Octahydrothiazolo[4,5-g]quinolines and use as prolactin secretion inhibitors

SUMMARY OF THE INVENTION 
This invention provides 
trans(.+-.)-2-permissibly-substituted-5-alkyl-4,4a,5,6,7,8,8a,9-octahydrot 
hiazolo[4,5-g]quinolines of the structure 
##STR1## 
wherein R is H, methyl, ethyl, allyl or n-propyl, R.sup.1 is H, OH, 
halogen, methyl, NH.sub.2, NHC.sub.1-3 alkyl, N(C.sub.1-3 alkyl).sub.2, 
1-pyrrolidinyl, NHCOC.sub.1-3 alkyl, or NHC.sub.1-2 alkylphenyl, and 
pharmaceutically-acceptable acid addition salts, thereof. 
Also falling within the ambit of this invention are quaternary C.sub.1-3 
alkyl halide salts of compounds according to I above when R.sup.1 is H and 
R has its previous meaning. Such quaternary salts include the methiodide, 
ethiodide, methylchloride, n-propylbromide and the like salts. 
While the compounds represented by I except when R is H, are active drugs; 
i.e., dopamine agonists, several are also useful intermediates; for 
example, compounds in which R.sup.1 is NH.sub.2 can be acylated to yield 
compounds in which R.sup.1 is NHCOC.sub.1-3 alkyl or a compound in which 
R.sup.1 is H can be treated with a C.sub.1-3 alkyl iodide, for example, to 
yield a quaternary salt. Compounds in which R is H are intermediates in 
that they can, in general, be alkylated to yield derivatives in which R is 
methyl, ethyl or n-propyl. 
Compounds, according to I in which R.sup.1 is halogen; i.e., 
trans-(.+-.)-2-bromo-5-C.sub.1-3 straight chain alkyl (or 
allyl)-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinolines, which shows 
D-2 dopamine agonist activity, are also useful intermediates for preparing 
certain of the 2-substituted derivatives described by I. 
As previously stated, compounds according to I are dopamine D-2 agonists, 
manifesting their activities in tests designed to demonstrate utility as 
prolactin secretion inhibitors, in treatment of Parkinson's Disease, in 
treating sexual dysfunction, anxiety or depression or as hypotensive 
agents. 
In the above formula, when R.sup.1 is OH, the compound is the enolic form 
of II 
##STR2## 
named as trans-(.+-.)-5-straight chain C.sub.1-3 alkyl or 
allyl4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinolin2(1H)-one. 
In the above formula, the term "C.sub.1-3 alkyl" includes methyl, ethyl, 
n-propyl and isopropyl while the term "straight-chain C.sub.1-3 alkyl" 
includes only the first three radicals. The term "halogen" means members 
of the 7th main group of the Periodic Table, preferably chlorine and 
bromine. 
Pharmaceutically-acceptable acid addition salts of the compounds of this 
invention include salts derived from non-toxic inorganic acids such as: 
hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, 
hydrobromic acid, hydriodic acid, phosphorous acid and the like, as well 
as salts derived from non-toxic organic acids such as aliphatic mono and 
dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic 
and alkandioic acids, aromatic acids, aliphatic and aromatic sulfonic 
acids, etc. Such pharmaceutically-acceptable salts thus include sulfate, 
pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, 
monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, 
chloride, bromide, iodide, acetate, propionate, caprylate, acrylate, 
formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, 
succinate, suberate, sebacate, fumarate, maleate, mandelate, 
butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, 
methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, 
phthalate, terephthalate, benzenesulfonate, toluenesulfonate, 
chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, 
phenylbutyrate, citrate, lactate, .beta.-hydroxybutyrate, glycollate, 
malate, tartrate, methanesulfonate, propanesulfonate, 
naphthalene-1-sulfonate, naphthalene-2-sulfonate and the like salts. 
Compounds according to I above have two asymmetric carbons (optical 
centers) at 4a and 8a and can thus exist as four stereoisomers occurring 
as two racemic pairs, ordinarily designated as the trans-(.+-.) racemate 
and the cis-(.+-.) racemate. The trans racemate (I) of this invention is 
composed of the trans-(-) stereoisomer (4aR,8aR stereoisomer) represented 
by III below and the trans-(+)(4aS,8aS) stereoisomer represented by IIIa. 
##STR3## 
wherein R and R.sup.1 have their previously assigned meanings. The 
trans-(-)-(4aR,8aR) stereoisomers represented by III wherein R is other 
than H and R.sup.1 is other than halogen are the active dopamine D-2 
agonist component of the racemate (I) and are preferred over the 
trans-(+)-stereoisomers. However, the corresponding 
trans-(+)-stereoisomers (IIIa) have dopamine D-1 agonist activity. 
The trans-(-) enantiomers according to III thus form a second and preferred 
aspect of this invention. Intermediates, such as the 
4aR,8aR-2-bromo-5-C.sub.1-3 straight-chain alkyl (or 
allyl)-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinolines or compounds 
according to III or IIIa in which R is H are also optically active 
compounds falling within the scope of this invention. 
