Note: Descriptions are shown in the official language in which they were submitted.
113Ç;6:~9
--1--
OCTAHYDRO PYRAZOLO [3,4-g]QUINOLINES
This invention in one aspect, provides octahydropyrazolo
[3,4-g]quinolines of the general formula:
~ 3~
R R
Ia Ib
wherein
R is (Cl-C3) alkyl or allyl;
R is H or CH2X wherein X is OCH3, SCH3, CN, SO2CH3 or CONH2;
and
pharmaceutically-acceptable acid addition salts thereof.
The compounds of formulae Ia and Ib above are prepared by
reacting a compound of the general formula
O ~ ~ Rl'
(cH3)2NcH N
R
wherein
R' is H, CN,(Cl-C3) alkyl or allyl;O
Rl is H, -COOH,- C-O(Cl-C2)alkyl,-C-O-substituted-
(Cl-C2)alkylphenyl;
113~ 9
~2.
with h~draz~ne fiydrate,
followed by, when R ~s CN, reacting with zinc and acetic acid
to form the compounds where R is H;
followed by, when R is H, reacting with an alkyl or allyl
halide or reductive alkylation with an appropriate aldehyde and metal
hydride to obtain the compounds of formulae Ia and Ib where R is
(Cl-C3)alkyl or allyl;
followed by, when Rl is other than H, reacting with a metal
hydride to obtain the intermediate compounds of formulae la and Ib
wherein Rl is CH2OH, followed by reacting with a nucleophilic reagent
to obtain the intermediate compounds of formulae Ia and Ib wherein
Rl is CH2Y where Y is Cl, sr, OSO2phenyl, O-tosyl, or OSO2(Cl-C3)-
alkyl, followed by reacting with sodium methylate, methyl mercaptan
sodium salt, sodium cyanide, sodium methanesulfinate, to obtain the
compounds of formulae Ia and Ib wherein Rl is CH2X where X is CN,
SCH3, SO2CH3, or OCH3; and
optionally followed by reacting the compounds of formulae Ia
and Ib where Rl is CH2CN with hydration to obtain the compounds of
formulae Ia and Ib where Rl is CH2CONH2, and where desired, forming
pharmaceutically acceptable acid addition salts of the aforesaid
compounds of formulae Ia and Ib.
The compounds of formulae Ia and Ib, together with their
pharmaceutically-acceptable salts thereof, are useful chiefly as
dopamine agonists.
Said compounds of formulae Ia and Ib and their pharmaceutically
acceptable salts and the process for their preparation, are disclosed
and are also claimed in our Canadian Application No. 330,552, filed
June 26, 1979, of which the present application is a divisional.
~, ,~.,
11366~g
--3--
Also provided by the invention, in another aspect, are
intermediates of the following general formulae:
N~'(X`' `~(XJ
R R
Ic Id
wherein
R is H, CN, C1-C3alkyl or benzyl;
R is H, -COOH, -COO(Cl-C3)alkyl, or CH2X wherein X is Cl,
Br, I, OH, OSO2-(Cl-C3)alkyl, OSO2tolyl, or OSO2phenyl;
with the proviso that when R is Cl-C3 alkyl, then R can not
be H; and
-the salts thereof.
All salts of these intermediates are useful in purification or
synthetic procedures.
This invention, in still another aspect, further provides a
process for preparing the above intermediates of formulae Ic and Id
wherein
R is H, CN, Cl-C3 alkyl or benzyl;
R is H, -COOH, -COO(Cl-C3)alkyl, or CH2X wherein X is Cl,
Br, I, OH, OSO2-(Cl-C3)alkyl, OSO2tolyl, or OSO2phenyl;
11366Z9
-3a-
with the provlso that when R is Cl-C3 alkyl, then Rl can
not be H; ard
the salts thereof, which comprises reacting a compound of
the general formula
H
` / \ ~ ~ ~4
R
wherein
R is defined as above, and
R is H or COOZ' where Z' is H, or (Cl-C3) alkyl,
with hydrazine hydrate;
lS followed by, when Z' is (Cl-C3)alkyl, reacting with a metal
hydride to obtain the compounds where R is CH2OH, followed by, if
desired, reacting with a nucleophilic reagent to obtain the compounds
where Rl is CH2Y where Y is Cl, Br, I/ OSO2-(Cl-C3)alkyl, OSO2tolyl
or OSO2phenyl, and where desired, forming a salt of said compound of
general formula Ic or Id.
The above intermediates of general formula Ic and Id, and
salts thereof, and the process for their preparation, are disclosed
and are also claimed in Canadian Application No. 379,594, filed
June 11, 1981, a divisional of the aforesaid Canadian Application No.
330,552.
In the above formulas, the term "(Cl-C2)alkyl" includes methyl
and ethyl and "(Cl-C3)alkyl" includes also n-propyl and iso-
propyl. The term "tolyl" includes p, m and o-tolyl.
The pharamaceutically-acceptable acid addition salts of
formulae Ia-Id include salts derived from inorganic acids such as:
hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid,
hydrobromic acid, hydriodic acid, nitrous acid, phosphorous acid and
the like, as well as salts derived from nontoxic
~ 1~36~
--4--
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 phar-
maceutically-acceptable salts thus include sulfate, pyrosulfate,
bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphos-
phate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride,
bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate,
acrylate, formate, isobutyrate, caprate, heptanoate, propiolate,
oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate,
mandelate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chloro-
benzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxy-
benzoate, phthalate, terephthalate, benzenesulfonate, toluenesul-
fonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate,
phenylpropionate, phenylbutyrate, citrate, lactate,~ -hydroxybutyrate,
glycollate, malate, tartrate, methanesulfonate, propanesulfonate,
naphthalene-l-sulfonate, naphthalene-2-sulfonate and the like salts.
Compounds according to Ia above are named systematically
as 4,4a,5,6,7,8,8a,9-octahydro-lH-pyrazolo[3,4-g]quinolines and
those according to Ib as 4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo
[3,4-g]quinolines. These two structures represent a tautomeric
pair and the tautomers represented by the structures are in dynamic
equilibrium. In addition, compounds represented by formulas Ia and
Ib above when Rl is H have two chiral centers, the ring junction.
i~ '
`113662~
-5-
carbons at 8a and 4a. Thus, the compounds can occur
as two racemates, ordinarily denominated as the
trans-dl racemate and the cis-dl racemate. ~t is
believed, however, according to the best evidence from
5 13C NMR spectral data, that the cyanoborohydride
reduction process which introduces hydrogens at the
quinoline bridge-head, a step in the synthetic procedure
used to prepare the compounds of formulae Ia and Ib,
yields a trans-fused decahydroquinoline. While the
arguments for the trans configuration based upon 13C
NMR spectral data are compelling, an X-ray crystal-
lographic investigation has also been carried out on
a nicely crystalline enaminoketone in the decahydro-
quinoline series (VIII, R=CH3 ) . This X-ray analysis
indicates clearly that the ring junction in the
quinoline moiety is trans. Further operations on the
decahydroquinoline molecule to condense a pyrazole
ring thereon do not alter the configuration of the
bridge-head hydrogens. Thus, only the trans racemate
is prepared by the synthetic procedures to be dis-
closed hereinafter and the compounds of formulae Ia
and Ib are preferably represented as the trans-dl
stereoisomers. The two trans stereoisomers of the 2H
tautomer can be represented as follows:
HN~ and Hl~\; ¦ i
R R
IIa IIb
1~36~
IIa and IIb represent a racemic pair. A similar
racemic pair can be drawn for the lH tautomer.
and
` R R
lQ IIc IId
IIc and IId also represent a racemic pair.
Resolution of these racemates into their
optical antipodes can be accomplished by procedures
known to those skilled in the art, and the individual
trans-d and trans-l isomers are included within the
scope of this invention.
In addition, when Rl is other than H, a
third chiral center is introduced at C-7. However, it
is presently believed that the configuration of ~he
C-7 group is chiefly beta relative to an alpha 8a
hydrogen as in IIa. In the mirror image, IIb, Rl is
alpha with respect to 8a being beta. Thus, the
trans-dl 7-substituted octahydropyrazolo[3,4-g]quino-
lines of formulae Ia and Ib are provided substantially
as a single racemate or diastereoisomeric pair.
The following compounds illustrate some
of formulae Ia and Ib:
trans-d1-5-methyl-7-methoxy~ethyl-4,4a,5,-
6,7,8,&a,9-octahydro-2H-pyrazolo[3,4-g]quinoline,
. . - : .
' :
.
.
113~
trans-Q-5-allyl-7-methylmercaptomethyl-
4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-
g]quinoline maleate,
trans-dl-5-ethyl-4,4a,5,6,7,8,8a,9-
octahydro-lH-pyrazolo[3,4-g]quinoline,
trans-dl-S-n-propyl-7-methylsulfonyl-
methyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrazolo-
[3,4-g]quinoline tartrate,
trans-d-5-methyl-7-cyanomethyl-4,4a,-
5,6,7,8,8a,9-octahydro-lH-pyrazolo[3,4-g]quinoline,
trans-dl-5-methyl-4,4a,5,6,7,8,8a,9-
octahydro-2H-pyrazolo[3,4-g]quinoline sulfate,
trans-dl-4,4a,5,6,7,8,8a,9-octahydro-
lH-pyrazolo[3,4-g]quinoline sulfate,
trans-dl-5-n-propyl-7-carboamidomethyl-
4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-
g]quinoline fumarate,
trans-dl-5-isopropyl-4,4a,5,6,7,8,8a,9-
octahydro-2H-pyrazolo[3,4-g]quinoline,
trans-dl-7-methylmercaptomethyl-4,4a,-
5,6,7,8,8a,9-octahydro-lH-pyrazolo[3,4-g]quinoline,
trans-dl-5-n-propyl-7-methoxymethyl-
4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-
g]quinoline maleate,
~5 trans-dl-5-ethyl-7-cyanomethyl-4,4a,-
5,6,7,8,8a,9-octahydro-2H-pyrazolol3,4-g~quinolin~, and
trans-dl-5-allyl-4, 4h, 5,6,7,8,8a,9-
octahydro-2H pyrazo'ol3,4-glquinolinP.
