NL8601763A - PSYCHOGERIATRIC DIAZINYLPIPERIDINE DERIVATIVES OF CYCLIC AMIDES AND IMIDES. - Google Patents

Description

VO 8260

Title: Psychogeriatric diazinylpiperidine derivatives of cyclic amides and imides.

This invention generally relates to heterocyclic carbon compounds with drug and biological influence properties and their preparation and use.

The invention particularly relates to disubstituted piperidine derivatives wherein one substituent is a cyclic amide or an imidation linked by a bridging methylene moiety to one or more carbon ring sites of the piperidine ring and the other substituent is a diazinyl ring system attached to the piperidine nitrogen atom. .

The compounds of this invention are useful for the treatment of various dementia diseases from which the elderly man suffers.

The clinical aspects of various dementia problems as well as the problems they cause in the particular geriatric subject are well known to those skilled in the art. Clearly, several drug treatments of this condition in the elderly are currently under study. Such drugs include a class of drugs known as nootropic agents and more generally as recognition promoters; some are currently under clinical evaluation in patients diagnosed with Alzheimer's disease, a serious and fairly common CNS disease in older people.

These drugs under clinical study are members of a class of N-substituted 2-pyrrolodinone derivatives of structure 11 of the formula sheet wherein: 25a: X = H; R = -CH 2 CONH 2 (piracetam) b: X = OH; R = -CH 2 CONH 2 (oxiracetam) c: X = H; R = -CH 2 CONH [CH 2 1 2N [CH (CH 3)] (pramiracetam) d: X = H; R = -GO- ^ -OCH ^ (aniracetam) For a representative reference describing the study and properties of a member of this series see Butler, et al, J. Med. Chem. 27, pp. 684-691 (1984).

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Preliminary clinical results with this class of agents, examples of which are structures 1a-d, show that these drugs have some beneficial effect in the treatment of dementia.

Related art can be considered in light of the following general structural formula 12 of the formula sheet, wherein X is a C 2-4 alkylene or a 1,2-benzo ring, Y a carbonyl or methylene; A a bridging unit such as alkylene, alkanoyl, alkylene amidoalkylene and the like; W nitrogen or CH and B is an aryl or pyrimidinyl ring system. The closest prior art is described and claimed in our pending U.S. application 799,670 filed November 11, 1985. The subject relates to a range of compounds of formula 12 of the formula sheet wherein W is nitrogen.

The closest compounds described in that application are characterized by structural formula 13 of the formula sheet wherein 1 2 15 R is hydrogen or lower alkyl; and R may also be hydrogen or lower alkyl. As can be seen, these earlier compounds are structurally distinguishable from the present series of compounds on the basis of chemical structure since these earlier compounds are piperazine ring derivatives (W = N in formula 12) while the present compounds, on the other hand, are piperidine derivatives ( W = CH in formula 12).

Other publications concerning formula 13 compounds. have been described by Malawska, et al., in "Synthesis and Pharmacological Properties of Some 2-Pyrrolidinone Mannich Bases" in the Polish Journal of Pharmacology, 1982, 34, 373-382.

They describe a series of compounds of which a subclass is represented by the structural formula 14 of the formula sheet, which is reported to exhibit analgesic properties as well as a weak anti-inflammatory activity. In this formula, X is hydrogen or chlorine.

A large number of psychotropic compounds with structures corresponding to formula 2, wherein Y is carbonyl, W is nitrogen and A is C 2 alkylene, have been described by Wu, Temple New and co-workers and others. These compounds consist of cyclic imidations, e.g. succinimide, glutaimide, phthalimide, etc. The shortest coupling determined by A in these compounds is ethylene, since compounds in which A methylene-lene are too unstable for practical use, especially acidic media .

For a more detailed description of these compounds, reference is made to U.S. Pat. Nos. 3717634, 4423049 and 452420 &.

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In the other prepublishments mentioned in the aforementioned application I

cited one finds increasingly increasing structural deviations from I.

the compounds of the present invention. In summary, the following I

such diazinylpiperidine compounds as structurally described herein I

5 new recognition promoter means and there is no mention in position I.

of the art by which these specific compounds of I

the invention would have been anticipated or obvious. I

The invention relates to a series of compounds with structural form

mule 1 of the formula sheet, wherein X is an ethylene chain or 1,2-benzo ring;

1 2 3 I

10 Y carbonyl or methylene; R is hydrogen or lower alkyl and Z is an R, R-disubstituted diazinyl ring selected from pyridazine; pyrimidine and

2 3 I

pyrazination systems, R and R are independently selected from water-I

substance, lower alkyl, lower alkoxy, lower alkylthio, cyano, trifluoromethyl and halogen. Compounds of this series can be included in pharmaceutical compositions for the intended purpose to treat geria

trical subjects suffering from dementia. I

A representative number of these compounds have been investigated and I.

thus, prevention of ECS-induced amnesia in rats has been demonstrated

strived. I

In its broadest aspect, the present invention relates to I

king of 1- (4-diazinyl) piperidinyl derivatives of N-methylene cyclic amides and imides with psychogeriatric properties characterized by structural formula 1. I

In this formula, X is a C 1 (ethylene) alkylene chain or an I

1,2-benzo ring connecting Y and the carbonyl group, where, for example, when I

Y also carbonyl is a phthalimide unit is obtained. Y is a carbon I

nyl group (but only when X is a 1,2-benzo ring) or · In Formula 1, R * may be either hydrogen or lower (C) alkyl and Z 2 3 is an R, R-disubstituted diazinyl ring selected from pyridazine; Pyrimidine and pyrazine ring systems, wherein R and R are independently selected from hydrogen, lower alkyl, lower perfluoroalkyl (such as trifluoromethyl or pentafluoroethyl), lower alkoxy, lower alkylthio, cyano and halogen. Lower alkyl means those groupings containing 1-4 carbon atoms. Halogen means F, C, Br or I. For preferred compounds, X is ethylene, Y methylene, R1 is hydrogen and 2-3 R and R are selected from hydrogen, trifluoromethyl and halogen, where Λ, -V. * - »·» "7

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- 4 - Γ halogen is preferably chloride. It is understood that the present invention encompasses the various stereoisomers eg optical isomers including individual enantiomers, mixtures of enantiomers, diastereomers and mixture of diastereomers which arise as a result of the structure asymmetry due to the presence of one or two asymmetric carbon atoms which may be present in some compounds of the present series. Separation of the individual isomers is accomplished by various methods known per se in the art. For medicinal use, the pharmaceutically acceptable acid addition salts or those in which the anion does not significantly contribute to the toxicity or pharmacological activity of the organic cation are preferred in some cases.

