MXPA98000925A - Use of adamantan derivatives to treat ear inte diseases - Google Patents

Abstract

The present invention relates to the use of adamantane derivatives of the formula I: in which R1 and R2 are identical or different, and can be hydrogen or straight or branched chain alkyl groups having from 1 to 6 carbon atoms, or together with the nitrogen atom, they may represent a heterocyclic group having 5 or 6 atoms in the ring, in which R3 and R4 are the same or different, and include hydrogen, straight or branched chain alkyl groups having 1 to 6 carbon atoms, groups cycloalkyl having 5 or 6 carbon atoms, or phenyl and wherein R 5 is hydrogen or a straight or branched chain alkyl group having 1 to 6 carbon atoms, to treat inter-ear diseases

Description

USE OF ADAMANTAN DERIVATIVES FOR TREATING INTERNAL EAR DISEASES DESCRIPTION OF THE INVENTION The present invention relates to the use of adamantane derivatives of the formula: wherein R x and R 2 are identical or different, and may be hydrogen or straight or branched chain alkyl groups having from the β carbon atoms, or together with the nitrogen atom, may represent a heterocyclic group having 5 or 6 atoms in the ring, in which R3 and R4 are identical or different, and may be hydrogen, straight or branched chain alkyl groups having between l and ß carbon atoms, or cycloalkyl groups having 5 or 6 carbon atoms, or a phenyl group, and in which R5 is hydrogen or a straight or branched chain alkyl group having between l and ß carbon atoms.

The use of adamantane derivatives that fall under the general formula I mentioned for the therapy of certain diseases is already known. Thus, for example, the dopamine-related influence of amantadine (1-adamantamine) is described in a series of publications. There is also an antiviral effect of certain ami or adamantans. In addition, EP Bl-392059 shows the use of adamantane derivatives to prevent and treat cerebral ischemia. According to this publication, the adamantane derivatives having the formula I described above can protectively prevent the destruction of brain cells following ischemia, the adamantane derivatives are used as antagonists for the NDMA receptor channels of the cells Nervous EP-B1-392059 discloses both general and special methods for producing adamantane derivatives that fall under formula I cited above. The publication by Ehrenberger and Felix in Acta Otalarygnol. (Stocol o) 115: 236-240 (1995) is related to neurotransmission between the inner hairy cell of the inner ear and the afferent neuron. An attempt is made to explain certain diseases of the inner ear in a model by a so-called neurotoxicity of glutamate, being indicated in this context to use antagonists that block the glutamate binding of the postsynaptic membrane. It is in this context that it is also conceivable to use antagonists for glycine binding, the redox modulation site, or for the NMDA receptor complex, for example an adamantane derivative. The quinoxaline derivative caroverine, tested in the publication of Ehrenberger and Felix can not, however, produce any satisfactory results in the treatment of tinnitus, which was thought to be induced by a glutamate. At the same time, it is to be understood that diseases of the inner ear are widespread, especially with respect to diseases or disorders in which a subjective noise occurs in the ear, the so-called tinnitus. It is estimated that in Germany alone, approximately 6 million people suffer from tinnitus. In about 800,000 cases, tinnitus is so pronounced that these patients need intensive treatment by a doctor, because the patient is seriously impeded by a tormenting noise in the ear. At this time, a safe effect therapy is not available. With regard to the complexity of internal ear diseases, especially in the case of tinnitus, which has not yet been conclusively explained, a series of drug therapies has been proposed to date. These include, in addition to the use of anesthetics, for example the application of agents of the lidocaine type, or antiarrhythmics or anticonvulsants, for example carbamazepine. However, in most cases, treatments of this kind can not produce satisfactory results. Hospital infusion therapy with procaine seems to be the only form of therapy for tinnitus that is superior to placebo, although only to a small degree. Here, too, the effect is only temporary, however. The object of the invention is thus to define a possibility of treating diseases of the inner ear, more particularly in the case of tinnitus, with which a perceptible compensation of the symptoms associated with the disease is achieved. More particularly, the tormenting noise of the ear is removed, or it is diminished to a degree that the patient retains its normal quality of life. This object is achieved by the use of adamantane derivatives of formula I claimed. Surprisingly it has been found that, more particularly, tinnitus can be effectively compensated for by the use of the compounds mentioned. Additional fields of application can be realized in the treatment of chronic deafness of the inner ear, sudden deafness or Meniere's morbus. An improvement in hearing can be achieved in the case of deafness of the inner ear, by the use according to the invention. The invention is interpreted from claims 1, 2 and 14. Preferred embodiments are interpreted from claims 3 to 12, and from 15 to 18, according to which the wording of all the claims is made with reference to the content of the description.

