LU86503A1 - DIAZINYLPIPERIDINIC DERIVATIVES OF CYCLIC AMIDES AND IMIDES FOR PSYCHOGERIATRIC USE - Google Patents

Description

52.546

0s '' 8 6 ^ 03 GRAND-DUCHY OF LUXEMBOURG

Patent No "..... Y ...... Y ...... Z. V

of ... July 7, 1986 Monsieur the Minister of the Economy and the Middle Classes

Title issued ......................................... Intellectual Property Service

Vplj? LUXEMBOURG

Patent Application I. Application ...... 3.4.5 ..... Eark.-Äveime .., ............... P) NEW YORK, ..... NY.10154, ..... United States of America, ...... represented by____ v .. Mr. ..... Ja.cgue.s ..... de .... Muyaer., ...... ag ± ss.ant ..... en „.. q.ual ± té ....._. De._manda.taire (2) deposit) ce seven july 1900 eighty ..... six ...................................... ... '- (3) at ______. ^ -. 5 ................. hours, at the Ministry of the Economy and the Middle Classes, in Luxembourg: V ”JL the present request for obtaining a patent for an invention concerning: ': "Diazinylpiperidin derivatives ... of cyclic amides and imides (4} for psychogeriatric use. 1 .......... .................................................. .................................................. ........................

2. the delegation of power, dated ......................................... .............................. the ................... ................................

3. description in language ...: §. £ .âb.S ™ ï —.............................. ... of the invention in two copies; 4. _______ /. / ............... drawing boards, in two copies; 5. the receipt of the taxes paid to the Luxembourg Registration Office, on July 7 ..... 1986 ......................... .................................................. .................................................. .................................................. ..........................

declares (s) assuming responsibility for this declaration, that the inventor (s) is (are): ------------------------- ---------------------------------------------------------- ---------------------------------------------------------- -----------------------------------------......... ......................................-........... .......................—. 45) 'LL * -...

.................................................. .................................................. .................... ............................. ~ ΨΖ

claim) for the aforementioned patent application the priority of one (s) application (s) of & J

(6) ...... patent ........................................ ...................... filed (s) 8X (7) at „Et.a.ts-Dnis. d.V & mërique .......

on. „„ ... 8 gui.ll.et ..- 19.85 .... 4.No — .7..53 .... 006 ..) ............ ......_........................................... .................................................. ............

on behalf of ..s ..... inven ±; eurs ................................... ..................................... ............. ..................-............................... ............................................ (9) éIit (éIi ^ 3ÇL'pici ^ him (her) and, if designated, for his representative, in Luxembourg .........................

35, boulevard Royal .............................................. ..................... ............................. ............................ (10) I solicit (s) the grant of a patent for the invention for the subject described and represented in the aforementioned appendices, - with postponement of this issue to ............... 6 ................... ...........................month. (11) \ t.p / mandatWire \ * A 63007_ ér \ x ^ j / _

Deposit Minutes

The aforementioned patent application has been filed with the Ministry of the Economy and the Middle Classes, Intellectual Property Service in Luxembourg, on: 7 itU-Llêt 1986 / s * _ ...... · * \ 15 ('"L \ Ér · Ie Minister at hours I * έ.ι of the Economy and the Middle Classes,!, 52.546

CLAIM OF PRIORITY

of the patent application / <fe: majdÈtex $ fcûyR &% X In the United States of America Of July 8, 1985 (No. 753.006) 'Brief Description filed in support of an application for

PATENT

at

Luxembourg

in the name of: BRISTOL-MYERS COMPANY

NEW YORK, N.Y.10154 (United States of America) for: "Diazinylpiperidine derivatives of cyclic amides and cyclic imides for psychogeriatric use."

V

* ïf '1 = Diazinylpiperidine derivatives of cyclic amides and cyclic imides for psychogeriatric use: State known of the question

The present invention relates generally to heterocyclic carbon compounds having pharmacological and biological properties, as well as their preparation and their use. In particular, the invention relates to piperidine derivatives di- CD.MJ - 1 - MJ - 0 6 2 4 ft substituted of which one of the substituents is a cyclic amide or imide joined by a methylenic bridge to one of the atoms of the piperidine ring and the other substituent of which is a diazinyl ring system linked to the nitrogen atom of the piperidine. The compounds of the present invention lend themselves to the treatment of various senile dementias.

3 The clinical aspects of various senile dementias, as well as the drawbacks they cause in the old man who is affected by them, are well known to the specialist. Various drugs are currently being studied for the treatment of this condition of advanced age. Among these drugs, there is a class of so-called nootropic agents or more commonly supporting lucidity, none of which are currently undergoing clinical evaluation in patients diagnosed with Alzheimer's disease which is a serious and relatively frequent disorder. of the central nervous system in old age. Chemically, the drugs under clinical study are N-substituted 2-pvrrolidinone derivatives of formula 1.

 N-R 1 a: X = H; R = -CH2CONH2 (piracetam) b: X = OH; R = -CH2CONH2 (oxiracetam) c: X = H; R = ~ CH2CONH [CH2] 2N [CH (CH3) 2] 2 (pramiracetam) d: X = H; R = -CO- ^ 0 ^ -OCH ^ (aniracetam)

Butler et al., 3. Med. Chem., 27, pages 684-691 (1984) is a representative reference describing the test and CD.MJ - 2 -> the properties of a term in this series 1_. Preliminary clinical results from agents in this class, such as la-d formulas, show that these drugs have certain favorable effects for the treatment of senile dementia.

Related compounds are those of formula ^ of general structure 2 below. 0 / \ X N-A-W N-B 2

W

where X represents a C2_4alkylene radical or a l, 2 ~ benzo ring; Y represents a carbonyl or methylene radical; A represents a bridge such as alkylene, alkanoyl, alkyleneamidoalkoylene or the like; W represents a nitrogen atom or CH radical and B represents an aryl or pyrimidinyl ring system. The most closely related compounds are the subject of patent application of the United States of America of the Applicant No. 799,670 of November 11, 1985. This relates to a series of compounds of formula 2 in which W represents an atom d 'nitrogen. The most related compounds described in this patent application are of formula 3.

(r - O-® ä

! H

where R represents a hydrogen atom or lower alkyl radical and R can also represent a hydrogen atom or lower alkyl radical. As can be observed, these already known compounds have a chemical structure which can be discerned from that of the compounds of the present invention, CD.MJ - 3 - ί \ * because these already known compounds are derivatives of piperazine (W = N in formula 2) while the compounds of the invention are derivatives of piperidine (W = CH in formula 2).

Other compounds close to those of formula 3 are described by Malawska et al. in "Synthesis and Pharmacological Properties of Some 2-Pyrrolidinone Mannich Bases" in Polish Journal of Pharmacology, ψ 1982, 34, 373-382. These authors describe a series of compounds, a subclass of which comprises those of formula 4 0 y Λ N —Ch, —NN - (() / 4 ky v_y vr7 where X represents a hydrogen or chlorine atom, which are noted as having analgesic properties and a weak anti-inflammatory effect.

