AP128A

AP128A - Bis-aza-bicyclic anxiolytic agents.

Info

Publication number: AP128A
Application number: APAP/P/1990/000158A
Authority: AP
Inventors: Kisor Amratal Desai; Gene Michael Bright
Original assignee: Pfizer
Priority date: 1989-01-23
Filing date: 1990-01-22
Publication date: 1991-03-20
Also published as: DE69000467T2; NZ232168A; RU2015977C1; ATE82574T1; GR3006925T3; EP0380217A1; IE62670B1; HU215154B; BA98302A; ES2053094T3; PT92919B; NO912863D0; DK0380217T3; IS1667B; PT92919A; CZ277698B6; BG51046A3; CA2008108A1; FI95381B; YU11190A

Abstract

The invention is directed to the provision of

Description

-13IS-AZA-BICYCLIC ANXIOLYTIC AGENTS

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 l-(2-pyrimidinyl)4-[4-(cyclic-imidc)butyl]piperidine derivatives have been disclosed as anxiolytic agents which are generally lacking such sedative activity. Amcr.g these are busipircne, where the cyclic-imido group is

AP 0 0 0 1 2 8

4.4- tetramethy lere-p iperidine-2,6-dicn- 1-yl (Wu et al., U.S. Patents 3,71’, 634 anc 3,90’,801; Caster, et al., U.S. Patent 4,182,763); gecircne, where the group is

4.4- dime thy Ipiper idir.e-2,6-dion-l-vl (Temple, Jr., U.S. Patent 4,423,049); and ipsapircne, where the group is

1,1-dicxobenzo(d]isothiazol—3 ( 2H)-on-2-yl bad original

I

-2(Dompert et al., German patent publication

3,321,969-A1). See also Ishizumi et al., U.S. Patents 4,507,303 and 4,543,355; Freed et al., U.S. Patent 4,562,255; Stack et al., U.S. Patent 4,732,983; and New et al., U.S. Patent 4,524,026.

Such agents as busipiror.e 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 (19S7). See also Stack, U.S. Patent 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.

The present invention is directed to certain bis-aza-bicyclic compounds, viz., racemic or optically active compounds of the formula

---(I) addition salts thereof, wherein

X is N or CH;

Y is

BAD ORIGINAL

-310

Ζ is

or

dc c

SCH₂, och₂,

-Υ* (CH-) or γΐ (CH.,) substituted on carbon with up to ί η i η ^r methyl groups;

n is 1 or 2; and

Y‘ is CH₂, NH or NCH₃.

In the compounds of the formula (I), for ease of preparation and high activity, the preferred values of Y are

AP000128

Within this subseries, regardless of the value of X, the most preferred value of Z is CH₂CH₂· The preferred value of X is N. For their maximal anxiolytic activity, the optically active compounds having absolute stereochemistry defined fcv the formula (I) are preferred. The most highly preferred compound is 7S,9aS-2-(2-pyrimidinyl)-7-(succinimidemethyl)-2,3,4,6, 7,8,9,9a-octahydro-lH-pyrido[1,2-aIpvrazine, i.e., the

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I optically active compound of the formula (I, wherein X is N, Y is

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-lH-pyrido[1,2-aJpyrazine, 2,4a-diazaperhydronaphthale.ne, and 1,4-dia2abicyclo[5.5.0]decane.

Said pharmaceutically acceptable acid addition salts include but are not limited to those with HC1, HNO₃, H₂SO₄, H₃PO₄, pCH₃C_gH₄SO₃H or HOOCCH^CHjCOOH.

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 cf a compound of the formula (I).

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-5ΙΟ

IS

The present invention is also directed to intermediate compounds which are racemic compounds of the formula

wherein, in a first alternative:

A is hydrogen;

B is alkoxycarbonyl; and

X¹ is C=0;

in a second alternative;

A is hydrogen or

X is N or CH;

X^I is CH₂; and ‘

B is HOCHj,· and in a third alternative A is

X‘ is CH₂;

is Y²CH₂;

AP000128

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R is alkyl, phenyl or tolyl;

and to optically active compounds of the formula

wherein X is N or CH;

Y³ is HO-, RSOjO-, R^COO-, or HjN-,

R is (C^-C^)alkyl, phenyl or tolyl; and

R^ is (C.-C.)alkyl; or an optically active acid ^{1 J} 3 salt thereof when Y is H^*¹· ^T^^e preferred salt is that with (-)-mandelic acid.

