SE463715B - PSYCHOGERIATRIC 1- (2-PYRIMIDINYL) -PIPERAZINYL DERIVATIVES OF 1-PYRROLIDIN-2-ONES AND PROCEDURES FOR PREPARING THESE - Google Patents

Description

Preliminary clinical results with this class of agents, which are exemplified by structures 1a-d, show that these drugs may have certain beneficial effects in the treatment of senile dementia in the elderly. Related art is represented by compounds having the following general structural formula 20 - v N-B A.N; IN wherein A is a bridging group such as alkyl, alkanoyl, alkylamidoalkyl and the like and B is a substituent group.

British Patent 2,023,594 discloses a series of 1-substituted alkyl-4- (3-trifluoromethylthiophenyl) -piperazines as being useful in the treatment of anxiety and depression. Specifically, compounds with the structure 30 are disclosed.

Es A 3 where n is 2 or 3.

U.S. Patent 4,144,347, issued March 20, 1979, discloses a series of N- (substituted aminoalkyl) -2-oxo-1-pyrrolidic acid amides as cognitive activators, which are potentially useful in treating patients suffering from senility. The most relevant compounds disclosed in this patent have the structural formula 40 - CN- (CE2) nN NR * \ __ / -GHz wherein R is C 1-4 alkyl, especially methyl and n is 1 -4.

A second U.S. patent No. 4,372,960, issued February 8, 1983, discloses a series of quaternary derivatives of N- (substituted aminoalkyl) -2-oxo-1-pyrrolidic acid amides. These compounds of structural formula 5 are disclosed as being useful in the treatment of senility, memory enhancement and amenorrhea. -cnzë- (cng given: m x ° Im wherein R is C 1-3 alkyl, n is 1-4 and Xs6) is a pharmaceutically acceptable anion.

European Patent Application 89900, published September 28, 1983, relates to a series of piperazine derivatives of formula 6, which are disclosed as medicaments particularly useful in the treatment of cerebral vascular disorders in the elderly in which R is hydrogen or C 1-3 alkyl and R 1 is allyl, cinnamyl or p-methoxybenzyl.

Malawska, et al., "Synthesis and Pharmacological Properties 463 715 10 15 20 25 30 35 of Some 2-pyrrolidinone Mannich Bases" in Polish Journal of Pharmacology, 1982, 34, 373-382, discloses a series of compounds, of which a subclass is represented by the structural formula 7 below. These compounds are said to have analgesic properties as well as weak anti-inflammatory activity. - x Q Z. wherein X is hydrogen or chlorine.

All of the above compounds differ from the compounds of the present invention, where B is a heterocyclic 2-pyrimidinyl ring compared to the reference compounds, where Bj is alkyl, aryl or aralkyl. The following reference compounds are even less related than those listed above.

A large number of psychotropic compounds with structures corresponding to formula 8 below have been revealed by Wu, Temple, New and co-workers. wherein n is 1-4. However, these compounds of structure 8 and similar analogs are N-substituted cyclic imide rings, for example succinimides, glutarimides, etc., and can be readily distinguished from the compounds of the present invention. In this connection, we refer to U.S. Patent 3,717,634, issued February 20, 1973, and U.S. Patent 4,423,049, issued December 27, 1983.

Similarly, the compounds disclosed in U.S. Patent 4,420,481, issued December 13, 1983 (see Formula 9), and in U.S. Patent 4,216,216, issued August 5, 1980 (see Formula 10), Iaf-fog is distinguished from the compounds of the present invention because these structures lack both a lactam ring as well as a 2-pyrimidinyl ring group.

In summary, it can thus be said that no information is disclosed in the art which makes the specific compounds of the present invention obvious or obvious.

Summary of the Invention The invention relates to a series of compounds of the structural formula I wherein R 1 is hydrogen or lower alkyl; R 2 is hydrogen, lower alkyl, phenyl or naphthyl optionally substituted in one or more several ring positions with lower alkyl, halogen, -cF3, -cN, -No2, -ÉRÄ -NR32, -co2R4 or 0115, where R3 is hydrogen or lower alkyl, R4 is R3, phenyl or phenalkyl een n? är 1 : 4 or -Q \ w / l fifl zln where n is 1 or 2; een “å f? X is a chemical bond, -C-, -CH2- or -CNHCHZCHZ.