For compounds listed above, it should be
understood that each name also comp~ehends the cther
tautomer since an equilibrium mixture of the two
,
. .
11~6~2~
-8-
tautomers is always present. The 2H tautomer
apparently predominates in several of the tautomeric
mixtures. In addition, the orientation of substitu-
ents is not given, nor is the configuration of the
hydrogens at 4a and 8a, but it is understood that the
hydrogens are trans to one another and that the 7
substituent is "trans" to the 8a hydrogen; i.e., when
the 8a hydrogen is alpha, the 7 substituent is beta
and when the 8a hydrogen is beta, the 7 substituent is
oriented in the alpha configuration.
The compounds of formulae Ia and Ib in
which Rl is H are prepared according to the following
procedure as outlined in Reaction Scheme I. In the
Reaction Scheme, only one stereoisomer of the racemic
pair, the 4a~, 8a~ isomer, has been drawn for con-
venience but it should be remembered that each deca-
hydroquinoline and each octahydropyrazolo[3,4-g]
quinoline exists as a racemate.
.,,
~13~9
g
Reaction Scheme I
o
I ! pyrrolidine \ acrylamide \
\~/ acid catalyst /
S o-co-z Z-C--I' `!' `I
0
III H
RX I NaH
z
CO
H0-1 ~! t / LiAlH4
V R IV R
HCI
NaCNBH3
H ~ H~S04 /I ~ ~
VI H R VII
H / ~ (CH3)2NCH(OZ'')
~S ~c~a~ ,I, (CH~ CH~ \~/i;i
/l\ R ~ VIII
. NH2NHz-H20
/-/
~ \N
IX R
11366~9
--10--
In the above reaction scheme, Z-CO is an acyl pro-
tecting group in which Z is (Cl-C3)alkyl, (C2-C3)-
alkenyl, (C2-C3)alkynyl, (C5-C6)cycloalkyl, phenyl or
substituted phenyl wherein the substituting group can
be methyl, methoxy, chloro and the like at any position
of the phenyl ring. Illustratively, Z-CO can be
acetyl, propionyl, butyryl, propiolyl, acrylyl,
benzoyl, p-toluyl, o-chlorobenzoyl, m-methoxybenzoyl,
and so on.
Z " is defined hereinbelow in the discussion
of Reaction Scheme II. In accordance with Reaction
Sche~e I, 4-acyloxycyclohexanone prepared by the
procedure of E.R.H. Jones and F. Sondheimer, J. Chem.
Soc., 615, (1949) for 4-benzoyloxycyclohexanone, is
reacted with pyrrolidine in the presence of an acid
catalyst to yield the pyrrolidine enamine. This
enamine i3 in turn reacted with acrylamide to produc~
a mixtu~e of dl-6-acyloxy-3,4,5,6,7,8-hexahydro-
2(lH)quinolinone and dl-6-acyloxy-3,4,4a,5,6,7-hexa-
2G hydro-2(1H)quinolinone represented by formula III, the
dotted lines indicating the alternative positions of
the double bond.
Next, the acidic nitrogen~(acidic since it
is alpha to a carbonyl group) is alkylated with an
alkyl halide RX wherein R has the same meaning as
hereinabove and X is a halogen such âS Cl, Br or I, in
the presence of sodium hydride to yield a mixture of
dl-l-(Cl-C3) alkyl (or allyl or ~enzyl)-6-acyloxy-
3,g,5,6,7,8-hexahydro-2(lH) quinolinone and its ~
~C isomer (IV). Reduction of this amide with lithium
. .
1136~
aluminum hydride or other suitable organometallic
reducing agent yields a mixture of dl-l-(Cl-C3)alkyl-
(or allyl or benzyl~-6-hydroxy-1,2,3,4,5,6,7,8-
octahydroquinoline and its ~8 isomer. In this re-
action mixture, conditions are encountered which alsoserve to hydrogenolyze the acyloxy group to a hydroxyl
group at C-6. This dl-l-(Cl-C3)alkyl (or allyl or
benzyl)-6-hydroxyoctahydroquinoline is next converted
to an ammonium salt by treatment with hydrochloric
acid, and the ammonium salt is then reduced with
sodium cyanoborohydride to yield trans-dl-l-(Cl-C3)-
alkyl (or allyl or benzyl)-6-hydroxydecahydroquinoline
(VI). Next, the trans-dl-l-(Cl-C3 alkyl, allyl, or
benzyl)-6-hydroxydecahydroquinoline (VI) is oxidized
using, preferably, chromium trioxide in acetic acid,
to yield the corresponding 6-oxo compound (VII). This
6-oxo compound (VII) is reacted with dimethylformamide
dimethylacetal to yield a 7-dimethylaminomethylene-
6-oxo-derivative (VIII). Reaction of this derivative
2~ with hydrazine hydrate yields a tautomeric mixture of
a tricyclic derivative, predominately trans-dl-5-
[(Cl-C3)alkyl, allyl or benzyl)3-4,4a,5,6,7,8,8a,9-
octahydro-2H-pyrazolo[3,4-g]quinoline (IX) and its lH
t~utomer (IXa) in smaller amount.
The compounds of formulae Ia and Ib wherein
R is C1-C3 alkyl or allyl, the dcpamine agonists, can
also be prepared from compounds in which R is benzyl.
In this procedure, the ~enzyl group is removed by
reductive cleavage or by treatment with cyanogen
3~ bromide to yield, eventually, a compound according to
113~6~9
-12-
IX or IXa in which R is H progressing thru an inter-
mediate when cyanogen bromide is used in which R is
CN. This debenzylated compound can then be alkylated
with a lower alkyl halide, or alternatively it may be
reductively alkylated using acetaldehyde, acrolein or
propionaldehyde in each instance with a metal hydride,
such as sodium cyanoborohydride, to yield the desired
N-alkyl or allyl derivative. The usual conditions for
removing an N-benzyl group are hydrogen with a palladium-
on-carbon catalyst or reaction with cyanogenbromide
followed by reductive (Zn and acetic acid) cleavage of
the N-cyano compound.
In the above reaction scheme, it is apparent
from an inspection of the dl-trans-l(substituted)-6-
ketodecahydroquinoline (VII) that reaction withdimethylformamide dimethylacetal could take place at
either C-5 or C-7 since both these carbons are alpha
to the ketone group and thus available for reaction.
The sa~e X-ray crystallographic analysis of the
ena~ine (VIII) discussed above clearly indicated tha~
reaction had taken place at C-7 rather than C-5.
Hence, the final tricyclic compounds, IX and IXa, are
the linear pyrazolo[3,4-g]quinolines rather than the
angular tricyclic compounds (which would be named as
4,4a,5,6,7,8,8a,9-octahydro-lH-pyrazolo~2,3-i~quino-
lines.
The compounds of this invention in which
is other than H are prepared accordins to a slightly
different procedure illustrated generally in Reaction
Scheme II. ~g in Reaction Scheme I the procedure is
exemplified with only (referring to the stereochem-
istry of the bridge-head) a single stereoisomer, the
4a~, 8a~ isomer.
1~3~
--13--
Reaction Scheme Il
' O
Il O
RNH2 \ ~ / \;/ \t-CZ'
CH2=C-COOZ' / \;i \N
CH2Ha I X
O-CO-Z R
¦ acid
BH4
lC /
HO~COQZ' / EtOH / OH I ~ - cooz~
15XII R XI R
pyridine HCI
CrO3
\ /
~ 2~~ H ~
; 0=~ t t-- cooz (~)2N ~ .
H ~ O 1 t I- COOZ'
Xl II R (CH~)~NCH = \ /~N/
XIV
¦ NH2NH2-H20
\ /
H I~. ~ I
~ XV R
_ --
,~ .
... .
1~366~
-14-
wherein Z and Z'' have the same significance as in
Reaction Scheme I, Hal is chloro or bromo and Z' is
part of a readily hydrolyzable group Z'O-CO such as
(Cl-C2)alkyl, phenyl substituted-(Cl-C2)alkyl, illus-
tratively benzyl, phenethyl, p-methoxybenzyl, methyl,
or ethyl.
In accordance with the Reaction Sche~.e II,
a 4-acyloxycyclohexanone is reacted with an a-halo-
methylacrylate ester, for illustrative purposes, the
ethyl ester and an amine, RNH2~ wherein R is Cl-C3
alkyl, allyl or benzyl. The product of this reaction
is a mixture of dl-l-substituted-3-ethoxycarbonyl-
6-acyloxy-1,2,3,4,5,6,7,8-octahydroquinoline and
dl-l-substituted-3-ethoxycarbonyl-6-acyloxy-1,2,-
3,4,4a,5,6,7-octahydroquinoline represented by X in
which the dotted line indicates the alternate positions
of the double bonds. The hydrochloride salts of these
isomers were prepared and the resulting mixture re-
duced with sodium cyanoborohydride to yield tran~-dl-
2~ 1-subetituted-3-ethoxycarbonyl-6-acyloxydecahydro-
quinoline (XI). Hydrolysis of this diester to yield a
6-hydroxy-3-carboxylic acid followed by reesterifi-
cation of the carboxylic acid group with ethanol or
other suitable alcohol in the presence of acid yields,
as a novel intermediate, trans-dl-1-substituted-
3-ethoxycarbonyl-6-hydroxydecahydroquinoline (XII).
~xidation of the hydroxy group with Sarett's Reagent
(pyridinP hydrochloride and chrcmium trioxide) pro-
duces tne corresponding novel intermeai~te 6-oxo
compound (XIII). TrPatment of this 6-oxo d~rivative
1~36~
-15-
with a dimethylformamide acetal, preferably dimethyl-
formamide dimethylacetal, results in reaction at C-7
(adjacent to the keto group) to give, as a novel
intermediate, trans-dl-l-substituted-3-ethoxycarbonyl-
6-oxo-7-(dimethylaminomethylene)decahydroquinoline
(XIV). Reaction of this derivative as in Reaction
Scheme I above with hydrazine hydrate results in a
mixture comprising trans-dl-5-substituted-7-ethoxy-
carbonyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrazolo-
[3,4-g~quinoline and its 2H tautomer (represented by
XV as a single stereoisomer). The compound can be
isolated and purified as the free base or as the
dihydrochloride salt, prepared according to conventional
procedures.
