CA1234112A - Pyrimido(4,5-g)quinolines and intermediates - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Trans-(+)-2-Amino (or substituted amino)-4-(permissibly-substituted)-6-C1-C3 alkyl (or allyl)-5,5a,-6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinolines, the corresponding trans-(-) and trans-(+)-stereoisomers and salts thereof, useful in treating Parkinson's Syndrome, sexual dysfunction, depression, hypertension, and prolactin related diseases, and intermediates useful for the synthesis thereof, are disclosed. The products are prepared by condensing an appropriate ketone with the appropriately substltuted guanidine.

Description

~3~Z

IMP~OVEMENTS IN AND RELATING TO
PYRIMIDO[4,5 g]QUINOLINES ~ND INTERNEDIATES

This invention concerns a class of novel pyrimido[4,5-g]quinoline derivatives, which have been discovered to be effective D-1 and D-2 d~pamine agonists.
The concept that various body tissues contain two dopamine receptors has only recentIy received general acceptance~ These receptors have be~n desig-nated as the D-1 and D-2 receptors. Several D-2 dopamine receptor agonists are ~nown, including lergo-trile and pergolide, both ergol~nes, and L~141865 (U.S. patent 4,198,415) an ergoline paxtial structure.
These D-2 agonists have been found useful in treating Parkinson's disease as well as conditions in which there is n excess o~ circulating prolactin such as galactor-rhea. LY141865 ~trans-~)-5-n-propyl-4,4a,5,6,7,8,8a,g-octahydro-lH(and 2H)-pyra~olo~3,4-g]quinoline] has also been found to reduce blood pressure in mammals without the occurrence of postural hypotension. This anti-hyper-tensive activity is stated to be present in only one of the stereoisomers of the trans-($) racemate, the trans-(-)isomer, named as 4aR,8aR-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-lH~and 2H)-pyrazolo[3,4~g]quinoline.
This in~ention provides trans-(+)-2,4,6-permissibly substituted-5,5a,6,7,8,9,9a,10-octahydro-pyrimidol4,5-g]quinolines represented by the formula ~11'~'~` /\

~ \o7 ~ ~

'1 .

., , . . - `'-..

~Z~ 2 wherein-R is C1-C3 alkyl, ~lyl, H or CN;
R2 is H, CH3, Cl or Br, Rl is NH2, NHR3 or NR R ;
wh~rein R3 is methyl, ethyl, n-propyl or R6-C0 where R6 is Cl-C3 alkyl or R7XO=~/
where R7 is independently H, Cl, F, Br, CH3, C2H5, CE30, C2H50 or CF3; and n is 0, 1 or 2;
wherein R4 and R5 are independently methyl, e~hyl or n~propyl; or a pharmaceutically~acceptable a~id addition salt thereof.
Various terms used in this application are defined as follows. The term "C1-C4 alkyl" includes - methyl, e~hyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. The term "Cl-C3 alkyl" is included within the Cl-C4 alkyl term. The term "Cl-C3 alkoxy"
includes methoxy, ethoxy, n-propoxy and isopropoxy.
Pharmaceutically-acceptable acid addition salts of the compounds of formula I include salts derived from non-toxic inorganic acids such as hydro-chloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydriodic acid! phosphorous acid and the like, as well as salts derived from non-toxic organic acids such as aliphatic mono and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic and alkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically~
acceptable salts thus include sulfate, pyrosulfate, .1 ,! ¦

. .
' ~3~ *2 bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dlhydrogenphosphate, metaphos-phate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxala-te, malonate, suc-cinate, suberate, sebacate, fumarate, maleate, mandelate, butyne-1,4-dic.)ate, hexyne-1,6-dioate, benzoate, chloro-benzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terepht~alate, benzene-sulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenyl-butyrate, citrate, lactate, ~-hydroxybutyrate, glycollate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-s~lfonate, naphthalene-2-sulfonate and the like salts.
Compounds of formula I have two asymmetric carbons ~optical centers) at Sa and 9a and can thus exist as four stereoisomers occurring as two racemic pairs, ordinarily designated as the trans-(~) racemate and the cis-(~) racemate. The trans racemate is composed of the trans-(-)-stereoisomer (5aR,9aR stereoisomer) represented by II below and the trans-(~)-(5aS,9aS
stereoisomer) represented by IIa.

25R~ R'~

II IIa L~

wherein R, Rl and R2 have their previously assigned meanings. These trans~ (5aR,9aR) stereoisomers rep~
resented by formula II are active dopamine D-2 agonists.
Compounds according to formula II thus form a second aspect of thl.s invention. The trans-(~)-(5aS,9aS) stereoisomers of formula IIa are active dopamine ~-1 agonists. Compounds according to formula IIa thus form a third aspect of this invention. Because the trans-(~) D-l agonists are less active on a dosage basis than the trans-(-) D-2 agonists, the trans-(i)~racemates (II ~
IIa) are chiefly useful for their content of the active trans-(-)-stereoisomer.
A preferred group of compounds are those of formulae I, II and IIa in which R is n-propyl. Another preferred group of compounds are those of formulae I, II and IIa in which Rl is NH2 and/or R2 is H.
Compounds of formulae I, II and IIa include, for example:
SaR,9aR-2-diethylamino-6-ethyl-5,5a,6,7, 8,9,9a,10-octahydropyrimido[4,5-g]guinoline sulfate, trans-(i)-2-methylethylamino~4-methyl-6-n-propyl 5,5a,6,7,8,9,9a,10-octahydropvrimido[4,5-g]-quinoline monohydrophosphate, trans-(~)-2 n-propylamino-6-n-propyl-5,5a,-6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline maleate, 5aR,9aR-2-amino-4-chloro 6-ethyl-5,5a,6,-7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline succinate, trans-(t)-2-amino 4-bromo-6-allyl-5,5a,6,-7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline phthalate, trans-(i)-2-n-propylamino-6-n-propyl-5,5a,-6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline mesyl~te, 3~2 trans-(~)-2-amino-6-methyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinollne hydrochloride, 5aR,9aR-2-amino-4,6-dimethyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline tosylate, 5a~,9aR-2-acetamido-6-methyl-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline dihydrobromide, 5aR,9aR-2-benzamido-6-ethyl-5,5a,6,7,8,9,9a,-10-octahydropyrimido[4,5-g]quinoline hexan-1,6-dioate, trans-(~)-2-n-propylamino-6-isopropyl-5,5a,-6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline dinitro-benzoate, SaS,9aS-2-methylamino-6-methyl-5,5a,6,7,8,9,-9a,10-octahydropyrimido~4,5-g]guinoline maleate, 5aS,9aS-2-amino-6-ethyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline sulfate, 5aS,9aS-2-dimethylamino-4 methyl-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline succinate, 5aS,9aS-2-ethylamino-4-chloro-6-ethyl-5,5a,-6j7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline mesylate, 5aS,9aS-2-allylamino-6-n-propyl-5,5a,6,7,8,9,-9a,10-octahydropyrimido[4,5-g]quinoline phosphate, 5aS,9aS-2-methylethylamino-6-allyl-5,Sa,6,7,-8,9,9a,10-octahydropyrimido[4,5-g]guinoline citrate, 5aS,9aS-2-methylamino-6-allyl-4-methyl-5,5a,6,7,8,9,9a,10-octahydropyrim.ido[4,5-g]quinoline lactate, 5aS,9aS 2-amino-6-allyl-4-bromo-5,5a,6,7,8,-9,9a,10-octahydropyrimido[4,5-g]quinoline sulfate, .

., .

~3~2 5aS,9aS-2-dimethylamino-6-n-propyl-5,Sa,6,7,-8,9,9a,10-octahydropyrimido[4,5-g]quinoline maleat~, 5aS,9aS-2-dimethylamino-6-ethyl-5,5a,6,7,8,-9!9a,10-octahydropyrimido[4,5-g]quinoline maleate, and the like.
The: compounds of formulae I, II and IIa are prepared by:
~a) condensing a compound of the formula ~\ /o\
~f t T

wherein R is as deined as above;
Y is R"CO, wherein R" is CH3 or Cl-C3 alkoxy, or (R10)2NCH=, wherein each R10 is independently Cl-C3 alkyl, or one R10 is H and the other is Cl-C3 alkyl;
with a compound or its salt of the formula N~
~ 2 HN=C VI
\Rl wherein R1 is defined as above to provide a compound of formula ~; or (b) alkylating a compound of the formula ~k~ f\~ la `~ :
34~2 wherein R1 and R2 are defined as above to provide the O
compounds of formula I; and (c) when Y is (Cl-C3 alkylj oC-t halogenatin~ the 4-OH compound of the formula R~

H

wherein R and R1 are defined as above,to provide the compounds of formula I where R2 is Cl or Br; or (d) optionally followed by salifying to form the pharmaceutically-acceptable acid addition salt of the pxoduct o formula I and/or resolving a racemic product to form the optically active product of formula I.
The compounds of fonmula 1, II or IIa are used as drugs either as the free base or as a pharma-ceutically~acceptable acid addition salt thereof~
Compounds represented by formulae I and II
are dopamine D-2 agonists substantially devoid of other agonist or antagonist (blocking) activities. As D~2 dopamine agonists, the compounds are useful in treating Parkinson's Syndxome, in treating sexual : - dysfunction, as anti-depressants or as anti-anxiety agents, in lowering blood pressure in hypertensive mammals and in inhibiting prolact.in secretion. Thus, the compounds of formulae I and II are useful in the .
~1 , ~ ., . , ., . , ~ . ~ . , ~2~ 2 treatment of hypertension, of depression, of anxiety, of Parkinson's disease, of sexual dysfunction and of disease states charactexized by an excess of prolactin secretion such as galactorrhea and inappropriate lac-tation.
Compounds represented by formula IIa are dopamine D-1 agonists. Dopamine D-1 receptors, when stimulated by a D-1 agonist, are characterized by an increased cyclic A~P efflux. This effect i5 inhibited by D-2 agonists. Stoof and Kebabian discuss these D-1 agonist effects in papers appearing in Nature, 294, 266 (1981) and Brain Res., 250, 263 (1982). The compounds of formula IIa are potentially useful as renal vaso-dilators and thus useful in the treatment of hypertension.
A still furt.her embodiment of this in~ention is the provision of pharmaceutical formulations for administering drugs of formulae I, II and IIa in the treatment methods outlined above. Encompassed within this invention are pharmaceutical formulations which comprise as an active ingredient a compound of formula I, II or IIa or a pharmaceutically-acceptable salt thereof, associated with one or more pharmaceutically-acceptable carriers or diluents therefor.
Intermediates useful in preparing the com-pounds of formula I, II or IIa are represented by theformulae ~ . Ill ~L~3~

H ~

/H ~ IV
R2 ,~

R~ ~ IVa

2 ~8 wherein R8 is H, CN or ~Cl-C3 alkoxy)-C0, and Rl and R have the same meanings as in formula I above, or an acid addition salt thereof.
Another class of intermediates useful in pre-paring ~he compound~ of formula I, II or IIa are repre-sented by the formula =~\~/ `T
~ Va ~12\~ ~
ll9 where R9 is ~, CN, Cl-C3 alkyl or allyl, and R12 is methyl, or Cl-C3 alkoxy.

