CA1136141A - 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 witn hydrazine hydrate. Also described herein are novel intermediates of the general formulae Ic Id wherein, R is H, CN, C1-C3 alkyl or benzyl;
R1 is H, -COOH, -COO(C1-C3,alkyl, or CH2X
wherein X is C1, Br, I, OH, OSO2-(C1-C3)alkyi, OSO2tolyl, or OSO2phenyl;
with the proviso tk.at when R is C1-C3 alkyl, then R1 can not be H; and the salts thereo, These intermediates are prepared by a process which comprises reacting a compound of the general formula wherein R is defined as above, and R4 is H or COOZ' where Z' is H, or (C1-C3)-alkyl, with hydrazine hydrate;
followed by, when Z' is (C1-C3) alkyl, reacting with a metal hydride to obtain the compounds where R1 is CH2OH, followed by, if desired, reacting with a nucleophilic reagent to obtain the compounds where R1 is CH2Y where Y is C1, Br, I, OSO2-(C1-C3)-alkyl, OSO2 tolyl or OSO2 phenyl, and where desired, forming a salt of said compound of general formula Ic or Id.

Description

1136~4~

OCTAHYDRO PYRAZOLO [3,4-g]QUINOLINES
This invention in one aspect, provides octahydropyrazolo [3,4-g]quinolines of the general formula:

\;H--~4~J \~ ~H--~4 )/~
3a 4 1 3a a N
R R
Ia Ib wherein R is (Cl-C3) alkyl or allyl;
Rl 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 20 O ~ ~ ~ R

(CH3)2N~H ~ 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-lCl-C2)alkylphenyl;

t~ ~

113ti14~
~2 with hydraz~ne fiydrate, followed hy, when R is 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 R is other than H, reacting with a metal hydride to obtain the intermediate compounds of formulae Ia 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, Br, 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.

-113~i14~

The invention, in another aspect, provides novel intermediates of the following general formulae:

~ N--~ 1 - R R
Ic Id wherein R is H, CN, Cl-C3alkyl or benzyl;
R is H, -COOH, -COO(Cl-C3)alkyl, or CH2X wherein X is Cl, Br, I, OH, OSO2-(C1-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, provides a process for preparin~ the above novel intermediates of formulae Ic and Id wherein R is H, CN, Cl-C3 alkyl or benzyl;
R is H, -COOH, -COO(C1-C3)alkyl, or CH2X wherein X is Cl, Br, I, OH, OSO2-(Cl-C3)alkyl, OSO2tolyl, or OSO2phenyl;

~136141 -3a-with the proviso that when R is Cl-C3 alkyl, then Rl can not be H; and the salts thereof, which comprises reacting a compound of the general formula H
C~ 4 (C~3)2NCN ~ ~ J

R
wherein R is defined as above, and R is H or COOZ' where Z' is H, or (Cl-C3) alkyl, with hydrazine hydrate;
followed by, when Z' is ~Cl-C3)alkyl, reacting with a metal hydride to obtain the compounds where Rl is CH2OH, followed by, if desiredi reacting with a nucleophilic reagent to obtain the compounds where R is CH2Y where Y is Cl, Br, I, OSO2-(C1-C3)alkyl, OSO2tolyl or OSO2phenyl, and where desired, forming a salt of said compound of general formula Ic or Id.
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 ~erm "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 113~i141 organic acids such as aliphatic mono and dicarboxylic acids phenyl-substituted alkanoic acids, hydrcxy alkanoic and alkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids. Such phar-maceutically-acceptable salts thus include sulfate, pyrosulfate, S 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 13,4-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 R1 is H have two chiral centers, the ring junction.

carbons at ~a and 4a. Thus, the compounds can occur as two racemates, ordinarily denominated as the trans-dl racemate and the cis-dl racemate. It is believed, however, according to the best evidence from 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 investiqation has also been carried out on a nicely crystalline enamino~etone in the decahydro-~uinoline 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 2 tautomer can be represented as follows:
H 7 H \

H ~ and H ~ ~ ¦

lIa IIb 113614~

IIa and IIb represent a racemic pair. A similar racemic pair can be drawn for the lH tautomer.

