DK170441B1 - Diazinylpiperidine derivatives of cyclic amides and imides, and process for their preparation - Google Patents

Description

in DK 170441 B1

The present invention relates to novel diazinylpiperidine derivatives of cyclic amides and imides wherein a cyclic amide or imidation via a methylene bridge is attached to one of the carbon ring positions of the piperidine ring and a diazinyl ring system is attached to the piperidine nitro atom, as well as a process for making them. The compounds of the invention are useful for treating various dementia senile ice conditions affecting the elderly.

The clinical aspects of various dementia senile conditions as well as the problems they cause to the affected geriatric patient are well known to those skilled in the art. It is also known that various drug treatments for this disorder in the elderly are constantly being investigated. Among such drugs are a class known as nootropic or more commonly recognized enhancement agents, some of which are continually undergoing clinical evaluation using patients diagnosed with Alzheimer's disease, a severe and fairly common CNS disorder in the elderly. These drugs, which are under clinical study, chemically belong to a class N-substituted-2-pyrrolidinone derivatives of structural formula 1 & 1a: X = H; R = -CH2 CONH2 (piracetam) b: X = OH; R = -CH 2 CONH 2 (oxiracetam) C: X = H; R = -CH2CONH [CH212N [CH (CHg) 2) 2 (pramiracetam) ά: X = H; R = -CO - ^^ hOCH3 (aniracetam) Testing and properties of compounds of structural formula 1 are representatively described by Butler, et al., J.Med.Chem., 27, pp. 684-691 (1984). Preliminary clinical results with such agents exemplified by structural formula la-d suggest that these agents may have some beneficial effects in the treatment of dementia senile conditions 35 in the elderly.

The related technique can be seen in the light of the following general structural formula 2 wherein NA is C 24 alkyl or one 1,2-benzo ring, Y is carbonyl or 5 methyl one, A is a compound such as alkyl, alkanoyl, alkylene amidoal, and the like, W is nitrogen or CH, and B is an aryl or pyrimidyl ring system. The most closely related compounds are described in DK Patent Application No. 3334/85. The compounds disclosed in DK Patent Application No. 3334/85 are compounds of the above formula 2 wherein W 10 is nitrogen. It is stated that these known compounds generally possess nootropic activity and that certain selected compounds counteract ECS-induced activity. The most closely related compounds disclosed in DK patent application no. 3334/85 can be indicated by structural formula

Cj; LO ^ D s

H

Wherein R is hydrogen or lower alkyl and R may also be hydrogen or lower alkyl. As can be seen, these related compounds differ structurally from the compounds of the present invention in that the related compounds are piperazine derivatives (W = N in formula 2), while the compounds of the invention are piperidine derivatives 25 (W = CH in formula 2).

A comparison of the activity of the closest known compounds shows that even minor structural changes, including e.g. substitution with a single methyl group at the 5-position of the pyrrolidone group affects the activity profile of these compounds, so it is not possible, on the basis of knowledge of these known compounds, to assume that the structurally more diverse compounds of the invention exhibit an activity. , which counteracts ECS-induced amnesia.

Others of formula 3 related compounds are described in 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 variety of compounds of which a subclass designated by structural formula 4 is known to exhibit analgesic properties as well as weak anti-inflammatory action s 1 t where X is hydrogen or chlorine.

A large number of psychotropic compounds having structures similar to Formula 2 wherein Y is carbonyl, U is nitrogen, and A is Cg_4 alkylene, 10 are described by Wu, Temple, New and their associates, and others. These compounds contain cyclic imide rings, e.g. succinimides, glutarimides, phthalimides, etc. The shortest compound group indicated by A in these compounds is ethylene, since compounds where A is methylene are too unstable for practical use in acidic media. A more detailed description of these compounds is found in Wu, et al., U.S. Patent No. 3,717,634, Temple, U.S. Patent No. 4,423,009, and New and Yevich, U.S. Patent No. 4,524,206.

Structurally distant related compounds are disclosed in the specification of the above-mentioned U.S. patent application. Thus, the diazinylpiperidine compounds of the invention are structurally novel recognition enhancers, and the prior art does not prejudice or make the specific compounds of the invention. The invention relates to a number of compounds of structural formula (I) wherein X is either an ethylene chain or a 1,2-benzene ring, Y is carbonyl 1 2 3 30 or methylene, R is hydrogen, and Z is an R, R -disubstituted diazinyl ring selected from pyridazine, pyrimidine and pyrazine ring systems. R and R are independently selected from hydrogen, lower alkyl, lower alkoxy, lower alkylthio, cyano, trifluoromethyl and halogen. Compounds of this kind can be incorporated into pharmaceutical compositions intended for use by geriatric persons suffering from dementia a senilis. A representative number of these compounds have been tested and shown to prevent ECS-induced amnesia in rats.