As dopamine D-2 agonists, compounds represented by III above in which R is 
other than H and R' is other than halogen may be employed as drugs either 
as the free base or as a pharmaceutically-acceptable acid addition salt 
thereof. 
A preferred group of drugs according to III are those in which 
(1) R is n-propyl 
(2) R.sup.1 is NH.sub.2 
(3) R.sup.1 is NHCH.sub.3 
(4) R.sup.1 is H 
(5) R.sup.1 is N(CH.sub.3).sub.2 
(6) R.sup.1 is NH--CO--CH.sub.3 
Compounds of this invention include, illustratively, 
Trans-(.+-.)-2-amino-5-ethyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quin 
oline maleate, 
Trans-(.+-.)-2-n-propylamino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo 
[4,5-g]quinoline sulfate, 
Trans-(.+-.)-5-ethyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinoline 
ethiodide, 
Trans-(.+-.)-2-dimethylamino-5-n-propyl-4,4a,5,6,7,8,8a,9,-octahydrothiazol 
o[4,5-g]quinoline dihydrobromide, 
4aR,8aR-2-methylethylamino-5-ethyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5- 
g]quinoline succinate, 
4aR,8aR-2-amino-5-methyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinolin 
e dihydrochloride, 
Trans-(.+-.)-2-phenethylamino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazol 
o[4,5-g]quinoline tartrate, 
4aR,8aR-2-benzylamino-5-ethyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]qui 
noline phosphate, 
4aR,8aR-2-acetylamino-5-methyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo-[4,5-g]q 
uinoline terephthalate, 
trans-(.+-.)-2-propionylamino-5-ethyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4 
,5-g]quinoline dinitrobenzoate, 
Trans-(.+-.)-2-chloro-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g] 
quinoline methanesulfonate (mesylate), 
Trans-(.+-.)-2-bromo-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]q 
uinoline p-toluene sulfonate (p-tosylate) and the like. 
Compounds represented by Formula III, as dopamine (D-2) agonists, are 
substantially devoid of other agonist or antagonist (blocking) activities. 
As D-2 dopamine agonists, the compounds are useful in treating Parkinson's 
Syndrome, in treating sexual dysfunction, as anti-depressants or as 
anti-anxiety agents, in lowering blood pressure in hypertensive mammals 
and in inhibiting prolactin secretion. Thus, other embodiments of this 
invention include the treatment, by the racemates (I) or the trans-(-) 
enantiomers, of hypertension, of depression, of anxiety, of Parkinson's 
disease and of disease states characterized by an excess of prolactin 
secretion such as galactorrhea and inappropriate lactation. 
A still further embodiment of this invention is the provision of 
pharmaceutical formulations for administering drugs according to I or III 
in the treatment methods outlined above. 
The 4aS,8aS enantiomers--formula IIIa--have, as previously stated, D-1 
dopamine agonist activity. However, this activity is manifested at higher 
dosage levels than those necessary to achieve D-2 dopamine agonist 
activity by the enantiomers of formula III. Thus, the trans-(.+-.) 
racemates represented by I can be used as D-2 agonists without substantial 
D-1 activity. The racemates are also useful as a source of the individual 
enantiomers. 
Racemic compounds of this invention when, in Formula I, R.sup.1 is 
NH.sub.2, NH(C.sub.1-3 alkyl), N(C.sub.1-3 alkyl).sub.2, or NH(C.sub.1-2 
phenyl), are readily synthesized according to the following reaction 
scheme: 
##STR4## 
wherein R has its previous meaning, R.sup.3 is NH.sub.2, NH(C.sub.1-3 
alkyl), NH(C.sub.1-2 alkylphenyl) or N(C.sub.1-3 alkyl).sub.2 and the 
4a,8a ring fusion is trans. Formula IV above represents an isothiourea 
tautomeric with the corresponding thiourea; i.e., if R.sup.3 is NH.sub.2, 
the compound becomes 
##STR5## 
The other starting material (V) is prepared by brominating an N-C.sub.1-3 
straight-chain alkyl-6-oxodecahydroquinoline. These latter compounds can 
be prepared by the method of Schaus, Ser. No. 384,817, filed June 2, 1982, 
whereby a 6-alkoxyquinoline of formula VI 
##STR6## 
wherein alk is lower alkyl, is quaternized with a C.sub.1-3 straight-chain 
alkyl halide (R.sup.4 X) and the quaternized salt hydrogenated to yield an 
N-C.sub.1-3 straight-chain alkyl-6-alkoxy-1,2,3,4-tetrahydroquinoline of 
formula VII 
##STR7## 
wherein R.sup.4 is C.sub.1-3 straight-chain alkyl. The particular 
C.sub.1-3 alkyl group (R.sup.4) remains intact through the next two 
reduction steps: a Birch reduction followed by a sodium cyanoborohydride 
(or borohydride) reduction to yield, ultimately, an octahydroquinoline of 
the formula VIII 
##STR8## 
wherein R.sup.4 is C.sub.1-3 straight-chain alkyl, alk has its previous 
meaning, and the ring junction hydrogens are trans. 