The acid addition salts are obtained either by the reaction of an organic base of structure 1 with an organic or inorganic acid, preferably by contacting in solution or by any of the standard methods available in the literature available to the skilled artisan is described.

Examples of useful organic acids are carboxylic acids, such as maleic, acetic, tartaric, propionic, fumaric, isethionic, succinic, pamolinic, cyclamic, pivalic, and the like; useful inorganic acids are hydrohalide acids such as HCl, HBr and Hl; sulfuric acids; phosphoric acids and the like. In addition, the invention includes any of the formula I compounds which exist in solvate form, such as a hydrate.

The compounds of the invention may conveniently be prepared by a general synthetic method shown in reaction scheme A of the formula sheet.

In diagram A, the symbols X, Y and Z are as previously defined.

Essentially, a piperidine carboxylate ester (9) is coupled with a suitable diazine halide (8). Although an ethyl ester and a chloride group are indicated in reaction scheme A in compounds 9 and 8 respectively, other equivalent groups, for example another alkyl carboxylate ester and / or another halogen, may also be used. These deviations are apparent to the organic chemist who is skilled in the art of the synthesis of these compounds. The reaction ** fs <3 λ. Typically, 1.1% by weight of 9 and 8 will occur in a reaction solvent, such as acetonitrile, in the presence of a base, such as potassium carbonate, to yield the product 7. The 7 product can either be reduced with lithium aluminum hydride in a suitable solvent, such as tetrahydrofuran, to the reaction intermediate 6 (R 2 = H) or optionally 7 can be converted to aldehyde 10 by ester transformation methods into an aldehyde unit and this may be followed by treatment with an organometallic reagent, R * M (wherein M. represents the appropriate metal cation or a Grignard complex} to yield the intermediate 6 '. The primary alcohol intermediate (6) or the secondary alcohol (6') is treated with thionyl chloride to give the corresponding chlorine compound (5) which is then coupled with a selected cyclic amide or imide (4) to the desired product of formula 1. This coupling reaction is similar to that of 9 and 8 with a preferred reaction solvent this case is dimethylformamide and a base is incorporated such as potassium carbonate It will be apparent to those skilled in the art that other sales Testings of 6 intermediates are practicable, which effectively convert the hydroxy group into another cleavable group (e.g. a tosylate or mesylate unit) is converted to facilitate the alkylation of the nitrogen atom in the cyclic amide / imide compound.

Another method is useful for the preparation of products of formula 1, as indicated in reaction scheme B of the formula sheet. This scheme concerns a synthetic method, wherein X is an ethylene.

In reaction scheme B, R *, X, Y and 2 have the aforementioned meanings.

While the process outlined in Scheme B generally provides higher yields of products of Formula 1 than the general process of Scheme A, it does not have the general utility of Scheme A.

Because of the catalytic reduction (conversion of 3 -> 2), only cyclic amides / imides that are untouchable for catalytic reduction can be used. For example, when X is a 1,2-benzo ring, for example, is 4 phthalimide, then the benzo ring unit is subsequently reduced to a 1,2-cyclohexyl derivative, thereby obtaining a hexahydro-language imidation system.

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In summary, one can say that a method is described for

preparing a compound of formula 1, wherein R, X, Y and Z

have the aforementioned meanings. This method is one selected from the group of methods consisting of 5 (a) (1) coupling compounds 9 and 8 of the formula sheet, wherein R is a C ... alkyl group and Q is a suitable cleavable group, 1-b such as chloride, bromide, iodide, sulfate, phosphate, tosylate, mesylate and the like, whereby an intermediate of formula 7 of the formula sheet is obtained; (2) treating the intermediate 7 with the metallic reagent R 1 M, wherein M is the appropriate metalloid ion or complex, for example lithium; aluminum hydride or Grignard reagent complex to yield the reaction intermediate of formula 6 of the formula sheet; (3) treating the intermediate 6 with a suitable reagent to convert the OH group of 6 into a cleavable group Q * in the compound of formula 5; and (4) reacting intermediate 5 with a cyclic amide / imide compound of formula 4 of the formula sheet to yield a product of formula 1; (b) (1) reacting a cyclic amide / imide compound of formula 4, wherein X is not 1.2 benzo, with a pyridine intermediate of formula 10 of the formula sheet, wherein the intermediate of formula 3 of the formula sheet is acquired; (2) catalytically reducing the compound of formula 3 to the piperidine intermediate of formula 2 and (3) coupling the compound of formula 2 with compound Z-Q to give a product of formula 1.

Compounds of the present invention have been evaluated for nootropic activity, the main trial of which is the reversal of electroconvulsive shock-induced amnesia for a passive step-avoidance reaction (compare: Banfis, et al., J. Pharmacol. Meth ,, 8,555 ( 1982), Kanvik, Ann Rev. Psychol., 23, 457 (1972); and McGaugh and Petrinovich, Int. Rev. Neurobiology, 8, 139 (1965)).

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Reference compounds such as pramiracetam, piracetam, aniracetam, etc., which have activity in this field and affect memory processes, may be useful for treatment of dementia and Alsheimer disease.

In this experiment, 12 animals are administered a drug and 30 minutes later they are trained to remain immobile to avoid leg shocks. The animals are given an electroconvulsive shock immediately after training. 24 hours later, the animals are examined to maintain the learned behavior; any animal that remains on the platform for 300 seconds without getting off it is considered to have retained the passive avoidance response.