The compounds of the above formula (1) are readily prepared by a number of methods. Cr.e 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 tc displace the

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-7sulfonate ester group of a racemic or optically active compound of the formula

---(IV) with an anion Y~, wherein R, X and Y are as defined above, and Y~ 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 Na₂CO₃ 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., 90-120*C, are generally preferred. Also for the purpose of forcing this second order disolacement reaction to ccmcletion within a

APO0012 8

BAD ORIGINAL Op)

-8reasonable 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 HC1 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

with the heterocycle or imide of the again X and Y are as defined above.

formula YH, where The preferred bad

-9coupling 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

AP 0 0 0 1 2 8 ₂₅ by the action of an anhydride of the formula

Z 0 ---(VIZ) wherein X and Z are as defined above. This is the preferred method for preparation of optically active

BAD ORIGINAL ft

-10compcunds 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 100-160’C in a reaction inert solvent. Particularly well suited as solvent here are mixed xylenes boiling in the range of about 138-142*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 transformations. Generally suitable conditions are found in the prior art. Particularly well-suited conditions are exemplified below.

The anxiolytic a’ctivity cf 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 43 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

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Flowsheet 1

MeO^C

(i)-cis/trans

HO

/

MeO-C (i)-(IV, (±) - (V)

Q = phthalimido or N, (i)-(VI)

Z I 0 0 0 dV (-)- (IV) 4i \'^V

R C0₂ H* \Ϋλ^Η

N

(-)

(-)-(V)

-12(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 al'so receiving present test compounds. Several studies have shown that clinically effective antidepressant treatments attenuate the behavioral responses induced by the alpha₂»adrenergic agonist, clonidine. For references, see Cohen et al., Eur. J. Pharmacol., v. 81, pp 145-148 (1982); Pile et al., 3rain Res., v. 238, pp 499-304 (1982, and Eur. J. Pharmaccl., v. 80, pp 109-113 (1932).

bad original }

-13For 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 fora 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 net limited to the details thereof.

AP000128

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-1410

EXAMPLE 1 cis-2-(2-Pyrimidinyl)-7-(succinimidomethyl)-2,3,4,6,7,

8,9,9a-octahydro-lH-pyrido[1,2-a)pyrazine

Me thcd 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 dimethyl formamide (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”C for 1 hour.

cis-7-(Methanesulfonylcxymethyl)-2-(2-pyrimidyl)-2,3,

4,6,7,8,9,9a-octahydro-lH-pyrido(1,2-a]pyrazine (1.56 g; 4.8 mmol) was added, and the stirred mixture heated at 110°C for 18 hours. Concentration in vacuo afforded a solid, which was dissolved in 25 ml of

CHjC^. An equal volume of water was added, and the pH of the well-stirred mixture was adjusted to

2.0 (6N HC1). 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

NajCO^). The basic aqueous phase was separated, and extracted 2 x 150 ml CHjCl^. The latter organic layers were combined, treated with activated carbon, dried (Na^SO.) and concentrated in vacuo to afford a z 4 — -—— colorless amorphous foam, which was crystallized from 35 ml of isoprocanol tc afford 1.14 g (72%) of title compound as colorless crystals, mp 133-184’C. TLC Rf 0.43 (9:1 CH₂C1₂:CH₃OH). HRMS 329.1906, calcd.

329.1854 .

¹³C-NMR(250MHz, CDC1₃, delta 177.4, 161.4, 157.7,

IC9.6, 61.0, 57.9, 54.7, 43.8, 43.5, 40.7, 32.2, 28.1

24.9, 24.4

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-15Method Β

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-lH-pyrido(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 HC1, 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^CO^. 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^SO^) 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.

Methcd C

A solution of cis-7-(aminomethyl)-2(2-pvrimidinyl) -2,3,4,6,7,8,9,9a-octahydro-lnpyrido[1,2-a’pyrazine (149 mg, 0.6 mmol), succinic anhydride (60 mg, 0.6 mmol) in xylenes (9 ml, constant boiling range 138-142’C) was refluxed for 18 hours.

APO 0 012 8

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-16The 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 wellstirred 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^CO^). 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_SO.)

4 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-lH-pyrido[l,2-a)pyrazines

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 ^³C-NMR indicate values at 30CMHz in CDCl^, unless otherwise specified. If unspecified, the TLC eluant was 9:1. CH^C^^CH^CH on 0.25 mm silica gel 60F₂$₄ plates.

