MXPA98003172A - Use of 2-amino-4- (4-fluorbencilamino) -1-etoxicarbonilaminobenceno for prophylaxis and the treatment of the consequences of the acute and chronic deficit of brain blood irrigation, as well as neurodegenerati diseases - Google Patents

Abstract

The present invention relates to the use of the compound 2-amino-4- (4-fluorobenzylamino) -1-ethoxycarbonylaminobenzene, (I) or its pharmaceutically usable salts for the preparation of a medicament for the prophylaxis and treatment of sequelae of the chronic deficit of cerebral blood supply, especially apoplexy

Description

UTILIZATION OF 2-AMINO-4- (4-FLUORBENCILAMINO) -l- ETOXICARBONILAMINOBENCENO FOR PROPHYLAXIS AND THE TREATMENT OF THE CONSEQUENCES OF THE ACUTE DEFICIT AND CHRONIC OF BLOOD BREAST IRRIGATION, AS WELL AS OF NEURODEGENERATIVE DISEASES.

The invention relates to the use of 2-amino-4- (4-fluorobenzylamino) -l-ethoxycarbonylaminobenzene of formula I or its pharmaceutically usable salts for the preparation of medicaments for the prophylaxis and treatment of the consequences of the acute and chronic deficit of cerebral blood supply and neurodegenerative diseases. Compound I is in development as an anticonvulsant. It presents a broad spectrum of action against various convulsions produced experimentally and in animal genetic models. The effectiveness in the animal is greater than that of many introduced anticonvulsants. In addition, effects of muscle relaxants, fever reducers and analgesics have been described (DE 42 00 259). A problem of many anticonvulsants introduced, especially, substances that strengthen GABA, such as phenobarbital, diazepam and clonazepam, but also phenytoin, a sodium channel blocker, is the negative influence on mental performance. Due to the accentuation of the inhibition in the brain, in addition to the anticonvulsive effect, central sedation also occurs, which reduces the assimilation capacity of the patient. Otherwise, these anticonvulsants have no neuroprotective effect in the experiment with animals or patients. The consequences of a cerebral blood supply deficit, as, for example, occurs in stroke, are not attenuated. In the epileptic seizure there is also a shortage of affected brain regions, but that is not due to a blood supply deficit, but to the strong cellular activation, by which reserves are overloaded and the supply is no longer enough. Therefore, an anticonvulsant that displays a neuroprotective effect on the overburdened brain is desirable.

A neuroprotective effect is also necessary for the therapy of other neurodegenerative diseases. For example, Alzheimer's disease, Huntington's chorea, multiple sclerosis, AIDS-induced encephalopathy and other encephalopathies caused by infections that are caused by rubella virus, herpes, borrelias and unknown pathogens can be counted among them. Creutzfeld-Ja ob disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, neurodegenerations induced by trauma and neuronal hyper-excitation states such as drug suppression or poisoning, as well as neurodegenerative diseases of the peripheral nervous system as polyneuropathies and polyneuritis. For the treatment of cerebral blood flow deficit and stroke today several strategies are followed. As a prophylaxis, drugs that inhibit the formation of thrombi and increase the properties of fluidity of the blood as acetylsalicylic acid can be used. But such treatment has only a purely prophylactic effect, a therapy with it is not possible. If there is a chronic deficit of cerebral blood supply, drugs that act as vasodilators are used as calcium antagonists.