nd R R
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 R1 is other than H, a third chiral center is introduced at C-7. However, it i~ presently believed that the configuration of the C-7 group is chiefly beta rel tive to an alpha 8a hydrogen as in IIa. In the mirror image, IIb, R1 is alpha with respect to 8a being beta. Thus, the trans-dl 7-substituted octahydropyrazolol3,4-g]quino-lines of formulae Ia and Ib are provided substantially as a single racemate or diastereoisomeric pair.
The follo~ing compound-~ illustrate some of formulae Ia and Ib:
trans-dl-S-methyl-7-methoxymethyl-4,4a,5,-6,7,8,&a,9-octahydro-2H-pyrazolo~3,4-g]quinoline, X-4988.B 7 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-5-n-propyl-7-meths~lsulfonyl-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-p~razolo[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,~,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-2~-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, trans-dl-S-ethyl-7--yanomethyl-4,4a,-5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline, and trans-dl-5-allyl-4,4a,5,6,7,8,82,9-octahydro-2H-pyrazo' 3 r 3,4-g 7 quinolin~.
For compounds listed above, it should be understood that each name al~o comprehends the other tauto~er since an e~uilibrium mixture o~ the two ~13614~

X-4988 s -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 sre 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~, 8aa 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.

2~

X-~988 B -9-Reaction Scheme I
o pyrrolidine \ acrylamide \
\~/ acid catalyst /
Z--CO--O-- / \t/
O-CO~Z ~ 0 III H
RX I NaH
z CO
H-!' `~' `I , LiAlH4 0 t ;t V R IV R

HCI
NaCNBH3 H0-I~v~ ;II

CH--\ ~ (CH )zNCH(OZ'') IX ~i / (CH3)2NCH~ N/
R ~ - VIII
,, NH2NH2-H20 ~H I'"`T-''I
R

113S~4~

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 o~ the phenyl ring. Illustratively, Z-CO can be acetyl, propionyl, butyryl, propiolyl, acrylyl, benzoyl, p-toluyl, o-chlorobenzoyl, m-methoxybenzoyl, and so on.
l~ Z'' is defined hereinbelow in the discussion of Reaction Scheme II. In accordance with Reaction Scheme I, 4-acyloxycyclohexanone prepared by the procedure of E.R.H. Jones and F. Sondheimer, J. Chem.
S ., 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 produce 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(lH)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 as Cl, Br or I, in the presence of sodium hydride to yield a mixture of dl-l-(C1-C3) alkyl (or allyl or benzyl)-6-acyloxy-

3,~,5,6,7,B-hexahydro-2(lH) quinolinone and its ~8 ~C isomer tIV)~ Reduction of this amide with lith-~m 113614~

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-1-(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 with hydrazine hydrate yields a tautomeric mixture of a tricyclic derivative, predominately trans-dl-5-~(Cl-C3)alkyl, allyl or benzyl)]-4,4a,5,6,7,8,8a,~-octahydro-2H-pyrazolo[3,4-g3quinoline (IX) and its iH
tautomer (IXa) in smaller amount.
The compounds of formulae Ia and Ib wherein R is Cl-C3 alk~l or allyl, the dcpamine agonists, can also be prepared from compounds in which ~ is benzyl.
In this proced~re, the benzyl group is removed by reductive cleavage or by treatment ~ith cyanogen 3~ bromide to yield, eventually, a compound according to ~ ,~

113614~

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 ox 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 i~spection of the dl-trans-l(substituted)-6-ketodecahydro~uinoline (VII) that reaction withdimethylformamide dimethylacetal could take place at either C-5 or C-7 since both these car~ons are alpha to the ketone group and thus available for reaction.
The sa~e X-ray crystallographic analysis of the en~ne (VIII) discussed above clearly indicated that reaction had taken place a~ C-7 rather than C-5.
Hence, the final tricyclic compounds, IX and IXa, are the linear pyrazolol3,4-g~quinolines rather than the angular tricyclic compounds (which would be named as

4,4a,5,6,7,8,8a,9-octahydro-1~-pyrazolol2,3-i~quino-lines.
The compoun~s of this invention in which ~1 i~ other than H are prepared accordins to a slightly different procedure iilustrated generally in Reaction Scheme II. ~-~ 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.

