GB2162843A - Piperazine derivatives - Google Patents

Abstract

Compounds of the general formula <IMAGE> (R<1> is hydrogen or alkyl; R<2> is hydrogen, alkyl or optionally substituted aryl; and X is a bond, <IMAGE> and their salts possess cognition enhancing and/or mild CNS stimulating activity.

Description

SPECIFICATION Psychogeriatric 1-(2-pyrimidinyl)-piperazinyl derivatives of 1-pyrrolidin-2-ones Background of the invention This invention generally pertains to heterocyclic carbon compounds having drug and bio-affecting properties and to their preparation and use. In particular, the invention is concerned with 1,4-disubstituted piperazine derivatives wherein one substituent is a pyrimidin-2-yl ring and the other is a 1-pyrrolidin-2-one ring linked by a bridging moiety to the piperazine nitrogen atom. The compounds of this invention are applicable in treatment of various senile dementias affecting the elderly.

The clinical aspects of various senile dementias as well as the problems they cause in the affected geriatric subject are well known to those skilled in the art. One will also appreciate that various drug treatments of this disorder of the elderly are currently under study. Among such drugs are a class of drugs known as nootropic agents or, more commonly, cognition enhancers; some of which 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 member of a class of N-substituted 2-pyrrolidinone derivatives of structure 1.

a: X = H; R = -CH2CONH2 (piracetam) b: X = OH; R = -CH2CONH2 (oxiracetam) c: X = H; R = -CH2CONH[CH2]2N[CH(CH)2J2 (pramiracetam) d: X = H; R = -CO--OCH3 (aniracetam) Preliminary clinical results with this class of agents, exemplified by structures said, indicates that these drugs may have some beneficial effects in treating senile dementias in the elderly.

Related art may be viewed in light of the following general structural formula 2

in which A is a bridging moiety such as alkyl, alkanoyl, alkylamido-alkyl, and the like; and B is a substituent group.

In Great Britain 2,023,594, a series of 1-substituted alkyl-4-(3-trifluoromethylthiophenyl)-piperazines were disclosed as being useful in treatment of anxiety and depression. Specifically disclosed were compounds of structure 3.

wherein n = 2, 3.

U.S. Patent 4,145,347, issued March 20, 1979 to L'ltalien, et al., disclosed a series of N-(substitutedaminoalkyl)-2-oxo-1-pyrrolidine acid am ides as cognition activators potentially useful in treating patients suffering from senility. The most relevant compounds disclosed in this patent have structural formula 4.

wherein: n=1-4 R = CIA alkyl, specifically methyl.

A second patent, U.S. 4,372,960, issued February 8, 1983 to L'ltalien disclosed a series of quaternary derivatives of N-(substituted-aminoalkyl)-2-oxo-1 -pyrrolidine acid amides. These compounds of structural formula 5 are disclosed as being useful in the treatment of senility, memory enhancement and amnesia reversal.

wherein: n=1-4 R = C1 3 alkyl = = a pharmaceutically acceptable anion.

European Patent Application 89,900, published September 28, 1983 concerns a series of piperazine derivatives of formula 6 which are disclosed as drugs especially useful in the treatment of cerebral vascular disturbances in the elderly.

wherein: R is hydrogen or C1.3 alkyl; and Ri is an alkyl, cinnamyl or p-methoxybenzyl group.

Malawska, et al., "Synthesis and Pharmacological Properties of Some 2-Pyrrolidinone Mannich Base" in Polish Journal of Pharmacology, 1982, 34, 373-382, disclose a series of compounds of which one subclass is represented by structural formula 7. These compounds reportedly displayed analgesic properties as well as weak anti-inflammatory action.

wherein X is hydrogen or chlorine, All of the above referenced compounds differ from the series of compounds of the instant invention in -which B is a 2-pyrimidinyl heterocyclic ring as compared with the reference compounds wherein B is alkyl, aryl, or aralkyl. The following reference compounds are even less related than the foregoing.

A large number of psychotropic compounds with structures corresponding to formula 8 have been disclosed by Wu, Temple, New, and co-workers.

wherein n is 1-4.

These compounds of structural 8 and similar analogs, however, are N-substituted cyclic imide rings, e.g. succinimides, glutarimides, etc. and easily distinguished from the compounds of the instant invention.

See: Wu, et al., U.S. Patent 3,717,634 patented Feb. 20, 1973. Temple, U.S. Patent 4,423,049 patented Dec.

27, 1983. New and Yevich, pending application Serial No. 531,519, filed Sept. 12, 1983.

