CA1136629A - Octahydro pyrazolo (3,4,-g) quinolines - Google Patents

Abstract

Abstract of the Disclosure Octahydropyrazolo[3,4-g]quinolines, dopamine agonists, useful in treatment of Parkinsonism and in inhibiting secretion of prolactin, are described herein. These novel compounds are prepared by reacting a corresponding 7-dimethylaminomethylene-6-oxo-derivative with hydrazine hydrate. Also disclosed herein are intermediates of the formula XII

wherein R is (C1-C3) alkyl, allyl or benzyl and Z' is (C1-C2) alkyl, benzyl, phenethyl or p-methoxybenzyl. These intermediates are prepared by a process which comprises subjecting a compound of general formula XI:

XI

wherein R and Z' are defined as before, and Z is (C1-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 reesterification with an alcohol in the presence of acid.

Description

113Ç;6:~9 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 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;

-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~

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~

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~

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

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 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 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~

Reaction Scheme Il ' O
Il O
RNH2 \ ~ / \;/ \t-CZ' CH2=C-COOZ' / \;i \N
CH2Ha I X
O-CO-Z R

¦ acid lC /

HO~COQZ' / EtOH / OH I ~ - cooz~

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~

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~

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 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~
-

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~

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 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 ~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~

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 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 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.

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~

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 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 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'~

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~

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~

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~

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 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 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 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.

' 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 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 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 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~

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 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 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 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 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~

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.

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~

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~

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~

,Y
o ~u ~ E
Q~ O ~ o ~ S~ o a ~ ~ _, S~ C) tn :~ E ~ tl Z E~ ~ In . o ~
E co co --I

o ~ " o o o O
~ ~_~
_I rl-~
.4 E~ 'S ~ ~ o g g o E~
C~
_I I I ~-~
o o ' ~a 0~
sl 17~ r I J ' O ~ _~ O
~a ~ 1 u ~ ~
~: ~ O ~S ~r o ~1 ~ ~ `~S I O ~
O ~ ~ ~D. ~ _1 o ~ ~ 01 q) ~-1 E ra N
O~ o _1 ~ ~ O ca a ~ _l ~ I a O I I Orl I ~ ~ ~ C
C 5~ N ~1C tl.O~ ~r~l 1 U ~-rl ~;I ` la o I ~ o ~
Ou~ ra s~ o r~ _ o I ~ CI ~ `5 a~O _~
~1_~ ` Q. U~ O ~ C ~ `_I C
E 1~ I O ~ E ` ~ a O t) tl~I ` 5 ~i L'~ N O
Z ;~~ ` C O C `
c ~ ~~ c ta ~ c ra ~
a ~~ c '~

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 ~ ~ I
c E ~
.~ ~n C
O

s u~
C o J~

C4 u~

~ C ~ ~ O
u~ C~ I` ~-I
~ C '--c E
I O o `_~ o I '--C ~ I C
~a~ 1 1 o-,~
o S~ ; C c EC o ~ o ~ ~ o~ ~ ~ C
U~ ~ ~ C~ 1 '~--ClI E O ~
O1~ ~ O ~ '~ O~ ~ ~--I 'O ~ I ~ O ~ I ~.
Eu~ ;~ N ~U~ 0 N ~Ul (~ S I
Z~ ,S rO C~ U ~ ~
U~ 1 ~ E O--~13G~

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.

Claims (2)

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

1. A process for preparing an intermediate compound of the formula XII

wherein R is (C1-C3) alkyl, allyl or benzyl and Z' is (C1-C2) alkyl, benzyl, phenethyl or p-methoxybenzyl, which comprises subjecting a compound of general formula XI:

XI

wherein R and Z' are defined as before, and Z is (C1-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 reesterification with an alcohol in the presence of acid.

2. An intermediate compound of the formula XII
wherein R is (C1-C3) alkyl, allyl or benzyl and Z' is (C1-C2) alkyl, benzyl, phenethyl or p-methoxybenzyl, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.