11~

~3~2 Compounds of formula I, II or IIa wherein R2 is H can be prepared as shown in the following reaction scheme:

Synthetic Route 1 ~NH ~f \T/ \
NH2 f VI (R10) NCH~ \~ \N/
R V

R~\/ ! la' wherein Rl, R9 and R10 have their previous meanings.
The procedure is equally app].icable to the synthesis oE the trans-(-)-stereoisomer (Ib3 or of the trans-(~-stereoisomer (Ic), Ib Ic :

~ ~3~2 wherein Rl and R9 have the same si~nificance as beforeO
Suitable solvents are polar organic solvents, such as C1-C4 alkanols, dimethylsulfoxide (DMS0), dimethyl-formamide (DMF), and acetonitrile. The reaction is run from room temperature to reflux, preferably in an inert atmosphere, such as nitrogen.
Optically active ketones (Xa and Xb below) are used to prepare the optically active intermediates Vb and Vc (R )2NC ~ ~ (R )2NCH=

Vb Vc wherein R9 and R10 have the same significance as befoxe.
The preparation of the optically active ketone Xa is de-scribed below. The preparation of the stereoisomeric ketone Xb is described below.
A similar synthetic route is used to prepare compounds according to formula I, II or IIa in which R2 is other than H.

q tf`~,J

~2~

Synthetic Route 2 Va ~ VI

lo I~ ~,f T

1 1a ~9 Ia"
wherein Rl and R9 have their previous significance and R12 is CH3, or Cl-C3 alko~y, and Rlla is CH3 or O~.
During the work-up of the ring closure reaction, the R12 of the ester group is replaced with OH to yleld a 4-OH derivative. This OH derivative is then halogenated to yield those compounds of formula I where R~ is Cl or Br. Suitable halogenating agents are POC13, PBr3, SOC12 or SOBr2. The reaction is usually run at reflu~
temperature. An ether solvent can optionally be present.
: 25 The same procedure starting with the trans-(-)-enantiomer pxoduces Id and with the trans-(+)-enantiomer produces Ie :.

.

, ~3~.2 ~ ' ~H ~ /H-~ 11 a ~9 11 a Id Ie and this product is transformed where Rlla is OH by halogenation to compounds of structure II or IIa.
The starting materials Va of synthetic route 2 are prepared according to the following procedure: the ketone (X for the trans racemate, Xa for the trans-( )-stereoisomer and Xb for the trans-(+)-stereoisomer) is metallated at C-? with a lithium amide, as for example lithium diisQp~opylamide, (LiN[CH(C~322J) to form an enc,late anion.
Thi~i anion then reacts wi~h acetyl chloride or an dialkylcarbonate to yield compounds represented by Va.
These latter compounds are transformed to the desired pyrimidine, and then purified from contaminants.
~ inally, compounds of formula I, II or IIa are most easily prepared by ùtilizing a ketone starting material (X, Xa or Xb) !~ i"~ "~,l X Xa Xb ;

~3~

wherein R is Cl-C3 alkyl or allyl. The ketones repre-sented by X, ~hen R is Cl-C3 alkyl, are preferably pre-pared by ~he process whereby a 6-alkoxyquinoline of the formula XI

wherein R13 is Cl-C3 alkoxy; is guaternized with a Cl-C3 alkyl halide and the quaternized salt reduced to yield an N-C1-C3 alkyl-6-alkoxy-1,2,3,4-tetrahydro-quinoline of the formula R10~

XIa wherein R14 is Cl-C3 alkyl and R13 is defined as above.
The particular C1-C3 alkyl group remains intact through the next two reduction steps: a Birch reduction fol-lowed by a sodium cyanoborohydride or borohydride reduction to yield, ultimately, an octahydroquinoline of the formula XII
f~
~ ~ ~
~1 4 XII

... ... ~
~,^~'1 ~34~

wherein R13 and R14 are defined as above. This enol ether yields X (where R is Cl-C3 alkyl~ upon treatment with acid. Xa is then produced by resolution of X as previously set forth.
Compounds according to I, II or IIa in which R is allyl can also be pxepared by a different procedure which is descxibed below. The optically active ketones Xa and Xb are prepared by resolution of the trans~
racemate as set foxth below.
The ketones X or Xa are readily transformed by treatment with dimethylformamide dimethylacetal to yield V, the starting material of Synthetic Route 1.
An aiternative preparation of the ketone X, when R is Cl-C3 alkyl, is set forth in United States Patent 4,198,415.
An alternative intermediate to V, Vb or Vc, is a l-alkyl-6-oxo-7-formyldecahydroquinoline disclosed in published European Patent Application No. 0110496, as is the method of preparing this intermediate from the 6-oxo derivative (X, Xa or Xb).
The intermediates V, Vb and Vc can also be prepared by treating the above l-alkyl-6-oxo-7-formyl-decahydroquinoline wi~h a primary or secondary amine in the presence of a dehydrating agent to yield the 7-mono- or dialkylaminomethylene derivative.
As can be seen from the above discussion, the group R in formula X carries through the synthetic pro-cedure intact. Thus, if it is desired to replace one alkyl group with another or with allyl, indirect syn-thetic routes must be used. For example, i~ R in X, Xaor Xb is methyl or n-propyl, reaction with cyanogen bro-i'~

.
.
. .

X-6062~ -16-mide yields a 1-cyano-6-oxodecahydroquinoline XV, XVa or XVb where R15 is cyano. Hydrolysis of the cyano group yields the secondary amine, XV, XVa or XVb where R15 is H. Similarly, reaction of X, Xa or Xb where R is methyl with ethyl chloroformate yields an intermediate, XV, XVa or XVb, wherein R15 is C2H5-0-C0, which can also be hydrolyzed to yield the corresponding compound XV, XVa or XVb wherein R15 is H.
lo ~ f~ o=f ~

~1 5 ~15 ~1 S

XV XVa XVb The secondary amine XV, XVa or XV~ where R15 is H can then be selectively alXylated, with the same or a different alkyl group, or can be allylated where it is desired to have an allyl group on the ring nitrogen. In this syn~hesis, the extremely reactive allyl halides can be used ~o ultimately yield X, Xa or Xb where R is allyl Again alternatively, XV, XVa or XVb in which R15 is CN can be reacted with guanidine to yield a novel intermediate of formula III, IV or IVa, where R1 is NH2, R2 is H, and R8 is CN (IVb, IVc and IVd):

~3~%

~2~ ; `f ~I H~N~E" `i 11~N~

IVb IVc IVd Hydrolysis of the cyano product yields com-pounds of formula III, IV or IVa in which R~ and R2 are both H and Rl is NH2. The hydrolysis is an acidic hydrolysis, such as aqueous hydrochloric acid, zinc chloride in acetic acid, or zinc in acetic acid, under standard conditions. Such compounds can then be selec-tively alkylated or allylated to yield drugs of formula~, II or IIa where Rl is NH~, R2 is H, and R is as de-fined before. The alkylation (allylation) is done by conventional methods. For example an alkyl halide (or allyl halide) in a polar organic solvent, such as DMF;
reduction amination in an alkanol or polar organic sol-vent, with an aldehyde and catalytic hydrogenation (H2/Pd-on-carbon), formaldehyde/formic acid, or with an aldehyde and sodium cyanoborohydride with a trace o acid; lithium aluminum hydride or diborane reduction of an amide formed by treating the above secondary amine with an acid halide or anhydride and a ~ase, such as triethylamine or pyridine, and a solvent, such as ether, dioxane, tetrahydrofuran (THF), or dimethoxyethane (DME).
This procedure is also a good method for introducing a tagged carbon into the R group at a late staye in the ; synthesis so as to avoid carrying the expensive lisotopic X-5062M -18~