Similarly, the compounds disclosed by Okazaki, etna!., in U.S. Patent 4,420,481 issued December 13, 1983, (cf: structural formula 9); and Weber, etna!. in U.S. Patent 4,216,216, issued August 5, 1980, (cf: structural formula 10);

can be distinguished from the compounds of the-instant invention by virtue of these structures lacking both a lactam ring as well as a 2-pyrimidinyl ring moiety.

In summary, there are no teachings in the art which would make the specific compounds comprising the instant invention anticipated or obvious.

Summary of the invention A series of compounds of structural Formula I

wherein Ri is hydrogen or lower alkyl; R2 is hydrogen, lower alkyl, unsubstituted aryl or aryl optimally substituted at one or more ring positions with lower alkyl, halogen, -CF3, -CN, -NO2,

-NR32, -CO2R4, or OR5 with R3 being H or lower alkyl, R4 being R3, phenyl or phenalkyl, and R5 being R4, or

wherein n = 1 or 2; and o o X is a chemical bond, -c-, -CH2-, or -CNHCH2CH2 has been prepared. Compounds of this series can be incorporated into pharmaceutical compositions for use in geriatric subjects afflicted with senile dementias. A number of these compounds have been tested and display cognition enhancing action and/or mild CNS stimulation.These actions have been demonstrated by EEG and prevention of ECS-induced amnesia in rats and maze-testing of aged rats.

Detailed description of the invention In its broadest aspect, the present invention is concerned with 1-(2-pyrimidinyl)piperazinyl 1-pyrrolidin2-one derivatives having psychogeriatric properties and characterized by structural Formula I

wherein Ri is hydrogen or lower alkyl; R2 is hydrogen, lower alkyl, unsubstituted aryl or aryl optimally substituted at one or more ring positions with lower alkyl, halogen, -CF3, -CN, -NO2,

-NR32, -CO2R4, or OR5 with R3 being H or lower alkyl, R4 being R3, phenyl or phenalkyl, and R5 being R4, or

wherein n = 1 or 2; and o 0 X is a chemical bond, -C- -CH2-, or By lower alkyl is meant that these groupings contain from one to four carbon atoms. Halogen means, F, Cl, Br, or I and aryl means phenyl or naphthyl. When R5 is a dioxyalkyl group, the aryl ring is necessarily disubstituted at adjacent ring positions to effect fusion of the dioxo ring. For preferred compounds, Ri and R2 are hydrogen, and for the most preferred compound, X is a chemical bond.

It is to be understood that the present invention is considered to include the various stereoisomers, e.g. optical isomers including individual enantiomers, mixtures of enantiomers, diastereomers, and mixtures of diastereomers, which can arise as a consequence of structural asymmetry due to the presence of one or two asymmetric carbon atoms which may be incorporated into some compounds of the instant series. Separation of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art.

For medicinal use, the pharmaceutically acceptable acid addition salts, those salts in which the anion does not contribute significantly to toxicity or pharmacological activity of the organic cation, may be preferred in some cases.The acid addition salts are obtained either by reaction of an organic base of structure I with an organic or inorganic acid, preferably by contact in solution, or by any of the standard methods detailed in the literature available to any practitioner skilled in the art. Examples of useful organic acids are carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, pamoic acid, cyclamic acid, pivalic acid, and the like; useful inorganic acids are hydrohalide acids such as HCI, HBr, HI; sulfuric acid; phosphoric acid; and the like.

The compounds of the instant invention can be prepared via several synthetic methods which are modifications of a unitary process which is shown in Scheme 1.

Scheme 1 Unitary Process

in this scheme, R1 andzR2 will have the same meanings as previously assigned to them in Formula I.

The symbol "A" can be N,H; 9; or N1-CH2CO3Me. The symbol "B" can be H-; [R2HC=]; or H2NCHR2-X-. The relationship between A and B is: Method No. A B C When A is: NH (Ila) O (llb) NCH2CO2Me (llc) then B is: [R2HC=] (Illa) H2NCHR2CH2-(lilb) H (Illc) or H2NCHR2CH2 (Illb) The grouping [R2HC=] (Illa) represents the intermediate reaction complex formed between Illc B=H; and RCHO.This transient reaction intermediate undergoes rapid attack by Ila, A=NH; to give 1, Accordingly, the process of the instant invention for preparation of compounds: of Formula I

wherein Rl, R2, and X are as previously defined comprises the condensation of a compound of Formula II

wherein A is

with a compound of Formula Ill

wherein B is [R2HC=], H2NCHR2CH2, or H; with the proviso that when A is NH, B is [R2HC=]; when A is O, B is H2NCHR2CH2-; and when A is NCH2CO2Me, B is H or H2NCHR2CH2.

