FI88300C - FOERFARANDE FOER FRAMSTAELLNING AV NYA TERAPEUTISKT ANVAENDBARA DIAZINYLPIPERIDINDERIVAT AV CYCLISKA AMIDER OCH IMIDER - Google Patents

Description

The present invention relates to a process for the preparation of new therapeutically useful cyclic amides and imides of the formula I in the preparation of diazinylpiperidine derivatives and their pharmaceutically acceptable acid additions. , 2-benzo ring, Y is carbonyl or methylene, provided that Y is carbonyl only when X is a 1,2-benzo ring, R 1 is hydrogen or lower alkyl and Z is a R 2, R 3 disubstituted diazinyl ring which is selected from the group consisting of pyridazine, pyrimidine and pyrazine, wherein R 2 and R 3 independently represent hydrogen, lower alkyl, lower alkoxy, lower alkylthio, cyano, trifluoromethyl, pentafluoroethyl or halogen.

The compounds according to the invention have medicinal effects and properties affecting vital functions and are suitable for the treatment of various age-related boredom in the elderly.

The clinical aspects of the various age-related boredom, as well as the problems they cause to the elderly affected, are known to those skilled in the art. Drugs useful in drug therapy include a group of drugs known as nootropic agents, or more generally attention enhancers; some of which are currently being evaluated clinically in patients diagnosed with Alzheimer's disease, a severe and fairly common CNS disease in the elderly. Chemically, these clinically investigated drugs are in the class of N-substituted 2-pyrrolidinone derivatives of structure 1.

& *

X

a: X = H; R * -CH 2 CONH 2 (pyracetam); b: X = OH; R = -CH 2 CONH 2 (oxiracetam); 10 c: X = H; R = -CH 2 CONH [CH 2] 2 N [CH (CH 3) 2] 2 (pramiracetam); d: X = H; R = -CO - ^ O ^ -ΟΟΗ3 (aniracetam).

As an example of a literature reference describing the testing and properties of a member of this series (1), mention may be made of Butler, et al., J. Med. Chem., 27, pp. 684-15,691 (1984). Preliminary clinical results obtained with this group of agents, exemplified by structures 1a-d, indicate that these drugs may have some beneficial effects in the treatment of senile boredom in the elderly.

20 The relevant knowledge can be examined in the light of the following general structural formula (2): f ~~ \

25 V T / ~ A ~ \ / B

wherein X is a C 2-4 alkene or 1,2-benzo ring; Y is carbonyl or methylene; A is a bridging moiety such as, for example, alkene, alkanoyl, alkeneamidoalkene or the like; W is nitrogen or CH; and B is an aryl or pyrimidinyl ring system. The closest to the relevant knowledge is in the presentation and claims of our own pending partial extension patent application USSN 799,670, filed November 11, 1985, 35. The application relates to a series of compounds of formula 2 in which W is nitrogen.

3 88300 The closest similar compounds described in that patent application can be represented by structural formula 3: (^ 0 ~ 0 2

• H

Wherein R 1 is hydrogen or lower alkyl; and R 2 may also be hydrogen or lower alkyl. As can be seen, these previous compounds differ in structure from the present series of compounds in chemical structure because these prior compounds are derivatives of the piperazine-15 ring (W = * N in formula 2), while the present compounds are derivatives of the piperidine ring (W = CH in formula 2). 2).

Other information on compounds of formula 3 has been reported by Malawska, et al., "Synthesis and pharmacological properties of some 2-pyrrolidinone-Mannich bases", Polish Journal of Pharmacology, 1982, 34, 373-382. one subclass of which is represented by structural formula 4, and which compounds have been shown to have analgesic properties as well as a weak anti-inflammatory effect,

0 X

wherein X is hydrogen or chlorine. A large number of psychotropic compounds having structures corresponding to kaa-35 vaa 2, where Y is carbonyl, W is nitrogen, and A is C2-4 alkene, have been reported by Wu, Temple, New, and their work. blood and others. These compounds consist of cyclic imide rings, e.g. succinimides, glutarimides, phthalimides, etc. The shortest bridge represented by A in these compounds is ethylene, as compounds in which A is 5 methylene are not sufficiently stable, especially acid -in which media, for practical purposes. These compounds are described in more detail in the following disclosures: Wu, et al., U.S. Patent 3,717,634, issued February 20, 1973; Temple, U.S. Patent 4,423,049, patented December 27, 1983; and New and Yevich, U.S. Patent 4,524,206, patented June 18, 1985.

An even greater structural difference from the compounds of the present invention can be found in other art knowledge referred to in our aforementioned patent application. Briefly, the diazinylpiperidine Compounds described herein are novel attention enhancers in structure, and there is no knowledge in the art to make the compounds of this invention predictable or self-evident.

A series of compounds of formula I wherein X is an ethylene chain or a 1,2-benzo ring; Y is carbonyl or methylene; R is hydrogen or lower alkyl; and Z is R 2 -, R 3 is a disubstituted diazinyl ring selected from pyridazine, pyrimidine and pyrazine ring systems, R 2 and R 3 are independently selected from hydrogen, lower alkyl, lower alkoxy-35, lower alkylthio, cyano, trifluoromethyl and halogen. A series of compounds can be included in pharmaceutical preparations for use in the treatment of the elderly suffering from aging boredom, and a representative number of these compounds have been tested and shown to inhibit ECS-induced memory loss in rats.