Acetals of dimethylformamide useful in
producing compound VIII in Reaction Scheme I and
compound XIV in Reaction Scheme II have the general
formula (CH3)2N-CH-(OZ'')2 in which Z'' is (Cl-C8)-
alkyl, (C5-C6)cycloalkyl, (C3-C4)alkenyl, (C3-C4)-
alkynyl and the like. We prefer to employ one of
the commercially available acetals of dimethyl-
formamide; l.e.; the dimethyl, diethyl, diisopropyl,
dibutyl, dicyclohexyl, dipropyl or dineopentyl
acetals.
In formula XV above, R is (Cl-C3)alkyl,
allyl or benzyl. The octahydropyrazolo~3,4-g]-
quinoline of Formula XV represents a single tau-
tomer, the 2H tautomer, and only one diastereo-
isomer. The mirror image of XV is also prepared and
is included within the scope of this invention. We
113~9
-16-
believe based upon analogy with the D-ergolines that the dia-
stereoisomer XV is the isomer having dopamine agonist activity.
The trans-dl racemate, which contains XV and its mirror image,
is of course useful as a dopamine agonist, even though most of
the desired activity resides in one of its component stereoi-
somers.
Intermediates described in Reactions Schemes I and II,
having the following structures, form a part of this invention
HO-I/ ~ -R = ~ ~ ~ -R~ O=
10 ./ \N \~ ~ and (CH3)2N-CH=
R R R
XII XIII XIV
wherein R is (Cl-C3)alkyl, allyl or benzyl and Rl is COOZ' where-
in Z is (Cl-C2)alkyl or phenyl-substituted (Cl-C2)alkyl. These
intermediates are prepared by the methods set forth in those re-
action schemes, in the accompanying detailed description and in
the Examples which follow.
Thus the invention, in a further aspect, resides in an in-
termediate compound of general formula XII:
HO- ( ~I \I-COOZ' XII
R
wherein R is (Cl-C3)alkyl, allyl or benzyl and Z' is (Cl-C2)
alkyl, benzyl, phenethyl or p-methoxybenzyl and in a process
for preparing this intermediate, which comprises subjecting a
compound of general formula XI:
H~ ~ XI
/ N
R
'~ .
.
1~36~2~
-16a-
wherein R and Z' are defined as before, and Z is (Cl-C3)alkyl,
(C2-C3) alkenyl, (C2-C3) alkynyl, (C5-C6) cycloalkyl, phenyl or
methyl, methoxy or chloro-substituted phenyl; to hydrolysis to
yield a 6-hydroxy-3-carboxylic acid, followed by reesterifica-
tion with an alcohol in the presence of acid.
Compounds according to formula XV above in which R is ethy~
allyl or n-propyl can be prepared by two different procedures.
First, the amine, RNH2, used in preparing X can be ethyl, n-
propyl or allyl thus introducing the group directly. Alter-
natively a compound according to formula XV in which R is methy
or benzyl can be transformed into a compound in which R is H by
removing the methyl or benzyl group by reaction with cyanogen
bromide. The intermediate
.
1~,
. .
- 113~i~2~
-
-17-
5-cyano (R is CN) derivative can be reductively
cleaved (zinc plus acetic acid) to yield a compound in
which R is H. In addition, the benzyl group can be
removed by hydrogenation with palladium-on-carbon to
yield those intermediates ~n which R=H. Alkylation of
the secondary amine can be accomplished by reaction
with an alkyl halide--RCl, RBr or RI. Alternatively,
the secondary amine group can be reacted with an
aldehyde, such as acetaldehyde, acrolein, or pro-
pionaldehyde under reducing conditions with a meta~hydride, (e.g. NaBH3CN) to yield an N-ethyl, N-allyl
or N-n-propyl derivative.
The dopamine agonists of this invention,
those compounds of formulae Ia and Ib in which Rl is
CH2X wherein X is CN, OCH3, SCH3, SO2CH3 or CO-NH2,
are prepared from compound XV according to Reaction
Scheme III below
_
. . .
.,~...
1~3~i6~
--18--
Reaction Scheme III
H~\N
LiAlH4 I XV
\ /
~H\~ XYI
tosy l -C lSOC l 2
(C1-C3)alkyl SO2Cl PCls
p heny l SOzC l POC l 3
PBr3
\ Etc .
/ \f
NaCN
2 5 CH3 SNa
CHsONa
\ CHsSO2Na
H ~ XVIII
1~36~9
--19--
wherein Y is a "leaving" group: Cl, Br, OSO2phenyl,
O-tosyl or SO2(Cl-C3)alkyl, R2 is H, SO2phenyl, tosyl
or SO2(Cl-C3)alkyl, and X is CN, SCH3, OCH3 or SO2CH3.
In Reaction Scheme III, as before, only one
tautomer, the 2H tautomer, is illustrated. Further-
more, the 2H tautomer exists as a racemate and only
one diastereoisomer is illustrated, the 4a~, 7t3, 8aa
isomer. The mirror image compound is, of course, also
produced since it constitutes half of the starting
material, XV. ~he trans-dl racemates of XVIII are
useful as dopamine agonists because of their content
of active agonist. The intermediate racemates, XV,
XVI and XVII are useful in that each contains a
diastereoisomer which can be chemically transformed to
an active dopamine agonist.
According to Reaction Scheme III, a trans-
dl-5-substituted-4,4a,5,6,7,8,8a,9-octahydro-2H-
pyrazolol3,4-g]quinoline-7-carboxylate ester is
reduced with a metal hydride reducing agent, such as
LiA1~4, to a pyrazolo[3,4-g]quinoline with a 7-
hydroxymethyl group (XVI). The thus-produced
hydroxyl is next replaced with a "leaving group";
i.e., a group readily displaced by a nucleophilic
reagent, including chlorine, bromine and the
halogen-like esters, tosylate (usually p-toluene
sulfonate), alkyl sulfonate, benzene sulfonate to
produce a compound of structure XVII. The Cl or Br
leaving groups are introduced by reaction with PC13,
SOC12, PC15, POC13, PBr3 and the like, and the
_ . _
1136~9
-20-
~ulfonate esters by reaction with the corresponding
sulfonyl chloride. Reaction of XVII with sodium
methylate, methylmercaptan sodium salt, sodium cyanide,
sodium methanesulfinate or other basic salts of
methanol, methylmercaptan and so forth yields com-
pounds according to formula Ia, Ib, Ic or Id in which
X is SCH3, OCH3, CN or SO2CH3. These basic reaction
conditions also serve to hydrolyze the sulfonyl group
in the pyrazole ring, if any, to produce a tautomeric
mixture XVIII (of which only the 2-tautomer is illus-
trated). Compounds in which X is CONH2 are prepared
by hydration of the corresponding cyano compound.
This invention is further illustrated by the
following specific examples.
STARTING MATERIALS
Example A
Preparation of trans-dl-5-Cyano-4,4a,5,6,7,8,8a,9-
octahydro-lH (and 2H)-pyrazolo~3,4-g]quinoline
A reaction mixture was prepared from 65 g.
of 4-benzoyloxycyclohexanone, 38 ml. of pyrrolidine,
a few crystals of p-toluenesulfonic acid monohydrate,
and 1000 ml. of benzene. The reaction mixture was
heated to refluxing temperature under a nitrogen
atmosphere for one hour in an apparatus equipped with
a Dean-Stark water trap. The reaction mixture was
then cooled and the volatile constituents removed by
evaporation in vacuo. The residue, comprising the
pyrrolidine enamine of 4-benzoyloxycyclohexanone
11366~
-21-
formed in the above reaction, was dissolved without
further purification in 1000 ml. of dioxane. 64 g. of
acrylamide were added. This new reaction mixture was
heated under a nitrogen atmosphere at reflux tem-
perature for two days after which time it was cooledand the volatile constituents removed by evaporation
in vacuo. The reaction mixture was diluted with ethyl
acetate and the ethyl acetate layer separated, washed
first with water and then with saturated aqueous
sodium chloride. The ethyl acetate layer was dried
and the volatile constituents removed by evaporation
in vacuo. The resulting residue, comprising a mixture
of 2-oxo-6-benzoyloxy-3,4,5,6,7,8-hexahydroquinoline
and 2-oxo-6-benzoyloxy-3,4,4a,5,6,7,-hexahydroquinoline
formed in the above reaction, was dissolved in chloro-
rOrm ar.d ~he chloroform solution chromatographed over
"~Lorisil" Chloroform containing increasing amounts of
eth~nol (0 to 2 percent) was used as the eluant.
Fractions found to contain 2-oxo-6-benzoyloxy-
3,4,5,6,7,8-hexahydroquinoline and its ~8(8a) isomer
by thin-layer chromatography were combined and the
solvent remcved therefrom in vacuo. The resulting
residue was crystallized by triturating with hexane to
yield a crystalline mixture of 6-benzoyloxy-3,4,5,6,7,8-
hexahydro-lH-quinolin-2-one and the corresponding
3,4,4a,5,6,7-hexahydro derivative. The mixture melted
in the range 130-150C. after recrystallization from
an etner-hexane solvent mixture.
~nalys s:Calculated: C, 70.83; H, 6.32; N, 5.16.
Found: C, 71.05; H, 6.19; ~, 5.33.
*Trademark for activated magnesium silicate in the form
of hard, porous, stable, white granules, used as an
adsorbent in chromatographic separations.
. ~ ~
1136~
NMR of the product isolated above indicated
that the mixture contained about 60 percent of 6-
benzoyloxy-3,4,5,6,7,8-hexahydro-lH-quinolin-2-one
and 40 percent of the 3,4,4a,5,6,7-hexahydro isomer.