Compounds belonging to this series may be incorporated into pharmaceutical compositions for the treatment of geriatric objects affected by senile dementia. A number of these compounds have been tested and show cognitive-enhancing effects and / or mild CNS stimulation. These effects have been demonstrated with EEG and by prevention of ECS-induced amnesia in rats and by labyrinth testing on elderly rats.

Detailed Description of the Invention In its broadest aspect, the present invention relates to 1- (2-pyrimidinyl) piperazinyl-1-pyrrolidin-2-one derivatives having psychogeriatric properties and having the structural formula IH:; ¿'*' O <: ® wherein R1, R2 and X have the meanings given above. 10 15 20 25 30 35 7 463 71% "By lower alkyl" is meant that this group contains 1-4 carbon atoms. "Halogen" means F, Cl, Br or I. When R 5 is a dioxialkyl group the aryl ring is necessarily disubstituted. row in adjacent ring positions to provide fusion of the dioxor ring For preferred compounds R 1 and R 2 are hydrogen and for the most preferred compound X is a chemical bond.

It is to be understood that the present invention also encompasses the various stereoisomers, for example optical isomers including individual enantiomers, mixtures of enantiomers, diastereomers and mixtures of diastereomers, which may arise as a result of the structural asymmetry due to the presence of a sr two asymmetric carbon atoms which may be included in certain compounds of the invention. Separation of the individual isomers is accomplished by the application of various methods well known to those skilled in the art.

For medical use, the pharmaceutically acceptable acid addition salts are preferred in some cases, i.e. such salts in which the anion does not contribute to any significant extent to the toxicity or pharmacological activity of the organic cation. The acid addition salts are obtained either by reacting an organic base of structural formula I with an organic or inorganic acid, preferably by contact in solution, or by any of the standard methods described in the literature and available to those skilled in the art.

Examples of useful organic acids are carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, acetionic acid, succinic acid, pamoic acid, cyclamic acid, pivalic acid and the like; useful inorganic acids are hydrohalic acids such as HCl, HBr, HI, sulfuric acid, phosphoric acid and the like.

The compounds of the present invention can be prepared via several synthetic methods, which constitute modifications of the unit process shown in Reaction Scheme 1. 463 10 15 20 25 30 35 715 Reaction Scheme 1 Unit Process 11 III In this reaction scheme, R 1 and R 2 have the meanings given in connection with formula I. The symbol A may be \ \ NH; 0 or N-CH 2 CO 2 Me. The symbol B may be H; [ä2HC§] 2 / _ or HZNCHR -X-. The relationship between A and B is: Method A B c When A is: NH (Ira) o (IIb) Ncnzcozme (Hc then B is: [R2HC = _7 (IIIa) Hzuc fl nzcnz- (IIIb) H (Inc) el.

HZNCImZCHZ (IIrb) (IIIa) represents the reaction complex ZCHO. The grouping ÄÉZHCÉY plex intermediate formed between IIIc B = H and R na volatile reaction intermediate is rapidly subjected to attack by IIa, A = NH, to obtain product I.

Accordingly, the process of the present invention for the preparation of compounds of formula I wherein R 1, R 2 and X have the meanings given above means that a compound of formula II is condensed. 715 wherein A is NH, O or NCH formula III. ß-OÅÖ III 2CO2Me, having a compound wherein B is ¿ä2Hc¿7, H2NcHR2cH2 or H, with the proviso that fi, näï A is NH, B is ÄRZHCÉ7; , when A is O, B is HZNCHRZCHZ-7 and, when A is NCH2CO2Me, B is H or HZNCHRZCHZ.