For the therapy of stroke as an acute cerebral blood supply deficit, preparations that have a thrombolytic effect can also be used to eliminate eventual vascular tamponade. But these can only be used when thorough examination has unequivocally clarified that the stroke is not due to cerebral hemorrhage. Clinically proven for apoplexy therapy, there are preparations of NMDA antagonist effect, which directly inhibit overactivation of underbased cells. However, these substances have a high potential for side effects. Because, according to the point of view of today, they can only be used under intensive medical supervision and after a univocal diagnosis. In addition, NMDA antagonists have a negative effect on learning ability due to the inhibition of brain plasticity. A prophylactic use of these preparations therefore from the point of view of today seems impossible, despite the good prophylactic effect in the experiment with animals. It is the object of the present invention to provide a medicament with good neuroprotective properties and a low potential for side effects, for the prophylaxis and treatment of stroke, of the cerebral blood supply deficit and other conditions that recharge the nerve cells. Surprisingly it was then found that compound I exhibits significant neuroprotective effects in the animal experiment. This opens completely new possibilities for the prophylaxis and treatment of the consequences of acute and chronic cerebral blood supply deficit, especially stroke, as well as neurodegenerative diseases.

Pharmacological examinations; The goal of the trial with compound I in models for learning performance and neuroprotection was to estimate the possible influence on these parameters, since compound I among others displays a GABA effect. As the epileptic patient for the repeated attacks frequently already suffers from a deficit in learning performance, these tests were performed on animals to which an amnestic factor had been added, that is, they had decreased learning performance. For this the animals were, either, repeatedly treated with electroshocks or were subjected to a suppression of alcohol; for the estimation of the direct neuroprotective effect in the animals a chronic deficit of cerebral irrigacón was produced by the ligature of the blood vessels that lead to the brain. All these damages lead to a reduction in learning performance, which is valuable as an indicator of nerve cell damage. In these models GABA-reinforcing drugs with antiepileptic effect such as diazepam and sodium channel blockers such as phenytoin do not present positive effects, in higher doses there may even be negative effects on learning performance.

Examination models: üañQ its performance in learning by decreasing cerebral blood supply In this model, one of the arteries of the neck (carotids) is linked to rats under anesthesia. The animals awaken from anesthesia and then present a diminished learning performance. This was verified by the jump to the stick test. In this test the animals must learn to avoid a small electrical shock in the foot that is announced to them previously by an acoustic signal, jumping on a vertical stick that hangs on the floor. The performance in the learning of the animals is measured as a percentage of the amount of conditioned reactions (jump to the stick during the phase of the acoustic signal). Animals untreated and apparently operated (anesthetized and vessels discovered but without ligature) learn very quickly the relationship een the acoustic signal and the unpleasant blow to the foot that follows). After 4 days of testing with 10 daily exposures the animals react to almost all the acoustic signals with a jump to the vertical rod. Due to the ligature of the left carotid, this learning capacity is reduced to almost half. Animals treated with 2 mg / Kg i.p. of the compound I one hour before each test phase unexpectedly learned so well, despite the existing damage by the ligature, with a tendency to even learn er, than the animals not operated. But if the animals were previously treated with diazepam (0.3 mg / kg i.p. an hour before each training phase), then the learning ability remained similarly bad as with the untreated but damaged animals. Something similar is true for a treatment with the anticonvulsant phenytoin (3 and 10 mg / kg), the performance in learning could not be improved. An improvement in learning performance despite the existing blood supply deficit should be considered an indicator of the cytoprotective effect, since only cells capable of functioning are capable of learning. Therefore, it is expected that the compound I exerts a cytoprotective effect, for example, on the verge of an infarction, where there is also a deficit of blood supply, or in overloaded cells that are subject to a relative deficit of energy. Thus, the volume of the infarction and the damage should remain smaller and survival should be possible for strongly charged cells.

Table 1: Amount of reactions conditioned in% in the jump to the stick after damage by ligature of the left carotid.

The significant differences een the control group with apparent ligature and the control group with ligature (test t) are marked with + p < 0.05 and ++ p < 0.01.