A large number of psychotropic compounds whose structure corresponds to the formula 2 where Y represents a carbonyl radical, W represents a nitrogen atom and A represents a C2_ ^ alkylene radical have been described by Wu, Temple, New and their collaborators, among other authors. These compounds include cyclic imides, for example succinimides, glutarimides, phthalimides, etc. The shortest bond defined by A in these compounds is an ethylene bridge because the compounds in which A represents a methylene bridge are too unstable, especially in acidic medium, for practical application. A more detailed description of these compounds can be found in Wu, et al., EÜA patent 3,717,634 of February 20, 1973; Temple, EUA patent 4,423,049 of December 27, 1983; besides New and Yevich, CD.MJ - 4 - EUA patent 4,524,206 of June 18, 1985.

Even greater structural differences with the compounds of the present invention emerge from the bibliography given in the aforementioned patent application of the Applicant. In summary, the diazinylpiperidines of the present invention are novel nootropic agents which have not been anticipated or made evident by any prior description.

J Overview of the invention

The subject of the invention is a series of compounds of formula I

r-t f.

X N -CH "t I

where X represents an ethylene chain or a 1,2-benzo radical; Y represents a carbonyl or methylene radical; represents a hydrogen atom or lower alkyl radical and Z represents a diazinyl ring R ^ .R - disubstituted chosen from pyridazines, pyrimidines and pyrazines. R and R are independently chosen from hydrogen atoms and lower alkyl, lower alkoxy, lower alkylthio, cyano, trifluoromethyl and halo radicals. The compounds of this series can be incorporated into pharmaceutical compositions for the treatment of patients with senile dementia. A number of representative compounds in this class have been tested and found to prevent amnesia induced by electroconvulsive shock in rats.

Detailed description of the invention

In its most general aspect, the invention CD.MJ - 5 - relates to 1- (4-diazinyl) piperidinyl derivatives of N-methylenic cyclic amides and imides which manifest psychogeriatric properties and correspond to formula I.

rfi1 Λ

x N-CH -4- l_z ^ --- Y

19 I

In formula I, X represents a C2 alkylene chain (ethylene) or a 1,2-benzo ring uniting Y and the carbonyl radical to form, for example when Y also represents a carbonyl radical, a phta-limid entity. Y represents a carbonyl radical (but only when X represents a 1,2-benzo ring) or a CH2 radical. In formula I, R1 can represent a hydrogen atom or lower alkyl radical (in C.) 2 3 1, and Z represents a diazinyl ring R, R -disubstituted chosen from pyridazines, pyrimidines and pyrazines, R and R being independently selected from hydrogen atoms and lower alkyl, lower perfluoroalkyl (such as trifluoromethyl or pentafluoroethyl), lower alkoxy, lower alkyl, cyano and halo radicals. By lower alkyl radical is meant a radical of 1 to 4 carbon atoms. By halogen or halogeno, we mean F, Cl, Br or I.

In the preferred compounds, X represents an ethylene radical, Y represents a methylene radical, R ^ represents a hydrogen atom and R and R are chosen from hydrogen atoms and trifluoromethyl and halo radicals, l the preferred halogen being chlorine.

It should be observed that the subject of the invention is also the various stereoisomers, for example optical isomers comprising the enantiomers dis CD.MJ - 6 - tincts, mixtures of enantiomers, diastereoisomers and mixtures of diastereomers, which may exist as a consequence of a structural asymmetry due to the presence of one or two asymmetric carbon atoms which may comprise certain compounds of the invention. The separation of the various isomers is carried out according to the various procedures well known to those skilled in the art. For * application in medicine, the pharmaceutically acceptable acid addition salts w, which are the salts whose anion does not contribute significantly to the toxicity or pharmacological activity of the organic cation, may be preferred in certain cases. . The acid addition salts are obtained by reaction of an organic base of formula I with an organic or inorganic acid, preferably by contacting in solution, or else by one or other of the usual methods described in specialist literature. Examples of useful organic acids are carboxylic acids such as maleic acid, acetic acid, tarric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, l pamoic acid, cyclamic acid, pivalic acid and the like, and useful inorganic acids are hydrohalic acids such as HCl, HBr or K1, sulfuric acid, phosphoric acid and the like. In addition, the invention also relates to any compound of formula I existing in the form of a solvate such as a hydrate.

The compounds in accordance with the invention can advantageously be prepared according to a general process illustrated in scheme 1.

CD.MJ - 7 - DIAGRAM 1

General synthesis process co2c2h5 ^ N '+ _> --C02C2H5 -> --CH0

1 "to Y

VIII z z

VII X

| lah | r1m / \ socl2 Af,

Ljch-r z I »Z z V \ VI VI '\ ο \ Λ

\ X NH

Yw

\ IV

Λ ^ ιΤί W O “CD.MJ - 8 -

In diagram 1, the symbols X, Y and Z are as defined above. Basically, a piperidine carboxylic ester (IX) is condensed with a diazine halide (VIII). An ethyl ester radical and a chloride radical are shown for compounds IX and VIII, respectively, in scheme 1, but "other equivalent radicals, for example another alkyl carboxylate and / or another halide, may" be used. Are these variants obvious for the S? specialist in organic synthesis. Typically, the reaction of IX and VIII is carried out in a reaction solvent such as acetonitrile in the presence of a base such as potassium carbonate and gives the product (VII). Product VII can be reduced by lithium aluminum hydride in a suitable solvent such as tetrahy-drofuran to give the reaction intermediate VI (R ^ = H) or, alternatively, product VII can be converted into the aldehyde X according to the usual methods for the transformation of an ester into an aldehyde and the latter can then be reacted with an organometail reactant R ^ M (where M represents the appropriate metal cation or Grignard complex) to give the intermediate product VI '. The intermediate primary alcohol (VI) or the intermediate secondary alcohol (VI ') is reacted with thionyl chloride to give the corresponding chlorine compound (V) which is then condensed with a cyclic amide or imide (IV) to give the desired compound of formula I. This condensation is carried out as the condensation of IX and VIII, a reaction solvent preferred in this case being dimethylformamide containing a base such as potassium carbonate. It is obvious to the specialist in the field that it is possible to carry out other conversions of intermediates VI which would effectively transform the hydroxyl radical into a radical CD.MJ - 9 - hence different (for example tosylate or mesylate ) in order to facilitate the alkylation of the nitrogen atom in the cyclic amide or imide.

Another process is applicable to the preparation of the compounds of formula I and is illustrated in scheme 2.

