CA1272725A - Psychogeriatric diazinylpiperidine derivatives of cyclic amides and imides - Google Patents

Abstract

PSYCHOGERIATRIC DIAZINYLPIPERIDINE
DERIVATIVES OF CYCLIC AMIDES AND IMIDES
Abstract of the Disclosure A series of nootropic compounds of Formula I

I
wherein X is an ethylene chain or a 1,2-benzo ring; Y is carbonyl or methylene; R1 is hydrogen or lower alkyl; and z is an R2, R3-disubstituted diazinyl ring selected from pyridazine, pyrimidine, and pyrazine ring systems.
Pharmacological testing demonstrates that the series possesses ability to reverse ECS-induced amnesia in a step-down passive avoidance response test. These pharmacological test results indicate that compounds of Formula I possess cognition and memory enhancing activity.

Description

~ 7~ ~rJ

~ E~ the Invention ;
~ his invention generally pertains to heterocyclic carbon compounds having drug and bio-affecting properties and to their preparation and use. In particular, th~
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 compounds of this 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 geriatric subject are well known to those skilled in the art. One will also appreciate that various drug treatments of this disord~r of the elderly are currently under study. Among such drugs are a class of drugs known as noot~opic agents or, more eommonly, cognition enhancers; some of which 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 2-pyrrolidinone derivatives of structure 1.

~ N-R

a: X = H; R = -CH2CONH2 (piracetam) b: X = O~; R = -CH~CON~2,(oxiracetam~
c: X = H; R - -CH2CoNHtCH2~2N~CH(CH3)2~2 ~pramiracetam) d: X z ~; R - -CO ~ OCH3 (aniracetam) For a representative reference describing the testing and properties of a member of this series 1, see Butler, et al., J. Med. Chem., 27~ pp. 684-691 (1984). Preliminarv clinical results wi~h this class of agents, exemplified by structures la-d, indicates that ~hese 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 O
X ~-A W ~ -B 2 ~ y / ,/

in which X i6 C2 4 alkylene or a 1,2-benzo ring; Y is carbonyl or methylene, A is a brid~ing 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 U.S. Patent No. 4,668,687, issued 26 May 1987. The subject :, ~,'7~

matter relates to a series of Po:rmula 2 compounds wherein W is nitrogen. The closest related compounds disclosed in that application may be characterized by structural formula 3. o CH~ 3 3 wherein Rl is hydrogen or lower alkyl; and R2 can also be hydrogen or lower alkyl. As can be seen, these earlier compounds are structurally distinguishable from the instant series of compounds on the basis of chemical structure as these earlier compound~ are piperazine ring derivatives (W = N in Formula 2) whereas the instant compounds are piperidine ring derivatives (W = C~ in Formula 2).
Other subject matter related to formula 3 compounds has been disclosed by Malawska, et al., in "Synthesis and Pharmacological Properties of Some

2-Pyrrolidinone Mannich Bases" in the Polish Journal of , 1982, 34, 373-382. They describe a series of compounds, of which one subclass is represented by structural formula 4, which repor~edly displav analgesic properties as well as weak anti-inflammatory action, O X

~ N-CH2- C ~ 4 wherein X is hydrogen or chlorine.

~ ~,'7~

A larae numher of psychotropic compounds with struckures corresponding to formula 2 wherein Y is car~onvl, W i9 nitrogen, and A is C2_~ alkylene have been disclosed by IrU I Temple, New, and their co-workers and others. These compounds are comprised of cyclic imide rings, e.~.
succinimides, glutarimides, phthalimides, etc. The shortest linkage defined by A in these compounds is ethvlene as compounds wherein A is methvlene are too unstable, par~icularly in acidic media, for practical usap~e. For more detailed disclosure of these compounds, see: Wu, et al., U.5. Patent 3,717,634 patented February 20, 1973; Temple, U.S. Patent 4,423,049 patented December 27, 1983; and New and Yevich, U.S. patent 4,524,~06 patented June 18, 1985.
Increasing structural departure from compounds of the instant invention is ~ound in other art cited in our above-referenced application. In summary, the instant diazinvlpiperidine compounds described herein are -structurally novel cognition~enhancing agents and there are no teachings in the art which would make the specific compounds comprising this invention anticipated or obvious.

Summary of the Invention A series of compounds of ~tructural Formula I

Z

wherein X is or ethylen~ chain or a 1,2-b~nzo ring: Y i~
carbonyl ~r methylene; Rl i5 hvdroge~ or low~r alkyl; and Z
is an R2,R3-disubstituted diazinyl ring sel~cted from pvrid~zin~, pyrimidine, and pyrazin~ ring systems. R2 and R3 are independently chosen from hydrogen, lower alkyl, lower alkoxy, lower alkylthio, cyano, trifluorometh~1 and halogen. Compounds o~ this ~erie~ can be incorporat~d into pharmaceutical compositions for intended use in geriatric subjects afflicted with ~e~ile dementia~. A repre~entative .
number of these compounds have been tested and demonstrate prevention of ECS-induced amnesia in rats.

