Applying derivatives of pyridazino[4,5-b]indole-1-acetamide for preparing drug used for treatment diseases associated with dysfunction of benzodiazepine receptors of peripheral type

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacology, pharmacy.

SUBSTANCE: invention relates to a medicinal agent used for prophylaxis and treatment of diseases and disorders associated with dysfunction of benzodiazepine receptors. This medicinal agent comprises compound of the formula (I)

. Compound of the formula (I) elicits high cardioprotective, neurotrophic, renoprotective activity and enhanced bioavailability.

EFFECT: valuable medicinal properties of compounds.

5 cl, 1 tbl, 1 ex

 

The present invention relates to a derivative of pyridazino[4,5-b]indole-1-ndimethylacetamide, showing affinity for the benzodiazepine receptors of the peripheral type.

In GB 2290292 described derivatives of 2-phenylpyridine[4,5-b]indole-1,4-dione, which has antagonistic activity against NMDA - and AMPA-receptors (NMDA - N-methyl-O-aspartate, AMPA 2-amino-3-hydroxy-5-methyl-4-isoxazolidinone acid). These derivatives can be used for the treatment and/or prevention of neurodegenerative disorders.

In WO 98/15552 described derivatives of 1H-pyrido[3,4-b]indole-4-carboxamide having an agonistic activity against benzodiazepine receptors type 1 and 2, located in the macromolecular complex GABAy-ω sites-chloride channel. These derivatives can be used for the treatment of diseases associated with disorders of GABA-ergicheskoi transmission, such as anxiety, sleep disorders, epilepsy, muscle spasticity, muscle contracture, disorder cognitive abilities and the like.

Compounds that bind to the benzodiazepine receptor, peripheral type, can be used for preparing medicaments for the prevention and treatment of peripheral neuropathies of various types of neurodegenerative diseases of the Central nervous system, kidney failure and is serdechnyh diseases.

In addition, recent data from the literature indicate that benzodiazepine receptors peripheral type are involved in the regulation of cell proliferation and cancer processes of rebirth.

In connection with the search of compounds that can stimulate the regeneration of axons in the peripheral nerve cells after injury, among the compounds of the international patent application PCT/FR98/01667 identified a subclass of compounds of General formula (I)

in which

X represents a halogen atom,

Y represents one or more than one atom or one or more than one group selected from hydrogen, halogen and hydroxyl, methyl, methoxy and nitro group,

R1is a (C1-C4)alkyl group,

R2and R3each independently from each other represents a hydrogen atom or (C1-C4)alkyl group, or alternatively R2and R3form together with the nitrogen atom carrying them, pyrrolidinyloxy, piperidinyloxy or morpholinyl group.

These compounds have high affinity for the benzodiazepine receptors peripheral type (R sites, or FGP), and some induce, in particular, the recovery loss of neurons in the facial nucleus after cutting the facial nerve. They also have cardio and renoprotective actions.

A particularly useful compound for use according to the invention is, for example, 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-ndimethylacetamide.

The above compound can be obtained according to the following procedure as an example.

Example (compound No. 1 of table below).

1. Ethyl ester of 6-chloro-1-methyl-1H-indole-2-carboxylic acid

A suspension of 1.8 g (45 mmol) of sodium hydride at a concentration of 60% (pre-washed with petroleum ether) and 8.0 g (35.8 mmol) of ethyl ester of 6-chloro-1H-indole-2-carboxylic acid in 80 ml of N,N-dimethylformamide is stirred for 2 h at room temperature, then added to 2.8 ml (45 mmol) iodomethane and the mixture was stirred at room temperature for 4 hours

Add 5 ml of absolute ethanol and the solvent is evaporated under reduced pressure. The residue is dissolved in water and this mixture is extracted with dichloromethane, the organic phase is dried, filtered, the solvent is evaporated under reduced pressure and the residue purified by chromatography on a column of silica gel.

Allocate 8.5 g (35,7 mmol) of a white crystalline substance.

Melting point: 75,5-76,5°C.