Diagram 2 - Synthesis process when X represents an ethylene chain r <·

X NH + ClCH - f J -> x 7 CH - kJ

K J W

IV X III

H2 Pt02 y r ~ ^ ° t vi11 / "~ fc î1

\ ^ N2 KJ

H

I II

In diagram 2,, X, Y and Z are as defined above. The process illustrated in scheme 2 generally gives the products of formula I with a higher yield than that achieved by the general process in scheme 1, but it does not have the general possibility of application of the latter. Because of the reduction in catalytic reduction (conversion from III to II), only cyclic amides / imides insensitive to catalytic reduction can be used. For example, when X represents a 1,2-benzo radical, for example when IV is a phthalimide, the benzo radical is then reduced to a 1,2-cyclohexy radical, thus leading to a hexahydrophthalimide.

In summary, the subject of the invention is a process "for preparing a compound of formula I

r <! * rfN

X N -CH -I— I

w K ^ n-z where r \ X, Y and Z are as defined above.

This method includes selecting an operating procedure from the class comprising

(a) (1) the condensation of compounds IX and VIII

--co2r z-q

^ NK H

IX VIII

where R represents a C ^ _galcoyl radical and Q represents a suitable leaving radical such as chloride, bromide, iodide, sulfate, phosphate, tosylate, mesylate or the like, leading to an intermediate of formula VII; f 3 ~ C02r ï

Z

VII

CD.MJ - 11 - ί (2) the reaction of the intermediate product VII with the metallic reactant R1M, where M represents the appropriate metal complex or ion, for example lithium aluminum --b ydrido or Grignard complex, leading to the intermediate reaction of formula VI; f ^ L'1

? —J— CHOH

S

- z

VI

(3) reacting intermediate VI with a suitable reactant converting the OH radical of VI into a leaving radical Q of the compound of formula V; r ^ i -1

—H- CHQ

Z

V

and

(4) the reaction of intermediate V with a cyclic amide / imide of formula IV

r-i

x NH

IV

leading to a product of formula I;

(b) (1) the reaction of a cyclic amide / imide of formula IV

yO

X NH

V / CD.MJ - 12 -

where X does not represent a 1,2-benzo radical, with an intermediate pyridine of formula X

Q-CH - Q

^ N ^

X

w

leading to the intermediary of formula III

R1 '\ i s ~ \ X N-CH--

III

(2) catalytic reduction of the compound of formula III to the intermediate piperidine of formula II

rt t rfS

X N-CH-- V'y

H

II

and (3) the condensation of the compound of formula II with the compound Z-Q giving a product of formula I.

The compounds which are the subject of the invention have been the subject of an evaluation of the nootropic activity according to a primary selection criterion which is the demotion of amnesia induced by electroconvulsive shock for an avoidance response passive by descent (see: Banfis, et al., J. Pharmacol. Meth., 8, 255 (1982); Janvik, Ann. Rev. Psycbol., 23, 457 (1972); McGaugh and Petrinovich, Int. Rev. Neurobiology, 8, 139 (1965)). Reference compounds such as prami- CD.MJ - 13, racetam, piracetam, aniracetam, etc., which exhibit activity in this model, have been mentioned as influencing memory processes and may be useful for the treatment of senile dementia and Alzheimer's disease. For this test, drugs are administered to 12 animals and 30 minutes later, they are trained to remain still to avoid ** shock to the paw. Immediately after this exercise, “animals are given an electroconvulsive shock.

24 hours later, it is checked whether the animals have retained the learned behavior and it is considered that any animal which remains on the platform for 300 seconds without descending from it has retained the passive avoidance response.

Two groups of control animals are taken for comparison, the animals of one of the groups receiving the vehicle and undergoing electroconvulsive shock and the animals of the other group receiving the vehicle and undergoing a dummy electroconvulsive shock. An experimental compound is considered active at a determined dose if the average latency to descent is statistically greater than the value for the control group receiving the electroconvulsive shock (placebo control group) and is simultaneously not statistically different. of the value for the control group receiving the dummy electroconvulsive shock.

An investigational compound is considered to have intermediate activity at a given dose if the results reported in the group receiving the drug are statistically different from those found in the two control groups. For the purposes of the comparison, all the drugs are subject to evaluation after subcutaneous administration, but the preferred compounds of the invention give, after oral administration, results which are little different from those achieved after subcutaneous administration .

CD.MJ - 14 -

In this respect, the following compounds are particularly preferred: l - [[l- (2-pyrimidinyl) -4-piperidinyl] -methyl] -2-pyrrolidinone, i - [[l- (2-chloro-4- pyrimidi-nyl) -4-piperidinyl] methyl] -2-pyrrolidinone, l - [[l- (6— chloro-2-pyrazinyl) -4-piperidinyl] -methyl3-2-pyrrolidi-none and especially l- [[1- (2-trifluoromethyl-4-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone.

The similarity of activity when switching from subcutaneous administration to oral administration constitutes a considerable pharmacological advantage which distinguishes the compounds of the invention from the compounds which have already been described. In addition, the compounds of the invention are not labile in an acid medium, which constitutes an additional advantage for their preparation, their formulation, their dispatch and their storage, as well as for their administration.

In summary, the compounds of the invention have nootropic properties making them particularly useful for improving lucidity and memory. In another aspect, the subject of the invention is therefore a method for improving lucidity and memory in a mammal in need of such treatment, according to which an effective dose of a compound of formula I is administered systemically to this mammal. a pharmaceutically acceptable acid addition salt thereof. The administration and the dosage of the compounds of formula I are regarded as similar to those of the references, namely 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, pages 243-245 (1980) and pramiracetam, see: Butler, et al, J. Med. Chem., 27, pages 684-691 (1984).

In addition to their usefulness as agents promoting CD.MJ - 15 - lucidity and moderate stimulants of the central nervous system, the compounds of formula I have proved useful also for preventing amnesia resulting from electroconvulsive shock. This activity is interesting for the conservation of memory despite the normal aging and senility processes, but would also be useful to protect against amnesia induced by electroconvulsive shock in clinical use. Electroconvulsive shock is used in psychiatry for the treatment of certain patients, in particular depressed patients, who are refractory to traditional pharmacological treatment. It is well known that electroconvulsive shock induces amnesia as an undesirable side effect in patients who have suffered it. The compounds of the invention which demonstrate, on the pharmacological test, a protective activity against amnesia induced by electroconvulsive shock would be useful adjuvants for psychiatric treatment by electroconvulsive shock.

The dose and the posology must in each case be adjusted carefully according to the good professional evaluation and taking into account the age, the weight and the state of the patient, the mode of administration, besides the nature and the degree of the alterations mental, but generally the daily dose will range from about 0.1 g to about 10 g and preferably from 0.5 g to 5 g for the oral route. Sometimes a sufficient therapeutic effect can be achieved with lower doses, but in other circumstances, larger doses are necessary. As is obvious to the specialist in clinical pharmacology, the amount of the compound of formula I constituting the daily dose can be administered in a single dose or in divided doses according to the principles of good professional practice.