The significant differences between the control group with ligature and the treated group are marked with * p < 0.05 and ** p < 0.01. Compound I had an excellent effect not only in this model, but also the decrease in learning ability produced by repeated application of electroshocks could be reduced by pre-treatment with 2 mg / Kg of compound I one hour before the test. While on the 4th day the damaged test animals showed only 32 ± 2.9% conditioned reactions, the treated animals were able to correctly perform 45 ± 4.5% conditioned reactions. This effect was also verifiable after a pre-treatment time of 2 hours. The number of reactions conditioned here increased from 35 ± 3.7% in the control group to 52 ± 3.9% in the treated group. The decrease in learning performance caused by alcohol suppression could also be favorably influenced. That is why the compound I can be used as a highly specific active substance for the treatment of the consequences of the acute and chronic cerebral blood supply deficit, especially of stroke, as well as in all the states during and after the overload of nerve cells. . Due to the few side effects of the substance in the animal experiment, compound I can also be used for the prophylaxis of the diseases and conditions mentioned above. Compound I is structurally related to flupirtine, a clinically introduced central analgesic. Whereas in flupirtine an NMDA antagonist effect was found (WO 95/05175), it could be excluded for compound I by in vitro experiments. Neither an affinity to the different areas of ligation of the NMDA receptor nor a direct influence on the current produced by NMDA was found. In deeper examinations of the central analgesic effect of compound I in the hot plate test, contrary to the case of flupirtine, a central analgesic effect could be excluded, as proved in the hot plate test in mice with flupirtine with a dose of effect median 30 mg / Kg. NMDA antagonists can cause severe psychotic disturbances such as ataxia with stereotyped symptoms. The compound I and processes for its preparation are known (DE 42 00 259). The compound can be transferred in a known manner to the usual formulations such as tablets, capsules, dragees, pills, granules, syrups, emulsions, suspensions and solutions using support substances or vehicles and / or inert auxiliary substances. Here the daily dose of compound I for oral or parenteral administration should amount to 50-500 mg. If necessary, it can be separated from the amounts mentioned, depending on the body weight and the special type of administration route.

Claims (12)

1. R E I V I N D I C A C I O N S 1. Use of compound I or its pharmaceutically usable salts for the preparation of medicaments for the prophylaxis and treatment of the consequences of the chronic deficit of cerebral blood supply, especially of apoplexy.
2. 2. Use of the compounds of formula I for the preparation of medicaments for the treatment of neurodegenerative diseases.
3. 3. Use of the compounds of formula I according to claim 2 for the preparation of medicaments for the treatment of Alzheimer's disease.
4. 4. Use of the compounds of formula I according to claim 2 for the preparation of medicaments for the treatment of Huntington's chorea.
5. 5. Use of the compounds of formula I according to claim 2 for the preparation of medicaments for the treatment of multiple sclerosis.
6. 6. Use of the compounds of formula I according to claim 2 for the preparation of medicaments for the treatment of amyotrophic lateral sclerosis.
7. 7. Use of the compounds of formula I according to claim 2 for the preparation of medicaments for the treatment of AIDS-induced encephalopathy and other encephalopathies caused by infections, which are caused by rubella virus, herpes, borrelias and by pathogenic agents unknown.
8. 8. Use of compounds of formula I according to claim 2 for the preparation of medicaments for the treatment of Creutzfeld Jakob disease.
9. 9. Use of compounds of formula I according to claim 2 for the preparation of medicaments for the treatment of Parkinson's disease.
10. 10. Use of compounds of formula I according to claim 2 for the preparation of medicaments for the treatment of neurodegenerations induced by trauma and neuronal overexcitation states such as in the suppression of drugs or by intoxications.
11. 11. Use of the compounds of formula I according to claim 2 for the preparation of medicaments for the treatment of neurodegenerative diseases of the peripheral nervous system such as polyneuropathies and polyneuritis.
12. 12. A drug of neuroprotective effect containing at least one compound of formula I or its pharmaceutically usable salts and, if appropriate, support substances or vehicles and / or auxiliary substances. SUMMARY The use of the compound (I) or its pharmaceutically usable salts for the prophylaxis and treatment of the consequences of the chronic deficit of cerebral blood supply, especially of stroke and for the treatment of neurodegenerative diseases is claimed.