-1~36141 Reaction Scheme II
O ' ~0 RNH2 \ ~ t t-COOZ' I~ ICH2=C--COOZ / $\ ;~
CH2Ha I X
O-CO-Z R

ac i d lC /

H~ cooz , EtOH / OH ~ cooz H ~ H

pyridine HCI
CrO3 \ /
2~ I-- cooz (c~ o~

XIII (CH;~) NCH
XIV
NH zNH ~: H zO
h `I cooz ~ , XV R
~.

-~13~141 wherein Z and Z'' have the same significance as in Reaction Scheme ~, 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 Scheme II, a 4-acyloxycyclohexanone is reacted with an ~-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. ~he hydrochloride salts of these isomers were prepared and the resulting mixture re-duced with sodium cyanoborohydride to yield trans-dl-1-~ubstituted-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 ~uitable alcohol in ~he presence of acid yields, as a novel intermediate, trans-dl-1-substituted-3-ethoxycarbonyl-6-hydroxydecahydroquinoline ~:~}I).
Oxidation of the hydroxy group with Sarett's Reagent (pyridine hydrochloride and chrc~ium trioxide) pro-d~ces the corres~onding novel intermeaiate 6-oxo compound (XIII). Trea~ent Gf this 6-oxo d~rivative ~.. ..

1~3~141 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-1~-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 ha~e the general formula (CH3)2N-CH-(OZ'')2 in which Z'' is (Cl-C~)-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 : ~, 113~141 believe based upon analogy with the D-ergolines that the diastereoisomer 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 stereoisomers.
Intermediates described in Reaction Schemes I and II, having the following structures, form a part of this invention.
HO_~ R ~ ~ ~ a O= f \ / ~ -R
~./ \N ~ / ~ nd (CH3)2N-CH= ~
I
R R R
XII XIII XIV
wherein R is (Cl-C3)alkyl, allyl or benzyl and Rl is COOZ' where-in Z' is (Cl-C~)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.
Compounds according to formula XV above in which R
is ethyl, allyl or n-propyl can be prepared by two different procedures. First, the amine, Rr~H2, used in preparing X can be ethyl, n-propyl or allyl thus introducing the group directly. Alternatively a compound according to formula XV in which R is ~ethyl or benzyl can be transformed into a compound in which R
is H by removing the methyl or benzyl group by re-action with cyanogen bromide. The intermediate 113~14~

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 in which R=H. Alkylation of the secondary amine can be accomplished by reaction with an alkyl halide--~Cl, 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 t (e.g. NaBH3CN) to yield an N-ethyl, N-allyl or ~-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, SC~3, SO2CH3 or CO-NH2, are prepared from compound XV according to Reaction Scheme III below . 20 3~

113~141 X-4988 ;3 -18-Reaction Scheme III

LiAlH I XV
\1~

tosyl-CI SOCI z (C1-C3)a I kyl SQ2CI PCI s p heny 1 502C I POC 13 PBr3 \ Etc .

~ H

NaCN
2 5 CH3 SNa CH30Na CH3SO2Na \ /

~N~ CH ~X

1~3614~

X-498r B -19- -wherein Y is a "leaving" group: Cl, Br, OSO2phenyl, O-tosyl or SO2(Cl-C3)alkyl, R 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~, 7~, 8a~
isomer. The mirror image compound is, of course, also produced since it constitute~ half of the starting material, XV. The 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 ~eaction Scheme III, a trans-dl-5-substituted-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline-7-carboxylate ester is reduced with a metal hydride reducing agent, such as LiAlH4, 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 ~136141 X-498<~ -20-sulfonate esters by reaction with the correspondingsulfonyl 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 S02CH3. 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-~,4a,5,6,7,8,8a,9-octahydro-l~ land 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 ,, X-4988~ -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 a~ueous 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 lS formed in the above reaction, was dissolved in chloro-f~rm ar.d ~he chloroform solution chromatographed over "~Lorisll" Chloroform containing increasing amounts of etnanol (0 to 2 percent) was used as the eluant.
Fractions found to contain 2-oxo-6-~enzoyloxy-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 yiald 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 solven. mixture.
Analys_s:Calculated: C, 70.83; H, 6.32; N, 5.16.
Found: C, 71.05; ~, 6.19; N, 5.33.

