CA1249277A - Hypotensive agents - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
A novel hypotensive agent, trans-4aR-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-1H(and 2H)pyrazolo-[3,4-g]quinoline, is disclosed herein. The trans-4aR stereoisomer is prepared from the trans-dl-racemate.

Description

X-59~9M -1-IMPROVEMENTS IN OR RELATING TO
NOVEL HYPOTENSIVE AGENTS
This invention relates to novel hypotensive agents and is also concerned with novel methods of preparing those compounds.
There are presently a number of commercial products avallable which are to a greater or lesser extent e~fective in reducing elevated blood pressure in humans, see, for instance, U.S. Patent No. 2,484,029 10 which describes the commercial product "Hydralazine", 1(2H)-phthalazinone hydrazone. However, these products all have various undesirable side-efects, for instance, postural hypotensive effects and tachycardia. Accordingly, there continues to be a need for new hypotensive agents l~ possessing fewer undesirable side-effects.
Surprisingly, in accordance with the present invention, lt has been discovered that a stereoisomer of the racemic form of the compound described in U.S.
Patent No. 4,198,415, see Example 2, possesses ex-

2~ tremely interesting hypotensive properties. It is tobe noted that this U.S. Patent teaches that such compounds are prolactin inhibitors, useful in the treatment of Parkinson's disease, a utility far .emcved from that now found for the novel isomer provided herein.
Thus, in accordance with the invention, the stereoisomer illustrated below in the form o its tautomers:

/8\ /i~\--/8\
~N_~a ~9a 7T --~~N--Toa t9a '-i~
~/Hi~ CH=~ o n~3H7 n~3H7 Ia Ib is an effective hypotensive agent.
The above stereoisomer can be alternatively 10 designated as: 5-n-propyl-4,4a~,5,6,7,8,8aa,9-octahydro-lH(and 2H)pyrazolo[3,4-g]-quinoline; as trans~ 5-n-propyl-4,4a~5,6,7,8,8a,9-octahydro-lH-(and 2H)pyrazolo[3,4-g]quinoline; as 4aR,8aR-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-lH(and 2H)pyrazolo-[3,4-g]quinoline; or as trans-4aR-5-n-pxopyl-4,4a,5,6,-7,8,8a,9-octahydro-lH(and 2H)pyrazolo[3,4-g]quinoline.
This invention also provides a novel method of blocking norepinephrine release from peripheral sym-pathetic nerve terminals that innervate arterial muscle fibers in mammals which comprises administering to a mammal having an elevated blood pressure an effective dose of a tautomeric mixture of trans-4aR-5-n-propyl-4,4a,5,6,7,8,~a,9-octahydro-lH(and 2H)-pyrazolo[3,4-g]quinoline, represented by formula Ia or Ih above, or 25 a pharmaceutically-acceptable salt thereof, thereby lowering the blood pressure of said mammal.
The above tau-tomeric pair (Ia and Ib) can be prepared in optically pure form by:
(a) reacting trans-dl-5-n-propyl-4,4a,5,6,-7,8,8a,9 octahydro-lH(and 2H)pyrazolo[3,4-g]qulnoline, ?d77 X-594~M _3_ with an excess of an optically active -tartaric acid of the formula HOOC- (CHOR ) 2-COOH II
O
wherein R2 is hydrogen or -C-R3 where R3 is Cl-C3 alkyl, phenyl, or substituted phenyl;
(b) separating the tartrate salt of the trans-stereoisomer, thus formed;
(c) fractionally recrystallizing the tartrate salt mixture to provide the desired trans-4aR tartrate salt;
(d) reacting an aqueous solution of the tartrate salt with excess base; and then (e) isolating the trans-4aR-5-n-propyl-4,~a,5,6,7,8,8a,9-octahydro-lH(and 2H)pyrazolo[3,4-g]-quinoline free base thus formed; and (f) optionally salifying the free base so obtaine~ so as to obtain a pharmaceutically-acceptable salt the-eof.
An optically active tartaric acid o, the formula HOOC-(CHOR )2-COOH II
O
whereln R2 is hydrogen or -C-R3 where R3 is Cl-C3 alkyl, or phenyl optionally substituted by groups such as methyl, chloro or methoxy, is used in the above process. The acid will of course be in the (D)-(-) form. A preferred class of reagents of formula II are 7~

