| PATENT ASSIGNEE'S COUNTRY | USA |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 17.10.2000 |
| PATENT TITLE |
Methods for treating neurodegenerative diseases and disorders using N-(2,6-disubstituted aromatic)-N'-pyridinyl ureas and other anticonvulsant compounds |
| PATENT ABSTRACT |
The instant invention is novel uses of known N-(2,6-disubstituted phenyl)-N'-3- and 4-pyridinyl ureas and pharmaceutically acceptable acid addition salts thereof. Such compounds as N-(2-chloro-6-methylphenyl)-N'-4-pyridinyl urea monohydrochloride or N-(2,3-dichlorophenyl)-N'-4-pyridinyl urea are used for treating neurodegenerative disorders, perinatal asphyxia, Alzheimer's disease, Huntington's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. The instant invention is similar novel uses of known anticonvulsant compounds as ralitoline, phenytoin, lamotrigine, tetrodotoxin, lidocaine, and carbamazepine. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | February 25, 1993 |
| PATENT REFERENCES CITED |
J. Am. Chem. Soc., 94:26 (1972), pp. 9219-9221, Y. Kishi, et al. TINS, vol. 10, No. 7, 1987, pp. 294-298, J. A. Kemp, et al. Merck Manual p. 1305-1313 (1982). Stedman's Medical Dictionary, 24.sup.th Edition (1982) p. 1334. Merck Manual pp. 1305-1313 (1982). |
| PATENT CLAIMS |
What is claimed is: 1. A method for treating neurodegenerative diseases or disorders which comprises administering to a mammal in need a therapeutically effective amount of a compound selected from ralitoline, phenytoin, lamotrigine, carbamazepine, lidocaine or tetrodotoxin. 2. A method for treating neurodegenerative diseases or disorders as in claim 1 which comprises administering a therapeutically effective amount of ralitoline. 3. A method for treating neurodegenerative diseases or disorders as in claim 1 which comprises administering a therapeutically effective amount of phenytoin. 4. A method for treating neurodegenerative diseases or disorders as in claim 1 which comprises administering a therapeutically effective amount of lamotrigine. 5. A method for treating neurodegenerative diseases or disorders as in claim 1 which comprises administering a therapeutically effective amount of carbamazepine. 6. A method for treating neurodegenerative diseases or disorders as in claim 1 which comprises administering a therapeutically effective amount of lidocaine. 7. A method for treating neurodegenerative diseases or disorders as in claim 1 which comprises administering a therapeutically effective amount of tetrodotoxin. 8. A method for treating neurodegenerative diseases or disorders which comprises administering to a mammal in need a therapeutically effective amount of a compound of formula ##STR3## wherein A is 4-pyridinyl; R.sub.1 and R.sub.2 are independently halogen, lower alkyl, lower alkoxy, or nitro, and R.sub.3 is hydrogen, halogen, lower alkyl, lower alkoxy, or nitro, or a pharmaceutically acceptable acid addition salt thereof. 9. A method according to claim 8 wherein the neurodegenerative disorder is acute brain injury. 10. A method according to claim 8 wherein the neurodegenerative disorder is stroke. 11. A method according to claim 8 wherein the neurodegenerative disease is Alzheimer's disease. 12. A method according to claim 8 wherein the neurodegenerative disease is Huntington's disease. 13. A method according to claim 8 wherein the neurodegenerative disease is Amyotrophic Lateral Sclerosis. 14. A method according to claim 8 wherein the neurodegenerative disease is Parkinson's disease. 15. A method according to claim 8 wherein the compound is N-(2-chloro-6-methylphenyl)-N'-4-pyridinyl urea monohydrochloride or a pharmaceutically acceptable salt thereof. 16. A method according to claim 8 wherein the compound is N-(2,3-dichlorophenyl)-N'-4-pyridinyl urea or a pharmaceutically acceptable salt thereof. 17. A method according to claim 8 wherein an individual dose is administered in the range from about 10 mg to about 1000 mg intravenously of the compound or a pharmaceutically acceptable salt thereof is administered. 18. A method according to claim 8 wherein an individual dose is in the range from about 50 mg to about 2000 mg parenterally or about 50 to about 5000 mg enterally of the compound or a pharmaceutically acceptable salt thereof is administered. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION The present invention relates to novel therapeutic uses of a known compound, N-(2,6-disubstituted aromatic)-N'-pyridinyl ureas, its derivatives, and pharmaceutically acceptable salts. The present invention also relates to novel therapeutic uses of various other anticonvulsant drugs, their derivatives, and pharmaceutically acceptable salts. The present invention concerns a method for treating neurodegenerative diseases and disorders in a mammal in need of such treatment. Such neurodegenerative diseases are, for example, Alzheimer's disease, Huntington's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. The present invention also covers treating neurodegenerative disorders termed acute brain injury. These include but are not limited to: stroke, head trauma, and asphyxia. Stroke refers to a cerebral vascular disease and may also be referred to as a cerebral vascular incidence (CVA) and includes acute thromboembolic stroke. Stroke includes both focal and global ischemia. Also included are transient cerebral ischemic attacks and other cerebrovascular problems accompanied by cerebral ischemia. A patient undergoing carotid endarterectomy specifically or other cerebrovascular or vascular surgical procedures in general, or diagnostic vascular procedures including cerebral angiography and the like. Other incidents are head trauma, spinal cord trauma, or injury from general anoxia, hypoxia, hypoglycemia, hypotension as well as similar injuries seen during procedures from embole, hyperfusion, and hypoxia. The instant invention would be useful in a range of incidents, for example, during cardiac bypass surgery, in incidents of intracranial hemorrhage, in perinatal asphyxia, in cardiac arrest, and status epilepticus. A skilled physician will be able to determine the appropriate situation in which subjects are susceptible to or at risk of, for example, stroke as well as those suffering from stroke for administration by methods of the present invention. After ischemia of the brain in vivo many changes take place. There is a rapid loss of synaptic activity, a large shift in extracellular voltage, a release of the neurotransmitter glutamate, and a loss of ion homeostasis. The excess release of glutamate may be especially important in ischemic injury. Glutamate is an excitotoxin, meaning that overstimulation of glutamate receptor-linked channels allows excess calcium and sodium influx into neurons leading to neuronal death. The overstimulation of receptors is thought to be involved in the etiology of several neurological disorders, i.e., epilepsy and cerebral ischemia. Evidence is also accumulating that the brain damage associated with anoxia, stroke, hypoglycemia, epilepsy, and perhaps neurodegenerative illnesses such as Alzheimer's or Huntington's diseases may be at least partially produced by excessive activation of N-methyl-D-aspartic acid (NMDA) receptors (Kemp J A, Foster A C, Wong E H F, Trends in Neurosciences 1987;10(7):294-8). The present invention employs the use of anticonvulsant compounds, such as the compounds of Formula I which are phenyl pyridinyl ureas as a method of blocking or delaying damage to neurons from conditions similar to ischemia. It is believed that by preventing neuronal damage, the compounds of Formula I, alone or together with a pharmaceutically acceptable carrier, can be used to treat neurological diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, myotropic lateral sclerosis, and disorders such as stroke, head trauma, and asphyxia. The present invention is also directed to similar uses and methods of treatment employing other anticonvulsant compounds disclosed herein. Various substituted phenyl pyridinyl ureas have been described but none having neuroprotective activity. For example, Bruce M I, Zwar J A, Proc Roy Soc (London), Sec. B. 165 (999), 1966;245-65 disclose many N-mono- and N,N'-disubstituted ureas having cytokinin activity. N-(3,4-dichlorophenyl)-N'-3- and 4-pyridinyl ureas show such activity whereas the corresponding 2,5-dichloro compounds were inactive. In general, the authors concluded that phenyl ring substitution enhanced activity with meta substituents providing highest activity and ortho substituents lowest activity. German Patent Publication 2,928,485 also describes various ureas including N-(3-chloro-4-trifluoromethyl-phenyl)-N'-3- and 4-pyridinyl ureas as being useful for inhibiting lipid absorption. French Patent Publication 2,155,856 teaches various 2-pyridinyl ureas including N-(3,4-dichlorophenyl)-N'-2-pyridinyl urea as having antiinflammatory and analgesic activity. U.S. Pat. No. 4,629,731 covers the phenyl pyridinyl urea compounds of the instant invention, methods for preparing them, and