Carbamoyl-2-pyrrolidinone compounds are disclosed as herbicides in French Patent No. 2018820, as horticultural fungicides in JP-A-52-25026, or as agents for improving the quality of citrus fruits in JP-A-54-66265, 55-81857 and 55-153763, whereas nothing has been described about their use in compositions for improving cerebral functions and in compositions for activating cerebral metabolism or protecting anoxic brain damage as disclosed in the present invention.
Furthermore, even if some of the compounds defined in the claims appended hereto should be included in the group of compounds represented by the broad general formulae in the above prior-art literature, they have been deleted during the examination procedures, or are not identified in any way in the detailed description of the specifications. Thus, they have not been disclosed in any way specifically and are novel compounds. The other compounds of the present invention are novel compounds which have not been described in any literature.
With an increase in the population of advanced ages in recent years, patients with senile dementia are expected to increase in number, posing a serious problem medically and socially. Although various antidementia drugs have been investigated and developed in view of the situation, no compounds have been provided with satisfactory efficacy up to date. It has been strongly desired to develop medicaments for treating the disease.
An object of the present invention is to provide novel carbamoyl-2-pyrrolidinone compounds which are very useful as medicaments for treating senile dementia, i.e., as cerebral function improving agents and cerebral metabolism activators or anoxic brain damage protectives. Disclosure of the invention
The present invention provides carbamoyl-2-pyrrolidinone compounds represented by the formula ##STR3## wherein R.sup.1 is a hydrogen atom, hydroxyl or lower alkyl substituted or unsubstituted with hydroxyl, and R.sup.2 is phenyl, tetrahydronaphthyl, pyridyl or thiazolyl having or not having methoxy or lower alkylamino as a substituent, provided that when R.sup.1 is a hydrogen atom or unsubstituted lower alkyl, R.sup.2 is not unsubstituted phenyl.
Exemplary of lower alkyl groups represented by R.sup.1 herein and unsubstituted with hydroxyl are straight-chain or branched-chain alkyl groups having 1 to 5 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and isopentyl. Examples of lower alkyl groups similarly represented and substituted with hydroxyl are lower alkyl groups containing 1 or 2 hydroxyl groups, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl, 2-hydroxy-1-methylethyl, 1,2-dihydroxyethyl, 1,2-dihydroxy-1-methylethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl and 1,2-dihydroxypropyl.
Examples of lower alkylamino groups included in groups represented by R.sup.2 are mono- or di-alkylamino groups such as methylamino, dimethylamino, ethylamino, diethylamino, propylamino, and dipropylamino.
When R.sup.2 is the formula (1) represents a substituted phenyl group, the group preferably has 1 to 3 substituents.
Among the compounds of the formula (1), preferable are those wherein R.sup.1 is a hydrogen atom, hydroxyl, methyl or hydroxymethyl, and R.sup.2 is phenyl, 5, 6, 7, 8-tetrahydro-1-naphthyl, pyridyl or thiazolyl having 1 to 3 methoxy groups or dimethylamino. More preferable are compounds of the formula (1) wherein R.sup.1 is a hydrogen atom or hydroxyl, and R.sup.2 is phenyl or tetrahydronaphthyl having methoxy.
We have further found that carbamoyl-2-pyrrolidinone compounds represented by the formula (2) ##STR4## wherein R.sup.1 is a hydrogen atom, hydroxyl or lower alkyl substituted or unsubstituted with hydroxyl, and R.sup.3 is phenyl, tetrahydronaphthyl, pyridyl or thiazolyl having or not having lower alkoxyl, lower alkylamino, a halogen atom or halogenomethyl as a substituent have an excellent cerebral function improving effect, cerebral metabolism activating or anoxic brain damage protecting effect and effect against senile dementia.
Accordingly, the present invention provides a cerebral function improving composition and a cerebral metabolism activating or anoxic brain damage protecting composition each comprising an effective amount of a compound of the formula (2) and a pharmacologically acceptable carrier.
The present invention further provides a method of improving cerebral functions and activating cerebral metabolism or protecting anoxic brain damage characterized by administering an effective amount of a compound of the formula (2).
Examples of lower alkoxy groups included in groups represented by R.sup.3 in the formula (2) are straight-chain or branched-chain alkoxy groups having 1 to 5 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy and isopentyloxy. Examples of halogen atoms are fluorine, chlorine, bromine, iodine and the like. Examples of halogenomethyl groups are trifluoromethyl, chloromethyl and the like. Examples of lower alkylamino groups are those exemplified for R.sup.2.
When R.sup.3 in the formula (2) represents a substituted phenyl group, the group preferably has 1 to 3 substituents.
The compounds of the formula (2) have pharmacological activities to ameliorate:
(1) cerebral damage in anoxia, and PA0 (2) amnesia induced by scopolamine in passive condition avoidance response.
These pharmacological properties are useful for activating injured nervous cells and ameliorate memory and learning disturbances.
Accordingly, the compounds of the present invention are usable not only as medicaments for use in treating deterioration of intelligence or neurasthenia, ammnesia, senile dementia or intellectual fatigue, cerebrovascular dementia, aftereffects of encephalopathy and Alzheimer's disease but also as medicaments for improving other cerebral functions or for activating cerebral metabolism or protecting anoxic brain damage.
The carbamoyl-2-pyrrolidinone compound of the present invention can be prepared by one of the following processes.
USPTO Backgrounds
USPTO Backgrounds