~-5949~ -4-those where R2 is hydrogen, R3 is methyl, phenyl or p-tolyl. An especially preferred reagent of formula II
is D-(-)-S-tartaric acid. The reaction can be effected using a solvent, such as a Cl-C4 alkanol, preferably methanol, and a-t a temperature from about 50C. to reflux.
Conversion of the salt, e.g. pyrazolo[3,~-g]-quinoline 3-(-)-S-tartrate, to the free base is readily effected by dissolving the salt in waker and then lO adding an excess of a base (NaOH, Na2C03, NH40~1). The pyrazolo[3,4-g]quinoline, being insoluble in the basic solution, separates and is extracted with a water-immiscible organic solvent. The organic layer is separated and dried. If it is desired to prepare a 15 different salt, a solution containing one equivalent of a second non-toxic acid can then be added, and the salt isolated by filtration or evaporation. Alternatively, the solvent can be removed from the dried organic extract and the free base obtained as a residue. The 20 free base can then be dissolved in a suitable solvent and the different non-toxic acid added as a solution.
Compounds according to the above stxucture ~ contain two basic groups, the alkylated quinoline ring - nitrogen and the pyrazole nitrogen not carrying the hydroyen (N-l or N-2). The quinoline ring nitrogen is the more basic of the two and forms acid addition salts readily. Strong inorganic acids such as the mineral acids or strong organic acids such as _-toluenesulfonic acid, can form di-salts when employed in excess.

Pharmaceutically-acceptable salts of the compounds of formula Ia or Ib thus include mono or di-salts derived from inorganic acids such as:
hydrochloric acid, nitric acid, phosphoric acid, sul-furic acid, hydrobromic acid, hydriodic acid, phos-phorous acid and the like, as well as salts derived from organic acids such as aliphatic mono- and di-carboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic and alkandioic acids, aromatic acids, 10 aliphatic and aromatic sulfonic acids. Such pharma-ceutically-acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, io-15 dide, fluoride, acetate, propionate, decanoa~e, capry-late, acrylate, formate, isobutyrate, caprate, heptano-ate, propiolate, oxalate, malonate, succinate, suber-ate, seba-ate, fumarate, maleate, mandelate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzo-ate, methylbenzoate, dinitrobenzoate, hydroxybenzoate,methoxybenzGate, phthalate, terephthalate, benzene-sulfonate, toluenesulfonate, chlorobenzenesul.onate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, ~-hydroxybutyrate, glycollate, malate, tartrate, methanesulfonate, pro-panesulfonate, naphthalene-l-sulfonate, naphthalene-2-sulfonate and the li~e salts.
The preferred salt of this invention is the mono HCl salt and can be prepared for example by addin~ an equivalent of hydrogen chloride to an g ~ 7~

ethanol solution of the free base, followed by evapo-ration of the ethanol and recrystallization of the salt. If it is desired to make a disalt such as a dihydrochloride salt, HCl gas can be passed into a solution of the free base to the point of saturation and the salt isolated by filtration.
The following examples further illustrate the preparation of the compounds of the invantion.
Example 1 One equivalent of trans-dl-5-n-propyl-4,4a,-5,6,7,8,8a,9-octahydro~lH~and 2H)pyrazolo[3,4-g]quino-line was dissolved in methanol. One and one-tenths equivalents of D-(-)-S-tartaric acid were added thereto 15 and the solution heated to boiling for about 10 min-utes. Upon cooling to room temperature, a crystalline precipitate formed which was separated by filtration.
Five-fold recrystallization of that precipitate from methanol (0.1 g of tartrate salt per 1 ml of methanol) 20 yielded crystalline trans-4aR-5-n-propyl-4,4a,5,6,7,-8,8a,9-octahydro-lH(and 2H)pyrazolo[3,4-g]quinoline, D-(-)-S-tartrate melting at 201-202C; [a]~ (H2O) = -95.5. The salt was of satisfactory optical purity since the last recrystallization did not substantially 25 changa the rotation of plane polarized light.
The above salt was dissolved in water and the aqueous solution made strongly basic with 14M aqueous ammonium hydroxide. The alkaline aqueous layer was extracted three times with an equal volume of a 3:1 30 chloroform:isopropanol solvent mixture. The or~anic ~%~f~