These methods comprising the unitary process are more fully illustrated by the reaction schemes shown in Scheme 2.

Scheme 2 Method A:

wherein R1 and R2 are as defined hereinabove.

Method A of Scheme 2 utilizes either a Mannich-type reaction of the appropriate pyrrolidinone, paraformaldehyde, and 1-pyrimidin-2-ylpiperazine or alternatively condensing an appropriate 2-pyrrolidinone, a selected aldehyde, and 1-pyrimidin-2-ylpiperazine with azeotropic removal of water. Method A will provide a product of structural Formula la.

In Method B, reaction of a -butyrolactone (llb) with an aminoalkyl derivative of 1-pyrimidin-2-ylpiperazine (Illb) yields an intermediate -hydroxyamide compound (IV) which upon treatment with thionyl chloride in an appropriate solvent, e.g. acetonitrile, undergoes cyclization to a compound of structural Formula Ib.

Method C comprises the base-catalyzed reaction of a pyrrolidinone acetate lIc) with either 1-pyrimidin2-ylpiperazine (Illc) or its aminoethyl derivative (Illb) to yield either Ic or Id.

The procedures to be used in preparing compounds of structural I by methods A-C are conventional and are readily available in the chemical literature to one skilled in the art.Examples of these methods, including synthesis of pertinent intermediates, will be exemplified later in the specification. Certain of the intermediate compounds used in the synthetic procedure discussed hereinabove are available commercially, e.g. compounds of Formula II as well as aldehydes of formula R2CHO, and therefore no examples nor description of their preparation need be given.

The compounds of the instant invention are useful pharmacological agents which enhance memory and learning mammals. In this regard, they display rat cortical EEG patterns consistent with mild CNS stimulation or patterns similar to that of a reference nootropic agent, aniracetam. Selected members of this series have been tested in a Y-maze test using aged rats and drug-induced enhancement of maze learning has been demonstrated. Additionally, other experimental procedures for determination of various CNS drug effects were carried out. The compounds of the instant series do not seem to elicit other CNS effects and thereby would seem to have an advantage as more selective agents.

The following in vivo tests were used to evaluate and classify the instant series of compounds.

Table 1 In Vivo Tests Used to Evaluate Formula I Compounds 1. Conditioned Avoidance Response (CAR) -- measure of a drug's tranquilizing activity as determined by its attenuation of avoidance response to electrical shock in trained fasted rats. Cf: Albert, Pharmacologist, 4, 152 (1962); Wu, etal., J. Med. Chem., 12,876-881(1969).

2. Catelepsy Reversal -- measure of a drug's ability to reverse neuroleptic-induced catelepsy in rats.

3. Vogel Anti-conflict -- a test of potential anxiolytic activity which measures a drug's ability to increase licking for water in thirsty rats by subduing the animal's aversion to electrical shock.

4. EEG -- a quantitive test which can serve to classify the effects of CNS compounds by comparison of their EEG profiles with those of various standard reference agents.

5. Consolidation of maze learning in aged rats -- aged rats (approximately 24 months old) are food deprived 24 hours prior to training in a Y-maze. On training trials, both goal-boxes at the end of the maze are baited with food pellets. The rat may select either arm of the maze to obtain food.When an arm is chosen, the rat is detained in the chosen arm and allowed to nibble on the food reward. Rats are next immediately dosed with test compound. The critical test is 24 hours later. Rats are again food deprived overnight and placed in the maze. However, neither goal-box is baited. A correct response is scored if the rat re-enters the arm chosen the previous day. Latency for the rat to progress from start-box to goal-box is timed with a stopwatch.

6. Prevention of ECS-induced Amnesia -- In the training phase of this test, animals are dosed with either drug or control solutions and 30 minutes later placed on an insulated platform atop an electified grid. When they step down from the platform, the receive an electric footshock until they scramble back to the safety of the platform. When placed upon the platform 24 hours later (a retention test), control rats do not step down; rather, they remain upon the safe platform, suggesting that they remember the aversive experience they encountered the previous day. Rats administered ECS (50 mA for 400 MSec through conrneal electrodes) immediately after training and tested 24 hours later, step down much sooner than controls. This memory deficit in ECS-treated rats reflects ECS-induced amnesia for the step-down task.