In its broadest sense, this invention relates to 1- (4-diazinyl) piperidinyl derivatives of N-methylenecyclic amides and imides having psychogeriatric properties and represented by Structural Formula I.

ÖK> i 15

In formula I, X is a C2 (ethylene) alkene chain or a 1,2-benzo ring connecting Y and a carbonyl group, whereby, e.g. when Y is also carbonyl, a phthalimide moiety is formed. Y is a carbonyl group (but only when X is a 1,2-benzo ring) or CH2. In formula I, R 1 may be either hydrogen or lower (C 1-4) alkyl; and Z is R 2, R 3 is a disubstituted diazinyl ring selected from pyridazine, pyrimidine and pyrazine ring systems, wherein R 2 and R 3 are independently selected from hydrogen, lower alkyl, lower perfluoroalkyl (such as trifluoromethyl). or pentafluoroethyl), lower alkoxy, lower alkylthio, cyano and halogen. Lower alkyl means that these moieties contain 1 to 4 carbon atoms. Halogen means F, Cl, Br or 30. Preferred compounds X are ethylene, Y is methylene, R 1 is hydrogen, and R 2 and R 3 are selected from hydrogen, trifluoromethyl and halogen, with chloride being preferred as the halogen.

It is intended that the present invention include various stereoisomers, e.g., optical isomers, including individual enantiomers, mixtures of enantiomers 6,8,800, diastereomers, and a mixture of diastereomers that may result from structural asymmetry due to the presence of one or two asymmetric carbon atoms. , such as may be present in some of the compounds in series 5 in question.

Separation of the individual isomers is accomplished using a variety of methods well known to those skilled in the art. In medical use, in some cases, pharmaceutically acceptable acid addition salts may be preferred, salts whose anion does not significantly affect the toxicity or pharmacological activity of the organic cation. The acid addition salts are obtained either from the fraction of the organic base of structure I with the organic or inorganic acid, preferably by contact with them in solution, or by any standard method described in detail in the literature available to those skilled in the art. Examples of useful organic ha-acids include carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, pamoic acid, cyclamic acid, pivalic acid and the like; useful inorganic acids include hydrohalic acids such as HCl, HBr, HI; sulfuric acids, phosphoric acids and the like. In addition, the present invention also relates to all compounds of the formula I in the form of a solvate, such as a hydrate.

The compounds of this invention can be readily prepared by the general procedure shown in Scheme 1.

7 88300

Figure 1

General synthetic method

[^ ^ CO2C2H5 + Z-Cl -> CO2C2H5- ^ 1 ^^ - CHO

H? ^ IX Vili z 1 vii x

LAH RlM

»'/ · Cy ^ σ a- * z 1 z L z V VI vr 0 Λ

IV

WO

β 83300

In Figure 1, the symbols X, Y and Z have the meanings previously given. In essence, it is a question of coupling the piperidine carboxylate ester (IX) to the appropriate diazine halide (VIII). Although the ethyl ester and chloride groups are present in compounds IX and VIII in Scheme-5, other similar groups may be used, e.g., another alkyl carboxylate ester and / or a different halogen. These changes would be known to an organic skilled in the art of compound synthesis. The reaction of IX and VIII typically takes place in a reaction solvent such as acetonitrile in the presence of a base such as potassium carbonate to give the product (VII). Product VII can either be reduced with lithium aluminum hydride in a suitable solvent such as tetrahydrofuran to give reaction intermediate VI (Rx = H), or alternatively VII can be converted to aldehyde X using standard methods for ester conversion to aldehyde followed by treatment with organometallic reagent R ^ M (where M represents a suitable metal cation or Grignard complex) to give intermediate VI '. The intermediate, which is a primary alcohol (VI) or a secondary alcohol (VI '), is treated with thionyl chloride to give the corresponding chlorine compound (V), which is then coupled with the selected cyclic amide or imide (IV) to give the desired product of formula I. This coupling reaction takes place in the same way as the reaction of IX and VIII, in which case the solvent is preferably dimethylformamide and contains a base such as potassium carbonate. It will be appreciated by those skilled in the art that other changes may be made to intermediates VI that would effectively convert the hydroxy group to a different leaving group (e.g., tosylate or mesylate group) to facilitate initialization of the nitrogen atom in the cyclic amide / imide compound.

Another method can be used to prepare the products of formula I, and this method is shown in Scheme 2.

i 9 88300

Figure 2

Synthesis method when X is the ethylene chain O + α * “- 0 -‘

IV x III

h PtO „2 2 v f ^ Z-Cl ΓΛ t X VcB - J - m,? N ™ -

1 H

I 11 10 88300

In Scheme 2, R 1, X, Y and Z are as defined above. Although the process shown in Scheme 2 generally produces products of formula I in higher yields than the general process of Scheme 1, it is not as generally applicable as Scheme 1. Due to catalytic reduction (conversion of III to II), only cyclic amides / imides can be used. which can withstand catalytic reduction. For example, when X is a 1,2-benzo ring, e.g., IV is a phthalimide, the benzo ring moiety is subsequently reduced to the 1,2-cyclohexyl derivative to give a hexahydrophthalimide ring system.