The present invention generally relates to 1- (4-diazinyl) piperidinyl derivatives of cyclic N-methylenamides or imides having psycho-geriatric properties and characterized by structural formula (I). & o 5 r ^ i x n-ck, -

V_y / 2 I

In formula (I), X is a C 1 (ethyl one) alkyl chain or a 1,2-benzo ring linking Y and the carbonyl group such that Y reaches e.g. is also carbonyl, a phthalimide group is formed. Y is a carbonyl group (but only 23 when X is a 1,2-benzo ring) or CH 2. In formula (I), Z is an R, R -di-substituted diazinyl ring selected from pyridazine, pyrimidine and pyrazine ring systems, wherein R and R are independently selected from hydrogen, lower alkyl, lower perfluorocarbon (such as trifluoromethyl or pentafluoroethyl), lower alkoxy, lower alkylthio, cyano and halogen. By lower alkyl is meant that these groups contain from 1 to 4 carbon atoms.

Halogen means F, Cl, Br or I. In preferred compounds, X is ethyl one, Y is methyl one, and R and R are selected from hydrogen, trifluoromethyl and halogen with chloride as the most preferred halogen.

Obviously, the present invention encompasses the various stereoisomers, e.g. optical isomers including individual enantiomers, mixtures of enantiomers, diastereomers, and mixtures of diastereomers which may occur as a result of structural asymmetry due to the presence of one or two asymmetric carbon atoms present in some of the compounds of the present invention. Separation of the individual isomers is carried out using various methods well known to those skilled in the art. For medical use, in some 30 cases, the pharmaceutically acceptable acid addition salts, salts in which the anion does not significantly contribute to toxicity or pharmacological activity of the organic cation are preferred. The acid addition salts are obtained either by reacting an organic base of structural formula (I) with an organic or inorganic acid, preferably by contact in solution, or by one of the standard methods described in the art available to the skilled artisan. Examples of useful organic acids are carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, pamoic acid, cyclohexylaminosulfuric acid, pivalic acid and the like, useful inorganic acids such as H sulfuric acids, phosphoric acids and the like. Furthermore, the present invention also encompasses all compounds of formula (I) in solvate form, such as hydrate form.

Conveniently, the compounds of the invention can be prepared by the general procedure shown in Scheme 1.

6 DK 170441 B1

Scheme 1

General Procedure «CO2C2H5 + Z-Cl * - CO2C2H5 - * H t i

Z Z

IX VIII

VII X

LAU

HM

* i

C1 PH OH

fV csoci2_ fJ

K? V 1 * 7 a 'z * z ^ z V VI VI ··· ri W * ·

IV

In Scheme 1, symbols X, Y and Z have the meaning given above. In principle, a piperidine carboxylate ester (IX) is coupled with a suitable diazine halide (VIII). Although an ethyl ester group and a chloride atom are shown in compounds (IX) and (VIII) of Scheme 1, other 5 equivalent groups and atoms, e.g. another alkyl carboxyl ester and / or other halogen atom is used. Those skilled in the art of synthesis of organic compounds are familiar with these changes. 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, thereby forming the product (VII). The product (VII) can either be reduced with lithium aluminum hydride in a suitable solvent such as tetrahydrofuran to form the reaction intermediate VI, or (VII) can alternatively be converted to the aldehyde X using standard methods to convert ester groups to aldehyde groups, after which treatment with an 15 (where M represents an appropriate metal cation) or a Grignard complex yields the intermediate (VI '). The primary alcohol flour limb product (VI) or the secondary alcohol (VI7) is treated with thionyl chloride to form the corresponding chlorine compound (V) which is then coupled with a selected cyclic amide or imide (IV) to form the desired product. formula (I). This coupling reaction proceeds in the same manner as the reaction between (IX) and (VIII), with a preferred reaction solvent in this case being dimethyl formamide and using as a base, for example, potassium carbonate. It will be known to those skilled in the art that the hydroxy group of the (VI) intermediates can otherwise be effectively converted to other leaving groups (e.g., a tosyl at or mesylate group) to facilitate all the cooling of the nitrogen atom in the cyclic amide / imidforbindelse.

Another method for producing products of formula (I) is described in Scheme 2.

30 8 DK 170441 B1

Scheme 2

Synthetic process when X is an ethylene chain ri ^ ri

* "" rØ - iJKO

iv x ® h2 L · r ^) Z'C1

\ / N "CH2 I N-Z, VIII $ ^ '^ 2 I

^ 4 ~ vYy

H

1 II

a 9 DK 170441 B1 In Scheme 2, X, Y and Z have the meaning given above. Although the process outlined in Scheme 2 generally produces products of formula (I) in higher yields than the general procedure of Scheme 1, it does not have the general utility as the method of Scheme 1. Due to the catalytic reduction (conversion of ( III) to (II), only cyclic amides / imides which are insensitive to catalytic reduction can be used. When, for example, X is a 1,2-benzoring, for example (IV) is phthalimide, the benzoring moiety is reduced accordingly. to a 1,2-cyclohexyl derivative to form a hexahydro-phthalimide ring system.

