CA1250291A - Psychogeriatric 1-(2-pyrimidinyl)-piperazinyl derivatives of 1-pyrrolidin-2-ones - Google Patents

Abstract

Abstract of the Disclosure A series of nootropic compounds of Formula I

I

wherein R1 is hydrogen or lower alkyl;
R is hydrogen, lower alkyl, or optionally substituted aryl; and X is a chemical bond,

Description

2g~

PSYCHOGERIATRIC 1-(2-PYRIMIDINYL)-PIPERAZINYL DERIVATIVES OF l-PY M OLIDIN-2-ONES

Background of the Invention This invention ~enerally 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 treatment6 of this disorder of the elderly are currently under study. Among such drugs are ~ class of drugs known as nootropic agents or, more commonly, cognition enhancers; some of which are currently under~oing clinical evaluation in patlents 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.

!
N-R

a: X = H; R = -CH2CONH2 (piracetam) b: X = OH; R = -CH2CONH2 (oxiracetam) c: X = H; R = -CH2CONH[CH2]2N[CH(CH3)2]2 (pramiracetam) 1~ d: X = H; R = -CO ~ -OCH3 (aniracetam) Preliminary clinical results with this class of agents, exemplified by structures la-d, 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 ~^
~ -A-N~__JN-B

in which A ls a bridglng moiety such as alkyl, alkanoyl, alkylamido-alkyl, and the like; and B i6 a substituent group.
In Great Brltain 2,023,594, a serles of l-substituted alkyl-4-(3-trifluoromethylthiophenyl)-piperazines were discloced ~s being useful in treatment of anxiety and depression. Specifically disclosed were compounds ~f structure 3.

~ N-(E~2)~-wherein n = 2, 3.
U.S. Patent 4,145~3479 issued March 20, 1979 to L'Italien, et al.,disclosed a series of N-(substltuted-aminoalkyl~ 2-oxo-1-pyrrolidine acid ~mides as cognition activators potentially useful intreaeing patients suffering from senility. The most relevant compounds disclosed in this patent have structural formula 4.

o ~ ~
~ 2C NH-(c~l23n-N N-R

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

A second patent, ~.S. 4,372,960, issued February ~, 1983 to L'Italien disclosed a series of quaternary derivatives of N (substituted-aminoalkyl)-2-o~o-1-pyrrolidine acid amides. These co~pounds of structural for~ula 5 are disclosed as being useful in the treatment of senillty, memory enhance~ent ~nd amnesia re~ersal.

~ CH2~ (CH2)n~

wherein:
n = 1-4 R = Cl_3 alkyl X~ S a pharmaceutically acceptable anion.
European Patene Application B9,900, published September 28, 19B3 concerns a series of piperazine derivatives of formula 6 which are disclosed as drugs especially useful in the treatmenL of cerebral vascular disturbances in the elderly.

~ N-~C-N N-R

wherein:
R ls hydrogen or Cl 3 alkyl; and R is an allyl, clnnamyl or p-methoxybenzyl group.
Malawska, et al., "Synehesis and Pharmacological Properties 15 of Some 2-Pyrrolidinone Mannich Bases~' in Polish Journal of Pharmacology, . .
1982, 34, 373-382, disclose a serles of compounds of which one subclass is represented by structural formuls 7 These compounds reportedly displayed analgesic properties ns well as weak anti-lnflammatory action.

~ ~-CH2-wherein X is hydrogen or chlorine.
All of the above referenced compounds differ from the series of compounds of the instant invention in whlch B is a 2-pyrimidinyl heterocyclic ring as compared with the reference compounds wherein B is alkyl, aryl, or aralkyl. The following referenc~
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, Temp]e, New, and co-workers.

~ -(C~ ~ N N

wherein n is 1-4.
These compounds of structure 8 and similar analogs, however, are N-substituted cyclic imide rings, P.g. succinimides, glutar-lmides, etc. and easily distinguished from the compounds of thP instant invention.

