| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | May 2, 1978 |
| PATENT TITLE |
Treatment of cranial dysfunctions using novel cyclic amino acids |
| PATENT ABSTRACT | The present invention is concerned with new cyclic amino acids and with the preparation thereof |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | April 28, 1977 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
We claim: 1. A method of treating certain forms of epilepsy, faintness attacks, hypokinesia and cranial traumas which comprises the enteral or parenteral administration to a mammal having such cranial dysfunction of an amount effective for such treatment of at least one compound or its pharmaceutically acceptable salt of the formula: ##STR6## wherein R is hydrogen or a lower alkyl and n is 4, 5, or 6. 2. The method of claim 1 wherein the compound is 1-Aminomethyl-1-cyclohexane-acetic acid. 3. The method of claim 1 wherein the compound is Ethyl 1-aminomethyl-1-cyclohexane-acetate. 4. The method of claim 1 wherein the compound is 1-Aminomethyl-1-cycloheptane-acetic acid. 5. The method of claim 1 wherein the compound is 1-Aminomethyl-1-cyclopentane-acetic acid. 6. The method of claim 1 wherein the compound is Methyl 1-aminomethyl-1-cyclohexane-acetate. 7. The method of claim 1 wherein the compound is n-Butyl 1-aminomethyl-1-cyclohexane-acetate. 8. The method of claim 1 wherein the compound is Methyl 1-aminomethyl-1-cycloheptane-acetate. 9. The method of claim 1 wherein the compound is n-Butyl 1-aminomethyl-1-cycloheptane-acetate . toluene sulfonate. 10. The method of claim 1 wherein the compound is 1-Aminomethyl-1-cyclopentane-acetate . benzene-sulfonate. 11. The method of claim 1 wherein the compound is n-Butyl 1-aminomethyl-1-cyclopentane-acetate. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
Compounds of the general formula: ##STR1## wherein R.sub.1 is a hydrogen atom or a lower alkyl radical and n is 4,5, or 6; and the pharmacologically compatible salts thereof, have been found to possess valuable pharmacodynamic properties. Lower alkyl radicals according to the present invention are straight or branched chain alkyl radicals containing up to 8, and preferably up to 4 carbon atoms, especially methyl, ethyl, isopropyl and tert.-butyl radicals. The compounds of general formula (I) show hypothermal and, in some cases, narcosis-potentiating or sedating properties. They are also characterized by an extremely low toxicity. In animal experiments, there was, surprisingly, also found a remarkable protective effect against cramp induced by thiosemicarbazide. Some of the compounds according to the present invention also possess a considerable protective action against cardiazole cramp. Thus these new compounds (I) can be used for the therapy of certain cerebral diseases, for example, they can be used for the treatment of certain forms of epilepsy, faintness attacks, hypokinesia and cranial traumas. They also bring about an improvement of the cerebral functions. Consequently, they are also especially useful for the treatment of geriatric patients. The compounds of general formula (I) according to the present invention can be prepared, for example, by one of the following methods: (A) CONVERTING A COMPOUND OF THE GENERAL FORMULA: ##STR2## wherein R.sub.2 is an alkyl radical containing up to 8 carbon atoms and n has the same meaning as above, via a reactive acid derivative thereof, into an azide which is then subjected to the Curtius rearrangement; or (B) SUBJECTING A COMPOUND OF THE GENERAL FORMULA: ##STR3## wherein n has the same meaning as above, to the Hofmann rearrangement; or (C) SUBJECTING A COMPOUND OF THE GENERAL FORMULA: ##STR4## wherein n has the same meanings as above, to the Lossen rearrangement. When a free amino acid is obtained, it may be esterified to give a corresponding lower alky ester and/or the product obtained may be converted into a pharmacologically compatible salt by reaction with an acid or a base. Since amino acids are amphoteric, pharmacologically compatible salts when R.sub.1 is a hydrogen atom can be salts of appropriate inorganic and organic acids, for example, hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, oxalic acid, lactic acid, citric acid, malic acid, salicylic acid, malonic acid, maleic acid, succinic acid or ascorbic acid, but also, starting from the corresponding hydroxides or carbonates, salts with alkali metals or alkaline earth metals, for example, sodium, potassium, magnesium or calcium. Salts with quaternary ammonium ions can also be prepared with, for example, the tetramethyl-ammonium ion. Of course, when R.sub.1 is a lower alkyl radical, it is