extracts were combined, the combined extracts washed with saturated aqueous sodium chloride and then dried.
Evaporation of the solvent yielded a colorless solid comprising trans-4aR-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-lH(and 2H)pyra~olo[3,4-g]quinoline. This solid was dissolved in methanol and precisely one equivalent of 0.2N aqueous hydrochloric acid added.
The volatile constituents were removed by evaporation ln vacuo and the resulting hydrochloride salt crystal-lized from a methanol/ether solvent mixture. Trans-4aR-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-lH(and 2H)-pyrazolo[3,4-g]quinoline, hydrochloride thus prepared melted at about 280C with decomposition; [a]D5(H20) = -120.6-15 Analysis Calculated: C, 61.04; H, 5.67; Cl, 13.86;
N, 16.43, Found: C, 61.30; H, 5.51; Cl, 14.14;N, 16.62.
The inactive trans-(+)- or trans-4aS-isomer is prepared by contacting the trans-dl-racemate with a slight excess of L-(+)~R-tartaric acid.
The absolute configuration of the inactive trans-(+) stereoisomer was shown by x-ray analysis of its D-(-)-R-_-butyloxycarbonylphenylglycine salt to be 4aS-configuration. Thus, the active isomer is, by process of elimination, the trans 4aR, or 4a~,8aa, or 4aR,8aR or trans-(-)-isomer.

~2~
X-59~9M -8-This invention also concerns a pharmaceutical composition comprising as active ingredient a tautomer oE formula Ia or Ib as defined above, or a pharma-ceutically-acceptable salt thereof, associated with a pharmaceutically-acceptable carrier therefor.
In using the therapeutic process, a pharma-ceutically-acceptable salt of a drug according to formula Ia or Ib above formed with a non-toxic acid is administered orally or parenterally to a mammal with an elevated hlood pressure in which it is desirable to lower blood pressure, by blocking norepinephrine re-lease from peripheral sympathetic nerve terminals that innervate arterial muscle fibers. For parenteral ad-ministration, a water soluble salt of the drug, trans-1 4aR-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H(and lH)-pyrazolo[3,4-g]isoquinoline, is dissolved in an iso-tonic salt solution and administered by the I.V. route.
Dose levels of from 0.5-500 mcg./kg. of mammalian weight are found to be effective to block norepineph-rine release and thereby reduce elevated blood pressurein spontaneously hypertensive rats (SHR). For oral admlnistration, a pharmaceutically-acceptable salt of the drug is mixed with standard pharmaceutical excipi-ents such as starch and loaded into capsules, each containing 0.1-15 mg. of active drug. Dosage levels of from 0.1-3 mg./kg. have been Eound to be effective in blocking norepinephrine release from sympathetic nerve terminals, thereby lowering blood pressure in SHR, for periods ranging up to six hours. Thus, the oral dosage X-5949M -9_ would be administered 3-4 times per day, giving a daily dosage range of about 0Ol to about 15 mg./kg. per day.
Other oral dosage forms, such as suspensions, elixirs and tablets, can also be utilized and are preparable by standard procedures.
The effect of the method o~ this invention in blocking norepinephrine release from peripheral sym-pathetic nerve terminals that innervate arterial muscle fibers, thexeby reducing the blood pressure in spontane-10 ously hypertensive rats, is shown by the followingexperiment:
Adult male spontaneously hypertensive rats (SHR) (Taconic Farms, Germantown, New York), weighing approximately 300 g. were anesthetized with pento-15 barbital sodium (60 mg./kg., i.p.). The trachea wascannulated and SHR respired room air. Pulsatile arteri-al blood pressure was measured from a cannulated carot-id artery using a Statham transducer (P23 ID). Mean arterial blood pressure was calculated as diastolic 20 blood pressure plus 1/3 pulse pressure. Cardiac rate ~ was monitored by a cardiotachometer which was triggered i by the systolic pressure pulse. Drug solutions were administered I.V. through a catheter placed in a fem-oral vein. Arterial blood pressure and cardiac rate 25 were recorded on a multichannel oscillograph (Beckman, Model R511A). Fi~teen minutes were allowed to elapse following surgery for equilibration of the preparation.

