GB2177692A - Diazinylpiperidine derivatives - Google Patents

Abstract

Nootropic compounds of Formula I <IMAGE> wherein X is an ethylene chain or a 1,2-benzo ring; Y is carbonyl or methylene; R<1> is hydrogen or lower alkyl; and Z is an R<2>, R<3>-disubstituted diazinyl ring selected from pyridazine, pyrimidine, and pyrazine ring systems, where R<2> and R<3> are selected from H, C1-4 alkyl, alkoxy or alkylthio, CN, CF3, C2F5 or halogen, possess cognition and memory enhancing activity.

Description

SPECIFICATION Diazinylpiperidine derivatives Backgroundoftheinvention This invention generally pertains to heterocycliccarbon compounds having drug and bio-affecting properties and to their preparation and use. In particular, the invention is concerned with disubstituted piperidine derivatives wherein one substituent is a cyclic amide or imide ring linked by a bridging methylene moiety to one of the carbon ring positions of the piperidine ring and the other substituent is a diazinyl ring system attached to the piperidine nitrogen atom. The compound ofthis invention are applicable in treatment of various senile dementias affecting the elderly.

The clinical aspects of various senile dementias as well as the problems they cause in the affected geriat ricsubjectarewell known to those skilled in the art. One will alsoappreciate that various drug treatments of this disorder ofthe elderly are currently under study. Among such drugs are a class of drugs known as nootropic agents or, more commonly, cognition enhancers; some ofwhich are currently undergoing clinical evaluation in patients diagnosed as having Alzheimer's disease, a serious and fairly common CNS disorder of the elderly. Chemically, these drugs under clinical study are members of a class of N-substituted 2pyrrolidinone derivatives ofstructure 1.

a: X = H; R = -CH2CONH2 (piracetam) b: X = OH; R = -CH2CONH2 (oxiracetam) c: X = H; R = -CH2CONH[CH2]2N[CH(CH3)2j2 (pramiracetam) d:X=H;

(aniracetam) For a representative reference describing the testing and properties of a member ofthis series 1, see Butler, etal., J. Med. Chem., 27, pp. 684-691(1984). Preliminary clinical results with this class of agents, exemplified by structures la-d, indicates that these drugs may have some beneficial effects in treating senile dementias in the elderly.

Related art may be viewed in light of the following general structural formula 2

in which Xis C24 alkylene or a 1, 2-benzo ring; Y is carbonyl or methylene; A is a bridging moiety such as alkylene, alkanoyl, alkyleneamidoalkylene, and the like; W is nitrogen or CH; and B is an aryl or pyrimidinyl ring system. The most closely related art is that disclosed and claimed in our own pending continuation-inpart application U.S.S.N. 799, filed November 1985. The subject matter relates two a series of formula 2 compounds wherein W is nitrogen.The closest related compounds disclosed in that application may be characterized by structural formula 3.

wherein R1 is hydrogen or loweralkyl; and R2 can also be hydrogen orloweralkyl. As can be seen, these earlier compounds are structurally distinguishablefrom the instant series of compounds on the basis of chemical structure as these earlier compounds are piperazine ring derivatives (W N in Formula 2) whereas the instant compounds are piperidine ring derivatives (W = CH in Formula 2).

Other subject matter related to formula 3 compounds has been disclosed by Malawska, petal, in "Synthesis and Pharmacological Properties of Some 2-Pyrrolidinone Mannich Bases" in the Polish Journalof Pharmacology, 1982,34,373-382. They describe a series of compounds, of which one subclass is represented by structural formula 4, which reportedly display analgesic properties as well as weakanti-inflammatory action,

wherein Xis 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 C24 alkylene have been disclosed by Wu, Temple, New, and theirco-workers and others. These compounds are comprised of cyclic imide rings, e.g. succinimides, glutarimides, phthalimides, etc. The shortest linkage defined byA in these compounds is ethylene as compounds wherein Ais methylene are too unstable, particularly in acidic media, for practical usage. For more detailed disclosure of these compounds, see: Wu, etal., U.S.Patent 3,717,634 patented February 20, 1973; Temple, U.S.Patent 4,423,049 patented December27, 1983; and New and Yevich, U.S.patent 4,524,206 patented June 18,1985.

Increasing structural departure from compounds of the instant invention is found in other art cited in our above-referenced application. In summary, the instant diazinylpiperidine compounds described herein are structurally novel cognition enhancing agents and there are no teachings in the art which would makethe specific compounds comprising this invention anticipated or obvious.

Summary ofthe invention Aseries of compounds of structural Formula I

wherein or ethylene chain or a 1,2-benzo ring; Y is carbonyl or methylene; R1 is hydrogen or loweralkyl; and Z is an R2, R3-disubstituted diazinyl ring selected from pyridazine, pyrimidine, and pyrazine ring systems.

R2 and R3 are independently chosen from hydrogen, lower alkyl, lower alkoxy, lower alkylthio, cyano,trifluoromethyl and halogen. Compounds ofthis series can be incorporated into pharmaceutical compositions for intended use in geriatric subjects afflicted with senile dementias. A representative number of these compounds have been tested and demonstrate prevention of ECS-induced amnesia in rats.

Detailed description of the invention In its broadest aspect, the present invention is concerned with 1 -(4iazinyl) piperidinyl derivatives of N-methylene cyclic amides and imides having psychogeriatric properties and being characterized by structural Formula I.