These methods, which are part of the unit process, are illustrated in more detail in Reaction Scheme 2 below. 463 715 10 15 20 25 30 35 wxetoae A = 10 Reaction scheme 2 2 ä: + - fl <> © a * QÉÄG © í II: Meümí B: + RI E Iïb Method C: 0 -cn Rl II: II: vari R1 R III: Ia 2 1 2 R F .. ROR v 'n' »aoåacaläåa-cn IV SOCl2 IIIb R2 -CH-CH '>' N- fi šäj) 2 \ / 1 LBR Ib 0 0 N 0 II II fa, J , M) _, -CH2. = .. <N 1 BR III: IC I 8 A + mb ---? 'Wgcmmgc fl g-Q y 1 _ B R Id and R2 have the meanings given above. Method A in Reaction Scheme 2 either utilizes a Mannich-type reaction by reacting the appropriate pyrrolidinone in question, paraformaldehyde and 1-pyrimidin-2-ylpiperazine or alternatively utilizes condensation of the appropriate 2- -pyrrolidinone in question, a selected aldehyde and 1-pyrimidin-2-ylpiperazine during azeotropic removal of water. Method A gives a product of structural formula Ia.

In method B, reaction of a Y'-butyrolactone (IIb) with an aminoalkyl derivative of 1-pyrimidin-2-ylpiperazine (IIIb) gives a Y-hydroxyamide intermediate (IV), which when treated with thionyl chloride in a suitable solvent, for example acetonitrile , undergoes cyclization to form a compound of structural formula Ib.

Method C involves base-catalyzed reaction of a pyrrolidinone acetate (IIc) with either 1-pyrimidin-2-ylpiperazine (IIIb) or its aminoethyl derivative (IIIb) to give either Ib or Id.

The procedures for use in preparing the compounds of structure I by methods A - C are conventional and readily available in the chemical literature to those skilled in the art. Examples of these methods, including synthesis of relevant intermediates, are illustrated in more detail in the working examples. Some of the intermediates used in the above synthetic procedures are commercially available, for example the compounds of formula II as well as the aldehydes of formula R 2 CHO, and therefore no examples or descriptions of their preparation are given.

The compounds of the present invention are useful pharmacological agents which improve the memory and learning of mammals. In this regard, the rat cortical EEG patterns show a similar mild CNS stimulation or pattern similar to that of a nootropic reference agent, aniracetane. Selected members belonging to this series have been tested in a Y-labyrinth test using aged rats and a drug-induced improvement in labyrinthine learning has been demonstrated. Furthermore, other experiments for determining different effects of the drug on the CNS have been performed. The compounds of the present invention do not appear to exert other CNS effects and therefore appear to have the advantage of being more selective agents.

The following in vivo experiments were performed to evaluate and classify the present compounds.

Table 1 In vivo tests used to evaluate the compounds of formula I 1. Conditional avoidance response (CAR) - measurement of a drug's psychosedative activity by determining its ability to reduce the avoidance response to electric shock in trained fasted rats. See Albert, Pharmacologist, 4, 152 (1962); Wu, et al., J. Med. Chem., Lg, 876-881 (1969). 2. Catalepsy reversal - measurement of a drug's ability to reverse neuroleptically induced catalepsy in rats. Vogel anti-conflict - a test of the potential anxiolytic activity, which measures a drug's ability to increase water licking in thirsty rats by suppressing the animal's aversion to electric shock. 4. EEC - a quantitative test, which can serve to classify the effects of CNS compounds by comparing their EEC profiles with the corresponding profiles of different reference standard agents. 5. Consolidation of labyrinthine learning in aged rats - aged rats (approximately 24 months old) are deprived of food 24 hours before exercise in a Y-labyrinth. In practice experiments, 10 15 20 25 30 35 13 463 71%: both target boxes are provided with feed pellets at the end of the labyrinth. The rat can choose either branch of the labyrinth to obtain food. When a branch is chosen, the rat is kept in it and the rat is allowed to nibble on the reward in the form of food. Thereafter, the rats are dosed immediately with the test compound. The critical test is performed 24 hours later. The rats are again deprived of food overnight and placed in the labyrinth. However, neither target box is grazed with feed. A correct answer means that the rat again chooses the branch chosen the previous day.

The time for the rat to get from the start box to the finish box is measured with a stopwatch.