This enol ether, upon treatment with acid, yields the N-substituted 
decahydroquinoline-6-one (IX) 
##STR9## 
in which the 4a,8a ring junction is transfused and the N-substituent 
(R.sup.4) is C.sub.1-3 straight-chain alkyl. 
Bromination of IX at C-7 using, for example, hydrogen bromide and bromine 
in glacial acetic acid and UV light, yields V, one starting material of 
Synthetic Route I. 
An alternate preparation of the trans-(.+-.)-1-C.sub.1-3 straight-chain 
alkyl-6-oxodecahydroquinoline (IX) is disclosed in U.S. Pat. No. 4,198,415 
Cols. 4-5 (where it is compound number VII in the Reaction Scheme). 
An additional procedure for preparing IX has been developed by Weigel 
following the procedure of Evans et al. J.A.C.S., 7593 (1970). Here the 
ring closure reaction yields a 1-C.sub.1-3 straight-chain 
alkyl-6-oxo-1,2,3,4,5,6,7,8-octahydroquinoline. Reduction of the 4a,8a 
double bond with NaBH.sub.4 at a temperature above 25.degree. C. yields a 
trans-(.+-.)-1-C.sub.1-3 straight chain alkyl-6-hydroxydecahydroquinoline, 
which type of compound can be oxidized to the corresponding 6-oxo 
derivative by standard procedures. Alternatively, the ketone group of the 
6-oxo-octahydroquinoline can be protected, as by ketal formation, and the 
NaBH.sub.4 reduction to yield the trans-(.+-.) derivative carried out on 
the ketal. Acid treatment of the reduced ketal yields the desired 6-oxo 
derivative (IX). 
The optically-active octahydrothiazolo[4,5g]quinoline of formulas III and 
IIIa can be prepared by resolution of the trans-(.+-.) racemates 
represented by I above. A preferred procedure, however, is to resolve the 
trans-(.+-.) ketone (IX) using the procedure of Schaus and Booher, Ser. 
No. 439,107 filed Nov. 1, 1982. The 4aR,8aR enantiomer thus prepared, IXa, 
##STR10## 
wherein R.sup.4 has its previous meaning can then be substituted for the 
racemic ketone IX in Synthetic Route I; i.e., bromination of IXa yields a 
4aR,8aR-1-C.sub.1-3 straight-chain alkyl-6-oxo-7-bromodecahydroquinoline 
(Va--V in which the bridgehead hydrogens are 4aR,8aR) which derivative 
then reacts with an isothiourea (IV) to yield compounds according to III 
in which R.sup.1 is R.sup.4, and R is C.sub.1 -C.sub.3 straight-chain 
alkyl. 
The D-1 agonists of this invention (IIIa) are prepared in analogous fashion 
from 4aS,8aS-1-C.sub.1-3 straight-chain alkyl-6-oxodecahydroquinoline, 
which is in turn obtained by resolution of the trans-(.+-.)racemate. 
Those drugs of this invention in which R.sup.1 is NH(C.sub.1-3 alkyl-CO) in 
I, III or IIIa are prepared by acylating the corresponding compound in 
which R.sup.1 is NH.sub.2. Compounds according to I, III, or IIIa in which 
R.sup.1 is H are prepared by diazotizing the primary amine group at C-2 
(I, III or IIIa where R.sup.1 is NH.sub.2) and treating the diazonium salt 
with hypophosphorous acid. Alternatively, a 
1-substituted-6-oxo-7-bromodecahydroquinoline (V or an enantiomer thereof) 
can be reacted with a thioamide of the formula (R.sup.6 ---CS--NH.sub.2 
where R.sup.6 is H or CH.sub.3) in acetonitrile or other suitable 
non-reacting mutual solvent, to yield those compounds according to I, III 
or IIIa in which R.sup.1 =H or methyl. The thioamide can be prepared in 
situ from P.sub.2 S.sub.5 and formamide or acetamide, or the thioamides 
can be obtained commercially in the case of thioacetamide. 
The quaternary salts of this invention are prepared by quaternizing those 
compounds wherein R.sup.1 is H (in I, III or IIIa) with a C.sub.1-3 alkyl 
halide or the like. 
Treatment of the above diazonium salt (I, III or IIIa wherein R.sup.1 would 
be N.sub.2.sup.+ X.sup.- where X is a suitable anion--phosphate, sulfate 
or the like) with HBr or HCl produces those compounds of this invention 
(I, III or IIIa) wherein R.sup.1 is Cl or Br. 
Those compounds according to I, III or IIIa wherein R.sup.1 is 
OH--tautomeric with the 2-oxo derivatives II--or the corresponding 4aR,8aR 
or 4aS,8aS derivatives are prepared by hydrolysing a 2-bromo or 2-chloro 
compound. 
Those compounds according to I, III or IIIa in which R.sup.1 is 
1-pyrrolidinyl are prepared by reacting the corresponding 2-bromo or 
2-chloro compound with pyrrolidine. 
Finally, compounds according to I, III or IIIa in which R is allyl are 
prepared by starting with a 6-oxodecahydroquinoline (X) according to 
Synthetic Route II below. 
