Claims
- 1. A compound of the formula ##STR46## wherein R.sub.1 is hydrogen or alkyl of 1 to 4 carbon atoms;
- R.sub.2 is 2-,3- or 4-pyridyl, phenyl or mono- or di-substituted phenyl, where the substituents are each iniviually alkoxy of 1 to 2 carbon atoms, fluorine, chlorine, bromine, trifluoromethyl, alkyl of 1 to 4 carbon atoms, hydroxyl or nitro; and
- R.sub.3 and R.sub.4, together with each other and the nitrogen atom to which they are attached, form an unsubstituted or methyl-substituted, saturated 6-membered heterocycle which contains an additional oxygen or nitrogen heteroatom;
- wherein the aminomethyl substituent is attached to the 4- or 5-position of the pyrrolidine ring, or a non-toxic, pharmacologically acceptable acid addtion salt thereof.
- 2. A compound of claim 1, which is 1-(4-fluoro-benzyl)-4-N-methylpiperazinomethyl-pyrrolidin-2-one, or a non-toxic, pharmacologically acceptable acid addition salt thereof.
- 3. A compound of claim 1, which is 1-(4-fluoro-benzyl)-4-morpholinomethyl-pyrrolidin-2-one, or a non-toxic, pharmcologically acceptable acid addition salt thereof.
- 4. A compound of claim 1, which is 1-benzyl-4-N-methyl-piperazinomethyl-pyrrolidin-2-one, or a non-toxic, pharmacologically acceptable acid addition salt thereof.
- 5. A compound of claim 1, which is 1-benzyl-5-morpholinomethyl-pyrrolidin-2-one, or a non-toxic, pharmacologically acceptable acid addition salt thereof.
- 6. A compound of claim 1, which is 1-benzyl-5-N-methylpiperazinomethyl-pyrrolidin-2-one, or a non-toxic, pharmacologically acceptable acid addition salt thereof.
- 7. A pharmaceutical composition consisting essentially of an inert pharmaceutical carrier and an effective amount of a compound of claim 1.
- 8. The method of alleviating conditions of impaired cerebral performance in a warm-blooded animal in need thereof, which comprises perorally or parenterally administering to said animal an effective nootropic amount of a compound of claim 1.
- 9. A compound of claim 1, where
- R.sub.1 is hydrogen or alkyl of 1 to 4 carbon atoms; R.sub.2 is 2-, 3- or 4-pyridyl, phenyl or mono-or di-substituted phenyl, where the substituents are each individually alkoxy or 1 to 2 carbon atoms, fluorine, chlorine, bromine, trifluoromethyl, alkyl of 1 to 4 carbon atoms, hydroxyl or nitro; and
- R.sub.3 and R.sub.4, together with each other and the nitrogen atoms to which they are attached, form a heterocycle selected from the group consisting of N-methylpiperizone and morpholino;
- wherein the aminomethyl substituent is attached to the 4- or 5-position of the pyrrolidine ring, or a non-toxic, pharmacologically acceptable acid addition salt thereof.
Priority Claims (1)
| Number |
Date |
Country |
Kind |
| 3336024 |
Oct 1983 |
DEX |
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THE PRIOR ART
This is a continuation-in-part of copending application Serial No. 657,219, filed Oct. 3, 1984 now abandoned.
This invention relates to novel 1-benzyl-4 or 5-amino-methyl-pyrrolidin-2-ones and non-toxic acid addition salts thereof, to methods of preparing these compounds, to pharmaceutical compositions containing them as active ingredients, and to a method of using them as nootropics and antihypoxics.
Japanese patent application No. 78 44 559 (JP-A-No. 78 44 559) discloses, inter alia, N-[(S)-.alpha.-methylbenyl]-6-oxo-2-(S)-pyrrolidyl-methylamine of the formula ##STR2## as an intermediate product and does not ascribe any pharmacological properties thereto.
Structurally related nootropics, such as 1-carbamoyl-methyl-pyrrolidin-2-one (piracetam), 1-(p-methoxybenzoyl)-pyrrolidin-2-one (aniracetam) and 1-carbamoylmethyl-4-hydroxy-pyrrolidin-2-one (oxiracetam) are disclosed in the literature; see B. J. R. Nicolaus, Drug Development Res. 2, 464 (1982, and P. L. Paytasch, J.Amer.Chem.Soc. 72, 1415 (1950).
More particularly, the present invention relates to a novel class of compounds represented by the formula ##STR3## wherein R.sub.1 is hydrogen or alkyl of 1 to 4 carbon atoms;
A preferred subgenus thereunder is constituted by those compounds of the formula I where
R.sub.1 is hydrogen;
R.sub.2 is phenyl or o- or p-monosubstituted phenyl, where the substituent is fluorine, chlorine, methyl or methoxy; and
R.sub.3 and R.sub.4 are each independently hydrogen, methyl or ethyl;
The compounds embraced by formula I are basic and therefore form addition salts with inorganic or organic acids. Examples of non-toxic, pharmacologically acceptable acid addition salts are those formed with hydrohalic acid, sulfuric, phosphoric, aminosulfonic, formic, acetic, propionic, lactic, glycolic, gluconic, maleic, fumaric, succinic, tartaric, benzoic, salicylic, citric, ascorbic, p-toluenesulfonic, oxyethane sulfonic acid or the like.