*Trademark for activated magnesium silicate in the form of hard, porous, stable, white granules, used as an adsor~ent in chromatographic separations.

` 113~;~4~

X-49~8~ -22-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.
S 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 witAout 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 etAyl 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-hexahydro~uinoline and l-~enzyl-2-oxo-6-benzoyloxy-3,4,4a,5,6,7-hexahydro-~5 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 mix~ure was heated to 113~14~

X-4988B -2~-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 a~ueous 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 1-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 hydroqen 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 po~tions. After the addition had been completed, the cooling batn was removed and the reaction mixture stirred at mbient temperature for 1.25 hours, after 113~141 X-49~ B -24-which time it was poured into a mixture o' 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 a~ueous sodium hydroxide and the alkaline mixture extracted several times with a chloroform-isopropanol solvent mixture. The organic extracts were combined, and the co~bined extracts washed with saturated aqueous sodi~ chloride and then dried. Evaporation of the solvent yielded trans-dl-l-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 dissolv~d in 1.5 l. of methylene dichloride and the solution cooled in an ice-water bath. 50 g. of cyanogen bromide were added and the resulting mixture stirred at room temperature for lS
2¢ 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"~lorisil~usiny 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.

1~36141 X-498~ -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 "~orisil"using chloroform containing 1 percent methanol as the eluant. Fractions shown by TLC to contain trans-dl-1-cyano-6-oxodecahydro~uinoline 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 which 100 g. of the dimethylace-cal of dimethylformamide had b~en dded. 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-dimethylaminomethylenedecahydro~uinoline ~d~E~
, 113~141 X-4988~ -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-S cyano-6-oxo-7-dimethylaminomethylenedecahydroquinoline melting at 159-163C. were obtained. The co~.pound was crystallized from toluene to yield crystals melting at 162-4C.
Analy~is;Calculated: C, 66.92; H, 8.21; N, 18.01.
Found: C, 67.14; H, 8.16; N, 18.~4.
10.2 g. of trans-dl-1-cyano-6-oxo-7-dimethylaminomethylenedecahydroquinoline were dis-solved in ~00 ml. of methanol. 2.8 g. of 85 percent hydrazine were added and the subsequent reaction lS mixture stirred for a~out 1 day under a nitrogen atmosphere. The volatile constituents were then removed by evaporation i~ vacuo. The residue was dissolved in chloroform and the chloroform solution chromatographed over 150 g. of"Florisil"using chloro-form containing increasing amounts (2-~) of methanol as the eluant. Fractions shown by TLC to con~ain the desired octahydropyrazoloquinoline were combined and the solvent evaporated ther~from to dryness; yield =
6.3 g. Recrystal~ization of the residue from ethanol yielded a mixture of trans-dl-5-cyano-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-gJquinoline and its lH
tautomex melting at 193-SC.
Analysis:Calcu'ated: C, 6S.32; H, 6.98; N, 27.70 Found: C, 65.48; H, 6.80; N, ~7.64 *Trademark ~13~i141 X-4988g -27-Example B
Preparation of trans-dl-4,4a,5,6,7,8,8a,9-Octahydro-lH (and 2H)-pyrazolo[3,4-g]quinoline 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 aqueous 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-g]quinoline and the lH tautomer formed in the above reac~ion. The residue was dissolved in e.hanol 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-pyrazolo[3,4-g3quinoline 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; ~, 16.83.

113~14~
X-4988g -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 L 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 ~-(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 temoerature for about 23 hours. The reflux condenser was equipped with a Soxhlet extractor containing a 5A 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-benzoy;oxy-1,2,3 t 4,4a,5,6,7-octahydroquinoline. The residue was dissolved in an ether-chloroform solvent mixture and the resulting solution saturated with 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 ~F were added and the resulting solution cooled in .:

113Ç141 X-~988~ -29-an ice-water bath. 1~ g. of sodium cyanoborohydride were added in 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 1~ 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 ~00 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 by 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 witA aqueous sodium bicarbonate and the al~aline mixture extracted several times with chloroform. The chloroform extracts were -ombined and the combined extracts washed with satu-rated aqueous sodium c~loride and then dried. Evapo-X-4988~ -30-ration of the chloroform yielded 10.3 g. of a residue comprising trans-dl-l-n-propyl-3-ethoxycarbonyl-~-hydroxydecahydroquinoline formed in the above hydrolysis after chromatography over 150 g. of~Florisiinusing 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 sodi~m acetate were added. Next, 10.8 g. of pyridine hydrochloride:chromium trioxide were added and the resulting mixture stirred for about 22 hour~.
The reaction mixture was filtered and the filtrate concent~ated in v~cuo~ The resulting concentrate was dissolved in chloroform and the chloroform solution chromatographed over 150 g. of"Florisil"using chloro-form ~ontaining increasing amounts (1-2~) of methanol as the eluant. Fractions shown by thin-layer chroma-~ograp~.y t~ contain trans-dl-l-n-propyl-3-ethoxyc~r-2C bonyl-6-oxodecahydroquinoli~e formed in the above reaction were combined and the solven~ removed from the com~ined e~tracts to yield 3.48 g. of the 6-oxo com2ound as a residue. ~he 6-oxo compound was dis-solved in 100 ml. O r toluene containing an added 25 ml. cf the dimethylacetal of dimethylfc~amide.
,he resulting mixture was heated to refluxing tem-perature under a nitrogen atmosphere for 44 hours and was then allowed to remain at room temperature for an add_tional 4 days. Volatile constituents were remove~
3~ b~ evaporation in VaCUQ and the residue, comprisir.g - *Trademark 113~141 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"~lorisil"
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 tsans-dl-l-n-propyl-3-ethoxycarbonyl-6-oxo-7-dimethyl-amincmethylene decahydroquinoline and lSO ml. of ethanol. 0.45 ml. of hydrazine hydrate were added and the resuiting mixture stirred at ambient temperature for about 17 hours. The reaction mixture was evapo-rated to dryness in vacuo. The residue containing a mixture of trans-dl-S-n-propyl-7-ethoxycarbonyl-4,4a,-5,6,7,8,8a,9-octahydro-2H-pyrazolol3,4-g]quinoline and trans-dl-5-n-propyl-7-ethoxyc~rbonyl-4,4a,5,6,7,8,8a,9-.0 octahydro-lH-pyrazolo[3,4-g]quinoline was dissolved in chloroform and the resulting solution chromatographed over 35 g. of"Florisil"using chloroform containing 2 percen. methanol as an eluant. Fractions shown to con_ain the desired pyrazoloquinoline ~y TLC were combined and the solvent evaporated therefrom in V2CUO. Re-rystallization from a mi~ture of ether and hexane yielded trans-dl-5-n-propyl-7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-octahyaro-2~-py.azolo r 3,4-g]quinoline and its 1~ tautomer melting at 125-7C.
~ndlysis:Calculated: C, 6;.9'; lI, &.65; N, 1~.42.
Found: C, 65.75; ~, ~.42; N, 14.16.

*Trademark 113S14i 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-car~onyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo-13,4-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 hollrs, and was then cooled.
Ethyl acetate and 10 percent aqueous sodium hydroxide were added thereto seriatim to react with any excess lithium aluminumhydride and to decompose orsanometallic compounds present. The r~action mixture so treated was then diluted wi~h wate~ and the aqueous mixture extracted several times with a chloroform-isopropanol solvent mixture. The o~ganic layers were separated and combined. The com~ined layers were washed with saturated aqueous sodium chloride and t~en dr~ed.
Evaporation of the solvent yielded a mixture of trans-dl-5-n-prop~1-7-hydrox~ethyl-4,4a,5,6,7,8,8a,g-oc~ahydro-2H-pyrazolo~3,4-g]quinsline and its lH
tautomer. The -esidue was dissolved in ethanol to which was added 0.2 ml. of 12N aqueous hydrochloric acid. Evaporatior. of the volatile const_tuents yielded a res~due comprising trans-dl-5-n-propyi-. .

