations, from 30 minutes to 6 hours after the dropping of the test compounds comprise from -4,2% to +4.7 per cent.

Table 3 summarizes the results observed under the same conditions when using clonidine.

In this table the first column gives the concentration of clonidine in percent (weight/volume); in the second column lists the maximum difference observed between the diameter of the pupil of the treated eyes (homolateral), the / establishment, which is from 30 minutes to 6 hours after dropping; in the third column lists the maximum difference observed in the same conditions on the diameter of the pupil of the opposite (contralateral) eyes.

This table shows that, in contrast to the compounds of the invention, a significant mydriasis (pupil dilation) homolateral eyes observed when using clonidine concentrations (0.1 and 0.5%), for which there is no z intraocular pressure.

4. Effects on the mucous membrane of the treated eyes (hookworm)

The effect of the compounds of the invention on the mucous membrane of the treated eyes demonstrated on a normal live rabbit (new Zealand white) both sexes by visual examination of the conjunctiva, to identify possible signs of modification or response to treatment after topical administration of the compounds in the animal's eyes. The hookworm is manifest in insufficient blood supply to the conjunctiva, which may cause local irreversible ischemia.

The studied compounds is injected, as in the previous test, in the form of a solution in 30 ál of sterile distilled water (eye drops) in concentrations from 0 (standard) up to 0.5% (weight per volume).

In doses effective for sne cause of hookworm. In contrast, clonidine at a concentration of 0.01% see the whitening of the conjunctive after 30 minutes; this effect is still there after 1 hour when using clonidine in a concentration of 0.1%.

5. Impact on the frequency of the beating heart

The effect on the frequency of the beating heart of the compounds is demonstrated in normal live rabbit (new Zealand white) of both sexes (weight of 2-2,5 kg) by measuring the beating heart at the level of the caudal artery after topical administration of the compounds in the left eye of the animal. The studied compound is administered in the form of a solution in 30 ál of sterile distilled water (eye drops) in concentrations from 0 (standard) up to 0.5% (weight per volume).

No obvious impacts on the frequency of the beating heart in animals treated with compounds of the invention. In contrast, in animals treated with clonidine in concentrations of 0.01%, see noticeable heartbeat slowing 10.7% after 3 hours, and in animals treated with clonidine in the concentration of 0.1%, see a significant decrease in the frequency of the beating heart by 17.9% after 1 hour.

6. Toxicity

The toxicity of the compounds of the invention is determined on the male mouse NMRI using test Irvine [(S. IRWIN, Psychopharmacologia, 13 (1968), 22-257].

Increasing the met lethal dose (dose, causing the death of two animals of the three within 24 hours).

The following table 4 is given a lethal dose observed for compounds of the invention. From this table it follows that these compounds very little toxic.

Compounds of the present invention is preferably introduced in the form of ophthalmic pharmaceutical compositions used (adapted) for topical injection into the eye, for example, in the form of solutions or ointments, or in the form applicable to the eyes of hard graft (injected subcutaneously medications).

Expressed as the percentage of the number of active product in the pharmaceutical compositions can vary in the range from 0.01 to 1 wt.% and preferably 0.05 to 0.5 wt.%. As for the daily dose, the compounds of the invention are typically administered in the eye at a dose of 1 μg to 1 mg, and preferably 50 μg to 0.5 mg of active product, individually or in the form of a mixture.

In ophthalmic pharmaceutical compositions of the compounds of the present invention for convenience can be associated with one or more non-toxic ophthalmologist acceptable excipients, solid or liquid.

Ophthalmologist acceptable excipients are, for example, water; CME is s, vegetable oils, polyalkylene glycols, ethylcellulose, etiloleat, carboxymethylcellulose, polyvinylpyrrolidone, isopropylmyristate or other conventional excipients.

Ophthalmic compositions can also contain non-toxic auxiliary substances, such as emulsifiers, conservatives, wetting, etc. as, for example, glycols 200, 300, 400, 600, 1000, 1500, 4000, 6000 and 10 000; bactericides, as Quaternary ammonium salts or salts of finalstate known sterilizing cold properties and does not have harmful effects; methylparaben, propylparaben; benzyl alcohol; 2-phenylethanol; buffers on the basis of sodium chloride, sodium borate, sodium acetate; gluconate buffers, etc.