3,3,4-TrImethyIsuccinimido (9.7%); crystallized from ethyl acetate : hexane; TLC Rf 0.58; ERMS 31.2274 , calcd. 371.2321.

¹³C-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 bad ORIGINAL

-17Thiazolidine-2,4-dion-3-yl (19.5%); amorphous;

HRMS 347.1478, calcd. 347.1426.

¹³C-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 CH₂C1₂; isopropanol,· mp 141-142’C; TLC Rf 0.56.

¹³C-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 (46.51); crystallized from CHjClj*isopropanol; mp 168-172^eC; TLC Rf 0.51; HRMS 344.2011, calcd. 344.2086.

¹³C-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-l-yl (28.9%) ;

crystallized from ether; mp 106-108^eC; TLC Rf 0.42; HRMS 344.1968, calcd. 344.1960.

¹³C-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-Azabicyclc [3.2.1]o£tane-2,4-dion-3-yl (21 %) ;

TLC Rf 0.44; HRMS 369.2205, calcd. 369.2167.

¹³C-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-l-yl (10%); crystallized from

AP000128

CH^Cl^ J hexane;	mp 146	-148’C; TLC Rf	0.37;
HRMS 343.2011,	calcd.	343.2011.
¹³C-NMR 172.7,	161.4,	157.7, 109.5,	61.1,	58.5, 54.3,
43.9, 43.6, 41	.4, 33.	0, 32.7, 25.0,	24.8,	17.2

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-184, 4-Dimethylpiperidine-2,6-dion-l-yl (14.5%);

crystallized from ethyl acetate; mp 212-213^eC; TLC Rf 0.51; HRMS 371.2276, calcd. 371.2322.

¹³C-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 1?2-173®C;

TLC Rf 0.49; HRMS 397.2450, calcd. 397.2480.

¹³C-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-yI (20.8%) ; crystallized from ethyl acetate:hexane; mp 162-163’C; TLC Rf 0.65; HRMS 359.1936, calcd. 359.1957.

¹³C-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-diorie-l-yl (33.6%); crystallized fron CH₂C1₂:ether; mp 191-192’C; TLC Rf 0.30; HRMS 330.1804, calcd. 330.1804.

¹³C-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 CH₂C1₂:isopropyl ether; mp 145-147’C; TLC Rf 0.53;

HRMS 357.2126, calcd. 357.2164.

¹³C-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, 24.9, 24.4 Pyrazolc (23.8%); crystallized frcrr. ether; mp 35-33^sC; TLC Rf 0.46; HRMS 298.1395, calcd. 298.1906.

¹³C-NMR 161.3, 157.8, 139.4, 129.8,

56.6, 54.7, 53.0, 49.0, 43.6, 34.6,

109.7, 104.8, 61.0, 25.0, 24.7

BAD

-191.2.4- Triazol-l-yl (62.3%); crystallized from ethyl acetate.-hexane; mp 150-152^eC; TLC Rf 0.37;

HRMS 299.1853, calcd. 299.1858.

¹³C-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-l-yl (25%) ; crystallized from CHjCl^zether, mp 189-190^eC;

TLC Rf 0.35; HRMS 358.2074, calcd. 358.2000.

¹³C-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.

¹³C-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- Pihydro-lH,3H-pyrimidine-2,6-dion-l-yl (46%); crystallized from isopropanol:ether, mp 190-192’C; TLC Rf 0.36; HRMS 344.1919, calcd. 344.1960.

¹³C-NMR 169.8, 161.4, 157.7, 155.5, 109.5, 61.1, 58.4,

54.9, 43.9, 43.6, 42.0, 35.3, 33.0, 31.8, 25.4, 24.8

5-Methyl-4,5-dihydro-lH,3H-pyrimidine-2,6-dione-l-yl (23%); crystallized ircm ethanol; mp 201-202^eC; TLC Rf 0.3-5; HRMS 358.2118, calcd. 358.2117.

¹³C-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-dihydrc-lH,3H-pyrimldine-2,6-dione-l-yl (55%); crystallized from CH^Cl^:ether; mp 202-208’C; TLC Rf 0.38; HRMS 353.2123, calcd. 353.2117.

