Anxiolytic agents which are racemic or optically active pyrido[1,2-a]pyrazine derivatives of the formula ##STR1## wherein x is N or CH and Y represents one of certain pyrazolo, triazolo, tetrazolo or cyclic imido radicals; and intermediates therefor.

BACKGROUND OF THE INVENTION 
The present invention is directed to certain racemic and optically active 
pyrido[1,2-a]pyrazine derivatives, as defined by the formula (I) below, 
which are useful as antidepressants and as anxiolytic agents; and to 
intermediates therefor, as defined by the formulas (II) and (III), below. 
Anxiety and depression are common afflictions which adversely affect a 
significant portion of the human population. These afflictions are 
frequently found in association in the same individual. It has been known 
for many years that the symptoms of anxiety in human subjects can often be 
alleviated by the administration of certain chemical substances, which in 
this context are called antianxiety agents, or anxiolytics. In modern 
medical practice, a widely-used class of anxiolytics is the 
benzodiazepines, such as diazepam, but these products suffer certain 
disadvantageous properties such as undesired sedative activity. More 
recently a number of 1-(2-pyrimidinyl)-4-[4-(cyclic-imido)butyl]piperidine 
derivatives have been disclosed as anxiolytic agents which are generally 
lacking such sedative activity. Among these are busipirone, where the 
cyclic-imido group is 4,4-tetramethylene-piperidine-2,6-dion-1-yl (Wu et 
al., U.S. Pat. Nos. 3,717,634 and 3,907,801; Casten et al., U.S. Pat. No. 
4,182,763); gepirone, where the group is 
4,4-dimethylpiperidine-2,6-dion-1-yl (Temple, Jr., U.S. Pat. No. 
4,423,049); and ipsapirone, where the group is 
1,1-dioxobenzo[d]isothiazol-3(2H)-on-2-yl (Dompert et al., German patent 
publication 3,321,969-A1). See also Ishizumi et al., U.S. Pat. Nos. 
4,507,303 and 4,543,355; Freed et al., U.S. Pat. No. 4,562,255; Stack et 
al., U.S. Pat. No. 4,732,983; and New et al., U.S. Pat. No. 4,524,026. 
Such agents as busipirone and gepirone have now been shown to possess 
antidepressant activity. See for example, Schweizer et al., Psychopharm. 
Bull., v. 22, pp. 183-185 (1986), and Amsterdam et al., Current. Therap. 
Res., v. 41, pp. 185-193 (1987). See also Stack, U.S. Pat. No. 4,788,290 
describing certain 2-pyrimidinylpiperazine derivatives as having combined 
anxiolytic and antidepressant activity. 
The present bis-aza-bicyclic compounds generally show minimal in vivo 
stimulation of dopaminergic systems, reflective of reduced or minimal 
neurological side effects in the clinical use of these compounds. 
SUMMARY OF THE INVENTION 
The present invention is directed to certain bis-aza-bicyclic compounds, 
viz., racemic or optically active compounds of the formula 
##STR2## 
and the pharmaceutically acceptable acid addition salts thereof, wherein 
##STR3## 
--Y.sup.1 (CH.sub.2).sub.n or Y.sup.1 (CH.sub.2).sub.n substituted on 
carbon with up to methyl groups; 
n is 1 or 2; and 
Y.sup.1 is CH.sub.2, NH or NCH.sub.3. 
In the compounds of the formula (I), for ease of preparation and high 
activity, the preferred values of Y are 
##STR4## 
Within this subseries, regardless of the value of X, the most preferred 
value of Z is CH.sub.2 CH.sub.2. The preferred value of X is N. For their 
maximal anxiolytic activity, the optically active compounds having 
absolute stereochemistry defined by the formula (I) are preferred. The 
most highly preferred compound is 
7S,9aS-2-(2-pyrimidinyl)-7-(succinimidomethyl)-2,3,4,6, 
7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine, i.e., the optically active 
compound of the formula (I) wherein X is N, Y is 
##STR5## 
Z is Y.sup.1 (CH.sub.2).sub.n, Y.sup.1 is CH.sub.2 and n is 1. 
The nomenclature employed herein is that of the I.U.P.A.C., Nomenclature of 
Organic Chemistry, 1979 Ed., Pergammon Press, New York. Alternative names 
for the nucleus of the present bis-aza-bicyclic compounds are 
perhydro-1H-pyrido[1,2-a]pyrazine, 2,4a-diazaperhydronaphthalene, and 
1,4-diazabicyclo[5.5.0]decane. 
Said pharmaceutically acceptable acid addition salts include but are not 
limited to those with HCl, HNO.sub.3, H.sub.2 SO.sub.4, H.sub.3 PO.sub.4, 
pCH.sub.3 C.sub.6 H.sub.4 SO.sub.3 H or HOOCCH.sub.2 CH.sub.2 COOH. 
The present invention also encompasses pharmaceutical compositions 
containing an anxiolytic or antidepressant amount of a compound of the 
formula (I) as the essential active ingredient in a pharmaceutically 
acceptable carrier; and methods for treating hyperanxiety or depression in 
a human being which comprises administering to said human an anxiolytic 
effective or antidepressant amount of a compound of the formula (I). 
The present invention is also directed to intermediate compounds which are 
racemic compounds of the formula 
##STR6## 
wherein, in a first alternative: A is hydrogen; 
B is (C.sub.1 -C.sub.3)alkoxycarbonyl; and 
X.sup.1 is C.dbd.O; 
in a second alternative; 
A is hydrogen or 
##STR7## 
X is N or CH; X.sup.1 is CH.sub.2 ; and 
B is HOCH.sub.2 ; 
and in a third alternative 
A is 
##STR8## 
X.sup.1 is CH.sub.2 ; B is Y.sup.2 CH.sub.2 ; 
Y.sup.2 is HO--, RSO.sub.2 O, H.sub.2 N--, N.sub.3 -- 
##STR9## 
R is (C.sub.1 -C.sub.3)alkyl, phenyl or tolyl; and to optically active 
compounds of the formula 
##STR10## 
wherein X is N or CH; Y.sup.3 is HO--, RSO.sub.2 O--, R.sup.1 COO--, or 
H.sub.2 N--, 
R is (C.sub.1 -C.sub.3)alkyl, phenyl or tolyl; and 
R.sup.1 is (C.sub.1 -C.sub.3) alkyl; or an optically active acid salt 
thereof when Y.sup.3 is H.sub.2 N. The preferred salt is that with 
(-)-mandelic acid.

DETAILED DESCRIPTION OF THE INVENTION 
The compounds of the above formula (I) are readily prepared by a number of 
methods. One general method, which is the preferred method for all racemic 
compounds and the preferred method for optically active compounds when Y 
is other than an imido group, is to displace the sulfonate ester group of 
a racemic or optically active compound of the formula 
##STR11## 
H with an anion Y.sup.-, wherein R, X and Y are as defined above, and 
Y.sup.- represents the anion of a salt MY where M is most simply an 
alkali metal such as sodium. When the required salt is not available 
commercially, as is most frequently the case, it is convenient to form the 
required salt in situ in the form of the sodium salt, e.g., irreversibly 
by the action of sodium hydride on the compound of the formula Y-H; or 
reversibly by reaction with a base such as Na.sub.2 CO.sub.3 which is not 
itself nucleophilic. This process is representative of such displacement 
reactions in general. It is generally carried out in a reaction 
inert-solvent, preferably one which is aprotic and certainly one which is 
less acidic than the compound Y-H. Particularly useful solvents in the 
present instance are acetonitrile and dimethylformamide. Temperature is 
not generally critical in this process, but, in order to achieve complete 
conversion within a reasonably short period of time, elevated 
temperatures, e.g., 90.degree.-120.degree. C., are generally preferred. 