Additionally, there may be used the corresponding liquid, ophthalmologist acceptable excipients. Examples of these liquid excipients include buffer solutions of phosphate-based; isotonic solutions of boric acid, sodium chloride, sodium borate, etc.

Ophthalmic compositions can also be in the form of a solid implant (injected subcutaneously drug) that is administered in the eye. In this case, it is possible to use, for example, solid, water-soluble polymer as is, actuarily in water the polymer, such as cellulose derivatives, as methylcellulose, carboxymethylcellulose sodium, hydroxyethylcellulose with the lowest alkilani as hydroxyethylcellulose, hydroxypropylcellulose, hypromellose; acrylates, as polyacrylic acid or polyacrylamides; natural products such as gelatin, alginates, pectins, hemitragus; derivatives of starch as starch acetate, hydroxyethyl-starch-hydroxypropyl-starch, in the same way as other synthetic derivatives as polyvinyl alcohol, polivinilpirolidon, polivinilbutilovy ether, polietilenoksid and mixtures of the above polymers.

In the case where use is applicable to solid eye implant, it is preferably prepared from cellulose derivatives such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose or hypromellose, or other synthetic materials such as polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide or polivinilbutilovy ether.

As not limiting the scope of protection of the invention of example, the compositions containing the compound of the invention, the following is an example of a sterile solution for topicaine - - 0.01 to about 1%

polyvinyl alcohol - 0 - 40%

benzylaniline - 0 - 15%

sodium chloride - 0 - 10%

the buffer is 0.01 - 10%

sterile distilled water up to 100%

The following examples illustrate the invention but do not limit its scope of protection.

In these examples, the melting temperature is determined by calorimetry differential scavenging (D. S. C.) with a temperature gradient of 20oC/min Spectra of nuclear magnetic resonance (NMR) are removed by using a Bruker instrument at 250 MHz in dimethyl sulfoxide using tetramethylsilane was as an internal standard. The chemical shift is indicated in (M. D.) Letter, S., D., DD., so, K., sh. and m denote, respectively, the singlet, doublet, double doublet, triplet, quadruplet, broad peak and multiplet.

Example 1: Retrieving the original 2-hydroxy-3-[1-(1H-imidazol-4-yl)- alkyl] -benzonitrile formula (II).

1. 2-Hydroxy-3-[1H-imidazol-4-yl-methyl)-benzonitrile

This compound is prepared as in the method described in example 3.1 European patent 341231.

2. 2-Hydroxy-3-[1H-imidazol-4-yl)-ethyl]-benzonitrile

This compound is prepared as in the method described in example 3.2 European patent 341231.

Example 2: Obtain timesensor-4-yl-methyl)-benzoperoxide.

a) is Cooled to -40oC a suspension of 10 g (0,050 mmol) 2-hydroxy-3-(1H-imidazol-4-yl-methyl)-benzonitrile [obtained in example 1.1 above] in 200 ml of methanol and saturate it with gaseous hydrogen chloride. Leave the temperature to rise to 0 to 5oC and the reaction mixture was kept at this temperature for 20 hours.

The solution is evaporated to 9/10 of its volume, to the residue add 300 ml of ice water and neutralized with aqueous sodium bicarbonate solution. The solution is extracted 4 times with 150 ml ethyl acetate and the combined organic phases.

The organic phase is washed with 100 ml of aqueous saturated solution of sodium chloride, then dried over magnesium sulfate, filtered and evaporated under reduced pressure.

b) the Obtained residue is treated with 150 ml of absolute ethanol.

The solution is cooled to a temperature below 10oC and saturated with ammonia. Leave the temperature to rise to room temperature and the reaction mixture was kept at this temperature for 15 hours. The solvent is evaporated under reduced pressure. The solid residue purified by preparative liquid chromatography (silica: 600 g; eluting agent: a mixture of 77.5 : 20 : 2,5 (by volume) of diethanol.

Get 4,55 g 2-hydroxy-3-(1H-imidazol-4-yl-methyl)- benzoperoxide. Yield = 42%. So pl. = 248,71oC. NMR spectrum : 3,68 (2H, s); 6,13 (1H, DD); is 6.61 (1H, s); 6,95 (1H, DD); 7,41 (1H, d); the 7.43 (1H, DD).

