MXPA01007550A - USE OF PYRIDAZINO[4,5-b - Google Patents

Abstract

The invention concerns the use of a compound of general formula (I) wherein:X represents a halogen atom;Y represents one or several atoms or groups selected among hydrogen, halogens and hydroxy, methyl, methoxy and nitro groups;R1 represents a C1-C4 alkyl group;R2 and R3 represent each a hydrogen atom or a C1-C4 alkyl group, or R2 and R3 together form with the nitrogen atom bearing them, a pyrrolidinyl, piperidinyl or morpholinyl group, for preparing a medicine for preventing or treating diseases and disorders related to the peripheral benzodiazepin receptor.

Description

' USE OF PYRIDAZINE DERIVATIVES [4-5-6] INDOL-1 »ACETAMID FOR PREPARING MEDICINES INTENDED FOR DISEASE-LINKED DISEASE OF PERIPHERAL-TYPE RECEPTORS THE BENZODIAZEPINAS In the framework of the investigation of compounds that can favor the regeneration of the axons of peripheral nerve cells after a lesion, a subclass of the compounds of the international patent application PCT / FR98 / 01667 has been identified. compounds of general formula (I) wherein: X represents a halogen atom, Y represents one or more atoms or groups chosen from hydrogen, Halogens and the hydroxy, methyl, methoxy and nitro groups, Rt represents a group (Ci-Cj alkyl, R2 and 3 each represent, independently of the other, a hydrogen atom or a group (Ct-C-alkyl, or R2 and R3 form, with the nitrogen atom carrying them, a pyrrolidinyl, piperidinyl, or morpholinyl group.