Prevention of ECS-induced amnesia by test compounds is reflected in step-down latencies 24 hours after "training plus ECS" that are significantly longer than those observed in rats treated with control solutions prior to "training plus ECS." According to the pharmacological profile established by the tests listed in Table 1, the instant compounds of Formula I have promising cognition enhancing potential in that they display EEG patterns consistent with mild CNS stimulation or they are qualitatively similar to the EEG pattern of the standard nootropic agent, aniracetam. Representative compounds selected from this series demonstrate enhanced learning in the aged rat Y-maze test and prevention of ECS-induced amnesia in normal age rats.In addition, these compounds appear to be selective agents in that low or negligible levels of activity are found in other tests indicative of different CNS effects.

The most preferred compound of the instant invention (Rl and R2 are hydrogen and X is a chemical bond) exhibits an EEG profile in the rat similar to that of the reference agent aniracetam, but is more potent than the latter. Enhanced potency of this compound relative to that of aniracetam has also been demonstrated in the Y-maze test employing aged rats, an appropriate behavorial model.

In summary of the foregoing discussion, the instant compounds have nootropic properties particularly suited to their use in cognition enhancementThus, another aspect of the instant invention concerns a process for enhancing cognition in a mammal in need of such treatment which comprises systemic administration to such mammal of an effective dose of a Formula I compound or a pharmaceutically acceptable acid addition salt thereof. The administration and dosage regimen of compounds of Formula I is considered to be done in the same manner as for the reference compound piracetam, cf: Reisberg, et al., in Drug Development Research, 2:475-480 (1982); Weng, et a/., in Rational Drug Therapy, 17(5), 1-4 (1983); Reisberg, et a/., in "Psychopathology in the Aged, Editors, Cole and Barrett, Raven Press, New York, pages 243-245 (1980). Although the dosage and dosage regimen must in each case be carefully adjusted, utilizing sound professional judgment and considering the age, weight and condition of the recipient, the route of administration and the nature and extent of mental deterioration, generally, the daily dosage will be from about 0.1 g to about 10 g, preferably 0.5 g to 5 when given orally.ln some instances, a sufficient therapeutic effect can be obtained at lower doses while in others, larger doses will be required. As is apparent to one skilled in clinical pharmacology the amount of Formula I compound comprising the daily dose may be given in a single or divided dose, taking into account those principles understood by the skilled practitioner and necessary for his practice of the art.

The term systemic administration as used herein refers to oral, rectal, and parenteral (i.e., intramuscular, intravensous and subcutaneous) routes. Generally, it will be found that when a compound of the present invention is administered orally which is the preferred route, a larger quantity of the active drug is required to produce the same effect as the smaller quantity given parenterally. In accordance with good clinical practice, it is preferred to administer the instant compounds at a concentration level that will produce effective nootropic effects without causing any harmful or untoward side effects.

Therapeutically, the instant compounds are generally given as pharmaceutical compositions comprised of an effective nootropic amount of a compound of Formula or of a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier. Pharmaceutical compositions for effecting such treatment will contain a major or minor amount (e.g. from 95 to 0.5%) of at least one compound of the present invention in combination with a pharmaceutical carrier, the carrier comprising one or more solid, semi-solid, or liquid diluent, filler and formulation adjuvant which is non-toxic, inert and pharmaceutically acceptable.Such pharmaceutical compositions are preferably in dosage unit forms; i.e. physically discrete units having a pre-determined amount of the drug corresponding to a fraction or multiple of the dose which is calculated to produce the desired therapeutic response. The dosage units can contain 1, 2,- 3 or more single doses, or alternatively, one-half, one-third, or less of a single dose. A single dosepreferably contains an amount sufficient to produce the desired therapeutic effect upon administration at one application of one or more dosage units according to the pre-determined dosage regimen, usually a whole, half, third or quarter of the daily dosage administered once, twice, three, or four times a day. It isenvis-ioned that other therapeutic agents can also be present in such a composition.Pharmaceutical -compositions which provide from about 0.1 to 1 g of the active ingredient per unit dose are preferred and are conventibnally prepared as tablets, losenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs, and aqueous solutions. Preferred oral compositions are in the form of tablets, capsules, and may contain conventional excipients such as binding agents (e.g., syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone), fillers (e.g. lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine), lubricants (e.g. magnesium stearate, talc, polyethyleneglycol or silica), disintegrants (e.g. starch) and wetting agents (e.g. sodium lauryl sulfate).Solutions or suspensions of a Formula I compound with conventional pharmaceutical vehicles are employed for parenteral compositions such as an aqueous solution for intravenous injection or an oily suspension for intramuscular injection. Such compositions having the desired clarity, stability and adaptability for parenteral use are obtained by dissolving from 0.1% to 10% by weight of the active compound in water or a vehicle consisting of a polyhydric aliphatic alcohol such as glycerine, propylene glycol, and the polyethylene glycols or mixtures thereof. The polyethylene glycols consist of a mixture of non-volatile, usually liquid, polyethylene glycols which are soluble in both water and organic liquids and which have molecular weights from about 200 to 1500.