In summary, it will be described that a process for the preparation of a compound of formula I is described wherein R 1, X, Y and Z are as previously defined. This method involves selecting a method from the following group of methods:

(a) (1) compounds IX and VIII are coupled together

25

- co2r Z-Q

B

'VIII

30 IX

wherein R is a C 1-6 alkyl group and Q is a suitable displaceable group such as, for example, chloride, bromide, iodide, sulfate, phosphate, tosylate, mesylate or the like to give an intermediate of formula VII; 11 88300 C02r f

5 Z

VII

(2) treating intermediate VII with a metal reagent R M, wherein M is a suitable metalloid ion or complex, e.g., lithium aluminum hydride or a Grignard reagent complex, to give a reaction intermediate of formula VI; r ^ x · 1

-A-CHOH

15 z

VI

(3) treating intermediate VI with a suitable reagent to convert the OH group in 2Q VI to the leaving group Q in a compound of formula V; ___ R1

CHQ

25

Z

· 'V

and (4) reacting intermediate V with a cyclic amide, imide compound of formula IV O-

35 IV

12 8 8 3 C O

to give a product of formula I; (b) (1) administering a cyclic amide / imide compound of formula IV

IV

1Q wherein X is not a 1,2-benzo ring, react with a pyridine intermediate of formula X

"-hQ

15

X

to give an intermediate compound of formula III; c/o

III

(2) reducing the compound of formula III from the catalytic process to give the piperidine intermediate of formula II, Ηί-Τι 30

B

II

and (3) coupling a compound of formula II to Z-Q to give a product of formula I.

The nootropic effect of the compounds of this invention has been evaluated using, as a preliminary screen, the reversal of memory loss caused by electroconvulsive shock in the passive avoidance reaction. (Vert.

5 Banfis, et al., J. Pharmacol. Meth., 8, 255 (1982); Janvik, Ann. Rev. Psychol., 23, 357 (1972); and McGaugh and Petrino-vich, Int. Rev. Neurobiology, 8, (1965)). Reference agents such as pramiracetam, piracetam, aniracetam, etc. that have activity in this paradigm have been claimed to affect memory processes and may be useful in the treatment of senile boredom and Alzheimer's disease. In this experiment, 12 animals are given drugs and 3Q minutes later they are taught to remain immobile to avoid foot shock. Immediately after training 15, the animals are given an electroconvulsive shock. After two to forty-four hours, the persistence of the learned behavior of the animals is examined; and any animal that remains on the podium for 300 seconds without stepping down is considered to have maintained a passive avoidance response. Two groups of control-2Q large animals are used as controls; one group receives a vehicle and an electric seizure shock and the other receives a vehicle and a false electric seizure shock. A test substance is considered to be active at a given dosage level if the mean delay before descent is both statistically longer than the value of the electroconvulsive shock control group (ineffective drug control group) and does not differ statistically from the value of the sham electroconvulsive control group.

A test compound is considered to have mild activity at a given dosage level if the results of a group of drugs differ statistically from the results of both control groups. For comparison, all drugs were tested subcutaneously; however, the best compounds in the series in question have an activity orally that differs slightly from the results obtained when the drug is administered subcutaneously. In this respect, the following compounds are considered to be particularly good: 1- [1- (2-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone, 5 1 - [1- (2-chloro-4-pyrimidinyl) - 4-piperidinyl-methyl-2-2-pyrrolidinone, 1 H-1- (6-chloro-2-pyrazinyl) -4-piperidinyl-methyl-2-pyrrolidinone and especially 1- [1- (2-trifluoromethyl- 4-pyrimidinyl) -4-piperidihyy1i7metyyli / -2-pyrrolidinone.

10 Maintaining comparable levels of efficacy in the transition from subcutaneous to oral administration is a significant dosage advantage and distinguishes the compounds in question from those described in the previous references. In addition, the compounds in question are not labile in acidic media, which is another advantage in their preparation, formulation, delivery and storage as well as in dosing.

In summary, it should be noted that the mild compounds in question have nootropic properties which are particularly suitable for use in improving perception and memory. Thus, one aspect of this invention relates to a method of improving perception and memory in a mammal in need of treatment comprising administering to the body of such a mammal an effective dose of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof. The administration and method of administration of the compounds of formula I are contemplated to be performed in the same way as the reference compound pyrazetamine, cf. Resiberg, et al., 30 Drug Development Research, 2: 475-480 (1982); Weng, et al., Rational Drug Therapy, 17 (5), 1-4 (1983); Reisberg, et al., Psychopathology in the Aged, edited by Cole and Barrett, Raven Press, New York, pp. 243-245 (.1980), and pramiracetam, cf. Butler, et al., J. Med. Chem. 27, pp. 684-691 (1984).