or radioactive) tagged molecule through several synthetic procedures with consequent loss of yield.
One still further synthetic route is available for preparing drugs in which R is allyl. This route involves adapting the Kornfeld-Bach synthesis disclosed in United States patent 4,1g8,415, Reaction Scheme I.
By using an allyl halide in step 2 of the procedure of that patent, a trans-(i)-l-allyl-6-oxodecahydroquinoline is produced. This N-allyl derivative is then converted to trans-(i)-l^allyl-6-oxo-7-(dimethylaminomethylene)-decahydro~linoline, formula V wherein R9 is allyl. The trans-(-)enantiomer or trans-(+)-enantiomer can then be produced from the racemate by resolution.
Compounds of formula I, II or IIa in which Rl is NHR3, R2 is H, CH3, Cl or Br, and R3 is R6 CO can be prepared by acylating Ia (or the 5aR,9aR stereoisomer or the 5aS,9aS stereoisomer) when R is NH2 with an acid chloride or anhydride under standard reaction conditions, such as a base (e.g. pyridine), a solvent (e.g. ether), and a catalyst (e.g. dimethylamine in pyridine).
Finally, there are two methods of providing the trans-(-) or 5aR,9aR derivatives, II or the trans-(+~ or 5aS,9aS derivatives IIa. The first method is the resolution of the trans-(~) racemate (I) using a resolving agent such as d-(-)-tartaric acid or other suitable optically-active acid which forms a salt with the trans-(-) component of trans-(~)-2-substituted -6-Cl-C3 alkyl (allyl)-5,5a,6,7,8,9,9a,10-octahydro-pyrimido[4,5-g]quinoline. Similarly, use of a resolving agent of the opposite configuration, e.g. Q-(+)-tartaric acid, yields the 5aS,9aS-stereoisomer. Preferably, however, a resolution is carried out on the bicyclic ketone, X or XV, to produce 4aR,8aR-1-alkyl (or allyl)-6-oxodecahydroquinoline, using (-)-di-~-toluoyltartaric acid to form a salt with the 4aR,~aR-ketone or (+)-di~~-toluoyltartaric acid to form a salt with the 4aS,8aS
ketone. The resolved ketone can then be reacted with dimethylformamide dimethylacetal, with tris(dimethyl-amino)methane or with ethyl formate followed by (CH3)2NH
to yield 4aR,8aR- (or 4aS,8aS)-1-alkyl (or allyl)-6-oxo-7~(disubstituted an.inomethylene)decahydroquinoline of the formula Vb or Vc (R10) NC~~ (R )2NC~
Vb Vc wherein R9 and R10 have their previously assigned meaning.
Formula Vb or Vc can then be reacted with Rl NH2-C=NH VI
wherein R1 is defined as before, to yield the optically--active derivatives II or IIa directly or indirectly.
- The above processes can yield salts. Conver-sion of the salt thus obtained to the corresporlding free base is readily effected by dissolving the salt in water and then adding an excess of an aqueous base (NaOH, Na2CO3 etc.). The free base, being insoluble in the ~L23~2 basic solution, separates and is extracted with a ~ater-immiscible organic solvent. The organic extract is then separated and dried. A solution containing one equiva-lent of a dlfferent non-toxic acid is then added, and the resulting salt isolated by filtration or ~y evapo-ration of the solvent. Alternatively, the sol~ent can be removed fr.om tha dried organic extract and the free base obtained as a residue. The free base can then be dissolved in a suitable solvent and the non-toxic acid added as a solu-tion. The preferred salt is the HCl salt which can be prepared, for example, by adding an e~uiva~
lent of ethanolic hydrogen chloride to an ethanolic solution of the free base, followed by evaporation of the ethanol and recrystallization of the residual salt.
1~ If it is desired to make a di salt such as a dihydro chloride salt, HCl gas can be passed into a solution of the free base to the point of saturation and the di salt isolated as above.
Compounds represented by formula I, II or IIa each have two or more basic centers. The most basic oE
these is the octahydroquinoline ring amino group. This group ~orms salts readily with pharmaceutically-acceptable acids. Amine groups of lesser basicity are also present and these groups will form salts with strong pharmaceu~
tically-acceptable inorganic acids, such as the minaral acids, or strong organic acids such as ~-toluenesul~onic acid, to yield di salts. Pharmaceutically-acceptable acid addition salts thus include mono or di sa].ts derived from inorganic acids such as those listed earlier in this application.

~L23~ L2 This invention is further illustrated by the following specific examples.

STARTING MATERIALS AND IN$ERMEDIATES

~ æ e A

Preparation of 4aR,8aR-l-n-propyl-6-oxodeca-hydroquinoline Ten g. of (-)-di-p-toluoyltartaric acid were dissolved in 75 ml. of warm methanol. The solution was added to a solution of 5.0S g. of trans-dQ-l-n-propyl-6-oxodecahydroquinoline in 15 ml. of methanol.
The reaction mixture was brought to a boil and was then allowed to cool to ambient temperature. After remaining at ambient temperature overnight, crystallization was induced by the addition of seed crystals previously obtained. The crystalline tartrate salt was isolated ~y filtxation and the filter cake washed with methanol;
yield = 2.813 gO (18.7%) of a white crystalline solid comprising the (-~-di-p-toluoyltartrate of 4aR,8aR-l-n propyl-6-oxodecahydroquinoline; ta]D5 = -107.49 (MeOH, c ~ Recrystallization of the salt from methanol gave 1.943 g. of the optically pure salt, [a]25 = ~108.29 (MeO~, c = 1).
The (-~-di-~-toluoyltartrate salt thus ob-tained was treated with dilute aqueous sodium hydroxide and the resulting alkaline solution extracted with methy-lene dichloride. The methylene dichloride extract was .
.

~23~2 X-6062M -~2-dried, concentrat~d and the solvent removed therefrom n vacuo. The resulting residue was distilled to yield a colorless oil comprising purified 4aR,8aR-1-n~propyl-6-oxodecahydroguinoline; [a]25 = -88.51 (MeOH, c = 1).
Other l-(alkyl, allyl, benzyl, or cyano)-6-oxodecahydroquinolines can be resolved iIl a similar manner.

Example B
Preparation of 4aS,8aS-1-n-propyl-6-oxodeca-hydroquinoline A resolution of trans-(~)-1-n-propyl-6-oxo-decahydroguinoline was carried out according to the following procedure: Ten grams of (-)-di-p-toluoyl-tartaric acid were dissolved in 75 ml. of warm methanol.
The solution was added to a solution of 5.05 g. of trans-[+]-l-n-propyl-6-oxodecahydroquinoline in 15 ml. of methanol. The reaction mixture was brought to a boil and was then allowed to cool to ambient temperature.
After remaining at ambient temperature overnight, crystallization was induced by the addition of seed crystals previously obtained. The crystalline tartrate was isolated by fil-tration and the filter cake washed with methanol; yield = 2.813 g. (18.7%) of a white crystalline solid comprising the (-)-di-p-toluoyltartrate of 4aR,8aR-1-n-propyl-6-oxodecahydroquinoline; [a]25 =
-107.49 (MeOH, c = 1).
Filtrates and mother liguors from the above procedure or from similar, larger scale procedures containing tartrates were combined and the combined solutions treated with alkali, thus forming the free bases which were extracted into a wa-ter-immiscible solvent to yield a solution of l-n-propyl-6-oxodeca-hydroquinoline enriched as regards the 4aS,8aS-isomer, and depleted as regards the 4aR,8aR isomer. The solu-tion was treated with (-~)-ditoluoyl tartaric acid mono-hydrate, in accordance with the above procedure, to yield 4aS,8aS-l-n-propyl-6-oxodecahydroisoquinoli.ne-(+) ditoluoyl tartrate of about 80% ee optical purity (ee =
enantiomeric excess). 20 g. of the salt were crystal-lized from 250 ml. of methanol to give 12 g. of a white crystalline powder melting at 167.5-169.5C. with decomposition; [~]25= +106.3 (methanol, c = 1.0);
[a]3565= +506.7 (methanol, c = 1.0). These fi~lres indicate an optical purity of about 90% ee. A second crop obtained from mother liquors from the above crys-talli~ation gave 2.3 g. of a white solid melting at about 166.0-166.5C. with decompos.ition; [a]25= 106.6;
~ [a]3565= +510.8 (methanol, c =1.0 for both~ indicating optical purity of about 94% ee. Recrystallization of first and second crop crystals from methanol gave a white solid from which the free base was obtained by standard procedures. The free base was distilled to yield 4.14 g. of a colorless oil boiling at 82-86C. at 0.13 torr., comprising 4aS,8aS-1-n-propyl-6-oxodecahydro-~uinoline; [~]25= ~86.2; [a]2565= ~376.6 (methanol, c =
1.0 for both rotations); optical purity = about 98% ee.
Al~ernatively, trans-(i)-1-n-propyl-6-oxodeca-hydro~uinoline can be treated directly with (~)-di-p-toluoyltartaric acid to yield the 4aS,8aS-1-n-propyl-6-~3~2 oxodecahydroquinoline-(~)-di-p-toluoyl tartrate which is purified by the procedures set forth above.

Example C
Preparation of trans-(i)-l-n-propyl-6-oxo-7-ethoxycarbonyldecahydroquinoline A suspension of 790 mg. of sodium hydride ~55% in mineral oil) was placed in a 50 ml. round bottom - flask and the mineral oil removed by three hexane washes. The solid residual sodium hydride was suspended in 8 ml. of THF and 1.45 ml. (1.41 g.) of diethyl carbonate added along with one drop of anhydrous ethanol.
The resulting solution was heated to refluxing tempera~
ture and 1.1 g. of trans-(i)-1-n-propyl-6-oxodecahydro-quinoline in 5 ml. of THF was added over a five minute period. The resulting mixture was heated to re~lux temperature overnight. TLC at this point indicated no remaining starting material and a new, slower moving spot was present. The reaction mixture was poured into water giving a pH of the aqueous la~-er of about 1~. The al~aline layer was extracted with methylene dichloride.
The pH of the aqueous layer was adjusted to about pH = 9 and again the alkaline layer was extracted with methylene dichloride. The methylene dichloride extracts were cor~ined and the combined extracts dried and the solvent removed therefrom to yield 1.56 g. of a yellow oil comprising trans-(i)-l-n-propyl-6-oxo-7-ethoxycarbonyl-decahydroguinoline formed in the above reaction.