2. Ethyl ester of 6-chloro-2-(etoxycarbonyl)-1-methyl-α-oxo-1H-indole-3-acetic acid

To a solution of 4 ml (36 mmol) of ethylchloroformiate in 100 ml of 1,2-dichlo the ethane add 4 ml of cases (36.4 mmol) of titanium tetrachloride. This reaction mixture is stirred for 30 min at room temperature, and then added to 7.8 g (32,8 mmol) of ethyl ester of 6-chloro-1-methyl-1H-indole-2-carboxylic acid and this reaction mixture is stirred for 4 h at room temperature.

Environment cool and add 200 ml of dichloromethane and 100 ml of water. The organic phase is drained, washed with water, dried over sodium sulfate, filtered, the filtrate is concentrated under reduced pressure and the residue purified by chromatography on a column of silica gel.

Allocate 9.4 g (29,0 mmol) of the product.

Melting point: 94-95°C.

3. Ethyl ester of 7-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxylic acid

At room temperature to a solution of 4.6 g (to 13.6 mmol) of the ethyl ester of 6-chloro-2-(etoxycarbonyl)-1-methyl-α-oxo-1H-indole-3-acetic acid in 120 ml of acetic acid, add 4 ml (40,6 mmol) of phenylhydrazine. This reaction mixture is stirred for 30 min at room temperature and then for 4 h under reflux. This environment cool and add 350 ml of dichloromethane and 100 ml of water. The organic phase is drained, washed with saturated aqueous sodium bicarbonate, then with water, dried over sodium sulfate, filtered, concentrated under reduced pressure and the residue purified by chromatogra the AI on a column of silica gel.

Allocate 4.1 g (of 10.7 mmol) of the product.

Melting point: 216-218,5°C.

4. 7-Chloro-1-(hydroxymethyl)-5-methyl-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-4-one

To a solution of 4.04 g (10.6 mmol) of the ethyl ester of 7-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxylic acid in 150 ml of tetrahydrofuran, add 2.5 g (66,1 mmol) of sodium borohydride. Then, while stirring, gradually add 2.25 ml of methanol, and then the mixture is heated under reflux for 5 hours

This mixture is poured over ice-cold 1 M hydrochloric acid and the insoluble substance produce by filtration on a porous glass, washed with water and diethyl ether, and then dried.

3,3 g (9.7 mmol) of the compound isolated in the form of a white solid, which is used as such in the next stage.

Melting point: 219-220,5°C.

5. 7-Chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxaldehyde

To a solution of 3.3 g (9.7 mmol) of 7-chloro-1-(hydroxymethyl)-5-methyl-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-4-she's in 300 ml of dichloromethane added 5.7 g (65,6 mmol) of manganese dioxide and the mixture is stirred for 24 h under reflux.

This environment is cooled, filtered on a membrane of TeflonTMand the solid is washed with dichloromethane, and then the filtrate is concentrated under reduced is the making.

2,88 g (8,53 mmol) of the compound isolated in the form of a white solid, which is used as such in the next stage.

Melting point: 235-236°C.

6. 7-Chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetonitrile

To a solution of 2.14 g (10,96 mmol) 1-[(isocyanatomethyl)-sulfonyl]-4-methylbenzene in 50 ml of 1,2-dimethoxyethane small portions added 1.27 g (10,96 mmol) 1,1-dimethylethylene potassium, this reaction mixture is stirred for 30 min at -60°add 2,88 g (8,53 mmol) 7-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxaldehyde and this reaction the mixture is stirred for 3 h 30 min at -60°C. Add 9 ml of methanol and the reaction mixture is again stirred for 30 min at room temperature and for 1 h under reflux.

The medium was cooled, concentrated under reduced pressure, to the residue water is added, 5 ml of acetic acid and 200 ml of dichloromethane, the organic phase is drained off and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with water, dried over sodium sulfate, filtered, concentrated under reduced pressure and the residue purified by chromatography on silica gel. Allot of 1.87 g (are 5.36 mmol) of the compound as a white solid, which is used as such in the next stage.