35 In addition to being useful as attention enhancers or mild central nervous system stimulants, the compounds of formula I have been found to be useful in preventing memory loss following electroconvulsive shock. Such an effect is not only related to memory retention in normal aging and old age events, but would be useful in protecting the clinically used electroconvulsive shock from the memory-causing effects. Electroconvulsive shock is used to treat some categories of psychiatric patients, especially depressed patients for whom conventional pharmacological treatment is not effective. It is well proven that these electroconvulsive shock treatments cause memory loss as a nasty side effect in the patients to whom they are administered. The compounds in question, which have been shown in pharmacological experiments to have protective activity against the memory-inducing effects of electroconvulsive shock, would be useful adjuvants in the use of electroconvulsive shock in clinical psychiatric treatment.

Although the dosage and dosage instructions must be carefully adjusted in each case, using sound professional judgment and taking into account the age, weight and condition of the recipient, the route of administration and the nature and degree of mental impairment, the daily dose will generally be about 0.1 to 0.1 g, preferably 0.5-5 g when administered orally.

In some cases, a lower therapeutic effect may be obtained at lower doses, while in others higher doses are required. As will be apparent to those skilled in the art of clinical pharmacology, a daily dose of a compound of formula I may be administered in a single or divided dose, taking into account principles understood by the skilled medical practitioner and necessary in the practice of his or her field.

35 As used herein, the phrase "administration" to the body 16 88300 means oral, sublingual, buccal, nasal, dermal, rectal, intramuscular, intravenous and subcutaneous. In general, it will be appreciated that when the compound of this invention is administered orally, preferably by the route used for 5 minutes, a slightly greater amount of active drug is required to produce the same effect as a somewhat lesser amount when administered parenterally. In accordance with good clinical practice, the compounds in question are administered mi.cluim-10 min in an amount that produces effective nootropic effects without causing harmful or unfavorable side effects.

For therapeutic use, the subject compounds are generally administered as pharmaceutical preparations containing an effective nootropic amount of a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier. Such pharmaceutical preparations for use in therapy contain mainly or in a small amount (e.g. 95-0.5%) of at least one compound of the present invention together with a pharmaceutical carrier comprising one or more solid, semi-solid or liquid diluents, excipients and a non-toxic, inert and pharmaceutically acceptable excipient. Such pharmaceutical preparations are preferably in unit dosage form; i.e., as materially separate units containing a predetermined amount of drug, the amount comprising a portion or multiple of a dose calculated to produce the desired therapeutic effect. Generally, dosage units will contain, in practice, a single dose or 1/2, 1/3 or less thereof. Preferably, a single dose contains an amount sufficient to produce the desired therapeutic effect when administered in a single administration of one or more dosage units according to predetermined dosage regimens, usually a full day dose or half, one third or less of which is administered once, twice, three times or more. times a day. It is intended that other therapeutic agents may also be present in such a preparation. Preferably, pharmaceutical preparations containing 0.1 to 1 g of active ingredient per unit dose are used and are usually prepared as tablets, lozenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs and aqueous solutions. The preferred oral formulations are tablets or capsules and may contain conventional excipients such as binders (e.g. syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (e.g. lactose, sugar, corn starch, sorghum phosphate, cesium phosphate). glycine), lubricants (e.g. magnesium stearate, talc, polyethylene glycol or silica), disintegrants (e.g. starch) and humectants (e.g. sodium lauryl sulphate). Solutions or suspensions of a compound of formula I formed with conventional pharmaceutical vehicles are used as parenteral preparations, for example, by intravenous injection of an aqueous solution or intramuscular injection of an oily suspension. Such preparations, which are desired to be clear, durable and suitable for parenteral administration, are obtained by dissolving about 0.1 to 10% by weight of the active compound in water or a vehicle consisting of an aliphatic alcohol containing more than two hydroxyls such as glycerin, propylene glycol and polyethylene glycols, or mixtures of these 30 den. Polyethylene glycols comprise a mixture of non-volatile, usually liquid, polyethylene glycols that are soluble in both water and organic liquids and have a molecular weight of about 200-1500.

The compounds of this invention, and methods for their preparation, as well as their biological activity, will become more fully apparent upon consideration of the following examples, which are intended to be illustrative only and are not to be construed as limiting the scope or scope of the invention. All temperatures are in degrees C unless otherwise indicated.

Nuclear magnetic resonance (NMR) spectral data refer to chemical shifts (ε) expressed in parts per million (ppm) compared to the tetramethylsilane (TMS) as a vertical element. The relative range indicated for the different transitions 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 transition, in terms of its multiplicity, is indicated by the terms broad singlet (bs), singlet (s), multiplet (m), doublet (d), doublet of 15 doublets (dd), triplet (t), or quartet (q). .

The abbreviations DMSO-dg (perdeuterodimethyl sulfoxide), CDCl-j (deuterochloroform) and other abbreviations are conventional. Infrared (IR) spectral descriptions include only absorption wavenumbers (cm) with a functional group identification value. IR assays were performed using potassium bromide (KBr) as a diluent. Elemental analysis results for all compounds were satisfactory.

Example 1 2 - [[1- (2-Pyrimidinyl) -4-piperidinyl] -methyl] -1H-isoindole-1,3- (2H) -dione This synthetic procedure is exemplified by the more general synthesis shown in Scheme 1, supra .