Further according to the present invention-there is provided a process to produce a compound of the Formula I

o R1 ~ N~ z ¦ which pr~cess comprises alternatively (A) r~actlng a compound o~ ~he ~onnula ~} C02R
N

IX

wherein R i6 a Cl to C6 alkyl group with a compound of the formula ~ - Q
wherein Z is ~s above ~nd Q is a suitable di6placement group;

tB) reacting the product of (A) with a metallic reagent o~
the formul A
Rl M
wherein Rl 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 o~ (B) to the substitutent ~; and . (D) reacting the product of ~C) with a cyclic amide/imide of the fo~mula ~o ~yJ

IV

wherein X and Y are as above to provide the product of Formula I or alternatively to produoe a Fo~mula I compound wherein X is an methylene chain and Y, Rl, R2, R3 and Z are ~s above (A ) reacting a cyclic ~mide/imide of the formula X

.~ ~y~

IV
with a oompound of the formula 6(a) ~'7~

wherein Rl and Q are as above (B ) catalytically reducing th~ product of (A ) and (C ) coupling the product of (B ) with a compound of the ~ormula Z - Q
wherein Z and Q are as above to produce ~ compound of Formula Io De'alled Description of the Invention In its broadest aspect, the present invention is concerned with 1-(4-diazinyl)piperidinyl derivatives of N-methvlene cvclic amides and imides having psychogeriatric properties and being characterized by structural Formula I.

X/~ CH--Q
.j Y

In Formula I, X is a C2 (ethylene) alkylene chain or a 1,2-benzo ring connecting Y and the carbonyl group to give, e.g. when Y is also carbonyl, a phthalimide moiety. Y is a carbonyl group (but only when X is a 1,2-bénzo ring) or 6~b) t~ l ~ 7~r~3 CH~. In ~ormula I, R~, can be either hydrogen or lower (C~ lkyl; and Z is an R2,R3-clisub~tituted di~zlnyl ring selected from pyridazine, pyrimid:Lne, and pyr~zin~ rirg svstems, with R2 and ~3 being irdependently chosen from hydrogen, lower alkyl, lower perfluoroalkyl (such as trifluoromethyl or pentafl~oroPthvl), lower alkoxy, lower alkylthio, cyano, and halogen. By lower alkyl is meant that these groupings contain from 1 to 4 carbon atoms. Halogen means F, Cl, Br, or I. For preferred compounds, X is 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 that the present invention is considered ~o include the various stereoisomers, e.g.
optical isomers including individual enantiomers, mixtures of enan~iomers, diastereomers, and mixture of diastereomers, which can arise as a consequence of structural asymetry due to the presence of one or two asymetric carbon atoms which may be incorporated in some compounds of the instant series.
Separation of the individual isomers is accomplished by application of vaxious methods which are well known to practitioners in the art. For medicinal use, the pharma-ceutically acceptable acid addition salts, those salts in which the anion does not contribute significantly to toxicity or pharmacological activitv of the organic cation may be preferred in some cases. The acid addition salts are obtained ei~her by reaction of an organic base of ,~ ~ ,7 .P,; . !; `

structure I with an organic or inorganic acid, preferably by contact in solution, or by any o~ the standard methods detailed in the ~iterature available to any practitioner skilled in the art. Examples of useful organic acids are carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acidt fumaric acid, isethionic acid, succinic acid, pamoic acid, cyclamic acid, pivalic acid, and the like; useful inoryanic acids are hydrohalide acids such as HCl, HBr, HI; sulfuric acids; phosphoric acids; and the like. Additionally, the present invention also encompasses any of the Formula I compounds existing in solvate form such as a hydrate.
The compounds of the instant invention can be conviently prepared by means of a general process which is shown in Scheme 1.

, .

Scheme 1 '' General ~nthetic Proces~:

C02C2H5 + Z-Cl ~¦3C2C2H5 ~ l3CHO
H z . Z
IX VIII
VII X

L~l RlM

[~}/ SOCl;~[~)H ~ cOHH_ Z Z
V VI VI ' < I .

IV
, ~ ~
~Z

I

~ 7~

In Scheme 1, the .symbols X, Y, and Z are as previouslv de~ined. Basically, a piperidine car~oxvlate ester (IX) i5 coupled with an appropriate diazine halide (VIII). While an ethyl ester and a chloride group are shown in compounds IX and VIII, respectively, in Scheme 1, other e~uivalent groups, e.g. another alkyl carboxylate ester and/or a different halogen may be used. These alterations would be familiar to an organic chemist skilled in synthesis o~ compounds. Typi.cally, the reaction of IX and VIII will take place in a reaction solvent such as acetonitrile in the presence of a base such as pota~sium carbonate, thereby giving the product (VII). The ~II product may-either be reduced with lithium aluminum hydride in an appropriate solvent such as tetrahydrofuran to give reaction intermediate VI (R1=~) or, alternatively, VII may be converted to the aldehyde X using standard methods for ester transformation into an aldehyde moiety, and this followed by treatment with an organo metallic reagent, R1M (wherein M
represents the appropriate metal cation or Grignard complex) to give the intermediate product VI'. The primary alcohol intermediate (VI) or secondary alcohol (VI') is treated with thionyl chloride to 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 a~d VIII
with a preferred reaction solvent in this case being dimethylformamide and incorporating a basé such as potassium carbonate. It will be understood by those skilled in the art that other conversions of VT intermedi~tes may be made ~hich would effectively convert the hydroxy group into a different leaving group (e.g. a tosylate or mesylate moiety) in order to facil1ta~e 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 i5 set forth as Scheme 2.
Scheme 2 Synthetic Proce ~