`z~
See:

Wu, et al., U.S. Patent 3,717,634 patented February Z0, 1973.

Temple, U.S. Patent 4,423,049 patented Dec. 27, 1983.

New and Yevish, pending application Serial No. 531,519, filed September 12, 1983, now U.S. Patent 4~524,206 issued 18 June 1985.

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

~ J~ N N~ ~N t 2)n N~
o 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.

Summarv of t~he Invention A series of compounds of structural Formula I

~ N-CH-X-N N
H

'~..,,~

~L~æ~s~

wherein Rl is hydrogen or lower alkyl;
R2 is hydrogen, lower alkyl, unsubstituted aryl or aryl optionally substituted at one or more ring positions with lower alkyl, halogen -CF3, -CN, -N02, -CR3, -NR32, with R3 being H or lower alkyl, -C02R4, with R4 being R3, phenyl or phenal~yl, -oR5, R5 being R4 or --O _ [C~2]n wherein n = 1 or 2; and O O
Il 11 X is a chemical bondt-C-, or -CNHCH2CH2 has been prepared. Compounds of this series can be incorporated into pharmflceutical 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-pyrrolidin-2-one derivatives having psychogeriatric properties and characterized by structural Formula I

~ R

-- 12 ~
wherein Rl is hydrogen or lower alkyl;
R2 is hydrogen, lower alkyl, unsubstituted aryl or aryl optionally substituted at one or more ring positions with lower alkyl, halogen -CF3, -CN, -N02, -CR , -NR32, with R3 being H or lower alkyl, -C02R4, with R4 being R3, phenyl or phenalkyl, -oR5, R being R4 or ,~CH2}n wherein n = 1 or 2;

and when R5 is O ,[CH2]n, 9aid aryl group being disubstituted at adjacent ring positions to effect fusion of the dioxo ring;

and O O
X is a chemical bond, -C-, -CH2-, or -CNHCH2CH2. 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, R1 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.
opticalisomers including individual enantiomers, mixtures of enantiomers, diastereomers, and mixtures oP 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 c~ses. The acid add~tion salts are obtained either by reaction of an organic base of struceure I witb an organic or inorganic acid, preferably by contact $n solution~ or by any of the standard methods detailed in the literature available to S any practitioner skilled in the art. Examples of ~seful organic acids are carbo-~lic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid~ isethionic acid, succinic acid, pamoic acid, cyclamic acld, plvalic acid, and the like; useful inorganic acids are hydrohalide acids such as HCl, HBr, HI; sulfuric acid; phosphoric acid; and the like.
The compounds of the instant invention can be prepared via several synthetic ~ethods which are modifications of a unitary process which is shown in Scheme 1.
Scheme 1 Unitary Process o B-N 3 ~

II III
In this scheme, R and R will have the same meanin~s as previously assigned to them in Formula I. The symbol "A" can be NH;
~; or ~-CH2C02Me. The symbol "B" can be ~-; [R2HC=]; or H2NCHR
The relationship between A and B is:

Method No. A _ C
When A ~s: NH (IIa) O (lIb) NCB2C02Me (IIc~

then B is: [R HC=] (IIIa) H2NCHR CH2- (IlIb) H (IIIc) or H2NCHR CH2 (IIlb) The grouping LR HC=] (IIIa) represents the intermediate reaction complex formed between IIIc B=H; and R CHO. This transient reaction intermediaee undergoes rapid attack by lIa, A=NH; to give I.
Accordingly, the process of the instant lnventlDn for preparation of compounds of Formula I

~ -ÇH-X-N ~ N ~

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

~ A
~R1 II
wherein A is ~ , or ~CH2C02Me; with a compound of Formula III
'3 ~
N

III
wheréin B is [R2HC=], H2NCHR2CH~, or H; with the proviso that when A is NH, B is lR2HC=]; when A is 0, B is H2NCHR2CH2-; and when A is NCH2C02Me, 3 is H ~r H2NCHR CH2.