Two groups of control animals are used for the comparison; one group receives a carrier with an electroconvulsive shock while the other receives a carrier with a fake electroconvulsive shock. A test compound is considered active at a given dose level if the mean latency for stepping is both statistically greater than the value for the electroconvulsive shock control group (placebo control group) and non-statically different from the value for the counterfeit electroconvulsive shock control group.

It is considered that a test compound has an intermediate activity at a given dose-20 level if the results for the drug group are statistically different from both control groups. For comparison, all drugs were tested after subcutaneous administration; however, preferred compounds of the present series exhibit activity after oral administration which is little different from the results after the subcutaneous administration of the drug. In this regard, particular preference is given to the following compounds:! - [[! - (2-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone, 1 - [[1- (2-chloro-4-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone, 1- [[1- (6-chloro-2-pyrazinyl) -4-piperidinyl] -methyl] -2-pyrrolidinone and especially, 1 - [[1- ( 2-Trifluoro-methyl-4-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone.

Maintaining comparable potency levels when transitioning from subcutaneous to oral administration is a significant dosing benefit and distinguishes the present compounds from those previously described.

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Also, the present compounds are not labile in an acidic medium which is another advantage for their preparation, composition, transportation and storage, as well as for dosing.

When summarizing the above discussion, the present compounds have nootropic properties, which make them particularly suitable for recognition and memory enhancement.

Thus, another aspect of the present invention relates to a method of promoting recognition and memory in a mammal in need of such treatment, which is to systematically administer an effective dose of Formula 1 to such a mammal compound or a pharmaceutically acceptable acid addition salt thereof.

The administration and dose schedule of the compounds of formula 1 are considered to be in the same manner as for the reference compound piracetam, compare 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," publishers Cole and Barrett, Raven Press, New York, pp. 243-245 (1980) and pramiracetam, compare: Butler, et al., J. Med. Chem., 27, 20 pages. 684-691 (1984).

In addition to the utility of the compounds of formula 1 as recognition enhancers or mild central nervous system stimulants, the compounds have been found to be useful in preventing amnesia due to electroconvulsive shock. Such activity is not only associated with memory retention in normal aging and senility processes, but is also useful in protecting against the amnesia-producing effects of an electro-convulsive shock as it is used clinically.

Electroconvulsive shock is used to treat certain groups of psychiatric patients, especially depressed patients who cannot be helped with traditional medical therapy.

There is much literature that these electroconvulsive shock treatments elicit the undesirable side effect of amnesia in those patients to whom they are administered.

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The present compounds which have activity to protect against the amnesia-producing effects of electroconvulsive shock in a pharmacological study are useful tools for the clinical use of electroconvulsive shock in psychiatric treatments.

Although the dose and dose regimen should be carefully prepared in each individual case, when using sound expert judgment and considering the age, weight and condition of the subject, the route of administration and the nature and degree of mental Deterioration, generally at the daily dose, are about 0.1 g to about 10 g, preferably 0.5 g to 5 g, if administered orally. In some cases, a sufficient therapeutic effect can be achieved at lower doses, while others require larger doses. As is apparent to one skilled in the art of clinical pharmacology, the amount of the formula 1 compound comprising the daily dose may be administered in a single or divided dose, taking into account those principles understood by those skilled in the art and that are necessary for practicing the technique. The term "systemic administration" as used herein refers to oral, sublingual, buccal, nasal, dermal, rectal, intramuscular, intravenous and subcutaneous routes.

Generally, it will be found that when a compound of the present invention is administered orally, which is the preferred route, a slightly larger amount of the active drug is required to produce the same effect against a slightly smaller amount administered parenterally. According to good clinical practice, it is preferable to administer the present compounds at a concentration level that will produce effective nootropic effects without causing any harmful or pleasant side effects.

The present compounds are therapeutically widely administered as pharmaceutical compositions consisting of an effective nootropic amount of a compound of formula 1 or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier. Pharmaceutical preparations for carrying out such a treatment contain a predominant or minor amount of 860 1 7 ï 3 ♦ ** - 10 - (eg 95-0.5%) of at least one compound of the present invention in combination with a pharmaceutical carrier, which carrier contains one or more solid, semi-solid or liquid diluents, fillers and formulation auxiliaries which are non-toxic, inert and pharmaceutically acceptable.

Such pharmaceutical compositions preferably have the dosage unit form, i.e., physically distinct units with a predetermined amount of the drug corresponding to a fraction or a multiple of the dose calculated to produce the desired therapeutic response. In normal use, the dose units contain 1, 1/3 or less of a single dose. A single dose preferably contains an amount sufficient to produce the desired therapeutic effect upon administration of one or more dose units, and according to the predetermined dose schedule, usually one whole, half, one third or less of the daily dose given per administered once, twice, three times or several times a day. It is not excluded that other therapeutic agents may also be present in such a preparation.

Pharmaceutical preparations providing 0.1 to 1 g of the active component per unit dose are preferred and are conventionally prepared as tablets, lozenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs and aqueous solutions. Preferred oral preparations are in the form of tablets, capsules and may contain conventional excipients such as binders (e.g.

Syrup, acazia, gelatin, sorbitol, dragant or polyvinylpyrrolidone), fillers (eg lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine), lubricants (eg magnesium stearate, talc, polyethylene glycol or silica), disintegrants ( e.g. starch) and wetting agents (e.g. sodium lauryl sulfate).

Solutions or suspensions of a formula 1 compound with conventional pharmaceutical carriers are used for parenteral preparations, such as aqueous solutions for intravenous injection or oily suspensions for intramuscular injections.

Such formulations have the desired clarity, stability and adaptability for parenteral administration, and they are obtained C. I 4 yjll I j · ί - 'ψ. 11 by dissolving about 0.1 to 10 weight percent of the active compound in water or a carrier consisting of a polyhydric alcoholic alcohol such as glycerol, propylene glycol and the polyethylene glycols or mixtures thereof. The polyethylene glycols consist of a mixture of a non-volatile, usually liquid, polyethylene glycols that are soluble in both water and organic liquids and with molecular weights of about 200-1,500.