+ ClCx ~ ~ ~ -CX ~ J

IV X VIII

N2 ¦PtO2 ~ ~ 2~C1 ~ ~ ~

~ ~ 7~

In Scheme 2, Rl, X, Y, and Z are as previously defined. While the process outlined in Scheme 2 generally produces products of For~ula I in h.igher yielels than the aeneral process of Scheme 1, i~ does not have the general appllcability o Scheme 1. Because of the catalytic reduction tconversion of III to II) only cyclic amides/imides impervious to catalytic reduction may be used.
For example, when X is a 1,2-benzo ring, e.g. IV is phthalimide, the ben~o ring moiety is subsequently reduced to a 1,2-cyclohexyl derivative, thereby giving a hexahydro-phthalimide ring system.
To summarize the foregoing, there is described a process for the preparation of a compound of Formula I
: o X -CH ~
N-Z
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~ coupling compounds IX and VIII

~ CO2 N

VIII
IX

t~V ~

wherein R is a Cl ~ alkyl group and Q i6 a suitable displacernent group such ~s chloride, bromide, iodide r sul~ate, phos~hate, tosylate, me~ylate, or the like to give an intermediate product of Formula Vll;

' ~3 CO 2R

Z
VII
(2) treating the intermediate product, VII, with the metallic reagent RlM, wherein M is the appropriate metalloid ion or complex, eOg.
lithium aluminum hydrido or Grignard reagent complex, to give the reaction intermediate of Formula VI;
~ Rl N
z YI

(3) treating intermediate VI with an appropriate reagent to con~ert the 0~ group of VI to a leaving group Q in the compound of Formula V;

CHQ
Z
V
.,~ .

~ 3 and

(4) reacting intermediate V with a cyclic amide/imide compound of E`ormula IV
~~

~Y~
IV

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

IV

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

to give the intermediate compound of Formula III;

X~_~

III

~2) catalytically reducing the compound of Formula III to giv,e the piperidine intermediate compound of Formula II
o x~-c~ ~\1 ~J ~J

ard (3) coupling the compound of Formula II with compound Z-Q to give a product of Formula I.

Compounds of the instant invention have been evalua~ed for nootropic activity using as a primary screen the reversal of electroconvulsive shock-induced amnesia for a step-down passive avoidance response (cf: Banfis, et al., J. Pharmacol. Meth., 8, 255 (1982~; Janvik, Ann. Rev.
Psy~hol., 23, 457 (1972); and, Mc~augh and Petrinovich, Int.
Rev. ~ , 8, 139 (1965))o Reference compounds such as pramiracetam, piracetam, aniracetam, etc., having ~5 activity in this paradigm have been purported to affect memory processes and may be useful in treatîng ~enile dementia and Alzheimer's disease. In this test, 12 animals are administered drugs and 30 minutes later are trained to remain immobile to avoid foot shock. Immedia~ely following the training, the animals ar2 given electroconvulsive shock.

, ~ ~ 7~t~

Twenty-four hours later the animals are tested for retention of the learned beha~rior~ and any animal which remains on the platform for 300 seconds without stepping down is considered to have retained the passive avoidance respon~e. T~o groups of control animals are used for comparison; one ~roup receives vehicle with electroconvulsive shock and the other receives vehicle with 6ham-electroconvulsive shock. A test compound is considered active at a given dosage level if the mean latency to step-down is both statistically greater than the value for the electroconvulsive shock control group (placebo control group) and not ~tatistically different from the value for the sham-electroconvulsive shock control ~roup.
A test compound is considered to have intermediate activi~y at a given dosage level if results or the drug qroup are statistically different from both control groups.
For ~he sake of comparison, all drugs were tested aftex sub-cutaneous 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-pyrimidinylj-4~piperidinyl]methyl]~2-pvrrolidinone, 1-[[1-(2-chloro-4-pyrimidinyl)-4-piperidinyl]methyl]-2-25 pyrrolidinone, 1-~1-(6-chloro-2-pyrazinyl)-4-piperidinyl]-methyl]~2-pyrrolidinone and, especially, 1-[[1-(2-trifluoro-methyl-4-pyrimidinyl) 4-piperidinyl]methyl]-2-pyrrolidinone.
Maintenance of comparable levels of potency in going from ~ 7~
subcutaneous to oral administration is a co~siderable dosing advantage and distinguishes the instant compouncls from agen~s described in prior art re~erences. Additionally, the instant compounds are not labile in acidic media which is another advantage in their manufacture, formulating, shipping and storage, as well as for dosing.
In summary of the foregoing discussion, the , instant compounds have nootropic properties particularly suited to their use in;cognition and memory enhancement.
~hus t another aspect o the instant invention concerns a process for enhancing cognition and memory in a mammal in need of such treatment which comprises systemic admin-istration to such mammal of an effective dosP of a Formula I
compound or a pharmaceutically acceptable acid addition salt thereof. The administration ~nd dosag~ regimen of compounds of Formula I is considered to be done in the same manner as for the r2ferencs compound piracetam, cf: Reisberg, et al., in ~ Developmen_ Researchj 2:~75-480 (1982); Weng, ~_ .
et al., in Rational Dru~ Therapy, 17(5); 1-4 (1983), Reisberg, et aI~, in 'Psychopathology in the Aged", Editors, ; ~ole and Barrett, Raven Press, New York, pages 243-245 (19801 and pramiracetam, cf: Butler, et al, J. Med. Chem., 27, pp 684 6gl (1984).