In Formula l,X is a C2 (ethylene) alkylene chain oral, 2-benzo ring connecting Yandthe carbonyl groupto give, e.g. when Y is also carbonyl, a phthalimide moiety. Y is a carbonyl group (but onlywhen Xis a 1, 2-benzo ring) orCH2. In Formula I, R', can be either hydrogen or lower (C14) alkyl; and Z is an R2, R3-disubstituted diazinyl ring selected from pyridazine, pyrimidine, and pyrazine ring systems, with R2 and R3 being independ ently chosen from hydrogen, loweralkyl, lower perfluoroalkyl (such astrifluoromethyl or pentafluoroethyl), lower alkoxy, lower alkylthio, cyano, and halogen. By lower alkyl is meantthatthese groupings contain from 1 to 4carbon atoms. Halogen means F, CI, Br, orl.For preferred compounds, Xis ethylene, Y is methylene, R1 is hydrogen, and R2 and R3 are selected from hydrogen, trifluoromethyl, and halogen, with the most preferred halogen being chloride.

It is to be understood thatthe present invention is considered to include the various stereoisomers, e.g.

optical isomers including individual enantiomers, mixtures of enantiomers, diastereomers, and mixture of diastereomers, which can arise as a consequence of structural asymetry due to the presence of one ortwo asymetric carbon atoms which may be incorporated in some compounds ofthe instant series. Separation of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. For medicinal use, the pharmaceutically acceptable acid addition salts, those salts in which the anion does not contribute significantly to toxicity or pharmacological activity of the organic cation may be preferred in some cases. The acid addition salts are obtained either by reaction of an organic base ofstructure I with an organic or inorganic acid, preferably by contact in solution, or by any of the standard methods detailed in the literature availableto any practitioner skilled in the art. 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, cyclamic acid, pivalic acid, and the like; useful inorganic acids are hydrohalide acids such as HCI, HBr, HI; sulfuric acids, phosphoric acids, and the like. Additionally, the present invention also encompasses any of the Formula I compounds existing in solvateform such as a hydrate.

The compounds ofthe instant invention can be conveniently prepared by means of a general process which is shown in Scheme 1.

Scheme 1 General Svnthetic Process

In scheme 1, the symbols X, Y, and Z are as previously defined. Basically, a piperidine carboxylate ester (IX) is coupled with an appropriate diazine halide (VIII).While an ethyl ester and a chloride group are shown in compounds IX and VII I, respectively, in Scheme 1, other equivalent groups, e.g. another alkyl carboxylate esterand/ora different halogen may be used. These alterations would be familiar to an organic chemist skilled in synthesis of compounds. Typically, the reaction of IX and VIII will take place in a reaction solvent such as acetonitrile in the presence of a base such as potassium carbonate, thereby giving the product(VII).

The VII product may either be reduced with lithium aluminum hydride in an appropriate solvent such as tetrahydrofuran to give reaction intermediate Vi (R1 =H) or, alternatively, VII may be converted to the aldehyde X using standard methods for ester transformation into an aldehyde moiety, and this followed bytreatment with an organo metallic reagent, R1 M (wherein M represents the appropriate metal cation or Grignard com plex) to givethe intermediate product VI'.The primary alcohol intermediate (VI) or secondary alcohol (VI') is treated withthionyl chloride give the corresponding chloro compound (V) which is then coupled with a selected cyclic amide or imide (IV) to give the desired product of Formula I. This coupling reaction proceeds similarly to that of IX and VIII with a preferred reaction solvent in this case being dimethylformamide and incorporating a base such as potassium carbonate. It will be understood by those skilled in the art that other conversions of VI intermediates may be made which would effectively convert the hydroxy group into a different leaving group (e.g. a tosylate or mesylate moiety) in order to facilitate alkylation of the nitrogen atom in the cyclic amide/imide compound.

Another process may be utilized to produce products of Formula I and this process is set forth as Scheme 2.

Scheme 2 Svnthetic Process When X is an Ethylene Chain

In Scheme 2, R1, X, Y, and Z are as previously defined. While the process outlined in Scheme 2 generally produces products of Formula I in higheryieldsthan the general process of Scheme 1, it does not havethe general applicabilityofScheme 1. Because of the catalytic reduction (conversion of III toll) only cyclicamidesl imides imperviousto catalytic reduction may be used. Forexample,when X is a 1, 2-benzo ring, e.g. IVis phthalimide, the benzo ring moiety is subsequently reduced to a 1,2-cyclohexyl derivative, thereby giving a hexahydrophthalimide ring system.

To summarize the foregoing, there is described a processforthe preparation of a compound of Formula I

wherein R1, X, Y and Z are as previously defined. This process comprises selection of a process from the group of processes consisting of (a) (1) coupling compounds IX and VIII

wherein R is a C16 alkyl group and Q is a suitable displacement group such as chloride, bromide, iodide, sulfate, phosphate,tosylate, mesylate, orthe liketo give an intermediate product of Formula VII;

(2) treating the intermediate product, VII, with the metallic reagent R1 M, wherein M is the appropriate metalloid ion or complex, e.g. lithium aluminum hydrido or Grignard reagent compiex, to give the reaction intermediate of Formula VI;;

(3) treating intermediate VI with an appropriate reagent to convertthe OH group of Vl to a leaving group Q in the compound of Formula V;

(4) reacting intermediateVwith a cyclicamide/imide compound Formula IV

to give a product of Formula I; (b) (1) reacting a cyclic amide/imide compound of Formula IV,

wherein X is not a 1, 2-benzo ring, with a pyridine intermediate of Formula X

to give the intermediate compound of Formula lil;

(2) catalytically reducing the compound of Formula Liy to give the piperidine intermediate compound of Formula II

and (3) coupling the compound of Formula II with compound Z - Qto give a product of Formula I.