, . . , ;~3~ 2 Chromatography of the residue over Woelm silica (100~200 mesh) using a 1:1 ether/hexane solvent mixture containing a trace of 14N aqueous ammonium hydroxide as the eluant.
Fractions containing the desired product were combined to yield eventually 880 mg. (55% yield) of a yellow oil.
The keto ester was shown by nmr to exist in an enol form represented hy the following structure.

o o H~ \T
~C2Hs ~ ~
~b~H7 The compound had the following nmr spectrum:
nmr (C~Cl3): 12.20 (s, lH); 4.28 (~, J=7, 2H); 3.20-1.10 (m, 16H); 1.36 (t, J=7, 3H); 0.95 (t, J=7, 3H) Example D
Preparation of trans~ 1-n-propyl-6-oxo-7-dimethylaminomethylenedecahydroquinoline Four grams of trans-(~ n-propyl-6~oxo-decahydroquinoline were added to a solution of 5.6 g.
of potassium t-butoxide in about 50 ml. of anhydrous redistilled tetrahydrofuran. The reaction mixture was stirred for 30 minutes under a nitrogen atmosphere.
Next, 3.6 ml. of ethyl formate were added in dropwise fashion while the reaction mixture was cooled in an z ice-alcohol bath. After the addition had been completed, the reaction mixture was stirred at ambient temperature under a nitrogen atmosphere overnight. The reaction mixture, at this point a solid slurry, was neutralized with glacial acetic acid. Methanol was added to the slurry, followed by l ml. of dimethylamine.
3A molecular sieves was added to aid dehydration. The subsequent reaction mixture was stirred under a nitrogen atmosphere for 48 hours, and was then filtered. The filtrate was evaporated to dryness ln vacuo. Water was added and the aqueous mixture extracted three times with equal volumes of methylene dichloride. The methylene dichloride extracts were combined and the combined extracts washed with water and then dried. Evaporation of the methylene dichloride yielded 4.15 g. (81.4%) yield of trans~ n-propyl 6-oxo~7-dimethylamino-methylenedecahydroquinoline.

ExamPle E
~0 Preparation of trans-($)-2-amino-6-cyano-5,Sa,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline A reaction mixture was prepared from 16 g. of trans-(*)-1-methyl-6-oxodecah~droquinoline (prepared by the procedure of Bach and Kornfeld U.S. Patent 4,198,415), 26 g. of cyanogen bromide and 450 ml. of methylene dichloride. The reaction mixture was stirred overnight at room temperature and was then extracted three times with lN aqueous hydrochloric acid. The acid extracted reaction mixture was washed with saturated ~3~2 aqueous sodium bicarbonate and then dried. Any volatile material were removed by evaporation in vacuo. The residue thus obtairled was 18.8 g. of a semi-solid oil comprising trans~(~)-1-cyano-6-oxodecahydroquinoline formed in the above reaction. Chromatography of the oil over"Flcrisil"using chloroform as the eluant yielded fractions of purified material weighing collectively 11.5 g. (66%) yield. The oil crystallized upon standing to yield white crystals.
A reaction mixture was prepared from 4.18 g.
of trans-(~)-1-cyano-6-oxodecahydroquinoline, 5.0 g. of tris-dimethylaminomethane and 50 ml. of toluene. The reaction mixture was refluxed under nitrogen temperature for five hours and then was concentrated ln vacuo. Five and seventy-six hundredths grams of a crude yellow solid comprising trans-~i)-1-cyano-6-oxo-7-dimethylamino-methylenedecahydroquinoline were obtained. This crllde product was mixed with 2.25 g. of guanidine sarbonate in 100 ml. of anhydrous methanol. This reaction mixture was heated to reflux under nitrogen overnight, and was then concentrated ln vac_o. The resulting solid residue was triturated with hot methanol and filtered. The filter cake was washed twice with methanol and once with ether. A yield of 4.11 g. (78%) of trans~ 2-amino-6-cyano-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline were obtained having the following physical characteris-tics. Mass spectrum, molecular ion at 229; infrared spectrum peaks (cm 1) at 3307.18, 3157.70, 2202.87, 1660.~3, 1599.10, 1564.38, 1486.26.
Analysis Calculated: C, 62.86; H, 6.59; N, 30.54;
Found: C, 63.18; H, 6.70; N, 30.24.

* Trademark for a porous, granular activated magnesium , silicate.
,~
` ' .

3~

Example F

Preparation of trans~ 2-amino-5,5a,6,7,8,-9,9a,10-octahydropyrimido L4, 5-g]quinoline A reaction mixture was prepared from 1.66 g.
of the 6-cyano compound of Example E, 9.7 g. of zinc dust, 200 ml. of acetic acid and 50 ml. of water. The reaction mixture was heated to reflux temperature under a nitrogen atmosphere for about 24 hours and then stirred at room temperature for a 48 hour period. Any volatile material was removed from the reaction mixture ln vacuo and the resulting residue dissolved in water.
The aqueous mixture was made basic with 50% a~ueous lS sodium hydroxide. (eventual pH was in the range 10-11).
A heavy white precipitate formed. The basic solution was filtered and the filtrate extracted three times with a 3:1 by volume chloroform/isopropanol solvent mixture.
The organic extracts were combined and dried. Removal of the solvent ln vacuo yielded 0.43 g. of a light yellow powder comprising trans~ 2-amino-5,5a,6,7,8,-9,9a,10-octahydropyrimido[4,5-g]quinoline free base.
The free base was converted to the hydrochloride salt which was recrystallized from a methanol/acetate solvent mixture to yield crystalline material, MP = above 230C.
Analysis (after drying at 150C.) Calculated: C, 47.66; H, 6.55; N, 20.21;
Found: C, 47.37; ~, 6.65; N, 19.91.

' ..
...

-.

~ ;~3~

Trans-(~)-2-amino-5,5a,6,7,8,9,9a,10-octa-hydropyrimido[4,5-g]quinoline khus prepared can be alkylated with a lower alkyl halide or allylated with an allyl halide to yield compounds coming within the scope of formula I above.
Some of the above preparations were carried out with the racemate. It will be apparent to those skilled in the art that these s~me chemical steps can be carried out on the separated trans-(-) or trans-(+)-stereoisomers to yield optically active intermediatesand final products.

Exa~ple G

Preparation of trans-(i)-2-Amino-4-hydroxy-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]-quinoline A reaction mixture was prepared from 2.0 g. of trans~ -1-n-propyl-6-oxo-7-ethoxycarbonyldecahydro quinoline (prepared in Example C), 20 ml. of anhydrous e~hanol and 0.67 g. of guanidine carbonate. The reac-tion mixture was heated to reflux temperature overnight under a nitrogen atmosphere. The white precipitate which formed was collected by filtration and the filter cake washed with ethanol and dried; yield = 1.36 g. The filter cake was dissolved in 52 ml. of O.lN aqueous hydrochloric acid. The acidic mixture was filtered and the filtrate concentrated ln vacuo. The solid residue was dissolved in boiling methanol. The methanol solu-tion was filtered and trans-(i)-2-amino-4-hydroxy-6-n-z propyl-5,5a,6,7,8,9,9a,10-octahydropyrimidoL4,5-g]quino-line hydrochloride thus prepared crystallized to yield 0.79 g. of product. The free base had the following physical characteristics: mass spectrum, molecular ion at 262.
Analysis Calculated: C, 64.09; H, 8.45; N, 21.36;
Found: C, 64.18; H, 8.51; N, 21.13.

The hydrochloride salt had the following physical characteristics: mass spectrum, molecular ion at 262.

FINAL PRODUCTS

Example 1 Preparation of trans-(~)-2-amino-6-methyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline A reaction mixture was prepared from 1.8 g. of ; trans~ methyl-6-oxodecahydroquinoline and 2.2 g. of tris-dimethylaminomethane in 18 ml. of toluene. The ' reaction mixture was refluxed under ni~rogen for about 12 hours. An additional 0.8 g. of tris-dimethylamino-methane were added and refluxing continued under nitro-gen for an additional 5 hours. Th,e reaction mixture was then concentrated to dryness ln vacuo. The resulting residue containing trans-(~ methyl-6-oxo~7-(dimethyl-aminomethylene)decahydroquinoline formed in the above reaction was dissolved in 40 ml. of ethanol to which was added 1.5 g. of guanidine carbonate. The resulting mixture was heated overnight to reflux temperature under 3~

a nitrogen atmosphere. On cooling, a crystalline pre-cipitate formed which was collected by filtration and the filter cake washed with ethanol; yield = 0.68 g.
(38%) of a llght yellow powder. The material was dis-solved in lN aqueous hydrochloric acid. The acidicsolution was then made basic with 10% agueous sodium hydroxide. Trans~ 2-amino-6-methyl-5,5a,6,7,8,9,-9a,10-octahydropyrimido[4,5-g]quinoline free base, being insoluble in the alkaline layer, separated and was extracted with chloroform. The chloroform ex~ract was dried and the chloroform xemoved in vacuo. The residue, comprising trans-ti)-2-amino-6-methyl-5,5a,6,7,8,9,-9a,10-octahydropyrimido[4,5-g]~uinoline, was suspended in ethanol and the ethanol solution saturated with gaseous hydrogen chlo~ide. The solvent was removed ln vacuo and the resulting residue, the dihydxochloride salt of trans~ 2-amino 6-methyl-5,5a,6,7,8,9,9a,10-octahydropyrimido~4,5-g]quinoline, was recrystallized from hot ethanol. Sixty-six mg. of dihydrochloridQ salt 20 were obtained, MP = 262-275C. (decomposition) and having the following analysis (after drying at 150C.):
Theory: C, 49.49; H, 6.92; N, 19.24 Found: C, 49.61; H, 7.03; N, 18.92 The higher temperature drying was necessary because it became apparent after drying at lower temper-atures that the dihydrochloride salt crystallizes as a solvate and the solvent must be removed by drying to obtain a reproducible analysis.