A mixture of 2-oxo-6-benzoyloxy-3,4,5,-
6~7~8-hexahydroquinoline and its ~8(8a) isomer obtained
from 65 g. of 4-benzoyloxycyclohexanone as above
without further purification was dissolved in a
mixture of 300 ml. of tetrahydrofuran (THF) and
300 ml. of dimethylformamide. 14 g. of sodium hydride
were added, thus forming the sodium salt of the
quinoline. This mixture was stirred at ambient
temperature for about 20 minutes under a nitrogen
atmosphere after which time 55 g. of benzyl bromide in
75 ml. of THF were slowly added over a 10 minute
period. The reaction mixture was stirred for an
additional hour in the range 32-45C. and was then
diluted with water. The aqueous mixture was extracted
with ethyl acetate. The ethyl acetate extract was
separated, washed with water and with saturated
aqueous sodium chloride, and then dried. Evaporation
of the ethyl acetate yielded a mixture of l-benzyl-
2-oxo-6-benzoyloxy-3,4,5,6,7,8-hexahydroquinoline and
l-benzyl-2-oxo-6-benzoyloxy-3,4,4a,5,6,7-hexahydro-
~S quinoline; yield = 106 g.
106 g. of the above mixture were dissolvedin 1 1. of THF and the solution cooled in an ice-
water bath. 40 g. of lithium aluminumhydride were
added thereto in portions. After the addition had
been compieted, the reaction mixture was heated to
113f~ 9
-23-
refluxing temperature under a nitrogen atmosphere for
about 4 hours. The reaction mixture was then cooled
and excess lithium aluminumhydride destroyed by the
addition of ethyl acetate. 10 percent aqueous sodium
hydroxide was added to decompose any organometallic
- compounds present in the mixture. At this point, the
reaction mixture was diluted with water. The re-
sulting aqueous mixture was extracted several times
with chloroform. The chloroform extracts were separated
and combined. The combined extracts were washed with
saturated aqueous sodium chloride and then dried.
Evaporation of the chloroform yielded a residue
comprising a mixture of l-benzyl-6-hydroxy-1,2,3,4,5,-
6,7,8-octahydroquinoline and 1-benzyl-6-hydroxy-
1,2,3,4,4a,5,6,7-octahydroquinoline. (80th the 2-oxo
group and the 6-benzoyloxy group reacted with the
lithium aluminum hydride to yield an octahydroquino-
line with a free alcohol at C-6). The mixture of
compounds thus obtained was dissolved in ether, the
ethereal solution cooled, and gaseous anhydrous
hydrogen chloride passed into the solution, thus
forming the hydrochloride salts of the quinoline
isomers. The quinoline hydrochlorides were insoluble
and were separated by decantantation of the ether.
The residual salts were dissolved in 100 ml. of
methanol and 400 ml. of THF. The solution was cooled
and 30 g. of sodium cyanoborohydride added thereto in
portions. After the addition had been completed, the
cooling batn was removed and the reaction mixture
stirred at ambient temperature for 1.25 hours, after
~: :
~136~9
-24-
which time it was poured into a mixture of lN aqueous
hydrochloric acid and ice. The acidic solution was
extracted with ether, and the ether extract discarded.
The acidic solution was then made basic with 10 percent
aqueous sodium hydroxide and the alkaline mixture
extracted several times with a chloroform-isopropanol
solvent mixture. The organic extracts were combined,
and the combined extracts washed with saturated
aqueous sodium chloride and then dried. Evaporation
of the solvent yielded trans-dl-1-benzyl-6-hydroxy-
decahydroquinoline formed in the above reaction; yield
= 53.6 g. Total yield in 6 steps was 73 percent based
upon recovered 4-benzoyloxycyclohexanone starting
material.
53 g. of trans-dl-1-benzyl-6-hydroxydeca-
hydroquinoline were dissolved in 1.5 l. of methylene
dichloride and the solution cooled in an ice-water
bzth. 50 g. of cyanogen bromide were added and the
resulting mixture stirred at room temperature for 15
2C hours. The reaction mixture was washed successively
with lN aqueous hydrochloric acid and water, and was
then dried. Evaporation of the solvent yielded a
residue containing trans-dl-l-cyano-6-hydroxydeca-
hydroquinoline formed in the above reaction. The
residue was dissolved in chloroform and the chloroform
solution chromatographed over 300 g. cf"Florisilnusing
chloroform containing increasing amounts (0-2%) of
methanol as the eluant. Fractions shown by TLC to
*Trademark for a highly selective adsorbent of hard
granular or powdered magnesium silicate, employed in
chromatography.
-25-
contain the desired cyano compound were combined and
the solvent removed from the combined fraction by
evaporation in vacuo. trans-dl-l-cyano-6-hydroxy-
decahydroquinoline thus prepared weighed 22.5 g.
22.5 g. of trans-dl-1-cyano-8-hydroxy-
decahydroquinoline were dissolved in 1200 ml. of
methylene dichloride. 33 g. of pyridine hydro-
chloride:chromium trioxide (Sarett's Reagent) were
added. The reaction mixture was stirred at room
temperature under nitrogen for about 6 hours, and was
then filtered. The filtrate was concentrated in vacuo
and the concentrate chromatographed over 300 g. of
"Florisil~using chloroform containing 1 percent methanol
as the eluant. Fractions shown by TLC to contain
trans-dl-1-cyano-6-oxodecahydroquinoline formed in the
above reaction were combined and the combined fractions
evaporated to dryness in vacuo. Recrystallization of
the resulting residue from an ether-chloroform solvent
mixture yielded trans-dl-l-cyano-6-oxodecahydroquinoline
melting at 86-8C.; yield = 18.9 g.
Analysis:Calculated: C, 67.39; H, 7.92; N, 15.72.
Found: C, 67.15; H, 7.75; N, 15.46.
17.6 g. of trans-dl-1-cyano-6-oxodecahydro-
quinoline were dissolved in 200 ml. of benzene to 25 which 100 g. of the dimethylacetal of dimethylformamide
had b~en added. The reaction mixture was heated to
re'luxing temperature under nitrogen for about 20
hours and was then cooled. Evaporation of the solvent
in vacuo yielded a residue comprising trans-dl-l-
cyano-6-oxo-7-dimethylaminomethylenedecahydroquinoline
*Trademark
_ .
.,
11366~
-26-
formed in the above reaction. The compound was
purified by chromatography over 300 g. of~Florisil"
using chloroform containing increasing amounts (0-2%)
of methanol as the eluant. 10.2 g. of trans-dl-l-
cyano-6-oxo-7-dimethylaminomethylenedecahydroquinoline
melting at 159-163C. were obtained. The compound was
crystallized from toluene to yield crystals melting at
162-4C.
Analy~is:Calculated: C, 66.92; H, 8.21; N, lB.Oi.
Found: C, 67.14; H, 8.16; N, 18.04.
10.2 g. of trans-dl-1-cyano-6-oxo-7-
dimethylaminomethylenedecahydroquinoline were dis-
solved in 400 ml. of methanol. 2.8 g. of 85 percent
hydrazine were added and the subsequent reaction
mixture stirred for about 1 day under a nitrogen
atmosphere. The volatile constituents were then
removed by evaporation in vacuo. The residue was
dissolved in chloroform and the chloroform solution
chromatographed over 150 g. of"Florisil"using chloro-
form containing increasing amounts (2-5%) of methanol
as the eluant. Fractions shown by TLC to contain the
desired octahydropyrazoloquinoline were combined and
the solvent evaporated therefrom to dryness; yield =
6.3 g. Recrystallization of the residue from ethanol
yielded a mixture of trans-dl-5-cyano-4,4a,5,6,7, a, 8a,9-
octahydro-2H-pyrazolo[3,4-g]quinoline and its lH
tautomer melting at lg3-5C.
Analysis:Calculated: C, 65.32; H, 6.98; N, 27.70
Found: C, 65.48; B, 6.80; N, 27.64
*Trademark
11 366'~9
-27-
Example B
Preparation of trans-dl-4,4a,5,6,7,8,8a,9-Octahydro-
lH (and 2H)-pyrazolo[3,4-glquinoline
A reaction mixture prepared from 860 mg of
trans-dl-5-cyano-4,4a,5,6,7,8,8a,9-octahydro-lH and
2H-pyrazolo[3,4-g]quinoline, (from Example A), 5 g.
of zinc dust, 10 ml. of water and 50 ml. of acetic
acid. The mixture was heated to refluxing temperature
under a nitrogen atmosphere for 18.5 hours after which
time it was filtered and the filtrate poured over ice.
The resulting aqueous mixture was then made basic with
14N ammonium hydroxide and the resulting alkaline
aqueous layer extracted several times with a chloro-
form-isopropanol solvent mixture. The organic extracts
were combined and the combined extracts washed with
saturated agueous sodium chloride and then dried.
Evaporation of the solvent yielded a residue com-
prising trans-dl-4,4a,5,6,7,8,8a,9-octahydro-2H-
pyrazolo[3,4-glquinoline and the 1~ tautomer formed in
the above reaction. The residue was dissolved in
ethanol and 0.70 ml. of 12N aqueous hydrochloric acid
added thereto. The mixture of trans-dl-4,4a,5,6,7,8,8a,9-
octahydro-2H-pyrazoloL3~4-g]quinoline and the lH-
tautomer dihydrochlorides formed as above melted at284-7C.; yield = 780 mg.
Analysis:Calculated: C, 48.01; H, 6.85; N, 16.80.
Found: C, 48.07; H, 7.05; N, 16.83.
~36~'~9
-28-
Example C
Preparation of trans-dl-5-n-Propyl-7-ethoxycarbonyl-
4,4a,5,6,7,8,8a,9-octahydro-lH (and 2H)-pyrazolo[3,4-
g]quinoline
A mixture of 10 ml. of n-propyl amine and
400 ml. of toluene were cooled in an ice-water bath.