Analysis for C11H12N4O in %:

calculated: C 61,10 H 5,59 N 25,91

found: 61,18 5,62 26,07

2. 2-Hydroxy-3-(1H-imidazol-4-yl-methyl)-N-methyl - benzoquinoneimine

a) a Suspension of 19.9 g (0.1 mol) of 2-hydroxy-3-(1H-imidazol-4-yl-methyl)-benzonitrile [obtained in example 1.1. above] in 600 ml of methanol, cooled to 10oC, saturated with gaseous hydrogen chloride. Add 60 ml of water, cool the suspension to -25oC and again saturated with gaseous hydrogen chloride.

The reaction mixture was kept at this temperature for 15 hours. The solution is evaporated and the residue is treated with 500 ml of ice water and neutralized with aqueous sodium bicarbonate solution. The solution is extracted 4 times with 250 ml of ethyl acetate and the combined organic phases. The organic phase is washed with 200 ml of aqueous saturated solution of sodium chloride, then dried over magnesium sulfate, filtered and evaporated.

Get to 19.1 g of methyl 2-hydroxy-3-(1H-imidazol-4-yl-methyl)-benzoperoxide that use benzoperoxide dissolved in 100 ml of absolute ethanol, the solution is cooled to 10oC and added 1.28 g (0,0413 mol) of methylamine.

The solution is left to raise to room temperature and left to react for 15 hours. The solvent is evaporated under reduced pressure. The residue is purified by preparative liquid chromatography [silica: 600 g; eluting agent: a mixture of 78:20:2 (by volume) of ethyl acetate with methanol and ammonia].

Allocate 9,49 g of product, which is stirred in 100 ml of acetonitrile at 50oC for 30 minutes. The solid product is filtered off and recrystallized from methanol. Obtain 4.5 g of 2-hydroxy-3-(1H-imidazol-4-yl-methyl)-N-methyl-benzoperoxide. Yield = 47%. So pl. = 235,84oC.

NMR spectrum : to 2.94 (3H, s); 3,70 (2H, s); of 6.20 (1H, DD)); 6,60 (1H, s); 6,95 (1H, DD)); 7,41 (1H, d); 7,47 (1H, DD)); of 8.47 (2H, m); 14,1 (1H, m).

Analysis for C12H14N4O in %:

calculated: C 62,59 H x 6.15 N 24,73

found: 62,53 6,15 14,30

3. 2-(4,5-Dihydro-1H-imidazol-2-yl)-6-(1H-imidazol-4-yl-methyl)-phenol

a) Methyl-2-hydroxy-3-(1H-imidazol-4-yl-methyl)-benzoperoxide receive, as specified above in paragraph (2A) and used as is in the next stage.

b) of 9.55 g (0,0413 mol) obtained in paragraph 3 (a) above dissolved in 100 ml of absolute and room temperature, then left to react for 15 hours. The formed precipitate is filtered off (1st party). The filtrate is evaporated under reduced pressure and the resulting residue purified by preparative liquid chromatography [silica: 400 g; eluting agent: a mixture of 78:20:2 (by volume) of ethyl acetate with methanol and ammonia].

Allot of 1.7 g of white solid compound (2nd party). Both parties unite and recrystallized twice from methanol. Gain of 3.3 g of 2-(4,5-dihydro-1H-imidazol-2-yl)-6-(1H-imidazol-4-yl-methyl)-phenol. Yield = 33%. So pl. = 260,92oC.

NMR spectrum : 3,71 (3H, s); of 3.77 (2H, s); 6,53 (1H, T.); only 6.64 (1H, s ); 7,07 (1H, d); 7,40 (1H, DD)); was 7.45 (1H, s); 11,1 (2H, m); 11,7 (1H, m ).

Analysis for C13H14N4O in %:

calculated: C 64,46 of 5.82 H N 23,13

found: 64,46 5,86 23,14

4. 2-Hydroxy-3-[1-(1H-imidazol-4-yl)-ethyl]-benzoperoxide.

a) is Cooled to -40oC a suspension of 10 g (0,047 mol) of 2-hydroxy-3-[1-(1H-imidazol-4-yl)-ethyl] -benzonitrile (obtained in example 1.2 above) in 100 ml of methanol and saturate it with gaseous hydrogen chloride. Leave the temperature to rise to 5oC, and the reaction mixture was kept at this temperature for 24 hours.

The solution is evaporated in the cold to 3/4 of its volume is Oia. The solution is extracted with 3 times 100 ml of ethyl acetate and the combined organic phases. The organic phase is washed with 100 ml of aqueous saturated solution of sodium chloride, then dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure at room temperature.

b) the Obtained residue is treated with 50 ml of absolute ethanol, the solution is cooled to a temperature below 10oC and saturated with gaseous ammonia.