Prevention of ECS-induced amnesia - In the exercise phase of this test, the animals are dosed with either drugs or control solutions and placed 30 minutes later on an isolated platform on top of an electrified grid. When they step down from the platform, they receive an electric shock in the paw until they return to safety on the platform. When placed on the platform 24 hours later (a retention test), the control knobs do not step down; instead, they remain on the secure platform, which shows that they remember the disgusting experience they had the day before. Rats administered ECS (50 mA for 400 milliseconds via corneal electrodes) immediately after exercise and were tested 24 hours later step down much earlier than the control animals. This memory deficiency in ECS-treated rats reflects ECS-induced amnesia in the task of stepping down. Prevention of ECS-induced amnesia by the test compounds is reflected in resuscitation latencies 24 hours after "exercise plus ECS", which are significantly longer than those observed in rats treated with control solutions before "exercise plus ECS".

According to the pharmacological profile determined by the tests given in Table 1, the present compounds of formula I have a promising cognition-enhancing potential by 463 10 15 20 25 30 35 715 1, that they exhibit EEG patterns in accordance with mild CNS stimulation or similar the qualitative EEC pattern of the standard nootropic agent, aniracetam.

Representative compounds of the invention show improved learning in the labyrinth test with an aged rat and prevention of ECS-induced amnesia in normal age rats. In addition, these compounds appear to be selective agents in that low or negligible activity levels are found in other tests indicative of various CNS effects.

The most preferred compound of the present invention 1 and R 2 have an EEG profile in rats similar to that of the reference compound (R is hydrogen and X is a chemical bond) exhibiting an aniracetam but are more potent than the latter compound. An improved potency of this compound relative to the potency of aniracetam has also been found in the Y-labyrinth test using elderly rats, a suitable behavioral model.

A summary of the discussion above suggests that the present compounds have nootropic properties which are particularly suitable for their use in cognitive enhancement. Another aspect of the present invention thus relates to a method of enhancing the cognition of a mammal in need of such treatment, which method comprises systemically administering to such a mammal an effective dose of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof. The administration and dosing schedule for the compounds of formula I can be carried out in the same way as for the reference compound piracetam; see Reisberg, et al., in Drug Development Research, 2: 475-480 (1982); Weng, et al., In Rational Drug Therapy, 17 (5), 1-4 (1983); Reisberg et al., In “Psychopathology in the Aged, Editors, Cole and Barrett, Raven Press, New York, p. 243- -245 (1980). Although the dosage and dosage schedule in each particular case must be carefully adjusted using a sound professional judgment and taking into account the age, weight and condition of the recipient, the mode of administration and the nature and degree of mental illness, 10 15 20 25 30 35 463 715; The daily dose is generally from about 0.1 g to about 10 g, preferably 0.5-5 g when administered orally. In some cases a sufficient therapeutic effect may be achieved with lower doses, while in other cases larger doses may be required. As will be apparent to those skilled in clinical pharmacology, the amount of the compound of formula I which constitutes the daily dose may be administered in a single dose or in divided doses, taking into account the principles which have been shown by experience to be appropriate.

By "systemic administration" in the present context is meant oral, rectal and parenteral (i.e. intramuscular, intravenous and subcutaneous) administration. It is generally found that when a compound of the present invention is administered orally, which constitutes the preferred mode of administration, a greater amount of the active drug is required to produce the same effect as the smaller amount given parenterally. In accordance with good clinical practice, it is preferable to administer the present compounds at a concentration level which provides an effective nootropic effect but does not cause any harmful or undesirable side effects.

Therapeutically, the present compounds are generally administered as pharmaceutical compositions comprising an effective nootropic amount of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier. Pharmaceutical compositions for effecting such treatment contain a greater or lesser amount (for example 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 additives in the form of diluents, fillers and preparation adjuvants, which are non-toxic, inert and pharmaceutically acceptable. Such pharmaceutical compositions are preferably in unit dosage form; i.e. physically separate units with a predetermined amount of the drug 463 715 10 15 20 25 30 35 16 corresponding to a fraction or multiple of the dose calculated to provide the desired therapeutic response.