Description of specific embodiments

Compounds of the invention and their preparation methods as well as their biblical activity are illustrated in the following examples which are illustrative only. All temperatures are itt ° C unless otherwise indicated.

The magnetic nuclear magnetic resonance (NMR) spectral properties refer to chemical shifts (<5) expressed in parts per 15 million (ppm) versus tetramethylsilane (IMS) as a reference standard.

The relative area reported for the different shifts in the proton (PMR) spectral data corresponds to the number of hydrogen atoms of a given functional type in the molecule.

The nature of the shift in multiplicity is indicated as a broad singlet (bs), singlet (s), multiplet (m), doublet (d), doublet of doublets (dd), triplet (t), or quartet (q) . Abbreviations used are DMSO-dg (perdeuterodimethylsulfoxide), CDCl 4 (deuterochloroform) and are otherwise conventional. The infrared (IR) spectral descriptions only include absorption wave numbers (cm) with a functional group identification value. The IR assays were used with potassium bromide (KBr) as a diluent. All compounds gave a satisfactory elemental analysis.

EXAMPLE I

2 - ([1- (2-Pyrimidinyl) -4-piperidinyl3-methyl] -1H-isoindole-1,3- (2H) -dione) This synthetic sequence explains the more general synthesis of reaction scheme A.

A. Ethyl 1- (2-Pyrimidinyl) piperidine-4-carboxylate (7).

A mixture of ethylisone pecotate (9; 31.44 g, 0.2 mol), 2-chloropyridine (8; 22.91 g, 0.2 mol) and potassium carbonate (27.69 g. *. ** · ** · ** ** h J J J J J J 4 4 4 4 4 4 - - 12 12 12 12 12 12 mol mol mol in in in acet acet acet acet acet acet acet acet werd werd werd 250 250 250 250 250 24 by 24 hours under reflux; the mixture was filtered and the filtrate concentrated in vacuo. The residue was distilled (130-170 ° at 0.32 Torr) to give 44.1 g (94%) of product as a clear oil.

5 B. 4-Hydroxymethyl-1- (2-pyrimidinyl) piperidine (6) ♦

A solution of the ester (7; 20 g, 0.085 mol) in tetrahydrofuran (200 ml) was cooled to 0-5 ° and lithium aluminum hydride (3.23 g, 0.085 mol) was added slowly over a 10 minute period. The mixture was stirred at room temperature for 30 minutes.

Excess LAH was quenched with acetone and the mixture diluted with 3.2 ml of water followed by adding 3.2 ml of a 15% sodium hydroxide solution and then 9.7 ml of water. The resulting mixture was filtered and the filtrate concentrated in vacuo; an oil was obtained which, after distillation, gave 15 g (91%) of a clear oil product (bp 140-190 °, 15 at 0.3 Torr.

C.4-Chloromethyl-1- (2-pyrimidinyl) piperidine (5).

A solution of the hydroxymethyl compound (6; 7.73 g, 0.04 mol) in methylene chloride (40 ml) was cooled to 0-5 ° and thionyl chloride (25 ml) was added slowly. The solution was stirred at ambient temperature for 12 hours and then concentrated under vacuum. The residue was dissolved in methylene chloride, extracted with aqueous sodium carbonate and the methylene chloride layer concentrated under vacuum. The residue was chromatographed on silica gel with ethyl acetate as an eluent to give 7.7 g (91%) of the product as an oil.

25 D. Reaction of intermediate 5 and phthalimide.

A mixture of potassium carbonate (2.76 g, 0.02 mol), phthalimide (1.47 g, 0.01 mol) and 4-chloromethyl-1- (2-pyrimidinyl) piperidine (5; 2.12 g, 0 0.01 mol) in dimethylformamide (50 ml) was heated to about 50 ° C for 24 hours. The dimethylformamide solvent was removed in vacuo and the residue dissolved in acetone and filtered.

The filtrate was concentrated in vacuo to give the crude product which was chromatographed on silica gel with 30% ethyl acetate-hexane as eluent. The product was then recrystallized from ethyl acetate to yield 0.95 g (20.5%) of the product in the form of white crystals.

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Analysis; Calculated for c 67.06; H, 5.64; M, 17.38.

Found: C, 66.95; H; 5.68; N, 17.17.

NMR (CDCl 3): 1/35 (2.2 m); 1/74 (2, m); 2.10 (1.1m); 2.85 (2. m); 5. 3.61 (2.d, 7.0 Hz); 4.76 (2. m); 6.40 (1.1 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 *.

EXAMPLE II

.10 l - [[1- (2-Pyrimidinyl) -4-piperidinyl] methyl) -2-pyrrolidinone

This experimental series illustrates the synthetic method useful when X of the formula 1 compound is an alkylene chain (see reaction scheme B).

A. 1 - [(4-Piperidinyl) methyl] -2-pyrrolidinone hydrochloride hydrate 15 (2).

A solution of 1- (4-pyridinylmethyl) -2-pyrrolidinone hydrochloride (3; 15.05 g, 0.0707 mol; prepared from 2-pyrrolidinone and 4-pyridinyl methyl chloride); HCl (10 ml of an 8N solution in absolute ethanol) and absolute ethanol (100 ml) was hydrogenated with (1.0 g) at 60 psi for 72 hours. The mixture was filtered and the filtrate concentrated in vacuo to a white solid. The crude product was recrystallized from isopropanol to give 13.03 g (83%) of the product as a white powder, mp 212-214 °.

B. Reaction of intermediate compound 2 with 2-chloropyrimidine.

A mixture of the piperidinylmethylpyrrolidinone (2; 5.08 g, 0.0232 mol), 2-chloropyrimidine (2.67 g, 0.0233 mol) and potassium carbonate (7.09 g, 0.0513 mol) in dimethylformamide ( 60 ml) was heated in a 50-100 ° oil bath for 14 hours. The mixture was cooled and filtered.