113~14~

X-4988~ -33-

7-hydroxymethyl-4,4a,5,6,7,8,8a,9-octahydro-2H and lH-pyrazolo[3,4-g]quinoline dihydrochlorides. The residue was dissolved in a mixture of methanol and acetone to yield crystals melting at 270-5C. with S 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-g3quinoline in ~F
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-1~ and 2H-pyrazolo~3,4-g~quinoline, was crystallized from a mixture of chloroform and ethanol to yield crystalline material melting at 167-9C.
L; 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 l-n-Propyl-6-benzoyloxy-3,4,S,6,7,8-hexahydro-2(lH)-quinolinone and 1-n-Propyl-6-benzoyloxy-3,4,4a,5,6,7-hexahydro-2tlH)-quinolinone A reaction mixture was prepared containing 4.4 g. of 4-benzoyloxycyclohexanone ~prepared by the procedure of E. R. H. Jones and ~. 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 r~fluxing 113f~141 X-498~B ~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 b~
evaporation in vacuo. Chromatoqraphy 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-2(lH)-quinolinone and l-n-propyl-6-benzoyloxy-3,4,4a,5,6,7-hexah~dro-2(1H)-quinolinone: yield =
15 2.15 g.
FINAL P~ODUCTS
Example Preparaticn of trans-dl-5--r.-Propyl-4,4a,5,6,7,8,-20 ~a,9-octah~dro-1~. (ar.d 2H)-pyrazolo[3,4-g]quinoline A reaction mix~ure was prepared from 6.3 g. of a mixture of trans-dl-5-cyano-4,~a,5,6,-7,8, 8a, 9-octahydro-2H-pyrazolo~3,4-g]quinoline and its l~-tautomer (prepared by the procedure of 25 Example ~, 30 g. cf zinc dust, 375 mi. of acetic acid and 7 5 ml . o' water. The react~on ~ixture was heated to refluxing temperature under nitrogen for 16 hours after which tirne it was filtered and the fil.rate *Trademark for a highly selective adsorbentOf hard granular or powdered magnesium silicate.
q~ ~

113~i141 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

~136141 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-g]quinoline 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-g3quinoline and its lH
tautomer which was isolated as a residue. This resldue 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 wlth water a~d the resulting aqueous mixture extracted several times with ethyl acetate. The ethyl acetate extracts were combined and the combined extracts washed success~vely with water and saturated aqueous sodiuM chloride and were then dried. Evapo-~13614~

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-propy1;-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-glquinoline 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 resultin~ 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 yielded a solid residue. A chloroform solution of the residue was chromatographed over 3Q 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]quinoline 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 113~i~4~

X-49B8~ -39-1 g. of methylmercaptan was dissolved in 40 ml. of dimethylformamide. The solution was cooled in an ice-water bath. A~out 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-pyrazolol3,4-g~quinoline containing some trans-dl-l-methanesulfonyl-5-n-propyl-7-mesyloxy-methyl-4,4a,5,6,7,8,8a,9-octahydro-lH-pyrazololS,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-~-n-propyl-7-methylmercaptomethyl-4,4a,5,6,7,8,8a,9-octahydro-lH and 2H-pyrazolol3,4-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 t~rned out to be noncrystalline. The free Dases 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-7-methyl-mercaptomethyl-4,4a,5,6,7,8,8a,9-octahydr~-lH and 113~141 X-4988~ -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; ~, 9.02; N, 15.04;
S, 11.47.
Found: C, 64.47; H, 8.96; N, 15.09;
S, 11.~9.
The above purified free base tautomeric mixture was dissolved in ethanol and an excess of 12N hydrochloric acid added. The volatile con-stituents were removed by evaporation and the resulting residue comprising the corresponding dihydrochloride salts cryst~llized from an acetone-methanol solvent mixture.
i5 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-g3quinoline 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~ of 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~ltins mixture cooled in an ice-water bath. 9.6 g. of sodiu~ hydride (as a 50 percent suspension in mineral o 1) we_e added in ~136141 X-4988.B -41-portions. After all of tne 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 5 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(1~)-quinolinone and the correspording 3,4,4a,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 cf 1-methyl-6-benzoyloxy-3, 4, 5,6,7,8-hexahydro-2~lH)-quinolinone and the corresponding 3,4,4a,5,6,7-hexahydro isomer as obtained above were dissolved in 800 ml. of THF and the solution cooled to a~out 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-hydrice destroyed oy the addition of ethyl ~cetate.
10% sodium hydrcxide was then add2d and the mixture diluted with water to decompose any orsanometa~'lcs X-498~ B -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 d_ssolved 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 T~F
and 50 ml. of methanol. This solution was cooled in an ice-water bath. 12 g. of sodium cyar.oborohydride wer~ added with cooling and stirring. After all of the cyanoborohydride had been added, 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 ~xtract discarded. The solu~ on was then ~ade basic with 14N aqueous ammoni~lm hydroxide. Trans-dl-1-methyl-6-hydroxydecahydroquinoline formed in the above reaction, being insoluble in th_ alkaline medium, i.. i. .