To summarize the foregoing, there is disclosed a process for preparing a compound of formula (I) o 'ΐΛν1 * wherein X, Y and Z have the meaning given above. This method involves (a) (1) coupling compounds (IX) and (VIII) 20 - co2r z-q ·

H

'VIII

IX

wherein R is a C 1-6 alkyl group and Q is an appropriate displacement group such as chloride, bromide, iodide, sulfate, phosphate, tosylate, mesylate or the like to form an intermediate of formula (VII)

-H— CO2R

VI1 (2) treats the intermediate (VII) with the metal reagent HM, where M is a suitable metalloid ion or complex, e.g. lithium aluminum hydride or Grignard reagent complex, to form the reaction intermediate of the formula (VI) -ch 2

WE

(3) treating the intermediate (VI) with a suitable reagent to convert the OH group of (VI) to a leaving group Q1 of the compound of formula (V), 10 - CH and (4) reacting the intermediate (V) with a cyclic amide / imide compound of formula (IV) 20 ri t nh w

IV

wherein X and Y are as defined above to form a product of formula (I) or (b) (1) reacting a cyclic amide / imide compound of formula (IV)>. r <X NH (IV) where X and Y have the meaning given above, except that X cannot be a 1,2-benzo ring, with a pyrimidine intermediate of formula (X) wherein Q has the meaning given for Q to form the intermediate of formula (III) 0 * 0, in (2) catalytically reduces the compound of formula (III) to form the piperidine intermediate compound of formula (II)

H

and (15) linking the compound of formula (II) with the compound Z-Q, 3 wherein Q is as defined for Q, to form a product of formula (I).

The compounds of the present invention have been investigated for nootropic activity, using as primary screening the elimination of electroconvulsive shock-induced amnesia in connection with a passive avoidance reaction, (see: Banfis, et al., J. Pharmacol.Meth., 8 , 255 (1982); Janvik, Ann. Rev. Psychol., 23, 457 (1972) and McGaugh and Petrinovich, Int. Neurobiology, 8, 139 (1965)). Reference compounds such as pramiracetam, piracetam, aniracetam, etc., which possess activity in this study method are said to affect memory processes and may be useful in the treatment of senile dementia and Alzheimer's disease.

In this test, drugs are administered to 12 animals who were trained to remain motionless 30 minutes later to avoid foot shock. Immediately after training, the animals are subjected to electroconvulsive shock. Twenty-four hours later, the animals are tested for preservation of the learned behavior, and all animals that remain on the platform for 300 seconds without stepping down are considered to have retained the passive avoidance response. Two groups of control animals are used for comparison, one group receiving vehicle with electroconvulsive shock and the other vehicle with simulated electroconvulsive shock. A test compound is considered to be active at a given dosage level if the average time before the animals step down is both statistically longer than the control group applied electroconvulsive shock (placebo control group) and is not statistically different from the time of 12 DK 170441 B1. the control group applied simulated electroconvulsive shock.

A test compound is considered to have intermediate activity at a given dosage level if the results for the drug group are statistically different from both control groups. For the sake of comparison, all drugs were tested after subcutaneous administration, however, preferred compounds of the invention exhibit an activity after oral administration which is only slightly different from the results after subcutaneous administration of the drug. In this regard, the following compounds are particularly preferred: 10 - [[1- (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-trifluoromethyl-4) -pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone. Maintaining comparable strength levels by going from subcutaneous to oral administration is a significant dosing advantage and separates the compounds of the invention from those known in the art. In addition, the compounds of the invention are not unstable in acidic media, which is yet another advantage in their preparation, formulation, shipping and storage as well as in dosing.

In summary, the compounds of the invention have nootropic properties which make them particularly suitable for use in recognition and memory enhancement. Thus, the compounds of the invention can be used in a method of increasing recognition and memory in mammals in need of such treatment, comprising a systemic administration to a mammal of an effective dose of the compound of formula (I) or a pharmaceutical acceptable acid addition salt thereof. It is to be expected that administration and dosing control of the compounds of formula (I) are carried out in the same way as for the reference compound piracetam, see: Reisberg, et al. in Drug Development Research, 2: 475-480 (1982), Weng, et al., in Rational Drug Therapy, 17 (5), 1-4 (1983), Reisberg, et al. in "Psychopathology in the Aged", ed. Cole and Barrett, Raven Press, New York, pp. 243-245 (1980) and pramiracetam, see. Butler, et al, J. Med. Chem., 27, pp. 684-691 (1984). In addition to the compounds of formula (I) useful as recognition enhancers or mild central nervous system stimulants, the compounds have been found to be useful in preventing amnesia caused by electroconvulsive shock. Such activity not only relates to memory retention in normal aging and senility processes, but is valuable in protecting against the amnesia-inducing effects of electroconvulsive shock when used clinically. Electroconvulsive shock is used to treat some psychiatric patients, especially depressed 5 patients, who are unaffected by traditional pharmacological therapy. It is well documented that these electroconvulsive shock treatments cause undesirable amnesia effects in patients undergoing such treatments. The compounds of the invention exhibit activity by protecting against amnesia-generated effects of electroconvulsive shock 10 during pharmacological testing and will be a useful adjunct to the clinical use of electroconvulsive shock in psychiatric treatment.

Although in each case the dosage and dosage schedule must be carefully adjusted, using professional judgment and taking into account the age, weight and condition of the recipient, the route of administration and the nature and extent of mental impairment, the daily dose generally ranges from about 10% to about 10%. 0.1 g and approx. 10 g, preferably 0.5 g and 5 g when administered orally. In some cases, a therapeutic effect may be achieved at lower doses, while larger doses may be required in others. As will be apparent to one of ordinary skill in the art of clinical pharmacology, the amount of compound of formula (I) comprising the daily dose may be administered in a single or divided dosage, taking into account what the practitioner deems necessary.