CD.MJ - 16 -

By "systemic administration" is meant oral, sublingual, buccal, nasal, dermal, rectal, intramuscular, intravenous and subcutaneous administration. Generally, a compound of the invention administered orally, which is the preferred route, should be taken in a slightly larger amount to have the same effect as if it were administered parenterally. Based on good clinical practice, w it is preferable to administer the compounds of the invention in an amount exerting the useful nootropic effect without any harmful or annoying side effect.

For therapeutic purposes, the compounds of the invention are generally administered in the form of pharmaceutical compositions consisting of an effective nootropic amount of a compound of formula I or of a pharmaceutically acceptable acid addition salt thereof. ci and with a pharmaceutically acceptable excipient. The pharmaceutical compositions for carrying out such a treatment contain a major or minor amount (for example from 95% to 0.5%) of at least one compound of the invention in combination with a pharmaceutical excipient, that comprising one or more several non-toxic, inert and pharmaceutically acceptable solid, semi-solid or liquid diluents or adjuvants. These pharmaceutical compositions are preferably presented in unit dosage forms, that is to say in physically distinct units containing a predetermined quantity of the drug which corresponds to a fraction or to a multiple of the dose calculated to induce the desired therapeutic response. . In current practice, the dosed units contain 1/1, 1/2, 1/3 if not less than a single dose. A single dose preferably contains an amount sufficient to exert the desired therapeutic effect by administration in one time of one or more units dosed CD.MJ - 17 - according to the dosage chosen beforehand, usually the whole, half, third if not less than the daily dose given once, twice, three times or more often per day. It is to be envisaged that other therapeutic agents may be contained in such a composition. Pharmaceutical compositions which provide 0.1 to 1 g of active principle per dose

V

are preferred and are advantageously presented in the form of tablets, lozenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs and aqueous solutions. The preferred compositions for oral use are presented in the form of tablets and capsules and may contain usual excipients such as binders (for example syrup, gum arabic, gelatin, sorbitol, gum tragacanth or polyvinylpyr-rolidone), fillers (e.g. lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine), lubricants (e.g. magnesium stearate, talc, polyethylene glycol or silica), disintegrants (for example starch) and wetting agents (for example sodium laurylsul-fate). The solutions or suspensions of a compound of formula I in usual pharmaceutical vehicles are used for compositions for parenteral use such as aqueous solutions for intravenous injection or oily suspensions for intramuscular injection. Such compositions having the clarity, stability and properties required for parenteral administration v. are obtained by dissolving approximately 0.1% to 10% by weight 7 of the active compound in water or a vehicle consisting of a polyhydroxylated aliphatic alcohol such as glycerol, propylene glycol or polyethylene glycols, in addition to their mixtures. The polyethylene glycols consis CD.MJ - 18 - are a mixture of usually liquid non-volatile polyethylene glycols which are soluble in both water and body fluids and which have molecular weights of about 200 to 1,500.

Description of specific embodiments

The compounds forming the subject of the invention and the processes for preparing them, in addition to their biological properties, are further illustrated by the following examples * which in no way limit the scope of the invention. Unless otherwise stated, all temperatures are in degrees Celsius. The characteristics of the nuclear magnetic resonance spectrum (NMR) are the chemical shifts (S) expressed in part per million (ppm) compared to tetramethyisilane (TMS) as a standard. The relative area mentioned for the different displacements of the proton spectrum (RMP) corresponds to the number of hydrogen atoms of a particular function in the molecule. The multiplicity of the displacement is expressed in the form of large singlet (si), singlet (s), multiplet (m), doublet (d), doublet of doublets (dd), triplet (t) or quadruplet (q). The abbreviations are DMSO-dg (perdeuterodimethylsulfoxide), CDCl ^ (deuterochlorcforme) or are otherwise traditional. The descriptions of the infrared spectrum include only the wave numbers (cm X) of the absorptions useful for the identification of the functions. The IR spectra are recorded on the compound diluted in potassium bromide (KBr). All the compounds give satisfactory results on elementary analysis. EXAMPLE 1 2 - [[1- (2-Pyrimidinyl) -4-piperidinyl3methyl] -1H-inoin-7 dole-1,3, (2H) dione

The sequence illustrates the general synthesis that relates to scheme 1 above.

CD.MJ - 19 - A. 1- (2-Pyrimidinyl) piperidine-4-carboxylate ethyl (VII)

A mixture of ethyl isonipecotate (IX; 31.44 g, 0.2 mole), 2-chloropyrimidine (VIII; 22.91 g, 0.2 mole) and carbonate is heated at reflux for 24 hours. potassium (27.69 g, 0.2 mole) in acetonitrile (250 ml). The mixture is filtered and the filtrate is concentrated in vacuo. The residue is distilled (130-170 ° at 0.32 torr) to obtain 44.1 g (94%) of the product in the form of a clear oil.

B. 4-Hydroxymethyl-1- (2-pyrimidinyl) piperidine (VI)

A solution of the ester (VII; 20 g, 0.085 mol) in tetrahydrofuran (200 ml) is cooled to 0-5 ° and lithium aluminum hydride (3.23 g is added slowly over 10 minutes) , 0.085 mole} The mixture is stirred at room temperature for 30 minutes.

The excess lithium aluminum hydride is destroyed with acetone and the mixture is diluted by adding 3.2 ml of water and then 3.2 ml of a 15% sodium hydroxide solution. % and finally 9.7 ml of water. The resulting mixture is filtered and the filtrate is concentrated under vacuum to obtain an oil which is distilled to collect 15 g (91%) of a clear oil, P.Eb. 140-190 ° at 0.3 torr.

C. 4-Chloromethyl-1- (2-pyrimidinyl) piperidine (V)

A solution of the hydroxymethylated compound (VI; 7.73 g, 0.04 mol) in methylene chloride (40 ml) is cooled to 0-5 ° and thionyl chloride (25 ml) is added slowly. The solution is stirred for 12 hours at room temperature, then concentrated in vacuo. The residue is dissolved in methylene chloride 7, the solution is extracted with aqueous sodium bicarbonate and the layer of methylene chloride is concentrated in vacuo. The residue is chromatographed on silica gel using ethyl acetate CD.MJ - 20 - as eluent to collect 7.7 g (91%) of the product which is an oil.

D. Reaction of intermediate V and phthalimide

A mixture of potassium carbonate (2.76 g, 0.02 mole), phthalimide (1.47 g, 0.01 mole) and 4-chloromethyl-1- (2) is heated to about 50 ° for 24 hours. -pyrimidinyl) piperidine (V; 2.12 g, 0.01 mole) in dimethylformamide (50 ml). Dimethyl-J formamide is removed in vacuo and the residue is dissolved in acetone, then the solution is filtered. The filtrate is concentrated under vacuum to obtain the crude product which is chromatographed on silica gel using 30% ethyl acetate in hexane as eluent.