Compounds of the instant invention have been evaluated for nootropic activity using as a primary screen the reversal of electroconvulsive shock-induced amnesia for a step-down passive avoidance response (cf: Banfis, etal., J. Pharmacol, Meth., 8,255 (1982); Janvik,Ann, Rev. Psychol., 23,457(1972); and, McGaugh and Petrinovich, Int Rev. Neurobiology, 8,139 (1965)). Reference compounds such as pramiracetam, piracetam, aniracetam, etc., having activity in this paradigm have been purported to affect memory processes and may be useful in treating senile dementia andAlzheimer's disease. Inthistest, 12 animals are administered drugs and 30 minutes lateraretrained to remain immobile to avoid foot shock. Immediatelyfollowingthetraining, the animals are given electroconvulsive shock.Twenty four hours laterthe animals are tested for retention of the learned behaviour; and any animal which remains on the platform for300 seconds without stepping down is considered to have retained the passive avoidance response. Two groups of control animals are used for comparison; one group receives vehicle with electroconvulsive shock and the other receives vehicle with sham-electroconvulsive shock. Atest compound is considered active at a given dosage level if the mean latencyto step-down is both statistically greaterthan the value for the electroconvulsive shock control group (placebo control group) and not statistically differentfrom the value forthe sham-electroconvulsive shock control group.

Atest compound is considered to have intermediate activity at a given dosage level if results for the drug group are statistically different from both control grou ps. Forthe sake of comparison, all drugs were tested after subcutaneous administration; however, preferred compounds of the instant series exhibit activity following oral administration that is little changed from the results following subcutaneous administration of drug.In this regard the following compounds are particularly preferred: 1-[[1 -(2-pyrimidinyl)-4- piperidinyl]methylj-2-pyrrolidinone, 1 -[[1-(2-chloro-4-pyrimidinyl)-4-piperidinyljmethyl]-2-pyrrolidinone, 1 - [[1 -(6-chloro-2-pyrazinyl)-4-piperidinyl]-methyl]-2-pyrrolidinone and, especially, 1 -[[1 -(2-trifl uoro-methyl-4- pyrimidinyl)-4-piperidinyl]methyl]-2-pyrrolidinone. Maintenance of comparable levels of potency in going from subcutaneous to oral administration is a considerable dosing advantage and distinguishes the instant compounds from agents described in prior art references.Additional ly, the instant compounds are not labile in acidic media which is another advantage in their manufacture, formulating, shipping and storage, aswell asfordosing.

In summary of the foregoing discussion, the instant compounds have nootropic properties particularly suited to their use in cognition and memory enhancement. Thus, another aspect ofthe instant invention concerns a processforenhancing cognition and memory in a mammal in need ofsuchtreatmentwhich comprises systemic administration to such mammal of an effective dose of a Formula I compound or a pharmaceutically acceptable acid addition salt thereof.The administration and dosage regimen of compounds of Formula I is considered to be done in the same manner as for the reference compound piracetam, cf: Reisberg, etal., in DrugDevelopmentResearch, 2:475-480 (1982); Weng, etal., in Rational Drug Therapy, 17(5), 1-4(1983); Reisberg, etal., in "Psychopathology in the Aged", Editors, Cole and Barrett, Raven Press, New York, pages 243-245(1980) and pramiracetam, cf: Butler, etal, J. Med. Chem., 27 pp 684-691 (1984).

In addition to the usefulness ofthe compounds of Formula las cognition enhancing agents or mild stimulants of the central nervous system, the compounds have been found to be useful in preventing amnesia which results from electroconvulsive shock. Such activity not only relates to memory retention in normal aging and senility processes but would be useful in protecting against the amnesia-producing effects of electroconvulsant shock as it is used clinically. Electroconvulsant shock is employed to treat somme classes of psychiatric patients, particularly depressed patients who are refractory to traditionally pharmacologic therapy. It is well documented thatthese electroconvulsant shocktreatments induce the undesirable side- effect of amnesia in those patients to whom it is administered.The instant compounds which exhibit activity in protecting againstthe amnesia-producing effects of electroconvulsant shock in pharmacologictesting would be useful adjuncts to the clinical use of electroconvulsant shock in psychiatrictreatment.

Although the dosage and dosage regimen must in each case be carefully adjusted, utilizing sound professional judgement and considering the age, weight and condition of the recipient, the route of administration and the nature and extent of mental deterioration, generally, the daily dose will be from about 0.1 9 to about 10g, preferably 0.5 g to 5 g, when given orally. In some instances, a sufficient therapeutic effect can be obtained at lower doses while in others, larger doses will be required. As is apparentto one skilled in clinical pharmacology, the amount of Formula I compound comprising the daily dose may be given in a single or divided dose, taking into accountthose principles understood by the skilled practitioner and necessary for his practice ofthe art.

The term "systemic administration" as used herein refers to oral, sublingual, buccal, nasal, dermal, rectal, intramuscular, intravenous, and subcutaneous routes. Generally, itwill befound thatwhen a com- pound of the present invention is administered orally which is the preferred route, a slightly larger quantity of the active drug is required to produce the same effect as a somewhat smaller quantity when given parenterally. In accordance with good clinical practice, it is preferred to administer the instant compounds at a concentration level which will produce effective nootropic effects without causing any harmful or untoward side effects.