Description of Specific Embodiments The compounds which constitute this invention and their methods of preparation will appear more fully from a consideration of the following examples which are given for the purpose of illustration only and are not to be construed as limiting the invention in sphere or scope. All temperatures are understood to be in degrees C when not specified.

The nuclear magnetic responance (NMR) spectral characteristics refer to chemical shifts (8) expressed as parts per million (ppm) versus tetramethylsilane (TMS) as reference standard. The relative area reported for the various shifts in the proton NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shifts as to multiplicity is reported as broad singlet (bs), singlet (s), multiplet (m), doublet (d), doublet of doublets (dd), or quartet (q). Abbreviations employed are DMSO-d6 (deuterodimethylsulfoxide), CDCI3 (deuterochloroform), and are otherwise conventional. The infrared (IR) spectral descriptions include only absorption wave numbers (cm-1) having functional group identification value.The IR determinations were employed using potassium bromide (KBr) as diluent. The elemental analyses are reported as percent by weight.

Synthesis of Intermediates Example 1 1-Pyrimidin-2-ylpiperazine (lllc) To a stirred, warm (approximately 50 ) solution of anhydrous piperazine (100 g, 1.16 mole) and sodium carbonate (58 g, 0.47 mole) in 465 mL water was added 2-chloropyrimidine (53 g, 0.46 mole) in portions over about 1 hour. External cooling was required to maintain the temperature in the 50-65" range. After the addition, the stirred reaction mixture was kept in the temperature range of 50-65" for one hour and then allowed to slowly cool to 35 over a 2 hour period. The mixture was filtered, removing 1,4-dipyrimidinylpiperazine, and the filtrate was extracted with 350 mL portions of chloroform.The chloroform extracts were dried (MgSO4) and concentrated to 62 g (82%) of an oily solid which can be purified by distillation (b.p. 118-120 /2 Torr.) or converted to a salt form.

Example 2 2-[4(2-Pyrimidinyl)-1-piperazinyly] ethanamine (lib) A mixture of N-bromethylphthalimide (38.19, 0.15 mole), 1-pyrimidin-2-ylpiperidine (24.6 9, 0.15 mole; prepared in Example 1), pulverized K2CO3 (20.7 g, 0.15 mole) and KI (1.5 g) in 450 mL acetonitrile was magnetically stirred and heated under reflux for 16 hr. The hot reaction mixture was filtered and the filtrate refrigerated.The crystalline precipite which formed was collected by filtration to give 21.4 9 white solid.A second crop which was obtained by partial concentration of the filtrate was recrystallized from isopropyl alcohol and combined with the initial crop for a total yield of 26.1 g (51%) of phthalimide intermediate, m.p. 119-122 .The latter intermediate (26.1 g, 0.077 mole) and 5.9 mL 99%:hydrazine hydrate in 210 mL ethanol was stirred and heated under reflux for 16 hr.The cooled reaction mixture was filtered and concentrated in vacuo to a solid residue which was triturated with 20 mL water and 75 mL chloroform. The aqueous phase was made strongly- alkaline with 50% NaOH solution, the organic phase separated and the aqueous phase extracted with several portions of chloroform.The combined chloroform fractions were dried (MgSO4) and concentrated in vacuo to a yellow oil which was purified by Kugelrohr distillation at 0.2 Torr. to afford 7.9 g (50%) of product.

Synthesis of I Products Example 3 I-4-/2-Pvrimidinvll- I-piperazinyl]methyl]-2-pyrrolidinone (Method AJ A mixture of 2-pyrrolidinone (13.6 g, 0,6 mole), 1-pyrimidin-2-ylpiperazine (26.2 g, 0.16 mole) and paraformaldehyde (19.6 g, 0.65 mole) and 420 mL ethanol was stirred and heated under reflux for 16 hour period. The hot solution was filtered and refrigerated and the crystalline precipitate which formed was collected by filtration and-recrystallized twice from ethanol to give 19.5 g (47%) of white solid, m.p. 161 163 .

Ana/. Calcd. for C,3H,9NSO: C, 59.75; H, 7.33; N, 26.80.

Found:C, 59.73; H, 7.38; N, 26.88.