~;25~

These methods comprisin~ the unitary process are more fully illustrated by the reaction schemes chown ln Scheme 2.
Scheme 2 ~Sethod A:

+ R2CI10 + L~ ~ ~ C

IIa IIIC IB

~Sethod B:

2 C~2 N 3 ~ HO-C~-[C~2~2CNH-c~-c~2 IIb lIIb ~ , -~H2-~ b Method C:
o C~2C M ~ ~ 2C

IIc IIIc Ic IIc ~IIIb ~ H2CNHCH CH~-Id wherein Rl and R2 are as defined hereinabove.

s~

Method A of Scheme 2 utilizes either A Mannich-typ~ reaction of the appropriate pyrrolidinone~ parafQrmaldehyde, snd l-pyrimidin-2-ylpiperazine or alternatively condensing an appropriate 2-py~rolldinone, a selected aldehyde, and 1-pyrlmidin-2-ylpiperazine with azeotropic removal of water. Method A wlll provide e product of structural Formula Ia.
In Method B, reaction of a y-butyrolactone (IIb) with an aminoalkyl derivative of l-pyrimidin-2-ylpipera~lne (IlIb) yields an intermediate y-hydroxyamide compound (IV) which upon treatment with thionyl chloride in an appropriate solvent9 e.g. acetonitrile, undergoes eyclization to a compound of struc$ural Formula Ib.
Method C comprises the base-catalyzed reaction of a pyrrolidinone acetate IIc) with either l-pyrimidin-2-ylpiperazine (IIIc) or lts aminoethyl derivative (IIIb) to yield either Ic or Id.
The procedures to be used ln preparing compounds of structure I
by methods A-C are conventional and are readily available in the chemical literature to one skilled in the art. Examples of these methods, including synthesis of pertinent intermedlates, will be exemplified later in the specificatlon. Certain of ~he intermediate compounds used in the synthetic procedure discussed hereinabove are available commerclally, e.g. compounds of Formula II as well as aldehydes of formula R CHO, and therefore no examples nor description of their preparation need be given.
The compounds of the instant invention are useful pharma-cological agents which enhance memory and learning in mammals. In this regard, ehey display rat cortical EEG patterns consistent with mild CNS stimulation or patterns similar to that of ~ reference nootropic agent, aniracetam. Selected members of this series have been tested in a Y-maze test using aged rats and drug-induced enhancement of maze learning h~s been demonstraeed. Additionally, other experimental procedures for determinatlon of various ~NS drug effects were carried Oue. The compounds of the instant series do not seem to elicit other CNS effects and thereby would seem to have an advantage as more selective agents.
The following in ~ivo tests were used to evaluate and classify the instant series of compounds.
Table 1 In Vivo Tests ~sed to Evaluate Formula I Compounds 1. Condit$oned Avoidance Response (CA~) - measure of a drug's tran-quili~ing activity as determined by its attenuation of avoidance response to electrical shock in trained fasted rats. Cf: Albert Pharmacologist, 4, 152 ~1962); Wu, et al., J. Med. Chem., 12, 87~-881 (1969).
2. Catelepsy Reversal -- measure of a drug's ability to reverse neuro-leptic-induced catelepsy $n rats.

3. Vogel Anti~conflict -- a test of potential anxi~lytic 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 quantitative test which can serve to classify the eEfects 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 (approxl-mately 24 months old) are food deprived 24 hours prior to training in a Y-ma~e. 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 the test compound. The critical te~t is 24 hours later. Rats are again food deprived overnight and placed in the maze. However, neither goal-box ls baited. A correct response is scored iE the rat re-enters the arm chosen the previous day.
Latency for the rat to progress fro~ 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 lnsulated platform atop an electified grid. When they step down from the platform, the receive an electriEied foo~shock 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 t~