Also for the purpose of forcing this second order displacement reaction to 
completion within a reasonable period of time, a molar excess of one of 
the reactants, usually the more readily available salt, MY, is generally 
employed in this process. Methyl is the preferred value of R in this 
process, for ease of preparation of the mesylate ester and for the facile 
displacement of the mesylate anion. The product is isolated by 
conventional methods of concentration, evaporation, extraction, 
chromatography and crystallization, with, if direct formation of an acid 
addition salt is desired, addition of an appropriate acid in an 
appropriate amount, e.g., addition of one molar equivalent of HCl if the 
mono-hydrochloride salt is desired. 
As used in the preceding paragraph and elsewhere herein, the expression 
"reaction-inert" solvent refers to a solvent which does not interact with 
reactants, reagents, intermediates or products in a manner which adversely 
affects the yield of the desired product. 
A second general method for preparation of compounds of the formula (I) is 
to directly couple an alcohol of the formula 
##STR12## 
with the heterocycle or imide of the formula YH, where again X and Y are 
as defined above. The preferred coupling reagent is an approximately 1:1 
molar mixture diethyl azodicarboxylate and triphenylphosphine. Usually, 
about 2 to 2.1 molar equivalents of these reagents are used in coupling 
equimolar amounts of YH and the alcohol (V). The preferred solvents are 
relatively polar ethers such as tetrahydrofuran, dioxane or 
1,2-dimethoxyethane, the first of these being particularly well-suited. 
Temperature is not critical, although somewhat elevated temperatures 
(e.g., the reflux temperature of tetrahydrofuran) are preferred, in order 
to achieve complete reaction in a reasonable period of time. 
The compounds of the formula (I) wherein the group Y is an imido group are 
also generally prepared from the corresponding amine of the formula 
##STR13## 
by the action of an anhydride of the formula 
##STR14## 
wherein X and Z are as defined above. This is the preferred method for 
preparation of optically active compounds of the formula (I) when Y is an 
imido group (excluding those compounds wherein the group Z contains an NH 
group, where the anhydride has the potential to polymerize). According to 
this alternative method, the amine (VI) and the anhydride (VII), generally 
in about molar equivalents, are heated to about 100.degree.-160.degree. C. 
in a reaction inert solvent. Particularly well suited as solvent here are 
mixed xylenes boiling in the range of about 138.degree.-142.degree. C. The 
reaction is then conveniently carried out at the reflux temperature of 
said mixed xylenes. 
The required racemic and optically active starting materials of the above 
formulas (IV), (V) and (VI) are prepared via the synthetic routes 
summarized in Flowsheet 1. While the overall route and the various 
intermediates are novel, the individual chemical steps are generally 
analogous to known chemical trans-formations. Generally suitable 
conditions are found in the prior art. Particularly well-suited conditions 
are exemplified below. 
The anxiolytic activity of the compounds of the formula (I) is demonstrated 
and measured using a variation of the Vogel anti-conflict test. See Vogel 
et al., Psychophamacologia, 21, 1 (1971). In this test, groups of rats are 
deprived of water for 48 hours, and then presented an opportunity to drink 
water from an electrified spout. The number of times that the rats drink 
water (and therefore also receive an electric shock) during a 10 minute 
period is measured for rats which have been dosed with a test compound 
##STR15## 
(treated rats). This number is compared with the number obtained for 
control rats, i.e., rats which have not received the test compound. An 
increase in the number of times that treated rats drink water, over the 
number of times that control rats drink water, is indicative of 
antianxiety activity in the compound being tested. 
The antidepressant activity of the compounds of the formula (I) is 
determined by examining their ability to attenuate clonidine-induced 
hypolocomotion in rats. In this test, groups of rats are dosed p.o. with 
vehicle and with test compound in vehicle once a day for four days. 
Twenty-four hours after the last treatment, half of the control, vehicle 
treated rats and all the remaining rats receive clonidine (0.1 mg/kg) s.c. 
in a second vehicle. The remaining control rats receive s.c. vehicle only. 
Horizontal locomotor activity is then measured for 6 hours. Clonidine 
significantly reduces exploratory locomotor activity ("crossovers"). This 
effect is significantly attenuated in rats also receiving present test 
compounds. Several studies have shown that clinically effective 
antidepressant treatments attenuate the behavioral responses induced by 
the alpha.sub.2 -adrenergic agonist, clonidine. For references, see Cohen 
et al., Eur. J. Pharmacol., v. 81, pp 145-148 (1982); Pilc et al., Brain 
Res., v. 238, pp 499-504 (1982) and Eur. J. Pharmacol., v. 80, pp 109-113 
(1982). 
For use in alleviating the symptoms of anxiety and/or depression in a human 
subject, a compound of the formula (I), or a pharmaceutically-acceptable 
salt thereof, is administered in an antianxiety or antidepressant amount 
of about 2-200 mg/day, in single or divided daily doses. In particular 
cases, dosages outside that range are prescribed at the discretion of the 
attending physician. The preferred route of administration is generally 
oral, but parenteral administration (e.g., intramuscular, intravenous, 
intradermal) will be preferred in special cases, e.g., where oral 
absorption is impaired as by disease, or the patient is unable to swallow. 
The compounds of the present invention are generally administered in the 
form of pharmaceutical compositions comprising at least one of the 
compounds of the formula (I), or a salt thereof, together with a 
pharmaceutically acceptable vehicle or diluent. Such compositions are 
generally formulated in a conventional manner utilizing solid or liquid 
vehicles or diluents as appropriate to the mode of desired administration: 
for oral administration, in the form of tablets, hard or soft gelatin 
capsules, suspensions, granules, powders and the like; and, for parenteral 
administration, in the form of injectable solutions or suspensions, and 
the like. 
The present invention is illustrated by the following examples, but is not 
limited to the details thereof. 
EXAMPLE 1 
cis-2-(2-Pyrimidinyl)-7-(succinimidomethyl)-2,3,4,6,7, 
8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine 
Method A 
A flame-dried flask -fitted with magnetic stirring and a nitrogen inlet was 
charged with succinimide (0.95 g; 9.6 mmol) in dry dimethylformamide (25 
ml). Sodium hydride (0.49 g of 60% mineral oil dispersion; 12.2 mmol) was 
added all at once, and the resulting mixture was stirred and heated at 
70.degree. C. for 1 hour. 
cis-7-(Methanesulfonyloxymethyl)-2-(2-pyrimidyl)-2,3,4,6,7,8,9,9a-octahydr 
o-1H-pyrido[1,2-a]pyrazine (1.56 g; 4.8 mmol) was added, and the stirred 
mixture heated at 110.degree. C. for 18 hours. Concentration in vacuo 
afforded a solid, which was dissolved in 25 ml of CH.sub.2 Cl.sub.2. An 
equal volume of water was added, and the pH of the well-stirred mixture 
was adjusted to 2.0 (6N HCl). The separated organic phase was extracted a 
second time with an equal volume of water at pH 2.0. Finally, the organic 
phase was extracted with an equal volume of water at pH 10.0 (saturated 
Na.sub.2 CO.sub.3). The basic aqueous phase was separated, and extracted 
2.times.150 ml CH.sub.2 Cl.sub.2. The latter organic layers were combined, 
treated with activated carbon, dried (Na.sub.2 SO.sub.4) and concentrated 
in vacuo to afford a colorless amorphous foam, which was crystallized from 
35 ml of isopropanol to afford 1.14 g (72%) of title compound as colorless 
crystals, mp 183.degree.-184.degree. C. TLC Rf 0.43 (9:1 CH.sub.2 Cl.sub.2 
: CH.sub.3 OH) HRMS 329.1906, calcd. 329.1854. 