A solution of 16.5 g. of ethyl a-(bromomethyl)acrylate
in 50 ml. of toluene was added thereto in dropwise
fashion. The resulting mixture was stirred with
cooling for about 25 minutes. Next, a solution of
11 g. of 4-benzoyloxycyclohexanone in 75 ml. of
toluene was added in dropwise fashion. This new
mixture was heated under a nitrogen atmosphere to
refluxing temperature for about 23 hours. The reflux
condenser was equipped with a Soxhlet extractor
containing a SA sieve to remove water. Next the
reaction mixture was cooled and the cooled mixture
filtered. Evaporation of the filtrate yielded a
residue comprising a mixture of 1-n-propyl-3-ethoxy-
carbonyl-6-benzoyloxy-1,2,3,4,5,6,7,8-octahydro-
quinoline and l-n-propyl-3-ethoxycarbonyl-6-benzoyioxy-
1,2,3,4,4a,5,6,7-octahydroquinoline. The residue was
dissolved in an ether-chloroform so~vent mixture and
the resulting solution saturated witA gaseous hydrogen
chloride while maintaining the temperature in the
range 0-5C. The solvent was decanted from the
crystalline hydrochloride salts thus formed. The
salts were dissolved in 100 ml. of methanol. 300 ml.
of THF were added and the resulting solution cooled in
11366'~
-29-
an ice-water bath. 15 g. of sodium cyanoborohydride
were added ir. portions to the stirred and cooled
reaction mixture. After the addition had been
completed, the reaction mixture was stirred for
another 1.25 hours after which time it was diluted
with aqueous sodium bicarbonate. The aqueous alkaline
mixture was extracted several times with ethyl
acetate. The ethyl acetate extracts were combined and
the combined extracts washed with saturated aqueous
sodium chloride solution and then dried. Evaporation
of the solvent yielded trans-dl-l-n-propyl-3-ethoxy-
carbonyl-6-benzoyloxydecahydroquinoline. The compound
was dissolved in a mixture of 400 ml. of methanol and
100 ml. of 2N aqueous sodium hydroxide. This mixture
was stirred at ambient temperature under a nitrogen
atmosphere for 64 hours after which time the volatile
constituents were removed by evaporation in vacuo.
The resulting residue was suspended in 800 ml. of
e~hanol and 15 ml. of 12N aqueous hydrochloric acid.
The esterification mixture was heated to refluxing
temperature and about 300 ml. of solvent removed ~y
distillation. 300 ml. of additional ethanol were
added and the reaction mixture heated to refluxing
temperature for 26 hours in an apparatus equipped with
a Soxhlet trap containing a 3A sieve. The reaction
mixture was cooled, diluted with aqueous sodium
bicarbonate and the alkaline mixture extracted several
times with chloroform. The chloroform extracts were
-ombined and the co~ined extracts washed with satu-
rated aqueous sodium chloride and then dried. Evapo-
.
~13~6~
-30-
ration of the chloroform yielded 10.3 g. of a residue
comprising trans-dl-l-n-propyl-3-ethoxycarbonyl-6-
hydroxydecahydroquinoline formed in the above hydrolysis
after chromatography over 150 g. of"~lorisil"using
chloroform containing increasing amounts (2-10%) of
methanol as the eluant.
A solution was prepared from 8.8 g. of
trans-dl-l-n-propyl-3-ethoxycarbonyl-6-hydroxydeca-
hydroquinoline and 400 ml. of methylene dichloride.
4.1 g. of sodium acetate were added. Next, 10.8 g. of
pyridine hydrochloride:chromium trioxide were added
and the resulting mixture stirred for about 22 hour~.
The reactlon mixture was filtered and the filtrate
concent-ated in vacuo. The resulting concentrate was
dissolved in chloroform and the chloroform solution
chromatographed over 150 g. of"Florisil"using chloro-
form _ontaining increasins amounts (1-2~) of methanol
as the eluant. Fractions shown by thin-layer chroma-
tograRhy to contain trans-dl-l-n-propyl-3-ethoxycar-
~onyl-6-oxodecahydroquinoline formed in the above
reaction were combined and the solvent removed from
the combined extracts to yield 3.48 ~. of the 6-oxo
compound as a residue. The 6-oxo compound was dis-
solved in 100 ml. O r toluene containing an added
25 ~1. cf tAa dimethylacetal of dimethylformamide.
The resulting mixture was heated to refluxing tem-
perature under a nitrogen atmosphere 'or 44 hours and
was then allowed to semain at room temperature for an
additional 4 days. Volatile cor.stituents were removed
~y evaporation in vacuo and the residue, comprising
~ *Trademark
1~3~9
trans-dl-l-n-propyl-3-ethoxycarbonyl-6-oxo-7-(di-
methylaminomethylene)decahydroquinoline formed in the
above reaction, was purified by chromatographing a
chloroform solution of the compound over"Florisil"
S using chloroform containing increasing amounts (2-5~)
of methanol as the eluant. Fractions shown by TLC to
contain the desired 7-dimethylaminomethylene compound
were combined and the solvent evaporated therefrom in
vacuo.
A solution was prepared from 2.24 g. of
trans-dl-l-n-propyl-3-ethoxycarbonyl-6-oxo-7-dimethyl-
aminomethylene decahydroquinoline and 150 ml. of
ethanol. 0.45 ml. of hydrazine hydrate were added and
the resulting mixture stirred at ambient temperature
lS for about 17 hours. The reaction mixture was evapo-
rated to dryness in vacuo. The residue containing a
mixture of tranR-dl-S-n-propyl-7-ethoxycarbonyl-4,4a,-
5,6,7,8,~a,9-octahydro-2H-pyrazolo~3,4-g]quinoline and
trans-dl-5-n-propyl-7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-
octahydro-lH-pyrazolo[3,4-g]quinoline was dissolved in
chloroform and the resulting solution chromatographed
over 35 g. or"Florisil"using chloroform containing 2
percen. methanol as an eluant. Fractions shown to
conLain the desired pyrazoloquinoline by TLC were
2i combined and the solvent evaporated therefrom in
vacuo. ~e-rystallization from a mixture of ether and
hexane yielded trans-dl-5-n-propyl-7-ethoxycarbonyl-
4,4a,5,6,7,8,8a,9-octahyaro-2K-pyrazoloE3,4-g]quinoline
and its 1~ tautomer melting at 125-7~C.
~ndlysis:Calculated: C, 6;.9'; ~, ~.65; N, 14.42.
~ound: C, 65.75; ~, ~.42; N, 14.16.
*Trademark
1~366'~
Example D
Preparation of trans-dl-5-n-Propyl-7-hydroxymethyl-
4,4a,5,6,7,8,8a,9-octahydro-lH (and 2H)-pyrazolo[3,4-g]-
quinoline
A mixture of trans-dl-5-n-propyl-7-ethcxy-
carbonyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo-
[3,4-g]quinoline dihydrochloride and the dihydro-
chloride salt of the lH tautomer (3.7 millimoles)
(prepared in Example C) was suspended in 200 ml. of
THF. 1 g. of lithium aluminumhydride was added
thereto in portions. The consequent reaction mixture
was stirred at ambient temperature under a nitrogen
atmosphere for about 16 hours, and was then cooled.
Ethyl acetate and 10 percent aqueous sodium hydroxide
were added thereto seriatim to react with any excess
lithium aluminumhyd_ide and to decompose orsanometallic
compounds present. The reaction mixture so treated
was ther. diluted with water and the aqueous mixture
extracted several times with a ch7oroform-isopropanol
solvent mixture. The o-ganic layers were separated
and combined. The combined layers were washed with
saturated aqueous sodium chloride and then dried.
Evaporation of the solvent y~elded a mixture of
trans-dl-5-n-propyl-7-hydrox~ethyl-4j4a,5,6,7,8,8a,5-
oc-ahydro-2H-pyrazolo~3,4-g]quinoline and its lH
tautomer. The -esidue was dissolved in ethanol to
which was added 0.2 ml. of 12N aqueous hydrochloric
acid. ~vaporation of the volatile const tuents
yielded a resid~e comprising trans-dl-5-n-propyi-
1~3f~
-33-
7-hydroxymethyl-4,4a,5,6,7,8,8a,9-octahydro-2H and
lH-pyrazoloL3,4-g]quinoline dihydrochlorides. The
residue was dissolved in a mixture of methanol and
acetone to yield crystals melting at 270-5C. with
decomposition; yield = 350 mg.
The above reaction was repeated with 1.55 g.
of trans-dl-5-n-propyl-7-ethoxycarbonyl-4,4a,5,6,7,-
8,8a,9-octahydro-2H-pyrazolo~3,4-g]quinoline in THF
being reduced with an excess of lithium aluminum-
hydride. The product of the reaction, trans-dl-5-
n-propyl-7-hydroxymethyl-4,4a,5,6,7,8,8a,9-octahydro-
lH and 2H-pyrazolo[3,4-g]quinoline, was crystallized
fr~m a mixture of chloroform and ethanol to yield
crystalline material melting at 167-9C.
Analysis:Calculated: C, 67.43; H, 9.30; N, 16.85;
Found: C, 67.21; H, 9.13; N, 16.62.
Example E
Alternate Preparation of 1-n-Propyl-6-benzoyloxy-
3,4,5,6,7,8-hexahydro-2(lH)-quinolinone and 1-
n-P~opyl-6-benzoyloxy-3,4,4a,5,6,7-hexahydro-2(lH)-
quinolinone
A reaction mixture was prepared containing
4.4 g. of 4-benzoyloxycyclohexanone lprepared by the
procedure of E. R. H. Jones and F. Sondheimer, J.
Chem. Soc., 615 (1949)], 2.5 ml. of n-propylamine
and 100 ml. toluene. The mixture was heated to
reflux temperature for about 2 hours under a nitro-
gen atmosphere using a Dean-Stark water trap. The
reaction mixture was then heated to rafluxing
. .