Melting point: 305-315°C.

7. Methyl ester of 7-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetic acid

To a solution of 1.83 g (a 5.25 mmol) 7-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetonitrile, 250 ml of methanol add hydrogen chloride to saturate the solution and the reaction mixture stirred for 4 h under reflux.

This medium is cooled, the reaction mixture was concentrated under reduced pressure and to the residue add 25 ml water and 25 ml of methanol. After stirring, the insoluble substance produce by filtration, washed with water and diethyl ether, dried and purified by chromatography on a column of silica gel.

Allot of 1.00 g (2,62 mmol) of the compound as a white solid.

Melting point: 188,5-190°C.

8. 7-Chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-ndimethylacetamide

To a solution of 0.49 g (6 mmol) of dimethylamine hydrochloride in 80 ml of toluene at 0°in argon atmosphere add 3 ml (6 mmol) of trimethylaluminum (2 M in toluene) and the reaction mixture stirred for 1 h 30 min at room temperature.

Added 0.21 g (0.55 mmol) of methyl ester of 7-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetic acid and this reaction mixture is stirred for 6 hours while heating the Institute under reflux.

This medium is cooled to 4°add 10 ml of water and 100 ml dichloromethane, the solution is filtered and the filtrate concentrated under reduced pressure.

To the residue add water, 1 M hydrochloric acid and 150 ml of dichloromethane, the organic phase is separated, washed with water, dried over sodium sulfate, filtered, concentrated under reduced pressure and the residue purified by chromatography on a column of silica gel.

After recrystallization from a mixture of dichloromethane and ethyl acetate allocate 0.2 g (0.51 mmol) of the compound as a white solid, fluffy in appearance.

Melting point: of 229.5-230°C.

Nielaba table illustrates the chemical structures and physical properties of some compounds that can be used according to the invention.

The inscription to the table

"Me" and "Et" refers to methyl and ethyl groups, respectively.

"Pyrrole", "paperid" and "morph" means pyrrolidinyloxy, piperidinyloxy and morpholinyl groups, respectively.

td align="center" namest="c0" nameend="c1"> 16
Table

No.XYR1NR2R3TPL (°)
1/td> ClNMeNme2of 229.5-230
2ClNMeNet2167-168
3ClNMePyrrolic260-263
4ClNMeMorph273,5-274,5
5Cl3-IUMeNMe2204-205,5
6Cl3-IUMeNet2200,5-201
7Cl3-IUMePyrrolic268-269,5
8Cl3-Cl MeNMe2231-232
9Cl3-ClMeNet2202,5-203
10Cl3-ClMePyrrolic257-258,5
11Cl3-ClMePiperid218-219
12Cl2-ClMeNMe2253-255
13Cl2-ClMeNet2206-208
14Cl2-ClMePyrrolic295-297
15Cl4-ClMeNMe2235-237
Cl4-ClMeNet2223,5-224,5
17Cl4-ClMePyrrolic265-266
18Cl3-OMeMeNMe2200,5-202,5
19Cl3-OMeMeNet2201-202
20Cl3-OMeMePyrrolic240-242
21Cl3-NO2MeNMe2275-277,5
22Cl3-NO2MeNet2228-228,5
23Cl 3-NO2MePyrrolic261-263
24Cl3-FMeNMe2225-226,5
No.XYR1NR2R3TPL (°C)
25Cl3-FMeNet2171-172
26Cl3-FMePyrrolic270-271,5
27Cl3,5-(Cl)2MeNet2239-240,5
28Cl4-ClMeNMeEt216,5-217,5
29ClNMe NHMe305-307
30ClNMeNH2292-293
31Cl4-OMeMeNMe2233-234
32Cl4-OMeMeNet2172-174
33Cl4-HEMeNMe2298-300
34Cl4-HEMeNet2271-272

The protocols and results of tests that were conducted are described below.

Study of the binding of [3H]Ro5-4864 to the benzodiazepine receptor, peripheral type

Determined the affinity of the compounds according to the invention to benzodiazepine receptors peripheral type (p website, or LRT).