These compounds have a strong affinity for the peripheral receptors of the benzodiazepines (p-sites or PBR), and some induce, especially, a reduction of the neuronal loss in the facial nucleus after the section of the facial nerve. They also have cardio and renoprotective effects. A particularly interesting compound for use according to the invention is, for example, 7-chloro-γ / γ /, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5 -o] -indol-1 -acetamide. The latter can be prepared according to the following procedure, given by way of example. Example (Compound No. 1 of the following table) 1. Ethyl 6-chloro-1-methyl-1 / - -indol-2-carboxylate. A suspension of 1.8 g (45 mmol) of 60% sodium hydride (previously washed with petroleum ether) and 8.0 g (35.8 mmol) of 6-chloro is stirred for 2 h at room temperature. 1 Ethyl H-indole-2-carboxylate in 80 ml of? /,? / - dimethylformamide, then 2.8 ml (45 mmol) of iodomethane are added and the mixture is stirred at room temperature for 4 h. 5 ml of absolute ethanol are added and the solvent is evaporated under reduced pressure. The residue is taken up in water and the mixture is extracted with dichloromethane, the organic phase is dried, filtered, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a silica gel column. 8.5 g (35.7 mmol) of a white crystalline compound are isolated. Melting point: TS.d-Zß ^ C. 2. 6-Chloro-2- (ethoxycarbonyl) -1-methyl-a-oxo-1 H-indol-3-ethyl acetate. To a solution of 4 ml (36 mmol) of ethyl chlorooxoacetate in 100 ml of 1,2-dichloroethane, 4 ml (36.4 mmol) of titanium tetrachloride are added. The reaction mixture was stirred for 30 min at room temperature, then 7.8 g (32.8 mmol) of ethyl 6-chloro-1-methyl-1 H-indole-2-carboxylate were added and the reaction mixture was stirred. for 4 h at room temperature. The medium is cooled, 200 ml of dichloromethane and 100 ml of water are added. The organic phase is decanted, washed with water, dried over sodium sulfate, filtered, the filtrate is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel. 9.4 g (29.0 mmol) of product are isolated. Melting point: 94-95 ° C. 3. ethyl 7-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino- [4,5-s] indol-1-carboxylate. To a solution of 4.6 g (13.6 mmol) of 6-chloro-2- (ethoxycarbonyl) -1-methyl-a-oxo-1 H-indole-3-ethyl acetate in 120 ml of acetic acid, 4 ml (40.6 mmol) of phenylhydrazine are added at room temperature. The reaction mixture is stirred for 30 min. at room temperature, then for 4 h at reflux. The medium is cooled, 350 ml of dichloromethane and 100 ml of water are added. The organic phase is decanted, washed with a saturated aqueous solution of sodium hydrogencarbonate, then with water, dried over sodium sulfate, filtered, concentrated under reduced pressure and the residue purified by chromatography on a silica gel column. . 4,1 g (1 0,7 mmoles) of product are isolated. Melting point: 216-21 8.5 ° C. 4. 7-Chloro-1 - (hydroxymethyl) -5-methyl-5-phenyl-3,5-dihydro-4f-pyridazino [4,5-D] indole -1 -one To a solution of 4.04 g (10.6 mmol) of 7-chloro-5-methyl-4-oxo-3-phenyl-3-t5-d-hydro-4 - / - pyridazino [4,5-jb] indole -1-ethylcarboxylate in 150 ml of tetrahydrofuran, 2.5 g (66.1 mmoles) of sodium borohydride are added. Under stirring, 2.25 ml of methanol are progressively added, then the mixture is heated under reflux for 5 h. The mixture is poured into a freezing solution of 1 M hydrochloric acid, an insoluble is isolated by filtration on sintered glass, which is washed with water and with diethyl ether, then dried. 3.3 g (9.7 mmol) of compound are isolated in the form of a white solid which is used as such in the next step. Melting point: 219-220.5 ° C. 5. 7-Chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-6] indole-1 - carboxaldehyde. It is added to a solution of 3.3 g (9.7 mmoles) of 7-chloro-1- (hydroxymethyl) -5-methyl-3-phenyl-3,5-dihydro-4 / Y-pyridazino [4,5 -)] indole-4-one in 300 ml of dichloromethane, 5.7 g (65.6 mmol) of manganese dioxide and the reaction mixture was stirred for 24 h under reflux. The medium is cooled, filtered on Teflon ™ membrane, the solid is rinsed with dichloromethane, then the filtrate is concentrated under reduced pressure. 2.88 g (8.53 mmol) of compound are isolated in the form of a white solid which is used as such in the next step. Melting point: 235-236 ° C. 6. 7-Chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4-pyridazino, -4,5-D] ind ?? 1 - . 1-acetonitrile. To a solution of 2.14 g (10.96 mmol) of 1 - [(isocyanomethyl) sulfonyl] -4-methylbenzene in 50 ml of 1,2-dimethoxyethane, 1.27 g (10.96 g) are added in small portions. mmoles) of potassium 1,1-dimethylethylate was stirred the reaction mixture for 30 min. at -60 ° C, 2.88 g (8.53 mmol) of 7-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4 / - -pyridazino are added [4,5 -D] indole-1-carboxaldehyde and the reaction mixture was stirred for 3 h 30 min. at -60 ° C. 9 ml of methanol are added and the reaction mixture is stirred for 30 minutes at room temperature and 1 h at reflux. The medium is cooled, concentrated under reduced pressure, water is added to the residue, 5 ml of acetic acid and 200 ml of dichloromethane, the organic phase is separated out and the aqueous phase is extracted with dichloromethane. The organic phases are combined, washed with water, dried over sodium sulfate, filtered, concentrated under reduced pressure and the residue is purified by chromatography on silica gel. 1.87 g (5.36 mmol) of compound is isolated in the form of a white solid which is used as such in the next step. Melting point: 305-315 ° C. 7. 7-Chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-6] indole-1-methyl acetate. To a solution of 1.83 g (5.25 mmole) of 7-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino [4,5-o] indole-1 -acetonitrile in 250 ml of methanol, hydrogen chloride is added until the solution is saturated and the reaction mixture is stirred for 4 h at reflux. The medium is cooled, the reaction mixture is concentrated under reduced pressure, 25 ml of water and 25 ml of methanol are added to the residue.