The solution is left to raise to room temperature and the reaction mixture was kept at this temperature for 6 hours. Then the solvent is evaporated under reduced pressure. The resulting residue is purified by preparative liquid chromatography (silica: 500 g; eluting agent: a mixture of 78:20:2) volume (dichloromethane with methanol and ammonia). Obtained after evaporation of the solvent the product is recrystallized twice from a mixture of 90/10 (by volume) of water with methanol.

Gain of 8.75 g of 2-hydroxy-3-[1-(1H-imidazol-4-yl)-ethyl] - benzoperoxide. Yield = 81%. So pl. 190,6oC.

NMR spectrum : of 1.40 (3H, s); 4,48 (1H, K.); 6,14 (1H, DD)); 6,63 (1H, s); to 6.88 (1H, DD)); 7,40 (1H, s); 7,41 (1H, DD.).

Analysis for C12H14

a) is Cooled to -40oC a suspension of 14.1 g (0,071 mol) of 2-hydroxy-3-(1H-imidazol-4-yl-methyl)-benzonitrile (obtained in example 1.1 above) in 420 ml of methanol and saturate it with gaseous hydrogen chloride. Leave the temperature to rise to 10oC and again saturate the suspension with gaseous hydrogen chloride.

The reaction mixture was kept at this temperature for 20 hours. The solution is concentrated up to 200 ml, concentrated solution was added 300 ml of ice water and 300 ml of ethyl acetate and neutralized with aqueous sodium bicarbonate solution. Filter and separate the aqueous phase from the organic phase, then the aqueous phase is extracted twice with 300 ml of ethyl acetate and three combined organic phases.

The organic phase is washed with saturated aqueous sodium chloride, then dried over magnesium sulfate, filtered and the solvent is evaporated under reduced pressure. Get to 15.4 g of methyl 2-hydroxy-3-(1H-imidazol-4-yl-methyl)-benzoperoxide in the form of a solid beige color, which is treated in 210 ml of absolute ethanol.

b) To 70 ml of a solution of methyl 2-hydroxy-3-(1H-imidazol-4-yl-methyl)- benzoperoxide in absolute ethanol, obtained in p. nnuu the mixture is left to react for 1 hour at 20oC. the Solvent is evaporated under reduced pressure and the oily residue is treated under ultrasound, using 100 ml of water. Allocate 4.5 g of a solid white product, which is recrystallized twice from methanol.

Obtain 3.4 g of N,2-dihydroxy-3-(1H-imidazol-4-yl-methyl)- benzoquinoneimine. Yield = 62%. So pl. = 227,81oC.

NMR spectrum : a 3.83 (2H, s); 6,24 (2H, s); to 6.67 (1H, s); of 6.75 (1H, T. ); 7,05 (1H, d); 7,49 (1H, s); 7,51 (1H, d); 10,07 (1H, m); 11,7 (1H, m ); 12,5: (1H, m).

Analysis for C11H12N4O in %:

calculated: C H a 56.88 to 5.21 N 24,13

found: 56,83 to 5.21 24,09

6. Hydrazide-2-hydroxy-3-(1H-imidazol-4-yl-methyl)-benzoperoxide acid.

a) is Cooled to -45oC a suspension of 14.1 g (0,071 mol) of 2-hydroxy-3-(1H-imidazol-4-yl-methyl)-benzonitrile (obtained in example 1.1 above) in 400 ml of methanol and saturate it with gaseous hydrogen chloride.

Leave the temperature to rise to 10oC and bubbled with gaseous hydrogen chloride through the suspension for 4 hours at this temperature. Cooled to 5oC and kept at this temperature the suspension for 20 hours. The formed precipitate is filtered off and obtain 11.4 g of methyl 2-hydroxy-3-(1H-imidazol-4-yl - methyl)benzoperoxide as Tverdov mol) of hydrazine hydrate is added in 20 ml of methanol at a time add a solution of 2 g (0,0066 mol) of methyl 2-hydroxy-3-(1H-imidazol-4-yl-methyl)-benzoperoxide, obtained in paragraph 6.(a) above.

Leave to react for 15 minutes, then add 40 ml of diethyl ether. The formed precipitate is filtered off and the filtrate is concentrated under reduced pressure. The residue after evaporation purified by preparative liquid chromatography (silica: 400 g; eluting agent: a mixture of 89:10:1 (by volume) dichloromethane with methanol and ammonia).