A. Ethyl 1- (2-pyrimidinyl) piperidine-4-carboxylate (VII)

A mixture of ethyl isonipecotate (IX, 31.44 g, 0.2 mol), 2-chloropyrimidine (VIII, 22.91 g, 0.2 mol) and potassium carbonate (27.69 g, 0.2 mol) in acetonitrile (250 ml) was refluxed for 24 hours. The mixture was filtered and the filtrate was 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.

B. 4-Hydroxymethyl-1- (2-pyrimidinyl) piperidine (VI) A solution of the ester (VII, 20 g, 0.085 mol) in tetrahydrofuran (200 ml) was cooled to 0-5 ° and lithium aluminum hydride ( 3.23 g, 0.085 mol) slowly over 10 minutes. The mixture was stirred at room temperature for 30 minutes. Excess LAH was quenched with acetonil-10a and the mixture was diluted by the addition of 3.2 mL of water followed by 3.2 mL of 15% sodium hydroxide solution and then 9.7 mL of water. The resulting mixture was filtered and the filtrate was concentrated in vacuo to give an oil which was distilled to give 15 g (91%) of a clear oil product, b.p. 140-190 ° 15 at 0.3 torr.

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

A solution of the hydroxymethyl compound (VI, 7.73 g, 0.04 mol) in methylene chloride (40 ml) was cooled to 0-5 ° in 20 ° C and thionyl chloride (25 ml) was added slowly. The solution was stirred for 12 hours at room temperature and then concentrated in vacuo. The residue was dissolved in methylene chloride, extracted with aqueous sodium bicarbonate, and the methylene chloride layer was concentrated in vacuo.

The residue was chromatographed on silica gel using ethyl acetate as eluent to give 7.7 g (91%) of product as an oil.

D. Intermediate V-Phthalimide reaction 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 (V, 2.12 g, 0.01 mol) in dimethylformamide (50 ml) was heated to about 50 ° for 24 hours. The dimethylformamide solvent was removed in vacuo and the residue was dissolved in acetone and filtered. The filtrate was concentrated in vacuo to give 20 8 8 300 crude product which was chromatographed on silica gel using 30% ethyl acetate-hexane as eluent. The product was then recrystallized from ethyl acetate to give 0.95 g (20.5%) of product as white crystals, mp 109-111 °.

Analysis for c 18 H 18 N 4 O 2:

Calculated: C 67.06, H 5.64, N 17.38%

Found: C 66.95, H 5.68, N 17.17% NMR (CDCl 3): 1.35 (2, m), 1.74 (2, m), 2.10 (1.1 m), 2 , 85 (2, m), δ 3.61 (2, d, 7.0 Hz), 4.76 (2, m), 6.40 (1.1, 4.8 Hz), 7.79 ( 4, m), 8.27 (2, d, 4.8 Hz).

XR (KBr): 730, 800, 1360, 1400, 1515, 1540, 1590, 1710, 1750 and 2930 cm-1.

Example 2 1- [Z1- (2-Pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone This experimental procedure is an example of a synthetic method that can be used when X is an alkene chain in a compound of formula I (see Scheme 2, supra). 20 A.] - [Z4-piperidinyl] methyl] -2-pyrrolidone hydrochloride hydrate (II)

A solution of 1- (4-pyridinylmethyl) -2-pyrrolidinone hydrochloride (III, 15.05 g, 0.0707 mol, prepared from 2-pyrrolidinone and 4-pyridinylmethyl chloride-25), HCl (10 mL of an 8N solution in absolute in ethanol) and absolute ethanol (100 mL) was hydrogenated at 60 psi using PtCl 2 (1.0 g) for 72 h. The mixture was filtered and the filtrate was concentrated in vacuo to give a white solid. The crude product was recrystallized 3q from isopropanol to give 13.03 g (83%) of the product as a white powder, mp 212-214 °.

B. Reaction of Intermediate II with 2-chloropyrimidine

A mixture of piperidinylmethylpyrrolidin-35 (II, 5.08 g, 0.0232 mol), 2-chloropyrimidine 21,8300 (2.67 g, 0.0233 mol) and potassium carbonate (7.09 g, 0.0513 mol) moles) in dimethylformamide (60 ml), heated in a 50-100 ° oil bath for 14 hours. The mixture was cooled and filtered. The solvent was then removed in vacuo and the residue was chromatographed on silica gel using ethyl acetate-acetone as eluent to give 4.7 g (78%) of product as white crystals, mp 144-147 °.

Analysis for C 11 H 19 N 2 O 2: 10 Calculated: C 64.59, H 7.74, N 21.52%

Found: C 64.26, H 7.78, N 21.20% NMR (CDCl 3): 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 (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 3 1- [2.1- (2-Chloro-4-pyrimidinyl) -4-piperidinyl] -methyl] -2-pyrrolidinone A mixture of 1 - [(4-piperidinyl) methyl] -2-pyrrolidinone hydrochloride (II, prepared above) in Example 2A, 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 of dimethylformamide were stirred in 14 For 25 hours at room temperature and then heated to 70 ° C for 1 hour. The mixture was filtered and concentrated in vacuo. The crude residue was chromatographed using silica and ethyl acetate / methanol (95: 5) as eluent, dividing the product residue into two components.