.sup.13 C-NMR(250 MHz, CDCl.sub.3) delta 177.4, 161.4, 157.7, 109.6, 61.0, 
57.9, 54.7, 48.8, 43.5, 40.7, 32.2, 28.1 24.9, 24.4 
Method B 
To a magnetically stirred solution of triphenylphosphine (262 mg, 1.0 mmol) 
and diethylazodicarboxylate (0.174 ml, 192 mg, 1.05 mmol) in 8 ml of dry 
tetrahydrofuran, a solution consisting of succinimide (99 mg, 1.0 mmol) 
and cis-7-(hydroxymethyl)-2-(2pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-p 
yrido[1,2-a]pyrazine (248 mg, 1.0 mmol) in 20 ml of dry tetrahydrofuran was 
added dropwise over one hour. The reaction was refluxed for 18 hours; and 
then concentrated in vacuo to an oil. The oil was dissolved in methylene 
chloride/water mixture (35 ml of each). The pH of the well-stirred mixture 
was then adjusted to 2 with 6N HCl, and the phases were then separated. 
The organic phase was combined with 10 ml of water, and the pH of the 
mixture likewise adjusted to 2. The two acidic aqueous extracts were 
combined and stirred with an equal volume of methylene chloride while the 
pH was adjusted to 10 with saturated Na.sub.2 CO.sub.3. The phases were 
separated and the aqueous phase was extracted twice with fresh 50 ml 
portions of methylene chloride. The three organic extracts were combined, 
treated with activated carbon, dried (Na.sub.2 SO4) and stripped to an oil 
which was crystallized from isopropanol to yield 31 mg (9.5%) of present 
title product identical with that of Method A. 
Method C 
A solution of 
cis-7-(aminomethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido 
[1,2-a]pyrazine (149 mg, 0.6 mmol), succinic anhydride (60 mg, 0.6 mmol) in 
xylenes (9 ml, constant boiling range 138.degree.-142.degree. C.) was 
refluxed for 18 hours. The reaction was concentrated in vacuo to an oil, 
which was taken up in methylene chloride (30 ml). An equal volume of water 
was added, and the pH of the well-stirred mixture adjusted to 2.0 (6N 
HCl). The phases were separated, and the organic phase was extracted with 
a fresh portion of water at pH 2. The combined acidic extracts were 
stirred with methylene chloride (40 ml) with the pH adjusted to 10.0 
(saturated Na.sub.2 CO.sub.3) The phases were separated, and the aqueous 
phase was extracted twice with fresh 40 ml portions of methylene chloride. 
The basic organic extracts were combined, treated with activated carbon, 
dried (Na and concentrated in vacuo to a solid which was crystallized from 
7 ml of isopropanol to yield 164 mg (83%) of the title compound as 
colorless crystals, identical with the products of methods A and B. 
EXAMPLE 2 
cis-7-(Substituted 
methyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyraz 
ines 
The following additional title compounds were prepared according to Method 
A of the preceding Example, substituting the appropriate imide or 
heterocycle for succinimide. Shown is the substituent, its yield, and its 
properties. All .sup.13 C-NMR indicate values at 300 MHz in CDCl.sub.3, 
unless otherwise specified. If unspecified, the TLC eluant was 9:1 
CH.sub.2 Cl.sub.2 : CH.sub.3 OH on 0.25 mm silica gel 60F.sub.254 plates. 
3,3,4-Trimethylsuccinimido (9.7%); crystallized from ethyl acetate:hexane; 
TLC Rf 0.58; HRMS 371.2274, calcd. 371.2321. 
.sup.13 C-NMR 183.2, 179.4, 161.3, 157.6, 109.5, 60.9, 57.9, 54.7, 48.8, 
45.8, 43.5, 43.0, 40.2, 32.3, 32.1, 24.7, 24.3, 21.2, 10.2 
Thiazolidine-2,4-dion-3-yl (19.5%); amorphous; HRMS 347.1478, calcd. 
347.1426. 
.sup.13 C-NMR 171 9, 171.6, 161.3, 157.6, 109.6, 60.9, 57.8, 54.7, 48.9, 
43.9, 43.6, 33.7, 32.2, 24.9, 24.5 
meso-3,4-Dimethylsuccinimido (50%); crystallized from CH.sub.2 Cl.sub.2 : 
isopropanol; mp 141.degree.-142.degree. C.; TLC Rf 0.56. 
.sup.13 C-NMR (250 MHz) 179.7, 161.5, 157.7, 109.5, 61.1, 58.0, 54.8, 49.0, 
43.7, 43.0, 40.6, 32.3, 25.0, 24.5, 15.2 
3-Methylsuccinimido (46.5%); crystallized from CH.sub.2 Cl.sub.2 : 
isopropanol; mp 168.degree.-172.degree. C.; TLC Rf 0.51; HRMS 344.2011, 
calcd. 344.2086. 
.sup.13 C-NMR (250 MHz) 180.7, 176.7, 161.5, 157.1, 109.6, 61.1, 58.1, 
54.8, 49.0, 43.7, 40.7, 36.5, 34.6, 32.3, 25.0, 24.5, 17.0 
3-Methylimidazolidine-2,5-dione-1-yl (28.9%); crystallized from ether; mp 
106.degree.-108.degree. C.; TLC Rf 0.42; HRMS 344.1968, calcd. 344.1960. 
.sup.13 C-NMR 170.0, 161.3, 157.7, 157.1, 109.5, 61.0, 57.9, 54.8, 51.6, 
48.9, 43.6, 40.9, 32.5, 29.6, 24.8, 24.4 
3-Azabicyclo[3.2.1]octane-2,4-dion-3-yl (21%); TLC Rf 0.44; HRMS 369.2205, 
calcd. 369.2167. 
.sup.13 C-NMR 176.7, 161.2, 157.6, 109.4, 60.9, 58.3, 54.7, 48.8, 44.8, 
44.7, 43.5, 40.5, 32.5, 32.4, 27.1(2), 24.8, 24.7 
Piperidine-2,6-dion-1-yl (10%); crystallized from CH.sub.2 Cl.sub.2 
:hexane; mp 146.degree.-148.degree. C.; TLC Rf 0.37; HRMS 343.2011, calcd. 
343.2011. 
.sup.13 C-NMR 172.7, 161.4, 157.7, 109.5, 61.1, 58.5, 54.8, 48.9, 43.6, 
41.4, 33.0, 32.7, 25.0, 24.8, 17.2 
4,4-Dimethylpiperidine-2,6-dion-1-yl (14.5%); crystallized from ethyl 
acetate; mp 212.degree.-213.degree. C.; TLC Rf 0.51; HRMS 371.2276, calcd. 
371.2322. 
.sup.13 C-NMR 172.2, 161.4, 157.7, 109.5, 61.1, 58.6, 54.9, 48.9, 46.5, 
43.6, 41.5, 32.9, 29.0, 27.7, 25.1, 24.8 
8-Aza-spiro[4.5]decane-7,9-dion-8-yl (31.9%); crystallized from 
isopropanol; mp 172.degree.-173.degree. C.; TLC Rf 0.49; HRMS 397.2450, 
calcd. 397.2480. 
.sup.13 C-NMR (250 MHz) 172.4, 161.4, 157.7, 109.5, 61.1, 58.5, 54.9, 48.9, 
45.0, 43.5, 41.5, 39.4, 37.6, 32.9, 25.0, 24.7, 24.2 
5,5-Dimethyloxazolidine-2,4-dione-3-yl (20.8%); crystallized from ethyl 
acetate:hexane; mp 162.degree.-163.degree. C.; TLC Rf 0.65; HRMS 359.1936, 
calcd. 359.1957. 