Obtained after evaporation of the solvents, the solid product is a pale yellow color will recrystallized from methanol. Obtain 1.2 g of the hydrazide 2-hydroxy-3-(1H-imidazol-4-yl-methyl)- benzonorbornadiene. Yield = 80%. So pl. = 187,8oC.

NMR spectrum : of 3.77 (2H, s); 5,09 (2H, sh); 6,34 (2H, sh); 6,56-only 6.64 (2H, m); 6,97 (1H, d); 7,44 (2H, m); 11,7 (1H, sh); 14,7 (1H, sh).

Analysis for C11H13N5O1/2H2O in %:

calculated: C 54,98 by 5.87 H N 29,15

found: 54,96 of 5.89 28,39

Example 3: Obtaining N,2-dihydroxy-3-(1H-imidazol-4-yl-methyl)- benzoperoxide.

3 g (0.015 mol) of 2-Hydroxy-3-(11H-imidazol-4-yl-methyl) -benzonitrile (obtained in example 1.1) is dissolved in 100 ml of methanol and there is added to 1.15 g (0,0165 mol) of hydroxylaminopurine and 1.84 g of sodium acetate.

The reaction mixture is refluxed in the second solution is neutralized to pH 7 by adding an aqueous solution of sodium bicarbonate.

The resulting white precipitate is filtered off, dried it in a vacuum and recrystallized from methanol. Obtain 1.6 g of N-2-dihydroxy-3-(1H-imidazol-4-yl-methyl)-benzoperoxide, connection, which is identical to that obtained in example a 2.5. Yield=46%.

Example 4: Obtaining optically active 2-hydroxy-3-[1-(1H-imidazol-4-yl)-ethyl] -benzoperoxide: (-) 2-hydroxy-3-[1-(1H-imidazol-4-yl-)-ethyl] -benzoperoxide and (+)-2-hydroxy-3-[1-(1H-imidazol-4-yl)-ethyl]-benzoperoxide.

a) Methyl-2-hydroxy-3-[1-(1H-imidazol-4-yl)-ethyl] - benzoperoxide get as in example 2.2 (a), based on 32 g (0,150 mol) of 2-hydroxy-3-[1-(1H-imidazol-4-yl)-ethyl] -benzonitrile (obtained in example 1.2). The crude residue methyl-2-hydroxy-3-[1-(1H-imidazol-4-yl)-ethyl] - benzoperoxide use what is, in the next stage.

b) Obtained above in paragraph (a) residue is treated with 150 ml of absolute ethanol and add back of 38.7 ml (0.1 mol) S-/-/- -- methylbenzyl-amine. Left to react at room temperature for 15 hours, then the solvent is evaporated under reduced pressure.

The resulting residue is purified by preparative liquid chromatography [silica: CNO purified diastereoisomers then chromatografic in an amount of 5 g [silicon dioxide: 1 kg; an eluting medium: mixture of 94.5:5:0.5 (volume) of ethyl acetate with methanol and ammonia] for the complete separation of diastereoisomers. Both almost pure diastereoisomer chromatographic even in recent times under the same conditions.

Thus, the gain of 18.9 g (yield=33%) diastereoisomer And, less polar, and therefore lirovannomu first, and 27.3 g (yield=47%) diastereoisomer B, more polar, and therefore lirovannomu last. These two compounds, respectively, used in the final dibenzylamine.

The NMR spectrum of diastereoisomer And : of 1.40 (3H, d); rate of 1.51 (3H, d); a 4.53 (1H, K.), 4,99 (1H, K.); of 6.29 (1H, DD)); of 6.65 (1H, s); 6,91 (1H, DD)); a 7.2 to 7.5 (7H, m); of 7.75 (1H, m).

The NMR spectrum of diastereoisomer B : of 1.40 (3H, d); of 1.52 (3H, d); a 4.53 (1H, K.); 4,99 (1H, K.); 6,27 (1H, DD)); to 6.67 (1H, s); 6.89 in (1H, DD)); a 7.2 to 7.5 (7H, m); of 7.75 (11H, m).

g) /-/-2-Hydroxy-3-[1-(1H-imidazol-4-yl)ethyl]- benzoperoxide.