X-606?M -32-Example 2 Preparation of trans-(i)-2-amino-Z-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g3guinoline The reaction of Example 1 was repeated except that 1 g. of trans-(~ n-propyl-6-oxo-7-dimethylamino-methylenedecahydroguinoline was reacted with 0.4 g. of guanidine carbonate in 20 ml. of anhydrous ethanol.
(Trans-($)-1-n-propyl-6-oxo-7-dimethylaminomethylene-decahydroquinoline was prepared from trans~ n-propyl-6-oxodecahydroquinoline and tris-dimethylamino-methane according to the above procedure). The reaction mixture was heated under reflux temperature overnight at which time a pracipitate was observed.
The reaction mixture was chilled in an ice bath and a light yellow crystalline precipitate comprising trans-($)-2-amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydro-pyrimido[4,5-g]quinoline formed in the above reaction was collected. The filter cake was washed with ethanol and then dried; MP = above 260~C. Yield = 0.6 g. (61%).
Analysis calculated: C, 68.26; H, 9.00; N, 22.74 Found: C, 68.45; H, 8.87; N, 22.26 Trans-($)-2-amino-6-n-pxopyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline was dissolved in lN
aqueous hydrochloric acid and the acidic solution ex-tracted with ether. The acidic solution was then made basic with 10% aqueous sodium hydroxide. Trans~ 2-30 amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido-[4,5-g]quinoline precipitated and was separa-ted by ....

filtration. The free base was dissolved in lN aqueous hydrochloric acid r and the water removed ln vacuo. The resulting residue was recrystallized from ho-t ethanol.
Yield = 0.54 g. t40%). Trans-(~)-2-amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline dihydrochloride -thus prepared had a MP = 225-270C. and had the following analysis.
Analysis calculated for C14H22N4-2HC1-H2O
C, 49.74; H, 7.75; N, 16.57; Cl, 20.97;
Found: C, 49.88; H, 8.03; N, 16.81; Cl, 20.87.

After drying at 120C., analysis indicated that water of hydration and one-half mole of hydrogen chloride had been lost to yield trans-(i)-2-amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]-quinoline sesquihydrochloride having the following ~ analysis.
; Analysis calculated for C14H22N4-1.5 HCl C, 55.86; H, 7.87; N, 18.61; C1, 17.03 Found: C, 55.49; H, 7.83; N, 18.35; Cl, 17.03.
~' Example 3 .
Preparation of 5aR,9aR-2-Amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline Following the procedure of Example l, 4aR,8aR-l-n-propyl-6-oxo-7-dimethylaminomethylenedecahydro-quinoline (prepared from 4aR,8aR-1-n-pxopyl-6-oxodeca-hydroquinoline and tris-dimethylaminomethane shown in Example A) was reacted with guanidine carbonate in ;

~ .

- ~ .

~L~3~

anhydrous ethanol solution. The reaction was carried out and the reaction mixture worked up as in Example 1 to yield 2.4 g. of 5aR,9aR-2-amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]guinoline.
The product was suspended in ethanol and gaseous hydro~en chloride bubbled through the suspension.
The resulting solution was evaporated to dryness ln vacuo and the residual yellow oil dissolved in about 10 ml. of ethanol. Ether was added to the point of incipient precipitation and the mixture heated on the steam bath. Upon cooling, fine, powdery crystals formed which were separated by filtration. The filter cake was washed with ethanol to yield .72 g. of the dihydro-chloride salt of 5aR,9aR-2-amino-6-n-propyl-5,5a,6,7,8,9,9a,10-oct~hydropyrimido[4,5-g~guinoline.
Analysis ~after drying at 180C.) C, 52.67; H, 7.58; N, 17.55 Found: C, 52.81; ~, 7.75; N, 17.65.
Molecular ion at 246i Optical rotation [a]259C = -99.6;

[a]2560C - _374 8c Example 4 Preparation of Trans-(+)-2-dimethylamino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]~
guinoline A reaction mixture was prepared from 4.7 g. of trans-(~3-1-n-propyl-6-oxo-7-dimethylaminomethylene-. , .. .. .. .

~:3~2 decahydroquinoline and 2.5 g. of N,N-dimethylguanidine hydrochloride in 50 ml. of anhydrous ethanol. ~he reaction mixture was heated overnight under a nitrogen atmosphere, and was then cooled and the volatile con-stituents removed ln vacuo. The resulting residue wasdissolved in ethyl acetate and the ethyl acetate solu-tion contacted with an excess of 10% aqueous sodium hydroxide. Trans-(i)-2-dimethylamino-6-n-propyl-5,5a,-6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline formed in the above reaction, being insoluble in the basic layer, remained in the ethyl acetate layer. The agueous layer was separated and the ethyl acetate layer extracted once with water and once with saturated agueous sodium chloride. The ethyl ace~ate layer was dried and the ethyl acetate removed in vacuo to leave 0.75 g. of an orange oil. The oily residue was chromatographed over '~lorisil"using hexane containing increasing amounts (1-50% by volume) of ethyl acetate as the eluant. Frac-tions shown by TLC to contain the desired trans-(~)-2-dimethylamino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydro-pyrimido[4,5-g]quinoline were combined and the solvent removed from the combined fractions in vacuo. The resulting residue was dissolved in ethanol and gaseous hydrogen chloride passed into the solution thus forming the corresponding dihydrochloride salt. ~he ethanol was removed therefrom ln vacuo and the dihydrochloride salt crystallized from a methanol-ethyl acetate solvent mixture to yield 0.170 g. of a white solid having a molecular ion at 274 and MP = above 250C.
Analysis calculated: C, 55.33; H, 8.13; N, 16.13 Found: C, 55.67; H, 8.19; N, 16.19.

* Trademark ~3~2 Example 5 Preparation of trans-(*)-2-methylamino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]-guinoline Following the procedure of Example 4, but sub-stituting N-methylguanidine for N,N-dimethylguanidine, trans-(~)-2-methylamino-6-n-propyl-5,5a,6,7~8,9,9a,10-octahydropyrimido[4,5-g]quinoline was prepared. The co~pound was purified by chromatography over Florisil"
using methylene dichloride containing increasing (0-10%
by volume) methanol as the eluanti yield = 0.66 g. The monohydrochloride salt was prepared by adding an equiva-lent of O.lN hydrochloric acid to the solid and recrys-tallizing the product from methanol; yield - 599 mg.
MP = above 240C.
Analysis calculated: C, 60.69; H, 8.49; N, 18.87;
; Cl, 11.94 20Found: C, 60.96; H, 8.53; N, 19.07;
Cl, 11.74.

In Examples 1,2,4 and 5, the optically active 5aR,9aR or 5aS,9aS derivatives can be prepared from the 25 desired 4aR,8aR- (or 4aS,8aS)-C1~C3 alkyl-6-oxo-7-dimethylaminomethylene decahydroquinoline and a suitable guanldine.

~ f ~

Example 6 Preparation of trans-(+)-2-Amino-4-methyl-6 n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]-5 quinoline A reaction mixture was prepared by adding 13.7 ml. of 1.6M n-butyllithium in hexane to a solution containing 3.1 ml. of diisopropylamine and 22 ml. of THF
at about 0C. under a nitrogen atmosphere. The reaction mixture was stirred for about 30 minutes. Next, 2.0 g.
of trans-~)-l-n-propyl-6-oxodecahydroquinoline in a small amount of THF was added while containing the reaction mixture at about -78C. The solution was stirred for two hcurs at which time 1.1 ml. of acetyl chloride was added. This new reaction mixture was stirred at about -78C. for about 30 minutes and then at room temperature for two hours. The reaction mixture was next poured into water and the consequent aqueous mixture acidiied to a pH = 9-10 with lN aqueous hydro-chloride acid. The a~leous solution was extracted three times with equal volumes of methylene dichloride.
The methylene dichloride extracts were combined and the combined extracts dried. Evaporation of the solvent yielded 2.7 g. of trans~ n-propyl 6-oxo-7 acetyl-- decahydroquinoline. The crude reaction product (without further purifica-tion) was mixed with about 0.9 g. of guanidine carbonate. Forty ml. of ethanol were added and the reaction mixture refluxed under a nitrogen atmosphere. The reac-tion mixture was then evaporated to ~L234~L2 dry~ess and the crude product chromatographed over ~lorisil. Fractions shown to contain trans~ 2-amino-4~methyl-6-n-propyl-5,5a,6,7,8,9,9a,10-octa-hydropyrimido[4,5-g]quinoline formed in the above reaction were combined to yield 270 mg of free base, and 10 ml. of O.lN aqueous hydrochloric acid were added thereto. The dihydrochloride salt thus formed was recrystallized from ethanoli m.p. = above 240C; mass spectrum molecular ion at 260, small peak at 268.
Analysis Calculated: C, 54.05; ~, 7.86; N, 16.81;
Found: C, 53O93; H, 7.98; N, 16.61.

Example 7 Preparation of trans-(~)-2-amino-4-chloro-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]-quinoline The 4-hydroxy product obtained in Example G
was refluxed with 4 ml. of phosphorus oxychloride. The reaction mixture, containing trans-(~)-2-amino-4-chloxo-6-n-propyl-5,5a,6~7,8,9,9a,10-octahydropyri~ido[4,5-g]-quinoline formed in the above reaction, was poured onto ice and the resulting aqueous mixture made basic. The basic mixture was filtered and the insoluble material (30 mg.) dissolved in O.lN aqueous hydrochloric acid.
The hydrochloride salt thus prepared was recrystallized from ethanol to yield 13.6 mg. of trans-(~)-2-amino-4-chloro-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido~

~23~L2 X-6062M -39~

[4,5-g]quinoline hydrochloride having the following physical characteristics. Mass spectrum, molecular ion at 280, smaller peak at 282.

Analysis Calculated: C, 53.00; H, 6.99; N, 17.66;
Found: C, 53.15; ~, 6.92; N, 17.77.

The 4-bromo derivative can be made similarly by substituting PBr3 for POCl3 in the above reaction.
Example 8 Preparation of Trans-(~)-2-acetylamino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]-quinoline A solution was prepared containing 0.75 g of trans-(~)-2-amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octa-hydropyrimido[4,5-g]quinoline in 20 ml. o~ pyridine and 0.34 g. of acetic anhydride was added thereto in dropwise fashion. The reaction mixture was heated to reflux - temperature under a nitrogen blan~et overnight. TLC at this point in time indicated that starting material was still present; therefore, about 1.5 ml. more acetic anhydride were added and the reaction mixture again heated to reflux temperature under a nitrogen blanket.
TLC, using a 9:1 by volume chloroform/methanol solvent system containing ammonia, indicated that the reaction had gone largely toward completion but that some start-, ing material was still present. The reaction mixture was therefore concentrated ln vacuo and the resulting residue triturated in hot ethyl acetate. On cooling, crystals ~ormed which were isolated by filtration, yielding 340 mg. of trans-(i)-2-acetylamino~6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline.
Rf at 0.7; MoLecular ion at 288; nmr and infrared spectra were in comformance with the proposed structure.