The term "systemic administration" refers to oral, subliminal, buccal, nasal, dermal, rectal, intramuscular, intravenous and subcutaneous routes. Generally, it is found that when a compound of the invention is administered orally, which is the preferred route, a slightly larger amount of the active drug is required to produce the same effect as a somewhat smaller amount given parenterally. In accordance with good clinical practice, it is preferred to administer the present compounds at a concentration level which will produce effective nootropic action, without causing deleterious or adverse effects.

Therapeutically, the present compounds are generally given as pharmaceutical compositions containing an effective nootropic amount of the compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier. Pharmaceutical compositions for carrying out such treatments contain a greater or lesser amount (e.g., from 95% to 0.5%) of at least one compound of the present invention in association with a pharmaceutical carrier, wherein the carrier comprises a or more solid, semi-solid or liquid diluents, fillers or formulation auxiliaries which are nontoxic, inert and pharmaceutically acceptable. Such pharmaceutical compositions are preferably in unit dosage form, i.e. physical discrete units having a predetermined amount of drug corresponding to a fraction or multiple of the dose intended to produce the desired therapeutic response. According to conventional practice, the dosage units contain 1, 1/2, 1/3 or less of a single dose. Preferably, a single dose contains a sufficient amount to produce the desired therapeutic effect after once administered by one. or more dosage units according to the predetermined dosage schedule, usually all, one half, one third or less of the daily dose administered one, two, three or more times a day. It is envisaged that other therapeutic agents may also be present in such a preparation. Pharmaceutical compositions which provide from 0.1 to 1 g of the active ingredient per day. unit dosage is preferred and 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 or capsules and may contain conventional excipients such as binders (e.g., syrup, acacia, gelatin, sorbitol, tragacanth or polyvinyl pyrrolidone), fillers (e.g., lactose, sugar, corn starch, calcium phosphate). , sorbitol or glycine), lubricants (e.g., magnesium stearate, talc, polyethylene glycol or silicon), disintegrants (e.g., starch), and wetting agents (e.g., sodium lauryl sulfate). Solutions or suspensions of a compound of formula (I) with conventional pharmaceutical vehicles are used for parenteral preparations, such as an aqueous solution for intravenous injection or an oily suspension for intramuscular injection. Such preparations having the desired clarity, stability and suitability for parenteral use are obtained by dissolving from ca. 0.1-10% by weight of the active compound in water or a vehicle consisting of polyhydride aliphatic alcohol such as glycerine, propylene glycol, * 35 and polyethylene glycols or mixtures thereof. Polyethylene glycols consist of a mixture of non-volatile, usually liquid polyethylene glycols, which are soluble in both water and organic liquids, and having molecular weights of approx. 200-1500.

DK 170441 B1

The compounds of the invention and the process for their preparation, as well as the biological activity of the compounds, will be described in more detail in the following Examples which are intended to illustrate only and not to limit the scope of the invention. All 5 temperatures are given in degrees Celcius, unless otherwise stated. The spectral characteristics of nuclear magnetic resonance (NMR) are attributed to chemical shifts (6) expressed as parts per minute. million (ppm) to tetra-methylsilane (TMS) as the reference standard. The relative areas indicated for different shifts in proton (PMR) spectral data correspond to the number of hydrogen atoms of a particular functional type in the molecule. The nature of multiplicity shifts is listed as broad singlet (bs), singlet (s), multiplet (m), doublet (d), doublet of doublet (dd), triplet (t) or quartet (q). Abbreviations used are DMSO-dg (per-deuterodimethylsulfoxide), CDC13 (deuterochloroform) and are otherwise conventional. The infrared (IR) spectral descriptions include only absorption wave numbers (cm-1) with functional group identification value. Potassium bromide (KBr) was used as the diluent for the IR assays. All compounds provided satisfactory elemental analysis.

Example 1 2-[(2-pyrimidinyl) -1,4-Diperidinylmethyl] -1H-isoindole-1,3-f2H) dione This synthesis series is an example of the more general synthesis described in Scheme 1 above.

A. Ethyl 1- (2-pyrimidinylpiperidine-4-carboxylate (VIII)

A mixture of ethyl isoneepecotate (IX), 31.44 g, 0.2 mole), 2-chloropyrimidine (VIII; 22.91 g, 0.2 mole) and potassium carbonate (27.69 g, 0.2 mole) in acetonitrile (250 ml) was refluxed for 24 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was distilled 30 (130-170 ° at 0.32 Torr) to give 44.1 g (94%) of the product as a clear oil.

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

A solution of the ester (VII, 20 g, 0.085 mol) in tetrahydrofuran (200 ml) was cooled to 0-5 ° and 1 in thi umalumi ni umhydri d (3.23 g, 0.085 mol) was slowly added over 10 minutes. . The mixture was stirred at room temperature for 30 minutes. The excess LAH was destroyed with acetone and the mixture was diluted by adding 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 ° at 0.3 torr.

5

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

A solution of hydroxymethyl compound (VI; 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 for 12 hours at ambient temperature and then concentrated in vacuo. The residue was dissolved in methylene chloride, extracted with aqueous sodium bicarbonate and the methylene chloride was concentrated in vacuo. The residue was chromatographed on a sieve in a cage! using ethyl acetate as eluant to give 7.7 g (91%) of the product as oil.