Therapeutically, the instant compounds are generally given as pharmaceutical compositions comprised of an effective nootropic amount of a compound of Formula I or a pharmaceutically acceptable acid addition saltthereof and a pharmaceutically acceptable carrier. Pharmaceutical compositions for effecting suchtreatmentwill contain a majororminoramount (e.g.from 95%to 0.5%) of at least one compound ofthe present invention in combination with a pharmaceutical carrier, the carrier comprising one or more solid, semi-solid, or liquid diluent, filler and formulation adjuvant which is non-toxic, inert and pharmaceutically acceptable.

Such pharmaceutical compositions are preferably in dosage unit forms; i.e., physically discrete units having a pre-determined amountofthe drug corresponding to afraction or multiple ofthe dose which is calculated to produce the desired therapeutic response. In usual practice, the dosage units contain 1, 1/2, 1/3, or less of a single dose. A single dose preferably contains an amount sufficient to produce the desired therapeutic effect upon administration at one application of one or more dosage units according to the pre-determined dosage regimen, usually a whole, half, third, or less ofthe daily dosage administered once, twice, three, or more times a day. It is envisioned that other therapeutic agents can also be present in such a composition.Pharmaceutical compositions which provide from 0.1 to 1 g of the active ingredient per unit dose are preferred and are conventionally prepared as tablets, losenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs, and aqueous solutions. Preferred oral compositions are in the form of tablets, capsules, and may contain conventional excipients such as binding agents (e.g., syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone), fillers (e.g. lactose, sugar, maize-starch, calcium phosphate, sorbitol orglycine), lubri- cants (e.g. magnesium stearate, talc, poly-ethylene glycol or silica), disintegrants (e.g. starch) and wetting agents (e.g. sodium lauryl sulfate).Solutions orsuspensions of a Formula I compound with conventional pharmaceutical vehicles are employed for parenteral compositions such as an aqueous solution for intravenous injection or an oily suspension for intramuscular injection.Such compositions having the desired clarity, stability and adaptability for parenteral use are obtained by dissolving from about0.l%to 10% by weightofthe active compound in waterora vehicle consisting of a polyhydricaliphaticalcohol such as glycerine, propylene glycol, and the polyethylene glycols or mixtures thereof.The polyethylene glycols con- sistofa mixture of non-volatile, usually liquid, polyethylene glycols which are soluble in both water and organic liquids and which have molecularweightsfrom about 200 to 1500.

Description ofspecific embodiments The compounds which constitute this invention and their methods of preparation as well as their biological activitywill appearmorefullyfrom a consideration ofthefollowing examples which are given forthe purpose ofillustration only and are notto be construed as limiting the invention in sphere orscope. All temperatures are understood to be in degrees C when not specified. The nuclear magnetic resonance (NMR) spectral characteristics referto chemical shifts (8) expressed in parts per million (ppm) versustetramethylsilane (TMS) as reference standard.The relative area reported for the various shifts in the proton (PMR) spectral data corresponds to the number of hydrogen atoms of a particularfunctional type in the molecule. The nature ofthe shift as to multiplicity is reported as broad singlet (bs), singlet(s), multiplet (m), doublet (d), doubletof doublets (dd), triplet (t), or quartet (q). Abbreviations employed are DMSO-d6 (perdeuterodimethylsulfoxide), CDCI3 (deuterochloroform) and are otherwise conventional. The infrared (IR) spectral descriptions include only absorption wave numbers (cm1) having functional group identification value. The IR determinations were employed using potassium bromide (KBr) as diluent. All compounds gave satisfactory elemental analysis.

Example 1 2-ffl-(2-Pyrimidin yl)-4-pip eridin ylj-meth ylJ- 1H-isoindole- 1, 3-F2H)-dione This synthetic sequence exemplifies the more general synthesis outlined in Scheme 1, supra.

A. Ethyl l-(2-Pyrimidinyl)piperidine-4-carboxylate (VII). - A mixture of ethyl isoni pecotate ( IX; 31.44 g, 0.2 mole), 2-chloropyrimidine (Vl11;22.91 g, 0.2 mole), and potassium carbonate (27.69 g, 0.2 mole) in acetonitrile (250 mL) was refluxed for 24 hour. 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 intheform of a clearoil.

B. 4-Hydroxymethyl- l-(2-pyrimidinyl)piperidine (VI).- A solution of the ester (VII; 20 g, 0.085 mole) in tetrahydrofuran (200 mL) was cooled to 0.50 and lithium aluminum hydride (3.23 g, 0.085 mole) was slowly added over a 10 minute period. The mixture was stirred at room temperature for 30 minutes. The excess LAH was quenched with acetone and the mixture diluted by adding 3.2 mL ofwaterfollowed by 3.2 mL of 15% sodium hydroxide solution and then 9.7 m L of water. The resulting mixture was filtered and the filtrate concentrated in vacuo to given an oil which was distilled to give 15 g (91 %) of a clear oil product, b.p. 140-1900at 0.3 torr.

C. 4-Chloromethyl- l-(2-p yrimidinyl)piperidine (V).-Asolution ofthe hydroxymethyl compound (VI; 7.73 g, 0.04 mole) 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 atambient temperature and then concentrated in vacuo. The residue was dissolved in methylene chloride, extracted with aqueous sodium bicarbonate, and the methylene chloride layer concentrated in vacuo. The residue was chromatographed on silica gel using ethyl acetate as the eluentto give 7.7 g (91 %) of product as an oil.