The product is then recrystallized from ethyl acetate to obtain 0.95 g (20.5%) of the product in the form of white crystals, mp 109-111 “.

Analysis for C] _gHisN4 ° 2: calculated C, 67.06; H, 5.64; N, 17.38% found C, 66.95; H, 5.68; N, 17.17% NMR (CDCl3): 1.35 (2, m); 1.74 (2, m); 2.10 (l, m); 2.85 (2, m); 3.61 (2, d, 7.0 Hz); 4.76 (2, m); 6.40 (l, t, 4.8 Hz); 7.79 (4, m); 8.27 (2, d, 4.8 Hz).

IR (KBr): 730, 800, 1360, 1400, 1515, 1540, 1590, 1710, 1750 and 2930 cm_i.

EXAMPLE 2! - [[! - (2-Pyrimidinyl) -4-piperidinylImethyl] -2-pyrrolidi-none

The present sequence illustrates the synthesis process applicable when X in the compound of formula I represents an alkylene chain (see diagram 2 above).

A. 1- [(4-piperidinyl) methyl] -2-pyrro-lidinone hydrochloride hydrate (II)

Hydrogenation is carried out for 72 hours under 414 kPa using PtO 4 (1.0 g) a solution of CD.MJ - 21 - hydrochloride of 1- (4-pyridinylmethyl) -2-pyrrolidinone (III; 15.05 g, O , 0707 mole; prepared from 2-pyrrolidinone and 4-pyridinylmethyl chloride), HCl (10 ml of an 8N solution in absolute ethanol) and absolute ethanol (100 ml). The mixture is filtered and the filtrate is concentrated under vacuum to obtain a white solid. The crude product is recrystallized from isopropanol to collect 13.03 g (83%) of the product in the form of a white powder, mp 212-214 °.

B. Reaction of intermediate II with 2-chloro-pyrimidine

Heated for 14 hours in an oil bath at 50-100 ° a mixture of piperidinylmethylpyrrolidi-none (II; 5.08 g, 0.0232 mole), 2-chloropyrimidine (2.67 g, 0.0233 mole ) and potassium carbonate (7.09 g, 0.0513 mole) in dimethylformamide (60 ml). The mixture is cooled and filtered. The solvent is then removed in vacuo and the residue is chromatographed on silica gel using an ethyl acetate-acetone mixture as eluent in order to collect 4.7 g (78%) of the product in the form of white crystals, PF 144 -147 °.

Analysis for C. .H ~ „N .0 1 - 14 20 4 calculated C, 64.59; H, 7.74; N, 21.52% found C, 64.26; H, 7.78; N, 21.20% NMR (CDCl3): 1.29 (2, m); 1.71 (2, m); 2.01 (3, m); 2.34 (2, t, 7.4 Hz); 2.84 (2, m); 3.16 (2, d, 7.0 Hz); 3.39 (2, t, 6.8 Hz); 4.73 (2, m); 6.40 (l, t, 4.7 Hz); 8.26 (2, d, 4.7 Hz).

IR (KBr): 800, 1360, 1440, 1515, 1540, 1585, 1675 and 2930 cm ^).

Γ EXAMPLE 3 1— [C1- (2-Chloro-4-pyrimidinyl) -4-piperidinyl] methyl] - 2-pyrrolidinone

Stirred for 14 hours at room temperature CD.MJ - 22 -, then heated to 70 ° for 1 hour a mixture of l - [(4-piperidinyl) methyl] -2-pyrrolidinone hydrochloride (II, prepared above in Example 2A; 20.1 g, 0.0922 mole), 2,4-dichloropyrimidine (14.90 g, 0.1 mole), sodium carbonate (26.5 g, 0.25 mole) and 200 ml of dimethylformamide. The mixture is filtered and concentrated in vacuo. The crude residue is chromatographed on silica gel using * ethyl acetate / methanol (95: 5) as eluent so as to separate the residual product into two components. The major component is collected in an amount of 16 g (59%) in the form of a white powder, mp 110-114 °, which is the desired 2-chloro-4-pyrimidinyl isomer. Analysis for ci4HiaclN4 °: calculated C, 57.04; H, 6.50; N, 19.01% found C, 56.73; H, 6.44; N, 18.97% NMR (CDCl3): 1.30 (2, m); 1.78 (2, m); 2.03 (3, m); 2.39 (2, t, 7.4 Hz); 2.92 (2, m); 3.17 (2, d, 7.0 Hz); 3.40 (2, t, 6.8 Hz); 4.35 (2, m); 6.39 (l, d, 6.0 Hz); 7.98 (1, d, 6.0 Hz).

IR (KBr): 965, 1150, 1350, 1360, 1490, 1590, 1685, 2860 and 2950 cm ^.

EXAMPLE 4 1 - [[1- (4-Chloro-2-pyrimidinyl) 3-4-piperidinylImethyl1-2-pyrrolidinone

The other isomer, namely the 4-chloro-2-pyrimidinyl compound, is isolated from the least abundant component obtained by chromatography and recrystallization from ethyl acetate of the reaction product of Example 3 (above). to obtain 1.1 g (4%) of white crystals, mp 143.5-145.5 °.

Analysis for C ^ H ^ CIN ^ O: calculated C, 56.04; H, 6.50; N, 19.01% found C, 56.66; H, 6.49; N, 19.81% NMR (CDCl3): 0.9-2.1 (5, m); 2.25 (2, t, 5 Hz); 2.75 CD.MJ - 23 - (2, t, 8Hz); 3.10 (2, d, 5Hz); 3.30 (2, t, 5 Hz); 4.5-4.8 (2, d); 6.45 (1, d, 4 Hz); 8.13 (l, d, 4 Hz).

IR (KBr): 1275, 1350, 1419, 1512, 1525, 1588 and 1688 cm “1. EXAMPLE 5 1 - [[1- (6-Chloro-2-pyrazinyl) -4-piperidinylJmethyl] -2-pyrrolidinone

According to the procedure described above in Examples 2 and 3, the mixture is stirred at ambient temperature for 14 hours, then a mixture of 1-C (4-piperidinyl) methyl] -2 hydrochloride is heated at 70 ° for 1 hour. -pyrrolidinone (II, 12.5 g, 0.0556 mole); 2,6-dichloropyrazine (8.37 g, 0.0556 mole); potassium carbonate (19.2 g, 0.139 mole) and DMF (150 ml). The mixture is filtered and the filtrate is concentrated in vacuo. The crude product is recrystallized twice from ethyl acetate to collect 11.16 g (68/0) of beige crystals, m.p. 139-142 °.

