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Agents for treating neurodegenerative disordersRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, In Vivo Diagnosis Or In Vivo Testing, Diagnostic Or Test Agent Produces In Vivo FluorescenceAgents for treating neurodegenerative disorders description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060140866, Agents for treating neurodegenerative disorders. Brief Patent Description - Full Patent Description - Patent Application Claims
BACKGROUND OF THE INVENTION [0001] 1. Field of the Invention [0002] The present invention relates to the use of chemical compounds in medicine, more specifically, to the use of the compounds selected from hydrogenated pyrido[4,3-b]indoles for the treatment of neurodegenerative diseases, and especially Alzheimer's disease (AD), due to the discovery of new properties intrinsic to these compounds. [0003] 2. Description of the Related Art [0004] Alzheimer's disease is currently one of the severest and widely spread neurodegenerative diseases. The most traditional approach to the treatment of this disease is compensatory therapy based on the compensation of the cholinergic system functions which are reduced in Alzheimer's disease. One of the therapeutic agents used in the alleged method of treatment is tacrine hydrochloride (hereinafter referred to as tacrine) which is 9-amino-1,2,3,4-tetrahydroacridine hydrochloride represented by the formula (A): [0005] The mechanism of action of the said agent involves inhibiting choline esterase (Volger B. W. "Alternatives in the treatment of memory loss in patient with Alzheimer's disease". (Clinical Pharmacy, 1991 Jun. 10 (6): 447-56). As for the choline esterase inhibiting activity, tacrine is an analogue of the world famous physostigmine and is a traditional anticholine esterase agent. However, the treatment with tacrine is not always effective. Besides, tacrine tends to cause undesirable side-effects. [0006] A wide range of neurological diseases such as Alzheimer's disease. Huntington chorea: amiotrophic lateral sclerosis as well as brain ischemia are known to be associated with an excitotoxic effect of neuromediatory excitatory amino acids (EAA) such as glutamate and aspartate (Excitatory Amino Acids and Drug Research, Ed. by M. R. Szewczak N. I. Hrib Alan R. Liss, Inc., New York, 1989, p. 380; The NMDA Receptor, Eds. Watkins & Collingridge G., 1989, IRL Press). In accordance with this mechanism, hyperexcitation of neurones in prolonged activation of their N-methyl-D-aspartate (NMDA) receptors with glutamate results in an excessive entry of potassium ions into the cell which initiates a number of pathological metabolic processes finally causing the death of nerve cells (Mattson, Neurone, 1990, v. 2, p. 105, Mill S. Kater, Neuron, 1990, v. 2, p. 149; Saitch et al., Lab Suvest, 1991, v. 64, p. 596). [0007] More specifically in Alzheimer's disease, death of numerous neurones is believed to occur as follows. An endogenic oligopeptide, such as .beta.-amyloid, is a neurotoxic factor inducing neurodegenerative processes in the neurones. .beta.-Amyloid is present in the neurotic plaques abundantly located on the surface of the brain of the patients suffering from Alzheimer's disease (Prelli et al.,--J. Neurochem., 1988, v. 51, p. 648; Yanuer et al.,--Science, 1990, v. 250, p. 279). As shown by the investigations of recent years, .beta.-amyloid significantly enhances the excitotoxic effect of glutamate which is effected through the NMDA-receptor system (Koh et al., Brain Res., 1990, v. 533, p. 315; Mattson et al., J. Neurosci., 1992, v. 12, p. 376). As a result, the glutamate mediator at concentrations that are nontoxic under normal conditions becomes toxic for neurones under conditions of the developing .beta.-amyloid dose and causes their death. [0008] In this connection, the search for effective antagonists of the brain NMDA-receptors capable of preventing the realization of the neurotoxic effect of EAA appears to be an original and promising approach to creation of neuroprotectors of a wide spectrum of activity including agents which can prevent the development of Alzheimer's disease and be useful for treatment of such diseases as Alzheimer's disease (Maragos W. F. et al., Trends Neurosci., 1987, No. 10, p. 65). [0009] A well known NMDA receptor antagonist is 2-amino-5-phosphonovaleric acid (AP5) (Evans et al.,--Brit. J. Pharmacol., 1982 , v. 75, p. 65). The main disadvantage of AP5 compound a side neurotoxic effect (such as the disturbance of coordination of movement and a sedative effect) which becomes apparent when AP5 is used in the doses in which it produces anti-NMDA effect (ED.sub.50=190 mg/kg) (Grigoriev et al., Chim. Pharm. Journal, 1988, No. 3, p. 275-277). A intensive search for and trials of the agents having the anti-NMDA properties but without the neurotoxic effects is currently under way for treatment of the neurodegenerative diseases. However, to date such agents have not been available in clinics. SUMMARY OF THE INVENTION [0010] The present invention provides compounds and methods of using these compounds to treat neurodegenerative diseases, especially Alzheimer's disease. [0011] According to the present invention, the compounds that are provided for the treatment of neurodegenerative diseases can be represented by a general formula (I): wherein R.sub.1 is Me, Et or PhCH.sub.2; R.sub.2 is H, PhCH.sub.2 or 6-Me-3-Py-(CH.sub.2).sub.2; and R.sub.3 is H, Me or Br. The solid line accompanied by the dotted line. i.e. represents a single or double bond and salts thereof with pharmacologically acceptable acids. [0012] When represents a single bond, then R.sub.2=R.sub.3=Me; R.sub.2=H; and the compound is in the form of a cis (.