After stirring, the insoluble material is collected by filtration, washed with water and with diethyl ether, dried and purified by chromatography on a column of silica gel. 1.00 g (2.62 mmol) of compound is isolated as a white solid. Melting point: 188.5-1906 ° C. 8. 7-Chloro -? /,? /, 5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4I / -pyridazino [4,5-6] indole-1 -acetamide. Under argon, it is added to a solution of 0.49 g (6 mmol) of dimethylamine hydrochloride in 80 ml of toluene, at 0 ° C, 3 ml (6 mmol) of trimethylaluminum (2M in toluene) and the mixture is stirred reacting for 1 h 30 min at room temperature. 0.21 g (0.55 mmol) of 7-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4-V-pyridazino [4,5-b] indole-1 is added. methyl acetate and the reaction mixture was stirred for 6 h under reflux. The medium is cooled to 4 ° C, add 10 ml of water and 100 ml of dichloromethane, filter the solution, and concentrate the filtrate under reduced pressure. Water, 1 M hydrochloric acid and 150 ml of dichloromethane are added to the residue, the organic phase is separated, washed with water, dried over sodium sulfate, filtered, concentrated under reduced pressure and the residue is purified for chromatography over column of silica gel. After recallization from a mixture of dichloromethane and ethyl acetate, 0.2 g (0.51 mmol) of the compound is isolated in the form of a white cotton-like solid. Melting point: 229.5-230 ° C. The following table illustrates the chemical structures and physical properties of some compounds usable according to the invention. Legend of the table "Me" and "Et" designate, respectively, a methyl and ethyl group. "Pyrrolid" "piperid '," and "morph" designate, respectively, a pyrrolidinyl, piperidinyl and morpholinyl group.

Table The procedures and results of the tests that have been performed are described below. Study of the linkage f3HlRo5-4864 with peripheral type receptors of the benzodiazepines The affinity of the compounds of the invention has been determined for peripheral type receptors of the benzodiazepines (p-site or PBR). The p-site receptors can be selectively labeled in rat kidney membranes incubated in the presence of [3 H] Ro5-4864. The compounds have been the subject of an in vitro study in terms of their affinity for these receptors. The animals used are male Sprague Dawley rats (Iffa Credo) of 180 to 300 mg. After decapitation, the kidney is removed and the tissue homogenized at 4 ° C by means of a Polytron ™ homogenizer for 2 min at 6/10 of the maximum velocity in 35 volumes of 50 mM Na2HPO phosphate buffer at a pH adjusted to 7.5 with Na2HPO. The membrane homogenate is filtered on gauze and diluted 10 times with buffer. Incubate the [3H] Ro5-4864 (Specific activity: 70-90 Ci / mmol, New England Nuclear), at a concentration of 0.5 nM, in the presence of 100 μl of the membrane homogenate in a final volume of 1 ml of buffer containing the compound to be tested. After an incubation of 3 h at 0 ° C, the membranes are recovered by filtration on Whatman GF / B ™ filters, which are washed 2 times with 4.5 ml of cold incubation buffer (0 ° C). The amount of radioactivity retained by the filter is measured by liquid scintigraphy. For each concentration of compound studied, the percentage of inhibition of the bond of [3H] Ro5-4864 is determined, then the concentration Cl50, concentration that inhibits 50% of the specific binding. The Ci50 of the most active compounds range from 0.6 nM to 20 nM. The compounds which can be used according to the invention are therefore high-affinity ligands for the peripheral type receptors of the benzodiazepines. Study of neurotrophic activity. Regeneration test of the injured facial nerve, by measurement of the functional recovery of the palpebral reflex, according to a modification of the method of K. Kujawa et al., Experimental Neurology (1989) 105 80-85. Injury to the facial nerve due to local freezing results in degeneration of the distal part of the facial nerve and loss of eyelid blinking function. The products to be studied are administered intraperitoneally or orally 2 times a day with a 6 to 8 h phase shift, every day for 10 days (duration of the experience). The first treatment is administered 30 min before the injury. Observation of the animals: the recovery of the function of the eyelids in the injured animals is observed every day, once a morning from JO to J5 and twice (morning and night with 6 to 8 h of phase shift) from J6 to J10, before each treatment, according to a theoretical score that goes from 0 to 4.