The receptors R sites can selectively mark in the membranes of pockrus, inkubiruemykh in the presence of [3H]Ro5-4864. The study in vitro was the connection with respect to their affinity for these receptors. Used animals represent male rats Sprague-Dawley weighing 180-300 mg (Iffa Credo). After decapitate extract kidney and 4°homogenize the tissue using a homogenizer transmitter stationTMfor 2 min at 6/10 maximum speed of 35 volumes of 50 mm phosphate buffer Na2PO4when the pH is brought to 7.5 NaH2PO4. The homogenate membrane filtered through cheesecloth and diluted with buffer 10 times.

[3H]Ro5-4864 (specific activity: 70-90 CI/mmol; New England Nuclear) at a concentration of 0.5 nm incubated in the presence of 100 μl of homogenate membrane in the final volume of 1 ml of the buffer containing the test compound.

After 3 hours of incubation at 0°With membrane secrete by filtration on filters Whatman GF/BTMthat washed twice with 4.5 ml of cold incubation buffer (0°). The amount of radioactivity remaining on the filter is measured by liquid scintigraphy.

For each concentration of tested compound determine the percentage of inhibition of binding of [3H]Ro5-4864, and then the concentration of the IC50the concentration that inhibits 50% of specific binding.

The values of the IC50the most active compounds are in the range of is from 0.6 nm to 20 nm.

Therefore, compounds that can be used according to the invention are ligands with high affinity to benzodiazepine receptors of the peripheral type.

The study neurotrophic activity

Test for the regeneration of damaged facial nerve by measuring functional recovery palpebral reflex,

according to modification of the method represented by K. et al., Experimental Neurology (1989)

10580-85.

Damage to the facial nerve by local freezing causes degeneration of the distal portion of the facial nerve and the loss of the blink function century. Investigational products injected intraperitoneal or oral twice a day with an interval of 6-8 hours daily for 10 days (duration of the experiment). The first treatment is carried out for 30 min prior to the damage.

Observation of animals: daily monitor recovery functions century the damaged animals, once in the morning from day 0 to day 5 and twice (morning and evening with an interval of 6-8 hours) from day 6 to day 10, before each treatment, according to theoretical points in the range from 0 to 4.

0 Points: eyes open; 1 point: eyes closed in degrees less than half of the eyes; 2 points: the degree of closure between 1/2 and 3/4; 3 points: the degree of closure of more than 3/4; 4 points: the eye is completely closed.

The results are expressed as the ratio of the values of PP is (area under the curve) for the treated group and the control group. Relationship CPD most active compounds are between of 1.12 and 1.20.

Therefore, these compounds increase the recovery palpebral reflex after damage to the facial nerve at 12-20%.

Test of survival of motoneurons after cutting the facial nerve in rats aged 4 days

After injury of the facial nerve in the immature rat motoneurons of the facial nucleus undergo death due to apoptosis. Evaluation of the survival of neurons is done using histological methods and methods for counting neurons.

Immature rats aged 4 days anaesthetize pentobarbital (3 mg/kg by intraperitoneal). The right facial nerve strip and cut where it emerges from the stylomastoid foramen. After recovery of consciousness of rats return to their mothers and treated for 7 days with one injection a day or two injections per day by oral or intraperitoneal doses in the range from 1 to 10 mg/kg After 7 days after injury in animals subjected to decapitate and brain frozen in isopentane at -40°C. the Facial nucleus of the entire cut into 10 μm sections using a cryostat. The motoneurons stained crazylove violet and counted using software HistoTM(BiocomTM).

In this model, the most active soy is inane increase the survival of neurons by about 10-30%. As an example, the compound described in example (No. 1 from table)increases neuronal survival by 31% when the intraperitoneal route of administration.

The results of the above tests show that the compounds of General formula (I) stimulate the regeneration of nerves.