In addition to the usefulness of the compounds of Formula I as cognition enhancing agents or mild stimulants ~ of the central nervous system, the compounds have been found ,~ to be useful in preventing amnesia which ~esults from ~ 7~
electroconvulsive shock. Such activity not only relates to memory retention in normal aging and senility processes but would be useful in protecting ayainst the amnesia-producing effects of electrocanvulsant shock as it i5 used clinically.
Electroconvulsant shock is employed to treat some classes of psychiatric patients, particularly depressed patients who are refractory to tradi~ional pharmacologic therapy. It is well documented that these electroconvulsant shock treatments induce the undesirable side-effect of amnesia in those patients to whom it is administered. The instant compounds which exhibit activity in protecting against the amnesia-producing effects of electroconvulsant shock in pharmacologic testing would be useful adjuncts to the clinical use of electroconvulsant shock in psychiatric treatment, Although the dosage and dosage regimen must in each case be carefully adjusted, utilizing sound professional judgment and considerin~ 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 g to about 10 g, 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 apparent to one skilled in clinical pharma-cology, the amount of Formula I compound comprising the daily dose may be given in a single or divided dose, taking ~ 7~7~j i~to account those principles understood by the skilled practitioner and necess~ry for his practice of the art.
The term "systemic administration" a~ used herein refers to oral, ~ublingual, buccal, nasal, dermal, rectal, intramuscular, intravenous, and subcutaneous routes.
Generally, it will be found that when a compound of the present invention is administered orally which i9 the preferred route, a slightly larger auantity of the active ; drug is required to produce the same e~fect as a somewhat ; lO smaller quantity when given parenterally. In accordance with good clinical practice, it is preferred to administer the instant compound at a concentration level which will produce effective nootropic effects without causing any harmful or untoward side eff~cts.
Therapeuticallv, the instant eompounds are generally given as pharmaceutical compositions comprised of an effective nootropic amount of a compound of Formula I or a pharmaceutically' acceptable acid addition salt thereof and a pharmaceutically acceptable carrier. Pharmaceutical compositions for effecting ~uch treatment will contain a major or minor amount (e.g. from 95% to 0.5%) of at least one compound of the present invention in combination with a pharmaceutical carrier, the carrier comprising one or more solid, semi-solid, or liquid diluent, ~iller 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 . 19 s~

a pre-determined amount of the drug corresponding to a fraction or multiple of the dose which i9 ca]culated to produce the desired therapeutic response. In usua] prac~
tice, the dosage units contain l, l/2, l/3, or less of a single dose. A single do~e 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, usuallv a whole, half, third, or less of the 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 composi~ions 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 ~inding ayents (e.g., syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone), fillers (e.g. lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine~, lubricants (e.g. magnesium stearate, talc, poly ethylene glycol or silica), disintegrants ~e.g. starch) and wetting agents (e.g. sodium lauryl sulfate). Solutions or suspensions of a Formula I compound with conventional pharmaceutical vehicles are employed for parenteral compo-sitions such as an aqueous solution for intravenous injec-tion or an oily suspension for intramuscular injection.

2n ~ ~71r~7~
Such composition~ having the desired claritv, stability and adaptability for parenteral use are obtained by dissolvlng from about 0.1~ to 10% by weight of the activ~ compound in w~ter or a vehicle consisting of a polyhydric aliphatic alcohol such as glycerine, propylene glycol~ and the polv-ethylene glycols or mixtures thereof. The polyethylene glycols consist of a mixture of non-volatile r usually llquid, polvethylene glycols which are soluble in both water and organic liquids and which have molecular weights from about 200 to 1500.