Score 0: open eye, score 1: closed eye with a degree less than half the eye; score 2: degree of closure between 1/2 and 3/4; score 3: degree of closure greater than 3/4; Score 4: eye completely closed. The results are expressed by the ratio of the AUC ("area under the curve") of the treated group and the control group. The AUC ratios of the most active compounds are between 1.12 and 1.20. These compounds therefore increase the recovery of the palpebral reflex after facial nerve injury from 12 to 20%. Proof of survival of the motor neurons after the section of the facial nerve in the 4-day-old rat. After injury to the facial nerve in the immature rat, the motor neurons of the facial nucleus suffer a neuronal death by apoptosis. The evaluation of neuronal survival is performed with the help of histological methods and neuronal counting. Immature rats were anesthetized 4 days by means of pentobarbital (3 mg / kg by i.p.). The right facial nerve is separated and sectioned, at the exit of the stylomastoid foramen. After they wake up, the mice are reintroduced with their mother and treated, for 7 d, by means of one or two daily administrations, orally or intraperitoneally, in doses ranging from 1 to 10 mg / kg. 7 d after the injury, the animals are decapitated, and the brains are frozen in isopentane at -40 ° C. The facial core is cut with a cryostat, in sections of 10 μm, in its entirety. The motoneurons are colored with cresyl violet and are counted with the help of Histo ™ software: (Biocom ™). In this model, the most active compounds increase neuronal survival by approximately 10 to 30%. By way of example, the compound described in the example (N | 1 of the table) increases neuronal survival by 31% via i.p. The results of the tests show that the compounds of general formula (I) favor nerve regeneration. Study of cardioprotective effects. Cardioprotective effects have been studied in isolated rabbit hearts subjected to regional ischemia and reperfusion. The infarct size has been measured as well as the recovery of contractile function with reperfusion. New Zealand rabbits (2.3 to 2.5 kg., ESD France) are anesthetized by means of a mixture of ketamine-xylasin and heparins. The heart is removed and a retrograde aortic perfusion is quickly perfused at a pressure of 75 mmHg with a Krabs Henselheit-type solution. A balloon is inserted into the left ventricle and a telediastolic pressure of 5 mmHg is imposed. After a stabilization period of 20 min., The compound to be studied (1 mM) or the vehicle is added in the perfusion solution 15 min. before ischemia and throughout the duration of the experience. Regional ischemia is created by total ligature of the left coronary artery for 30 min. and then reperfusion of the heart is carried out for 2 h. The parameters of ventricular pressure, heart rate and coronary flow during the whole experience are followed. At the end of the reperfusion, the coronary artery is again occluded and perfusion of Chinese ink is carried out in order to delimit the risk area. Cross sections are then made and incubated in a 1% triphenyl tetrazolium solution, in order to measure the infarct size. The quantification of the necrosis zone, expressed in% of the risk zone, is obtained thanks to an image analysis software. By way of example, the compound described in the Example (No. 1 of the table) leads to a significant reduction in infarct size by 47% (controls: 41, 7; t_5.3 vs. studied compound: 22 +3.3; < 0.01).