As already mentioned, the. Use of adamantane derivatives is possible or conceivable in many cases of diseases of the inner ear. Preferably, the adamantane derivatives can be used in the case of diseases of the inner ear in which an annoying noise occurs in the ear, the so-called tinnitus, especially in the case of treating such forms of tinnitus as chronic tinnitus, subacute tinnitus or also acute permanent tinnitus, because it is just these patients who require intensive therapy. In addition to other diseases of the inner ear, those in which tinnitus occurs, which frequently involve hearing loss (deafness), are also concerned. In the existence of a tinnitus, this hearing loss falls in the frequency range of tinnitus, and impaired hearing is associated with a so-called positive recruitment and / or reduction (amplitude) or defect of otoacoustic emissions. The so-called positive recruitment is a phenomenon in audiometry, when a volume comparison is attempted in the case of deafness on one side. In the case of positive recruitment, a slight amplification in the ear with hearing damage is needed to achieve the same sensitivity to volume as for the healthy ear, that is, hearing loss is compensated by increasing the volume. The so-called otoacoustic emissions are noise events that occur in the external channel, which have to do with the condition of the middle ear or the inner ear. The otoacoustic emissions can occur spontaneously, that is to say without the ear receiving external stimulation, or also being evoked externally, for example with the help of a sound emitter. Both, the occurrence of positive recruitment and the reduction or defect of otoacoustic emissions can be measured, and thus an internal ear dysfunction assigned to the patients concerned. If a patient is afflicted simultaneously with a tinnitus and a reduction in hearing in the corresponding frequency range of tinnitus associated with a positive recruitment and / or reduction or defect of otoacoustic emissions, it can be concluded that a deterioration or dysfunction of the cells is involved. outer hair and its cochlear amplifier. Since this dysfunction is improved or eliminated by the use according to the invention, a new active mechanism must be at the bottom of this, which is not in conformity with the applications for the adamantane derivatives known to date. It is known that, for example, there are no NMDA receptors on the outer hair cells, thus eliminating any antagonistic effect for such receptors. A glutamate otoneurotoxicity, postulated by Ehrenberger / Felix, is irrelevant, since glutamate is not toxic to hair cells.

One possible explanation may be that the adamantane derivatives directly affect other receptors present on the outer hair cells, eg, purine receptors and acetylcholine receptors. In addition to this, there are indications as to an additional mechanism, which is related to the effect of the adamantane derivatives with subsequent steps in the transmission of stimulation, by which the adamantane derivatives can clog the cation transporter that regulates the transport of return of the neurotransmitters from the synaptic interval at the presynapse, resulting in a decrease of the neurotransmitter at the efferent presynapsis, and thus (indirectly) in a reduced stimulation of the receptors. This mechanism is developed in the presynapsis, that is, before the synaptic interval could be effective in the way described, together with the complete auditory passage to the auditory cortex. The adamantane derivatives of formula I can be used as described by the formula, or preferably in the form of their pharmaceutically acceptable salts, hydrobromides, sulfates, acetates, succinates., tartrates, for example, or, more particularly, the hydrochlorides belonging to these additional salts. Likewise, other usual salts can be represented and used. The amount of the adamantane derivative used is usually not critical, materializing for the person skilled in the art as is usual for values obtained from experience, or implementing trial and error tests before their application. Conveniently, the amounts used are typically between about 0.01 and about 100 mg / kg of body weight, preferably from about 0.1 to about 1 mg / kg of body weight, whereby amounts of from about 0.1 to about 0.5 mg / kg are preferred. body weight in the last mentioned interval. As mentioned, the invention covers the use of all amino adamantanes of formula I for the treatment of diseases of the inner ear. Examples of such compounds are listed, for example, in EP-Bl-392059, the content of which is therefore included in the present disclosure. Preferred compounds of formula I are those in which Ri and R2 signify H, and compounds in which R5 and, more particularly, additionally Ri and R2 signify the hydrogen residue. In the preferred compounds already mentioned, and also in other compounds of formula I, the residues R3 and R4 are optionally a residue of methyl or ethyl. A particularly preferred compound usable according to the invention is memantine, ie 1-amino-3,5-dimethyladamantane, or the hydrochloride thereof, memantine.HCl. This compound or its salt is particularly suitable for the treatment of diseases of the inner ear, especially for treating tinnitus. The invention on the other hand also involves a method of treating diseases of the inner ear, in which an effective amount of an adamantane derivative having the general formula I is administered. A corresponding method is suitable, more particularly for the treatment of tinnitus, with reference being made to the particular aspects of administration already described with respect to the usable compounds and the amounts used. A preferred embodiment of the use according to the invention is embodied in the description of an example of clinical application described in the following, whereby the individual aspects resulting therefrom can be achieved individually, or in combination with one another. Example In a control study of a clinical case in perspective, 104 patients were treated with a drug that contained the adamantane derivative l-amino-3,5-dimethyl adamantane (memantine). All patients suffered from a cochlear tinnitus associated with deafness in the frequency interval in which tinnitus existed. A positive recruitment, and a significant reduction of the amplitude or defect of otoacoustic emissions existed, diagnosed by the usual audiometric methods. The group of patients treated, which made a total of 104 in number, included patients who had chronic tinnitus, subacute tinnitus and permanent acute tinnitus. The medication used was the preparation Akatinol Memantine "from the Merz Company &; Co., GmbH & Co., Frankfurt am Main. The active substance of this preparation is memantine.HCl, together with lactose, magnesium stearate, polyaminomethacrylate, inter alia, as the usual pharmaceutical medium and excipients. Such a pharmaceutical medium and excipients may, of course, be present as is usual in all embodiments of the invention, so that they can be administered, for example, in the form of tablets, dragees, solutions or sterile injections. In the clinical study, patients were initially administered the active substance by infusions. Up to the 5th day, they typically received an amount of 10 mg / d (daily), and this amount was increased to 20 mg / d in the 6th. day. Depending on the patient concerned, abrupt improvement occurred in patients between the 6th and 8th day in the group of those who responded to treatment. The treatment by infusion was continued until the 10th day, with an amount of 20 mg / d. On the 10th day, two tablets were administered, each containing 10 mg of the active substance memantine.HCl.