only possible to form salts with acids. The reaction of the compounds of general formula (II) takes place according to the well-known Curtius rearrangement. The free carboxyl group is first activated by conversion into a reactive derivative, for example an acid halide or a mixed anhydride, and subsequently reacted with an appropriate azide, for example, sodium azide. The acid azide thus obtained is then subjected to thermal decomposition in an organic solvent, for example, benzene, toluene or an alcohol, such as ethanol, during which nitrogen is split off and an intramolecular rearrangement to an isocyanate or, in the presence of an alcohol, to a urethane takes place. The isocyanates and the urethanes can easily be converted into the desired primary amines by basic or acid hydrolysis. The well-known Hofmann rearrangement of compounds of general formula (III) also takes place via isocyanates. In this case, the acid amides are reacted with alkali metal hypohalites. Upon hydrolysis of the isocyanate formed by anionotropic rearrangement, the desired amine is formed, together with carbon dioxide. The Lossen rearrangement of hydroxamic acids of general formula (IV) also takes a similar course. In this case, formally water is split off, the corresponding isocyanate first being formed, hydrolysis of which gives the desired amine. Usually the hydroxamic acids are reacted with bases via their O-acyl derivatives as, for example, the O-acetyl-, O-benzoyl- and preferably O-sulfonyl- derivatives. If R.sub.1 is to be a lower alkyl radical, the carboxyl group of the amino acids obtained is esterified under known protocols. Most simply, the reaction can be carried out by dissolving a free amino acid of general formula (I) or a salt thereof in an excess of the alcohol serving as the esterification component and the solution then saturated with hydrogen chloride. The corresponding amino acid ester hydrochloride is thus directly obtained. If it is desired to work without an excess of alcohol, then it is possible to employ the esterification methods known from amino acid chemistry, with masking of the amino group. The compounds of general formula (II) used as starting materials can be prepared by reacting an acid anhydride of the general formula: ##STR5## wherein n has the same meaning as above, with one mole of an alcohol of the general formula: HO -- R.sub.2 (VI), wherein R.sub.2 has the same meaning as above. The compounds of general formula (V) are known (cf. J.C.S., 115, 686/1919; Soc., 99, 446; J.C.S., 117, 639/1920). Some of the compounds of general formula (III), as well as processes for the preparation thereof, are known (cf. Austral. J.C., 13, 127/1960) and can, for example, also be prepared by reacting a compound of general formula (V) with ammonia. In this case, it is advantageous to work at the lowest possible temperature. However, it is also possible first, as described above, to prepare a hemi-ester, then to react the free carboxylic acid group with, for example, ethyl chloroformate and subsequently to carry out a reaction with ammonia. The hydroxamic acids of general formula (IV) can be prepared analogously by reacting the anhydride of general formula (V) with hydroxylamine. Because of their low toxicity, the compounds of general formula (I) according to the present invention can be administered enterally or parenterally within wide dosage ranges in liquid or solid form. As injection solution, water is preferably employed which contains the usual additives for injection solutions, such as stabilising agents, solubilising agents and/or buffers. Additives of this kind include, for example, tartrate and citrate buffers, ethanol, complex-forming agents (such as ethylenediamine-tetraaacetic acid and the non-toxic salts thereof), as well as high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Solid carrier materials include, for example, starch, lactose, mannitol, methyl cellulose, talc highly-dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycol); compositions suitable for oral administration can, if desired, also contain flavouring and/or sweetening agents. The individual dosage for the compounds according to the present invention can be 5 - 50 mg. parenterally and 20 - 200 mg. enterally. Thus, the present invention also provides pharmaceutical compositions containing at least one compound of general formula (I) and/or at least one pharmacologically compatible salt thereof, in admixture with a solid or liquid pharmaceutical diluent or carrier. |
| PATENT EXAMPLES | available on request |
| PATENT PHOTOCOPY | available on request |
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