The study cardioprotective actions

Cardioprotective actions investigated hearts extracted from rabbits subjected to regional ischemia and reinfused. He measured the size of the infarct, as well as the recovery of contractile function after reinfused.

New Zealand rabbits (weighing 2.3-2.5 kg, ESD France) anaesthetize with a mixture of ketamine and xylazine and heparinized. Remove the heart and quickly spend infusion retrograde aortic through at a pressure of 75 mm Hg (9,999 kPa) solution type Krebs and Henseleit. The balloon is introduced into the left ventricle and use teledistantiale a pressure of 5 mm Hg (RUB 666.6 PA). After a stabilization period of 20 min for 15 min before ischemia and during the whole experiment in the infusion solution add the analyzed compound (1 mm) or the media. Regional ischemia create by complete ligation of the left coronary artery for 30 min, after which the heart is subjected to reinfused within 2 hours

During the whole experiment control ventricular pressure, heart rate and parameters of the coronary release

After reinfused coronary artery again subjected to occlusion and spend the infusion of Chinese ink, in order to determine the boundary of risk. Then prepare cross sections and incubated in 1% solution of triphenyltetrazolium to determine the size of the infarct. Quantitative determination of the area of necrosis, expressed as % of risk area, obtained using the software image analysis.

As an example, the compound described in example (No. 1 from table), leads to a significant reduction of infarct size - 47% (control: 41,7±5,3 against the tested compound: 22±3,3; p<0,01). Areas with a risk of about 50% are comparable in both groups.

Connection # 1 reduces contracture during reinfused and greatly reduces the pressure of the left ventricle (percent predicamento recovery is 36% after 2 h reinfused in control animals vs. 65% in treated animals), maximum and minimum values of dP/dt and double the frequency of the pressure.

The study renoprotective action

An experiment conducted on male rats Sprague-Dawley (Charles River, France) weighing 270-330 g anaesthetize Animals by pentobarbital (60 mg/kg intraperitoneally), inkubiruut and artificially ventilated, the temperature of the support between 37 and 38°C.

On the animal exercise 3 cm laparotomy in point is the situation lying on his back, the right and left renal artery naked and subjected to occlusion for 30 min, and then spend reinfusion kidney under visual control and the incision is closed. In blood samples taken in the orbital sinus at day 0 (before anesthesia), and then a day 1, 2, 3, 4, 8 (after 1 occlusion - reinfused)determine the levels of serum creatinine and urea nitrogen.

The investigational compound or vehicle (tween 80 at a concentration of 2%) was injected at a dose of 3 mg/kg by intraperitoneal for 60 min prior to occlusion.

As an example, compound No. 1 reduces creatininemia 56% and uremia by 49% compared with media per day 3. It also reduces mortality in animals: 1/12 against 4/9 animals that received only the carrier.

Two of the above tests show that, on the one hand, compounds that can be used according to the invention, to reduce the size of myocardial infarction-induced cardiac ischemia - reinfuse, rabbits and enable better recovery of contractile function after reinfused, and that, on the other hand, they limit acute renal failure, caused by an episode of renal ischemia - reinfused.

Therefore, compounds of General formula (I) can be used for preparing medicaments for the prevention and treatment of peripheral neuropathies of various types, such as neuropathy, SV is related to trauma, or ischemic neuropathy, infectious neuropathy associated with alcohol-related drugs, or genetic neuropathy, as well as States of motoneurons, such as vertebral disease and amyotrophic lateral sclerosis. These drugs are also used in the treatment of neurodegenerative diseases of the Central nervous system, or the acute type, such as stroke and traumatic brain injury, or chronic type, such as autoimmune diseases (multiple sclerosis), Alzheimer's disease, Parkinson's disease and any other disease in which believe that the introduction of neurotrophic factors has a therapeutic effect.

Compounds that can be used according to the invention can also be applied in the treatment of acute or chronic renal insufficiency, glomerulonephritis, diabetic nephropathy, cardiac ischemia and failure, myocardial infarction, lower limb ischemia, coronary vasospasm, angina, pathological conditions associated with heart valves, inflammatory heart disease, side effects of cardiotoxic drugs or residual effects heart surgery, atherosclerosis and thromboembolic complications, restenosis, transplant rejection, conditions related to improper proliferate the th or migration of smooth muscle cells.