The solvent was removed in vacuo and the residue was chromatographed over silica gel with ethyl acetate-acetone mixture as eluent to give 4.7 g (78%) of product as white crystals.

Melting point 144-147 °.

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Analysis: Calculated for C14H20N40: C '64'59? H '7.74? N, 21.52.

Found: C, 64.26? H, 7.78; N, 21.20.

NMR (CDCL1): 1.29 (2. m); 1.71 (2. m); 2.01 (3.3 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 (1.1, 4.7 Hz); 8.26 (2.d, 4.7 Hz).

IR (KBr): 800, 1360, 1440, 1515, 1540, 1585, 1675, and 2930 cm -1. EXAMPLE III

1- [[1- (2-chloro-4-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone 10 A mixture of 1- [(4-piperidinyl) methyl] -2-pyrrolidinone hydrochloride (2, as above prepared in Example IIA; 20.1 g, 0.0922 mol), 2,4-dichloropyrimidine (14.90 g, 0.1 mol), sodium carbonate (26.5 g, 0.25 mol) and 200 ml dimethylformamide was stirred at room temperature for 14 hours and then heated to 70 ° for 1 hour. The mixture was filtered and concentrated in vacuo. The crude residue was chromatographed on silica with ethyl acetate / methanol (95: 5) as the eluent, separating the product residue into two components. The main component was obtained as 16 g (59%) of an off-white powder, m.p. 110-114, and represented the desired 2-chloro-4-pyrimidinyl isomer.

Analysis: Calculated for C 3 H 13 ClN 3 O: C, 57.04? H, 6.50; N, 19.01.

Found: C, 56.73; H, 6.44? N, 18.97.

NMR (CDCl 3): 1.30 (2. m); 1.78 (2. m); 2.03 (3.3 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 l, d, 6.0 Hz IR (KBr): 965, 1150, 1350, 1360, 1490, 1590, 1685, 2860 and 2950 cm -1.

EXAMPLE IV

1 - [[1- (4-chloro-2-pyrimidinyl)] -4-piperidinyl] methyl] -2-pyrrolidinone The other isomer, the 4-chloro-2-pyrimidinyl compound, was obtained from the smaller component obtained by chromatography and recrystallization from ethyl acetate of the reaction product of Example III (as above) to give 1.1 g (4%) of white crystals, mp 143.5-145.5 °.

λ - /. ; - / o n w »- - 15 -

Analysis; Calcd for C 14 H 16 ClN 3 O: C 56.04; H, 6.50; N, 19.01.

Found: C, 56.66; H, 6.49; N, 19.81.

NMR (CDCl 3): 0.9-2.1 (5, m); 2.25 (2.5 t, 5 Hz); 2.75 (2.8, 8 Hz); 3.10 (2.1 d, 5 Hz); 3.30 (2.5, 5 Hz); 4.5-4.8 (2, d; 5 6.45 (l, d, 4 Hz); 8.13 (l, d, 4 Hz).

IR (KBr): 1275, 1350, 1419, 1512, 1525, 1588, and 1688 cm -1.

EXAMPLE V

1 - [[1- (6-chloro-2-pyrazinyl) -4-piperidinyl] methyl] -2-pyrrolidinone

Using the same procedure as described in Examples II and III, a mixture of 1- [(4-piperidinyl) methyl] -2-pyrrolidinone hydrochloride (2.12 g, 0.0556 mol); 2,6-dichloropyrazine (8.37 g, 0.0556 mol); potassium carbonate (19.2 g, 0.139 mol) and DMF (150 ml) stirred at room temperature for 14 hours and then heated to 70 ° C for 1 hour. The mixture was filtered and the filtrate concentrated in vacuo.

The crude product was recrystallized twice from ethyl acetate to yield 11.16 g (68%) of tan crystals, mp 139-142 °.

Analysis Calculated for C 1 H 21 ClN 2 O: C, 57.04; H, 6.50; N, 19.01.

Found: C, 57.02; H, 6.40; N, 19.03.

NMR (CDCl 3): 1.34 (2.0 m); 1.77 (2. m); 2.05 (3.3 m); 2.40 (2.1, 7.2 Hz); 2.91 (2, m); 3.18 (2, d, 7.0 Hz); 3.40 (2.1, 6.8 Hz); 4.30 (2.2 m); 7.74 (l, s); 7.96 (l, s).

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

EXAMPLE VI

1-C [1- [2-Trifluoromethyl) -4-pyrimidinyl] -4-piperidinyllmethyl] -2-pyrrolidinone

Using the procedure described in Examples II and III, a mixture of 1- - ((4-piperidinyl) methyl] -2-pyrrolidinone hydrochloride (2.21,85 g, 0.1 mol) and sodium carbonate (26.5 g, 0.25 mol) in methanol (150 ml) refluxed for 1 hour. The methanol was then removed in vacuo and acetonitrile (150ml) added to the residue. The mixture was cooled and stirred adding 4-chloro-2- (trifluoromethyl) pyrimidine (18.28 g, 0.1 mol). The mixture was stirred at room temperature for 18 hours and then / · * - · / * - ·>. Filtered and the filtrate concentrated in vacuo to give a thick residue which solidified after washing with hexane (100ml). The light tan powder (23.8 G, 73%) that formed was chromatographed (5% methanol / ethyl acetate on silica) to give 9.8 g of white crystals, mp 118.5-120.5 °.

Analysis: Calculated for C 1 H 15 gF N 2 O: C, 54.87; H, 5.83? N, 17.07.

Found: C, 54.50? H, 5.86? N, 16.80.

Similarly, a number of additional compounds of formula 1 which are listed in Table A were prepared.