'; ~-' Table 1 which follows gives the results of this experiment using trans-4aR-5-n-propyl-4,4a,5,6,7,-8,8a,9-octahydro-2H(and lH)pyrazolo[3,4-g3quinoline, D-(-)-S-tartrate, plus the corresponding trans-4aS-enantiomer and the parent trans-dl-racemate as the hydrochloride salt for comparison purposes. Each drug was administered I.V. to groups of four SHR at a series of dose levels.

Relative potencies of trans-5-n-propyl-4,-4a,5,6,7,8,8a,9-octahydro-2H(and lH)pyrazolo[3,4-g]-quinolines isomers and racemate.
Mean Arterial Dose Blood Pressure Compoundmcg./kg. % Change (~) Trans-4aR 0.1 - 7.7 + 1.6 1 -14.3 + 1.6 -25.2 ~ 2.1 100 -38.6 + ~.3 Trans-4aS 0.1 - 8.5 + 0.8 1 - 5.1 ~ 0.8 - 5.0 + 0.3 100 - 4.6 + 0.3 1000 - 6.4 + 1.1 Trans-dl 1 -12.7 + 2.2 -22.4 + 0.7 100 -32.0 -~ 2.1 1000 -52.2 t 6.9 It is apparent that all the hypotensive action of trans-dl-5-n-propyl-4,4a,5,6,7,8,8a,9-octa-hvdro-lH(and 2H)-pyrazolo[3,4-g]quinoline resides in 30 the levo or trans-4aR stereoisomer.

x-5949~ -11-l~ore direct evidence that trans-dl-5-n-propyl-4,4a,5,6,7,~,8a,9-octahydro-lH(and 2H)-pyra-zolo[3,4-g]quinoline blocks norepinephrine release from peripheral sympathetic nerve terminals is illustrated by the following experiment. In this experiment, SHR
were pithed by passing a steel rod through the right orbit and down the entire length of the spinal column.
The rod was left in position for the duration of the experiment. Immediately after pithing, SHR were venti-10 lated with room air delivered from a rodent respirator(Harvard, Model ~80; tidal volume of 1 ml./100 g. body weight, 60 cycles/min). The pithing rod was used to stimulate the entire sympathetic outflow from the spinal cord. Portions of the rod which lay in the 15 cervical and sacral cord were insulated. The sympathet-ic outflow was stimulated by square wave pulses (50 volts, 1 msec duration for 30 sec) of frequencies of 0.25, 1, 4 and 8 Hz delivered from a stimulator (Grass, Model S44). The pithing rod served as the stimulating 20 electrode while a needle inserted into the right hind-limb musculature was the indifferent electrode. Skele-tal muscle twitches were prevented by administration of d-tubocurarine (1 mg./kg., I.V.). Increments in dia-stolic blood pressure produced by electrical stimula-25 tion of the sympathetic outflow were monitored from acannulated carotid arter~. The test drug was adminis-tered I.V. at two dose levels to groups of four SI~R.
Table 2 which follows indicates that elec-trical stimulation of the sympathetic outflow or I.V.

~-5949M -12-administration of exogenous norepinephrine each pro-duced the expected vasoconstrictor responses in control pithed SHR, as indicated by the increments in diastolic blood pressure. Pretreatment of other S~ with the trans-dl-racemate attenuated neurogenic vasoconstrictor responses in a dose-related manner. rrhis attenuation was selective in that the test drug produced no con-comitant antagonism of comparable vasoconstrictor re-sponses resulting from administration of exogenous nore-10 pinephrine. Thus, the composite data of Tables 1-2 indicate that doses of the trans-dl-racemate (and by implication, of the trans-4aR isomer, the active com-ponent of the racemate) which are hypotensive in intact SHR, result in selective inhibition of norepinephrine 15 release from peripheral sympathetic nerve terminals.