+-.) isomer. [0013] When represents a double bond, then [0014] (i) R.sub.1=Et or PhCH.sub.2, R.sub.2=R.sub.3=H. [0015] (ii) R.sub.1=R.sub.3=Me, R.sub.2=PhCH.sub.2. [0016] (iii) R.sub.1=Me, R.sub.2=6-Me-3-Py-(CH.sub.2).sub.2, R.sub.3=H. [0017] (iv) R.sub.1=R.sub.3=Me, R.sub.2=6-Me-3-Py-(CH.sub.2).sub.2, [0018] (v) R.sub.1=Me, R.sub.2=H, R.sub.3=H or Me. [0019] (vi) R.sub.1=Me, R.sub.2=H, R.sub.3=Br. [0020] and salts thereof with pharmacologically acceptable acids and quaternized derivatives. [0021] Particular examples of the compound described above are: [0022] 1. 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; [0023] 2. 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and its methyliodide; [0024] 3. cis(.+-.) 2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole and its dihydrochloride; [0025] 4. 2-methyl-8-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and its hydrochloride; [0026] 5. 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; [0027] 6. 2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; [0028] 7. 2,8-dimethyl-5-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and its hydrochloride; [0029] 8. 2-methyl-5-[2-(6-methyl-3-pyridyl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3- -b]indole and its sesquisulfate monohydrate; [0030] 9. 2,8-dimethyl-5-[2-(6-methyl-3-pyridyl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido- [(4,3-b]indole and its dihydrochloride. DETAILED DESCRIPTION OF THE INVENTION [0031] The object of the invention is to provide compounds having a high anti-NMDA activity and producing no side- and toxic effects. [0032] As one of the approaches is to search for such agents in the known chemical compounds, from which the inventors have tried to reveal new unexpected (in this case, anti-NMDA) properties which are not due to the chemical structure of the compounds. [0033] The inventors have carried out large-scale investigations of some known compounds which are tetra- and hexahydro-1H-pyrido[4,3-b]indole derivatives that manifest a broad spectrum of biological activity. In the series of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles the following types of activity were found: antihistamine activity (OS-DE NN 1.813 229, Dec. 6, 1968; 1.952.80, Oct, 20, 1969), central depressive and antiinflammatory activity (U.S. Pat. No. 3,718,657 Dec. 13, 1970), neuroleptic activity (Herbert C. A., Plattner S. S., Wehch W. N.--Mol. Pharm. 1980, v. 17, N 1, p. 38-42) and others. 2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole derivatives show psychotropic (Welch W. H., Herbert C. A., Weissman A., Koe K. B. J. Med. Chem., 1986, vol. 29, No. 10, p. 2093-2099), antiaggressive, antiarrhythmic and other types of activity. [0034] Several drugs such as diazoline (mebhydroline), dimebon, dorastine, carbidine(dicarbine), stobadine, hevotroline based on tetra- and hexahydro-1H-pyrido[4,3-b]indole derivatives are being manufactured. Diazoline(2-methyl-5-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole dihydrochloride) (Klyuev M. A., Drugs, used in "Medical Pract.", USSR, Moscow, "Meditzina" Publishers, 1991, p. 512) and dimebon (2,8-dimethyl-5-(2-(6-methyl-3-pyridyl)ethyl-2,3,4,5-tetrahydro-1H-pyrido- [4,3-b]indole dihydrochloride) (M. D. Mashkovsky, "Medicinal Drugs" in 2 vol. Vol. 1--12th Edition, Moscow, "Meditzina" Publishers, 1993, p. 383) as well as its closest analogue dorastine(2-methyl-8-chloro-5-[2-(6-methyl-3-pyridyl)ethyl]-2,3,4,5-tetra- hydro-1H-pyrido[4,3-b]indole dihydrochloride) (USAN and USP dictionary of drugs names (United States Adopted Names, 1961-1988, current US Pharmacopeia and National Formular for Drugs and other nonproprietary drug names), 1989, 26th Edition, p. 196) are known as antihistamine drugs; carbidine (dicarbine) (cis(.+-.)-2,S-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole dihydrochloride) is a national neuroleptic agent having an antidepressive effect (L. N. Yakhontov, R. G. Glushkov, Synthetic Drugs, ed. by A. G. Natradze, Moscow, "Meditzina" Publishers, 1983, p. 234-237), and its (-)isomer, stobadine, is known as an antiarrythmic agent (Kitlova M., Gibela P., Drimal J., Bratisl. Lek. Listy, 1985, vol. 84, No. 5, p. 542-549); hevotroline (S-fluoro-2)(3-(3-pyridyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole dihydrochloride) is an antipsychotic and anxiolytic agent (Abou-Gharbi M., Patel U. R., Webb, M. B., Moyer J. A., Ardnee T. H., J. Med. Chem., 1987, vol. 30, p. 1818-1823). [0035] However no NMDA receptor antagonists have been found so far among tetra- and hexahydro-1H-pyrido[4,3-b]indole derivatives. [0036] The inventors have quite unexpectedly found that hydrogenated pyrido[(4,3-b]indole derivatives are endowed with such properties. It has been found in particular, that a number of known hydrogenated pyrido[3,4-b]indole derivatives have NMDA antagonist properties, which makes them useful for treating neurodegenerative diseases, especially Alzheimer's disease. Continue reading about Agents for treating neurodegenerative disorders... 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