: ·,,! I f Λ a? V W “* *> v»: * - 17 -

TABLE A

Compounds of formula 1 (1)

(Vch-i-Z

Λ

Piperidine · a 0

Ex, R1 X Y Ring coupling Z, Formula Smp. (} 5 VII H -CjV CH2 3- C14H20N4 ° VIII H “C2H4- CH2 2- C14H20N4 ° Π0-113 IX H -CjH4- CHj 4- ^ C1 C14Hi9C1N'4 °“ JCK3 10 XH -C2H4- CH2 4-C15H21 ? N4CS S6 "10 ° XI H -C2S 4-CH2 4- C14K19FN4 ° 134-136

Cl XII H -C2H4- CH2 4- -4 ^^ 5 'C14H18C12N40 140-144 XIII H -C2H4- CH2 4- ,, C14H18C12N40 111- ^ 15 XIV H -C2H4- CH2 4-7. C14H19C1N4 °' "ijj, ; VC1 ί. · '* V

** \ J i * 4 J

Table A - continued - 18 - 1 Piperidine

Ex. R "X Y ring head coupling Z Formula 3 Mp. (°)

Cl XV H -C2H4- CH2 4- 8 'C15H21C1N4 ° 133-135 ch3

Cl 5 XVI H -C2H4-CH2 4-9 'C15H21C1N4C 104-107. .. · ch3 XVII H "C2H4" CH2 4 "- ^)) - Br C14H19BrN4C 143-146 10"

N

XVIII η ~ C2H4- CH2 4- - {0) -Cl C14K19CiN4 ° 130-133 N-7 11 'XIX H -S2H4- CH2 4- \ Q / 1 c14H19IN4 ° 129.5- N' 12 '131.5 _SHe 10 XX H - C2H4- CE2 4- ηC15E2] C1NJ) S 134-137 ^ C1

Cl Cl XXX H -C2H4- CH2 4-14 'C14H18C12S4P 135-138 XXII H -C2H4- CH2 4-15' C1 ^ gBrClN ^ O 105-115

Br OMe XXIII h -C2H4- CH2 4- 15 'C15H22N4 ° 2 116-121

CN

XXIV H -CH- CH, 4- -¾¾ C..H1QNcO 139.5- 15 2 4 ^ αο.γη: ο 142 17 '3:; T0' * * f \, 1 = 7 ^ * 7 ύ ό yi ƒ o 3

Table A - continued - 19 -

Piperidine

Ex. r1 x Y ring coupling z Formula Skip. () XXV H lf2-C6H4 CH2 4-1 C18H2 (JN40 176-178 n- ^ 2F3 XXVI H -C2H4- CH2 4-13 'C16H19F5N4 ° 105'107'5

CF

ƒ- / 3 XXVII H ~ C2S4 "cs2 4 * 191 C15H18C1F3K4 ° 10 *" 4 5

Cl 'XXVIII H -C-HCH, 4- 20' C16H18F £ N4 ° 132.5-24 2 0.075 fi20 134 C? 3 a. C, H and N analyzes were all within + 0.4% of the calculated value .

“7 7 * 7 7 7

V. 7 2 w * O

i ^ - 20 -

i EXAMPLE XXIX

| Reversal of ECS-induced amnesia for a step-down passive avoidance response.

In the step-down passive avoidance procedure, rats are trained to remain immobile in order to avoid shock from the legs. Two control groups (n-36 / group) were required, as well as an ECS control and a counterfeit ECS control. ECS control animals were individually placed on a platform over an activated shock grid (0.8 mA) 30 minutes after administration of the vehicle. The animals quickly disembarked from the platform, immediately experienced a shock to the legs and quickly learned to escape to the platform. An animal was believed to have acquired a passive avoidance response if left on the platform for 2 minutes without getting off after administration of the shock through the legs. Immediately after this teaching, 15 ECS control animals were administered ECS via transcorneal electrodes at an intensity of 50nA for 400m seconds. The pseudo-ECS control animals were treated in an identical manner as described for the ECS control, except that no current was passed through the transcorneal electrodes. Both groups were subjected to a retention test 24 later. The animals were placed on the platform individually and the latency to step off the platform onto the non-activated shock grid was noted. A given subject animal was considered to have memorized the passive avoidance response if it remained on the platform for 300 seconds without dismounting. Pseudo-ECS controls remained on the platform during this test and showed normal retention; ECS controls quickly got off within 300 seconds and showed lack of retention (i.e., amnesia).

Step-off latencies were converted to percent retention counts where 300 seconds equals 100% retention.

The percentage retention counts for all drug groups were evaluated against both the ECS and pseudo-ECS control groups with the Dunnett's test. A compound was considered active in this trial if the mean retention score obtained from at least one dose group is both significantly greater than the ECS control group retention but not significantly different from pseudo-ECS control group

• λ * a · η >> * T

λ · <!] 4. / vu, -os - 21 - retention. This demonstrates that the test compound reversed the amnesia for the passive avoidance command induced by the ECS. The compounds that statistically elevated the animal's performance above that of the ECS control group, but did not increase the performance sufficiently to make it statistically different from the pseudo-ECS control group were counted as an "intermediate activity". to own.

These compounds do statistically increase the performance of the animals, where they are not sufficient to give total protection against amnesia.

The biological activities of selected Formula 1 compounds from the test described in Example XXIX are listed in Table B.

4 ^!

- 22 TABLE B

Biological activity of selected formula 1 compounds in the reversal of SCS-induced amnesia for a passive step-avoidance reaction 5 ECS-induced

Ex. Name amnesia reversal pramiracetam '(reference active4 at 10 mg / kg s.c.

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

Piperidinyl} methyl] -1H- isoindole-1,3- (2H) -dione II 1 - [(1- (2-Pvrimidinyl) -4- active) at 10 mc / kg s.c.

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

pyrrolidinone 15 III 1 - [[1- (2-Chloro-4- active at 0.5 mg / kg s.c.

pyrimidinyl) -4-piperidinyl] - and p.o. methyl] -2-pyrrolidinone V 1 - ((1- (6-Chloro-2 - active at 0.5 mg / kg s.c.

pyrazinyl) -4-piperidinyl] - 20 methyl] -2-pyrrolidinone VI .l - [(1- (2- (Trifluoro ·) -4- active at 0.25 to 10 pyrimidinyl] -4-piperidinyl] - mg / kg po , active at methyl] -2-pyrrolidinone O. Stot'10 mg / kg sc

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

Piperidinyllmethyl] -2-pyrrolidinone.