ExamPle 9 Preparation of trans-(~)-2-benzoylamino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]-quinoline Following the procedure of Example 8, trans-~ 2-amino-6-n-propyl-5,5a,6,7,8,9,9a,1Q-octahydro-pyrimido[4,5-g]quinoline was reacted with benzoyl chloride in pyridine solution. The residue of 450 mg.
of yellow-orange oil obtained after working up the reaction mi~.ture as indicated above was chromatographed over"Florisil"using chloroform with increasing amounts (0-10% by volume) of methanol as the eluant. Fraction ten contained the desired 2-benzoylamino compound (shown by TLC). The solvent was removed therefrom ln vacuo.
The resulting residue was dissolved in ethanol and gaseous hydrogen chloride passed into the ethanol solution. Addition of ether to the point of incipient precipitation yielded trans~ enzoylamino-6 n-* Trademark `?~

~3~2 propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]-quinoline dihydrochloride; molecular ion at 350.
Analysis (ater drying at 130C.) C, 59.57; H, 6.67; N, 13.23 5Found: C, 59.35; H, 6.85; N, 12.99.

Example 10 Preparation of 5aS,9aS-2-amino-6-n-propyl-105,5a,6,7,8,9,ga,10-octahydropyrimido[4,5-g]quinoline A solution was prepared from 3.37 g. of 4aS,8aS l-n-propyl-6-oxodecahydroquinoline (prepared in Example B) in 60 ml. of toluene. Six and twenty-six hundredths grams (7.5 ml.) of tris(dimethylamino)methane were added in dropwise fashion. The resulting mixture was heated to reflux temperature for about four hours, at which time tlc indicated no spot corresponding to starting material. Concentration of the reaction mix-ture yielded 4.813 g. of a yellow oil which was chro-matographed over a 50 mm. X 30 cm. silica gel column using 8% methanol in methylene dichloride plus concen-trated ammonium hydroxide as the eluant. Fractions -shown by tlc to contain 4aS,8aS-1-n-propyl~6-oxo-7-dimethylaminomethylenedecahydroquinoline were combined to give 3.651 g. of a yellow oil. This material, with-out further purification, was dissolved in 30 ml. of ethanol, and the solution was added to a suspension of 2.56 g. of guanidine carbonate in 70 ml. of anhydrous ethanol. The reac-tion mixture was heated to refluxing .
' -~3~

tempera-ture for about 18 hours, after which time it was cooled in an ice bath. The precipitate which had formed was collected by filtration to yield 3.506 g. of fine, light yellow needles comprising a salt of 5aS,9aS-2-amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido-[4,5-g]quinoline. The salt thus obtained was converted to the dihydrochloride salt by standard procedures. The dihydrochloride salt was dissolved in water. The resulting acidic aqueous solution was made basic with aqueous sodium hydroxide. The free base, being insolu-ble in the alkaline layer, separated and was extracted into methylene dichloride. Evaporation of the extract to dryness yielded a white foam which was dissolved in a l:1 methanol/methylene dichloride solvent mlxture and the solution saturated with gaseous HCl. Concentration of the solution yielded a yellow foam which was r crys-tallized from methanol/ethyl acetate to yield a white powder comprising the dihydrochloride salt of 5aS,9aS-2-amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido-[4,5-g]quinoline having the following elemental analysis:
Calculated: C, 52.67; H, 7.58; N, 17.55; Cl, 22.21;
Found: C, 52.39, H, 7.36, N, 17.31, Cl, 22.40, ~a]D25 = -~108.3, [a]25365 = +405.2 (both in methanol, c = 1.0).
As previously stated the compounds of formulae I and II above are dopamine D-2 agonists without any other pronounced phaxmacologic action. One of such dopamine D-2 agonist activities is the inhibition of prolactin secretion, as demonstrated according to the following procedure.

Adult male rats of the Sprague-DawlPy strain weighing about 200 g. were housed in an air-condikioned room with controlled lighting (lights on 6 a.m. - 8 p.m.) and fed lab chow and water ad libit m. Each rat received an intraperitoneal injection of 2.0 mg. of reserpine in a~ueous suspension 18 hours before administration of the test drug. The purpose of the reserpine was to keep the rat prolactin levels uniformly elevated. The test com-pound was dissolved in 10 percent ethanol, and injected intraperitoneally at doses from 100 ~g./kg. to 1 ~g./kg.
The test compound was administered at each dose level to : a group of 10 rats, and a control group of 10 intact males received an equivalent amount of 10 percent ethanol. One hour after trea-tment, all rats were killed hy decapitation, and 150 ~1 aliquots of serum were assayed for prolactin.
The difference between the prolactin level of the treated rats and prolaGtin level of the control - rats, divided by the prolactin level of the control rats gives the percent inhibition of prolactin æecretion attributable to the given dose. Inhibition percentages are given in Tables 1 and 2 below for compounds of formulae I or II above, respectively. In the tables, columns 1 2 ~Id3give substitution patterns for the basic structures at the head o the Table, column 4 the form ~salt or ree base--FB), column 5 the route of adminis-tration, and columns~, 7, 8, 9 and 10 the percent pxo-lactin inhibition at the speciied dose le~els. In some instances a compound was tested more than once at a par-ticular dose level and the present prolactin inhlbitionfigures in the tables are averages from these multiple tests.
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The compounds of formulae I and II are also active by the oral route. Trans-~)-2-amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline dihydrochloride, the second compound in Table 1, at 10 ~g. by the oral route gave a 74% inhibition and 50 ~g./kg. a 91% inhibition.
Compounds of formulae I and II, dopamine D-2 agonists, have been found to affect turning behavior in 6-hydroxydopamine-lesioned rats in a test procedure ~esigned to uncover compounds useful for the treatment of Parkinsonism. In this test, nigroneostriatal-lesioned rats are employed, as prepared by the procedure of Ungerstedt and Arbuthnott, Brain Res, 24, 485 (1970). A
compound having dopamine agonist activity causes the rats to turn in circles contralateral to the side of the lesion. After a latency period, which varies from compound to compound, the number of turns is counted over a 15-minute period.
Results obtained from such testing are set forth in Table 3 below. In the table, columns 1 and 2 give the substitution pattern for the compound at the head of the table, column 3, percent of test animals exhibiting turning behavior, and column 4, average number of turns observed in first 15 minutes after end - 25 of latency period.

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34~2 X-6062M ~48-The compounds of formula I and II are also active in affecting turning behavior by the oral route, although somewhat higher doses are required to give significant effects.
The compounds of formulae I and II reduce the blood pressure of spontaneously hypertensive rats, as illuminated by the following experiment:
Adult male spontaneously hypertensive rats (SHR) (Taconic Farms, Germantown, New York), weighing approximately 300 g. were anesthetized with pentobarbital sodium (60 mg./kg., i.p.). The trachea was cannulated and the SHR respired room air. Pulsatile arterial blood pressure was me2sured from a cannulated *
carotid artery using a Statham t~-ansducer (P23 ID).
Mean arterial blood pressure was calculated as diastolic blood pressure plus 1/3 pulse pressure. Cardiac rate was monitored by a cardiotachometer which was triggared by the systolic pressure pulse. Drug solutions were administered i.v. through a catheter placed in a femoral ~0 vein. Arterial blood pressure and cardiac rate w*e*re recorded on a multichannel oscillograph (Beckman, Model R511A3. Fifteen minutes were allowed to elapse follow-ing surgery for equilibration of the preparation.
Table 4 which follo~s gives the results of 25 this test for trans~ 2-amino-6-n-propyl-5,5a,6,7,8,-9,9a,10-octahydropyrimido[4,5-g]~uinoline. In Table 4, column 1 gives the dose level, column 2 the change in mean arterial blood pressure with standard error, and column 3, the percent change in cardiac rate with standard error.

* Trademark ** Trademark ~3~

Table 4 Percent Changes*
Dose level Mean Arterial Cardiac in mcg/kg Blood Pressure** Rate 0.1 -4.0~0.9 -2.0~0.
1 -14.8~1.1 -5,9iO.8 -46.5~6.8 -29.0~2.3 100 -37.1~7.0 -31.0~4.2 *Change was measured immediately after injection.
Baseline mean arterial blood pressure was 181~1.0 mm Hg and mean cardiac rate was 366~15 beats/min.
**Mean response for 4SHR.
In addition, trans-(~)-2-amino-6-n-propyl-S,Sa,6,7,8,9,9a,l0-octahydropyrimido[4,5-g]quinoline and its trans-(-)-stereoisomer are potent activators of cholinergic neurons in rat striatum leading to an eleva-tion of striatal acetyl choline concentrations.
The ability of a trans-(~) or trans-(-)-2-amino-4-permissibly-substituted-6-alkyl(or allyl)-octa-hydropyrimido[4,5-g]guinoline or a salt thereof (com-pounds of formulae I and II, respectively) to affect sexual behavior in male mammals is illustrated by the following experiment:
Male rats that re~ired at least 5 minutes to achieve ejaculation were used. The behavioral tests were initiated with the introduction of a sexually receptive female rat into the behavioral arena and were stopped immediately following the first mount after ejaculation. The following behavioral indicies were measured:

BEHAVIORAL INDEX DEFINITION

1. Mount Latency (ML): Time from introduction of female to the first mount 2. Intromission Lakency (IL): Time from introduction of female to the first intromission 3. Ejaculatory Latency (EL): Time interval from intro-mission to ejaculation

4. Postejaculatory Interval Time interval from (PEI): ejaculation to next mount ~ '

5. Mount Frequency (MF): Total number of mounts required to achieve ejaculation

6. Intromission Frequency Total number of mounts with (IF): intromission required to achieve ejaculation Each male rat was given a solution containing either the vehicle alone (1 millimolar acetic acid plus 1 milli-molar ascorbic acid) in water or trans~ 2-amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]-L%

guinoline dihydrochloride at 25 mcg./kg. in the same vehicle by subcutaneous injection 30 minutes prior to behavioral testing. One week after the drug test, the vehicle alone was retested.
The results of the above experiment are given in Table 5 below. In the Table, column 1 gives the treatment, and columns 2-7 the behavioral indices (x ~ SE
for 9 rats) for each treatment in column 1.