The compounds embraced by formula I may be prepared by the following methods:
For the preparation of a compound of the formula I wherein R.sub.3 and/or R.sub.4 are other than hydrogen, by reacting a 4- or 5-hydroxymethyl-pyrrolidin-2-one of the formula ##STR4## wherein R.sub.1 and R.sub.2 have the meanings previously defined, with a thionyl halide, a phosphorus halide, a tosyl halide or a mesyl halide to form an intermediate compound of the formula ##STR5## wherein R.sub.1 and R.sub.2 have the meanings previously defined, and
A compound of general formula II is converted either with a thionyl or phosphorus halide into the corresponding 4-halomethyl compound or with a tosyl or mesyl halide into the corresponding 4-tosyl or 4-mesyl ester. The reaction is preferably carried out in an inert organic solvent such as chloroform, methylene chloride, tetrahydrofuran or dimethylformamide at temperatures between room temperature and the boiling point of the solvent which is used. In the case of esterification a tertiary organic base such as triethylamine or pyridine is preferably added. The 4-halomethyl compounds produced as intermediates or the 4-tosyl or 4-mesyl esters may be isolated or may be reacted further in situ. When they are subsequently treated with a primary or secondary amine, the corresponding end products of the formula I are obtained. The reaction may be carried out in tetrahydrofuran, dioxane, acetonitrile or, preferably, in dimethylformamide at a temperature between about 50.degree. and 150.degree. C., the individual reaction conditions depend on the basicity and the boiling point of the amine. The reaction may also be carried out without the use of a solvent in an excess of the amine. In the case of low-boiling-point amines, the reaction must be carried out in an autoclave under certain circumstances.
The end products of the formula I with a free amino group are preferably synthesized by reacting a compound of the formula III with phthalimide or an alkali metal salt of phthalimide, and cleaving the 4-phthalimidomethyl compound thus obtained with hydrazine.
The reaction with phthalimide is carried out in an inert organic solvent such as acetonitrile or an alcohol, or preferably in dimethylformamide, at elevated temperatures up to the boiling point of the reaction mixture. The 4-phtalimidomethyl compound may be isolated or reacted further in situ; the phtalimide group may be split off with hydrazine. For this purpose, alcohols, tetrahydrofuran, dioxane, dimethylformamide or mixtures of alcohols and dimethylformamide may be used as solvents. Frequently, the reaction starts even at room temperature; if desired; a higher temperature may be used in order to speed up the reaction.
Another method of preparing the nor compound comprises hydrogenating a compound of the formula ##STR7## wherein R.sub.1 and R.sub.2 have the meanings previously defined, and
An azide of the formula V (Y=--CH.sub.2 N.sub.3) is obtained by reacting a compound of the formula III wherein X is halogen, or mesyl, with sodium azide in an inert organic solvent, for instance an alcohol or an ether such as tetrahydrofuran or dioxane.
A nitrile of the formula V (Y=--CN) may be prepared, for example, by reacting a solution of a carboxylic acid of the formula VI ##STR8## wherein R.sub.1 and R.sub.2 have the meanings previously defined, in acetonitrile with chlorosulfonyl isocyanate and subsequently with triethylamine, or by dehydration of the corresponding carboxylic acid amide with POCl.sub.3, for example (cf. H. Vorbruggen, Tetrahedron Letters 1968, pages 1631-1634).
The novel compounds of the formula I have a center of asymmetry and therefore occur as racemates. These racemates may be converted in the usual way, for instance by salt formation with optically active acids, into the corresponding diastereoisomers, which can then be converted into the optically active end products.
If desired, the alcohols of the formula II may be converted by ester formation with optically active acids into the corresponding mixtures of diastereoisomers which can then be resolved into the individual diastereoisomers by corventional methods, for instance by column chromatography or fractional crystallization. After hydrolysis of these esters, the enantiomeric alcohols are obtained from which the corresponding amines are prepared by method A or B.
Starting from the enantiomerica nor compounds, the corresponding optically pure diethyl compounds may be obtained by reductive alkylation, for example with acetaldehyde/H.sub.2 /catalyst, or the corresponding optically pure dimethyl compounds may be obtained with formaldehyde/formic acid.
The starting materials for methods A and B described above are known or may be obtained by known methods. Thus, a pyrrolidinone carboxylic acid of the formula VI is prepared by reacting equimolar quantities of itaconic acid and a corresponding amine. The starting compounds of the formula II can be obtained from the acid via the ester by selective reduction with a complex alkali metal borohydride (cf. German Offenlegungsschrift No. 3,326,724).
In the case of the 5-aminoalkyl compounds, the commercially available 5-pyrrolidinone-carboxylic acids may be used as starting materials; these are esterified, alkylated at the nitrogen with an optionally substituted benzyl halide, and reacted further as described above.
The following end products of the formula I may be obtained, for example, using the methods described above, possibly in the form of their acid addition salts and possibly in the form of the pure enantiomers:
US Referenced Citations (2)
| Number |
Name |
Date |
Kind |
| 4239770 |
Kyburz et al. |
Dec 1980 |
|
| 4670456 |
Weber et al. |
Jun 1987 |
|
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| Number |
Date |
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| 0136658 |
Sep 1985 |
EPX |
| 0026970 |
Nov 1964 |
JPX |
| 0002628 |
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JPX |
| 956253 |
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GBX |
| 1047257 |
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GBX |
Continuation in Parts (1)
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Number |
Date |
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| Parent |
657219 |
Oct 1984 |
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Patent Grant
4767759