.sup.13 C-NMR 176.1, 161.2, 157.5, 154.6, 109.5, 83.2, 60.8, 57.5, 54.6, 
48.8, 43.5, 41.5, 32.0, 24.6, 24.3, 23.5, 23.4 
Imidazolidine-2,5-dione-1-yl (33.6%); crystallized from CH.sub.2 Cl.sub.2 
:ether; mp 191.degree.-192.degree. C.; TLC Rf 0.30; HRMS 330.1804, calcd. 
330.1804. 
.sup.13 C-NMR 171.8, 161.3, 159.1, 157.6, 109.6, 61.0, 57.7, 54.7, 48.9, 
46.4, 43.5, 40.4, 32.4, 24.7, 24.4 
3,3-Dimethylsuccinimido (55.6%); crystallized from CH.sub.2 Cl.sub.2 
:isopropyl ether; mp 145.degree.-147.degree. C.; TLC Rf 0.53; HRMS 
357.2126, calcd. 357.2164. 
.sup.13 C-NMR 183.4, 175.9, 161.3, 157.6, 109.5, 61.0, 57.9, 54.7, 48.8, 
43.5(2), 40.4, 39.8, 32.2, 25.6, 24.8, 24.4 
Pyrazolo (23.8%); crystallized from ether; mp 86.degree.-88.degree. C.; TLC 
Rf 0.46; HRMS 298.1895, calcd. 298.1906. 
.sup.13 C-NMR 161.3, 157.8, 139.4, 129.8, 109.7, 104.8, 61.0, 56.6, 54.7, 
53.0, 49.0, 43.6, 34.6, 25.0, 24.7 
1,2,4-Triazol-1-yl (62.3%); crystallized from ethyl acetate:hexane; mp 
150.degree.-152.degree. C.; TLC Rf 0.37; HRMS 299.1853, calcd. 299.1858. 
.sup.13 C-NMR 161.3, 157.6, 152.0, 145.7, 109.8, 60.9, 56.2, 54.6, 50.4, 
48.9, 43.6, 33.9, 24.9, 24.6 
4,4-Dimethylimidazolidine-2,5-dion-1-yl (25%); crystallized from CH.sub.2 
Cl.sub.2 : ether, mp 189.degree.-190.degree. C.; TLC Rf 0.35; HRMS 
358.2074, calcd. 358.2000. 
.sup.13 C-NMR 177.8, 161.2, 157.6, 156.9, 109.5, 60.9, 58.4, 57.6, 54.6, 
48.8, 43.5, 40.0, 32.3, 25.0, 24.6, 24.3 
Tetrazol-2-yl (30.5%); amorphous; TLC Rf 0.64; HRMS 300.1792, calcd. 
300.1809. 
.sup.13 C-NMR 161.2, 157.5, 152.8, 109.6, 60.8, 56.6, 54.5, 54.1, 48.8, 
43.5, 34.3, 24.9, 24.4 
4,5-Dihydro-1H,3H-pyrimidine-2,6-dion-1-yl (46%); crystallized from 
isopropanol:ether, mp 190.degree.-192.degree. C.; TLC Rf 0.36; HRMS 
344.1919, calcd. 344.1960. 
.sup.13 C-NMR 169.8, 161.4, 157.7, 155.5, 109.5, 61.1, 58.4, 54.9, 48.9, 
43.6, 42.0, 35.3, 33.0, 31.8, 25.4, 24.8 
5-Methyl-4,5-dihydro-1H,3H-pyrimidine-2,6-dione-1-yl (23%); crystallized 
from ethanol; mp 201.degree.-202.degree. C.; TLC Rf 0.35; HRMS 358.2118, 
calcd. 358.2117. 
.sup.13 C-NMR 172.9, 161.4, 157.7, 155.4, 109.5, 61.1, 58.4, 54.9, 48.9, 
43.6, 42.4, 42.3, 42.1, 35.8, 33.2, 33.0, 24.9, 13.4 (extra peaks due to 
diastereomers) 
4-Methyl-4,5-dihydro-1H,3H-pyrimidine-2,6-dione-1-yl (55%); crystallized 
from CH.sub.2 Cl.sub.2 :ether; mp 202.degree.-208.degree. C.; TLC Rf 0.38; 
HRMS 358.2128, calcd. 358.2117. 
.sup.13 C-NMR 169.6, 161.4, 157.7, 155.2, 109.5, 61.1, 58.4, 54.9, 48.9, 
43.5, 42.4, 42.0, 39.3, 33.2, 32.9, 24.9, 24.8, 20.8 (excess peaks due to 
diastereomers) 
EXAMPLE 3 
cis-7-(Substituted 
methyl)-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazines 
Substituting the analogous 2-(2-pyridyl)mesylate ester for the 
2-(2-pyrimidinyl)mesylate ester, the following additional title compounds 
(specified as in the preceding Example) were prepared by Method A of 
Example 1. 
3-Methylimidazolidine-2,5-dion-1-yl (8.9%); crystallized from CH.sub.2 
Cl.sub.2 :isopropyl ether; mp 142.degree.-143.degree. C.; TLC Rf 0.43; 
HRMS 343.1978, calcd. 343.2018. 
.sup.13 C-NMR 170.0, 159.2, 157.0, 147.8, 137.3, 112.8, 106.8, 60.7, 57.7, 
54.6, 51.5, 50.5, 45.0, 40.7, 32.5, 29.5, 24.7, 24.5 
4,4-Dimethylpiperidine-2,6-dion-1-yl (31.7%); crystallized from ether; mp 
134.degree.-135.degree. C: HRMS 370.2321, calcd. 370.2368. 
.sup.13 C-NMR 172.2, 159.3, 147.9, 137.4, 112.9, 106.9, 60.9, 58.5, 54.8, 
50.6, 46.5, 45.0, 41.5, 32.9, 29.1, 27.7, 25.1, 24.9 
Succinimido (36.3%); crystallized from CH.sub.2 Cl.sub.2 :ether; mp 
164.degree.-165.degree. C.; TLC Rf 0.41; HRMS 328.1880, calcd. 328.1899. 
.sup.13 C-NMR 177.4, 159.2, 147.8, 137.3, 112.9, 106.8, 60.7, 57.9, 54.6, 
50.5, 45.0, 40.6, 32.1, 28.1, 24.8, 24.5 
8-Azospiro[4.5]decane-7,9-dion-8-yl (25.3%); TLC Rf 0.42 (ethyl acetate); 
HRMS 396.2562, calcd. 396.2525. 
.sup.13 C-NMR 172.4, 159.3, 147.9, 137.3, 112.9, 106.9, 60.9, 58.5, 54.8, 
50.6, 45.0(2), 41.5, 39.3, 37.6, 32.9, 25.0, 24.9, 24.2 
5,5-Dimethyloxazolidine-2,4-dion-3-yl (27.3%); crystallized from CH.sub.2 
Cl.sub.2 : ether; mp 171.degree.-173.degree. C.; HRMS 358.2040, calcd. 
358.2005; TLC Rf 0.56. 
.sup.13 C-NMR 176.3, 159.2, 154.8, 147.9, 137.4, 113.0, 106.9, 83.4, 60.7, 
57.5, 54.6, 50.6, 45.1, 41.6, 32.1, 24.7, 24.5, 23.6(2) 
4-Methylsuccinimido (28%); crystallized from isopropyl alcohol; mp 
145.degree.-150.degree. C.; TLC Rf 0.47; HRMS 342.2036, calcd. 342.2056. 
