Note: Descriptions are shown in the official language in which they were submitted.
~3~Z
X-6062M -1-
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
X-6062M -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
X-6062M -3
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~
X-6062M -4-
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
X-6062M -5-
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
X-6062M -6-
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
X-6062M -7-
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
X-6062M -8-
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~
X-6062M -9-
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
X-6062M -10-
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
X-6062M 11-
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~
X 6062M -12-
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
X-6062M -13-
~ ' ~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~
X-6062M 14-
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~
X-6062M -15-
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~%
X-6062M -17-
~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
X-6062M -19-
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
X-6062M -20-
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
X 6062M -21-
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
X-6062M -23-
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
X-6062M -24-
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
X-6062M -25-
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
X-5062M 26-
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
X-6062M -27-
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~
X-6062M -23-
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~
X-6062M -29-
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
X-6062M -30-
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~
X-6062M -31-
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
....
X-6062M -33-
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~
X-6062M -34-
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
X-6062M -35-
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
X-6062M -36-
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 ~
X-6062M -37-
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
X-6062M -38-
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-
,
X-6062M -40-
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
X-6062M -41-
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~
X-6062M -42-
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.
X-6062M -43-
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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X-6062M -44-
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X-6062M -45--
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X-6062M -46-
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.
-
3L2
X-6062M -a~7-
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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~
X-6062M -49-
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
X-6062M -50-
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%
X-6062M 51-
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.
, .
~23~
X-6062M -52-
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X-6062M -53-
A repeat run at 0.25 mcg. was carried out with
the following results (Table 6) ~values represent x ~ SE
for 11 rats).
~.
25- 6 0 6 2M - 5 4 -
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~1 ~ ,, ~ o
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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
X-6062M -56-
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.
3~ 2
X-6062M -57-
t~ o ,~ a~
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X-6062M -58-
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
X-6062M -59-
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.
L2
X-6062M -60-
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
., ,
... .
L2
X-6062M -61-
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
X-6062M -62-
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~
X-6062M -63-
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
X-6062M -64-
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
.
X-6062M -65-
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
.......... : .
~, '
~L2~ Z
X-6062M -66-
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.
'