A solution containing 30 g of diastereoisomer And (outlined in paragraph (C) above) in 300 ml of water 12 n hydrochloric acid and 30 ml of toluene is refluxed for 24 hours. After removal by filtration of the residual solids organic phase is decanted and the aqueous phase is washed with a small kDa sodium. This aqueous solution is extracted with a mixture of 80:20 (by volume) of ethyl acetate with methanol. Evaporation of organic solvent extraction gives a solid residue (1st party).

Also, the organic phase is evaporated and the resulting residue is treated with 30 ml of 2.5 n solution of ammonia in isopropyl alcohol. The insoluble salts are filtered off and the isopropyl alcohol is evaporated, obtaining a solid residue (2nd party).

Both United party purified twice by preparative liquid chromatography performed in the same conditions [silicon dioxide: 1 kg; eluting agent: a mixture of 78:20:2 (by volume) dichloromethane with methanol and ammonia]. Provide 10 g of white solid product, which is recrystallized from water. Get 7,18 g monohydrate /-/-2-hydroxy-3-[1-(1H-imidazol-4-yl)ethyl]-benzoperoxide. Yield = 32%.

So pl. = 125,18oC.

NMR spectrum : of 1.40 (3H, d); 44,4 (1H, K.); 6,16 (1H, T.); of 6.65 (1H, s ); make 6.90 (1H, DD)); 7,41 (1H, DD)); 7,44 (1H, s).

[]2D5= -232,36o(C=1, methanol.

Analysis for C12H14N4OH2O in %:

calculated: C 58,04 of 6.49 H N 22,57

found: 57,86 6,54 22,65

d) (+)-2-Hydroxy-3-[1-(1H-imidazol-4-yl)ethyl]- service 12 n hydrochloric acid and 27 ml of toluene, refluxed for 24 hours. The organic phase is removed by decantation and the aqueous phase is washed with a small amount of toluene.

The aqueous phase is evaporated under reduced pressure and the residue is treated with 100 ml of ethanol. Then the ethanol solution is neutralized with 40 ml of 2.5 n solution of ammonia in isopropyl alcohol. The insoluble salts are filtered off and the filtrate is evaporated. The resulting residue is purified twice by preparative liquid chromatography performed in the same conditions (silicon dioxide: 800 g; eluting agent: a mixture of 78:20:2 (by volume) dichloromethane with methanol and ammonia).

Allocate to 6.22 g of white solid product, which is recrystallized from water. Get is 4.93 g of the monohydrate of (+)-2-hydroxy-3-[1-(1H-imidazol-4-yl)ethyl]-benzoperoxide. Yield = 24%. So pl. = 139,07oC.

NMR spectrum : of 1.40 (3H, d); 4,48 (1H, K.); 6,14 (1H, T.); 6,63 (1H, s ); 7,40 (1H, s); 7,41 (1H, DD.).

[]2D5= +237,44o(C=1, methanol.

Analysis for C12H14N4OH2O in %:

calculated: C 58,04 of 6.49 H N 22,57

found: 58,11 6,53 22,65

Example 5: obtain the substituted 2-hydroxy-3-[1-(1H-imidazol-4-yl)-alkyl]-bentler) of 11.3 ml (0,0088 mol) of S - ( -) - methylbenzylamine added to 140 ml of a solution of methyl 2-hydroxy-3-(1H-imidazol-4-yl-methyl)-benzene-carboxamide in absolute ethanol, obtained in example 2.5 a) above.

Leave to react for 15 hours at 20oC, then the solvent is evaporated under reduced pressure. The resulting residue is purified by preparative liquid chromatography [silica: 1 kg; eluting agent: the 94.5:5:0.5 (volume) mixture of ethyl acetate with methanol and ammonia].

So get a 13.9 g of 2-hydroxy-3-(1H-imidazol)-4-yl-methyl)-N- -- methylbenzyl - benzoperoxide, which is used as is in the next stage.

b) for the purposes of analysis chromatographic again 2 g 2-hydroxy-3-(1H-imidazol-4-yl-methyl)-N- -- methylbenzyl - benzoperoxide obtained in paragraph (a) [silicon dioxide: 500 g; eluting agent: mixture 92,3:7:0,7 (by volume) dichloromethane with methanol and ammonia].

NMR spectrum : of 1.52 (3H, d); 3,74 (2H, m); 5,00 (1H, K.); 6,28 (1H, T. ); only 6.64 (1H, s); of 6.96 (1H, DD)); 7,25 was 7.45 (6H, m); 7,51 (1H, DD)); 7,80 (1H, sh).