platform, suggesting that they remember the aversive experience they encountered the previous day. Rats admlni6tered ECS
(50 mA for 4~0 MSec through corneal electrodes) immediately --after tralning and tested 24 hours later, step down much sooner thsn controls. This memory deficit ln ECS-treated rats reflects ECS-induced amnesia for the step-down task. Preventlon of ECS induced amnesia by test compounds is reflected in step-down latencies 24 hours after "training plus ECS" that are signlficantly longer than those observed ln rats treated with control solutions prior to "training plus ~CS."
According to the pharmacologlcal profile established by the tests listed in Table 1, the instant compounds of Formula I have promising cognition enhancing potential ln that they display EEG
pateerns consistent with mlld CNS stimulation or they are qualltat:Lvely similar to the EEG pattern of the standard nootropic agent, aniracetam.
Representative compounds selected from this series demonserat~ 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 ~ffects.
The most preferred compound of the instant lnvention ~Rl and R2 are hydrogen and X is a chemical bond) exhibits an EEG pTofile 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 be~n demonstrated in the Y-maze test employing sged rats, an appropriate behavorial model.
In summary of the foregoing discufision, the instant compounds have nootropic properties particularly suited to their use in cognition enhancement. Thus, 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 ~al~ thereof. The administration ~nd do~age regimen of cDmpounds of Formula I is c~nsidered to be done ln the same ~nner a~
for ~he reference compound pir~cet~m, cf: Reisberg, et al., in Drug Development Research, 2:475-480 (1982); Weng, ~t al. 9 ln Ratlonal ~ Therapy, 17(5)~ 1-4 (1983); Reisberg, et al , in "Psy~hopatholozy in the ARed, Editors, Cole and Barrett, Raven ~ress, New iork, p~ges 243-245 (1980). Although the dosage and dosage regimen must in each case be rarefully ~djusted~ utlliæing sound professional ~ud~mPnt and considering the ~ge, weight and condition of the recipient, the route of administration and the nature and extent of ~ental deterioratiDn, generally, the daily dosage will be from aboue 0.1 g to about 10 g, preferably D.5 ~ to 5 g, when given orally. In some instances, ~
sufficient therapeutic effect csn be obtained ~t lower doses while in others, l~rger doses will be required. As is apparent to one skilled in clinical pharmacology the ~mount of Formula I compound comprising the daily dose may be given in a single or divided dose, taking into accoun~ those principles understood by the skilled practitioner and necessary for his practice of the are.
The term systemic administration as used herein refers to oral, rectal, and parenteral (i.e., intramuscular, intraveneous and ~ubcutaneous) routes. Generally, it will be found that when a compound of the present invention is administered orally which is the preferred route, ~ larger quantity of the active drug ls required to produce the same effect as the smaller quantity given parenterally.
In accordance with ~ood clinical practice, lt ls preferred to admlnister the instant compounds ~t a concentration level that wll' produce effective nootropic effeces wlthout causing any harmful or untoward side effects.

Therapeut~cally, the instant compounds are generally given as pharmaceucical compositions comprised ~f an effective nootropic amount of a compound of Formula I or ~:E a Pharmaceuticall~ acceptable acid addition 631t thereof and a pharmaceutically acceptable carrier.
Pharmaceutical compositions for effecting su h treatment ~ill 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 compo-sitions are preferably in dosage unit forms; i.e., physically discrete unlts having a pre determined amount of the drug corresponding to a fraction or multiple Df the dose which is calculated ~o produce the desired therapeutic response. The dosage units can contain 1, 2, 3 or lS more single doses, or alternatively, one-half, one-third, or less of a single dose. A single dose preferably contains an amount sufficient to produce the desired therapeutic effect upo~ 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 is envisioned that other therapeutic agents can also be present in such a composition. Pharmaceutical compositions ~hich provide from sbout 0.1 to 1 g of the active $ngredient per unit dose are preferred and are conventionally prepared as tablets, lo~enges. capsules, powders, aqueous or oily suspensions, syrups, ellxirs, and aqueous solutions.
Preferred oral compositions are in the form of tablets, capsules, and may contain conventional excipients such as binding ~gents (e.g., syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone), fillers (e.g. lactose, sugar, maize-starch~ calclum phosphate, sorbitol or glycine), lubr~cant~ (e.g. magneslum stearate, t~lc, polyethyleneglycol or silica), disintegrants (e.g. starch) and wett~ng agents (e.g. sodium lauryl sulfate). Solutions or suspensions of a Formula I compound with conventlonal pharmaceutical vehicles are employed for parenteral compositions such ~s an aqueous solutlon 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 lOZ by welght of ehe active compound $n water or a vehlcle consisting ~f a polyhydric aliphatic alcohol such as glycerine, prDpylene glycol, and the polyethylene glycols or mixtures thereof. The polyethylene glycols consist of a mixture of non-volatile, usually liquid, poly-ethylene glycols which are soluble i~ both water snd organic liquids and which hav2 molecular weights from about 200 to 15~0.