.sup.13 C-NMR 180.8, 176.6, 159.3, 147.9, 137.4, 113.0, 106.9, 60.9, 58.0, 
54.7, 50.7, 45.1, 40.6, 36.4, 34.6, 32.3, 24.9, 24.6, 16.9 
Tetrazolo (36%); amorphous; TLC Rf 0.48 (ethyl acetate); HRMS 299.1778, 
calcd. 299.1859. 
.sup.13 C-NMR 159.1, 152.7, 147.8, 137.3, 113.0, 106.9, 60.6, 56.6, 54.4, 
54.1, 50.5, 45.1, 34.3, 24.9, 24.5 
4,4-Dimethylsuccinimido (40%); crystallized from ethyl acetate:hexane; TLC 
Rf 0.45 (ethyl acetate); HRMS 356.2230, calcd. 356.2218 
.sup.13 C-NMR 183.5, 176.0, 159.3, 147.9, 137.4, 113.0, 106.9, 60.9, 57.9, 
54.7. 50.6, 45.1, 43.6, 40.6, 39.9, 32.3, 25.6(2), 24.8, 24.6 
4,4-Dimethylimidazolidine-2,5-dion-1-yl (37%); crystallized from CH.sub.2 
Cl.sub.2 ; isopropyl ether; mp 170.degree.-171.degree. C.; TLC Rf 0.28 
(ethyl acetate); HRMS 357.2203, calcd. 357.2166. 
.sup.13 C-NMR 177.8, 159.3, 157.0, 147.9, 137.5, 113.0, 107.0, 60.9, 58.6, 
57.7, 54.7, 50.7, 45.1, 40.3, 32.5, 25.1(2), 24.7, 24.6 
Imidazolidine-2,5-dion-1-yl (45%); TLC Rf 0.22; HRMS 329.1903, calcd. 
329.1854. 
.sup.13 C-NMR 171.9, 159.3, 159.1, 147.8, 137.5, 113.1, 107.1, 60.8, 57.7, 
54.6, 50.7, 46.5, 45.1, 40.5, 32.4, 24.7, 24.6 
1,2,4-Triazol-1-yl (18.7%); crystallized from isopropyl ether:hexane; mp 
109.degree.-110.degree. C.; HRMS 298.1943, calcd. 298.1906; TLC Rf 0.37. 
.sup.13 C-NMR (250 MHz) 159.2, 152.1, 147.9, 143.6, 137.4, 113.2, 107.0, 
60.8, 56.2, 54.6, 50.6, 50.5, 45.2, 33.9, 25.0, 24.7 
Piperidine-2,6-dion-1-yl (22.8%); crystallized from CH.sub.2 Cl.sub.2 
:isopropyl ether; mp 114.degree.-115.degree. C.; TLC Rf 0.44; HRMS 
342.2043, calcd. 342.2055. 
.sup.13 C-NMR (250 MHz) 172.8, 159.3, 147.9, 137.4, 112.9, 106.9, 60.9, 
58.4, 54.8, 50.6, 45.0, 41.5, 33.0, 32.8, 25.0(2), 17.2 
4-Methyl-4,5-dihydro-1H,3H-pyrimidine-2,6-dion-1-yl (47%); crystallized 
from isopropanol; mp 184.degree.-186.degree. C.; TLC Rf 0.35; HRMS 
357.2155, calcd. 357.2164. 
.sup.13 C-NMR 169.6, 159.3, 155.0, 147.9, 137.4, 112.9, 106.9, 60.9, 58.3, 
54.8, 50.6, 45.0, 42.4, 42.1, 39.4, 33.2, 32.9, 24.9, 20.8 (excess peaks 
due to diasteromers). 
5-Methyl-4,5-dihydro-1H,3H-pyrimidine-2,6-dione-1-yl (40%); crystallized 
from isopropanol; mp 182.degree.-183.degree. C.; TLC Rf 0.34; HRMS 
357.2147, calcd. 357.2165. 
.sup.13 C-NMR 172.9, 159.4, 155.5, 147.9, 137.4, 113.0, 107.0, 60.9, 58.4, 
54.8, 50.6, 45.1, 42.4, 42.3, 42.0, 35.7, 33.3, 33.0, 25.0, 13.4 
Dihydro-1H,3H-pyrimidine-2,6-dione-1-yl (67%); crystallized from 
isopropanol; mp 190.degree.-191.degree. C.; TLC Rf 0.28, HRMS 343.1975, 
calcd. 343.2011. 
.sup.13 C-NMR 169.8, 159.4, 155.4, 147.9, 137.4, 113.0, 107.0, 60.9, 58.3, 
54.8, 50.6, 45.1, 42.0, 35.3, 33.0, 31.8, 25.0, 24.9. 
Thiazolidine-2,4-dion-3-yl (63%); crystallized from isopropanol; mp 
159.degree.-160.degree. C.; TLC Rf 0.47 (19:1 ethyl acetate:CH.sub.3 OH); 
HRMS 346.1528, calcd. 346.1463. 
.sup.13 C-NMR 171.9, 171.7, 159.3, 148.0, 137.5, 113.1, 107.0, 60.8, 57.8, 
54.6, 50.6, 45.1, 44.0, 33.7, 32.2, 24.9, 24.6. 
EXAMPLE 4 
cis-7-(Succinimidomethyl)-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octahydro-1H-Pyrid 
o[1,2-a]pyrazine 
By method B of Example 1, 
cis-7-(hydroxymethyl)-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octrahydro-1H-pyrido[ 
1,2-a]pyrazine (247 mg, 1.0 mmol) and succinimide were converted to 231 mg 
(70%) of present title product as crystals from isopropyl alcohol, 
identical to the material prepared in the preceding Example. 
EXAMPLE 5 
cis-7-[(8-azaspiro[4.5]decane-7,9-dion-8-yl)methyl]-2-(2-pyrimidinyl)-2,3,4 
,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine 
By method C of Example 1, 
cis-7-(aminomethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-H-pyrido- 
[1,2-a]pyrazine (142 mg, 0.57 mmol) and 3,3-tetramethyleneglutaric 
anhydride (96 mg, 0.57 mmol) were converted to 105 mg (46%) of present 
title product as colorless crystals from isopropyl alcohol, identical to 
the material prepared in Example 2. 
EXAMPLE 6 
(7S,9aS)-2-(2-Pyrimidyl)-7-(succinimidomethyl)-2,3,4,6,7,8,9,9a-octahydro-1 
H-pyrido[1,2-a]pyrazine 
A mixture of 
(7R,9aS)-7-(Aminomethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octrahydro-1H- 
pyrido-[1,2-a]pyrazine (6.30 g, 0.025 mol) and succinic anhydride (2.80 g, 
0.028 mol) in 280 ml of mixed xylenes (b.p. 139.degree.-143.degree. C.) 
was heated to 100.degree. C., at which point dimethylformamide (4 ml) was 
added to affect complete solution. Using a Dean-Stark trap, the mixture 
was vigorously refluxed for two hours. The reaction solution was decanted 
from a tarry residue and concentrated in vacuo to amorphous solids, which 
were transferred to a well-stirred mixture of methylene chloride and water 
(250 ml of each) and the pH adjusted to 11 with 6N NaOH. The organic phase 
was separated, dried (Na.sub.2 SO.sub.4), and concentrated in vacuo to a 
colorless foam (6.4 g). Crystallization of the entire sample from hot 
isopropyl alcohol (250 ml) afforded 4.7 g (56%) of present title product, 
mp 211.degree.-212.degree. C.; [alpha].sub.D.sup.25 =-35.degree. (CH.sub.2 
Cl.sub.2). HRMS 329.1809, calcd. 329.1854. The .sup.13 C-NMR was identical 
to that of the racemic product of Example 1. 