In addition, recent data from the literature indicate that benzodiazepine peripheral receptor type may play a significant role in the regulation of cell proliferation and cancer processes of rebirth. In General, and compared to normal tissues in various types of tumors and cancer, there is increased density of benzodiazepine receptors in the peripheral type.

In astrocytoma person the level of expression of benzodiazepine peripheral receptor type correlates with the degree of malignancy of the tumor, the index of proliferation and survival of patients. In tumors of the human brain, the increase in the number of benzodiazepine receptors in the peripheral type is used as a diagnostic indicator for medical imaging and as a therapeutic target for conjugates comprising a ligand of benzodiazepine peripheral receptor type and cytotoxic drugs. The high density of benzodiazepine receptors in the peripheral type is also observed in ovarian carcinomas and cancers of the breast. In the latter demonstrated that the level of expression of benzodiazepine receptors in the peripheral-type is associated with aggressive potential of the tumor; in addition, the presence of agonist benzodiazepine peripheral receptor type will timuerunt growth of cell lines of breast cancer.

All these results, which suggest a harmful function benzodiazepine peripheral receptor type in the processes of cancer rebirth, form the basis of relevance to the search for synthetic ligands that are specific for the benzodiazepine receptor, peripheral type, which is able to block its action.

Therefore, these compounds can be used to treat tumors and cancers.

Benzodiazepine receptors peripheral type are also present in the skin, and because of this connection, which can be used according to the invention can be used for prophylaxis or treatment of skin stress.

The phrase "skin stress" understand the different situations that can cause lesions, in particular the epidermis, regardless of the agent that causes this stress. This agent may be inside and/or outside the body, as, for example, the chemical agent or the agent is a free radical, or outside, such as ultraviolet radiation.

Thus, compounds that can be used according to the invention, designed to combat skin irritations, psoriasis, eritem, disesteem, sensations of heat and itching of the skin and/or mucous membranes, aging, and/or to prevent, and also they can be used for skin disorders, yet is how, for example, psoriasis, diseases accompanied by itch, herpes, photodermatosis, atopic dermatitis, contact dermatitis, psoriasis, prurigo, pruritus, insect bites, fibrosis and other disorders of maturation of collagen, immunological disorders or dermatological conditions such as eczema.

Thus, an object of the present invention is the use of compounds of General formula (I) for the preparation of pharmaceutical compositions containing an effective dose of at least one compound of General formula (I) in the form of a pharmaceutically acceptable base, salt, or MES, and in the form of a mixture, as appropriate, with suitable excipients.

These excipients selected depending on the pharmaceutical form and the desired method of administration.

Thus, the pharmaceutical compositions of the present invention can be designed for oral, sublingual, subcutaneous, intramuscular, intravenous, local, intratracheal, intranasal, transdermal, rectal or intraocular injection.

The standard form for injection may represent, for example, tablets, gelatin capsules, granules, powders, oral or injectable solutions or suspensions, transdermal patches or suppositories. For local injection can be considered the AMB ointment, lotions and lotions for the eyes.

These standard forms are in doses that give the possibility of daily injections from 0.001 to 20 mg of active ingredient per kg of body weight depending on the galenical form.

For the preparation of tablets the active ingredient, powdered or processed in any other way, add a pharmaceutical carrier which can be composed of diluents, such as, for example, lactose, microcrystalline cellulose, starch, and adjuvants used in the preparation of medicines, such as binders (polyvinylpyrrolidone, hypromellose, and the like), moving substances such as silicon dioxide, lubricants such as magnesium stearate, stearic acid, glyceryltrinitrate, sodium fumarate. You can also add moisturizing agents or surfactants such as sodium lauryl sulfate.

Methods of implementation can be direct compression, dry granulation, wet granulation or hot melting.