D. Reaction oflntermediate VandPhthalimide. A mixture of potassium carbonate (2.76 g, 0.01 mole), phthalimide (1.47 g, 0.02 mole), and 4chloromethyl-1-(2-pyrimidinyl) piperidine (V; 2.12 g, 0.01 mole) in dimethyl-formamide (50 mL) was heated to about 500 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 the crude product which was chromatographed on silica gel using 30% ethyl acetate-hexane as the eluent. The product was then recrystallized from ethyl acetate to yield 0.95 g (20.5%) of product in the form of white crystals, m.p. 1091110.

Anal. Calcd. for C18H18N402: C, 67.06; H, 5.64; N, 17.38. Found: C, 66.95; H, 5.68; N, 17.17.

NMR (CDCI3): 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, 4.8Hz).

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

Example2 1-[[1-(2-Pyrimidinyl)-4-piperidinyl]-2-methyl]-2-pyrrolidinone This experimental sequence exemplifies the synthetic process that can be used when X ofthe Formula I compound is an alkylene chain (see Scheme 2,supra.) A.1-[(4-Piperidinyl)methyl]-2-pyrrolldinone Hydrochloride Hydrate (11).- A solution of 1 -(4-pyridinylmethyl)2-pyrrolidinone hydrochloride (III; 15.05 g, 0.0707 mole; prepared from 2-pyrrolidinone and 4pyridinylmethyl chloride), HCI (10 mLofan 8N solution in absolute ethanol) and absolute ethanol (100 mL) was hydrogenated at 60 psi with PtO2 (1.0 g) for 72 hour. The mixture was filtered and the filtrate reduced in vacuo to give a white solid.The crude product was recrystallized from isopropanol to give 13.03 9 (83%) of product as a white powder, m.p.212-214 .

B. Reaction ofintermediate compoundll with 2-chloropyrimidine. - A mixture of the piperidinylmethyl pyrrolidinone (Il; 5.08 g, 0.0232 mole), 2-chloropyrimidine (2.67 g, 0.0233 mole) and potassium carbonate (7.09 g, 0.0513 mole) in dimethylformamide (60 mL) was heated in a 50-100 oil bath for 14 hour. 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 the eluent to give 4.7 9 (78%) of product as white crystals, m.p.

144-147 .

Anal. Calcd.forC14H20N4O: C, 64.59; H,7.74; N,21.52. Found: C,64.26; H,7.78; N,21.20 NMR (CDCI3):1.29(2, m); 1.71(2, m); (2, m); 2.01 (3,m);2.34 (2,t, 7.4Hz); 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,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-[[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 mole), 2,4-dichloropyrimidine (14.90 g, 0.1 mole), sodium carbonate (26.5 9, 0.25 mole),and 200 mL dimethylformamide was stirred for 14 hour at room temperature and then heated to 70 for one hour.

The mixturewasfiltered and concentrated in vacuo. The crude residue was chromatographed on silica using ethyl acetate/methanol (95:5) as the eluentthereby separating the product residue into two components. The major component was obtained as 16 g (59%) of off-white powder, m.p.1 10-114, and represented the desired 2-chloro-4-pyrimidinyl isomer.

Ama/. Calcd. for C14H19ClN4O: 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, 7.4Hz); 2.92 (2,m); 3.17 (2, d, Hz); 3.40 (2,t, 6.8 Hz); 4.35 (2,m); 6.39(1, d, Hz); 7.98 1 ,d, Hz).

IR (KBr): 965,1150,1350,1360, 1490,1590,1685,2860, and 2950 cm~1.

Example 4 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 ob tained by chromatography and recrystallization from ethyl acetate of the reaction product of Example 3 (above) to give 1.1 g (4%) of white crystals, m.p. 143.5-145.5 .

Anal. Calcd. for C14H19CIN4O: C, 56.04; H, 6.50; N, 19.01. Found C. 56.66; H, 6.49; N, 19.81.

NMR (CDCI3): 0.9-2.1 (5,m); 2.25 (2,t, 5Hz); 2.75 (2,t,8Hz); 3.10 (2,d, 5Hz); 3.30 (2,t, 5Hz); 4.5-4.8 (2,d; 6.45 (1,d,4Hz);8.13(1,d,4Hz).

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

Example 5 1-[[1-(6-Chloro-2-pyrazinyl)-4-piperidinyl]methyl]-2-pyrrolidinone Using the procedure described above in Examples 2 and 3, a mixture of 1 -[(4-piperidinyl)methyl]-2 pyrrolidinone hydrochloride (11, 12.5 g, 0.0556 mole); 2, 6-di-chloropyrazine (8.37 g, 0.0556 mole); potassium carbonate (19.2 g,0.139 mole); and DMF (150 mL) was stirred at room temperature for 14 hourandthen heated to 700 for one hour. The mixture was filtered and the filtrate concentrated in vacuo. The crude product was recrystallized twice from ethyl acetate to provide 11.16 g (68%) oftan crystals, m.p. 139-1420.

Anal. Calcd. for C14H19CI N4O: C, 57.04; H, 6.50; N, 19.01. Found: C, 57.02; H, 6.40; N, 19.03.

NMR(CDCI3): 1.34(2,m); 1.77(2,m);2.05(3,m);2.40(2,t,7.2Hz);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 2945cm-1.