16 g (59%) of the main component were obtained as an off-white powder, mp 110-114, and was the desired 2-chloro-4-pyrimidinyl isomer.

Analysis for C 1 H 2 Cl 2 N 2 O:

Calculated: C 57.04, H 6.50, N 19.01% 35 Found: C 56.73, H 6.44, N 18.97% 22 38 300 NMR (CDCl 3): 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, 6.9 Hz), 4.35 (2, m), 4.39 (1, d, 6.0 Hz), 7.98 (1, d, 6.0 Hz).

Δ IR (KBr): 9.65, 1150, 1350, 1360, 1490, 1590, 1685, 2860 and 2950 cm-1.

Example 4 1- [71- (4-Chloro-2-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone IQ The second isomer, the 4-chloro-2-pyrimidinyl compound, was obtained from the reaction product of Example 3 (above). by recrystallization from a smaller amount of the component obtained by recrystallization from ethyl acetate to give 1.1 g (4%) of white crystals, mp 143.5-145.5 °.

Analysis for C 18 H 19 ClN 2 O:

Calculated: C 56.04, H 6.50, N 19.01%

Found: C 56.66, H 6.49, N 19.81% NME (CDCl 3): 0.9-2.1 (5, m), 2.25 (2, t, 5 Hz), 2.75 (2, t, 8 Hz), 3.10 (2, d, 5 Hz), 3.30 (2, t, 5 Hz), 4.5-4.8 (2, d), 2Q 6.45 (1, d, 4 Hz), 8.13 (1.1, 4 Hz).

IR (KBr): 1275, 1350, 1419, 1512, 1525, 1588 and 1688 cm -1. Example 5 1 - [3- (6-chloro-2-pyrazinyl) -4-piperidinyl] methyl] -2 -pyrrolidinone Using the procedure described in Examples 2 and 3 above, a mixture of 1- [4-piperidinyl) methyl] -2-pyrrolidinone hydrochloride (II, 12.5 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), were stirred at room temperature for 14 hours and then the moon was heated to 70 ° for one hour. and the filtrate was concentrated in vacuo The crude product was recrystallized twice from ethyl acetate to give 11.16 g (68%) of tan crystals, mp 139-142 °.

23 38300

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 (CDCl 3): 1.34 (2, m), 1.77 (2, m), 2.05 (3, m), 2 .40 (2, t, δ 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 (l, s), 7.96 (l, s).

IR (KBr): 8.35, 1140, 1275, 1415, 1460, 1490, 1500, 1565, 1685, 2840 and 2945 cm-1.

Example 6 10-1- [1-, 2- (Trifluoromethyl) -4-pyrimidinyl] -4-piperidinyl] methyl] -2-pyrrolidinone Using the procedure described in Examples 2 and 3 above, a mixture of 1-7. (4-Piperidinyl) methyl-2-pyrrolidinone hydrochloride (II, 21.85 g, 0.1 mol) and sodium carbonate (26.5 g, 0.25 mol) in methanol (150 ml) were refluxed for one hour. The methanol was then removed in vacuo and acetonitrile (150 ml) was added to the residue. The mixture was cooled and stirred while 4-chloro-2- (trifluoromethyl) -20 pyrimidine (18.28 g, 0.1 mol) was added. The mixture was stirred at room temperature for 18 hours and then filtered and the filtrate was concentrated in vacuo to give a thick residue which solidified on washing with hexane (100 mL). The resulting pale leather powder 25 (23.8 g, 73%) was chromatographed (using silica and 5% methanol / ethyl acetate as eluent) to give 19.8 g of white crystals, mp 118.5-120.5 °.

Analysis for ci5HigF3N4O:

Calculated: C 54.87, H 5.83, N 17.07% Found: C 54.50, H 5.86, N 16.80%

A number of other compounds of formula I were prepared in a similar manner and are shown in Table 1.

24 8 8 300

table 1

Compounds of formula I v s (I)

Eg R1 X Y Piper- Z Formula (a) Sp (° C) di- Ring.

subscriptions.

______point _ 7 H -C2H4- CH2 j. C14H20N4H102H4H2N4O2H -2-FC15H21FN4OS 96-100 11 C14H20N4O10-1139HCH2H4N4O10-1139H H -C2H4- CH24_C14H19FN4 ° 134-136

Cl 12 H -C2H4- CH2 4. -O C14H18Cl2N4 ° 14 ° -144 13 H -C2H4 "CH2 4- C14H18Cl2N4 ° * Jj4 5 14 H -C2H4-CH2 4_c14H19ClN4 ° ^

Cl

25 S 8 3 O O

Eg R1 X Y Piper- Z Formula (a) Sp (° C) didine-Ring.