##STR11## 
where R.sup.5 is lower alkyl or benzyl. The N-allyl product XIII can be 
brominated to yield V in which R is allyl in Synthetic Route I, being 
careful not to brominate the N-allyl group in producing this compound. 
Alternatively, a compound according to X wherein R.sup.5 is benzyl and the 
6-oxo group is protected by ketal formation can be hydrogenated so as to 
hydrogenolyze the benzyl group to form a secondary amine. Removal of the 
ketal protecting group with acid yields XIII. The above procedures are 
outlined in the copending application of Titus and Bach, Ser. No. 535,522 
filed 9-26-83. 
This invention is further illustrated by the following specific examples.

EXAMPLE 1 
Preparation of 
Trans-(.+-.)-2-amino-5-n-propyl-4,4a,5,6,7,8,8a-9-octahydrothiazolo[4,5-g] 
quinoline 
Five grams of trans-(.+-.)-1-n-propyl-6-oxodecahydroquinoline were 
dissolved in 30 ml. of glacial acetic acid. Five and eight tenths 
milliliters of 37% by weight hydrogen bromide in glacial acetic acid were 
added followed by the dropwise additions of 1.5 ml. of bromine dissolved 
in glacial acetic acid. The reaction mixture was illuminated with 
ultraviolet radiation using a commercially available sunlamp. The 
illuminated reaction mixture was stirred for one-half hour after all the 
reactants had been added. Volatile constituents were removed from the 
reaction mixture in vacuo yielding, as a residue, 
trans-(.+-.)-1-n-propyl-6-oxo-7-bromodecahydroquinoline hydrobromide. One 
hundredth mole of this salt was dissolved in 50 ml. of ethanol. 
Eighty-four hundredths grams of thiourea were added thereto. The resulting 
mixture was refluxed for about 18 hours under a nitrogen blanket. A 
colorless solid began to form after about 20 minutes. The reaction mixture 
was cooled to about 0.degree. C. and the solid, which had continued to 
form, was separated by filtration. The filter cake was dried in vacuo. One 
and fifteen hundredths grams of 
trans-(.+-.)-2-amino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g] 
quinoline dihydrobromide salt were obtained. The salt melted above 
255.degree. C., tlc (9:1 chloroform:methanol plus a trace of ammonium 
hydroxide) R.sub.f =0.13. 
Analysis Calculated: C, 38.02; H, 5.33; N, 10.30; S, 7.78. Found: C, 37.79; 
H, 5.61; N, 10.17; S, 7.76. 
The dihydrobromide salt prepared as above was converted to the free base by 
standard procedures using aqueous ammonium hydroxide. The free base thus 
obtained crystallized; m.p.=184.degree.-185.degree. C. with decomposition. 
One hundred fifty milligrams of the free base were dissolved in methanol. 
Two and ninety-eight hundredths milliliters of 0.2M aqueous hydrochloric 
acid (one equivalent) were added and the resulting mixture warmed on the 
steam bath. The volatile constituents were removed in vacuo and the 
residue, the hydrochloride salt of 
trans-(.+-.)-2-amino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g] 
quinoline, melted above 240.degree. C. after recrystallization from 
anhydrous ethanol. 
Analysis Calculated: C, 54.24; H, 7.70; N, 14.60; Cl, 12.32. Found: C, 
54.52; H, 7.91; N, 14.43; Cl, 12.56. 
The dihydrochloride salt of 
trans-(.+-.)-2-amino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g] 
quinoline was prepared by dissolving 1 g. of the free base in methanol, 
saturating the solution with gaseous hydrogen chloride and adding ether to 
the solution to the point of incipient precipitation. Cooling the 
crystallization mixture produced crystals which were separated by 
filtration. The filter cake was recrystallized first from an ether/ethanol 
solvent mixture and then from ethanol alone. Sixty-five hundredths grams 
of the dihydrochloride salt were recovered melting at 274.degree. C. with 
decomposition. 
Analysis Calculated: C, 48.14; H, 7.15; N, 12.96. Found: C, 48.29; H, 7.04; 
N, 12.85. 
The above series of reactions was repeated using 
4,aR,8aR-1-n-propyl-6-oxodecahydroquinoline as the starting material. The 
ketone was alpha brominated by the above procedure to yield 
4aR,8aR-1-n-propyl-6-oxo-7-bromodecahydroquinoline hydrobromide which was 
in turn reacted with thiourea in anhydrous ethanol. Two and four tenths 
grams of a colorless solid dihydrobromide were obtained from 1.01 g. of 
thiourea. The dihydrobromide salt was dissolved in water and the free base 
isolated by treatment with aqueous ammonia; yield=1.5 g. The free base was 
transformed to the hydrochloride salt by the above procedures. One and 
eight hundredths grams of 
4aR,8aR-2-amino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quino 
line hydrochloride were obtained having the following physical 
characteristics. 
tlc (9:1 CHCl.sub.3 /MeOH+tr. NH.sub.4 OH) R.sub.f =0.58. 