D. Reaction of intermediate (V) and phthalimide

A mixture of potassium carbonate (2.76 g, 0.02 mole) of phthalimide (1.47 g, 0.01 mole) and 4-chloromethyl-1- (2-pyrimidinyl) piperidine (V, 2.12 g, O (1 ml) in dimethyl formamide (50 ml) was heated to ca. 50 ° for 24 20 hours. Dimethylformamide solvent was removed in vacuo and the residue was dissolved in acetone and filtered. The filtrate was concentrated in vacuo to give the crude product which was chromatographed on silica gel using 30% ethyl acetate-hexane as eluant. The product was then recrystallized from ethyl acetate to give 0.95 g (20.5%) of white crystals, m.p. 109-111 °.

Analysis for c18 H18 N4 ° 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 (1, m); 2.85 (2, m); 3.61 (2, d, 7.0 Hz); 4.76 (2, m); 6.40 (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 -1.

c Example 2 1- [Rri-[2-Pyrimidinyl] -4-Diperidinyl] methylmethyl] -2-Pyrrolidinone

This synthesis series exemplifies the synthesis process that can be used when X in the compound of formula (I) is an alkylene chain (see Scheme 17 DK 170441 B1, supra).

A. 1-Γ (4-piperidinylmethylene-2-pyrrolidinone hydrochloride hydrate (II)

A solution of 1- (4-pyridinylmethyl) -2-pyrrolidinone hydrochloride 5 (III, 15.05 g, 0.0707 mol, prepared from 2-pyrrolidinone and 4-pyridinylmethyl chloride), HCl (10 ml of an 8N solution in absolute ethanol) and absolute ethanol (100 mL) were hydrogenated at 414 kPa with PtO 2 (1.0 g) for 72 hours. The mixture was filtered and the filtrate reduced in vacuo to give a white solid. The crude product was recrystallized from 10 isopropanol to give 13.03 g (83%) of product as a white powder, m.p. 212-214 °.

B. Reaction of Intermediate Compound II with 2-chloropyrimidine

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

Analysis for C14HH₂NN40O:

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 (2h, 6.8 Hz); 4.73 (2, m); .

6.40 (1, t, 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-Rhin-12-chloro-4-pyrimidinyl 1-4-piperidinylmethyl-2-pyrrolidone A mixture of 1- ((4-piperidinyl) methyl] -2-pyrrolidinone hydrochloride (II) , prepared in Example 2A, 20.1 g (0.0922 mole) of 2,4-dichloropyrimidine (14.90 g, 0.1 mole), sodium carbonate (26.5 g, 0.25 mole) and 200 ml of dimethyl formamide was stirred for 14 hours at room temperature and then heated to 70 ° for 1 hour. · The mixture was filtered and concentrated in vacuo.

The crude residue was chromatographed on silica gel using ethyl acetate / methanol (95: 5) as the eluent, separating the residue product into two components. As the main component, 16 g (59%) of off-white powder, m.p. 110-114 ° which was the desired 2-chloro-4-pyrimidinyl isomer.

Analysis for C ^H ^ gClNClO:

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 (1, d, 6.0 Hz); 7.98 (1, d, 6.0 Hz).

IR (KBr): 965, 1150, 1350, 1360, 1490, 1590, 1585, 2860 and 2950 cm -1.

Example 4 1- [1- [4-Chloro-2-Pyrimidinyl] -4-piperidinyl] methyl] -2-pyrrolidinone

The second isomer, the 4-chloro-2-pyrimidinyl compound, was obtained from the minor component obtained by chromatography and recrystallization from ethyl acetate of the reaction product of Example 3 (above) to give 1.1 g (4). %) white crystals, m.p. 143.5 to 145.5 °.

Analysis for C

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 (2, t, 8Hz); 3.10 (2, d, 5Hz); 3.30 (2, t, 5 Hz); 4.5-4.8 (2, d); 6.45 (1, d, 4Hz); 8.13 (1, d, 4 Hz).

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

25

Example 5 1- [1- (6-Chloro-2-dyrazinyl) -4-piperidinyl] methylmethyl] -2-pyrrolidine

Using the procedure described above in Examples 2 and 3, a mixture of 1 - [(4-piperidinyl) methyl] -2-pyrrolidinodone hydrochloride (II, 12.5 g, 0.0556 mol) was stirred. , 6-dichloropyrazine (8.37 g, 0.0556 mol), potassium carbonate (19.2 g, 0.139 mol) and DMF (150 ml) at room temperature for 14 hours and then heated to 70 ° for 1 hour.

The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was recrystallized twice from ethyl acetate to give 11.16 g · 35 (68%) of brown crystals, mp 139-142 °.

Analysis for C- HjH₂ClN₂O:

Calculated: C, 57.04; H, 6.50; N, 19.01.

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

19 NMR (CDCl 3): 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 (1, s) 7.96 (1, s).

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

Example 6 1- [1- (2-Trifluoromethyl) -4-pyrimidinyl] -4-pyridinylmethyl] -2-pyrrolidinone 10 Using the procedure described above in Examples 2 and 3, a mixture of 1 - [(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). 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) pyrimidine (18.28 g, 0.1 mole) was added. 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 (100 ml). The light brown powder (23.8 g, 73%) thus obtained was chromatographed (5% methanol / ethyl acetate on silica gel) to give 19.8 g as white crystals, m.p. 118.5 to 120,

Analysis for C ^ ig ^ ^N ^O:

Calculated: 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 (I) prepared in Table 1 were prepared.