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X-6062M _55-According to the data presented in Table S, the drug produced statistically significant improvements iIl ejaculatory latency (EL) and mount frequency (MF) compared to either pre- or postcompound vehicle treat-ments and in intromission latency (IL~ compared to priorvehicle treatment. These data are indicative of dramatic improvements in sexual performance specifically related to the effects of the drug. According to the data presented in Table 6, a single subcutaneous dose of drug of 250 ng/Kg produced s~atistically significant improve-ments in ejaculatory latency (EL) compared to priox vehicle treatment. Although there were no statistically significant differences in the comparison of the mean performance ~alues between drug and subsequen~ vehicle responses, it is important to note that 6 of 11 rats showed better performance in each performance index fol-lowing drug treating compared to the subsequent vehicle trea~ment, 9 and 8 of the 11 rats showed improvements in mount frequency and intromission frequency, respectively.
These data are supportive of the view that trans-~ 2-amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido-[4,5-g]~uinoline dihydrochloride has behavioral effects in doses as low as 250 ng/Kg. Similar behavior experi-ments were conducted using drug doses of 2.5 ng/~g, s.c., but no behavioral effects were observed.
The effects of trans-(-)-2~amino-6-n~propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline dihydrochloride on male rat sexual behavior were also evaluated in rats that showed no mating behavior or were unable to achieve ejaculation in the 30 minute test period. The effects of 25 mcg/Kg, s.c. of dru~ on :~23~L2 the mating performance of these animals are summarized in Table 7. The drug appeared to have the capacity to initiate sexual behavior in animals that showed no prior sexual behavior and to amplify sexual behavior in animals that were unable to achieve ejaculation. The mating performance of rats from these groups that were able to achieve ejaculation after drug treatment and subsequent vehicle treatments were evaluated. These animals showed a significant reduction in the number of mounts required for ejaculation (mount fre~uency) with drug treatment compared to vehicle treatment.

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The effects of trans-($)- and trans-~ 2-amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido-[4,5-g]quinoline dihydrochloride on sexual behavior of female mammals were evaluated in ovariectomized, estrogen-treated rats. The change in the lordosis-to mount ratio was measured (increase in presenting by the female for mounting by a male per mount). The protocol of Foreman and Moss, Physioloqy and Behavior, 22, 283 (1979), was used. Table 8 which follows gives the results of this experiment. In the Table, column 1 gives the name OI the drug used, if any, column 2 the dose in mcg./kg. and column 3 the change in lordosis-to-mount ratio with standard error.

Table 8 Change in Dose (s.c.)Lordosis-to-Mount Treatment(mcg./kg~) Ratio ~ ~ SE
Vehicle .158 ~ .042 Trans~
Racemate 25 .580 _ .063*
Trans-(-)-Stereoisomer25 .760 ~ .058**
* Significantly greater than vehicle P<.05 **Significantly greater than trans-~) P<.05 A similar experiment was carried out on the two stereoisomers; trans-(-)-2-amino-6-n-propyl 5,5a,6,-

7,8,9,9a,10-octahydropyrimido~4,5-g]quinoline and the trans-(+)-isomer. Response to the trans-(~)-isomer was not significantly greater than the response to vehicle ~2~ 2 alone (.093 ~ .063 to .035 ~ .018) whereas the trans-(-)-isomer gave a highly significant change .753 _ .031.
Table 9 below gives the effect of a series of dose levels of trans-(-)-2-amino~6-n-propyl-5,5a,6,7,8,-9,9a,10-octahydropyrimido[4,5-g]quinoline on the lordosis-to-mount ratio in ovariectomized, estrogen-treated rats.

Table 9 Dosage Change In mcg./kq.~oute Lordosis-To~Mount Ratio**
0 SC 0.074 ~ 0.025 2.5 SC 0.28~ i 0.064 7.5 SC 0.405 ~ 0.083 SC 0.786 ~ 0.028 o oral 0.008 ~ 0.021 2.5 oral 0.467 -~ 0.033 oral 0.558 ~ 0.063 All values are X ~ SE for 19 animals (S~C.) and for 8 animals oral (water as the vehicle).
Behavioral response to vehicle was significantly lower (P<.01) than response to drug at each dosage and route of administration.
The compounds of formula IIa, the trans-(+)-stereoisomers or 5aS,9aS-stereoisomers, are dopamine D-l agonists. Compounds represented by the formula IIa manifest their dopamine D-l agonist activity in several ways; for example, one way is in stimulating cyclic AMP formation in rat striatal membrane.

In this determination, the procedure of Wong and Reid, Communications in Psychopharmacology, 4, 269 (1980) was employed. 5aS,9aS-2-amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g~quino-line (formula IIa), the SaR,9aR enantiomer (formula II),and the corresponding racemate (formula I) were tested for their ability to activate adenylate cyclase in rat striatal membrane as measured by an increase in cyclic AMP concentration. The results o this determination are given in Table 10. Dopamine was used as a positive control. In the table, column 1 gives the drug used, column 2, drug concentration in the reaction mixture, column 3, cyclic AMP formation as percent of control, and column 4, confidence level or significance.
Table lO
Cyclic AMP
Formation Conc. in as a percent Drua micromoles of control P
~ .
Dopamine 100 160.0 ~ 14.8 <0.01 Racemate 1 130.8 ~ 0.8 <0.05 5aR,9aR enantiomer 1 119.2 ~ 1.3 ~0.001 5aS,9aS enantiomer 1 165.0 ~ 3.1 <0.01 _ In the presence of 10 micromolar GTP, the basal adenyl-ate cyclase activity in rat striatal membranes has a mean ~ S.E. value of 196.2 ~ 20.3 pmole/min/mg of pro-tein. Compounds were examined in triplicate.
According to the inormation presented in Table 10, the 5aS,9aS enantiomer of formula IIa sig-nificantly increased cyclic AMP formation, indicating ., , ... .

significant D-1 dopamine agonist activity. It was more effective than the racemate while the increase of cyclic AMP induced by the 4aR,9aR enantiomer of formula II
barely met the required significance level.
A second, particularly sensitive indicator of D-1 agonist activity is the determination of the cyclic AMP efflux in tissue slices using a procedure based on Stoof and Kebabian, Nature, 294, 266 (1981~ and Brain Res., 250, 263 (1982). In this procedure, striatal tissue is dissected from rat brains and chopped into 0.3 mm. x .03 mm.
fragments. The tissue fragments are suspended in the appropriate buffer system (Earl's balanced salt solution, for example) and the suspension is continuously aerated with 95:5 O2/CO2 while being maintained at 37C. Just prior to use, the tissue fragments are transferred to fresh media to which is added bovine serum albumin (2.5 mg./ml.) and 3-isobutyl-1-methylganthine (1 millimolar) to blocX degradation of cyclic AMP. The tissue frag ments are incubated in buffer without drugs and are then transferred to the same media with added drug. Aliquots of incubation media, with and without drugs, are assayed for cyclic hMP concentration by a specific radioimmuno-assay. The effect of the drug or drugs on efflux is ex-pressed as a percentage of the resting efflux.

~239;~2 The following medium was employed:
Medium Ingredient Conc. mg./Liter NaCl 6800 KCl 402.6 NaHCO3 2201.1 NaH2P 4 137.99 MgSO 7H2O 147.88 d-glucose 1009 CaCl2 2H2 191.1 phenol red 10 In the experiments described in the above-mentioned reference, Stoof and Kebabian employed sul-piride to repress the negative (anti D-l) effect of any drug acting as a dopamine D-2 agonist. The authors had previously demonstrated that a D-2 agonist repressed cyclic AMP formation (an opposite effect from that pro-duced by a D-l agonist). Sulpiride is known to be an antagonist on pituitary D-2 receptors. Addition of sulpiride to a test system7 such as that described above, blocks any D-2 effect of a drug in reducing cyclic AMP production. Stoof and Kebabian were able to demonstrate a lack of effect of sulpiride on cyclic AMP
production in striatal tissue using SKF 3839~ (1,2,3,4-tetrahydro-7,8-dihydroxy-1-phenyl-lH-3-benzazepine) as a pure D-1 agonist, an indication that D~2 receptors were not involved and the compound did not have D-2 agonist activity.
The results of one such determination for 5a5,9aS-2-amino-6-n-propyl 5,5a,6,7,8,9,9a,10-octahydro-* Trademark ~23~

pyrimido[4,5-g]quinoline dihydrochloride ~compound A~
are given in Table 11. In the table, column 1 gives the added drug, if any; column 2, the drug concentration;
column 3, the level of cyclic AMP present; and column 4, the percent increase in cyclic AM2 concentration.

Table ll % Increase Cyclic AMP in Drug Concentration Concentration Cyclic AMP
None 71.6 ~ 8.2 0 15 A 5 x 10 6M 114.0 ~ 11.2 60 The compounds of formula I, II or IIa are administered for therapeutic purposes in a variety of formulations as illustrated below. However, it should be remembered that the dosage amounts of the trans~
and (5aR,9aR)-stereoisomers, the dopamine D-2 agonists of formulae I and II, are far less than the dosage amounts of the (5aS,9aS)-stereoisomers, the dopamine D-l agonists of formula IIa.
Hard gelatin capsules are prepared using the following ingredients:
Quantit~ (mg./capsule) Active compound .1-2 mg Starch dried 200 30 Magnesium stearate10 The above ingredients are mixed and filled into hard gelatin capsules.