Mass spectrum:molecular ion at 251. 
Melting point above 225.degree. C. after recrystallization from ethanol. 
[.alpha.].sub.D.sup.20 (water)=-140.4.degree.; [.alpha.].sub.365.sup.20 
=-497.8.degree.. 
Analysis Calculated: C, 54.24; H, 7.70; N, 14.60. Found: C, 54.01; H, 7.86; 
N, 14.86. 
EXAMPLE 2 
Preparation of 
Trans-(.+-.)-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinolin 
e 
A solution of 0.24 g. of 
trans-(.+-.)-2-amino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g] 
quinoline in 10 ml. of 85% phosphoric acid was cooled to about -8.degree. 
C. A saturated solution of 1.17 g. of sodium nitrite in water was added 
below the surface of the phosphoric acid solution at such a rate as to 
keep the reaction temperature from going above about -4.degree. C. The 
reaction mixture was then added in dropwise fashion to 10 ml. of 50% 
aqueous hypophosphorus acid kept at a temperature of about 0.degree. C. 
This new reaction mixture was stirred until gas evolution had ceased, at 
which time it was poured over ice. The aqueous mixture was made strongly 
basic with aqueous ammonium hydroxide. The aqueous layer was extracted 
several times with chloroform. The chloroform extracts were combined, and 
the combined extracts washed, first with water and then with saturated 
aqueous sodium chloride, and then dried. Removal of the chloroform in 
vacuo yielded 
trans-(.+-.)-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinolin 
e free base having the following physical characteristics: tlc (9:1 
CHCl.sub.3 /MeOH+Tr.NH.sub.4 OH)R.sub.f =0.70. 
The free base was chromatographed over florisil using chloroform containing 
increasing amounts (0-3%) of methanol as the eluant. Fractions shown by 
tlc to contain the free base were combined and the solvents evaporated 
therefrom to yield a residue which was dissolved in ethanol. The ethanol 
solution was saturated with gaseous hydrogen chloride to yield 
trans-(.+-.)-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinolin 
e dihydrochloride; yield=0.1 g.; m.p.=above 240.degree. C. 
Analysis Calculated: C, 50.48; H, 7.17; N, 9.09. Found: C, 50.69; H, 6.87; 
N, 9.18. 
Alternatively, the above compound can be prepared by the following 
procedure: 
One and seven tenths grams of phosphorus pentasulfide were slurried in 5 
ml. of p-dioxane. One and five tenths milliters of formamide were added 
and, when the reaction mixture began to exotherm, it was cooled in an 
ice/water bath. Next, 2.54 millimoles of 
trans-(.+-.)-1-n-propyl-6-oxo-7-bromodecahydroquinoline hydrobromide in 10 
ml. of acetonitrile were added in dropwise fashion and the resulting 
mixture heated to refluxing temperature for about one hour. Five 
milliliters of water plus 1 ml. of 12N aqueous hydrochloric acid were 
added and the reaction mixture heated for an additional hour, after which 
time it was cooled and the cooled reaction mixture diluted with water. The 
acidic reaction mixture was extracted with ether and the ether extract 
discarded. The acidic aqueous layer was then made basic with 10% aqueous 
sodium hydroxide and the basic layer extracted several times with equal 
volumes of chloroform. The chloroform extracts were combined and the 
chloroform removed by evaporation in vacuo. The residue, containing 
trans-(.+-.)-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinolin 
e formed in the above reaction, was chromatographed over florisil using 
chloroform containing increasing amounts (0-2%) of methanol as the eluant. 
Fractions shown to contain the desired product were combined, and the 
combined fractions rechromatographed to yield about 1.2 g. of a dark 
orange-red transparent oil. NMR indicated that the oil contained about 53% 
of the desired product. This oil was then rechromatographed over basic 
alumina using chloroform containing 2% methanol as the eluant. Fractions 
containing 
trans-(.+-.)-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinolin 
e were combined, and the solvent evaporated therefrom. The product thus 
obtained had identical properties with that previously found, including 
mass spectrum, M+=236. 
The methiodide salt of 
trans-(.+-.)-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinolin 
e was prepared from 0.22 g. of the free base in acetonitrile to which was 
added 15 ml. of methyliodide. The reaction mixture was refluxed overnight 
and then cooled to room temperature. The solid which had formed, 
comprising trans-(.+-.)-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5 
-g]quinolinium methiodide hydroiodide formed in the above reaction, was 
separated by filtration and the filter cake dried; yield=0.2 g.; melting 
point=above 225.degree. C.; mass spectrum, M+=251. 
Analysis Calculated: C, 33.22; H, 4.78; N, 5.53 Found: C, 33.42; H, 4.57; 
N, 5.50 
EXAMPLE 3 
Preparation of 
Trans-(.+-.)-2-bromo-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g] 
quinoline 
Four and thirteen hundredths grams of 
trans-(.+-.)-2-amino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g] 
quinoline dihydrobromide were dissolved in 30 ml. of 85% phosphoric acid 
and the solution cooled to about -10.degree. C. Nine milliliters of nitric 
acid were added followed by 1.72 g of sodium nitrite in water added in 
dropwise fashion via a syringe placed below the surface of the solution. 