VIII 1- [[1- (2-Pyrimidinyl) -2- active at 25 mg / kg s.c.

piperidinyl] methyl] -2-pyrrolidinone, 30 IX 1 - ([1- (6-Chlo.pr-3-active at 25 mg / kg s.c.

pyridazinyl) -4-piperidinyl] -methyl] -2-pyrrolidinone X 1- [(1- (5-Fluoro-4- (methyl-intermediate activity thio) -2-pyrimidinyl] -4- at 10 and 25 mg / kg sic.

Piperidinyl] methyl] -2-pyrrolidinone.

XI 1- [fl- (5-Fluor -2- active bijio mg / kg s.c.

pyrimidinyl) -4-piperidinyl] -methyl] -2-pyrrolidinone.

t; ** 7 ** * '7 V w j / -5- *

Tab el B - continued '- 23 - ECS-Induced .vb Haam amnesia reversal XII 1-Γfl- (2,6-Dichlcor-4- active at 1.0 mg / kg s.c.

Pyrimidinyl) -4-piperidinyl] -methyl] -2-pyrrolidinone · XIII 1-Γ [1- (4,6-Dichlcor-2-interactivity pyrimidinyl) -4- at 10 mg / Jcg s.c.

piperidinyl-methyl] -2-pyrrolidinone XIV 1 - [[1- (6-Chloro-4-intermediacy pyrimidinyl) -4- at 1 mg / kg s.c.

piperidinyl] methyl] -2-pyrrolidinone. XV 1- [[1- (2-Chloro-6-methyl-intermediate 4-pyrimidinyl) -4- at 10 mg / kg s.c.

piperidinyl] methyl] -2-pyrrolidinone-XVII 1— [[1— (5-Bromo-2-active- at 10 & 25 mg / kg pyrimidinyl) -4-piperidinyl] -p.o.

methyl) -2-pyrrolidinone XVIII 1— [El— (5-Chloro »2— active at 10 mg / kg po, pyrimidinyl) -4-piperidinyl] -methyl] -2-pyrrolidinone 25 XIX 1-f [1- 5-iodo-2 active at 25 rac / kg po

pyrimidinyl) -4-piperidinyl] -methyl] -2-pyrrolidinone XXII 1- [[1- (5-Brobm-2-chloro-4-active at 0.5-1.0 mg / kg pyrimidinyl) -4-piperidinyl] - p.o.

30 methyl] -2-pyrrolidinone XXIII 1 - [[1- (2-Methoxy-4-intermediate activity pyrimidinyl) -4-piperidinyl] - at 10 mg / kg po methyl] -2-pyrrolidinone XXIV 4- [4 - [( 2-Oxcpyrrolidire active at 25 rog / kc po

35 1-y1) methyl] -1-piperidinyl] - 2-pyrimidine carbonitrile, XXVI 1-f [1- [2- (Pentafluoro.ethyl) - intermediate 4-pvrimidinyl] -4-piperi at 10 mg / kg diny1] methylJ-2-pyrrolidinone - .1-7 '** - ·, V -' '"I' jo '(«! - - 24 -

Table B - continued ECS-induced

Ex Name amnesia reversal XXVII 1 - [[1- [5-Chloro-2-inter activity (trifluoromethyl) -4- at 10 mg / kg p.o.

pyrimidinyl] -4-piperidinyl] - 'methyl] -2-pyrrolidinone XXVIII 1 - [[1- [2,6-bis (trifluoro-active at 10 mg / kg p.o.

methyl) -4-pyrimidinyl] -4-piperidinyl] methyl] -2-pyrrolidinone a. "Active" means compounds that completely reversed ECS-induced amnesia while "intermediate activity" has less than complete protection.

Q Λ Λ -> = ξ

W & * - f f V

Claims (11)