The dosage units may contain 1, 2, 3 or more single doses or alternatively 1/2, 1/3 or less of a GDRGIÖOS- A single dose preferably contains an amount sufficient to provide the desired therapeutic effect in administering one or more dosage units according to the predetermined dosage schedule; usually the whole, half of, a third of or a quarter of the daily dose is administered one, two, three or four times daily. It will be appreciated that other therapeutic agents may also be present in such a composition. Pharmaceutical compositions providing from about 0.1 to 1 g of the active ingredient per unit dose are conventionally preferred and formulated as tablets, lozenges, capsules, powders, aqueous or oleaginous suspensions, syrups, tinctures. and mixtures and aqueous solutions. Preferred oral compositions are in the form of tablets and capsules and may contain conventional excipients such as binders (for example, syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (for example lactose, sugar, corn starch, calcium phosphate , sorbitol or glycine), lubricants (for example magnesium stearate, talc, polyethylene glycol or silica), disintegrants (for example starch) and wetting agents (for example sodium lauryl sulphate). Solutions or suspensions of a compound of formula I with conventional pharmaceutical vehicles are used for parenteral compositions, such as an aqueous solution for intravenous injection or an oil suspension for intramuscular injection. Such compositions with the desired clarity, stability and utility for parenteral use are obtained by dissolving 0.1-10% by weight of the active compound in water or a vehicle consisting of a polyhydric aliphatic alcohol, such as glycerol, propylene glycol, polyethylene glycol or mixtures thereof. The polyethylene glycols are a mixture of non-volatile, usually liquid polyethylene glycols, which are soluble in both water and organic liquids and have molecular weights from about 200 to 1500. Description of specific embodiments The compounds encompassed by the invention and the method of their preparation are further illustrated in the following working examples. All temperature indications refer to degrees Celsius unless otherwise stated.

Nuclear Magnetic Resonance (NMÉ) spectral data refer to the chemical displacements (8), expressed as parts per million (PPm) relative to tetramethylsilane (TMS) as the reference standard.

The relative surface area indicated for the various shifts in proton NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the displacements in terms of multiplicity is given as broad singlet (bs), singlet (s), multiplet (m), doublet (d), doublet of doublets (dd) or quartet (q). Abbreviations used are DMSO-de (deuterodimethylsulfoxide), CDCl3 (deuterochloroform) and have other conventional meanings. Infrared (IR) spectra include only the absorption wavelengths (cm_1) with the identification value of the functional group. The IR determinations were performed using potassium bromide (KBr) as diluent. The elemental analyzes are given in% by weight.

Synthesis of intermediates Example 1 1-Pyrimidin-2-ylpiperazine (IIIc) To a stirred hot (about 50 °) solution of 100 g (1.16 mol) of anhydrous piperazine and 58 g (0.47 mol) of sodium carbonate in 465 ml of water 53 g (0.46 mol) of 2-chloropyrimidine were added portionwise over about 1 hour. External cooling was required to keep the temperature in the range of 50 - 650. After the addition, the stirred reaction mixture was kept in the temperature range of 50 - 650 for 1 hour and then allowed to slowly cool to 350 over a period of time. of 2 hours.

The mixture was filtered to remove the 1,4-β-pyrimethylpiperazine and the filtrate was extracted with 350 ml portions of chloroform. The chloroform extracts were dried over magnesium sulphate and concentrated to 62 g (82%) of an oily solid which could be purified by distillation (b.p. 118 DEG-120 DEG / 2 DEG C.) or converted to a salt form.

Example 2 2- [N- (2-Pyrimidinyl) -1-piperazinyl] ethanamine (IIIb) A mixture of 38.1 g (0.15 mol) of N-bromomethylphthalimide, 24.6 g (0.15 mol) of 1-pyrimidinyl. 2-ylpiperidine (prepared according to Example 1), 20.7 g (0.15 mol) of powdered potassium carbonate and 1.5 g of potassium iodide in 450 ml of acetonitrile were stirred magnetically and refluxed for 16 hours. The hot reaction mixture was filtered and the filtrate was cooled. The crystalline precipitate which formed was collected by filtration to obtain 21.4 g of a white solid.