The nitrite solution was added at such a rate as to keep the temperature 
below about -5.degree. C. After the addition had been completed, the 
reaction mixture was stirred for an additional half hour in the range 
-5.degree.-0.degree. C. This solution was added with vigorous stirring to 
a mixture of 3 g. of copper powder in 50 ml. of 48% aqueous hydrobromic 
acid cooled to -5.degree. C. The reaction mixture was stirred for about 15 
minutes at -5.degree. C. during which time a vigorous evolution of gas 
ensued. The reaction mixture was next slurried with ice, and the resulting 
mixture made basic with concentrated aqueous ammonium hydroxide. The 
aqueous alkaline layer was extracted several times with equal volumes of 
chloroform. The chloroform extracts were combined and the combined 
extracts washed successively with water and with saturated aqueous sodium 
chloride. The combined extracts were then dried, and the solvent removed 
therefrom in vacuo. TLC using the system of Example 1 gave two major spots 
(R.sub.f =0.72 and 0.57). The residues obtained above were therefore 
chromatographed over florisil using chloroform as the eluant. Compounds 
corresponding to the two spots appearing on TLC were separated by this 
chromatographic procedure. Fractions containing the faster moving compound 
were combined, and the solvent removed therefrom in vacuo. The resulting 
residue was dissolved in methanol, and the monohydrochloride salt prepared 
by the procedure of Example 1. Five tenths grams of 
trans-(.+-.)-2-bromo-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g] 
quinoline hydrochloride melting above 235.degree. C. were obtained. 
Analysis Calculated: C, 44.39; H, 5.73; N, 7.96; Br, 22.72; Cl, 10.08. 
Found: C, 44.40; H, 5.69; N, 7.84; Br, 22.50; Cl, 9.98. 
The second product obtained in similar fashion--weight=0.70 g.--was shown 
to be 
trans-(.+-.)-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinolin 
e hydrochloride (no substituent at C-2), a compound which had been 
previously prepared. 
The above procedure was repeated with 2.5 g. of starting material, except 
that the diazotization mixture was added to 2 g. of cupric sulfate 
pentahydrate and 5.5 g. of sodium bromide in 10 ml. of water. The product 
obtained after purification showed essentially one spot on TLC. Total 
yield=1.7 g. of 
trans-(.+-.)-2-bromo-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g] 
quinoline free base. 
EXAMPLE 4 
Preparation of 
Trans-(.+-.)-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinolin 
-2(1H)-one 
About 1.9 millimoles of 
trans-(.+-.)-2-bromo-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g] 
quinoline were dissolved in 10 ml. of 20% aqueous sulfuric acid. The 
solution was heated at about 100.degree. C. for about five hours and then 
was cooled. The cooled solution was allowed to remain at ambient 
temperature for an additional 48 hours. The reaction mixture was then made 
basic with concentrated aqueous ammonium hydroxide. The aqueous mixture 
was extracted several times with equal volumes of chloroform. The 
chloroform extracts were combined, and the combined extracts washed with 
saturated aqueous sodium chloride and then dried. Evaporation of the 
chloroform in vacuo yielded 
trans-(.+-.)-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinolin 
-2(1H)-one which was one spot material by TLC (9:1 CHCl.sub.3 /MeOH+trace 
NH.sub.4 OH); R.sub.f =0.37. The compound showed a strong band at 1650 
cm.sup.-1 in the infrared indicating a carbonyl. 
The residue was dissolved in methanol and the methanolic solution saturated 
with gaseous hydrogen chloride. The solvent was removed in vacuo and the 
residue crystallized from ethanol. 
Trans-(.+-.)-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinolin 
-2(1H)-one hydrochloride thus prepared melted at about 250.degree. C. after 
recrystallization from a methanol/ether solvent mixture; yield=0.18 g. 
Analysis Calculated: C, 54.06; H, 7.33; N, 9.70. Found: C, 54.29; H, 7.25; 
N, 9.63. 
EXAMPLE 5 
Preparation of 
Trans-(.+-.)-2-(1-pyrrolidinyl)-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothia 
zolo[4,5-g]quinoline 
A reaction mixture, prepared from 6.6 g. of 
trans-(.+-.)-2-bromo-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g] 
quinoline and 20 ml. of pyrrolidine, was heated to reflux temperature for 
about 18 hours and was then cooled. The volatile constituents were removed 
in vacuo and the resulting residue diluted with water. The aqueous mixture 
was made strongly basic with concentrated aqueous ammonium hydroxide. The 
alkaline layer was extracted several times with equal volumes of 
chloroform. The chloroform extracts were combined, and the combined 
extracts washed with water and with saturated aqueous sodium chloride and 
were then dried. The solvent was evaporated therefrom in vacuo. TLC (9:1 
CHCl.sub.3 /MeOH+a trace of aqueous ammonium hydroxide) showed one spot, 
more polar than starting material. The residue was therefore dissolved in 
chloroform and the chloroform solution chromatographed over a florisil 
column using chloroform as the eluant. Seventeen hundredths grams of a 
light yellow glass were obtained by this procedure. The glass was 
dissolved in ether and 0.06 g. of maleic acid in ethereal solution added 
thereto. A solid maleate salt precipitated. The ether was removed by 
decantation and the solid salt recrystallized from a mixture of ethanol 
and ether. Five hundredths grams of 
trans-(.+-.)-2-(1-pyrrolidinyl)-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothia 
zolo[4,5-g]quinoline maleate were obtained melting with decomposition at 
184.degree. C. 