Example 6 l-[[l-[2-(Trif/uorom eth yll-4-p yrimidin y//-4-pip eridin y//meth y//-2-p yrrolidinone Using the procedure described above in Examples 2 and 3, a mixture of 1 -[(4-piperidinyl)methyl]-2- pyrroiidinone hydrochloride (11,21.85 g, 0.1 mole) and sodium carbonate (26.5 g 0.25 mole) in methanol (150 mL)was 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 as 4-chloro-2-(trifluoro-methyi)-pyrimidine (18.28 g, 0.1 mole) was added. The mixture was stirred at room temperature for 18 hours and then filtered andthe filtrate concentrated in vacuo to give a thick residue which solidified upon being washed with hexane (100 mL).The light tan powder (23.8 g, 73%) which resulted was chromatographed (5% methanol/ethyl acetate on silica)to give 19.8 gas white crystals, m.p. 118.5-120.5 .

Anal. Calcd.forC1H19F3N4O: C, 54.87; H,5.83; N, 17.07. Found C, 54.50; H, 5.86; N, 16.80.

In similar manner a number of additional compounds of Formula I were prepared and are tabulated in Table 1.

TABLE 1 Compounds of Formula I

Piperidine Ex. R X Y Ring-link Z Formula m.p.( ) 7 H -C 2H4 - CH2 3- 4 C14H20N4 0 105.5 8 H -C2H4- CH2 2- C14H20N40 110-113 9 H -C2H4- CH2 4- (0)-C1 C14H19C1N40 1339 5 10 H -C2H4- CH2 4- F C15A21FN40S 96-100 11 H -C2H4 - CH2 4- C14H19 N 40 134-136 C1 12 H C 2 9 CH2 4- - C14H15C12N40 140-144 13 H -C2H4- CH2 4- ~ C14H18C12N40 11114.5 14 H -C24- CH2 4- frizz C14H19ClN40 114412.5 TABLE 1 (continued)

PiPeridine Ex. 1 Piperidine Formula a Ex Ring Link Z ~~~~~~~ tn-j--..t0) Cl 15 H -C 2H4 - CH2 4- ANH C15H21C1N40 133-135 3 3 Cl 16 H -C2H4- CH2 4- ) C 15H21ClN40 104-107 CH3 17 H -C2H4- CH2 4- Br C14H19BrN40 143-146 18 H -C2H4- CH2 4- ~ < O } C1 C14H19C1N40 130-133 r7 19 H -C2H4- CH2 4- A ;;I 129.5 H2 C14H19TN40 129.5 Me 20 H -C2H4- CH2 4- Q C15E121C1N4OS 134-137 Cl C1 C1 21 H- -C2H4 - CH2 4- ĭN C14H18C12N4O 135-138 K~El 22 H -C2H4 - CH2 4- C14H18BrC1N40 105-115 Br OMe 23 H 4 2 4 CH2 4- C15H22N402 116-121 CN 24 H 4 2 4 -C2H4- CH2 4- A) 'C H N 0 139.5 (1.2 H30 142 3 25 H 1,2-C6H4 CH2 4- ( ) Cl8H20N40 176-178 iu 26 H -C2H4- CH2 4- X C16H19F5N4O 105-107 5 CF 27 H -CH- CH2 18 3 C15H18C1F3N40 102 104.5 28 H 2 ss -C2H4- CH2 4- F3 C6 H F N 0 132.5 F3 0 2 134 a. C, H, and N analyses were all within + 0.4% of the calculated value.

Example 29 Reversal of ECS-induced amnesia forstep-down passive avoidance response In the step-down passive avoidance procedure, rats are trained to remain immobileto avoid footshock.

Two control groups (n=36/group) were required; and ECS control and a sham-ECS control. ECS control animals were placed individually on a platform over an activated shock grid (0.8 mA) 30 min. aftervehicle administration. The animals readily stepped down from the platform, immediately experienced the foot shock, 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 for 2 minutes without stepping down following foot shock delivery. Immediately after acquisition, the ECS control animals were delivered ECS via transcorneal electrodes atan intensity of 50 nAfor400 msec.The sham-ECS control animals were treated in a manneridenticalto that described for the ECS controls, with the exception that current was not passed through the transcorneal electrodes. Both groups were administered a retention test 24 hours later. Animals were placed individually on the platform, and the latency to step down from the platform onto the unactivated shock grid was recorded; a given subject animal considered to have retained the passive avoidance response if it remained on the platform for300 seconds without stepping down. Sham-ECS controls remain on the platform during thistest, showing normal retention; ECS controls readily stepped down within 300 seconds, exhibiting a deficit in retention (i.e., amnesia).

Step-down latency scores were transformed into percent retention scores with 300 seconds equal 100% retention. The percent retention scores for all drugs groups were evaluated against both the ECS and sham ECS control groups using Dunnett'stest. A compound was considered to be active in this test if the mean retention score obtained from at least one dose group is both significantly greaterthan the ECS control group retention and not significantly different from the sham-ECS control group retention. This indicatesthatthe test compound reversed the amnesia forthe passive avoidancetask induced by the ECS.The compounds which statistically raised the animal's performance above that of the ECS control group, but did not raisethe performance sufficiently to be not statistically different from the sham-ECS control group were scored as possessing "intermediate activity". These compounds, then, do statistically raise the animals' performance, but notsufficientlyto give total protection against the amnesia.

The biological activities of selected Formula I compounds in the test outlined in Example 29 are given in Table 2.

TABLE 2 Biological activities of selected formula I compounds in reversal of ECS-induced amnesia fora step-down passive avoidance response Ex. Name ECS-lnduced Amnesia Reversal - pramiracetam (reference activea at 10 mg/kg s.c.