A second batch, obtained by partial concentration of the filtrate, was recrystallized from isopropyl alcohol and combined with the original batch to give a total yield of 26.1 g (51%) of phthalimide intermediate, m.p. 119-122 °. The latter intermediate (26.1 g, 0.077 mol) and 5.9 ml of 99% hydrazine hydrate in 210 ml of ethanol were stirred and refluxed for 16 hours. The cooled reaction mixture was filtered and concentrated in vacuo to a solid residue, which was triturated with 20 ml of water and 75 ml of chloroform. The aqueous phase was strongly alkalized with a 50% sodium hydroxide solution, the organic phase was separated and the aqueous phase was extracted with several portions of chloroform. The combined chloroform fractions were dried over magnesium sulfate and concentrated in vacuo to a yellow oil which was purified by Kugelrohr distillation at 0.2 torr to give 7.9 g (50%) of product. Synthesis of products of formula I Example gel 3 1- [ZA- (2-pyrimidinyl) -1-piperazinyl] methyl] -2-pyrrolidinone (methode A) A mixture of 13.6 g (0 6 mol) of 2-pyrrolidinone, 26.2 g (0.16 mol) of 1-pyrimidin-2-ylpiperazine and 19.6 g (0.65 mol) of paraformaldehyde and 420 ml of ethanol were stirred and refluxed for 16 hours. The hot solution was filtered and cooled and the crystalline precipitate which formed was collected by filtration and recrystallized twice from ethanol to give 19.5 g (47%) of a white solid, m.p. 161 DEG-163 DEG.

Analysis Ber. for C 13 H 19 N 5 O: C 59.75 H 7.33 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 H27), 2.57 14, m1; 3.49 <2, t ¿B, s Hg71; 3.81 (4, m), 4.02 (2, S1 ; 6.43 (1, t 12.8 H¿7); 8.27 (2, a ¿ä, s H¿7).

IR (KBr) = 795, 950, 10000, 1250, 1355, 1515, 1545, 1555, 1575, 2780, 2000, 2910 and 2950 cm -1.

Example 4 4-Methyl-1- [2- (2-pyrimidinyl) -1-piperazinyl] methyl] -2-pyrrolidinone hydrochloride This compound can be prepared in a similar manner using the procedure set forth in Example 3. The crude base product was an oil, b.p. 190-2000 / 0.1 torr, which was converted to the HCl salt by treatment with ethanolic hydrochloric acid. Recrystallization of the HCl salt from ethanol gave 68% of a white solid, mp 188 - 1900. 463 715 20 10 15 20 25 30 35 Analysis Ber. for CHNO HCl: 14 21 5 C 53.93 C 53.64 H 7.11 H 7.04 N 22.46 Found: N 22.49 Example 5 1- [T2-chlorophenyl) [N- (2-pyrimidinyl) -1-piperazinyl7methyl7 -2-pyrrolidinone A solution of 4.25 g (0.05 mol) of 2-pyrrolidinone, 8.2 g (0.05 mol) of 1-pyrimidin-2-ylpiperazine and 7.05 g (0 mol .05 mol) of 2-chlorobenzaldehyde in 200 ml of toluene were stirred and heated for 16 hours with a connected Dean-Stark trap for azeotropic removal of water. The solution was concentrated in vacuo to give 16.2 g (87%) of product. Recrystallization from ethanol gave white crystals, m.p. 166-1770.

Analzs Ber. for C 19 H 22 ClN 5 O: 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 (CDCl 3): 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 Há7); 7.32 (3.m); 7.80 (1, m); 8.27 (2, d [4.7 HQ7) IR (KBr): 770, 795, 980, 1260, 1360, 1450, 1500, 1545, 1585, 1690 cm -1.

Example 6 1-113-Chlorophenyl (11- (2-pyrimidinyl) -1-piperazinyl] methyl7-2-pyrrolidinone Using 3-chlorobenzaldehyde This compound was prepared in a similar manner using the procedure set forth in Example 5. Recrystallization from cyclohexane gave a 62% yield of a white powder with a melting point 136 - 13s, s °.

(C10 H22 ClN5 O: N 18.83; N 18.75 Cl 9.53 Cl 9.66 H 5.96 H 6.03 C 61.34 Found: C 61, Example 7 1- [1Z2-Methoxyphenyl) -β- (g-pyriminyl) -1-piperazinyl-7-methyl-7--2-pyrrolidinone Using 4-methoxybenzaldehyde, this product was prepared in a similar manner using the basic procedure set forth in in Example 5. Recrystallization of the product from cyclohexane gave an 81% yield of white crystals with a melting point of 166.5 - 169.50.