Alternatively 5.0 mg (17%) of identical product, likewise crystallized from 
isopropanol, was prepared from (7S, 
9aS)-7-(hydroxymethyl)-2-(2-pyrimidinyl)2,3,4,6,7,8,9,9a-octahydro[1,2-a]p 
yrazine (17.1 mg, 0.069 mol) by Method A of Example 1. 
EXAMPLE 7 
cis-7-(Pyrazolomethyl)-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1 
,2-a]pyrazine 
cis-7-(Methanesulfonyloxymethyl)-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octahydro-1 
H-pyrido[1,2-a]pyrazine (350 mg, 1.0 mmol), pyrazole (439 mg, 6.5 mmol) and 
sodium carbonate (228 mg, 2.2 mmol) and 15 ml of acetonitrile were 
refluxed for 18 hours. The reaction mixture was cooled, stripped of 
solvent and the residue distributed between 20 ml each of CH.sub.2 
Cl.sub.2 and water. The well-stirred, 2-phase mixture was adjusted to pH 
10 with saturated Na.sub.2 CO.sub.3. The aqueous layer was extracted 
1.times.20 ml from CH.sub.2 Cl.sub.2. The organic layers were combined, 
dried (Na.sub.2 SO.sub.4) and stripped to solids, which were flash 
chromatographed on 6 g of silica gel with ethyl acetate as eluant to yield 
134 mg (42%) of title product as an amorphous solid. TLC Rf 0.43 (9:1 
CH.sub.2 Cl.sub.2 :CH.sub.3 OH); HRMS 297.1962, calcd. 297.1957. 
.sup.13 C-NMR (300 MHz, CDCl.sub.3) delta 159.3, 147.9, 139.3, 137.4, 
129.8, 113.1, 107.0, 104.9, 60.9, 56.6, 54.6, 53.1, 50.7, 45.2, 34.7, 
25.0, 24.9. 
PREATION 1 
Dimethyl Pyridine-2,5-dicarboxylate 
To a stirred slurry of 2,5-pyridinedicarboxylic acid (2407 g; 14.4 mol) in 
methanol (8.0 liter) at -5.degree. to -10.degree. C., thionylchloride 
(3430 g; 2.10 liters; 28.8 mol) was added dropwise while maintaining the 
temperature in the -5.degree. to -10.degree. C. range. After completing 
the addition, the reaction was allowed to warm to ambient temperature, and 
stirred for 18 hours. The resulting solution was concentrated in vacuo to 
a volume of 4 liters, and an equal volume of water was added. The pH of 
the well-stirred mixture was then adjusted to 10 with saturated aqueous 
sodium carbonate. Solids were removed by filtration. The organic layer of 
the filtrate was separated, washed with water (8 liters), and dried in 
vacuo to afford the title compound (2250 g; 80% yield) as an amorphous 
solid. 
PREATION 2 
Dimethyl cis- and trans-Piperidine-2,5-dicarboxylate Acetate 
The product of the preceding Preparation (2250 g; 11.53 mol) in glacial 
acetic acid (25 liters) was hydrogenated in the presence of 57 g platinum 
oxide as catalyst at 3.52 kg/cm.sup.2 pressure for 18 hours. The catalyst 
was recovered by filtration, and the filtrate concentrated in vacuo to 
afford a mixture of title acetate salts as a viscous amber syrup (2300 g, 
100% yield), sufficiently pure for use directly in the next step. 
PREATION 3 
Dimethyl cis- and trans-1-(Cyanomethyl)piperidine-2,5-dicarboxylate 
A well-stirred mixture of title product of the preceding Preparation (3000 
g, 11.53 mol), chloroacetonitrile (1.00 kg; 13.25 mol; 1.1 equivalents), 
sodium carbonate (8.00 kg; 75.5 mol; 6.5 equivalents), and potassium 
iodide (320 g; 1.90 mol; 0.17 equivalents) in methylisobutyl ketone (36 
liters), was refluxed vigorously for 18 hours. The reaction was cooled to 
room temperature, and solids were removed by suction filtration. The 
filter cake was extracted, first with methyisobutyl ketone (12 liters), 
and then with methylene chloride (30 liters). The original filtrate and 
both filtered extracts were combined and then concentrated in vacuo to 
afford the mixed title products (1400 g; 51% yield) as an amber oil. 
PREATION 4 
Methyl 
cis-1-Oxo-2,3,4,6,7,8,9,9a-octahydro-1H-Pyrido[1,2-a]pyrazine-7-carboxylat 
e 
Title product of the preceding Example (60.0 g, 0.25 mol) in methanol (1 
liter) and ethyl acetate (0.4 liter) was hydrogenated over Raney nickel 
(washed with water to pH 9 on a filter funnel; 93 g water wet) at 3.52 
kg/cm.sup.2 pressure for 18 hours. The catalyst was filtered, and the 
filtrate was concentrated in vacuo to an oil. Overnight crystallization 
from a methylene chloride/isopropyl ether (90 ml/120 ml respectively) 
afforded exclusively the desired cis isomer (title product) as colorless 
crystals, mp 166.degree.-168.degree. C. (dec.), (24.99 g; 47% yield); HRMS 
212.1156, calcd. 212.1162. 
.sup.13 C-NMR (300 MHz, CDCl.sub.3) delta 173.9, 171.2, 64.8, 64.7, 56.3, 
56.2, 51.7, 50.8, 40.6, 39.5, 25.0, 24.4 
PREATION 5 
cis-7-Hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine 
A flame-dried flask fitted with a magnetic stirrer, condenser, and nitrogen 
inlet was charged with a slurry of lithium aluminum hydride (14.88 g, 0.46 
mol) in 500 ml of dry tetrahydrofuran. Title product of the preceding 
Preparation (53.61 g, 0.25 mol) was added portionwise, in solid form, to 
the well-stirred mixture over a one hour period. The mixture was then 
reluxed under nitrogen for 18 hours. After cooling to 15.degree. C., the 
reaction was quenched by cautious dropwise addition of water (100 ml). The 
mixture was then filtered, and the filter cake was washed with 150 ml of 
tetrahydrofuran. The filtrate was concentrated in vacuo to a solid, which 
was extracted three times with one liter portions of methylene chloride. 
The tetrahydrofuran and methylene chloride extracts were concentrated in 
vacuo to afford the title compound (42.06 g, 97.8% yield) as an amorphous 
solid. HRMS 170.1413, calcd. 170.1419. 
.sup.13 C-NMR (300 MHz, CDCl.sub.3) delta 65.6, 62.6, 57.8, 56.0, 51.8, 
45.8, 34.7, 26.4, 26.0 
PREATION 6 
cis-7-Hydroxymethyl-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[ 
1,2-a]pyrazine 
A solution consisting of title product of the preceding preparation (19.7 
g; 0.12 mol), sodium carbonate (30.45 g; 0.29 mol) and 2-chloropyrimidine 
(13.6 g; 0.12 mol) in water (150 ml) was stirred and heated at 95.degree. 
C. for 14 hours. The reaction mixture was cooled, and then extracted with 
200 ml of methylene chloride. The organic extract was washed with water 
and then with brine (200 ml of each), stirred with activated carbon, 
filtered, dried (anhydrous sodium sulfate, and concentrated to an amber 
oil. Crystallization of the entire sample from methylene chloride/hexane 
(45 ml/150 ml, respectively) afforded 21.5 g (76.7% yield) of the title 
compound as colorless crystals, mp 135.degree.-136.degree. C. HRMS 
248.1622, calcd. 248.1637. TLC Rf 0.3 (CH.sub.2 Cl.sub.2 : CH.sub.3 OH 
9:1). 