Tablets can be without the shell may be coated with a sugar shell, such as sucrose, covered with shells of various polymers or other suitable materials. They can be performed with a fast, slow or extended release of the active is the first ingredient through the polymer matrix or specific polymers, used in the shell.

For the preparation of gelatin capsules the active ingredient is mixed with dry (easy mixing, dry or wet granulation or hot melting), liquid or semi-solid pharmaceutical carriers.

Gelatin capsules may be hard or soft, can be covered with a film or otherwise, so as to provide rapid, prolonged or delayed activity (for example, intestinal forms).

The composition is in the form of a syrup or elixir or for administration in the form of drops can contain the active ingredient together with a sweetener, preferably containing no calories, methyl paraben or propyl paraben as an antiseptic, Corrigendum and the coloring agent.

Powders and granules which are dispersible in water, may contain the active ingredient in the form of a mixture with dispersing agents or wetting agents, or dispersing agents such as polyvinylpyrrolidone, as well as with sweeteners and agents that enhance the taste.

For rectal use of suppositories which are prepared with binders, melting at rectal temperature, for example cocoa butter or polyethylene glycols.

For parenteral use injectable aqueous suspensions, isotonic physiological races of the thieves or sterile solutions, which contain pharmacologically compatible dispersing agents and/or moisturizing agents, for example propylene glycol or butyleneglycol.

The active ingredient can also be prepared in the form of microcapsules, possibly with one or more than one carrier or one or more than one additive or polymer matrix or a cyclodextrin (percutaneous patches, forms a long-release).

Compositions for local injection according to the invention contain a medium compatible with the skin. They can be represented, in particular, in the form of aqueous, alcoholic or aqueous-alcoholic solutions, gels, emulsions water in oil or oil-in-water, having the form of cream or gel, microemulsions, aerosols, or in the form of vesicular dispersions containing ionic and/or nonionic lipids. These herbal forms are prepared in accordance with conventional methods in this field.

In conclusion, the pharmaceutical compositions according to the invention, in addition to compounds of General formula (I)may contain other active ingredients that may be useful in the treatment of the above disorders and diseases.

1. Medicinal product for the prevention and treatment of diseases and disorders associated with dysfunction of the benzodiazepine receptor, peripheral type, consisting of compounds of General formula (I)

in which X represents a halogen atom;

Y represents one or more than one atom or one or more than one group selected from hydrogen, halogen and hydroxyl, methyl, methoxy and nitro group,

R1is a (C1-C4)alkyl group,

R2and R3each independently from each other represents a hydrogen atom or (C1-C4)alkyl group, or alternatively R2and R3form together with the nitrogen atom carrying them, pyrrolidinyloxy, piperidinyloxy or morpholinyl group.

2. The drug according to claim 1, characterized in that the compound of General formula (I) is 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-ndimethylacetamide.

3. The drug according to any one of claims 1 and 2, wherein the disease or disorder is a degenerative disease of the Central or peripheral nervous system.

4. The drug according to any one of claims 1 and 2, wherein the disease or disorder is a cardiac disease or disorder.

5. The drug according to any one of claims 1 and 2, wherein the disease or disorder is a nephropathy.



 

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The invention relates to the field of medicine and for the application of cyclic ether (R)-3-hydroxybutyrate of formula (1) for the treatment of disease conditions mediated by free radicals, toxic agents, such as peptides and proteins, and genetic defects, harmful to the cell metabolism, insulin resistance or other defects in glucose metabolism or conditions that cause the defect, ischemia, head injury, and/or improve the efficiency of cells

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

The invention relates to chemical-pharmacological industry and relates to an inhibitor of the expression of integrin, comprising as active ingredient a compound sulfonamida formula IaIbthat means, containing an inhibitor of the expression of integrin formula IaIbfor the treatment of arteriosclerosis, psoriasis, osteoporosis, angiogenesis, retinal angiogenesis, diabetic retinopathy, inflammatory diseases, and how to prevent, treat or alleviate disease associated with increased expression of integrin

The invention relates to the field of pharmacy

The invention relates to medicine, namely to liquid pharmaceutical compositions of a wide spectrum of action on the basis of alkaloids aberamentho stimulants and vitamins, which can be used to improve blood circulation of the brain, in particular in the treatment of the effects of traumatic brain injury, as well as for the prevention and treatment of ischemic lesions of the brain, stimulate brain activity, for the adaptation of the vestibular apparatus to the overload

FIELD: medicine.