Analysis Ber. for C 20 H 25 N 5 O 2: N 19.06 N 19.14 C 65.38 C 65.33 H 6.86 Found: H 6.97 Example 8 1- [14-cyanophenyl) [N- (2-pyrimidinyl) -1-piperazinyl] methyl] - -2-pyrrolidinone Using 4-cyanobenzaldehyde, this product was prepared as in Example 5. Chromatography on silica gel eluting with ethyl acetate gave a 16% yield of the product, m.p. 185-1880.

Analysis Ber. for C 20 H 22 N 6 O: C 66.28 H 6.12 N 23.19 Found: C 66.55 H 6.40 N 22.59 465 715 22 10 15 20 25 30 35 Example 9 1-j2- [Ã- (2- pyrimidinyl) -1-piperazinylethyl-2-pyrrolidinone hydrochloride hydrate (Method B) 3 A solution of 1.81 g (0.02 mol} '- butyrolactone, 4.52 g (0.02 mol) of 2- [Ä (2-Pyrimidinyl) -1-piperazinyl] ethanamine (prepared in Example 2) and a catalytic amount of p-toluene, sulfonic acid in 28 ml of benzene were stirred and refluxed for 6 hours. The precipitate which crystallized when the mixture was allowed to stand at room temperature was collected by filtration. and air dried to give 3.78 g (61%) of the * - hydroxyamide intermediate (IV) m.p. 93-97 °. A mixture of 3.6 g (0.012 mol) of IV and 1.45 g (0.012 mol) of thionyl chloride in 30 ml of acetonitrile was stirred and refluxed for 16 hours. A crystalline precipitate was obtained after cooling to room temperature and this was recovered and recrystallized from isopropyl alcohol to give 2.66 g (69%) of a white solid, m.p. 185-1870.

Analysis Ber. for C 14 H 21 N 5 O.2 -2HCl · 0.2H 2 O: C 46.05 H 6.60 N 19.60 Cl 21.83 H 2 O, 0.50 Found: C 46.90 H 6.68 N 20.09 Cl 21.83 H 2 O 0.48 NMR (nmso-α6) = 1.96 (2, m1, 2.30 (2, m), 3.20 (4, m1, 3.55 (6, m), 3.64 (2, 6 ¿5.7 H¿7); 4.56 (2, m1; 5.40 11, be), 6.75 (1, t ¿š, 9 H¿7); 8.49 (2, a ¿ Z, 9 ng7); 11.50 (1, bs) in (KBr) = 795, 950, 980, 1370, 1435, 1475, 1555, 1590, 1665 cm -1.

Example Gel 1- [X2-oxo-1-pyrrolidinyl) acetate 7-4- (2-pyrimidinyl) piperazine-2-propanolate (Method C) 12.58 g (0.08 mol) of methyl 2-oxo-1- pyrrolidine acetate, 13.12 g of 23 463 715 (0.08 mol) of 1-pyrimidinyl-2-ylpiperazine and 1.84 g (0.08 mol) of sodium in 200 ml of methanol were stirred and refluxed for 16 hours. The cooled reaction mixture was diluted with a saturated sodium chloride solution and extracted with methylene chloride. The extract dried over magnesium sulphate was concentrated in vacuo and the solid residue was recrystallized twice from isopropanol to give 7.66 g (32%) of a white solid, m.p. 185-1870.

Analysis Ber. for C 14 H 19 N 5 O 2 ° 0.1C 3 H 8 O: C 58.15 H 6.76 N 23.71 Found: C 57.76 H 6.80 N 23.55 NMR (CDCl 3): 2.06 (2.m); 2.42 (2.m); 3.61 (6.m); 3.78 (4, m); 4.19 (2.5); 6.50 (1, t [4.8 Hg7); 8.28 (1, d [4.8 Hé7) IR (KBr): 795, 980, 1240, 1260, 1305, 1355, 1490, 1545, 1580, 1645, 1680, 2860, 2930, 3020 cm-1 Example 11 2-Oxo-N-12- [4- (2-pyrimidinyl) -1-piperazinylethyl] -1-pyrrolidineacetamide hydrate This compound was prepared using a procedure similar to that of Example 10. Recrystallization from isopropyl alcohol gave a % yield of an off-white solid with a melting point of 105-107.50.