113~

X-4988~ -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 S solvent yielded 15 ~. 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 1~ 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 ayueous solution made ~asic with 14N
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 com~ined extracts washed with saturated aqueous sodi~n chloride and then dried. Evaporation of the solver.t in vacuo yielded trans-dl-l-methyl-6-oxodecahydroquinoline boiling in the ranse 105-116C.
a. 6 torr; yield = 7.7 g. (45%).

113614~

X-4988~ -44-A reaction mixture was prepared frGm 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. ~his solution was heated to refluxing tempera~ure under nitrogen for 20 hours. The reaction mixture was then evaporated in vacuo and a chloroform solution of the residue chromatographed over 150 g. of"Florisil~using as the eluant, methylene dichloride containing increasing amounts (1-5~) of methanol~ Fractions containing similar substances as shown by TLC were combined.
The third sub~tance to be eluted was a yellow so;id (wt = 3 g.) ~he solid was heated with 100 ml. of elher and _he resultin~ solution filtered. Cor.-cer.t~ation of t~e f ltrate to about 50 ml. yielded 590 mg. of c_ystals of trans-dl-1-meth~1-6-oxo-7-d methylaminomet~.~lenedecahydroquino7ine meltin~ at L't)7--109C.
Analysis:Calculated: C, 70.23; H, 9.9,; ~i, 12.60.
Found: C, 7G.17; H, 9.74; ~ 7 3~

*Trademark ~.~.

113~i141 X-498~ -45-A solution was prepared by dissolving 175 mg. of trans-~1-l-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 ov~r 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 ori~in and different than starting material were combined and the solvent removed from the com~ined fractions by evaporation.
trans-al-5-methyl-4,4a,5,6,7,8,8a,4-oct2hydro-lH-(and 2H)-pyrazolo[3,4-g]quinoline free base gave a molecular ion ~M ) at l91 by mass spectroscopy.
The resulting residue was dissol~ted in ethanol and 2 ml. of l~ hydrochloric acid were 2~ added. The acidic solution was e~aporated to dryness. Crystallization of the residue from ethanol yielded a tautomeric mix.ure contain ng txans-dl-5-methyl-4,4a,5,6,7,8,8a,9-octahydro-lH-(and 2H)-pyrazolo~3,4-g]~uinoline diAydrochlor des melting at 268-70C. with decomposit cr.; yield -14~ mg.
~nalysis:Calculated: C, 50.01; H, 7.25; ~, 15.9C;
Cl, ~6.84.
Found: C, 49.~2; H, ~.OB; N, 15.66;
Cl, 26.~0.

~ *Trademark 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-Stark 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 er.amine 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 about one day after which time it was cooled and the volatile constituents removed by evapora~ion. 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 sodium chloride and then d_ied. 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 com~ination 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 113~i14i X 498~B -47-mixture stirred in order to completely form the sodium salt of the quinoline-2-one. Next 30 g. of allyl bromide 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 aqueous mixture 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 solvent yielded a mixture of l-allyl-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 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 de ompose any organometallic compounds present and the mixture thus treated was diluted with water. The aqueous mixture was then extracted several tlmes with chlorororm and the chloroform extracts combined. The combined ex~racts 113~i141 X-~988g -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 saturated 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 THF. 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 la~er W2S
2~ extracted several times with chloroform. The chloro-form extracts were combined and the combined ext~acts washed with saturated aqueous sodium chloride and then dried. Evaporation of the solvent yielded about 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 ~00 ml. of methylene di~hloride to which had been added 8.2 g. of sodium acet~te. Next 21.6 g. of pyridine hydrochloride/chromium trioxide were added.