1~366~
-34-
temperature for an additional 2 hours in the presence
of a molecular sieve to remove water. The reaction
mixture was cooled and the solvent removed by
evaporation in vacuo. 4 ml. of methyl acrylate and
100 ml. of dioxane were added to the residue and the
resulting mixture was refluxed overnight under a
nitrogen atmosphere. The reaction mixture was again
cooled and the volatile constituents removed by
evaporation in vacuo. Chromatography of an ethereal
solution of the resulting residue over 200 g. of
"~lorisil"using ether as an eluant yielded a mixture
of l-n-propyl-6-benzoyloxy-3,4,5,6,7,8-hexahydro-
2tlH)-quinolinone and l-n-propyl-6-benzoyloxy-
3,4,4a,5,6,7-hexahyd-o-2~1H)-quinolinone: yield =
2.1~ g.
FINAL PRODUCTS
Example 1
-
Preparaticn of trans-dl-5-n-Propyl-4,4a,5,6,7,8,-
8a,9-octahydro-lH (ar.d 2~)-pyrazolo[3,4-g]quinoline
A reaction mixture was prepared from
6.3 g. of a mixture of trans-dl-5-cvano-4,4a,5,6,-
7,8,8a,9-octahydro-2H-pyrazolol3,4-g]quinoline and
its lH-tzutomer (prepared by the procedure of
Example .~, 30 g. of zinc dust, 375 ml. of acetic acid
and ~5 ml. o' water. The reaction mixture was heated
to refluxing temperature under nitrogen for 16 hours
after which t~ne it was filtered and the filtrate
*Trademark for a highly selective adsorbentof hard
granular or powdered magnesium silicate.
1~36~Z9
-35-
poured over ice. The resulting aqueous mixture was made basic by
the addition of 14N aqueous ammonium hydroxide and the alkaline layer
extracted several times with a chloroform-isopropanol solvent mixture.
The organic extracts were combined, the combined extracts washed with
saturated aqueous sodium chloride and then dried. Evaporation of the
solvent yielded a residue comprising trans-dl-4,4a,5,6,7,8,8a,9-
octahydro-2H-pyrazolo[3,4-g]quinoline and its lH-tautomer formed in
the above reaction. The residue was dissolved in 500 ml. of methanol
to which was added 1.9 g. of sodium cyanoborohydride. Next 20 ml. of
propionaldehyde were added and the resulting mixture stirred at
ambient temperature under a nitrogen atmosphere for 28 hours. The
reaction mixture was then poured into lN aqueous hydrochloric acid.
The aqueous layer was extracted with ether and the ether extracts
discarded. The aqueous layer was then made basic by the addition of
an excess of 14N aqueous ammonium hydroxide and the resulting alkaline
layer extracted several times with a chloroform-isopropanol solvent
mixture. The organic extracts were combined and the combined extracts
washed with saturated aqueous sodium chloride and then dried. Evap-
oration of the solvent yielded a residue comprising trans-dl-5-n-
propyl-4~4a~5~6~7~8~8a~9-octahydro-lH and 2H-pyrazolo[3~4-g~
quinoline formed in the above reaction. Mass spectrum: M+ = 219.
The residue was dissolved in 100 ml. of boiling acetone to
which were added 5 ml. of 12N
~: '
1~36~i;29
-36-
aqueous hydrochloric acid in dropwise fashion. The
mixture was cooled and the dihydrochlorides of trans-
dl-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-lH and 2H-
pyrazolo[3,4-glquinoline thus formed separated by
filtration; yield = 4.6 g.; m.p~ = 250-7C.
Analysis:Calculated: C, 53.43; H, 7.93; N, 14.38;
( Cl, 24.26.
Found: C, 53.15; H, 7.91; N, 14.47;
Cl, 24.33.
Example 2
Preparation of trans-dl-5-n-Propyl-4,4a,5,6,7,8,8a,9-
octahydro-lH (and 2H)-pyrazolo[3,4-g]quinoline
Using the procedure of Example 1, 1.2 g. of
a mixture of trans-dl-5-cyano-4,4a,5,6,7,8,8a,9-
octahydro-2H-pyrazolo[3,4-g~quinoline and its mixture
of lH-tautomer were reacted with zinc dust and acetic
acid to form a mixture of trans-dl-4,4a,5,6,7,8,~a,9-
octahydro-2H-pyrazolo[3,4-g]quinoline and its lH
tautomer which was isolated as a residue. This
residue dissolved in 50 ml. cf DMF to which were added
1.7 g. of potassium carbona~e. Next, 0.6 ml. of
n-propyl iodide were added and the resulting mixture
stirred at ambient temperature for about 4 hours under
a nitrogen atmosphere. The reaction mixture was
diluted with water and the resulting aqueous mixture
extracted several times with ethyl acetate. The ethyl
acetate extracts were combined and the combined
extracts washed successively witb water and saturated
aqueous sodium chloride and were then dried. Evapo-
11366~9
-37-
ration of the ethyl acetate yielded a residue comprising trans-dl-
5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline
and its lH tautomer which was purified by chromatography over 30 g.
of "Florisil"* using chloroform containing increasing amounts (2-
10%) of methanol as the eluant. Fractions shown by TLC to contain
trans-dl-5-n-propyl;-4,4a,5,6,7,8,8a,9-octahydro-2H and lH-pyrazolo-
[3,4-g]quinoline were combined and the combined extracts evaporated
to dryness to yield 0.28 g. of trans-dl-5-n-propyl-4,4a,5,6,7,8,8a,9-
octahydro-2H-pyrazolo[3,4-g]quinoline and its lH tautomers. The
residue was dissolved in ethanol to which was added 0.16 ml. of 12N
aqueous hydrochloric acid, thus forming the dihydrochlorides of trans-
dl-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline
and the lH tautomer. The reaction mixture was concentrated in vacuo
and the concentrate diluted with ether. A mixture of trans-dl-5-n-
propyl-4,4a,5,6,7,8,8a,9-octahydro-lH and 2H-pyrazolo[3,4-g]quinoline
dihydrochloride crystallized and was separated by filtration; m.p.-
276-8C.
Example 3
Preparation of trans-dl-5-n-Propyl-7-methylmercaptomethyl-4,4a,5,6,7,
8,8a,9-octahydro-lH (and 2H)-pyrazolo[3,4-g]quinoline
A suspension was prepared from 1 millimole of trans-dl-5-n-
propyl-7-hydroxymethyl-4,4a,5,6,7,8,8a,9-octahydro-lH and 2H-pyrazolo-
[3,4-g]quinoline
*Trademark for a highly selective adsorbent of hard granular or
powdered magnesium silicate.
'
11366Z9
-38-
in 100 ml. of pyridine. 1 Ml. of methanesulfonyl chloride
(mesyl chloride) was added and the resulting mixture left over
night at ambient temperature. The mixture was diluted with
dilute aqueous ammonium hydroxide and the resulting alkaline
layer extracted several times with chloroform. The chloroform
extracts were combined and the combined extracts washed with
saturated aqueous sodium chloride and then dried. Evaporation
of the solvent yield'ed a solid residue. A chloroform solution
of the residue was chromatographed over 30 g. of "Florisil"*
using chloroform containing increasing amounts (1-2%) of
methanol as the eluant. Fractions shown by TLC to contain
trans-dl-2-methanesulfonyl-5-n-propyl-7-mesyloxymethyl-4,4a,-
5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinGline were com-
bined and the solvent was removed therefrom by evaporation.
Trans-dl-2-methanesulfonyl-5-n-propyl-7-mesyloxymethyl-4,4a,-
5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline melted
152-4C. after recrystallization from ether.
Analysis:Calculated: C,47.39; H, 6.71; N, 10.36;S, 15.81.
Found: C, 47.60; H, 6.71; N, 10.32; S, 15.69.
A second fraction was obtained from the chromatography
was shown by NMR to be a 2:1 mixture of trans-dl-5-n-propyl-
7-mesyloxymethyl-2-methanesulfonyl-4,4a,5,6,7,8,8a,9-octahydro-
2H-pyrazolo[3,4-g]quinoline and its l-methanesulfonyl-lH isomer.
*Trademark
,~
1131~9
-39-
1 g. of methylmercaptan was dissolved in
40 ml. of dimethylformamide. The solution was cooled
in an ice-water bath. About 1 g. of sodium hydride
(as a 50% suspension in mineral oil) was added thereto
in portions. The cooling bath was removed and a
solution containing 0.4 g. of trans-dl-2-methane-
sulfonyl-5-n-propyl-7-mesyloxymethyl-4,4a,5,6,7,8,8a,9-
octahydro-2H-pyrazolo[3,4-g]quinoline containing some
trans-dl-l-methanesulfonyl-5-n-propyl-7-mesyloxy-
methyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrazolo[5,4-
g]quinoline in 10 ml. of DMF prepared above was
added. The reaction mixture was stirred at ambient
temperature for about 5 hours and was then diluted
with water. The aqueous mixture was extracted several
times with ethyl acetate. The ethyl acetate extracts
were separated and combined. The combined extracts
were washed with water and with saturated aqueous
sodium chloride and then dried. Evaporation of the
solvent yielded an oily residue comprising trans-
dl-5-n-propyl-7-methylmercaptomethyl-4,4a,5,6,7,8,8a,9-
octahydro-lH and 2H-pyrazolo[3,4-g]quinoline; yield =
0.17 g~ The residue was dissolved in ethanol and
attempts made to prepare both the hydrochloride and
the oxalate salts. Both salts initially turned out to
be noncrystalline. The free bases were then recovered
from the non-crystalline oxalate by dissolving the
oxalate in water, adding base and ex~rac_ing the
mixture with ether. trans-dl-5-n-Propyl-'-methyl-
mercaptomethyl-4,4a,5,6,7,8,8a,9-octahydro-lH and
1136~i29
-40-
2H-pyrazolo[3,4-g]quinoline thus purified crystallized
on evaporation of the ether; melting point = 175-7C.;
yield = 40 mg.
Analysis:Calculated: C, 64.47; H, 9.02; N, 15.04;
S, 11.47.
Found: C, 64.47; H, 8.96; N, 15.09;
S, 11.29.
The above purified free base t~utomeric
mixture was dissolved in ethanol and an excess of
12N hydrochloric acid added. The volatile con-
stituents were removed by evaporatior. and the
resulting residue comprising the corresponding
dihydrochloride salts crystallized from an acetone-
methanol solvent mixture.