¹³C-NMR 163.6, 161.4, 157.7, 155.2, 109.5, 61.1, 58.4,

54.9, 43.9, 43.5, 42.4, 42.0, 39.3, 33.2, 32.9, 24.9,

24.8, 20.8 (excess peaks due to diastereomers)

APO00128

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-20EXAMPLE 3 cis-7- (Substituted methyl)-2-(2-pyridyl)-2,3,4,6,7,8,9, 9a-octahydro-lH-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-Methylimida2olidine-2,5-dion-l-yl (8.9%) ;

crystallized from CHjClj: isopropyl ether; mp 142-143^OC; TLC Rf 0.43; HRMS 343.1978, calcd. 343.2018.

¹³C-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-l-yl (31.7%);

crystallized from ether; mp 134-135^eC; HRMS 370.2321, calcd. 370.2368.

¹³C-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

Succinlmido (36.3%); crystallized from CH₂C1₂:ether; mp 164-165’C; TLC Rf 0.41; HRMS 328.1S80, calcd. 328.1899.

¹³C-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, 23.1, 24.3, 24.5 8-Azospiro .5 ] decar.e-7,9-dion-8 -y 1 (25.3%);

TLC Rf 0.42 (ethyl acetate); HRMS 396.2562, calcd. 396.2525.

^:3C-NMR 172.4, 1=9.3, 147.9, 137.3, 112.9, 106.9, 60.9,

53.5, 54.8, 50.6, 45.0(2), 41.5, 39.3, 37.6, 32.9,

25.0, 24.9, 24.2

BAD original

5,5-Dlmethyloxazolidine-2,4-dion-3-yl (27.3%);

crystallized from CH^Cljsether; mp 171-173’C;

HRMS 358.2040, calcd. 358.2005; TLC Rf 0.56.

¹³C-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 145-150’C; TLC Rf 0.47;

HRMS 342.2036, calcd. 342.2056.

¹³C-.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

Tetrazclo (36%); amorphous; TLC Rf 0.48 (ethyl acetate); HRMS 299.1778, calcd. 299.1859.

¹³C-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 ¹³C-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-l-yl (37%);

crystallized from CHjClj; isopropyl ether; mp

170-171^eC; TLC Rf 0.28 (ethyl acetate); HRMS 357.2203, calcd. 357.2166.

¹³C-NMR 177.8, 159.3, 157.0, 147.9, 137.5, 113.0,

107.0, 00.9, 53.6, 57.7, 54.7, 50.7, 45.1, 40.3, 32.5, 25.1(2), 24.7, 24.6

Imidazolidine-2,5-dion-l-yl (45%); TLC Rf 0.22;

HRMS 329.1903, calcd. 329.1854.

¹³C-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

BAD ORIGINAL

-221,2,4-Triazcl-l-yl (18.7%); crystallized from isopropyl ether:hexane; mp 109-110°C; HRMS 298.1943, calcd. 298.1906; TLC Rf 0.37.

¹³C-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-l-yl (22.81); crystallized from CHjClj: isopropyl ether; mp 114-115’C; TLC Rf 0.44;

HRMS 342.2043, calcd. 342.2055.

¹³C-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-lH, 3H-pyria>idine-2,6-dion-l-yl (47%); crystallized from isopropar.ol; mp 184-186’C; TLC Rf 0.35; HRMS 357.2155, calcd. 357.2164.

¹³C-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-lH, 3H-pyrimidir.e-2,6-dione-l-yl (40%); crystallized from isoprcpanol; mp 182-183^eC; TLC Rf 0.34; HRMS 357.2147, calcd. 357.2165.

¹³C-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-pyrimidi.ne-2,6-dlone-l-yl (6 ' %);

crystallized from isoprcpanol; mp I?C-19i’C; TLC Rf 0.28, HRMS 343.1975, calcd. 343.2011.

¹³C-NMR 169.8, 159.4, 155.4, 14^.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.

bad original

-23Thiazolidine-2,4-dion-3-yl (63%); crystallized from isopropanol; mp 159-160’C; TLC Rf 0.47 (19:1 ethyl acetate:CH₃OH); KRMS 346.1528, calcd. 346.1463.

¹³C-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-octahydrc-lH-Pyrido[1,2-a]pyra2ine

By method 3 of Example 1, cis-7-(hydroxymethyl)-2(2-pyridyl,-2,3,4,6,7,8,9,9a-octrahydro-lH-pyrido(1,2a]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-1Hpyrido(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 frcm isopropyl alcohol, identical to the material prepared in Example 2.