Description of Specific Embodiments The compounds which constitute this invention and their methods of preparation will sppear 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 (~) 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 2~

type in the molecule. The nature ~f the shifts as to multiplicity ls reported as broad s~nglet ~bs), singlet (s), multiplee (~), doublet ~d), doublet of doublets (dd~, or quartet (q). Abbreviations employed are DMSO-d6 ~deuterodimethylsulfoxide), CDC13 (deuterochloroform), and are other~ise conventional. The lnfrared (IR) spectral descriptlons include only absorption wave numbers (cm ) having functional group identification value. The IR determinat~ons were employed UsiDg potassium bromide (KBr) as diluent. The elemental analyses are reported as percent by weight.

Synthesis of Intermediates l-Pyrimidin-2-yipiperazine (IIIc) To a stirred, warm (approximately 50 ) solution of anhydrous piperazine (100 g, 1.16 mole) and sodium carbonate ~58 g, 0.47 mole) 1~ ln 465 mL water was added ~ chloropyrimidine (53 ~, 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-dipyrimidinylpipera~ine, and the filtrate was extracted with 350 mL portions of chloroform. The chloroform extract~ were dried (MgS04) and concentrated to 62 g (82~) of an oily solid which can be purified by distillation (b.p. 118 120/2 Torr.) or ronverted to a salt form.

2-14-(2-Pyrimidlnyl~ plperazinyl~
ethanamine (IIIb) A mixture of N-bromethylphthalim~de (38.1 g, 0.15 ~ole), 1-pyrimidin-2-ylpiperidine t24~6 g, 0.15 mole; prepared ln Example 1), pulveri~ed ~2C03 (20.7 g, 0.15 mole) and KI (1.5 g) in 450 mL aceto-nitrile was ~agnetically 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 g white solid. A second crop which was obtained by partial concentration of the filtrate was recrystallized from isopropyl alcohol and combined with the init~al crop for R total yield of 26.1 g (51~) of phthalimide intermediat~9 m.p. 119-122 . The latter intermediate (26.1 g, 0.077 mole~ and 5.9 mL 99% hydrazine hydrate in 15 210 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 or~anic phase separated and the aqueous phase extracted with several portions of chloroform. The combined chloroform fractions were dried (MgS04) 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 4-t2-PYrim~dinYl)-l-PiPerazinYlJmethYl]-_ 2-pyrrolldinone ~Method A) A mixture of 2-pyrrolidinone (13.6 g, 0.6 ~ole), l-pyrimidin-2-ylpiperazine (26.2 g, 0.16 mole) and paraformaldehyde ~i9.6 g, 0.6S
mole) and 420 mL ethanol was s~irred 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 nd 10 recrystallized twlce from ethanol eO give 19.5 g (47%) of white solid, m.p. 161-163D.
Anal. Calcd. for C13HlgN50: C, 59.75; ~, 7O33; N, 26.80.
Found: C, 59.73; H, 7.38; N, 26.88.
NMR (CDC13): 2.00 (2, m); 2.39 (2, t [7.0 ~z~);
15 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, 980, 1000, 1280, 1365, 1515, 1545, 1585, 1675, 2780, 2800, 2910, and 2950 cm 1.