.sup.13 C-NMR (300 MHz, CDCl.sub.3) delta 161.2, 157.6, 109.7, 65.5, 60.9, 
57.3, 54.8, 48.9, 43.4, 34.8, 26.1, 25.8 
PREATION 7 
cis-7-(Methanesulfonyloxymethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahyd 
ro-1H-pyrido[1,2-a]pyrazine 
To a well-stirred solution of the title product of the preceding 
Preparation (1.5 g; 6.0 mmol) and triethylamine (1.68 ml, 12 mmol) in 
methylene chloride (28 ml) chilled to 5.degree. C., a solution of 
methanesulfonyl chloride (0.70 ml; 9.0 mmol) in methylene chloride (7 ml) 
was added dropwise over 15 minutes. Within 10 minutes of stirring 
(5.degree. C.) following the methanesulfonylchloride addition, inspection 
of a reaction aliquot by thin layer chromatography (silica gel plates; 
elution with methylene chloride/methanol=9.1 by volume; UV detection) 
showed complete reaction. Water (50 ml) was added to the reaction mixture, 
and the pH of the well-stirred mixture was adjusted to 9.5 with saturated 
sodium carbonate. The organic phase was separated, washed five times with 
150 ml portions of water, dried (anhydrous sodium carbonate), and 
concentrated in vacuo to afford the title compound (1.87 g, 95.4% yield), 
sufficiently pure for use in the next step without further purification. 
The entire sample was dissolved in 3 ml of hot methylene chloride, to 
which hexane was added dropwise (ca 3 ml) until the solution became 
turbid. Stirring for one hour afforded 1.10 g of crystalline title product 
(colorless crystals), mp 141.degree.-142.degree. C. 
.sup.13 C-NMR (250 MHz, CDCl.sub.3) delta 161.3, 157.6, 109.7, 71.1, 60.8, 
55.7, 54.6, 48.9, 43.5, 36.9, 33.4, 24.7, 24.2 
PREATION 8 
cis-7-Hydroxymethyl-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2- 
a]pyrazine 
A mixture consisting of title product of Preparation 5 (9.10 g; 53.4 mmol), 
sodium carbonate (14.1 g; 0.13 mol), and 2-bromopyridine (25.5 ml; 42.3 g; 
0.27 mol) in isoamylalcohol (25 ml) was refluxed for 72 hours. The 
reaction was filtered while hot, and the filter cake washed with 50 ml of 
methylene chloride. The filtrate was concentrated in vacuo to an oil, 
which was taken up in 100 ml ethyl acetate. An equal volume of water was 
added, and the pH of the well-stirred mixture was adjusted to 11.5 
(saturated sodium carbonate). The organic phase was separated, treated 
with activated carbon, dried (anhydrous sodium sulfate), and concentrated 
in vacuo to an oil. Flash chromatography of the entire sample (125 g 
silica gel, 2-63 mesh; elution with methylene chloride/methanol=7:3 by 
volume) with TLC monitoring of fractions [product R.sub.f =0.26 (methylene 
chloride:methanol 9:1 in volume), detection by U.V. and Dragendorf's 
spray] afforded 7.50 g (56.6% yield) of the title compound as a pale 
yellow amorphous solid. 
.sup.13 C-NMR (300 MHz, CDCl.sub.3) delta 159.1, 147.8, 137.4, 113.2, 
107.0, 65.8, 60.7, 57.3, 54.7, 50.6, 45.0, 34.7, 26.2, 26.0 
PREATION 9 
cis-7-(Methanesulfonyloxymethyl)-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octahydro-1 
H-pyrido[1,2-a]pyrazine 
By the method of Preparation 7, the title product of the preceding Example 
(240 mg, 0.97 mmol) was converted to present title product (0.30 g, 94.7%) 
as a colorless oil. TLC Rf 0.34 (ethyl acetate). RMS 325.1475, calcd. 
325.1460. 
.sup.13 C-NMR (250 MHz, CDCl.sub.3) delta 159.2, 147.9, 137.5, 113.2, 
107.1, 71.2, 60.7, 55.7, 54.6, 50.7, 45.2, 37.0, 33.5, 24.9, 24.2 
PREATION 10 
cis-7-(Pthalimido)methyl-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-py 
rido[1,2-a]pyrazine 
Method A 
By Method A of Example 1, phthalimide (4.13 g, 36.5 mmol) and the title 
product of Preparation 7 (7.93 g, 2.43 mmol) was converted to present 
title product, as colorless crystals from warm isopropyl alcohol (1.86 g, 
20%); mp 161.degree.-162.degree. C. HRMS 377.1815, calcd. 377.1852. 
.sup.13 C-NMR (300 MHz, CDCl.sub.3) delta 168.4, 161.3, 157.6, 133.8, 
132.0, 123.0, 109.5, 61.0, 57.8, 54.7, 48.9, 43.5, 39.8, 32.9, 24.8, 24.4 
Method B 
By Method B of Example 1, phthalimide (147 mg, 1.0 mmol) and the title 
product of Preparation 6 (248 mg, 1.0 mmol) were converted to 31 mg (9.5%) 
of identical title product. 
PREATION 11 
cis-7-(Azidomethyl)-2-(2-pyrimidyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1, 
2-a]pyrazine 
Title product of Preparation 7, (57.1 g; 0.175 mol) and sodium azide (71.5 
g; 1.1 mol) in dry dimethylformamide (500 ml) was stirred 17 hours at 
100.degree. C. (oil bath). Stirring and heating was stopped, and the 
slurry of excess sodium azide was allowed to settle. The supernatant was 
carefully decanted, and then concentrated in vacuo to a light yellow oil. 
The residual sodium cake was extracted twice with 500 ml portions of 
methylene chloride. The oil was dissolved in the combined methylene 
chloride extracts. An equal volume of water was added, and the pH of the 
well-stirred mixture adjusted to 11.5 (6N sodium hydroxide). The organic 
phase was separated, dried (anhydrous sodium sulfate), and concentrated in 
vacuo to afford 48.2 g of title compound as a light-yellow oil. TLC Rf 
0.53 (ethylacetate). HRMS 273.1735, calcd. 273.1705. 
.sup.13 C-NMR (250 MHz, CDCl.sub.3) delta 161.3, 157.6, 109.6, 60.9, 56.7, 
54.6, 52.8, 48.9, 43.5, 33.7, 25.3, 24.7 
PREATION 12 
cis-7-(Aminomethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[ 
1,2-a]pyrazine 
Method A 
A suspension of the title product of Preparation 10 (1.86 g; 4.9 mmol) in 
ethanol (15 ml) and anhydrous hydrazine (0.156 ml; 158 mg; 4.9 mmol) was 
refluxed for 2.5 hours. The mixture was concentrated in vacuo to an oil. 
Concentrated hydrochloric acid (10 ml) was added, and the mixture refluxed 
for 3.5 hours. The reaction was filtered and the filtrate was concentrated 
in vacuo to a solid, all of which was dissolved in 15 ml of water and the 
pH adjusted to 10.0 (6N sodium hydroxide). The basic solution was 
extracted with 5.times.50 ml of methylene chloride, and the organic 
extracts combined, dried (anhydrous sodium sulfate) and concentrated in 
vacuo to afford 1.07 g (88%) of present title product as an amber oil. TLC 
Rf 0.50 (CH.sub.2 CH.sub.3 OH:conc. NH.sub.3 3:1:0.3). HRMS 247.1784, 
calcd. 247.1787. 
.sup.13 C-NMR (300 MHz, CDCl.sub.3) delta 161.3, 157.6, 109.5, 61.1, 57.0, 
54.9, 48.9, 43.4, 42.9, 36.6, 25.6, 24.9 
Method B 
A solution of the title product of the preceding Preparation (48.0 g; 0.176 
mol) in 800 ml of ethanol and 70 ml of ethyl acetate was hydrogenated at a 
pressure of 3.5 kg/cm.sup.2 in the presence of 24 g of 5% 
palladium-on-carbon catalyst for 2 hours. Filtration of the catalyst and 
in vacuo concentration of the filtrate afforded 34.8 g (80%) of title 
compound as a colorless oil which crystallized upon standing, with the 
product of method A. 