Mass spectrum: 305 (M.sup.+). 
EXAMPLE 6 
Preparation of 
Trans-(.+-.)-2-acetylamino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[ 
4,5-g]quinoline 
A solution was prepared from 0.15 g. of 
trans-(.+-.)-2-amino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g] 
quinoline (from Example 1) in 3 ml. of tetrahydrofuran (THF) to which has 
been added two drops of dimethylformamide (DMF). Five hundredths 
milliliters of acetyl chloride were added and the solution stirred at room 
temperature for 15 minutes. In time, the reaction mixture became a solid 
colorless mass. The solid was suspended in ether and the ethereal 
suspension filtered. The solid was then recrystallized from a 
methanol/ether solvent mixture to give purified 
trans-(.+-.)-2-acetylamino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[ 
4,5-g]quinoline hydrochloride; yield=30.3%; melting point above 200.degree. 
C. 
Analysis Calculated: C, 54.61; H, 7.33; N, 12.74. Found: C, 54.39; H, 7.08; 
N, 12.74. 
EXAMPLE 7 
Preparation of 
Trans-(.+-.)-2-methylamino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[ 
4,5-g]quinoline 
Following the procedure of Example 1, 
trans-(.+-.)-1-n-propyl-6-oxo-7-bromodecahydroquinoline was reacted with 
N-methylthiourea in ethanol. The reaction mixture was heated to reflux 
temperature. A solid began to appear after about five hours of refluxing. 
Heating of the reaction mixture to reflux was continued for about 18 
hours. The reaction mixture was then cooled to ambient temperature. The 
colorless solid which precipitated was separated by filtration and the 
filter cake was dried. The filter cake was dissolved in water and excess 
aqueous ammonium hydroxide was added to the solution. The alkaline 
solution was extracted with chloroform. The chloroform extract was 
separated, and the chloroform removed in vacuo to yield 1.14 g. (from 0.01 
mole of starting material) of 
trans-(.+-.)-2-methylamino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[ 
4,5-quinoline. The compound chromatographed over florisil using chloroform 
containing increasing amounts (0-5%) of methanol as the eluant. Fractions 
containing the more rapidly moving material were collected to yield 0.7 g. 
of a colorless solid. The solid was dissolved in methanol, and the 
methanol solution saturated with gaseous hydrogen chloride. Ether was 
added to the solution to the point of incipient precipitation, and the 
mixture was chilled. Thirty-four hundredths grams of crystalline 
trans-(.+-.)-2-methylamino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[ 
4,5-g]-quinoline dihydrochloride were thus obtained melting above 
220.degree. C. 
Analysis Calculated: C, 49.85; H, 7.17; N, 12.46; Cl, 21.02. Found: C, 
49.71; H, 7.22; N, 12.31; Cl, 20.87. 
Following the procedure of Example 1 but substituting N-benzylthiourea for 
thiourea, there was prepared 
trans-(.+-.)-2-benzylamino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothioazolo 
[4,5-g]quinoline. The compound was purified by chromatography over florisil 
using chloroform as the eluant. The dihydrochloride salt was prepared by 
the above procedure. This salt was collected, dissolved in water and 
excess alkali added. The free base was extracted into chloroform and the 
chloroform removed by evaporation in vacuo to leave the free base as a 
residue. The maleate salt of the base was then prepared in ethanol 
solution, and was recrystallized from an ethanol/ether solvent mixture to 
yield 
trans-(.+-.)-2-benzylamino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[ 
4,5-g]quinoline maleate; yield=0.17 g. (from about 10.2 millimoles of 
trans-(.+-.)-1-n-propyl-6-oxo-7-bromodecahydroquinoline). The maleate 
melted above 210.degree. C. and gave a single spot on TLC using the 
solvent system from Example 1. 
Analysis Calculated: C, 63.00; H, 6.83; N, 9.18. Found: C, 63.22; H, 6.99; 
N, 8.95. 
Other compounds according to I, III or IIIa in which R.sup.2 is C.sub.1-2 
alkylphenyl are prepared in similar fashion. 
Following the procedure of Example 1, 25.6 millimoles of 
trans-(.+-.)-1-n-propyl-6-oxo-7-bromodecahydroquinoline were reacted with 
N,N-dimethylthiourea in ethanol solution. The free base of 
trans-(.+-.)-2-dimethylamino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazol 
o[4,5-g]quinoline was obtained as a yellow viscous oil. The oil was 
dissolved in methanol and the methanolic solution saturated with gaseous 
hydrogen chloride. Ether was added to the solution to the point of 
incipient precipitation, and the mixture was chilled. One and twenty-five 
hundredths grams of a colorless solid comprising the dihydrochloride salt 
of 
trans-(.+-.)-2-dimethylamino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazol 
o[4,5-g]quinoline were obtained; melting point=above 230.degree. C. 