Analysis for C ^ H ^ CIN ^ O: calculated C, 57.04; H, 6.50; N, 19.01% found. C, 57.02; H, 6.40; N, 19.03% NMR (CDCl3): 1.34 (2, m); 1.77 (2, m); 2.05 (3, m); 2.40 (2, t, 7.2 Hz); 2.91 (2, m); 3.18 (2, d, 7.0 Hz); 3.40 (2, t, 6.8 Hz); 4.30 (2, m); 7.74 (b, s); 7.96 (l, s).

IR (KBr): 835, 1140, 1275, 1415, 1460, 1490, 1500, 1565, 1685, 2840 and 2945 cm "1.

EXAMPLE 6 1 - [[1- [2- (Trifluoromethyl) -4-pyrimidiny1] -4-piperidinyl] methyl-2-pyrrolidinone

By applying the procedure described above in examples 2 and 3, a mixture of 1 - [(4-piperidinyl) methyl] -2-pyrrolidinone hydrochloride (II, 21.85 g) is refluxed for 1 hour. L 0.1 mole) and sodium carbonate (26.5 g, 0.25 mole) in methanol (150 ml). The methanol is then removed in vacuo and CD.MJ - 24 - acetonitrile (150 ml) is added to the residue. The mixture is cooled and stirred while adding 4-chloro-2- (tri-fluoromethyl) pyrimidine (18.28 g, 0.1 mole). The mixture is stirred at room temperature for 18 hours and then filtered, then the filtrate is concentrated in vacuo to obtain a thick residue which is solidified by washing with hexane (100 ml). The resulting light beige powder (23.8 g, 73%) is subjected to chromatography (5% methanol in ethyl acetate on silica) to collect 19.8 g of crystals, PF 118.5-120 , 5 °.

Analysis for C] _5H ^ 9F3N4 °: calculated C, 54.87; H, 5.83; N, 17.07% found C, 54.50; H, 5.85; N, 16.80%

In a similar way, a certain number of other compounds of formula I are shown, indicated in Table 1.

TABLE 1

Compounds of formula I CH

Sx. R “X Y Liaison with Z Formula P.F.

_ _ _ piperidine _ _ (°) 7 H ~ C2UA ~ CH2 3 ~ "(O ^ C14H20N4 ° U— * 107.5 N —-v 8 H -C2H4- CH2 2- - / Q \ C14H20N4O 110-113 9 hk: 2h4- ch2 4- c14h19cin4o 133 ^ • Ν-Γ3 10 H -C2H4 "CH2 4_ <0> -F C15H21FN4OS 96-100 N- 'CD.MJ - 25 - TABLE 1 (continued)

Ex. R · * - X Y Connection with Z Formula P.F.

_ _ _ _ piperidine _ _ (**) 11 H -C2H 4- CH2 4- C14H19FN4 ° 134-136 // 1 12 H -C2H4 "CH2 4- - \ On C14H18C12N4 ° 140" 144

Cl 13 H ^ 2h4- ch2 4- c14h18ci2n4o m-

N — N

14 H -C2H - CH2 4- - (On C14H19C1N4 ° 141 '\ - / 142 p

Cl N- / 1 15 H -C2H4- CH2 4- - / Qn C15H21C1N40 133-135 16 H -C2H4- CH2 4- C15H2iClN40 104-107 CH3 17 H -C2H4- CH „4- C14H19BrN4 ° 143-146 18 H - C2H4- CH2 4- - ^^ - Cl C14H19C1N40 130-133 CD.MJ - 26 - TABLE 1 (continued)

Ex. R "* · X Y Connection with Z Formula P.F.

_ _ _ _ piperidine _ _ (° C) 19 H -C2H4- CH2 4- KoV1 C14H19IN4 ° 129'5_ N- '131.5 ".SMe 20 H -C2H4 ~ CH2 4- -¾ 134-137

Cl

Cl .Cl 21 H ~ C2H4 "CU,> 4- C14H18Ci2N4 ° 135-138

"-VS

22 H -C2H4 ~ CH2 4- - <O N Ci4Ki8BrClN4 ° 105-115

Br OMe 23 H -C2H4 "CH2 4_“ (Ojv C15H22N4 ° 2 H6-121 24 B ^ 2H4- CH2 4- - / on C15H19N50 139 5- 0.2 H, 0 ~ u 25 H 1,2-CB CH, 4- - (θ \ C18H20N4 ° 176-178 N- '* U 26 H - ° 2Η4- CH2 4- C16H19F5N4 ° ^ CD.MJ - 27 - TABLE 1 (continued)

Ex. R · 1 · X Y Connection with Z Formula P.F.

_ _ _ _ piperidine _ _ (°) 27 H -CA- CH2 4- / 0 |, C15H18CiF3N40 102-_

Cl: 28 H CH2 4- - (On Cl6hl8F6K40 132,5- 'CF °' 075 H2 °

J

at. The analyzes C, H, N are located at + 0.4% of the calculated value.

EXAMPLE 29 Regression of amnesia induced by electroconvulsive shock for the passive avoidance response with descent

For the passive avoidance with descent test, rats are trained to remain immobile to avoid a shock to the paw. Two control groups (n = 36 / group) are required, including a control group undergoing electroconvulsive shock and a control group undergoing a dummy electroconvulsive shock. The control animals undergoing the electroconvulsive shock are brought individually on a platform surmounting a grid exerting the electric shock (0.8 mA) 30 minutes after receiving the vehicle. The animals descend rapidly from the platform as soon as they feel the shock to the paw and quickly learn to escape from the platform. An animal is considered to have acquired the passive avoidance response if it remains on the platform for 2 minutes without getting off after having received the shock to the paw. Immediately after acquisition, the control animals with electro-CD.MJ - 28 - convulsive shock are administered an electroconvulsive shock of 50 nA for 0.4 seconds by means of electrodes crossing the cornea. The control animals receiving the dummy electro-convulsive shock are treated exactly like the control animals receiving the electroconvulsive shock, but with the difference that the current does not pass through the electrodes passing through the cornea. The animals of the two groups are given 24 hours later an in-V test indicating whether the behavior is retained. The animals are brought individually onto the platform and the latency time is noted until the animal descends from the platform on the grid, giving no electric shock; an animal is considered to have retained the passive avoidance response if it remains on the platform for 300 seconds without getting off.

Control animals receiving the dummy electroconvulsive shock remain on the platform during this experiment and show normal behavioral retention, while control animals receiving the electroconvulsive shock descend rapidly before 300 seconds and show a retention deficit ( that is, manifest amnesia).

