This invention generally pertains to heterocyclic compounds having drug and bio-affecting properties and to their preparation and use. In particular, the invention is concerned with oxygenated derivatives of 1-[[1-[2-(trifluoromethyl)-4-pyrimidinyl]-4-piperidinyl]methyl]-2-pyrrolid inone, or more commonly known as BMY-21502. The compounds of this invention are cerebral function enhancers useful in treating various dementias due to degenerative processes as well as in enhancing memory and learning.
Clinical aspects of various degenerative dementias, as well as the socioeconomic problems they cause in affected populations, are well known to those skilled in the art. One will also appreciate that various drug treatments of these disorders are currently under study. Among such drugs are a class of drugs known as nootropic agents or, more commonly, cognition enhancers; some of are currently undergoing clinical evaluation in patients diagnosed as having Alzheimer's disease, a serious and fairly common CNS disorder of the elderly. Chemically, these drugs under clinical study are members of a class of N-substituted 2-pyrrolidinone derivatives of structure 1. ##STR2## a: X.dbd.H; R.dbd.--CH.sub.2 CONH.sub.2 (piracetam) b: X.dbd.OH; R.dbd.--CH.sub.2 CONH.sub.2 (oxiracetam)
c: X.dbd.H; R.dbd.--CH.sub.2 CONH[CH.sub.2 ].sub.2 N[CH(CH.sub.3).sub.2 ].sub.2 PA1 d: X.dbd.H; ##STR3## (aniracetam) PA1 R.sup.3 is selected from hydrogen, hydroxy, or oxo, with the proviso that R.sup.3 can only be oxo when R.sup.1 and R.sup.2 are hydrogen, and further that R.sup.1, R.sup.2, and R.sup.3 cannot all be hydrogen or hydroxy at the same time; and PA1 the solid and dotted lines refer to either a double covalent bond or a single covalent bond with another hydrogen atom covalently bonded to the carbon terminus end.
For a representative reference describing the testing and properties of a member of this series, see: Butler, et al., J. Med. Chem., 27, pp. 684-691 (1984). Preliminary clinical results of this class of agents indicate that the drugs may have some beneficial effects in treating senile dementias in the elderly.
A series of patents disclose a number of compounds with structures corresponding to formula 2. ##STR4## wherein X is usually C.sub.2-4 substituted or unsubstituted alkylene; Y is carbonyl or methylene; A is a bridging moiety such as alkylene, alkanoyl, alkyleneamidoalkylene, and the like; W is nitrogen; and B is a pyrimidinyl, pyridinyl, or benzisothiazolyl ring system. Members of this series are reported to have psychotropic, anxiolytic, antiemetic, tranquilizing, cognitive enhancing, as well as other nootropic activities. For more detailed disclosure of these compounds, see: Yevich and Mattson, U.S. Pat. No. 4,668,687 issued May 26, 1987; Wu, et al., U.S. Pat. No. 3,717,634 issued Feb. 20, 1973; Temple, U.S. Pat. No. 4,423,049 issued Dec. 27, 1983; and New and Yevich, U.S. Pat. No. 4,524,206 issued June 18, 1985.
Other subject matter related to formula 2 compounds was disclosed by Malawska, et al., in "Synthesis and Pharmacological Properties of Some 2-Pyrrolidinone Mannich Bases" in the Polish Journal of Pharmacology, 34, pp. 373-382 (1982). They described a series of compounds, of which one subclass is represented by structural formula 3, which reportedly display analgesic properties as well as weak anti-inflammatory action, ##STR5## wherein X is hydrogen or chlorine.
The most relevant art is believed to be in the patent to Mattson, et al., U.S. Pat. No. 4,826,843 issued May 2, 1989, wherein compounds of general formula 4 were disclosed as having cognition and memory enhancing activities. ##STR6##
For formula 4, X is an ethylene chain or 1,2-benzo ring; Y is carbonyl or methylene; R.sup.1 is hydrogen or lower alkyl; and Z is an R.sup.2, R.sup.3 -disubstituted diazinyl ring selected from pyridazine, pyrimidine, and pyrazine ring systems. A preferred compound of the series was 1-[[1-[2-(trifluoromethyl)-4-pyrimidinyl]-4-piperidinyl]methyl]-2-pyrrolid inone (4a), hereinafter referred as BMY-21502. ##STR7##
BMY-21502 is currently under clinical evaluation for the treatment of memory and cognitive disorders.