A compound of formula 1, wherein X is an ethylene chain or a 1,2-benzo ring; Y is a carbonyl group or -CH 2 - provided that Y is only carbonyl when X is a 1,2-benzo ring; R1 is selected from hydrogen or C1-4 alkyl; and Z is an R 2, R 3 disubstituted diazinyl ring selected from pyridazine, pyrimidine and pyrazine ring systems, wherein R 2 and R 3 are independently selected from hydrogen, lower (C 1) alkyl, lower alkoxy, lower alkylthio, cyano, trifluoro- methyl, pentafluoroethyl and halogen; and the pharmaceutically acceptable acid addition salts thereof. 2 B <5 6 6 Λ h <y o r ~ \, ^ s k V \ ". > · 4 '"? ·? *: · _ Is / V' V: r * · * ·. * Jm X« H + C1CH — L) * $ N-CH - t *) Vy ^ Sry k .n 3 10 H PtO. 2 2 W ίΑ m Ϋ AN 1, /% ^ «- ^ - H 1 2 3 5 .o r1 Y * X v / _CH V) V.Y'7 N 2 12 A compound according to claim 1, characterized in that X is ethylene and R 1 is hydrogen. Compound according to claim 1, characterized in that R2 and R3 are independently selected from hydrogen, halogen and trifluoromethyl. 4. A compound according to claim 2, characterized in that R2 and R3 are independently selected from hydrogen, halogen and trifluoromethyl. A compound according to claim 1, consisting of 2 - [[1- (2-pyrimidinyl) -4-piperidinyimethyl] -1H-isoindole-1,3- (2H) -dione. A compound according to claim 1, consisting of 1- [[1- (2-pyrimidinyl} -4-piperidinyl] methyl -2-pyrrolidinone. The compound of claim 1, consisting of 1-CC (2-chloro-4-pyrimidinyl) -4-piperidinyl] -methyl] -2-pyrrolidinone. A compound according to claim 1 consisting of 1 - [[1 "(4-chloro-2-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone. 9. A compound according to claim 1, consisting of 1 "CC1" (6-chloro-2-pyrazinyl) -4-piperidinyl] -methyl] -2-pyrrolidion. 10. A compound according to claim 1, consisting of SIE 2 ~ (• fzrx-fluoromethyl) -4-pyrimidinyl] methyl] -2-pyrrolidinone. A compound according to claim 1 consisting of 1-CC 1 "(2-pyrimr-dinyl) -3-piperidinyl] methyl] -2-pyrrolidinone. The compound of claim 1, consisting of 1- [C 1- (2-pyrimidinyl) -2-piperidinyl] methyl] -2-pyrrolidinone. 2 i π r '' & V v? sj - f 'J - 26 - i' -! The compound of claim 1, consisting of 1-CCl- (6-chloro-3-pyridazinyl) -4-piperidinyl] -methyl] -2-pyrrolidinone. The compound of claim 1, consisting of 1- [[1- (5-Fluoro-4- (methylthio) -2-pyrimidinyl] -4-piperidinyl-3methyl] -2-pyrrolidinone. The compound of claim 1, consisting of 1-L [1- {5-fluoro-2-pyrimidinyl) -4-piperidinyl] -methyl] -2-pyrrolidinone. The compound of claim 1, consisting of 1-CCl- (2,6-dichloro-4-pyrimidinyl) -4-piperidinyl] -methyl] -2-pyrrolidinone. The compound of claim 1, consisting of 1-CCl- (4,6-di-chloro-2-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone. A compound according to claim 1, consisting of 1 - [[1- (6-chloro-4-pyrimidiny1) -4-piperidiny1] methyl] -2-pyrrolidinone. A compound according to claim 1 / consisting of 1-Q [1- (2-chloro-6-methyl-4-pyrimidinyl) -4-piperidinylmethyl] -2-pyrrolidinone. The compound of claim 1, consisting of 1 - [[1- (4-chloro-6-methyl-2-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone. The compound of claim 1, consisting of 1 - [[1- (5-bromo-2-pyrimidiny1) -4-piperidinyl] methyl] pyrrolidinones. The compound of claim 1, consisting of 1 - [[1- (5-chloro-2-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone. The compound of claim 1, consisting of 1 - [[1- (5-iodo-2-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone. v The compound of claim 1, consisting of 1 - [[1- 6-chloro-2- (methylthio) -4-pyrimidinyl] -4-piperidinyl] methyl] -2-pyrrolidinone. The compound of claim 1, consisting of 1 - [[1- (5,6-dichloro-4-pyridazinyl) -4-piperidinyl] methyl-2-pyrrolidinone. The compound of claim 1, consisting of 1 - [C 1- (5-bromo-2-chloro-4-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone. 27. A compound according to claim 1, consisting of 1 - CCl - (2-methoxy-4-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone. The compound of claim 1, consisting of 4- [4- (2-oxo-pyrrolidin-1-yl) methyl] -1-piperidinyl] -2-pyrimidine carbonitrile. The compound of claim 1, consisting of 1 - [[1 - [2 - (penta-fluoroethyl) -4-4-pyrimidinyl] -4-piperidinyl] methyl] -2-pyrrolidinone. The compound of claim 1, consisting of 1- [[1- [5-chloro-2- (trifluoromethyl) -4-pyrimidinyl] -4-piperidinyl] methyl] -2-pyrrolidinone. . > '- 1 -¾ yard η / λ »; * -j, ·; n λ V o '"- · ^ *. I ** - 27 - The compound of claim 1, consisting of 1- [[1- [2,6-bis- (trifluoromethyl) -4-pyrimidinyl] -4-piperidinyl] methyl] -2-pyrrolidinone. The compound of claim 1, consisting of 1 - [[1- (6-chloro-3-pyridaziny1) -4-piperidinyl] methyl] -2-pyrrolidinone. A method for improving recognition and memory in a mammal in need of such treatment, comprising systemically administering to the mammal an effective dose of a compound according to claim 1. 34. A method of preparing a compound of formula 1, 10 wherein X is an ethylene chain or a 1,2-benzo ring; Y is carbonyl or methylene; hydrogen or lower alkyl; Z is a R2, r3-disubstituted diazinyl ring selected from the group consisting of pyradizine, pyrimidine and pyrazine; and R2 and R3 are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, lower alkyl-15 thio, cyano, trifluoromethyl and halogen, optionally comprising (A) reacting the compound of formula 9, wherein R is a C 1 alkyl group with a compound of the formula Z-Q, wherein Z has the aforementioned meanings and Q is a suitable cleavable group, (B) reacting the product of (A) with a metallic reagent with the formula R ^ M wherein R ^ has the aforementioned meaning and M is a metalloid ion or complex, (C) reacting the product (B) with a reagent. capable of converting the hydroxy group of the product of (B) into the substituent Q and (D) reacting the product of (C) with a cyclic amide / imide of formula 4, wherein X and Y have the aforementioned meanings, whereby the product of formula 1 is obtained or, optionally, a formula 1 compound is prepared, in which X is a methylene chain and Y, R1, R2, R3 and Z have the aforementioned meanings, (A ') it reacting a cyclic amine / imide of formula 4 with a compound of formula 10, wherein R1 and Q have the aforementioned meanings (B ') catalytically reducing the product of (A1) and (C *) coupling the product of (B ') of the compound of the formula ZQ, wherein Z and Q have the aforementioned meanings, to prepare a compound of the formula 1. *. 1 .i. »'· V J v 5 / · - - 28 - V -W A method according to claim 34, characterized in that Q is a replaceable group selected from a chloride, bromide, iodide, sulfate, phosphate, tosylate or mesylate group. V v J J ~ 0 C 4_ / _Α_ C02C2H5 + Z-C1 - —C07C2H, f ^^ X-CHO Τ. ^ 9 7 2 10 ΙΛΗ R2H «l · rvcl sod ^ yH? H, L T (- * - l J f —cH-R Ύ r ^ 11 O »o X NA NB r ~ \ 's ^' \ _ / J NR ΛΙΓ ', ^} Ó"' - Q ^ Ó y, w ^ H £ · Λ, \ i 7 *. -¼ ^ V \ ** * '