_liitt. __

Cl 15 H "C2H4 ~ CH2 4" XCf C15H21ClN4O 133-135

Cl 16 H ~ C2H4 ~ CH2 4_ c15H21 Cl1N4 ° 104-107 <* 3 17 H -C2H4- CH2 4- -O) _Br C14H19BrN40 143-146

OF

18 H -C 2 H 4 -CH 2 4 - (O) ~ C 1 H 14 ClN 4 O 130-133 N-7 19 H -C 2 H 9 -CH 2 4- c 14 H 19 IN 4 ° SMe 20 H -C 2 H 4 -CH 2 4- / (¾ C15K21ClN4OS 134- 137 ^ C1 Cl Cl 21 H -C2H4- CH2 4- C14H18Cl2N4O 135-138 22 H -C2H4- CH2 4- C14H1BrrClN40 105-115

Br OMe 23 H -C 2 H 4 -CH 2 4- C 15 H 22 N 4 O 2 116 * m

CN

24 H -c ^ - CH2 4- -ö 'ui5 · 26 3 8300

Eg R · * · XY Piperidine-Z Formula ^ Sp (° C) ring-linking point 25 H 1,2-C6H4 CH2 4- ^ C18H20B4 ° 176 * 178 _ ^ 2F5 26 H -C2H4-CH2 4- C16H19F5N4 ° 105-107.5 CF3 27 H -C2H4- CH2 4- -01 C15H18ClF3N4O 102-

Cl '28 H -C2H4- CH2 4 - <Q C16o3§FC6 ° ^ 345- CF3 (a) = The results for C, H and N were all within + 0.4% of the calculated value 27 88 300

Example 29 Reversal of ECS-induced memory loss in a passive avoidance avoidance response 5 In passive avoidance avoidance methods, rats are taught to remain immobile to avoid foot shock. Two control groups (n = 36 / group), ECS control and Vale-ECS control, were required. ECS control animals were placed one at a time on a pod above the shock-absorbing grid (0.8 mA) for 30 min. after administration of the vehicle. The animals soon stepped off the podium, immediately experienced foot shock and quickly learned to flee to the podium. An animal was considered to have adopted a passive avoidance reaction if it remained on the podium for 15 2 minutes without stepping down after being given a foot shock. Immediately after this, ECS control animals were administered via ECS transcorneal electrodes at 50 nA for 400 milliseconds. False ECS control animals were treated in the same manner as the ECS controls described as treated, with the difference that no current was conducted through the transcorneal electrodes. Both groups underwent a retention test 24 hours later. Animals were individually placed on the podium and a delay was recorded before descending from the podium to the Akti-25 powerless shock lattice; the experimental animal was considered to have maintained a passive avoidance reaction in each case if it remained on the podium for 300 seconds without stepping down. False ECS control animals remain in the test on a pod showing normal preservation; ECS-kontrol-30 large animals easily stepped down within 300 seconds, indicating deficient retention (i.e., memory loss).

The subsidence delay results were converted to percentage retention results so that 300 seconds 35 corresponded to 100% retention. The 28 8 8 300% retention results for all drug groups were evaluated compared to both the ECS and Vale-ECS control groups using the Dunnett's test. A compound was considered active in this test if the mean retention result obtained in at least one dose group is significantly greater than the retention age of the ECS control group significantly different from that of the Vale-ECS control group. This indicates that the test compound reversed the passive avoidance function of ECS-induced memory loss.

1Q Compounds that statistically elevated animal performance above that of the ECS control group but did not increase performance sufficiently to not be statistically different from the Vale-ECS control group were reported to have "mild activity."

^ 5 These compounds thus statistically improve the performance of the animal, but are not sufficient to completely protect against memory loss. Table 2 shows the biological activities of the selected compounds of formula I in the assay set forth in Example 29.

20

Table 2

Biological activity of selected compounds of formula I in reversing ECS-induced memory loss in relation to the passive avoidance response

Eg Name Undo memory loss caused by ECS

Pramiracetam Active at a dose of 10 mg / kg subcutaneously 30 mg / 1- (2-pyrimidinyl) active at a dose of 10 mg / 4-piperidinylmethyl / kg subcutaneous 1H-isoindole-1,3- ( 2H) -dione 2 1 - [1- (2-pyrimidinyl) - active at a dose of 10 mg) - [4-piperidinyl] methyl] - [(c-piperidinyl)] administered subcutaneously and orally with 2-pyrrolidinone 35 3 1 - //. - (2-chloro-4-pyrimea active at a dose of 0.5 mg t-dinyl) -4-piperidinyl kg subcutaneously and orally n-methyl-2-pyrrole dinone 29 8 8 300

Eg Name Reversal of ECS-induced memory loss 5 1 - [1- (6-chloro-2-pyratactive at a dose of 0.5 mg / -sinyl) -4-piperidinyl] - kg subcutaneously - 2-pyrrolidinone 6 1 - [1- [2- (trifluoro) -4-active at a dose of 0.25-10 pyrimidinyl] -4-piperine mg / kg orally, active N-diphenyl 7'2 "PYr ' at a dose of 0.5-10 mgAg subcutaneously.