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

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

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

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

pyrimidinyl)-4-piperidinyl]- and p.o.

methyl]-2-pyrrolidinone 5 1 -[[1 -(6-Chloro-2- active at 0.5 mg/kg s.c.

pyrazinyl)-4-piperidinyl] methyl]-2-pyrrolidinone 6 1 -[[1 -[2-(Trifluoro)-4- active at 0.25 to 10 pyrimidinyl]-4-piperidinyl]- mg/kg p.o., active at methyl]-2-pyrrolidinone 0.5 to 10 mg/kg s.c.

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

piperidinyl]methyl]-2 pyrrolidinone 8 1 -[[1 -(2-Pyrim idinyl )-2- active at 25 mg/kg s.c.

piperidinyl]methyl]-2 pyrrolidinone 9 1 -[[1 -(6-Chloro-3- active at 25 mg/kg s.c.

pyridazinyl)-4-piperidinyl] methyl]-2-pyrrolidinone TABLE 2 (continued) Ex. Name ECS-lnduced Amnesia Reversal 10 1-[[1 -(5-Fluoro-4-(methyl- intermediate activity thio)-2-pyrimidinyl]-4- at 510 and 25 mg/kg s.c.

piperidinyl]methyl]-2 pyrrolidinone 11 1 -[[1 -(5-Fluoro-2- active at 10 mg/kg s.c.

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

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

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

pipendinylmethyIj-2- pyrrolidinone 15 1 -[[1 -(2-Chloro-6-methyl- intermediate activity 4-pyrimidinyl)-4- at 10 mg/kg s.c.

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

methyl]-2-pyrrolidinone 18 1 -[[1 -(5-Chloro-2- active at 10 mg/kg p.o.

pyrimidinyl)-4-piperidinyl] methyl]-2-pyrrolidinone 19 1-[[1-(5-lodo-2- active at 25 mg/kg p.o.

pyrimidinyl)-4-piperidinyl] methyl]-2-pyrrolidinone 22 1 -[[1 -(5-Bromo-2-chloro-4- active at 0.5-1.0 mg/kg pyrimidinyl)-4-piperidinyl]- p.o.

methyl]-2-pyrrolidinone 23 1 -[[1 -(2-Methoxy-4- intermediate activity pyrimidinyl)-4-piperidinyl]- atl0mg/kg p.o.

methyl]-2-pyrrolidinone 24 4-[4-[(2-Oxopyrrolidin- active at 25 mg/kg p.o.

1 -yl)methyl]-1 -piperidinyl]- 2-pyrimidinecarbonitrile 26 1 -[[1 -[2-Pentafl uoroethyl )- intermediate activity 4-pyrimidinyl]-4-piperi- at 10 mg/kg dinyljmethylj-2- pyrrolidinone 27 1-[[1-(5-Chloro-2- intermediate activity (trifluoromethyl)-4- at 10 mg/kg p.o.

pyrimidinyl]-4-piperidinyl] methyl]-2-pyrrolidinone 28 1 -[[1 -[2,6-bis(trifluoro- active at 10 mg/kg p.o.

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

Claims (38)

1. Acompoundof Formula i

wherein Xis an ethylene chain or a 1,2-benzo ring; Yis a carbonyl group or -CH2-,with the provisothatY is carbonyl only when X is a 1, 2-benzo ring; R1 is selected from hydrogen orC14aIkyI; and Z is an R2-, R3- disubstituted diazinyl ring selected from pyridazine, pyrimidine, and pyrazine ring systems, with R2 and R3 being independently chosen from hydrogen, lower (via) alkyl, lower alkoxy, lower alkylthio, cyano, trifluoromethyl, pentafluorethyl, and halogen; and the pharmaceutically acceptable acid addition salts thereof.