their use as an anticonvulsant. The term convulsions is intended to mean the characteristic body movements which are associated with the group of chronic central nervous system disorders termed epilepsies. The patent is hereby incorporated by reference. There is no disclosure in the above references to suggest the present invention's novel uses of compounds of U.S. Pat. No. 4,629,731 to treat neurodegenerative diseases and disorders in a mammal in need of such treatment. SUMMARY OF THE INVENTION The present invention relates to novel uses of anticonvulsant compounds such as the known compounds of the formula ##STR1## wherein A is 3- or 4-pyridinyl; R.sub.1 and R.sub.2 are each independently halogen, lower alkyl, lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, or nitro, and R3 is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, or nitro, or a pharmaceutically acceptable acid addition salt thereof. The present invention also relates to novel uses of various other anticonvulsant compounds such as ralitoline, phenytoin, lamotrigine, tetrodotoxin, lidocaine, and carbamazepine. The present invention further includes novel uses of a pharmaceutical composition comprising a neuroprotective effective amount of a compound of Formula I or other anticonvulsant compounds together with a pharmaceutically acceptable carrier. The novel uses of the instant invention concerns a method for treating neurodegenerative diseases or disorders in mammals suffering therefrom by administering to such mammals a neuroprotective effective amount of a compound of Formula I or the additionally disclosed anticonvulsants, or a compound of Formula I or the additionally disclosed anticonvulsants together with a pharmaceutically acceptable carrier, in unit dosage form. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 are graphs reporting oxygen-tension measurements made with an oxygen-sensitive microelectrode in Example 3. FIG. 2 is a graph reporting that the percentage of slices that recovered at least half of their Prehypoxic-Hypoglycemic Synaptic Potential Amplitude increased with increasing concentrations of a compound of Formula I. FIG. 3 are graphs of the mean EPSP Amplitudes at the end of the experiments conducted in Example 3. FIG. 4 is a graph indicating that the percentage of slices that recovered at least half of their Prehypoxic-Hypoglycemic Synaptic Potential Amplitude varied with drug treatments. DETAILED DESCRIPTION OF THE EMBODIMENTS The term "halogen" as used herein in the definition of the compounds of the Formula I includes fluorine, chlorine, bromine, and iodine. The term "lower" in reference to alkyl, alkoxy, alkanoyl, and alkoxycarbonyl pertains to a straight or branched carbon chain of from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, or t-butyl. The compounds of structural Formula I are basic in nature and form pharmaceutically acceptable salts with both organic and inorganic acids. Examples of such acids are acetic, hydrochloric, phosphoric, nitric, sulfuric, fumaric, citric, maleic, malic, and the like. The salts are prepared by contacting the free base form of the pyridinyl urea with an equivalent amount of the desired acid in the conventional manner. The free base forms may be regenerated by treating the salt form with a base. For example, dilute aqueous basic solutions may be utilized. Dilute aqueous sodium hydroxide, sodium carbonate, or ammonia are suitable for this purpose. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention. The compounds of the invention of Formula I can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol, and the like are equivalent to the unsolvated forms for purposes of the invention. A preferred embodiment of the compound of the Formula I employed as a neuroprotective agent is where R.sub.3 is hydrogen or a pharmaceutically acceptable acid addition salt thereof. Another preferred embodiment of the compound of the Formula I is where R.sub.1 and R.sub.2 are each independently halogen or lower alkyl, or a pharmaceutically acceptable acid addition salt thereof. Still another preferred embodiment of the compound of Formula I is where R.sub.1 and R.sub.2 are each independently chlorine or methyl. Particular embodiments are the following compounds: N-(2-chloro-6-methylphenyl)-N'-4-pyridinyl urea monohydrochloride; N-(2,3-dichlorophenyl)-N'-4-pyridinyl urea; N-(2,6-dichlorophenyl)-N'-4-pyridinyl urea; N-(2,6-dichlorophenyl)-N'-3-pyridinyl urea; N-(2,6-dimethylphenyl)-N'-4-pyridinyl urea; N-(2,6-dimethylphenyl)-N'-3-pyridinyl