The compounds which constitute this invention and their methods of preparation as well as their biological activity will appear more fully from a consideration of the following examples which are given for the purpose of illustration only and are not to be constru~d as limiting the invention in sphere or scope. All temperatures are understood to be in degrees C when not specified, The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (~) expressed in parts per million tppm) versus tetramethylsilane (TMS) as reference standard.
The relative area reported for the various shifts in the proton (PNR) spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature o the shift as to multiplicity is reported as broad singlet (bs), singlet (~), multiplet (m), doublet (d), doublet of doublets (dd), triplet (t), or ~7~

quartet (q). Abbreviations employed are DMSO-d6 (perdeuterodimethylsulfoxide), CDC13 (deuterochloroform) and are otherwise conventional. The inErared (IR) spectxal deseriptions include only absorption wave numbers (cm 1) having functional group identification value. The IR
determinations were employed using potassium bromide (KBr) as diluent. All compounds gave satisfactor~ elemental analysis.

2 [[1-~2-Pyrimidinyl)-4-piperidinyl]-methvl]-l~-isoindole- ~
This synthetic sequence exemplifies the more general synthesis outlined in Scheme 1, supra.
A. Ethyl 1-(2 ~ e 4-carboxylate (VII).- A mixture of ethyl isonipecotate (IX;
31.44 g, 0.2 mole), 2-chloropyrimidine (VIII; 22.91 g, 0.2 mole), and potassium carbonate l27O6g g, 0.2 mole) in acetonitrile t250 mL~ was refluxed for 24 hour. The mixture was filtered and the filtrate concentrated in acuo. The residue was distilled (130-170 at 0.32 Torr.) to give 44.1 g ~94%) of product in the form of a clear oil.
B. 4-~ydrox~methyl-1~(2 pyrimidinyl?piperidine (VI).~ A solution of the ester (VII; 20 g, 0.085 mole) in tetrahydrofuran (200 mL) was cooled to 0-5 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 m~ 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 th~ filtrate concentrated in vacuo to given an oil which was distilled to give 15 g (91%) of a clear oil produet~ b.p. 140-190 at 0.3 torr.
C. 4-Chlorometh 1-1-(2- rimidin 1) i eridine .___ _ _ Y _ ~ ~
(V).- A solution of the hydrox~methyl compound (VI; 7.73 gr 0.04 mole) in methylene chloride (40 mL) was cooled to 0-5 and thionyl c~loride (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 so~ium bicarbonate, and the methylene chloride layer concentrated ln vacuo. The residue was chromatographed on silica gel using ethyl acetate as the eluent to give 7.7 g (91%) of product as an oil.
D. Reaction of Intermediate V and Phthalimide.-A mixture of potassium carbonate (2.76 g, 0.02 mole), ; phthalimide (1.47 g, 0.01 mole), and 4-chloromethyl-1-(2~
~o pyrimidinyl)piperidine ~V; 2.12 g, 0.01 mole) in dimethyl-- formamide (50 mL) was heated to about 50 for 24 hour~ the dimethylformamide solvent was removed ln 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 yiel~ 0.95 g (20.5%) of product in the form of white crystals, m.p. 109-111.

~ ~ 7~ ~
Anal. Calcd. for C~8H18NqO : C, 67-06; H, 5-64;

~, 17.38. FCUnd: C, 66.95; H, 5.68; ~, 17.17, NMR (CDC13): 1.35 (2,m); 1.74 ~2,rn); 2.10 (l,m);

2,85 (2,m); 3.61 (2,d, 7.0 HZ); 4.76 (2,m); 6.40 (l,t, 4.8 ~z); 7,79 (4,m) r 8.27 (2,d, 4.8 ~z).

IR (KBr): 730, 800, 1360, 1400, 1515, 1540, 1590, ~710, 1750, and 2930 cm 1, 1-[[1-(2-Pyrimidinyl;-4-piperidinyl]methyl]-2-pvrrolidlnone This experimental sequence exemplifies the synthetic process that can be used when X of the Formula I
compound is an alkylene chain (see Scheme 2, ~E~
A 1-[(4 Pi eridinYl)meth 1]-2- rrolidinone _ P __ Y _E~.Y
~ 15 H drochloride Hvdrate (II).- A solution of Y~
1-(4-pvridinylmethyl)-2-pyrrolidinone hydrochloride (III;
15.05 g, 0.0707 mole; prepared from 2-pyrrolidinone and 4~pyridinylmethyl chloride), HCl (10 mL of an 8N solution in absolute ethanol) and a~solute ethanol ~100 m~) was ~; 20 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 g (83%) of product as a white powder, m.p. 212-214.

B R action of Intermediate Com ound II With , e 2 Chlorop~rim dine.- A mixtuxe of the piperidinylmethyl-pyrrolidinone (II; 5.08 g, 0.0232 mole), 2-chloropyrimidine (2.67 g, 0.0233 mole) and potassium carbonate (7.09 g, 0.0513 mole) in dime~hylformamide (60 mL) was heated in a 50-100 oil bath for 14 hour. ~he mixture was cooled and filtered. The solven~ was then removed ~n vacuo and the residue chromatoyraphed on silica gel using an ethyl acetate-acetone mixture as the eluent to give 4.7 g l78%) of product as white crystals, m.p. 144-147.
Anal- Calcd- for C14H20N4 C~ 64-59; H~ 7-74;
N, 21.52~ Found: C, 64,26; ~, 7.78; N, 21.20.
NM~ (CDCl3): 1.29 (2,m); 1.71 (2,m); 2.01 (3,m);
2.34 ~2,t, 7.4 Hz); 2,84 (2,m); 3.16 (2,d, 7.0 Hz); 3 39 (2,t, 6.8 Hz); 4.73 ~2,m); 6.40 (l~t, 4.7 ~z); 8.26 (2,d, 4.7 Hz).
IR (KBr): 800, 1360, 1440, 1515, 1540~ 1585, 1675, and 2g30 cm 1~.