Table 1

Compounds of Formula (I)

Piperidine ring- 10 Ex. X Y bond Z Formula 3 m.p. (0) 7 -C2H4- CH2 3- - <y> CuH20N40 105.5- '107.5

15 N

8 -C2H4- CH2 2- - <Q> C14H20N40 110-113 N-k9 -C2H4- CH2 4- "O" 01 C14H19C1N4 ° 138 "20 139.5 10 -C2H4- CH2 4- - / Qk C15H21FN40S 96 -100 25 11 -C2H4- CH2 4- C14H19FN40 134-136

Cl 12 -C2H4- CH2 4- C14H18C12N4 ° 140-144

Cl 30 Cl 13 -C2H4- CH2 4- C14H18C12N4 ° 111- N ti 114.5 14 -C2H4- CH2 4- “O’ C14HigClN40 141- 142.5

Cl 15 -C2H4- CH2 4- C15H21C1N40 133-135 Ή, DK 170441 B1

Table 1 (continued)

Compounds of Formula (I) 21

Piperidine Ring- 5 Ex. X Y bond Z Formula 3 m.p. (°)

Cl 16 -C2H4- CH2 4- c15H21C1N4 ° 104-107 ch3 10 17 -C2H4- CH2 4- _ ^ _ Br C14HigBrN40 143-146

N

18 -C2H4- CH2 4- -h (Q) -c1. ci4Hi9C1N4 ° 130-133

15 N

19 -C2H4- CH2 4- ~ Q ^ ~ 1 C14H19IN4 ° 129'5- "131.5 ^ SMe 20 -C2H4- CH2 4- O C15H21C1N40 $ 134-137 21 -C2H4- CH2 4- C14H18C12N4 ° 135'138 25 nJ 1 1.2 -C2H4- CH2 4- C14H18BrClN40 105-115 ·

Br OMe 23 -C2H4- CH2 4- CJ5H22N402 116-121 30

CN

24 -C2H4- CH2 4- C15H19N5 ° 139> 5- 0.2 H30 142 35 1,2-C6H4 CH2 4- C18H20N4 ° 176-178 DK 170441 B1

Table 1 (continued)

Compounds of Formula (I) n

For example, 5 Ex. X Y bond Z Formula3 Snip. (°) J2Y s 26 -C2H4- CH2 4- C] 6H19F5N40 105- 107.5 10 Kf3 27 -C2H4- CH2 4- JH, C15H18C1F3N40 102- 104.5 “JF3 28 -C2H4- CH2 4- JH C16HI8F6N40 132.5-15 ' Ml 0.075 FLO 134 C? 3 2 20 a, C, H and N analyzes were all within + 0.4% of the calculated value.

• v 23 DK 170441 B1

Example 29

Counteracting ECS-induced amnesia in the context of a passive avoidance reaction

In the passive avoidance reaction, rats were trained to remain calm to avoid foot shock. Two control groups (n = 36 / group) were used as ECS control group and simulated ECS control group. The animals in the ECS control group were individually placed on a platform over an activated shock grid (0.8 mA) for 30 minutes after vehicle administration.

The animals, which quickly stepped down from the platform, immediately emerged from the foot-10 chock and quickly learned to escape to the platform. An animal was considered to have acquired the passive avoidance response if it remained on the platform after foot shock delivery for two minutes without stepping down. Immediately after the training, the ECS control animals were exposed to ECS via transcorneal electrodes using an intensity of 50 nA for 15 400 msec. The simulated ECS control group animals were treated in the same way as the ECS control group animals, except that the current did not pass through the transcorneal electrodes. Both groups underwent a memory test 24 hours later. The animals were individually placed on the platform, and the time before stepping off the platform to the unactivated shock grating was recorded, with a given animal considered to have maintained the passive avoidance response if it remained on the platform for 300 seconds without stepping down. The simulated ECS control animals remained on the platform during this test and showed normal memory, whereas the ECS control animals rapidly descended within 300 seconds and thus exhibited a memory failure (i.e., amnesia).

The time period before the animals stepped down was converted to percentage memory points by 300 seconds corresponding to 100% memory. Percentage memory points for all drug groups were evaluated against both the ECS and simulated ECS control groups using Dunnett's 30 tests. A compound was considered to be active in this test if the mean memory score obtained from at least one dose group is both significantly greater than ECS control group memory and does not differ significantly from simulated ECS control group memory.

This indicates that the test compound counteracts ECS-induced amnesia associated with the passive avoidance reaction. The compounds that statistically raise the animal's performance over the ECS control group performance but do not raise the performance sufficiently that it does not differ statistically from the simulated ECS control group were designated as possessing "intermediate activity". Thus, these compounds statistically raise the performance of the animal, but not sufficiently to provide total protection against amnesia.

The biological activity of selected compounds of formula (I) 5 in the test set forth in Example 29 is shown in Table 2.

Table 2

Biological Activity of Selected Formal File Compounds in Tests to Counteract ECS-Induced 5 Amnesia After Learning Passive Avoidance Response 25 DK 170441 B1

Counteracting ECS

Ex. Designation induced amnesia 10 pramiracetam active3 at 10 mg / kg s.c.