NMR (CDCl3): 2.00 (2, m); 2.39 (2, t [7.0 Hzl); 2.57 (4, m); 3.49 (2,-t [6.8 Hz]); 3.81 (4, m); 4.02 (2, s); 6.43 (1, t [4.8 Hz]); 8.27 (2, d [4.8 Hz]).

IR (KBr): 795, 1000,1280,1365-1515, 155, 1545, 1585, 1675, 2780, 2800,2910, and 2950 cm-1.

Example 4 5-Methyl- 1-[[4-(2-pyrimidinyl)- 1-piperazinyl]-methyl]-2-pyrrolidinone Hydrochloride This compound can be prepared in a similar fashion by use of the procedure outlined in Example 3.

The crude base product was-an oil, b.p 190-200 /0.1 Torr, which was converted to the HCI salt by treatment with ethanolic HCI. Recrystallization of the HCI salt from ethanol gives a 68% yield of white solid, m.p. 188-190 .

Anal. Calcd. for C,4H2,NsO HC1: E, 53.93; H, 7.11; N, 22.46.

Found: C, 53.64; H, 7.04; N, 22.49.

Example 5 i-f(2- Chlorop 4en yljf4- (2-p yrimidin yI)- i-pip erazin yljmeth ylj-2-p yrrolldin one A solution of 2-pyrrolidinone (4.25 g, 0.05 mole), 1-pyrimidin-2-ylpiperazine (8.2 g,0.05 mole) and 2chlorobenzaldehyde (7.05 g, 0.05 mole) in 200 mL toluene was stirred and heated for 16 hour with an attached Dean-Stark trap for azeotropic removal of water.The solution was concentrated in vacuo to provide 16.2 g, (87%) of product. Recrystallization from ethanol gave white crystals, m.p. 166-177 .

Anal. Calcd. for C19H22CIN5O C, 61.37; H, 5.96; N, 18.83; Cl, 9.53. Found: C, 61.00; H, 6.15; N, 18.75; Cl, 9.32.

NMR (CDCl3): 1.92 (2, m); 2.42 (2, m); 2.55 (4, m); 2.86 (1, m); 3.31(1, m); 3.85 (4, m); 5.84 (1, s); 6.47 (1, t [4.7 Hz]); 7.32 (3, m); 7.80 (1, m); 8.27 (2, d [4.7 Hz]).

IR (KBr): 770, 795, 980, 1260, 1360, 1450, 1500, 1545, 1585, 1690 cm-1.

Example 6 1-[(3-Chlorophenyl)[4-(2-pyrimidinyl)- 1-piperazin yljmethylj-2-pyrrolldinon e Employing 3-chlorobenzaldehyde, this compound was prepared in a similar manner following the procedure outlined in Example 5. Recrystallization from cyclo-hexane gave a 62% yield of white powder, m.p. 136-138.5; Anal. Calcd. for C,9H22CIN5O:Cr 61.34; H, 5.96; N, 1S.83; Cl, 9.53. Found: C, 61.14; H, 6.03; N, 18.75; Cl, 9.66.

Example 7 i-f(4-Meth oxyp hen yl)f4- (2-p yrimidin yl)- i-pip erazin yUm e th yl]-2-p yrro lidin one Employing 4-methoxybenzaldehyde, this product was similarly prepared utilizing the basic procedure outlined in Example 5. Recrystallization of the product from cyclohexane gave an 81% yield of white crys tals, m.p. 166.5-169.5".

Anal. Calcd. for C20H20N6O2: C, 65.38; H, 6.86; N, 19.06.

Found: C,65.33; H, 6.97; N, 19.14.

Example 8 i-f(4-Cyanoph enylff4- (2-p yrimidin yl)- i-pip erazin yljmethyfj-2-p yrrolldinone Employing 4-cyanobenzaldehyde, this producet was prepared as in Example 5. Chromatography on silica gel eluting with ethyl acetate gave a 16% yield of product, m.p. 185-188".

Anal. Calcd. for C20H22N5O: C, 66.28; H, 6.12; N, 23.19.

Found: C, 66.55; H, 6.40; N, 22.59.