1-[ll-(2-Chloro-4-pyrimidinyl)-4-piperidinyl~methy~l]-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 (14.30 g, 0.1 mole), sodium carbonate (26.5 g, 0.25 mole), and 200 mL dimethylformamide was stirred for 14 hour at room ~emperature and then heated ko 70 for one hour. The mixture was filtered and concentrated in vacuo. The crude residue was chromatographed on silica usin~ ethyl acetate/methanol (95:5) as the eluent thereby separating the product residue into two comyonents. The major component was obtained as 16 g (59%~ of off-white powder, m.p.

110-114, and represented the desJred 2-chloro-4-pyrimidinyl i~om~r.
Anal. Calcd. for C14~19ClN4O: C, 57.04; H, 6.50;
N, 19.01. Found: C, 56.73; H, 6.44; M, 18.97.
NMR (CDC13l: 1.30 (2,m); 1.78 (2,m); 2.03 (3,m);
2.3g (2,t, 7.4 Hz); 2.92 (2,m); 3.17 (2,d, 7.0 Hz); 3 40 (2,t, 6.8 Hz); 4.35 ~2,m); 6.39 (l,d, 6.0 Hz); 7.98 1,d, 6.0 Hz).
IR (XBr): 96S, 1150, 1350, 1360, 1490, 1590, 1685, 2860, and 2950 cm 1.

1-~[1-(4-Chloro-2-pyrimidinyl)]-4~

The other isomer, the 4-chloro-2-pyrimidinyl compound, was obtained from the smaller component obtained by chromatography and recrystallization from ethvl acetate of the reaction product of Example 3 (above) to give 1.1 g (4%) of white crystal~, m.p. 143.5-145.5.
Anal. Calcd. for C14H1gClN4O: 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 (l,d, 4 Hz); 8.13 (l,d, 4 Hz).
IR (KBr): 1275, 1350, 1419, 1512, 1525, 1588, and 1688 cm 1.

: ~6 1-[~1-(6-Chloro 2 pyrazinyl)-4-i eridinYl~methvl~-2-pyrrolidinone P P . ~
Using the procedure described above in Examples 2 and 3, a mixture of 1-[(4-piperidinyl)methyl]-2-pvrroli-dinone hydrochloride ~II, 12.5 g, 0.0556 mole); 2,6-di-chloropyrazine ~S.37 g, 0.0556 mole); potassium carbonate (19.2 g, 0.139 mole); and DMF (150 mL) was stirred at room temperature for 14 hour and then heated to 70 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%) of tan crystals, m~p.
139-142.
Anal. Calcd. for C14HlgClN4O: C, 57.04; H, 6.50;
N, 19,01. Found: C, 57.02; H, 6.40; N~ 19.03.
NMR (CDC13): 1.34 (2,m); 1.77 (2,m); 2.05 (3,m~;
2.40 (2,t, 7.2 ~z); 2.91 (2,~); 3.18 (2,d, 7.0 Hz); 3.40 (2,t, 6.8 H2); 4.30 (2,m); 7.74 ~l,s); 7.96 (l,s~.
IR (KBr): 835, 1140, 1275, 1415, 1460, 1490, 1500, 1565, 1685, 2840, and 2945 cm 1.

1-[[1-[2-tTrifluoromethyl)~4-pyrimidinyl]-4-piperidinyl]meth~]-2-pyrrolidinone Using the procedure des~ribed above in Examples 2 and 3, a mixture of 1-[(4-piperidinyl)methyl]-2-pyrroli-dinone hydrochloride (II, 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 ln vacuo, and acetonitrile ~150 mL) was added to the residue.

7~

~he mixture was cool.ed and stirred as 4-chloro-2 (trifluoro~
methyl)-pyrimidine 118.28 g, 0.1 mole) was added. The mixture was stirred at room temperature for 18 hours and then filtered and the filtrate concentrated l.n vacuo to give a thick residue which solidiied 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 g as white crystals, m.p. 118.5-120.5.
Anal. Calcd. for C15 19 3 4 N~ 17.07. Found: C, 54.50; ~, 5.86; N, 16.80.