urea; N-(2-chloro-6-methylphenyl)-N'-4-pyridinyl urea; N-(2-chloro-6-methylphenyl)-N'-3-pyridinyl urea; N-(2,6-diethylphenyl)-N'-4-pyridinyl urea; N-(2,6-diethylphenyl)-N'-3-pyridinyl urea; N-(2,6-dimethyl-4-bromophenyl)-N'-4-pyridinyl urea; N-(2,6-dimethyl-4-bromophenyl)-N'-3-pyridinyl urea; N-(2,4,6-trimethylphenyl)-N'-4-pyridinyl urea; N-(2,4,6-trimethylphenyl)-N'-3-pyridinyl urea; N-(2,4,6-trichlorophenyl)-N'-4-pyridinyl urea; N-(2,4,6-trichlorophenyl)-N'-3-pyridinyl urea; or a pharmaceutically acceptable acid addition salt thereof. The compounds of Formula I may be prepared by reacting an isocyanate of the formula ##STR2## with an equimolar amount of 3- or 4-aminopyridine in an inert solvent, such as tetrahydrofuran, dioxane, and the like, at elevated temperatures, such as at the boiling point of the solvent used. The starting materials such as the various isocyanates are known and can be purchased commercially or synthesized by known methods. The additional compounds, which are anticonvulsant compounds and can be used as agents for treating neurogenerative diseases or disorders as heretofore discussed, include ralitoline, phenytoin, lamotrigine, tetrodotoxin, lidocaine, and carbamazepine. The methods for making and administering each of these compounds are known to those skilled in the art and can be shown respectively by reference to the following publications: European Patent 124,911, U.S. Pat. Nos. 2,409,754 and 4,602,017, Kishi et al, Am Chem Soc 1972;94:9219, U.S. Pat. Nos. 2,441,498 and 2,948,718. As it will be illustrated at a later point, each of these compounds have been shown in vitro to have neuroprotective capabilities. It should be understood that the present invention is not limited to the use of the anticonvulsant compounds disclosed herein. Similar compounds which prevent irreversible neuronal damage from conditions similar to ischemia are also included in the present invention. In addition, anticonvulsant compounds that bind to sodium channels or that cause a voltage-dependent block to sodium currents or that modulate ion channels without simply blocking them are also included in the present invention. The compounds of structural Formula I, and the additionally disclosed anticonvulsant compounds, can be prepared and administered in a wide variety of oral and parenteral dosage forms. The compounds of structural Formula I or the other disclosed anticonvulsant compounds can also be administered intravenously. For example, a useful oral dosage is between 50 and 5000 mg, a useful parenteral dosage is between 50 and 2000 mg, and a useful intravenous dosage is between 10 and 1000 mg. For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active compounds of the present invention. In the tablet the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5% to 10% to about 70% of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is thus in association with it. Similarly, cachets are included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Liquid form preparations include solutions, suspensions, and emulsions. As an example, water or water-propylene glycol solutions may be mentioned for parenteral injections. Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other well-known suspending agents. Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself or it can be the appropriate number of any of these in packaged form. The quantity of active compound in a unit dose of preparation may be varied or adjusted from 10 mg to 1000 mg according to the particular application and the potency of the active ingredient. In therapeutic use as agents for treating neurodegenerative diseases or disorders, the compounds utilized in the pharmaceutical methods of this invention are administered at the initial dosage of about 1 mg/kg to about 30 mg/kg daily. A daily dose range of about 3 mg/kg to about 10 mg/kg is preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for the particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. The advantages of using the compounds of the instant invention include the relatively nontoxic nature of the compound, the ease of preparation, the fact that the compound is well tolerated, and the ease of administration of the drug. The following nonlimiting examples illustrate the preferred methods for preparing and using the compounds of the invention. |
| PATENT EXAMPLES | This data is not available for free |
| PATENT PHOTOCOPY | Available on request |
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