5-Methyl~ [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 ~ICl salt by treat~ent with ethanolic HCl. Recrystallization of the HCl salt irom ethanol gives a 68% yield of white solid, m.p. 188-190~.
Anal. Calcd. for C14H21N50 HCl: E, 53.93, H, 7.11; N, 22.46.
Found: C, 53.64; R, 7.04, N, 22.49.

l-[(~-Chlorophenyl)[4-(2 pyrimidinyl)-l-piperazinyl]methyl]-2-pyrrolidinone A solution of ~pyrrolidlnone (4.25 g, 0.05 mole), 1-pyrimidin-2-ylpiperazine (3.2 g, 0.05 mole3 and 2 ch~orobenz-aldehyde ~7.05 g, 0.05 mole) in 200 mL toluene was stirred and heated for 16 hour with an sttached 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, 10 m.p. 166-177.
Anal. Calcd. for C H ClN50: C, 61.37; H, 5096; N, 13.83;

Cl, 9.53. Found: C, 61.00; ~, 6.15; N, 13.75; Cl, 9.32.
NMR (CDC13~: 1.92 (2, ~); 2.42 (2, m), 2.55 (45 ~); 2.86 (1~ m); 3.31 (13 m); 3.85 ~4, m); 5.84 (1, s); 6.47 (1, t 14-7 ~z~);
15 7.32 (3, m); 7.80 (1, ~); 8.27 (2, d 14.7 Hz]).
IR (KBr): 7703 795, 980, 1260, 1360, 1450, 1500, 1545, 1585, 1690 m 1.

1-[(3-Chlorophenyl)[4-(2-pyrimidinyl)-1-piperazinyl]methyl]-2-pyrrolidinone _ Employing 3-chlorobenzaldehyde, ~h1s 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 C19~122ClN5G C, 61-34; H~ 5-96; N~ 18-83;
Cl, 5.53. Found: C, 61.14; H, S.03; N, 18.75; Cl, 9.66.

l-[(~-Methoxyphenyl)[4-(2-pyrimldinyl)-1-~ iperazinyl]methyl]-2-pyrrolidinone Employing b-methoxybenzaldehyde, this product was similarly prepared utillzing the basic procedure outllned in Example 5. Recrystal-lization of the product from cyclohexane gave an 81% yield of ~hite crystals, m.p. lS6.5-169.5.
Anal- Calcd- for C20H25N502 C~ 65-33; H, 6-86; N~ 19-06-Found: C, 65.33; ~, 6.97; N, 19.14.

1-[(4-Cyanophenyl)[4-(2-pyrimidinyl)-l-piperazinyl]methyl]-2-pyrrolidinone Employing 4-cyanobenzaldehyde, this product 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 C20H22N60: C, 66-28; ~, 6-12; ~ 23-19-Found: C, 66.55; ~, 6.40; ~9 22.59.
EXA~LE 9 1-12-[4-(2-Pyrimidinyl)-l-piperazinyl]ethyl]-2-pyrrolidinone hydrochlorid~ hydrate (Method B) A solution of y-butyrolactone (1.81 g, 0.02 mole), 2 [4-(2-pyrimidinyl)-l-piperazinyl]ethanamine (4.52 g, 0.02 mole: prepared ln 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 standin~ at room temperature was collected by filtration and air dried to afford 3.78 g (61%) of the y-hydroxyamide intermediate (IV), m.p. 93-97. A ~ixture of IV ~3.$ g, 0.012 mol~) 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 - ~2 -~hich resulted after cooling to room temperature ~nd was collected and recrystallized from isopropyl alcohol to gi~e 2.66 g (69%) o white solid, m.p. 185-187.
Anal. CPlcd. for C14H21N50.2-2HCl-0.2H20: C, 46.05; H, 6.60;
N, 19.60; Cl, 21.83; H20, 0 50 Found: C, 46.90; H, 6.68; N, 20.09, Cl, 21.83; H20, 0.48.
NMR (DMSO-d6): 1.96 ~2, m); 2.30 (2, m); 3.20 (4, m);
3.55 (6, ~); 3.64 ~2~ t [6.7 Hz]); 4.5g (2, m); 5.40 (1, bs); b.75 (1, t [4.9 Hz]); 8.49 (2, d ~4.9 Hz]); 11.50 (1, bs).
IR (KBr): 795, 950, 980, 13737 1435, 1475, 1555, 1590, 1665 cm 1.