The latency times until descent are converted into centesimal retention ratings, taking 100% retention for a latency time of 300 seconds. By applying the Dunnett test, the centesimal retention scores are calculated for all groups of animals receiving the drugs, compared to the control groups receiving the electroconvulsive shock and receiving the dummy electroconvulsive shock. A compound is considered active in this model if the mean retention score observed in at least one group ^ receiving a certain dose is simultaneously significantly higher than the retention rating in the control group receiving electroconvulsive CD shock .MJ - 29 - d and not significantly different from the retention rating in the control group receiving the dummy electroconvulsive shock. This result indicates that the experimental compound causes amnesia to regress for the passive avoidance behavior induced by electroconvulsive shock. Compounds which statistically bring the performance of the animal to a higher value than in the control group receiving the electroconvulsive shock, but do not improve the performance enough so that it is statistically different from that observed in the control group receiving the dummy electroconvulsive shock are qualified as intermediate activity compounds. These compounds therefore statistically improve the performance of the animal, but not enough to offer him complete protection against amnesia.

The biological activities manifested by various compounds of formula I in the test described in Example 29 are listed in Table 2.

TABLE 2

Biological activity of various compounds of formula I for the retrogradation of amnesia induced by electroconvulsive shock for a passive avoidance response by _ descent____

Ex. Compound Downgrading of _ _ 11 amnesia_ pramiracetam (compound of active ingredient a at 10 mg / kg s.c.

reference) 1 2 - [[1- (2-Pyrimidinyl} -4- active at 10 mg / kg s.c.

piperidinylümethyl] -1H- isoindole-1,3- (2H) -dione 2 l - [[1- (2-Pyrimidinyl) -4- active at 10 mg / kg s.c.

piperidinyl] methyl] -2- and p.o.

pyrrolidinone 3 1-CCl- (2-Chloro-4-pyrimidi- active at 0.5 mg / kg s.c.

λ nyl) -4-piperidinyl] -methylü- and p.o.

u 2-pyrrolidinone 5 l - [[l- (6-Chloro-2-pyrazinyl) - active at 0.5 mg / kg s.c. 4-piperidinyllmethyl] -2-pyrrolidinone CD.MJ - 30 - TABLE 2 (continued)

Ex. Compound Retrogradation of _ ________ 11 amnesia 6 l - [[l- [2- (Trifluorome- active from 0.25 to 10 mg / kg thyl) -4-pyrimidinyl3-4- po, active from 0.5 to piperidinyl Jmethyl] -2- 10 mg / kg sc

pyrrolidinone 7 l - [[1- (2-Pyrimidinyl) -3- active at 25 mg / kg s.c.

φ piperidinyl] methyl] -2- pyrrolidincne 8 l - [[l- (2-Pyrimidinyl) -2- active at 25 mg / kg s.c.

piperidinyl3methyl3-2- pyrrolidinone 9 l- [Cl- (6-Chloro-3-pyrida- active at 25 mg / kg sc zinyl) -4-piperidinyl3methyl] -2-pyrrolidinone 10 l - [[l- (5- Fluoro-4- (methyl- thio intermediate activity) -2-pyrimidinyl] -4- at 10 and 25 mg / kg sc

piperidinylImethyl3-2- pyrrolidinone 11 l - [[l- (5-Fluoro-2-pyrimi- active at 10 mg / kg sc dinyl) -4-piperidinyl] methyl3-2-pyrrolidinone 12 l- [t1— (2 , 6-Dichloro-4- active at 1.0 mg / kg sc

pyrimidinyl) -4-piperidinyl] methyl3-2-pyrrolidinone 13 1 - [[1 - (4,6 — Dichloro — 2— intermediate activity pyrimidinyl) -4-piperi- at 10 mg / kg s.c.

dinyl3methyl] -2-pyrroIidinone 14 l - [[1- (6-Chloro-4-pyrimi- dinyl intermediate activity) -4-piperidinyl3me- at 10 mg / kg s.c.

tyl3-2-pyrrolidinone 1 2 3 4 5 CD.MJ - 31 - i - [[1- (2-Chloro — 6 — mefinyl- intermediate activity 4-pyrimidinyl) -4-piperidi- at 10 mg / kg s.c.

2 nyl3methyl3-2-pyrrolidinone 3 l - [[1- (5-Bromo-2-pyrimidi- active at 10 and 25 mg / kg 4 nyl) -4-piperidinyl3methyl3- p.c.

2-pyrrolidinone * 18 l- [[l- (5-Chloro-2-pyrimidi- active at 10 mg / kg p.o.

w nyl) -4-piperidinyl3methyl3- 2-pyrrolidinone 5 1 - [[1— (5 — Iodo — 2 — pyrimidi - active at 25 mg / kg p.o.

nyl) -4-piperidinyljn) ethyl3-2-pyrrolidinone TABLE 2 (continued)

Ex. Compound Retrogradation of _ 11 amnesia_ 22 1 ~ [[1- (5-Bromo-2-chloro-4- active at 0.5-1.0 mg / kg pyrimidinyl) -4-piperidinyl] - p.o.

methyl3-2-pyrrolidinone 23 1-L [1- (2-Methoxy-4-pyrimi- dinyl intermediate activity) -4-piperidinyl] - at 10 mg / kg p.o.

v, methyl] -2-pyrrolidinone 5 24 4 —C4 - [(2-Oxopyrrolidin-l- active at 25 mg / kg p.o.

. yl) methyl3-1-piperidinyl3-2-pyrimidinecarbonitrile 26 l - [[l- [2- (Pentafluoro- ethyl intermediate activity) -4-pyrimidinyl3-4- at 10 mg / kg piperidinyl3methyl3-2-pyrrolidinone 27 1 - [[ 1— [5 — Chloro — 2— (triflu— intermediate activity oromethyl) -4-pyrimidinyl] - at 10 mg / kg po

4-piperidinyl3methvl3-2-pyrrolidinone 28 l- [C1 - E2,6-bis (trifluoro-active at 10 mg / kg p.o.

methyl) -4-pyrimidinyl3-4-piperidinyl3methyl3-2-pyrrolidinone a. "Active" denotes a compound which completely suppresses amnesia induced by electroconvulsive shock, while "intermediate activity" denotes less complete protection.

CD.MJ - 32 -

Claims (35)