EXAMPLE 6 (7S,9a5,-2-(2-?yrimidyl)-7- (succinimidcmethyl)-2,3,4,

6,7,8,9,9a-cc :ahydrc-lH-pyrido(1,2-a'pyrazine

A mixture of (?R,9aS)-7-(Aminomethyl)-2-(2pyrimidinyl)-2,3,4,6,7,8,9,9a-octrahydro-lH-pyrido[1,2-a]pyrazine (6.30 g, 0.025 mol) and succinic

ΑΡ000 1 2 8

BAD ORIGINAL

-24anhydride {2.80 g, 0.C28 mol) in 280 ml of mixed xylenes (b.p. 139-143*0 was heated to 100’C, at which point dimethyl formamide (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^SO^), 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 211-212’C; [alpha]³^ = -35« (ΟΗ₂Ο1₂)·

HRMS 329.1809, calcd. 329.1854. The ¹³C-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-aJpyrazine (17.1 mg, 0.069 mol, by Method A of Example 1.

EXAMPLE 7 cis-7-(Pyrazolomethyl)-2-(2-pyridyl)-2,3,4,6,7,8,9,9aoctahydro-lH-pyrido[1,2-a? pvrazine cis-7-(Methanesulfonyloxymethyl)-2-(2-pyricyl)2,3,4,6,7,8,9,9a-octahydro-iH-pyrico[1,2-a’pyraz ine (350 mg, 1.0 mmol), pyrazole (439 mg, 6.5 mmcl) and sodium carbonate (229 mg, 2.2 mmol) and 15 mi of acetonitrile were refluxed for 18 hours. The reaction mixture was cooled, stripped of solvent and the residue bad original

I

-25distributed between 20 ml each of Cf^Cl^ and water.

The well-stirred, 2-phase mixture was adjusted to pH 10 with saturated NajCO^. The aqueous layer was extracted 1 x 20 ml from CH^Clj. The organic layers were combined, dried (Na₂SO^) 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 CH₂C1₂:CH₃OH); HRMS 297.1962, calcd. 297.1957.

ⁱ³C-NMS (300 MHz, CDC1₃) 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.

APO 0012 8

BAD ORIGINAL Λ

-26PREPARATION 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* to -10*C, thionylchloride (3430 g; 2.10 liters; 28.8 mol) was added dropwise while maintaining the temperature in the -5* to -10^eC 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.

PREPARATION 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^ 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 visccus amber syrup (2300 g, 100% vield), sufficiently pure for use directly in the next

BAD

OFUGANAL

-27PREPARATION 3

Dimethyl cis- and trans-1-(Cyanomethyl) piperidine2,5-dicarboxvlate

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 ketor.e (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.

PREPARATION 4

Methyl cis-l-Oxo-2,3,4,6,7,8,9,9a-octahydro-lHPyrido (1,2-a] pyrazine-7-carboxy late

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 2

3.52 kg/cm 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)

AP 0 0 0 1 2 8

BAD ORIGINAL &

-2810 afforded exclusively the desired cis iscmer (title product) as colorless crystals, mp 166-168’C (dec.), (24.99 g? 47% yield); HRMS 212,1156, calcd. 212.1162. ¹³C-NMR (300 MHz, CDC1₃) 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

PREPARATION 5 cis-7-Hydroxymethyl-2,3,4,6, 7,8,9,9a-octahydro-lHpyrido[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’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.

HPJiS 170.1413, calcd. 170.1419.

¹³C-NMR (300 MKz, CDC1₃) delta 65.6, 62.6, 57.8, 56.0,

51.8, 45.8, 34.7, 25.4, 26.0

BAD S

-2910

PREPARATION 6 cis-7-Hydroxymethy1-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9aoctahydro-lH-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^eC 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 135-136^eC. HRMS 248.1622, calcd. 248.1637. TLC Rf 0.3 (CH₂C1₂:CH₃OH 9:1).

¹³C-NMR (300 MHz, CDC1₃) 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

PREPARATION 7 cis-7- (Methanesulfcnyloxymethyl)-2-(2-pyrimidinyl)-2,3, 4,6,7,8,9,9a-octahydro-lH-pyrido f1,2-a]pyraz ine

To a well-stirred solution of the title product of the preceding Preparation (1.5 g; 6.0 mmol) and triethylamine (1.68 mi, 12 mmol) in methylene chloride (28 mi) chilled to 5*C, a solution of methanesulfonyl chloride (0,70 mi; 9.0 mmol) in methylene chloride (7 ml) was added dropwise over 15 minutes. Withir. 10 minutes of stirring (5’C) following the methanesulfonylchioride addition, inspection of a

AP 0 0 0 1 2 8

BAD ORIGINAL

-30reaction 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 scdium 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 141-142*0.