(reference compound) 1 2 - [[1- (2-pyrimidinyl) -4-piperidinyl] - active at 10 mg / kg s.c. methyl] -1H-indole-1,3- (2H) -dione 15 2- [1- [1- (2-pyrimidinyl) -4-piperidinyl] - active at 10 mg / kg s.c.

methyl] -2-pyrrolidinone and p.o.

3 L - [[1- (2-Chloro-4-pyrimidinyl) -4- active at 0.5 mg / kg 2 s.c.

20 piperidinylmethyl-2-pyrrolidinone and p.o.

1- [E1- (6-chloro-2-pyrazinyl) -4- active at 0.5 mg / kg s.c.

piperidinyl] methyl-2-pyrrolidinone 6 1- [[1- (2- (trifluoro) -4-pyrimidinyl]) - 4- active at 0.25 to 10 mg / kg piperidinyl] methyl] -2-pyrrolidinone po, active at 0.5 to 10 mg / kg sc

7 1-E [1- (2-pyrimidinyl) -3-piperidine at 25 mg / kg s.c.

30 dinyl] methyl] -2-pyrrolidinone 8-1 - [[1- (2-pyrimidinyl) -2-piperidine at 25 mg / kg s.c.

diyl] methyl] -2-pyrrolidinone 9 1- [[1- (6-chloro-3-pyridazinyl) -4- active at 25 mg / kg s.c.

piperidinylmethyl] -2-pyrroli di non 40

Biological activity of selected compounds of formula (Ϊ) in tests to counteract ECS-induced 5 amnesia after learning of passive avoidance reaction 26 DK 170441 B1

Table 2 (continued)

Counteracting ECS

Ex. Designation induced amnesia 10 10 l - [[1- (5-Fluoro-4- (methyl thi o) -2- intermediate activity pyrimidinyl] -4-piperidinyl] methyl] - at 10 and 25 mg / kg s.c.

2-Pyrrolidinone 11-1 - [[1- (5-Fluoro-2-pyrimidinyl) -4- active at 10 mg / kg s.c.

15 piperidinyl] methyl] -2-pyrrolidinone 12 1- [[1- (2,6-dichloro-4-pyrimidinyl) - active at 1.0 mg / kg s.c.

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

14 1- [[1- (6-Chloro-4-pyrimidinyl) - intermediate activity 4-piperidinyl] methyl] -2-pyrrolidinone at 10 mg / kg s.c.

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

17 1- [[1- (5-Bromo-2-pyrimidinyl) -4- active at 10 and 25 mg / kg piperidinyl] methyl-2-pyrrolidinone p.o.

18 l - [[1- (5-Chloro-2-pyrimidinyl) -4- active at 10 mg / kg p.o.

piperidinylmethyl-2-pyrrolidinone 19 19 - [[1- (5-iodo-2-pyrimidinyl) -4- active at 25 mg / kg p.o.

piperidinylmethyl] -2-pyrrolidinone 10 mg / kg s.c.

40

Biological activity of selected compounds of formula m in tests to counteract ECS-induced 5 amnesia after learning of passive avoidance reaction 27 DK 170441 B1

Table 2 (continued)

Counteracting ECS

Ex. Designation induced amnesia 10 22 l - [[1-5-bromo-2-chloro-4-pyrimidinyl) - active at 0.5 mg / kg p.o.

4-piperidinyl] methyl] -2-pyrrolidine 23 - [[1- (2-methoxy-4-pyrimidinyl) -4- intermediate activity of piperidinyl] methyl] -2-pyrrolidinone at 10 mg / kg p.o.

15.

24 4- [4 - [(2-oxopyrrolidin-1-yl) - active at 25 mg / kg p.o.

methyl] -1-piperidinyl] -2-pyrimidinecarbonitrile 26 1 - [[1-E2- (pentafluoroethyl) -4- intermediate activity pyrimidinyl] -4-piperidinyl] methyl] - at 10 mg / kg p.o.

2-Pyrrolidinone 27 1 - [[1- [5-Chloro-2- (trifluoromethyl) - intermediate activity 4-pyrimidinyl] -4-piperidinyl] methyl] - at 10 mg / kg p.o.

2-pyrrolidinone 28 1 - [[1- (2,6-bis (trifluoromethyl) - active at 10 mg / kg p.o.

4-pyrimidinyl] -4-piperidinyl] -30-methyl] -2-pyrroli di non a. "Active" indicates compounds that completely counteract ECS-induced amnesia, while "intermediate activity" indicates less complete protection.