1-1(2-Oxo-l-pyrrolidinyl~acetate~-4-(2-p~rimidinyl)piperazin~-2-propanolate (Method C) A ~olution of methyl 2-oxo-1-pyrrolidin~acetate (12.5B g, O.08 mole~ pyrimidinyl-2-ylpiperazine (13.12 g, 0.08 mole) and sodium (1.84 g, 0.08 mole) in 200 ~L m~th~nol was stirr~d and heated under reflux for 16 hour. The cooled reactlon mi~ture w s diluted with saturated sodium chloride sol~tion and ~xtracted with ~ethylene chloride. The dried (MgS04) extract was concentrated in vacuo and the residual sol!d recrystallized twice from isopropanol to afford

7.66 g ~32%) of white solid, m.p. 185-187~.
Anal. Calcd- for C14H19N502 0-1C3H80 C~ 58.15; ~ 6-76;
N, 23.71. Found: C, 57.76; ~, 6.80; N, 23.55.
NMR (CD U 3): 2.06 (2, D); 2.42 (2, m); 3.61 ($, ~); 3-78 (4, m); 4.19 (2, 5); 6.50 (1, t [4.8 Hz]); 3.28 (1, d 14.8 Hz]).
IR ~KBr): 795, 9~0, 1240, 1260, 1305, 1355, 1490, 1545, 1580, 1645, 1680, 2860, 2930, 3020 cm 1.

2-Oxo-N-[2-[4-t2-pyrimidinyl)-l-pipera2inylJ
ethyl~-l-pyrrolidineace~amide hydrate _ This compound was prepared using a procedur~ similar to that outllned in Example 10. Recrystalli~ation from isopropyl alcohol gave a 40% yield of an off-white solid, m.p. 105-107.5.
Anal. Calcd. for C16H24N602 0.2H2O: C, 57-19; ~, 7-32;
N, 25.01; H20, 1.07. Found: C, 56.98; H, 7.25; N, 24.71;
H20, 0.39.

Claims (16)

WHAT IS CLAIMED IS:

1. A compound of Formula I

wherein R1 is hydrogen or lower alkyl;
R2 is hydrogen, lower alkyl, unsubstituted aryl or aryl optionally substituted at one or more ring positions with lower alkyl, halogen, -CF3, -CN, -NO2, -?R3, -NR32, with R3 being H or lower alkyl, -CO2R4, with R4 being R3, phenyl or phenalkyl, -OR5, R5 being R4 or wherein n = 1 or 2;

and when R5 is , said aryl group being disubstituted at adjacent ring positions to effect fusion of the dioxo ring; and X is a chemical bond, -?-, -CH2-, or ;
and the pharmaceutically acceptable acid addition salts thereof.

2. A compound of Claim 1 wherein R1 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 R1 and R2 are hydrogen.

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

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

8. The compound of Claim 1, 1 [(2-chlorophenyl)[4-2-pyrimidinyl)-1-piperazinyl]methyl]-2-pyrrolidinone.

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

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

11. The sompound of Claim 1,1-[(4-cyanophenyl)[4-(2-pyrimidinyl)-1-piperazinyl]methyl]-2-pyrrolidinone.

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-pyrrolidinyl) acetyl]-4-(2-pyrimidinyl)piperazine-2-propanolate.

14. The compound of Claim 1, 2-oxo-N-[2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl]-1-pyrrolidineacetamide.

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