SUBSTANCE: method involves intravenously administering 0.1-1% aqueous solution of khlorin, selected from group containing photolon, radachlorine or photoditazine at a dose of 0.2-0.5 mg/kg or 0.2-1% aqueous solution of porphyrin like photogem at a dose of 0.2-1 mg/kg. Laser irradiation of blood is carried out 5-15 min later after beginning photosensitizer injection into cubital vein of one arm via laser light guide set in advance in the cubital vein of the other arm during 10-40 min at wavelength of 661-666 nm and power of 20-50 mW one session per day during 3-10 days with the aqueous solution of khlorin used as the photosensitizer, or laser irradiation of blood with wavelength equal to 630-633 nm during 10-45 min with power of 20-50 mW one session per day with the aqueous solution of porphyrin used as the photosensitizer. Repeated intravenous administration of photosensitizer is carried out 1-3 months later combined with repeated laser irradiation of blood.

EFFECT: reduced risk of tumor cells dissemination and metastasis development.

2 cl

The invention relates to new S-4 carbonate-bearing similarly to taxanes of formula 1 and their pharmaceutical salts:

where R denotes phenyl, isopropyl or tert.butyl; R1denotes-C(O)RZin which RZmeans (CH3)3CO-, (CH3)3CLO2-, CH3(CH2)3Oh, cyclobutyl, cyclohexyloxy or 2-furyl and R2denotes CH3C(O)O-, and also to pharmaceutical compositions based on them and their use as protophobic agents to treat diseases of humans and animals

The invention relates to medicine, Oncology
The invention relates to medicine, in particular to cancer, and can be used in the treatment of resectable, including locally common forms of lung cancer

The invention relates to compositions and methods for the treatment and prevention of such diseases and conditions as graft rejection, surgical adhesions, inflammatory bowel disease, nasal polyps, and includes delivery to the site of inflammation antimicrotubular agent is paclitaxel, or an analogue or derivative
The invention relates to medicine, in particular to cancer, and can be used in the treatment of locally common forms of lung cancer, including inoperable

The invention relates to compounds of formula (I) or (II)

or their pharmaceutically acceptable salts, where Y and Z each for each case independently represents a D - or L-natural or unnatural-amino acid; n in each case independently is 0 or 4, (I) provided that both n cannot simultaneously be 0; and 0 or 4 (II)

moreover, these amino acids (I) are chain: X1-X2-X3-X4where X1represents Tyr or Trp, which may be protected by a BOC group; X2represents D-Trp; X3represents Lys, which may be protected by a BOC group; X4is a Nal, Tyr or Thr; m is 0; a represents N or R1b means HE or OR1; (II) X1is a natural or non-natural D - or L-isomer of Phe, Trp or Tyr, where in the case when X1is Tyr, an aromatic ring in its side chain optionally substituted by R6; X2is a D - or L-isomer of Trp; X3represents Lys; X4represents Opticheskie ring, disposed in its side chain may be optionally substituted by R6or in the case when X4is either Ser or Thr, the oxygen atom located in its side chain, optionally may be substituted by one or more R1

The invention relates to the objects of the invention characterized in the claims, i.e

The invention relates to medicine, namely to compositions and methods for potentiating the therapeutic effects of interferon, and can be used for preparation of medicines interferon for use in medicine and veterinary medicine

The invention relates to medicine, in particular to Oncology, and for the treatment of various cancers

Drug // 2234331
The invention relates to the field of pharmaceuticals, namely, to medicines, and can be used to adjust the chemical composition of food, for example, metabolic disorders in patients with chronic renal failure
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