In some cases, the dose was higher, without, however, never exceeding an amount of at most 30 mg / d. In the long-term study, compensation for tinnitus was achieved in the case of approximately 72% of patients who had chronic tinnitus, 82% who had subacute tinnitus and all patients who had permanent acute tinnitus. Although in the majority of cases it was necessary to administer two 10 mg tablets daily and continuously to maintain the effect, a few patients remained symptom free even after the preparation was stopped. The study already clearly demonstrates, however, a considerable improvement compared to the known attempts of therapy that indicate as a rule only a temporary relief, in spite of the permanent medication. In this context, the advantages of the invention are evident, directly compared to a control group of patients treated with the preparation of Lidocaine, as already mentioned. This group also showed internal ear dysfunction with chronic tinnitus, subacute tinnitus or permanent acute tinnitus. Thus, the proportion of patients in whom a significant improvement occurred between the 6th and 10th day was significantly lower in the case of the administration of lidocaine.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (13)

1. R E I V I N D I C A C I O N S 1.- Use of adamantane derivatives of the formula (I) wherein R1 and R2 are identical or different and may be hydrogen or straight or branched chain alkyl groups having from 1 to 6 carbon atoms, or together with the nitrogen atom may represent a heterocyclic group having 5 or 6 atoms in the ring; R3 and R4 are identical or different and may be hydrogen, straight or branched chain alkyl groups having between l and ß carbon atoms, cycloalkyl groups having 5 or 6 carbon atoms or a phenyl group and R5 is hydrogen or an alkyl group straight or branched chain that has between l and ß carbon atoms, to treat diseases of the inner ear.
2. 2. - Use of adamantane derivatives of the formula (I) wherein R1 and R2 are identical or different and may be hydrogen or straight or branched chain alkyl groups having from 1 to 6 carbon atoms, or together with the nitrogen atom may represent a heterocyclic group having 5 or 6 atoms in the ring; R3 and R4 are identical or different and may be hydrogen, straight or branched chain alkyl groups having between l and ß carbon atoms, cycloalkyl groups having 5 or 6 carbon atoms or a phenyl group and R5 is hydrogen or an alkyl group straight or branched chain that has between l and ß carbon atoms, to prepare a drug to treat diseases of the inner ear.
3. 3. - Use according to claim 1 or 2, wherein the disease of the inner ear is associated with the occurrence of tinnitus.
4. 4. - Use according to claim 1 or 2, wherein the tinnitus is subacute or chronic tinnitus.
5. 5. - Use according to any of the preceding clauses, wherein the disease of the inner ear is associated with an uneven hearing, and more particularly at the frequency scale of tinnitus.
6. 6. - Use according to claim 5, wherein a so-called positive recruitment and / or a reduction or failure of oto-acoustic emissions occurs.
7. 7. - Use according to any of the preceding claims, wherein the adamantane derivatives are used in the form of their pharmaceutically acceptable salts.
8. 8. Use according to any one of the preceding claims, wherein the adamantane derivatives are provided in an amount of from about 0.01 to about 100 mg / kg per body weight, preferably from about 0.1 to about 1 mg / kg per body weight.
9. 9. - Use according to claim 8, wherein the adamantane derivatives are provided in an amount of about 0. 1 to about 0.5 mg / kg per body weight.
10. 10. - Use according to any of the preceding claims, wherein Rl and R2 are hydrogen residues H.
11. 11. - Use according to any of the preceding claims, wherein R5 is the hydrogen residue H.
12. 12. - Use according to any of the preceding claims, wherein R3 and R4 are methyl or ethyl residues.
13. 13. Use according to any of the preceding claims, wherein the adamantane derivative is 3,5-dimethyl-l-adamantanamine or its hydrochloride.