Analysis:Calculated: C, 51.13; H, 7.72; N, 11,93;
Cl, 20.10; S, 9.10;
Found:- C, 50.89; H, ?.57; N, 12.15;
Cl, 20.18; S, 9.31.
Example 4
Preparation of trans-dl-5-Methyl-4,4a,5,6,7,8,8a,9-
octahydro-lH (and 2H)-pyrazolo[3,4-g]quinoline
46.5 g. of the isomer mixture containing
about 60 percent of 6-benzoyloxy-3,4,5,6,7,8-
hexahydro-lH-quinoline-2-one and 40~ o~ the 3,4,4a,-
5,6,7-hexahydro isomer were dissolved in 400 ml. of
tetrahydrofuran (THF). 80 ml. of methyl iodide were
added and the re-~ulting mixture cooled in an ice-
water bath. 9.6 g. of sodium hydride (as a 50
percent suspension in mineral oil) were added in
1~366~9
-41-
portions. After all of the sodium hydride sus-
pension had been added, the cooling bath was removed
and the reaction mixture stirred at ambient tem-
perature under a nitrogen atmosphere for about 4
hours. The reaction mixture was then diluted with
water and the aqueous m xture thoroughly extracted
with chloroform. The chloroform extracts were
combined and the combined extracts washed with
saturated aqueous sodium chloride and then dried.
The chloroform was removed by evaporation to dryness
in vacuo leaving as a residue an orange oil weighing
47.3 g. Crystallization of the residue from an
ether-hexane solvent mixture yielded crystals of 1-
methyl-6-benzoyloxy-3,4,5,6,7,8-hexahydro-2(1H)-
quinolinone and the correspor.ding 3j4,4a,5,6,7-
hexahydro isomer.
Analysis:Calculated: C, 71.56; H, 6.71; N, 4.91.
Found: C, 71.33; ~, 6.90; N, 4.67.
A solution of 47.3 g. of a mixture of 1-
methyl-6-benzoyloxy-3,4,5,6,7,8-hexahydro-2(1H)-
~uinolinone and the corresponding 3,4,4a,5,6,7-
hexahydro isomer as obtzined above were dissolved in
800 ml. of ~HF and the solution cooled to about 0C.
20 g. of iithium aluminumhydride were added thereto
in portior.s and the resulting mixture refluxed for
four hours under a nitrogen atmosphere. The reaction
mixture was cooled and excess lithium aluminum-
hydride destroyed by the addition of ethyl acetate.
10% sodius. hydrcxide was then addad and the mixture
diluted with water to decompose any orsanometal'ics
.
1~366Z9~
-42-
present. The aqueous mixture was extracted several
times with a chloroform-isopropanol solvent mixture.
The organic extracts were combined and the combined
extracts washed with saturated aqueous sodium
chloride and then dried. Evaporation of the solvent
yielded as a residue a mixture of the enamines--
l-methyl-6-hydroxy-1,2,3,4,5,6,7,8-octahydroquinoline
and l-methyl-6-hydroxy-1,2,3,4,4a,5,6,7-octahydro-
quinoline-- formed in the above reaction. (The
lithium aluminumhydride reduction served to remove
the benzoyl group at C-6 as a benzyl alcohol moiety,
leaving a free hydroxyl in that position). The
above residue, without further purification, was
dissolved in a~out 300 ml. of ether and the ethereal
solution saturated with gaseous hydrogen chloride,
thus forming the hydrochloride salt of the enamine
mixture. The e~her was removed by decantaticn and
the residue dissolved in a mixture of 200 ml. of THF
and 50 ml. of methanol. This solution was cooled in
an ice-water bath. 12 g. of sodium cyasoborohydride
were added with cooling and stirring. After all of
the cyanoborohydride had been addedj the reaction
mixture was stirred for another 60 minutes and then
poured over a mixture of ice and lN aqueous hydro-
chloric acid. The acidic aqueous solution wasextracted with chloroform and the chloroform extract
discarded. ~he solut-on was then made basic with
14N aqueous ammonium hydroxide. T-ans-dl-l-methyl-
6-hydroxydecahydroquinoline formed in the above
- reaction, being insoluble in the alkaline medium,
, ^ , ~ ,
113ti6Z9
-43-
separated and was extracted several times with a
chloroform-isopropanol solvent mixture. The
combined extracts were washed with saturated aqueous
sodium chloride and then dried. Evaporation of the
solvent yielded 15 g. of trans-dl-1-methyl-6-
hydroxydecahydroquinoline.
Fifteen grams of trans-dl-l-methyl-
6-hydroxydecahydroquinoline were dissolved in
250 ml. of 6N aqueous sulfuric acid. The solution
was cooled in an ice-water bath. A solution of 9 g.
of chromium trioxide in 60 ml. of 6N aqueous sul-
furic acid were added thereto with stirring in
dropwise fashion over a 10-minute period. The
cooling bath was removed and the reaction mixture
stirred for an additional 60 minutes at ambient
temperature. The excess oxidizing agent was decom-
posed by adding isopropanol to the reaction mixture.
The reaction mixture was next poured over ice and
the acidic aqueous solution made basic with 14~
aqueous ammonium hydroxide. trans-dl-l-Methyl-
6-oxodecahydroquinoline thus formed, being insoluble
in the alkaline layer, separated and was extracted
several times with a mixture of chloroform and
isopropanol. The extracts were combined and the
combined extracts washed with saturated aqueous
sodiusn chloride and then dried. Evaporation of the
solver.t in vacuo yielded trans-dl-l-methyl-6-
oxodecahydroquinoline boiling in the range 105-116C.
a~ 6 torr; yield = 7.7 g. (45%).
1136~29
-44-
A reaction mixture was prepared frcm
7.7 g. of trans-dl-1-methyl-6-oxodecahydroquinoline,
36 g. of the dimethyl acetal of dimethylformamide
and 250 ml. of benzene. Benzene was removed by
distillation at atmospheric pressure under nitrogen
until about 1/2 the original volume remained (1.25
hours). Sufficient benzene was then added to make
up the vo~ume to the original volume and the process
was repeated (four times). All of the benzene was
finally removed by evaporation in vacuo and the
resulting residue dissolved in 100 g. of dimethyl-
formamide dimethylacetal. This solution was heated
to refluxing temperature under nitrogen for 20
hours. The reaction mixture w~s then evaporated in
vacuo and a chloroform solution of the residue
chromatographed over 150 g. of"Florisil"using as the
eluant, methylere dichloride containing increasing
amounts (1-5%) of methanol. Fractions containing
simila_ substances as shown by TLC were combined.
The third substance to be eluted was a yellow so;id
(wt z 3 g~) mhe solid was heated with 100 ml. of
e'her and the resulting solution filtered. Cor.-
cer.tration of the f-ltrate to about ~0 ml. yielded
590 ms. of c~ystals of trans-dl-1-methyl-6-oxo-7-
~ methylaminometr.ylenedecahydroquinoline meltin~ at1~7-109C.
Analysis:Caiculated: C, 70.23; H, 9.9,; ~i, 12.60.
Found: C, 70.17; ~, 9.7~; ~, 12.87
*Trademark
11366~
A solution was prepared by dissolving
175 mg. of trans-dl-1-methyl-6-oxo-7-dimethylamino-
methylenedecahydroquinoline in 10 ml. of methanol.
0.05 ml. of hydrazine hydrate were added and the
resulting reaction mixture stirred at room tempera-
ture under a nitrogen atmosphere for 4.5 da~s. The
volatile constituents were removed by evaporation.
A chloroform solution of the residue was chromato-
graphed over 25 g. of"Florisil"using chloroform
containing increasing amounts (2-15%) of methanol as
the eluant. Fractions shown by TLC to contain a
substance moving close to the origin and different
than starting material were combined and the solvent
removed from the com~ined fractions by evapvration.
15 trans-al-5-methyl-4,4a,5,6,7,8,8a,3-octahydro-lH-
land 2H)-pyrazolo[3,4-g]quinoline free base gave a
molecular ion (~ t 191 by mass spectroscopy.
The resulting resitue was dissolved in
ethanol and 2 ~1. of lN hydrochloric acid were
2C added. The acidic solution was evaporated to
dryness. Crystallization of the residue from
~ ethanol yielded a tautomeric mixture containing
- trans-dl-5-methyl-4,4a,5,6,7,8,8a,9-octahydro-lH-
tand 2H)-pyrazolo[3,4-g]quinoline dihydrochlorides
melting at 26~-70C. with decompositicn; yizld =
14~ mg.
~nalysis:Calcul2ted: C, 5~0.01; H, 7.25; ~, 15.9C;
Cl, 26.84.
Founa: C, 4g.82; H, 7.08; N, 15.66;
C1, 26.80.
~ *Trademark
~,l3G6~9
-46-
Example 5
Preparation of trans-dl-5-Allyl-4,4a,5,6,7,8,8a,9-
octahydro-lH(and 2H)-pyrazoloL3,4-g]quinoline
Following the procedure of Example A,
65 g. of 4-benzoyloxycyclohexanone, 38 ml. of
pyrrolidine and a few crystals of p-toluenesulfonic
acid monohydrate were dissolved in 1000 ml. of
cyclohexane. The resulting mixture was heated to
reflux in a nitrogen atmosphere using a Dean-Star~
water trap for about 1/2 hour. The mixture was then
cooled and the solvents removed by evaporation ln
vacuo. The residue, comprising the pyrrolidine
enamine of 4-benzoyloxycyclohexanone, was mixed with
53 g. of acrylamide in 1000 ml. of dioxane. The
reaction mixture was heated to reflux temperature in
a nitrogen atmosphere for abou!t one day after which
time it was cooled and the volatile constituents
removed by evaporation. The resulting residue was
diluted with water and the aqueous mixture extracted
with ethyl acetate. The ethyl acetate extract was
separated, washed with water and with saturated
a~ueous sodiu~. chloride and then dried. Evap-
oration of the solvent yielded a mixture of 6-
benzoyloxy-3,4,5,6,7,8-hexahydro-lH-quinoline-2-
one and the corresponding 3,4,4a,5,6,7,-hexahydro
compound.