Example 9 i-f2-l4-(2-Pyrimidln yl)- ipioeraz,n yljeth yl]-2-p yrrolidinone hydrochloride hydrate (Method B) A solution of &gamma;-butyrolactone (1.81 9, 0.02 mole), 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethanamine (4.52 g, 0.02 mole: prepared in Example 2), and a catalytic amount of p-toluene-sulfonic acid in 28 mL benzene was- stirred and heated at reflux for 6 hours. The precipitate which crystallized upon standing at room temperature was collected by filtration and air dried to afford 3.78 g (61%) of the a-hydroxyamide intermediate (IV), m.p. 93-97.A mixture of IV (3.6 g, 0.012 mole) and thionyl chloride (1.45 g, 0.012 mole) in 30 mL acetonitrile was stirred and heated at reflux for 16 hour.A crystalline precipitate which resulted after cooling to room temperature and was collected and recrystallized from isopropyl alcohol to give 2.66 g (69%) of white solid, m.p; 1851879 Anal. Calcd. for C14H21N50.2 2HCI-0.2H2O: C, 46.05; H, 6.60; N, 19.60; Cl, 21.83; H2O, 0.50. Found: C, 46.90; H, 6.68; N, 20.09; Cl, 21.83; H2O, 0.48, NMR (DMSO-d6): 1.96 (2, m); 2.30 (2, m); 3.20 (4, m); 3.55 (6, m); 3.64 (2, t [6.7Hz]); 4.58 (2, m); 5.40 (1-, bs); 6.75 (1, t [4.9 Hz]); 8.49 (2, d [4.9 Hz]); 11.50 (1, bs).

IR (KBr): 795, 950, 980, 1370, 1435, 1475, 1555, 1590, 1665 cm-1.

Example 10 1-[r2-Oxo-1-pyrrolidinyl)acetate]-462-pyrimidinyl)piperazine-2-propanolate (Method C) A solution of methyl 2-oxo-1-pyrrolidineacetate (12.58 g, 0.08 mole), 1-pyrimidinyl-2-ylpiperazine (13.12 g, 0.08 mole) and sodium (1.84 g, 0.08 mole) in 200 mL methanol was stirred and heated under reflux for 16 hour. The cooled reaction mixture was diluted with saturated sodium chloride solution and extracted with methylene chloride. The dried (MgSO4) extract was concentrated in vacuo and the residual solid recrystallized twice from isopropanol to afford 7.66 g (32%) of white solid, m.p. 185-187".

Anal. Calcd. for C,4H,9N502.0.1C3H8O: C, 58.15; H, 6.76; N, 23.71. Found: C, 57.76; H, 6.80; N, 23.55.

NMR (CDCl3): 2.06 (2, m); 2.42 (2, m); 3.61 (6, m); 3.78 (4, m); 4.19 (2, s); 6.50 (1, t [4.8 Hz]); 8.28 (1, d [4.8 Hz]).

IR (KBr): 795, 980, 1240, 1260, 1305, 1355, 1490, 1545, 1580, 1645, 1680, 2860, 2930, 3020 cm-1.

Example ii 2-0xo-N-1;2-4-(2-pyrimidinyll- 1-piperazinyl] ethyl]- 1-pyrrolidineacetamide hydrate This compound was prepared using a procedure similar to that outlined in Example 10. Recrystallization from isopropyl alcohol gave a 40% yield of an off-white solid, m.p. 105-107.5 .

Anal. Calcd. for C,6H24N502.0.2H2O: C, 57.19; H, 7.32; N, 25.01; H2O, 1.07. Found: C, 56.98; H, 7.25; N, 24.71; H2O, 0.39.

Claims (30)

1. A compound of Formula I

wherein R is hydrogen or lower alkyl; R2 is hydrogen, lower alkyl, unsubstituted arvl or arvl oDtimallv substituted at one or more rina nosi- tions with lower alkyl, halogen, -CF3, -CN, -NO2,

-CO2R4, or OR5 with R3 being H or lower alkyl, R4 being R3, phenyl or phenalkyl, and R5 being R4 or

wherein n = 1 or 2; and X is a chemical bond1

and the pharmaceutically acceptable acid addition salts thereof.

2. A compound of Claim 1 wherein RI is hydrogen.

3. The compound of Claim 1 wherein R2 is hydrogen.

4. The compound of Claim 1 wherein X is a chemical bond,

5. The compound of Claim 1 wherein R' and R2 are hydrogen.

6. The compound of Claim 1, 1-[[4-(2-pyrimidinyl)-1-piperazinyljmethyl]-2-pyrrolidinone.

7. The compound of Claim 1 5-methyl-l-[[4-(2-pyrimidinyl)-1-piperazinyl]methyl]-2-pyrrolidinone.

8. The compound of Claim 1, 1-[(2-chlornphenyl)[4-2-pyrimidinyl)1-piperazinyl]methyl]-2-pyrrolidi- none.

9. The compound of Claim 1, 1-[(3-chlorophenyl)[4-(2-thyl]-2-pyrrolidinone.

10. The compound of Claim 1, 1-[(4-methoxyphenyl)[4-(2-pyrimidinyl)-1 -piperazinyllrimidinyl)-1 -pipera- zinyll methyl]-2-pyrrolidinone.