[]2D5= +225o(C=1, methanol).

in the autoclave enter 1 g (0,0031 mol) of 2-hydroxy-3-(1H-imidazol-4-yl-methyl)-N -- methylbenzyl - benzoperoxide obtained in paragraph (1A) above, and 15 ml of ammonia and heated at 100oC for 40 hours.

The solvent is evaporated and the residue purified by liquids is n-methanol-hydroxide ammonium]. After evaporation of the solvents to obtain 0.5 g of 2-hydroxy-3-(1H-imidazol-4-yl-methyl)-benzoperoxide, connection, which is identical to that obtained in example 2.1. Yield = 75%.

2. 2-Hydroxy-3-(H-imidazol-4-yl-methyl)-N-(1-methylethyl)- benzoperoxide.

In the autoclave enter 5 g (0,0156 mol) of 2-hydroxy-3-(1H-imidazol-4-yl-methyl)-N -- methylbenzyl - benzoperoxide obtained in example 5.1 (a) above, and 50 ml of 2-propanamine and heated for 54 hours at 80oC, then for 46 hours at 100oC.

The solvent is evaporated and the residue purified by preparative liquid chromatography [silica: 600 g; eluting agent: a mixture of 89:10:1 (by volume) dichloromethane-methanol-hydroxide ammonium]. After evaporation of the solvents to obtain 3.6 g of the solid product is a light yellow color, which is recrystallized twice from acetonitrile.

Earn 1.25 g of 2-hydroxy-3-(1H-imidazol-4-yl-methyl)-N-(1-methylethyl) -benzoperoxide. Yield = 31%. So pl. = 138 - 139oC (decomposition).

NMR spectrum : 1,24 (6H, d); 3,70 (2H, s); 3,91 (1H, m); of 6.20 (1H, T. ); 6,60 (1H, s); 6,94 (1H, d); the 7.43 (1H, s); of 7.48 (1H, DD)); 7,98 (1H, sh. ); 11,7 (1H, sh):

Analysis for C14H18N4OH2O in %:

calculated: C 60,85 H 7 idemity, their optical isomers and racemic mixtures that meet the General formula I

< / BR>
where R1denotes a hydrogen atom or an alkyl radical with 1-4 C-atoms;

R2denotes a hydrogen atom, hydroxyl group, amino group or alkyl radical with 1-4 C-atoms;

R3denotes a hydrogen atom, or R2and R3together represent a group-CH2-CH2-,

and their non-toxic, ophthalmologist acceptable salt accession acids.

2. Connection on p. 1 representing 2-hydroxy-3-(1H-imidazol-4-yl-methyl)-benzoperoxide and its non-toxic, ophthalmologist acceptable salt accession acids.

3. Connection on p. 1, representing N, 2-dihydroxy-3-(1H-imidazol-4-yl-methyl)-benzoperoxide and its non-toxic, ophthalmologist acceptable salt accession acids.

4. Connection on p. 1 representing 2-hydroxy - 3-(1H-imidazol-4-yl-methyl)-N-methyl-benzoperoxide and its non-toxic, ophthalmologist acceptable salt accession acids.

5. Connection on p. 1 representing 2-hydroxy-3-[ 1-(1H-imidazol-4-yl)-ethyl] benzoperoxide and its non-toxic, ophthalmologist acceptable salicyl] benzoperoxide and its non-toxic, ophthalmologist acceptable salt accession acids.

7. Connection on p. 1, representing the (-)-2-hydroxy-3-[ 1-(1H-imidazol-4-yl)-ethyl] benzoperoxide and its non-toxic, ophthalmologist acceptable salt accession acids.

8. Connection on p. 1 representing 2-(4,5-dihydro-1H-imidazol-2-yl)-6-(1H-imidazol-4-yl-methyl)-phenol and its non-toxic, ophthalmologist acceptable salt accession acids.

9. Connection on p. 1 representing 2-hydroxy-3-(1H-imidazol-4-yl-methyl)-N-(1-methylethyl)-benzoperoxide and its non-toxic, ophthalmologist acceptable salt accession acids.

10. Connection on p. 1, representing the hydrazide-2 - hydroxy-3-(1H-imidazol-4-yl-methyl)-benzonorbornadiene and its non-toxic, ophthalmologist acceptable salt accession acids.