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

,7 ~ t"
7~ "~
Table 1 Compounds of Formula I

Xr~-CH ~-Z
~Y~
I

; Piperidine a o ~ Ex. R1 X Y Rinq-link Z Formula m.p.( ) 7 H ~2H4 2 ~ C14H20 4 lOi.5 H -C2H4- C~2 ~ ~ C14H20N4 110-113 9 H C2~4 2 ~ Cl C14Hl9CIN4 138-K -C2K4- CK2 4~ ~ ~ C15K21FF4S 96-100 C H4- CH2 4~ ~ } C14H19 4 134-136 12 H -C2H4- C~ 4~ ~ Cl4Hl8cl~N4o 140-144 13 H C2H4 2 ~ 1 C14H18C12N4 114.5 N

14 H C2 4 ~ ~ C14Hl9ClN4 142 5 Cl ~Lqf~'7f ~
Table 1 - Continued Piperidine z a Ex. R X Y _n~ C,1 Formula m~ ~ ) HC2 4 2 ~ C15H21ClN4 16 E~_C2~4-CH2 4- ~ C15H21ClN4104-107 17 HC2H4 2 ~ Br C14Hl91~rN4143-146 18 H-C2H4--CH2 4~ ~O}Cl C14Hl9ClN4130-133 19 H-C2H4- CH2 ~(~ I cl4HlgIN4 13i . 5 5Me H-C2H4 CH2 ~ C15~l21C1N4S134-137 C1 Cl 21 Ei-C2H4-C:E12 ~ C1~H18C12N4O135-138 22 H-C2H4- CH2 4- ~ cl4~1gBr(~lN4O 105-115 Br OMe 23 H--C H4-CH2 4-- ~ C15E~22N4O2116-121 CN
2 4 H -C2H4 CEI2 ~ ~ . 2 H30 142 Table 1 - Continued Piperidine ~ O
Ex. Rl X Y ~ Z Formula' m~.~( ) H1~ 2-C6E~4 CH2 4~ C18 20 4 176 178 26 HC21~4 CH2 ~ C16H19F5N4 105-107-5 27 H-C2H4- C~2 Cl C15H18ClF3N4O 102-N~F3 28 H--C2H4- CH2 4- _~ ~60~'~F~N~ 132 5--a. C, H, and N analyses were all within ~ 0.4% of the calculated value .

d ~' f .~

EXAMPLE ;29 Reversal o~ ECS-induced Amn~sia for ~ ld~nce ~ y~
In the step-down passiv~e avoidance procedure, rats are trained to remain immobile to avoid foot shock. Two control ~roups (n=36/group~ were required; and ECS control and a sham-ECS control. ECS control animals were placed individually on a plat~orm over an activated shock grid (O.8 mA) 30 min. after vehicle administration. The animals readily ~tepped down from the platform, immediately experienced the ~oot shock, and quickly leaxned to escape to the platform. An animal was considered to have acquired the passive avoidance response if it remained on the platform ~or 2 minutes without stepping down following foot shock delivery~ Immediately after acquisition, the ECS control animals were delivered ECS via transcorneal electrodes at an intensity o~ 50 nA for 400 msPc. ~he sham-ECS control animals were treated in a manner identical ko that described for the ECS controls, with the exception that current was not passed through ~he transcorneal electrodes. Both groups - were administered a retention test 24 hours later. Animals were plased individually on the platform, and the latency to step down from the platform onto the unactivated shock grid was recorded; a given subject animal ~onsidered to have retained the passive avoidance response if it remained on the platform for 300 seconds without steppina down.
Sham-ECS controls remain on the platform during this test, ~ 7~j showing normal retention; ECS controls readily stepped down within 300 seconds, exhibitin~ a deficit in retention (i.e., amnesia).
St~p-down latency scores w~re trans~ormed into percent retention scores with 300 seconds equal lO0~
retention. The ~ercent retention scores for all drugs groups were evaluated against both the ECS and sham-ECS
control groups using Dunnett's test. A compound was considered to be active in this test if the mean retention score obtained from at least one dose group i~ both significantly greater than the ECS control group retention and not significantly different from the sham-ECS control group retention. This indicates that the test compound reversed the amnesia for the passive avoidance task induced by the ECS. The compounds which statistically raised the animal's performance above that of the ECS control group, ; but did not raise the 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 animal~' performance, but not suf~iciently to give tota~ protection against the amnesi~.
The biological activities o~ 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 o~ ECS-incluced Amne~ia ECS-Induced Ex. Name Amnesia Reversal -- pramiracetam (reference activea at 10 mg/kg s.c.
compound) 1 2 [[1-(2-Pyrimidinyl)-4- active at 10 mg/kg s.cO
piperidinyl]methyl]-lH-isoindole-1,3-(2H)-dione 2 1 [[1-(2-Pyrimidinyl)-4~ act ve at 10 mg/kg s.c.
piperidinyl]methyl~-2- and p.o.
pyrrolidinone 15 3 1~[[1-(2-Chloro-4 active at 0.5 mg/kg s.c.
pyrimidinyl~-4-piperidinyl~- and p.o.
methyl]-2-pyrrolidinone 1-[~1~(6-Chloro-2 active at 0.5 mg/kg s.c.
pyrazinyl)-4-piperidinyl]-methyl]-2-pyrrolidinone 6 1-l[1 [2-(Trifluoro)-4- active at 0.25 to 10 pvrimidinyl]-4-piperidinyl3- mg/kg p.o., active at methyl]-2-pyrrolidinone 0.5 to 10 mg/kg s.c.
7 1-[[l-(2-Pyrimidinyl) 3- active at 25 mg/kg s.c.
: 25 piperidinyllmethyl]-2-pyrrolidinone 8 1-[[l-(2-Pyximidinyl~-2- active at 25 m~/kg s.c.
piperidinyl]methyl]-2-pyrrolidinone 30 9 1-[11-(6-ChlorQ-3- active at 25 mg/kg s.c.
pyridazinyl)-4-piperidinyl~
methyl]-2-pyrrolidinone 1-[11-(5~Fluoro-4-(methyl- intermediate activitv thio)-2-pyrimidinyl]-4- at 10 and 25 mg/kg s.c.
piperidinyl]methyl]-2-pyrrolidinone l-t5-Fluoro-2- active at 10 mg/kg s.c.
pyrimidinyl)-4-piperidinyl]-methyl]-2-pyrrolidinone Table 2 - Continued ECS-Induced EY. Name Amnesia Reversal _.__ __ _ 12 1-[[1-(2,6-Dichloro-4- active at 1.0 mg/kg s.c.
pyrimidinyl)-4-piperidinyl~-methyl]-2-pyrrolidinone 13 1-[fl-(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.
piperidinyl]methyl]-2 pyrrolidinone lS 15 1-[[1-(2-Chloro-6-methyl- intermediate activity 4-pyrimidinyl)-4- a~ 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.
methylJ-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-Iodo-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-piperidinvl]-- p.o.
methyl]-2-pyrrolidinone : 23 1-[[1~(2-Methoxy-4- intermediate activity pyrimidinyl)-4-piperidinyl]- at 10 mg/kg p.o.
methyl]-2-pyrrolidinone 24 4-f4 f(2-Oxopyrrolldin- active at 25 mg/kg p.o.
1-yl)methyl]-1-piperidinyl]-2-pyrimidinecarbonitrile 26 1-~ [2-(Pentafluoroethyl)- intermediate activity 4-pyrimidinyl]-4-piperi- at 10 mg/kg dinylJmethyl]-2-pyrrolidinone ~ ~ 7~7 Table 2 ~ Continued EC~ Induced Ex. Name Amnesia Rever~al 27 1-[[1 [5-Chloro-2~ intermediate activity ~tri~luoromethyl)~4~ at 10 mg/kg p.o.
pyrimidinyl]-4-piperidinyl]-methyl~-2-pyrrolidinone 28 1-[[1-~,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 pxotection.