The reaction wa~ 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 113~14~

trans-dl-5-all~1-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline and its lH tautomer wese combined and the solvent removed therefrom by evaporation in 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; N, 1.48;
Cl, 24.43 Found: C, 53.52; H, 7.13; N, 1.65;
Cl, 24.17.
As evidence of t~.e 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, 435 (1970). A compound having dopamine gonist activity causes the rats to turn in circles contralateral to the side of the lesion. After a latenc,~ period, which varies from compound to com-pound, the number of turns is courted over a i5-3C minute period.

1~3614~

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 column 3, average number of turns observed in first 15 minutes after end of latency period.

113~14~

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e ~ s 113~14~
X-49~8~ -53-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 t~e 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 weigning about 200 g. were housed in an air-conditioned room with controlled lighting (lights on 6 a.m. - 8 p.m.) and fed ,ab chow and water ad li~itum.
~ach rat received an intraperitoneal injection of 2.0 mg. cf reserpine in aqueous suspension 18 hours before administration of the test drug. The purpos2 of the reserpine was to keep prolactin levels uni-formly eievated. The compounds under test were dissolved in 10 percent ethanol, and 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 ~ ed by decapitation, and 150 ~1 ali~uots of serum were assayed for prolactin.
The difference between the prolactin level of th^ treated rats and prolactin level of the control ~ats, divided by the prolactin level o~ the control ` ~136141 X-4988B _54_ 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 0.5 and 5 mg./kg. dose levels.

1~3~141 O?
C~
~ _l ~ ~
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~ U~
C~
C

,0, ~
., Q tr r~ ~ I ~ ~0 S
~ o c a~ o~
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O i~ ~ I I
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5: 1 ` I
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s~ C ~r ~ C
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,~ O ~ ~ ~ O er ~ Q~
o !~ C 0 ~ S~ C S :~ O
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I '~ O
O ~1 7a 0 O ~ O U ~ O h ~ ~ ~ O `1~ i O ~ ~ 'O--a~ I ' o ~ o ~ C ` ~ ~ C ` ~ ~ C U ~ ~
z (a ~ ~1 ~ 115 ~ h ~ ~S ~ ~ ' h ~ h a~ U /~
,~ ~ r- S:l,~ ~ E O--113~141 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 ta~lets. The oral dosage range is from a~out 0.01 to 10 mg./kg. of mammalian weight and the parenteral dose range from about 0.0025 to 2.5 mg./kg.
Intraperitoneal dosases of 10-100 mg./kg. of trans-dl-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-lH(and 2H)-pyrazolol3,4-g]quinoline dihydrochloride resulted in no deaths, ~ut dosages of 300 mg./kg. were fatal, indicatiny an LD50 in the range 100-300 mg./kg.

Claims (2)

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

1. A process for preparing, as novel intermediates, compounds of the general formulae:

Ic Id wherein:
R is H, CN, C1-C3 alkyl or benzyl;
R1 is H, -COOH, -COO(C1-C3) alkyl, or CH2X wherein X is C1, Br, I, OH, OSO2-(C1-C3)alkyl, OSO2tolyl, or OSO2phenyl;
with the proviso that when R is C1-C3 alkyl, then R1 can not be H; and the salts thereof, which comprises reacting a compound of the general formula wherein R is defined as above, and R4 is H or COOZ' where Z' is H, or (C1-C3) alkyl, with hydrazine hydrate;
followed by, when Z' is (C1-C3)alkyl, reacting with a metal hydride to obtain the compounds where R1 is CH2OH, followed by, if desired; reacting with a nucleophilic reagent to obtain the compounds where R
is CH2Y where Y is C1, Br, I, OSO2-(C1-C3)-alkyl, OSO2 tolyl or OSO2 phenyl, and where desired forming a salt of said compound of general formulae Ic and Id.

2. As novel intermediates compounds of the general formulae:

Ic Id wherein R is H, CN, C1-C3 alkyl or benzyl;
R1 is H, -COOH, -COO(C1-C3)alkyl, or CH2X wherein X is C1, Br, I, OH, OSO2-(C1-C3)alkyl, OSO2tolyl, or OSO2phenyl;
with the proviso that when R is C1-C3 alkyl, then R1 can not be H; and the salts thereof, whenever prepared by the process of claim 1 or an obvious chemical equivalent thereof.