11. Substituted 2-hydroxy-3-[ 1-(1H-imidazol-4-yl)-alkyl] - benzoperoxide according to any one of paragraphs.1-10, or their non-toxic, ophthalmologist acceptable salt accession acids exhibiting agonistic activity against2- adrenergic receptors.

12. The method of obtaining substituted 2-hydroxy-3-[ 1-(1H-imidazol-4-yl)-alkyl]-benzoporphyrin formula II

< / BR>
where R1has specified in paragraph (1 value,

enter into interaction with alkanols with 1-4 C-atoms in the presence of gaseous hydrogen chloride, and then the thus obtained alkyl-2-hydroxy-3-[ 1-(1H-imidazol-4-yl)-alkyl]-benzoperoxide formula III

< / BR>
where R1has specified in paragraph (1 value;

alk denotes an alkyl radical with 1-4 C-atoms,

enter into interaction with one of the enantiomers of methylbenzylamine and the thus obtained 2-hydroxy-3-[ 1-(1H-imidazol-4-yl)-alkyl]-N -- methylbenzyl-benzoperoxide formula IV

< / BR>
where R1has specified in paragraph (1 value,

enter into interaction with nitrogen-containing compound of the formula

R2NH2, (V),

where R2denotes a hydrogen atom, hydroxyl group, amino group or alkyl radical with 1-4 C-atoms, if R3denotes hydrogen, or with Ethylenediamine, if R2and R3together represent-CH2-CH2group

and if you want to obtain the compound of formula I in the form of optical isomers, the pre-shared N -- -methylbenzylamine diastereoisomer formula IV in which R1denotes an alkyl radical with 1-4 C-atoms, and if you want to connect selinou group by hydrolysis with concentrated hydrochloric acid at a temperature of 80 110oC, and, if necessary, the target product is transferred and additive salt and acid.

13. The method of obtaining substituted 2-hydroxy-3-[ 1-(1H-imidazol-4-yl)-alkyl] -benzoperoxide formula I, characterized in that they are subjected to the interaction of alkyl-2-hydroxy-3-[ 1-(1H-imidazol-4-yl)-alkyl]-benzoperoxide formula III obtained by the method described in paragraph 12, with nitrogen-containing compound of the formula

R2and NH2, (V),

where R2denotes a hydrogen atom, hydroxyl group, amino group, or an alkyl radical with 1-4 C-atoms, if R3denotes hydrogen, or with Ethylenediamine, if R2and R3together represent a group-CH2-CH2- and, if necessary, the resulting product was transferred to an additive salt.

14. The method of obtaining substituted 2-hydroxy-3-[ 1-(1H-imidazol-4-yl)-alkyl]-benzoperoxide formula I, in which R2means a hydroxyl group, and R3means a hydrogen atom, characterized in that 2-hydroxy-3-[ 1-(1H-imidazol-4-yl)-alkyl] -benzonitrile formula II in which R1matter specified in paragraph 1 of the claims, is subjected to the interaction with hydroxylamine and, if necessary, translate the resulting product in addit the main beginning and ophthalmologist acceptable additives, characterized in that the active agent it contains one or more 2-hydroxy-3-[ 1-(1H-imidazol-4-yl)-alkyl]-benzoperoxide according to any one of paragraphs. 1 - 10 or their non-toxic, ophthalmologist acceptable salt accession acids in an amount of 0.01-1 wt.%.

 

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< / BR>
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R4- translated in vivo in carboxyl group, carboxyl, cyano, 1H-tetrazolyl, 1-triphenylmethyl-tetrazolyl or 2-triphenylmethyl-tetrazolyl,

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FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating patients with uterine cervix cancer with relapses in parametral fiber and in case of no possibility for radical operative interference and effect of previous radiation therapy. During the 1st d of therapy one should intravenously inject 30 mg platidiam incubated for 1 h at 37 C with 150 ml autoblood, during the next 3 d comes external irradiation per 2.6 G-r. During the 5th d of therapy one should introduce the following composition into presacral space: 60 ml 0.5%-novocaine solution, 1 ml hydrocortisone suspension, 2 ml 50%-analgin solution, 1 ml 0.01%-vitamin B12 solution, 1.6 g gentamycine, 800 mg cyclophosphan, 10 mg metothrexate. These curative impacts should be repeated at mentioned sequence four times. The method enables to decrease radiation loading and toxic manifestations of anti-tumor therapy at achieving increased percent of tumor regression.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

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