7 1 - [1- (2-pyrimidinyl) -3-active at a dose of 25 mg / piperidinyl] methyl] -2- kg subcutaneously pyrrolidinone 8 1 - [1- (2-pyrimidinyl) - active at a dose of 25 mg / -2- piperidinyl / methyl7-kg subcutaneously 2-pyrrolidinone 9 1 - [. 1- (6-chloro-3-pyridactive at a dose of 25 mg / azinyl) -4-piperidi / kg subcutaneously] pyrrolidinone 10 1 - [[1 - [.] - 5-fluoro-4- (mildly active dose-thio) -2-pyrimidinyl 10 and 25 mg / kg subcutaneously 1'-4-piperidinyl / methyl Styl 2-pyrrolidinone 11 1 - [- (5-fluoro-2-pyractive in a dose of 10 mg) midinyl) -4-piperidine kg subcutaneouslyl 7'-methyl-2-pyrrolidone 12 1- 7I- (2,6-dichloro-4-active at a dose of 1.0 mg / • • pyrimidinyl) -4-pipe- kg subcutaneously ridinyl7methyl7-2-pyrrolidinone 13 1- [7I- (4,6-dichloro-2-slightly) active dose pyrimidinyl) -4-piper 10 mg / kg subcutaneously ridinyl / methyl-2-pyrrolidinone 14 1 H - (6-chloro-4-pyril active dosoximinyl) -4-piperidine 10 mg / kg subcutaneouslynyl7-methyl-2-pyrrolidinone 1- [21- (2-chloro-6-mildly active dosoxyl-4-pyrimidinyl) - as 10 mg / kg subcutaneously 4-piperidinyl / methyl] -2-pyrrolidinone 17 1 - [1- (5-bromo-2-pyractive active in doses of 10 & imidinyl) -4-piperidine 25 mg / kg oral nyl / methyl / -2-pyrrolidinone 30 3 8 300

Eg Name Reversal of ECS-induced memory loss 18 1 - [1- (5-chloro-2-pyractive at a dose of 10 mg / midinyl) -4-piperidine / kg oral oral] 17-2-pyrrolidinone 19 1 H-1- (5-iodo-2-pyrimino active in a dose of 25 N, N-dinyl) -4-piperidinyl kg oral 1-methyl-2-pyrrolidinone 22 1 - 1- 1- (5-bromo-2-chloro active at a dose of 0.5-4-pyrimidinyl) -4-pipe- 1.0 mg / kg orally didinyl / methyl / -2-pyrrolidinone 23 1 - // 1- (2-Methoxy-4-pyrilonely active amoximidinyl) -4-piperidine 10 mg / kg orally N-methyl / methyl--2-pyrrolidinone 24 4- / 4 - / (2-oxopyrrolidine) - active at a dose of 25 mg (1-yl) methyl-1-piperegally oral ridinyl / -2-pyrimidinecarbonitrile 25 1 - [. 1- [2- (pentafluoro- slightly active dose ethyl] 4-pyrimidinyl as 10 mg / kg 4-piperidinyl-7-methyl-2-pyrrolidinone 27 1 H-1- [5-chloro-2- (tri-active active fluoromethyl) -4-pyr as 10 mg / kg orally via midinyl--4-piperidinyl 7methyl-2-pyrrolidinone 28 1 - [[1- (2,6-bis (trifluoroactive at a dose of 10 mg) -rimethyl] -4-pyrimide / kg orallyl] -4-piperidinyl] methyl] -2-pyrrolidinone (a) = "active" means compounds that completely reverse the memory loss caused by ECS, while "mildly active" means less than complete protection.

i

Claims (2)

31 s 8 300 A process for the preparation of novel therapeutically useful diazyl-piperidine derivatives of cyclic amides and imides of the formula I and their pharmaceutically acceptable acid addition salts, Wherein X is an ethylene chain or a 1,2-benzo ring, Y is carbonyl or methylene, provided that Y is carbonyl only when X is a 1,2-benzo ring, R 1 is hydrogen or lower alkyl and Z is an R 2, R 3 disubstituted diazinyl ring selected from the group consisting of pyridazine, pyrimidine and pyrazine, wherein R 2 and R 3 are independently hydrogen, lower alkyl, lower al-coke, lower alkylthio, cyano, trifluoromethyl, pentafluoroethyl, or halogen, characterized in that either a compound of formula (A) of the formula O-c ° 2 * H wherein R is a C 1 -C 5 alkyl group is reacted with a compound of formula ZQ where z is as defined above, and Q is a suitable displaceable group. 32 3 3 300 (B) the product obtained in (A) is reacted with a metal reagent of formula R * M 5 where R1 is as defined above and M is a metalloid ion or complex, (C) the product obtained in (B) is reacted reacting with a reagent capable of converting the product of (B) 10 to a hydroxy group substituent Q, and (D) reacting the product of (C) with a cyclic amide / imide of formula 15 wherein X and Y are as defined above, to give a compound of formula I, or alternatively, for the preparation of a compound of formula I wherein X is ethylene and Y is methylene and R 1, R 2, R 3 and Z are as defined above, (A ') cyclic amide / imide of formula 25 NH (IV) 30 wherein X is ethylene and Y is methylene is reacted with a compound of formula 35 i 33 3 β <n ρ Q-CH— (x) 5 wherein R1 and Q has the same meaning as above, (B ') the product obtained in (A') p catalytically eluted, and (C) the product obtained in (B ') is coupled to a compound of formula Z-Q wherein Z and Q are as defined above. Process according to Claim 1, characterized in that Q is a displaceable group which is chloride, bromide, iodide, sulphate, phosphate, tosylate or mesylate. 34 8 8 300