Selective antagonism of neurogenic vasocon-strictor responses produced by trans-dl-5-n-propyl-20 4,4a,5,6,7,8,8a,9-octahydro-lH-(and 2H)-pyrazolo-[3,4-g]~uinoline.
Increase ln Dlastolic Blood Pressure (mm. Hg.) Produced by Electrical Stimulation of the Sympathetic Outflow Trans-dl-racemate 25 (mcg /ka , I V.) 0.25 Hz1 Hz 4 Hz 8 Hz J ~ _ none 34+3 72+3 118+8 129+7 100 14+2 47~2 105~8 115+9 1000 10+1 26+4 65~8 89+12 -X-59~9M -13-Increase in Diastolic Blood Pres-sure (mm. Hg~) Produced by Exogenous Norepinephrine Trans-dl-racemate 0.01 0~1 l lO
(mcg./kg., I.V.) mcy./kg. mcg./kg. mcg./kg. mc~./kg.
none 8+1 27~1 78+3 140~5 100 7+1 29+2 74~1 128~5 1000 10~l 30+2 80+1 1~0~4 The lack of alpha adrenergic receptor activi-10 ty for trans-4aR-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-lH(and 2H)pyrazolo[3,4-g]quinoline is illustrated by the following experiment in which vasoconstrictor activity (or lac~ thereof) can be demonstrated in pithed SHR as a rise in baseline blood pressure, 15 vasoconstrictor activity resulting in a blood pressure rise.
The effects on blood pressure as a measure of the vasoconstrictor effects of trans-dl-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-lH(and 2H)-pyrazolo[3,4-g]-20 quinoline and the trans-4aR stereoisomer were deter-mined using norepinephrine as a control substance. Two oth~r dopamine agonists, pergolide and lergotrile, were also included plus the 7-methylmercaptomethyl deriva-tive of trans-dl-5~n-propyl-4,4a,5,6,7,8,8a,9--octahydro-25 lH(and 2H)pyrazolo[3,4-g]quinoline. Table 3 which follows gives the results of this comparison. In the table, column l, gives the name of the test compound, column 2, the dose and column 3, the change in diastolic blood pressure. Four pithed SHR rats were used at each 30 dose level for each drug.

~ t~ 7 Pelative blood pressure effects of trans-dl-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-lH(and 2H)pyra-zolo[3,4-g]quinoline, the trans-4aR stereoisomer and related compounds.
IV Change .in Diastolic Dose in Blood Pressure Compound mcg./kg. (mm. Hg ) Trans-dl 1 -t S + 1 + 2 + 3 100 ~ 2 + 4 1000 + 7 + 1 Trans-4aR 1 - 4 + 1 - 5 + 1 100 - 4 + 1 1000 - 3 + 1 15 Norepinephrine ~01 + 8 + 1 .1 +27 + ~
1 +78 + 3 +140 + 5 Pergolide 1 -t 4 +19 100 +62 Lergotrile 10 -t 6 100 + 6 1000 +18 Trans-dl-5-n-propyl- 1 + 2 + 2 7-methylmercapto- 10 + 5 + 1 methyl-4,4a,5,6,7,- 100 -~17 + 1 25 3,8a,9-oCtahydro-lH- 1000 +49 + 1 (and 2H)-pyrazolo-: [3,4-g]quinoline From the above da-ta, it would also be expected that the trans-4aR stereoisomer would not increase cardiac 32~
X-5949M -lS-rate as does norepinephrine and this hypothesis has been affirmed by experiment.
It is apparent from the data presented in Tables 2-3 that trans-4aR-5 n-propyl-4,4a,5,6,7,8,8a,9-octahydro-lH(and 2H)pyrazolo[3,4-g]quinoline and the trans-dl racemate are neither a-receptor agonists nor antagonists, and that their hypotensive action is not caused by any a-receptor ef ect, but is probably at~rib-utable solely to their abllity to block norepinephrine 10 release from peripheral sympathetic nerve terminals that innervate arterial muscle fiber.
Trans-4aR-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-lH-(and 2H)quinoline can be considered as related to the ergoline part structure (IV) except that 15 the pyrrole function is replaced by a pyrazole functio-.
: (Va and Vb).