PREATION 13 
cis-7-(Pthalimido)methyl-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido 
[1,2-a]pyrazine 
By method B of Example 1, pthalimide (0.595 g, 4.1 mmol) and title product 
of Preparation 8 (1.00 g, 4.1 mmol) were converted to 1.02 g (67%) of 
present title product as colorless crystals from isopropanol, mp 
167.degree.-168.degree. C. HRMS 376.1900, calcd. 376.1900. .sup..sup.13 
C-NMR (300 MHz, CDCl.sub.3) delta 168.6, 159.3, 147.9, 137.4, 133.9, 
132.1, 123.2, 113.0, 107.0, 60.9, 57.8, 54.7, 50.7, 45.1, 39.9, 33.0, 
24.9, 24.6 
PREATION 14 
cis-7-(Azidomethyl)-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2- 
a]pyrazine 
By the method of Preparation 11, title product of Preparation 9 (1.0 g, 
3.06 mmol) was converted to 0.70 g (84%) of present title product as a 
colorless oil. HRMS 272.1739, calcd. 272.1750. 
.sup.13 C-NMR (300 MHz, CDCl.sub.3) delta 159.2, 147.7, 137.2, 112.8, 
106.8, 60.9, 56.9, 54.8, 50.5, 44.9, 43.1, 37.0, 25.6, 25.0 
PREATION 15 
cis-7-(Aminomethyl)-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2- 
a]pyrazine 
By Method A of Preparation 12, title product of Preparation 13 (0.484 g, 
1.29 mmol) was converted to 0.311 g (98%) of present title product as a 
colorless, viscous oil. TLC Rf 0.51 (CH.sub.2 Cl.sub.2 : CH.sub.3 OH: 
conc. NH.sub.3 1:0.3). HRMS 246.1861, calcd. 246.1844. 
Identical product (0.60 g, 95%) was prepared from title product of the 
preceding Preparation (0.70 g, 2.6 mmol) by Method B of Preparation 12. 
PREATION 16 
(7R-9aS)-7-(Aminomethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-py 
rido[1,2-a]pyrazine 
To a solution of the title product of Preparation 12 (33.54 g, 0.136 mol) 
in 1.44 1 of near-boiling isopropanol, (-)-mandelic acid (20.63 g, 0.136 
mol) was added with stirring to effect total dissolution. The stirred 
solution was allowed to cool slowly to ambient temperature; and 24 hours 
later a heavy crystalline mass was isolated by suction filtration, and 
dried in vacuo. The entire sample was dissolved in 1.85 l of hot 
isopropanol, and the resulting solution was allowed to cool to ambient 
temperature, and stir at that temperature for 72 hours, during which time, 
a heavy colorless crystalline mass formed. [14.0 g, 51.7% yield of the 
(-)-mandelic acid salt of present title product, mp 
202.degree.-203.degree. C. (dec.)]. The entire sample was dissolved in 
water (200 ml). An equal volume of methylene chloride was added, and the 
pH of the well-stirred mixture was adjusted to 9.5 with 6N NaOH. The 
organic phase was separated, dried, and concentrated in vacuo to afford 
6.30 g (37.6%) of present title product as a colorless solid. 
EQU [alpha .sub.D.sup.25 =-36.7.degree. in methylene chloride (C=0.0337 g/ml)] 
The title product o the preceding Preparation is resolved by the same 
method to form (7R, 
9aS)-7-(Aminomethyl)-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1, 
2-a]pyrazine. 
PREATION 17 
(7S-9aS)-7-(Acetoxymethyl)-2-(2-pyrimidinyl)-2,3,4,5,6,7,8,9,9a-octahydro-1 
H-pyrido[1,2-a]pyrazine 
To title product of the preceding Preparation (180.4 mg, 0.73 mmol) in 2 ml 
of CHCl.sub.3 was added acetic acid (0.125 ml, 2.19 mmol) and isoamyl 
nitrite (0.108 ml, 0.802 mmol). The resulting mixture was refluxed for 4 
hours, cooled, diluted with 25 ml CHCl.sub.3 and then 10 ml H.sub.2 O, and 
adjusted to pH 10 with saturated Na.sub.2 CO.sub.3. The aqueous layer was 
separated and extracted with 20 ml CH.sub.2 Cl.sub.2. The organic layers 
were combined, treated with activated carbon, dried (Na.sub.2 SO.sub.4) 
and stripped to yield 188.5 mg of an oil, which was chromatographed on 
silica gel using 500 ml of 3:2 ethyl acetate:hexane as eluant, monitored 
by TLC (ethyl acetate). Desired product fractions (Rf 0.30) were combined 
and stripped to yield 58.5 mg (28%) of present title product. 
[alpha].sub.D.sup.25 =-35.9.degree. (CH.sub.2 Cl.sub.2). HRMS 290.1752 , 
calcd. 290.1742. 
.sup.13 C-NMR (300 MHz, CDCl.sub.3) delta 171.2, 161.4, 157.7, 109.6, 65.5, 
61.0, 56.4, 54.8, 48.9, 43.5, 33.0, 24.9, 24.7, 21.1 
By the same method the 2-(2-pyridyl) derivative of the preceding 
Preparation is converted to (7S, 
9aS-7-(acetoxymethyl)-2-(2-pyridyl)-2,3,4,6,7,8,9a-octahydro-1H-pyrido[1,2 
-a]pyrazine. 
PREATION 18 
(7S,9aS)-7-(Hydroxymethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H- 
pyrido[1,2-a]pyrazine 
Title product of the preceding Preparation (51.4 mg, 0.177 mmol) was 
dissolved in 1 ml of 1:1 H.sub.2 O:CH.sub.3 OH, and 6N NaOH (0.06 ml, 3.6 
mmol) was added. After stirring for 3 hours, the mixture was stripped of 
CH.sub.3 OH, the aqueous residue diluted with 25 ml CH.sub.2 Cl.sub.2 and 
10 ml H.sub.2 O, and the pH of the 2 phase system adjusted to 10. The 
separated aqueous layer was extracted 2.times.10 ml CH.sub.2 Cl.sub.2, and 
the organic layers combined, dried (Na.sub.2 SO.sub.4), stripped and the 
residue crystallized from CH.sub.2 Cl.sub.2 and isopropyl ether to yield 
27 mg of title product mp 160.degree.-162.degree. C. [alpha].sub.D.sup.25 
=-34.2.degree. (CH.sub.2 Cl.sub.2). HRMS 248.1647, calcd. 248.1638. 
By the same method, the pyridyl analog of the preceding Preparation is 
converted to (7S, 
9aS)-7-(hydroxymethyl)-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[ 
1,2-a]pyrazine. 
PREATION 19 
(7S-9aS)-7-(Methanesulfonyloxymethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-oc 
tahydro-1H-pyrido[1,2-a]pyrazine 
By the method of Preparation 9, the title product of the preceding 
Preparation (20.5 mg) was converted to present title product in 
essentially quantitative yield. TLC Rf 0.50 (9:1 CH.sub.2 Cl.sub.2 : 
CH.sub.3 OH). 
By the same method, the pyridyl analog of the preceding Preparation is 
converted to (7S, 
9aS)-7-(methanesulfonyloxymethyl)-2-(2-pyridyl)-2,3,4,6,7,8,9,9a-octahydro 
-1H-pyrido[1,2-a]pyrazole.