The above mixture was dissolved in a
combination of 250 ml. of tetrahyrofuran and 250 ml.
of dimethylformamide. 12 g. of sodium hydride as a
50% suspension in mineral oil was added and the
~1366~9
-47-
mixture stirred in order to completely form the
sodium salt of the quinoline-2-one~ Next 30 g. of
allyl brcmide as a solution in 75 ml. of THF were
added and the resulting mixture stirred for 24
hours. The temperature of the reaction mixture rose
rapidly and external cooling was supplied. After
the reaction had been completed, the reaction mixture
was diluted with water and the agueous mixture
extracted with ethyl acetate. The ethyl acetate
extract was separated, washed with water and with
saturated aqueous sodium Ghloride and then dried.
Evaporation of the solvent yielded a mixture of
l-allyl-6-benzoyloxy-3,4,5,6,7,~-hexahydro-lH-
quinoline-2-one and the corresponding 3,4,4a,5,-
6,7-hexahydro compound.
The N-allyl derivative thus prepared was
dissolved in 750 ml. of THF and the solution cooled
in an ice-water bath. 20 g. of lithium aluminum
hydride were added thereto in portions. Afte_ the
addition had been completed, the resulting mixture
was heated to reflux temperature under a nitrogen
atmosphere for about three hours. The reaction
mixture was then cooled in an ice-water bath and the
excess lithium aluminum hydride decomposed by the
addition of ethyl acetate. 10~ aqueous sodium
hydroxide was added to decompose any organometallic
compounds present and the mixture thus treated was
diluted with water. The aqueous mixture was then
extracted several times with chloroform and the
chloroform extracts combined. The combined extracts
.
.
11366Z~
-48-
were washed with saturated aqueous sodium chloride
and dried. Evaporation of the solvent yielded a
residue comprising a mixture of l-allyl-6-hydroxy-
1,2,3,4,5,6,7,8-octahydroquinoline and its 1,2,3,4,-
4a,5,6,7-octahydro isomer. The residue was dissolved
in 750 ml. of ether and the ethereal solution sat~rated
with anhydrous gaseous hydrogen chloride. The
hydrochloride salt of the octahydroquinoline
mixture, being insoluble in ether, precipitated and
the ether was separated by decantation. The hydro-
chloride was dissolved in a mixture of 100 ml. of
methanol and 300 ml. of T~IF. This solution was
cooled in an ice-water bath. 20 g. of sodium cyano-
borohydride were added thereto in portions while the
reaction mixture was being cooled. After the addi-
tion had been completed, the cooling bath was ,emoved.
The reaction was stirred at ambient temperature for
about 1 hour, and was then diluted with saturated
aqueous sodium bicarbonate. The alkaline layer was
extracted several times with chloroform. The chloro-
form extracts were combined and the combined extracts
washeh with saturated aqueous sodium chloride and
then dried. Evaporation of the solvent yielded
a~out 12.8 g. of trans-dl-1-allyl-6-hydroxydeca-
hydroquinoline.
The trans-dl-l-allyl-6-hydroxy-deca-
hydroquinoline thus prepared was dissolved in
500 ml. of methylene dichloride to which had been
added 8.Z g. of sodi~m acetate. Next 21.6 g. of
~yridine hydrochloride/chromium trioxide were added.
11366Z9
-49-
The reaction was stirred for 7.5 hours under a nitrogen atmosphere
at ambient temperature, and was then filtered. The filtrate was con-
centrated in vacuo. Chromatography of the filtrate over 150 g. of
"Florisil"* using chloroform containing increasing amounts ~1-5%)
methanol as the eluant yielded 3.2 g. of trans-dl-1-allyl-6-oxodeca-
hydroquinoline formed in the above reaction. The 6-oxo compound was
dissolved in toluene and 25 ml. of dimethylformamide dimethylacetal
were added. The reaction mixture was heated to reflux temperature
under a nitrogen atomosphere for 24 hours after which time it was
cooled and the solvent removed by evaporation. The resulting residue
was chromatographed over 150 g. of "Florisil"* using chloroform con-
taining increasing amounts (2-20%) of methanol as the eluant. Frac-
tions shown by TLC to contain the desired trans-dl-l-allyl-6-oxo-7-
dimethylaminomethylenedecahydroquinoline formed in the above reaction
were combined to yield after evaporation of the solvent 1.3 g. of the
desired product. This material was dissolved in 75 ml. of methanol
to which was added 0.5 ml. of hydrazine hydrate. The reaction mixture
was stirred at room temperature for about 20 hours after which
time the volatile constituents were removed by evaporation ln vacuo.
A chloroform solution of the residue was chromatographed over 35 g.
of "Florisil"* using chloroform containing increasing amounts (2-4~)
of methanol as the eluant. Fractions shown by TLC to contain the
desired
*Trademark
1~366~
-50-
trans-dl-5-all~1-4,4a,5,6,7,8,8a,9-octahydro-
2H-pyrazolo[3,4-g]quinoline and its lH tautomer were
combined and the solvent removed therefrom by
evaporation _ vacuo. Mass spectroscopy of the
residue gave a molecular ion at 217. The residue,
weighing 0.55 g., was dissolved in 75 ml. of acetone
and the acetone solution heated to reflux. 0.5 ml.
of 12N aqueous hydrochloric acid were added thereto
in dropwise fashion. The reaction mixture was
allowed to cool. Trans-dl-5-allyl-4,4a,5,6,7,-
8,8a,9-octahydro-2H(and lH)-pyrazolo[3,4-g~quinoline
dihydrochloride thus prepared melted at about 215C.
with decomposition; weight = 495 mg.
Analysis calculated: C, 53.80; H, 7.29; ~, 1.48;
Cl, 24.43
Found: C, 53.52; H, 7.13; N, 1.65;
Cl, 24.17.
As e~idence of the utility of the compounds
of formulae Ia and Ib, it has been found that they
affect turning behavior in 6-hydroxydopamine-lesioned
rats in a test procedure designed 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 ~r~uthnott,
Brain Res, 24, 485 (i970). A compound having dopamine
~gonist activity causes the rats to turn in circles
contralateral to the side of the lesion. After a
latency period, which varies from compound to com-
pound, the number of turns is cour.ted over a i;-
minute period.
~136~
-51-
Results obtained from testing representative
compounds of formulae Ia and Ib in the rat turning
test are set forth in Table 1 below. The compounds
were dissolved in water and the aqueous solution
injected into the rat by the intraperitoneal route at
dose levels of 1 mg/kg. and 100 mcg/kg. In the table,
column 1 gives the name of the compound, column 2,
percent of test animals exhibiting turning behavior,
and cclumn 3, average number of turns observed in
first 15 minutes after end of latency period.
'
11366;2S~
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1136~i~9
The compounds of formulae Ia and Ib are
also useful as prolactin inhibitors and as such they
can be employed in the treatment of inappropriate
lactation such as postpartum lactation and galac-
torrhea. As evidence of their utility in the treat-
ment of conditions in which it is desirable to reduce
the prolactin level, the compounds of formulae Ia
and Ib have been shown to inhibit prolactin according
to the following procedure.
Adult male rats of the Sprague-Dawley
strain weighing about 200 g. were housed in an air-
conditioned room with controlled lighting (lights on 6
a.m. - 8 p.m.) and fed lab chow and water ad libitum.
Each rat received an intraperitoneal injection of
2.0 mg. cf reserpine in aqueous suspension 18 hours
before administration of the test drug. The purpose
of the reserpine was to keep prolactin levels uni-
formly eievated. The compounds under test were
dissolved in 10 percent ethanol, an~ were injected
intraper,toneally at doses of 50 mcg/kg and 0.5 and 5
mg/kg. Each compound was administered at each dose
~ level to a grcup of 10 rats, and a control group of 10
intact males received an equivalent amount of 10
percent etnanol. One hour after treatment, all rats
were killed by decapitation, and 150 ~1 aliquots of
serum were assayed for prolactin.
The difference between the prolactin level
of the treated rats and prolactin level of the control
r ats, divided by the prolactin level of the control
113t~
rats gives the percent inhibition of prolactin
secretion attributable to the compounds of formulae
Ia and Ib. These inhibition percentages are given in
Table 2 below. In the table, column 1 gives the name
of the compound; and columns 2, 3 and 4, the percent
prolactin inhibition at 50 mcg./kg, and O.S and
5 mg./kg. dose levels.
11366~3
--55--
~ ~ I
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-56-
In using the compounds of formulae Ia
and Ib to inhibit prolactin secretion or to treat
Parkinson's syndrome or for other pharmacologic
action, a compound according to formula Ia or Ib
above or a salt thereof with a pharmaceutically-
acceptable acid, is administered to a subject suf-
fering from Parkinsonism or in need of having his or
her prolactin level reduced in an amount effective to
treat Parkinsonism or to reduce prolactin. Oral
administration is preferred. If parenteral adminis-
tration is used, the injection is preferably by the
subcutaneous route using an appropriate pharmaceutical
formulation. Other modes of parenteral administration
such as intraperitoneal, intramuscular, or intravenous
routes are equally effective. In particular, with
intravenous or intramuscular administration, a water
soluble pharmaceutically-acceptable salt is employed.
For oral administration, the compound either as the
free base or in the form of a salt thereof, can also
be mixed with standard pharmaceutical excipients and
loaded into empty telescoping gelatin capsules or
pressed into tablets. The oral dosage range is from
about 0.01 to 10 mg./~g. of mammalian weight and the
parenteral dose range from about 0.0025 to 2.5 mg./kg.
Intraperitoneal dosages of 10-100 mg./kg. of trans-
dl-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-lH(and
2H)-pyrazolo[3,4-g]quinoline dihydrochloride resulted
in no deaths, but dosages of 300 mg./kg. were fatal,
indicating ar. LD50 in the range 100-300 mg./kg.