~3~2 A tablet formulation is prepared using the ingredients below:
Quantity (mq./tablet~
Active compound .1-2 mg Cellulose, microcrystalline 400 Silicon dioxide, fumed 10 Stearic acid 5 The components are blended and compressed to form tablets.
Alternatively, tablets each containlng .1-2 mg. of active ingredient are made up as follows:
Active ingredlent .1-2 mg.
Starch 45 mg.
Microcrystalline cellulose 35 mg.
Polyvinylpyrrolidone (as 10% solution in water) 4 mg.
Sodium carboxymethyl starch 4.5 mg.
Ma~nesium stearate 0.5 mg.
Talc 1 mg.

The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50-60C. and passed through a No.
18 mesh U.S. sieve. The sodium carboxymethyl s-tarch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules .

which, after mixing, are compressed on a table-t machine to yield tablets.
Capsules each containing 0.1-2 mg. of medicament are made as follows:
Active ingredient .1-2 mg.
Starch 59 mg.
Microcrystalline cellulose 59 mg.
Magnesium stearate 2 mg.
The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard yelatin capsules.
Suspensions each containing .1-2 mg. of medicament per 5 ml. dose are made as follows:
Active ingredient .1-2 mg.
Sodium carboxymethyl cellulose 50 mg.
Syrup 1.25 ml.
Benzoic acid solution 0.10 ml.
Flavor q.v.
Color q.v.
Purified water to 5 ml.
The medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymetbyl-cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are dilutPd with some of the water and added, with sti~ring. Sufficient water is then added to produce the required volume.
For oral administration, tablets, capsules or suspensions containing from about .l to about 2 mg. of an active D 2 agonist per dose are given 3-4 times a .......... : .

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day, giving a daily dosage of .3 to 8 mgs. or, for a 75 kg person, about 4.0 to about 107 mcg/kg. The intravenous dose is in the range from about .1 to about 100 mcg./kg.
For the D-l agonists, the dose level sufficient to stimulate D-l receptors varies from .01~15 mg./kg./day depending on the active compound employed. The aboye formulations using .01-15 mg. of active ingredient are employed.

'

Claims (28)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a compound of the formula I

wherein R is C1-C3 alkyl, allyl, H or CN;
R2 is H, CH3, Cl or Br;
R1 is NH2, NHR3 or NR4R5;
wherein R3 is methyl, ethyl, n-propyl or R6-CO
where R6 is C1-C3 alkyl or where R7 is independently H, Cl, F, Br, CH3, C2H5, CH3O, C2H5O or CF3; and n is 0, 1 or 2;
wherein R4 and R5 are independently methyl, ethyl or n-propyl; or a pharmaceutically-acceptable acid addition salt thereof;
which comprises:
(a) condensing a compound of the formula V

wherein R is as defined as above:
Y is R"CO, wherein R" is CH3 or C1-C3 alkoxy, or (R10)2NCH=, wherein each R10 is independently C1-C3 alkyl, or one R10 is H
and the other is C1-C3 alkyl;
with a compound or its salt of the formula VI

wherein R1 is defined as above to provide a compound of formula I; or (b) alkylating a compound of the formula Ia wherein R1 and R2 are defined as above to provide the compounds of formula I; and (c) when Y is (C1-C3 alkyl) O?-, halogenating the 4-OH compound of the formula If wherein R and R1 are defined as above to provide the compounds of formula I where R2 is Cl or Br; or (d) optionally followed by salifying to form the pharmaceutically-acceptable acid addition salt of the product of formula I and/or resolving a racemic product to form the optically active product of formula I.

2. A compound of the formula I

wherein R is C1-C3 alkyl, allyl, H or CN;
R2 is H, CH3, Cl or Br;
R1 is NH2, NHR3 or NR4R5;
wherein R3 is methyl, ethyl, n-propyl or R6-CO
where R6 is C1-C3 alkyl or where R7 is independently H, Cl, F, Br, CH3, C2H5, CH3O, C2H5O or CF3; and n is 0, 1 or 2;
wherein R4 and R5 are independently methyl, ethyl or n-propyl; or a pharmaceutically-acceptable acid addition salt thereof.

3. A process according to claim 1 for preparing the trans-(-)-stereoisomer of the formula II
wherein R, R1 and R2 are defined as in claim 1, which comprises either (a) resolving the trans-(?) racemate of the compound of formula (I) as defined in claim 1 using a known resolving agent to provide said trans-(-)-stereo-isomer of formula (II), or (b) resolving the racemic form of a compound of the formula wherein R is as defined in claim 1, to the trans-(-)-stereoisomer thereof, and then converting said resolved compound to the trans-(-)-stereoisomer of the ketone compound of formula (V) as recited in claim 1, and then reacting with a compound of the formula (VI) wherein R1 is as previously defined.

4. The trans-(-)-stereoisomer of a compound of claim 2 of the formula II
wherein R, R1 and R2 are defined as in claim 2.

5. A process according to claim 1 for preparing the trans-(+)-stereoisomer of the formula IIa wherein R, R1 and R2 are defined as in claim 1, which comprises either (a) resolving the trans-(?) racemate of the compound of formula (I) as defined in claim 1 using a known resolving agent to provide said trans-(+)-stereoisomer of formula (IIa), or (b) resolving the racemic form of a compound of the formula wherein R is as defined in claim 1, to the trans-(+) stereoisomer thereof, and then converting said resolved compound to the trans-(+)-stereoisomer of the ketone compound of formula (V) as recited in claim 1, and then reacting with a compound of the formula (VI) wherein R1 is as previously defined.

6. A compound of claim 2 of the formula IIa wherein R, R1 and R2 are defined as in claim 2.

7. The process of claim 1 for preparing trans-(+)-2-amino-6-methyl-5,5a,6,7,8,9,9a,10-octa-hydropyrimido[4,5-g]quinoline which comprises reacting trans-(+)-1-methyl-6-oxo-7-(dimethylaminomethylene)-decahydroquinoline with guanidine carbonate.

8. Trans-(+)-2-amino-6-methyl-5,5a,6,7,8,9,-9a,10-octahydropyrimido[4,5-g]quinoline.

9. The process of claim 1 for preparing trans-(+)-2-amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octa-hydropyrimido[4,5-g]quinoline which comprises reacting trans-(+)-1-n-propyl-6-oxo-7-(dimethylaminomethylene)-decahydroquinoline with guanidine carbonate.

10. Trans-(+)-2-amino-6-n-propyl-5,5a,6,7,8,-9,9a,10-octahydropyrimido[4,5-g]quinoline.

11. The process of claim 1 for preparing 5aR,9aR-2-amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octa-hydropyrimido[4,5-g]quinoline which comprises reacting 4aR,8aR-1-n-propyl-6-oxo-7-(dimethylaminomethylene)-decahydroquinoline with guanidine carbonate.

12. 5aR,9aR-2-Amino-6-n-propyl-5,5a,6,7,8,9,-9a,10-octahydropyrimido[4,5-g]quinoline.

13. The process of claim 1 for preparing trans-(?)-2-dimethylamino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoiine which comprises react-ing trans-(?)-1-n-propyl-6-oxo-7-(dimethylaminomethy-lene)decahydroquinoline with N,N-dimethylguanidine hydrochloride.

14. Trans-(?)-2-dimethylamino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline.

15. The process of claim 1 for preparing trans-(?)-2-methylamino-6-n-propyl-5,5a,6,7,8,9,9a,10 octahydropyrimido[4,5-g]quinoline which comprises reacting trans-(?)-1-n-propy1-6-oxo-7-(dimethylamino-methylene)decahydroquinoline with N-methylguanidine.

16. Trans-(?)-2-methylamino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline.

17. The process of claim 1 for preparing trans-(?)-2-amino-4-methyl-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline which comprises reacting trans-(?)-1-n-propyl-6-oxo-7-acetyldecahydro-quinoline with guanidine carbonate.

18. Trans-(?)-2-amino-4-methyl-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline.

19. The process of claim 1 for preparing trans-(?)-2-amino-4-chloro-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline which comprises react-ing trans-(?)-2-amino-4-hydroxy-6-n-propyl-5,5a,6,7,8,-9,9a,10-octahydropyrimido[4,5-g]quinoline with phos-phorus oxychloride.

20. Trans-(?)-2-amino-4-chloro-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline.

21. The process of claim 1 for preparing trans-(?)-2-acetylamino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline which comprises reacting trans-(?)-2-amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline with acetic anhydride.

22. Trans-(?)-2-acetylamino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline.

23. The process of claim 3 for preparing 5aS, 9aS-2-amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydro-pyrimido[4,5-g]quinoline which comprises reacting 4aS, 8aS-1-n-propyl-6-oxo-7-(dimethylaminomethylene)deca-hydroquinoline with guanidine carbonate.

24. 5aS-9aS-2-amino-6-n-propyl-5,5a,6,7,8,-9,9a,10-octahydropyrimido[4,5-g]quinoline.

25. The process of claim 11 which includes the further step of forming a pharmaceutically acceptable acid addition salt of the compound 5aR, 9aR-2-amino-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido [4,5-g]quinoline so prepared.

26. The process of claim 11 which includes the further step of forming the dihydrochloride salt of the compound 5aR, 9aR-2-amino-6-n-propyl-5,5a,6,7,8,9,9a,-10-octahydropyrimido [4,5-g]quinoline so prepared.

27. A pharmaceutically acceptable acid addition salt of trans-(-)-2-amino-6-n-propyl-5,5a,6,7,-8,9,9a,10-octahydropyrimido[4,5-g]quinoline.

28. Trans-(-)-2-amino-6-n-pxopyl-5,5a,6,7,8,-9,9a,10-octahydropyrimido[4,5-g]quinoline dihydrochloride.