The risk zones of approximately 50% are comparable in the two groups. "Compound No. 1 decreases reperfusion contracture and significantly restores left ventricular pressure (percentage of pre-ischemic recovery of 36% after 2 h of reperfusion in controls versus 65% in treated animals), dP / dt max and and the double product frequency-pressure Study of the renoprotective effects The experience is carried out in male Sprague-Dawley rats (Charles Ríver France) from 270 to 330 g. The animals are anesthetized with pentobarbital (60 mg / kg i.p.), intubated and ventilated artificially, maintaining their temperature between 37 and 38 ° C. A 3 cm laparotomy is performed on the animal in do decubitus, the right and left renal arteries are separated and occluded for 30 min. then, reperfusion of the kidneys is carried out under visual control and the incision is closed. The serum percentages of creatinine and urea nitrogen are determined from blood samples taken at the level of the orbital sinus, in JO (before anesthesia), then in J 1, J2, J3, J4, J8 (after occlusion) -reperfusion). The compound you wish to study, or your vehicle (2% Tween 80) is administered in the dose of 3 mg / kg via l. p. 60 min. before the occlusion. By way of example, compound No. 1 reduces creatininemia by 56% and uremia by 49%, compared to the vehicle in J3. It also reduces the mortality of the animals: 1/12 against 4/9 in the animals that have received only the vehicle. The two foregoing tests show, on the one hand, that the compounds usable according to the invention reduce the size of the infarct induced by cardiac ischemia-reperfusion in the rabbit and allow a better recovery of the contractile function to reperfusion, and on the other hand, limit acute renal failure caused by an episode of renal ischemia-reperfusion. Therefore, the compounds of general formula (I) can be used for the preparation of medicaments for the prevention and treatment of periphery neuropathies of different types, such as traumatic or ischemic neuropathies, infectious, alcoholic, medicinal or genetic neuropathies, as well as in the affections of the motor neuron, such as spinal amyotrophies and amyotrophic lateral sclerosis. These medications will also find an application in the treatment of neurodegenerative diseases of the central nervous system, whether of the acute type such as cerebrovascular accidents and head and spinal cord injuries, whether of the chronic type such as autoimmune diseases (sclerosis on plates). , Alzheimer's disease, Parkinson's disease and any other disease in which the administration of neurotrophic factors is considered to have a therapeutic effect. The compounds which can be used according to the invention can also be used in the treatment of acute or chronic renal failure, glomerulonephritis, diabetic nephropathy, ischemia and heart failure, myocardial infarction, ischemia of the lower limbs, coronary vasospasm, angina pectoris, pathologies associated with heart valves, inflammatory heart diseases, side effects due to cardiotoxic drugs or after cardiac surgery, atherosclerosis and its thromboembolic complications, restenosis, graft rejections, conditions linked to incorrect proliferation or migration of smooth muscle cells. On the other hand, recent data from the literature indicate that the peripheral type receptor of the benzodiazepines could play a fundamental role in the regulation of cell proliferation and cancerization processes. In a general way, and in comparison with normal tissues, a growing density of peripheral type receptors of benzodiazepines is observed in different types of tumors and cancers.