¹³C-NMR (250 MHz, CDCip 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

PREPARATION 8 cis-7-Hydroxymethyl-2-(2-pyridy1)-2,3,4,6,7,9,9,9aoctahydro-lH-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-bromcpyridine (25.5 ml;

42.3 g; 0.27 mol) in iseamylalcohcl (25 ml) was refluxed for 72 hours. The reaction was filtered while hot, and the filter cake washed winh 50 ml of methylene chloride. The filtrate was concentrated in vacuo to an bad ORIGINAL

-31oil, 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, 32-63 mesh; elution with methylene chloride/methanol = 97:3 by volume) with TLC monitoring of fractions (product Rf · 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.

¹³C-NMR (300 MHz, CDC1₃) 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

PREPARATION 9 cis-7-(Methanesulfonyloxymethyl)-2-(2-pyridyl)-2,3,4,6, 7,8,9,9a-octahydro-lH-pyrido[1,2-a]pyrazine

By the method of Preparation 7, the title product «

of the preceding Example (240 mg, 0.9 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.

¹³C-NMR (250 MHz, CDC1₃) delta 159.2, 147.9, 137.5,

113.2, 107.1, 71.2, 60.7, 55.7, 54.6, 50.7, 45.2, 3’.0,

33.5, 24.9, 24.2

AP 0 0 0 1 2 8

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-32?REPARATION 10 cis-7- (Pthalimido)methyl-2-(2-pyrimidinyl )-2,3,4,6,7,8, 9,9a-octahydro-lH-pyrido[1,2-aIpyraz ine

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 161-162’C. HRMS 377.1815, calcd. 377.1852.

¹³C-NMR (300 MHz, CDC1₃) 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.

PREPARATION 11 cis-7-(Azidomethyl)-2-(2-pyrimidyl)-2,3,4,6,7,8,9,9aoctahydro-lH-pyrido[1,2-a? pyrazlne

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^eC (oil bath). Stirring and heating was steeped, 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 porticos 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 wellstirred mixture adjusted to 11.5 (6N sodium hydroxide).

bad origin ^al

-33The organic phase was separated, dried (anhydrous sodium sulfate), and concentrated in vacuo tc afford 48.2 g of title compound as a light-yellow oil.

TLC Rf 0.53 (ethylacetate,. HRMS 273.1735, calcd. 273.1705.

¹³C-NMR (250 MHz, CDC1₃) 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

PREPARATION 12 cis-7-(Aminomethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9, 9a-octahydro-lH-pyrido(l,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 x 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 (CH₂C1₂ : CH-j.CH: cone . NH₃ 3:1:0.3). HRMS 247.1784, calcd. 247.1787.

^1JC-NM3 (300 MHz, CDCl-j) delta 161.3, 157.6 , 109.5, 6x.l, 57.0, 54.9, 48.9, 43.4, 42.9, 36.6, 25.6, 24.5

APO00128

BAD ORIGINAL

-34Method B

A solution of the title product of the preceding Preparation (48.0 g; 0.176 mol, in 800 mi of ethanol and 70 ml of ethyl acetate was hydrogenated at a pressure of 3.5 kg/cm^ 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.

PREPARATION 13 cis-7-(Pthalimido)methyl-2-(2-pyridyl)-2,3,4,6,7,8,9, 9a-octahydro-lH-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 167-168^eC. HUMS 376.1900, calcd. 376.1900.

¹³C-NMR (300 MHz, CDClj, 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

PREPARATION 14 cis-7-(Azidomethyl)-2-(2-pyridyl) - 2,3,4,6,7,8,9,9aoctahydro-lH-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 (34%) of present title product as a colorless oil. HRMS 272.1739, calcd. 272.2750.

¹³C-NMR (3CC MHz, CDC1₃) delta 159.2, 14'.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

-3510

PREPARATION 15 cis-7- (Am in erne thy I) - 2- (2-pyridyl) -2,3,4,6,7,8,9,9aoctahvdro-IH-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 (981) of present title product as a colorless, viscous oil. TLC Rf 0.51 (CHjClj:CH₃OH; cone. NH^ 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.