11. The compound of Claim 1, 1 -[(4-cyanophenyl)[4-(2-pyrimidinyl)-1 -piperazinyl]methyl]-2-pyrrolidi- none.

12. The compound of Claim 1, 1-[2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl]-2-pyrrolidinone.

13. The compound of Claim 1, 1-[(2-oxo-1-pyrroiidinyl) acetyl]-4-(2-pyrimidinyl)piperazine-2-propano- late.

14. The compound of Claim 1, 2-oXo-N-[2-[4-(2-pyrimidinyi)-1-piperazinyl]ethyl]-1-pyrrolidineacetam- ide.

15. A pharmaceutical composition in unit dosage form suitable for systemic administration to a mammalian host comprising a pharmaceutically acceptable carrier and from about 0.1 to 1 g of a compound claimed in claim 1.

16. The pharmaceutical composition of claim 15 wherein the Formula I compound is 1-[[4-(2-pyrimidi nyl)-1 -piperazinyl]methyll-2-pyrrolidinone.

17. A pharmaceutical compound as defined in any one of claims 1 to 14 for use in a method of treatment of the human or animal body.

18. A compound according to claim 17 for use as a cognition enhancing agent.

19. A compound according to claim 1 substantially as herein before specifically described in each of the examples for the use hereinbefore specifically described.

20. A compound as described in claim 1 substantially as hereinbefore specifically described in each of the examples.

21. A pharmaceutical composition according to claim 15 substantially as hereinbefore specifically described in the examples.

22. A process for preparing a compound of Formula I

wherein RI is hydrogen or lower alkyl; R2 is hydrogen, lower alkyl, unsubstituted aryl or aryl optimally substituted at one or more ring positions with lower alkyl, halogen, -CF3, -CN, -NO2,

-NR3,, -CO2R4, or OR5 with R3 being H or lower alkyl, R4 being R3, phenyl or phenalkyl, and R5 being R4, or

wherein n = 1 or 2; and X its a chemical bond,

which comprises the condensation of a compound of Formula II

wherein A is

with a compound of Formula Ill

wherein B is [R2HC=], H2NCHR2-X- or H-; with the proviso that when A is NH, B is [R2HC=]; when A is O, B is H2NCHR2CH2; and when A is NCH2CO2Me, B is H or H2NCHR2CH2.

23. A process for making a compound as defined in claim 1 substantially as hereinbefore specifically described in the Examples.

24. A compound when produced by a process as claimed in either of claims 22 and 23.

25. A compound according to claim 17 for use as a stimulator of mild CNS in a mammal in need of such treatment, in the form of a daily dosage unit within the range from 0.1 grams to 10 grams from oral administration.

26. A compound according to claim 25 wherein said dosage unit is within the range from 0.1 grams to 10 grams.

27. A compound according to claim 25, wherein said dosage unit is within the range from 0.5 grams to 5 grams.

28. A compound to claim 17 for use as a treatment for various senile dementias affecting elderly humans.

29. A compound according to claim 28 which is

1. 1 -[[4-(2-pyrimidinyl)-1 -piperazinyl]methylj-2-pyrrolidinone;

2. 5-methyl-I -[[4-(2-pyrimidinyl)-1 -piperazinyl] methyl]-2-pyrrolidinone;

3. 1 -[(2-chlorophenyl)[4-2-pyrimidinyl)-1 -piperazinyl] methyl]-2-pyrrolidinone;

4. 1 -[(3-chlorophenyl)[4-(2-pyrimidinyl)-1 -piperazinyl] methyl]-2-pyrrolidinone;

5. 1 -[(4-methoxyphenyl)[4-(2-pyrimidinyl)-1 -piperazinyl] methyl]-2-pyrrolidinone;

6. 1 -[(4-cyanophenyl)[4-(2-pyrimidinyl)-1 -piperazinyl] methyl]-2-pyrrolidinone;

7. 1 -[2-[4-(2-pyrimidinyl)-1 -piperazinyl]ethyl-2-pyrrolidinone; ;

8. 1 -[(2-oxo-1 -pyrrol idinyl )acetyl]-4-(2-pyrim idinyl ) pi perazine-2-propanolate; or

9. 2-oxo-N-[2-[4-(2-pyrimidinyl)-1 -piperazinyl]ethyl]-1 -pyrrolidineacetamide

30. The use of a substance according to claim 1 for the manufacture of a medicament which is a cognition enhancing agent for treatment of senile dementias or a stimulator of mild CNS.