~ O
!
S

.. . ... .

t~ 7T fV``t ~ N-alkyl H~/-\ /N-alkyl t1 ~ 01 1 5T~ T t~H
~ T/~/ IV

ergoline III
where y is H and alkyl is CH3 Y Y

~ 6T I ~ T

Hll ~ Va ~ ~ Vb where Y is H and alkyl is n_propyl.
Pergolide (see Table 2) is an ergoline where 25 alkyl i5 n-propyl and Y is methylmercaptomethyl. Ler-gotrile ~from Table 21 is an ergoline where alkyl is methyl, Y is CH2CN and there is a chlorine at 2~ The related compound, trans-dl-5-n-propyl-7-methylmercapto-methyl ~,4a,5,6,7,8,8a,9-octahydro-lH(and 2H)pyrazolo-[3,4-g]~uinollne (Va and Vb where alkyl is n-propyl and ~ 2~ 7~

X-5949.~ -17-Y is mPthylmercaptomethyl), is disclosed in U.S.
Patent 4,198,415, and is a substituted derivative of the compound used in the process of this invention, the trans~4aR derivative, Va and Vb where alkyl is also 5 n-propyl but Y is H. From the data in Table 2, it can be seen that pergolide and trans-dl-5-n-propyl-7-methylmercaptomethyl-4,4a,5,6,7,8,8a,9-octahydro-lH(and ~ 2H)pyrazolo~3,4-g]quinoline behave like norepinephrine F in the pithed SHR. Thus, while these later compounds -10 are dopamine agonists, they also act on a-receptors.
Lergotrile, while it resembles the trans-4aR isomer use-~- ful in the process of this invention in that it does ..
not act as a vascoconstrictor in pithed SHR, has unde-sirable central effects such as a potential for produc-15 ing hallucinations in humans and is thus not a purepresynaptic dopamine agonist as is the trans-4aR
isomer. The trans-4aR isomer is apparently unique as a presynaptic dopamine agonist. As a consequence, it is unique in its ability to lower an elevated blood pres-20 sure in mammals by blocking norepinephrine release fromperipheral sympathetic nerve terminals that innervate arterial muscle fibers withou~ other major pharmaceu-tical activity.

.: ~

Claims (8)

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

1. A process for preparing trans-4aR-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-1H(and 2H)-pyrazolo[3,4-g]quinoline of formula Ia or Ib:

or a pharmaceutically-acceptable salt thereof, which comprises:
(a) reacting trans-dl-5-n-propyl-4,4a,5,6,-7,8,8a,9-octahydro-1H(and 2H)pyrazolo[3,4-g]quinoline with an excess of an optically active tartaric acid of the formula HOOC-(CHOR2)2-COOH II

wherein R2 is hydrogen or where R3 is C1-C3 alkyl, phenyl, or substituted phenyl;
(b) separating the desired tartaric salt of the trans-stereoisomer, thus formed;
(c) fractionally recrystallizing the tartrate salt mixture to provide the trans-4aR tartrate salt;
(d) reacting an aqueous solution of the tartrate salt with excess base; and then (e) isolating the trans-4aR-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-1H(and 2H)pyrazolo[3,4-g]-quinoline free base thus formed; and (f) optionally salifying the free base so obtained so as to obtain a pharmaceutically-acceptable salt thereof.

2. Trans-4aR-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-1H(and 2H)-pyrazolo[3,4-g]quinoline of formula Ia or Ib or a pharmaceutically-acceptable salt thereof, whenever prepared by the process of claim 1.

3. The process of claim 1 wherein the hydrochloride salt is formed.

4. Trans-4aR-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-1H(and 2H)-pyrazolo[3,4-g]quinoline, hydro-chloride, whenever prepared by the process of claim 3.

5. The process of claim 1 wherein the optically active tartaric acid of formula II is one where R2 is hydrogen, or R3 is methyl, phenyl or p-tolyl.

6. The process of claim 1 or 3 wherein the optically active tartaric acid of formula II is D-(-)-S-tartaric acid.

7. Trans-4aR-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-1H(and 2H)-pyrazolo[3,4-g]quinoline of formula Ia or iB;

Ia Ib or a pharmaceutical-acceptable salt thereof.

8. Trans-4aR-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-1H(and 2H)-pyrazolo[3,4-g]quinoline hydrochloride.
9. A pharmaceutical composition comprising, as the active ingredient, an amount of the compound defined in claim 7 effective for providing hypotensive properties to said composition, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutical acceptable carrier therefor.
10. A pharmaceutical composition according to claim 9 wherein the active ingredient is the compound of

claim 8.