PREPARATION 16 (7R-9aS) -7- (Amincmethyl) -2- (2-pyrimidinyl)-2,3,4,6,7,8, 9,9a-octahydro-lH-pyrido[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 1 of hot isopropa.nol, 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 (-)-ma.ndelic acid salt of present title product, mp 202-203’C (dec.)]. The entire sample was dissolved in water (200 mi). An equal volume of methylene chloride was added, and the pH of the wellAP 0 0 ο τ 2 8

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-36stirred 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.

[alpha]_D = -36.7® in methylene chloride (C = 0.0337 g/ml)]

PREPARATION 17 (7S-9aS)-7-(Acetoxymethyl,-2-(2-pyrimidinyl)-2,3,4,5,6, 7,8,9,9a-octahydro-lH-pyrido Γ1,2-a]pyrazine

To title product of the preceding Preparation (180.4 mg, 0.73 mmol) in 2 ml of CHC1₃ 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 CHC1₃ and then 10 ml H₂O, and adjusted to pH 10 with saturated Na₂CO₃. The aqueous layer was separated and extracted with 20 ml CH₂C1₂. The organic layers were combined, treated with activated carbon, dried (Na₂SO₄, 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 rag (28%) of present title product. [alpha]³⁵ = -35.9® (CH₂C1₂). HRMS 290.1752, calcd. 290.1742.

bad original

)

-37¹³C-NMR (300 MHz, CDC1₃) 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

PREPARATION 18 5 (7S,9aS)-7-(Hydroxymethyl)-2-(2-pyrimidinyl,-2,3,4,6,7, 8,9,9a-octahydro-lH-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 HjOsCH^OH, and 6N NaOH (0.06 ml, 3.6 mmol) was added. After stirring for 3 hours, the mixture was stripped of CH^OH, the aqueous residue diluted with 25 ml CH^C^ and 10 ml H₂O, and the pH of the 2 phase system adjusted to 10. The separated aqueous layer was ₁₅ extracted 2 x 10 ml CH₂C1₂, and the organic layers combined, dried (Na₂SO₄), stripped and the residue crystallized from CH₂C1₂ and isopropyl ether to yield 27 mg of title product mp 160-162^eC.

(alpha)p⁵ = -34.2° (CH₂C1₂). HRMS 248.1647, calcd.

248.1638.

AP o 0 012 8

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-38PREPARATION 19 (7S-9aS)-7-(Methanesulfonyloxymethyl)-2-(2pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-lHpyrido[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 CH₂C1₂:CH₃OH).

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Claims

1. A racemic or optically active compound of the

--- (1) or a pharmaceutically acceptable acid addition sal' thereof, wherein

X is N or CH;

Y is

N1 »N.

Z n i s 1 c r Z; and or

Z N- carrcn wrth uc ro

T is CH_?, NH or NCH,.

AP 0 0 0 1 2 8

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-402. A compound of claim 1 wherein X is N and Y is

3. An optically active compound of claim 1 or 2.

4. A compound of claim 3 wherein 2 is Y^fCHx,) or

1 2 n

Y (CH_) substituted on carbon with up to 2 methvl

2 n groups .

5. The compound of claim 4 wherein Z is Y^(CH_) ,

1 ^{z n}

Y is CH₂ and n is 1.

6. A compound of claim 1 wherein Y is

7. A compound of claim 1 wherein X is CH and Y is

8. A racemic compound of the formula bad ORIGINAL wherein, in a first alternative:

A is hydrogen;

B is (Cj-C^)alkoxycarbonyl; and X¹ Ϊ3 C=0;

in a second alternative;

A is hydrogen or

X is N or CH;

X^I is CH₂; and 8 is hcch₂;

and in a third alternative A is

r)

X¹ is CH₂;

3 is Y²CH,;

2 . * ί ls hc-, aso₂o, 3₂n-,

APO00 1 28

R is (C,-C«)alkyl, phenyl or tolyl

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-429. An optically active compound of the formula wherein X is N or CH;

Y³ i3 HO—, RSO^O-, R¹COO-, or H^N-,

R is (Cj-C₃)alkyl, phenyl or tolyl; and

R¹ is (C^-Cpalkyl; or an optically active acid salt thereof when Y³ is H^N.

10. A pharmaceutical composition comprising an