In human astrocytomas, the level of expression of the peripheral type receptor of the benzodiazepines correlates with the degree of malignancy of the tumor, the rate of proliferation and the survival of patients. In human brain tumors, the increase in the number of peripheral type receptors of the benzodiazepines is used as an indication of medical imaging and as a therapeutic target for conjugates formed by a receptor ligand of the peripheral type of benzodiazepines and a drug cytostatic A high density of peripheral-type receptors of benzodiazepines is also observed in ovarian carcinomas and breast cancers. With respect to the latter, it has been shown that the level of expression of peripheral type receptors of benzodiazepines is linked to the aggressive potential of the tumor; On the other hand, the presence of a peripheral receptor agonist of the benzodiazepines stimulates the growth of a breast cancer line. The combination of these results, which suggests a deleterious function of the peripheral type receptor of benzodiazepines in cancerization processes, constitutes a relevant basis for the investigation of specific synthetic ligands of the peripheral type receptor of benzodiazepines capable of blocking the effects of East. The compounds can therefore be used for the treatment of tumors and cancers. Peripheral type receptors of the benzodiazepines are also present at the level of the skin, and in this regard, the compounds usable according to the invention can be used for the prophylaxis or treatment of skin stresses. Skin stress is understood as the different situations that could cause data in particular at the level of the epidermis, whatever the agent that causes that stress. This agent can be internal and / or external to the organism, such as a chemical or radical agent, or external, such as ultraviolet radiation. In this way, the compounds which can be used according to the invention are intended to prevent and fight against skin irritations, herpes, erythemas, dysaesthetic sensations, sensations of flushing, pruritus of the skin and / or mucous membranes, aging and can also be used in skin disorders such as, for example, psoriasis, pruritic diseases, herpes, photodermatosis, atopic dermatitis, contact dermatitis, lichen, prurigo, itching, insect bites , in fibrosis and other disorders of the maturation of collagens, in immune disorders or also in dermatological conditions such as eczema. Thus, the subject of the present invention is the use of the 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 a basic or salt state or of pharmaceutically acceptable solvate, and in admixture, if appropriate, with suitable excipients. Said excipients are chosen according to the pharmaceutical form and the desired mode of administration. The pharmaceutical compositions according to the invention can thus be intended for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal, intraocular administration. The unit administration forms can be, for example, tablets, capsules, granules, powders, oral or injectable solutions or suspensions, transdermal patches ("patch"), suppositories. For topical administration, ointments, lotions and eye drops may be considered. Said unit forms are dosed to allow a daily administration of 0.001 to 20 mg of active principle per kg of body weight, according to the galenic form. To prepare tablets is added to the active ingredient, micronized 'or not, a pharmaceutical vehicle that may be composed of diluents, such as lactose, microcrystalline cellulose, starch, and formulation additives such as binders, (polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc.), glidants such as silica, lubricants such as magnesium stearate, stearic acid, glycerol tribehenate, sodium stearyl fumarate. Wetting agents or surfactants such as sodium lauryl sulfate can also be added. Embodiment techniques can be direct compression, dry granulation, wet granulation or heat fusion. The tablets may be bare, presented as dragees, for example by sucrose, or coated with various polymers or other appropriate materials. They can be designed to allow a rapid, delayed or prolonged release of the active principle thanks to polymer matrices or to specific polymers used in the coating. To prepare capsules, the active ingredient is mixed with dry pharmaceutical vehicles (simple mixture, dry or wet granulation, or heat fusion), liquid or semi-solid. The capsules can be hard or soft, film-coated or not, so as to have a rapid, prolonged or delayed activity (for example for an enteric form). A composition in the form of a syrup or an elixir or for administration in the form of drops may contain the active ingredient together with a sweetener, preferably caloric, methylparaben or propylparaben as an antiseptic, a flavoring agent and a dye. Powders and granules dispersible in water may contain the active ingredient in admixture with dispersing agents or wetting agents, or dispersing agents such as polyvinylpyrrolidone, as well as sweeteners and flavor correction agents. For rectal administration, suppositories prepared with binders that melt at the rectal temperature, for example cocoa butter or polyethylene glycols, are used. For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injected solutions containing pharmacologically compatible dispersants and / or wetting agents, for example propylene glycol or butylene glycol, are used. The active principle can also be formulated in the form of microcapsules, optionally with one or various supports or additives, either with a polymeric matrix or with a cyclodextrin (transdermal patches, prolonged release forms). The topical compositions according to the invention comprise a medium compatible with the skin. They can be present especially in the form of aqueous, alcoholic or hydroalcoholic solutions, gels, water-in-oil or oil-in-water emulsions, which have the appearance of a cream or a gel, microemulsions, aerosols, or else in the form of vesicular dispersions which they contain ionic and / or non-ionic lipids. These galenic forms are prepared according to the usual methods of the areas considered. Finally, the pharmaceutical compositions according to the invention may contain, together with a compound of general formula (I), other active ingredients that may be useful in the treatment of the disorders and diseases indicated previously.

Claims (7)

1. CLAIMS 1. Use of a compound of general formula (I): wherein: X represents a halogen atom, Y represents one or more atoms or groups chosen from hydrogen, halogens and hydroxy, methyl, methoxy and nitro groups, R represents a (C1-C4) alkyl, R2 and R3 represent each, independently of the other, a hydrogen atom or a group (C ^ CHjalkyl, or R2 and R3 form, with the nitrogen atom carrying them, a pyrrolidinyl, piperidinyl, or morpholinyl group, for the preparation of A medicine for the prevention and treatment of diseases and disorders linked to the dysfunction of the peripheral type receptors of benzodiazepines
2. 2. Use according to claim 1, characterized in that the compound of general formula (I) is 7-chloro -? /,? /, 5-trimethyl-4-oxo-3-phenyl-3, 5-dihtdro-4H-pyridazino- [4,5- / j] indol-1 -acetamide
3. 3. Use according to one of the claims 1 and 2, characterized in that the disease or disorder is a degenerative disease of the nervous system c entral or peripheral.
4. 4. Use according to one of claims 1 and 2, characterized in that the disease or disorder is a heart disease or disorder.
5. 5. Use according to one of claims 1 and 2, characterized in that the disease or disorder is a nephropathy.
6. 6. Use according to one of claims 1 and 2, characterized in that the disease or disorder is a skin stress.
7. 7. Use according to one of claims 1 and 2, characterized in that the disease or disorder is a tumor or a cancer.