Analxs Ber. for C 16 H 24 N 6 O 2 ~ 0.2H 2 O: C 57.19 H 7.32 N 25.01 H 2 O 1.07 Found: C 56.98 H 7.25 N 24.71 H 2 O 0.39

Claims (8)

463 715 24 EAIENIKBAY Compounds of formula I §Åë- = ~ o «í <:> R: are hydrogen or lower alkyl; R is hydrogen, lower alkyl, phenyl or naphthyl optionally substituted in one or two lower alkyl ring positions, halogen, ° =; H3 where the R is hydrogen or lower alkyl, R is R, phenyl or phenylkyl and R is R or -o chemical bond -C-, -CH2- or ü-CNHCH2CH and pharmaceutically acceptable acid addition salts thereof. f? 463 71b 25 Compounds according to claim 1, characterized in that in formula I R is hydrogen. Compounds according to claim 1 or 2, characterized in that R is hydrogen. Compounds according to any one of the preceding claims, characterized in that in formula I X is a chemical bond. The compounds 1- [ZZ- (2-pyrimidinyl) -1-piperazinyl] methyl] -2-pyrrolidinone, 5-methyl-1- [Z- (2-pyrimidinyl) -1-piperazinyl] methyl7-2-pyrrolidinone, 1 -L (2-chlorophenyl) [Z-2-pyrimidinyl) -1-piperazinyl] methyl] -2-pyrrolidinone, 1-113-chlorophenyl) [N- (2-pyrimidinyl) -1-piperazinyl] methyl] -7-zipyrrolidinone, 1- [4-methoxyphenyl) [α- (2-pyrimidinyl) -1-piperazinylmethyl] -7-2-pyrrolidinone, 1- [14-cyanophenyl) α- (2-pyrimidinyl) -1-piperazinyl] methyl] -2-pyrrolidinone 1-12-ZZ- (2-pyrimidinyl) -1-piperazinyl] ethyl] -2-pyrrolidinone, 1- [X2-oxo-1-pyrrolidinyl) acetyl7-4- (2-pyrimidinyl) piperazine 2-propanolate and 2-oxo-N- [2-β- (2-pyrimidinyl) -1-piperazinyl] ethyl] -1-pyrrolidineacetamide according to claim 1. A pharmaceutical composition in unit dosage form intended to be administered systemically to a host mammal, characterized in that it comprises a pharmaceutically acceptable carrier and 0.1 to 1 g of a compound of formula I according to claim 1 463 715 wherein 26 çígåfí fl f? I is hydrogen or lower alkyl; is hydrogen, lower alkyl, phenyl or naphthyl optionally substituted in one or two ring positions with lower alkyl, halogen, -CFBy -CNI 1 y or lower alkyl, R is R, phenyl or phenalkyl and R is R or -O 2 - [CH 27n, where n is 1 or 2 and OH is a chemical bond, -C-, -CH 2 - or N -CNHCH CH or a pharmaceutically acceptable acid addition salt thereof Pharmaceutical composition according to claim 6, characterized in that the compound of formula I is 46-71Z-1-LZ A process for the preparation of a compound according to claim 1 of formula I wherein. § is hydrogen or lower alkyl; 2 is hydrogen, lower alkyl, phenyl or naphthyl optionally substituted in one or two ring positions with lower alkyl, halogen, -cF, -cN, -No, -cR, -NR 2, -co21z4 eneš oR, where R is hydrogen or lower alkyl R is R, phenyl or phenalkyl and R is R or ¿§Há7, where n is 1 or 2 and n “ü is a chemical bond, -C-, -CH2- or 0 || -CNHCHZCH2, can be characterized by condensing a compound of formula II A 1111 ~ JJ wherein A is :::> NH, :: 30 or f: j: NCH2CO2Me with a a compound of formula III wherein B is [R2HCf7, H NCHR2-X- or H-; with the proviso that when A is NH, B is [R HC§7; when A is O, B is H NCHR 2 CH - and when A is NCH 2 CO 2 Me, B is H or H NCHR CH. 2 2