Claims (34)

WHAT IS CLAIMED IS:

1. A compound selected from the group of 1,2-,1,3-, and 1,4-disubstituted piperidines of Formula I

I

wherein X is an ethylene chain or a 1,2-benzo ring;
Y is a carbonyl group or -CH2-, with the proviso that Y is carbonyl only when X is a 1,2-benzo ring;
R1 is selected from hydrogen or C1-4alkyl;
and Z is an R2-, R3-disubstituted diazine bonded through a carbon atom thereof and selected from pyrimidine, pyridazine and pyrazine, with R2 and R3 being independently chosen from hydrogen, lower (C1-4)alkyl, lower alkoxy, lower alkylthio, cyano, tri-fluoromethyl, pentafluorethyl, and halogen and connected at carbon atoms of the diazine;
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. A compound of claim 2 wherein R2 and R3 are independently selected from hydrogen, halogen, and trifluoromethyl.

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

6. The compound of claim 1, 1-[[1-(2-pyrimi-dinyl)-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-piperidinyl]methyl]-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-pyrimi-dinyl)-3-piperidinyl]methyl]-2-pyrrolidinone.

12. The compound of claim 1, 1-[[1-(2-pyrimi-dinyl)-2-piperidinyl]methyl]-2-pyrrolidinone.

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

22. The compound of claim 1, 1-[[1-(5-chloro-2-pyrimidinyl)-4-piperidinyl]methyl]-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-pyrroli-: dinone.

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

: 40

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

28. The compound of claim 1, 4-[4-(2-oxo-pyrrolidin-1-yl)methyl]-1-piperidinyl]-2-pyrimidine-carbonitrile.

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

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. A process to produce a compound of the Formula I

I

as defined in claim I, which process comprises alternatively (A) reacting a compound of the formula IX
wherein R is a C1 to C6 alkyl group with a compound of the formula Z - Q
wherain Z is as above and Q is a suitable displacement group;
(B) reacting the product of (A) with a metallic reagent of the formula wherein R1 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 Q; and (D) reacting the product of (C) with a cyclic amide/imide of the formula IV

wherein X and Y are as above to provide the product of Formula I or alternatively to 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 of the formula IV
with a compound of the formula wherein R1 and Q are as above (B') catalytically reducing the product of (A') and (C') coupling the product of (B') with a compound of the formula Z - Q
wherein Z and Q are as above to produce a compound of Formula I.

34. The process of claim 33 wherein Q is a displacement group selected from the group consisting of a chloride, bromide, iodide, sulfatel phosphate, tosylate or mesylate group.