2. A compound of claim 1 wherein X is ethylene and R1 is hydrogen.

3. A compound of claim 1 wherein R2 and R3 are independently selected from hydrogen, halogen, and trifluoromethyl.

4. Acompound of claim 2 wherein R2 a nd R3 are independently selected from hydrogen, halogen, and trifluoromethyl.

5. The compound of claim 1,2-[[1 -(2-pyrimidinyl)-4-piperidinyl]methyl]-1 H-isoindole-1 ,3-(2H)-dione.

6. The compound of claim 1, 1-[[1-(2-pyrimidinyl)-4-piperidinyl]methyl]-2-pyrrolidinone.

7. The compound of claim 1, 1 -[[1 -(2-chloro-4-pyrimidinyl)-4-piperidinyl]-methyl]-2-pyrrolidinone.

8. The compound of claim 1, 1 -[[1 -(4-chloro-2-pyrimidinyl)-4-piperidinyljmethylj-2-pyrrolidinone.

9. The compound of claim 1, 1 -[[1 -(6-chloro-2-pyrazinyl)-4-piperidinyl]-methyl]-2-pyrrolidinone.

10. The compound of claim 1, 1 -[[1 -[2-(trifluoro-methyl)-4-pyrimidinyl]methyl]-2-pyrrolidinone.

11. The compound of claim 1, 1-[[1-(2-pyrimidinyl)-3-piperidinyljmethyl]-2-pyrrolidinone.

12. The compound of claim 1, 1 -[[1 -(2-pyrimidinyl)-2-piperidinyljmethyl]-2-pyrrolidinone.

13. The compound of claim 1, 1 -[[1 -(6-chloro-3-pyridazinyl)-4-piperidinyl]-methylj-2-pyrrolidinone.

14. The compound of claim 1, 1 -[[1 -(5-fluoro-4-(methylthio)-2-pyrimidinyl]-4-piperidinyl]methyl]-2- pyrrolidinone.

15. The compound of claim 1, 1 -[[1 -(5-fluoro-2-pyrimidinyl)-4-piperidinyl]-methyl]-2-pyrrolidinone.

16. The compound of claim 1, 1 -[[1 -(2-6-dichloro-4-pyrimidinyl)-4-piperidinyl]-methyl]-2-pyrrolidinone.

17. The compound of claim 1, 1-[[1-(4,6-dichloro-2-pyrimidinyl)-4-piperidinyl]methyl]-2-pyrrolidinone.

18. The compound of claim 1, 1 -[[1 -6-chloro-4-pyrimidinyl)-4-piperidinyl]methyl]-2-pyrrolidinone.

19. The compound of claim 1, 1 -[[1 -(2-chloro-6-methyl-4-pyrimidinyl)-4-piperidinyl]methyl]-2- pyrrolidinone.

20. The compound of claim 1, 1 -[[1 -(4-chloro-6-methyl-2-pyrimidinyl)-4-piperidinyl]methyl]-2- pyrrolidinone.

21. The compound of claim 1, 1 -[[1 -(5-bromo-2-pyrimidinyl)-4-piperidinyl]methylj-2-pyrrolidinone.

22. The compound of claim 1, 1 -[[1 -(5-chloro-2-pyrimidinyl)-4-piperidinyl]methylj-2-pyrrolidinone.

23. The compound of claim 1, 1 -[[1 -(5-iodo-2-pyrimidinyl)-4-piperidinyl]methyl]-2-pyrrolidinone.

24. The compound of claim 1, 1 -[[1 -[6-chloro-2-(methylthio)-4-pyrimidinyl]-4-piperdinyl]methyl]-2- pyrrolidinone.

25. The compound of claim 1,1 -[[1-(5,6-dichloro-4-pyridazinyl)-4-piperidinyl]methyl-2-pyrrolidinone.

26. The compound of claim 1,1 -[[1-(5-bromo-2-chloro-5-pyrimidinyl)-4-piperidinyl]methyl]-2- pyrrolidinone.

27. The compound of claim 1, 1 -[[1 -(2-methoxy-4-pyrimidinyl)-4-piperidinyljmethyl]-2-pyrrolidinone.

28. The compound of claim 1, 4-[4-(2-oxo-pyrrolidin-1 -yl)methyl]-1 -piperidinylo]-2-pyrimidinecarbonitrile.

29. The compound of claim 1, 1 -[[1 -[2-(penta-fluoroethyl)-4-pyrimidinyl]-4-piperidinyl]methyl]-2- pyrroli dinone.

30. The compound of claim 1, 1 -[[1 -[5-chloro-2-(trifluoromethyl)-4-pyrimidinyl]-4-piperidinyl]methyl]-2- pyrrolidinone.

31. The compound of claim 1, 1 -[[1 -[2,6-bis-(trifluoromethyl)-4-pyrimidinyl]-4-piperidinyl]methyl]-2- pyrrolidinone.

32. The compound of claim 1, 1 -[[1 -(6-chloro-3-pyridazinyl)-4-piperidinyl]methyl]-2-pyrrolidinone.

33. The method for enhancing cognition and memory in a mammal in need of such treatmentwhich comprises systemic administration to the mammal of an effective dose of a compound claimed in claim 1.

34. A process to produce a compound of the formula

wherein X is an ethylene chain oral, 1,2 -benzo ring; Y is carbonyl or methylene; R1 is hydrogen or loweralkyl; Z is a R2, R3 - disubstituted diazinyl ring selected from the group consisting of pyridazine, pyrimidine, and pyrazine; and R2 andR3 are independently selected from the group consisting of hydrogen, lower alkyl, lower alyoxy, loweralkylthio, cyano, trifluoromethyl and halogen which comprises alternatively (A) reacting a compound oftheformula

wherein R is a C1 to C6 alkyl group with a compound oftheformula Z-Q wherein Z is as above and 0 is a suitable displacement group (B) reacting the product of (A) with a metallic reagent of the formula R1 M wherein R' is as above and M is a metalloidion or complex (C) reacting the product of (B) with a reagent capable of converting the hydroxy group of the product of (B) to the substitutent 0 and (D) reacting the product of (C) with a cyclic amide/imide oftheformula

wherein Xand Yare as above to providethe product of Formula I oralternativelyto produce a Formula I compound wherein X is an methylene chain and Y, R1, R2, R3 and Z are as above (A') reacting a cyclic amide/imide oftheformula

with a compound oftheformula

wherein R1 and 0 are as above (B') catalytically reducing the product of (A') and (C') coupling the product of (B') with a compound oftheformula Z-Q wherein Z and 0 are as above to produce a compound of Formula I

35. The process of claim 34 wherein Q is a displacement group selected from the group consisting of a chloride, bromide, iodide, sulfate, phosphate, tosylate or mesylate group.

36. A process for producing a compound orsaltas claimed in claim 1, substantially as described in re- spect of any of the foregoing Examples.

37. Acompound orsalt as claimed in claim 1, produced bya process as claimed in claim 34,35 or36.

38. Apharmaceutical composition comprising a compound or salt as claimed in any of claims 1 to 32, or claim 37, and a pharmaceutically acceptable carrier.