1. Compound of formula I ri W Ky-S i where X represents an ethylene chain or a 1,2-benzo ring; Y represents a carbonyl radical or -CH2-, with the restriction that Y represents a carbonyl radical only when X represents a 1,2-benzo radical; R · '"represents a hydrogen atom or alkyl radical, and Z represents an R2fR2-disubstituted diazinyl ring chosen from pyridazines, pyrimidines and pyrazines, R and R being chosen independently from hydrogen atoms and lower alkyl radicals (C ^ _4), lower alkoxy, lower alkylthio, cyano, trifluoromeye, pentafluoroethyl and halo; and the pharmaceutically acceptable acid addition salts of this compound. 2. Compound according to claim 1, in the formula in which X represents an ethylene radical and R1 represents a hydrogen atom. 3. Compound according to claim 1, in 2 3 the formula of which R and R are independently chosen between hydrogen atoms and halo and trifluoromethyl radicals. 4. Compound according to claim 2, in * ”2 3 i the formula of which R and R are independently chosen il * between hydrogen atoms and halo and trifluoromethyl radicals. 5. A compound according to claim 1, which CD.MJ - 33 - is 2 ~ [[1- (2-pyrimidinyl) -4-piperidinylImethyl] -1H-isoindole-1,3- (2H} -dione. 6. The compound of claim 1 which is l - [[1- (2-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone. 7. A compound according to claim 1, which is 1 ~ [[1- (2-chloro-4-pyrimidinyl) -4-piperidinyl] -methylJ-2-pyrrolidinone. O. 8. The compound of claim 1 which "is l - [[1- (4-chloro-2-pyrimidinyl) -4-piperidinyl] -methyl] -2-pyrrolidinone. 9. A compound according to claim 1 which is l - [[1- (6-chloro-2-pyrazinyl) -4-piperidinyl] mes-thyl] -2-pyrrolidinone. 10. The compound of claim 1 which is l - [[1- [2- (trifluoromethyl) -4-pyrimidinyl] -4-piperidinyl] methyl] -2-pyrrolidinone. 11. The compound of claim 1, which is l - [[1- (2-pyrimidinyl) -3-piperidinyl] methyi] -2-pyrrolidinone. 12. A compound according to claim 1, which is i - [[1- (2-pyrimidinyl) -2-piperidinyl] rnethyl] ~ 2-pyrrolidinone. 13. A compound according to claim 1, which is l - [[1- (6-chloro-3-pyridazinyl) -4-piperidinyl] ~ methyl] -2-pyrrolidinone. 14. The compound of claim 1 which is 1 - [[1- (5-fluoro-4- (methylthio) ”2-pyrimidinyl] -4_ piperidinylmethyl] -2-pyrrolidinone. 15. The compound of claim 1 which - ^ is l - [[1- (5-fluoro-2-pyrimidinyl) -4-piperidinyl] - t methyl] -2-pyrrolidinone. 16. The compound of claim 1 which is 1 - [[1- (2,6-dichloro-4-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone. CD.MJ - 34 - 17. The compound of claim 1 which is l - [[1- (4f6-dichloro-2-pyrimidinyl) -4-piperidi-nyl] methyl] -2-pyrrolidinone. 18. A compound according to claim 1 which is l - [[1- (6-chloro-4-pyrimidinyl) -4-piperidinyl3-methyl] -2-pyrrolidinone. 19. The compound of claim 1 which v is 1 - [[1- (2-chloro-6-methyl-4-pyrimidinyl) -4-pip-% ridinyl] methyl] -2-pyrroiidinone. 20. The compound of claim 1 which is 1 - [[1- (4-chloro-6-methyl-2-pyrimidinyl) -4-pipé-ridinyllméthyl] -2-pyrrolidinone. 21. The compound of claim 1 which is l - [[1- (5-bromo-2-pyrimidinyl) -4-piperidinyl3-methyl] -2-pyrrolidinone. 22. The compound of claim 1 which is l - [[1- (5-chloro-2-pyrimaininyl) -4-piperidinyl] -methyll-2-pyrrolidinone. 23. The compound of claim 1 which is l - [[1- (5-iodo-2-pyrimidinyl) -4-piperidinyl3methyi3-2-pyrrolidinone. 24. A compound according to claim lt which is l - [[1- [6-chloro-2- (methylthio) -4-pyrimidinyl] -4-piperidinyl] methyl3-2-pyrrolidinone. 25. The compound of claim 1 which is l - [[1- (5,6-dichloro-4-pyridazinyl) -4-piperidi-nyl] methyl] -2-pyrrolidinone. 26. The compound of claim 1 which is 1 - [[1- (5-bromo-2-chloro-4-pyrimidinyl) -4-piperi-dinyl] methyl3-2-pyrrolidinone. 27. The compound according to claim 1, which is 1 - [[1- (2-methoxy-4-pyrimidinyl) -4-piperidinyl] - J * methyl] -2-pyrrolidinone. f, 28. The compound of claim 1, which is 4- [4 - [(2-oxopyrrolidin-1-yl) methyl] -1-piperidinyl3-CD.MJ - 35 - V »> 2-pyrimidinecarbonitrile. 29. The compound of claim 1 which is l - [[1- [2- (pentafluoroethyl) -4-pyrimidinyl] -4-piperidinyl] methyl] -2-pyrrolidinone. 30. The compound of claim 1 which is 1 - [[1- [5-chloro-2- (trifluoromethyl) -4-pyrimidi-nyl] -4-piperidinyl] roethyl] -2-pyrrolidinone. 31. A compound according to claim 1 which is 1- [[1- [2,6-bis (trifluoromethyl) -4-pyrimidinyl] -4-piperidinyl] methyl] -2-pyrrolidinone. 32. The compound of claim 1, which is 1 - [[1- (6-chloro-3-pyridazinyl) -4-piperidinyl] -methyl] -2-pyrrolidinone. 33. Method for improving lucidity and memory in a mammal in need of such treatment, characterized in that an effective dose of a compound according to claim 1 is administered systemically to this mammal. 34. Process for the preparation of a compound of formula where X represents an ethylene chain or a 1,2-benzo radical; Y represents a carbonyl or methylene radical; R · * "represents a hydrogen atom or alkyl radical, · lower;: àr r 2 3 v Z represents a diazinyl ring R, R -disubstituted r chosen from pyridazines, pyrimidines and pyrazines,> - 2 3, R and R being independently chosen from hydrogen atoms and lower alkyl radicals, alkoxy in- CD.MJ - 36 -% a *> lower, lower alkylthio, cyano, trifluoromethyl and halo, characterized in that, (A) is reacts a compound of formula [4 — c ° 2r Λ ^ •; - K IX where R represents a C 1 to C 6 alkyl radical, with a compound of formula Z - Q where Z is as defined above and Q represents a appropriate leaving radical, (B) reacting the product of (A) with a metallic reactant of formula ra m where R ^ "is as defined above where M represents a metal ion or complex, (C) reacting the product of (E) with a reactant capable of converting the hydroxyl radical of the product of (B) by substituting it Q, and (D) the product is reacted of (c) with a cyclic amide / imide of formula rf v XV ÎP * - l where X and Y are as defined above, to obtain the product of formula I, or alternatively, to obtain a compound CD. MJ - 37 - t * s. of formula I where X represents a methylene chain and Y, 12 3 R, R, R and Z are as defined above, (A1) a cyclic amide / imide of formula X NH IV is reacted with a compound of formula t Q-CH - QX where R ^ and Q are as defined above, (B ') catalytically reduces the product of. (A') and (C) condenses the product of (B ') with a compound of formula Z - Q ου Z and Q are as defined above, to obtain a compound of formula I 35. Process according to claim 34, characterized in that Q represents a leaving radical chosen from the chloride, bromide, iodide, sulphate, phosphate, tosylate and mesylate radicals. * te V 'CD.MJ - 38 -