Claims (7)

A diazinylpiperidine derivative of cyclic amides and imides of the general formula (I) rT ^ Nz wherein X is an ethylene chain or a 1,2-benzo ring, Y is carbonyl or -CHg- provided that Y is only carbonyl when X is represents a R, R - disubstituted diazinyl ring selected from pyridazine, pyrimidine and pyrazine ring systems wherein R and R are independently hydrogen, lower (C 14) alkyl, lower alkoxy, lower alkyl thio, cyano, trifluoromethyl, pentafluoroethyl or halogen, and pharmaceutically acceptable acid addition salts thereof. 20 A compound according to claim 1, characterized in that X is ethyl one. A compound according to claim 1, characterized in that R 1 and R 2 are independently hydrogen, halogen or trifluoromethyl. 25 A compound according to claim 2, characterized in that R 1 and R 2 are independently hydrogen, halogen or trifluoromethyl. 5. A compound according to claim 1, characterized in that it is 2 - [[1- (2-pyrimidinyl) -4-piperidinyl] methyl] -1H-isoindole-1,3- (2H) -dione, 1- [ [1- (2-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone, 1- [[1- (2-chloro-4-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone, 1- [ [1- (4-Chloro-2-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone, 1- [[1- (6-chloro-2-pyrazinyl) -4-piperidinyl] methyl ] -2-pyrrolidinone, 1 - [[1- [2- (trifluoromethyl) -4-pyrimidinyl] -4-piperidinyl] methyl-2-pyrrolidinone, 1 - [[1- (2-pyrimidinyl) -3- piperidinyl] methyl] -2-pyrrolidinone, DK 170441 B1 1- [[1- (2-pyrimidinyl) -2-piperidinylmethyl] -2-pyrrolidinone, 1- [[1- (6-chloro-3-pyridazinyl) -4 -piperidinylmethyl] -2-pyrrolidinone, 1- [[1- (5-fluoro-4- (methylthio) -2-pyrimidinyl] -4-piperidinyl] methyl] -2-pyrrolidinone, 5-1 - [[1- (5-Fluoro-2-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidine, 1 - [[1- (2,6-dichloro-4-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrroli -dinone, 1 - [[1- (4,6-dichloro-2-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone , 1- [[1- (6-Chloro-4-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone, 1- [[1- (2-Chloro-6-methyl-4-pyrimidinyl) ) -4-piperidinylmethyl] -2-pyrrolidinone, I - [[1- (4-chloro-6-methyl-2-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone, 1 - [[ 1- (5-bromo-2-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone, 1 - [[1- (5-chloro-2-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone, 1- [[1- (5-Iodo-2-pyrimidinyl) -4-piperidinyl] methyl] -2-pyrrolidinone, 1- [[1- [6-chloro-2- (methylthio]) - 4-Pyrimidinyl] -4-piperidinylmethyl-1,2-pyrrolidinone, 1 - [[1- (5,6-dichloro-4-pyridazinyl) -4-piperidinylmethyl] -2-pyrrolidinone, 1 - [[1 - (5-bromo-2-chloro-4-pyrimidinyl) -4-piperidinylmethyl-2-pyrrolidinone, 1- [[1- (2-methoxy-4-pyrimidinyl) -4-piperidinylmethyl] -2-pyrrolidinone, 4 - [[4- (2-oxo-pyrrolidin-1-yl) methyl] -1-piperidinyl] -2-pyrimidine carbonitrile, 1- [[1- (1- [2- (pentafluoroethyl) -4-pyrimidinyl] -4-piperidinylmethyl] -2-pyrrolidinone, 1- C [1- [5-chloro-2- (trifluoromethyl) -4-pyrimidinyl] -4-pipe [1- (2,6-bi s- (trifluoromethyl) -4-pyrimidinyl] -4-piperidinyl] methyl 1-2-pyrrolidinone or 2- [[ -1- (2-pyrimidinyl) -4-piperidinylJmethyl1-IH-isoindol-L- (2 H) -one. DK 170441 B1 A process for preparing diazinylpiperidine derivatives of cyclic amides and imides of the general formula (I). 'wherein 10. is an ethylene chain or a 1,2-benzo ring, Y is carbonyl or -CH 2 - provided that Y is only carbonyl when X is a 1,2-benzo ring and 2 3 Z represents an R, R disubstituted diazinyl ring selected from pyridazine, pyrimidine and pyrazine ring systems wherein R and R are independently hydrogen, lower (C1-4) alkyl, lower alkoxy, lower alkylthio, cyano, trifluoromethyl, pentafluoroethyl or halogen, and pharmaceutically acceptable salts thereof, characterized in that (A) is coupled to a compound of formula O + H H wherein R is a C 1-4 alkyl group having a compound of formula 25 Z - Q wherein Z has the meaning given above and Q is a suitable displacement group, 30 (B) reactes the product of (A) with a metal reagent of formula 9 · HM wherein M is a metal oidion or a complex, 35 (C) reacts the product of (B) with a reagent which is in capable of converting the hydroxy group of the product from (B) to the substituent Q *, where Q * has that of Q and (D) react the product of (C) with a cyclic amide / imide of formula DK 170441 B1 in M <lv) where X and Y have the meaning given above to form the product of formula (I) or alternatively to form a compound of formula (I) wherein X is a methylene chain and Y, R, R and Z are as defined above, 10 (A ') reacting a cyclic amide / imide of formula X NH 15 wherein X and Y have the meaning given above, except that X cannot be a 1,2-benzo ring, having a compound of the formula O wherein Q has the meaning given to Q, (B1) catalytically reduces the product of (A1) and 25 (C1) decouples the product from (B1) with a compound of formula I - Q3 3 wherein Z has the meaning given above, and Q has the meaning given to Q for preparing a compound of formula (I). Process according to claim 5, characterized in that Q is a displacement group in the form of chloride, bromide, iodide, sulfate, phosphate, tosylene or mesylate.