Analysis Calculated: C, 51.13; H, 7.72; N, 11.93; Cl, 20.12. Found: C, 
51.03; H, 7.46; N, 11.78; Cl, 19.83. 
EXAMPLE 8 
Preparation of 
Trans-(.+-.)-2-methyl-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g 
]quinoline 
A solution was prepared from 0.01 mole of 
trans-(.+-.)-1-n-propyl-6-oxo-7-bromodecahydroquinoline hydrobromide and 
35 ml. of anhydrous ethanol. Eighty-three hundredths grams of 
thioacetamide were added thereto and the mixture heated to reflux 
temperature for about 18 hours. The reaction mixture was then cooled and 
the cooled mixture poured into water. The aqueous mixture was made basic 
with concentrated aqueous ammonium hydroxide. Alkali-insoluble materials 
were extracted several times with chloroform. The chloroform extracts were 
combined and the combined extracts washed successively with water and with 
saturated aqueous sodium chloride and were then dried. Evaporation of the 
solvent in vacuo yielded in residue which was dissolved in chloroform, and 
the chloroform solution chromatographed over florisil using chloroform as 
the eluant. Fractions shown by TLC to contain 
trans-(.+-.)-2-methyl-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g 
]quinoline formed in the above reaction were combined and the solvent 
evaporated therefrom in vacuo. The resulting residue was dissolved in 
methanol, and the methanolic solution saturated with gaseous hydrogen 
chloride. The methanol solution was decolorized with activated charcoal 
and filtered. Ether was added to the filtrate to the point of incipient 
precipitation. 
Trans-(.+-.)-2-methyl-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g 
]quinoline dihydrochloride thus prepared was recrystallized from anhydrous 
ethanol to yield 0.11 g. of a colorless solid salt melting above 
225.degree. C.; R.sub.f (9:1 CHCl.sub.3 /MeOH+a trace of aqueous ammonium 
hydroxide)=0.9. 
Analysis Calculated: C, 52.01; H, 7.48; N, 8.66. Found: C, 51.98; H, 7.28; 
N, 8.77. 
EXAMPLE 9 
Preparation of 
Trans-(.+-.)-2-amino-4,4a,5,6,7,8,8a9-octahydrothiazolo[4,5-g]quinoline 
Four grams of trans-(.+-.)-1-cyano-6-oxodecahydroquinoline prepared 
according to the procedure of Example 1, U.S. Pat. No. 4,198,395, were 
dissolved in 20 ml. of chloroform to which was added, in dropwise fashion, 
a solution of 1.44 ml. of bromine in chloroform. The reaction mixture was 
illuminated with a sunlamp as in Example 1. A colorless solid formed as 
the reaction progressed. After all the bromine had been added and the 
bromine color discharged, the solvent was removed in vacuo. The residue, 
comprising trans-(.+-.)-1-cyano-6-oxo-7-bromodecahydroquinoline, showed a 
molecular ion at 256 by mass spectrum. The material was used without 
further purification. 
Following the procedure of Example 1, 22.5 millimole of 
trans-(.+-.)-1-cyano-6-oxo-7-bromodecahydroquinoline were dissolved in 50 
ml. of ethanol to which was added 28.1 millimoles of thiourea. The 
reaction was carried out and the product isolated by the procedure of 
Example 1. The production of an equivalent of H.sub.2 O and an equivalent 
of HBr during the formation of the thiazole ring provided sufficiently 
acidic conditions to hydrolyze the N-cyano growth. 
Trans-(.+-.)-2-amino-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-]quinoline 
thus prepared had a molecular ion at 209 by mass spectrum; yield=0.6 g. 
The free base was triturated with acetone to yield 0.15 g. of a solid 
which melted above 215.degree. C. 
Analysis Calculated: C, 57.38; H, 7.22; N, 20.08. Found: C, 57.61; H, 7.46; 
N, 19.80. 
EXAMPLE 10 
Preparation of 
Trans-(.+-.)-2-amino-5-methyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]qu 
inoline 
Two grams of trans-(.+-.)-6-oxodecahydroquinoline furnished by the 
procedure of Titus and Bach, in their copending application Ser. No. 
535,522, filed Sept. 26, 1983, were dissolved in 75 ml. of acetone to 
which was added 2.71 g. of potassium carbonate and 0.9 ml. of methyl 
iodide. The reaction mixture was stirred at reflux temperature over the 
week end, and was then cooled to room temperature and diluted with water. 
The aqueous mixture was extracted with a 3:1 chloroform/isopropanol 
solvent mixture. The extracts were combined, and the combined extracts 
washed with saturated aqueous sodium chloride and then dried. The solvent 
was removed in vacuo to yield 1.8 g. of a yellow oil comprising 
trans-(.+-.)-1-methyl-6-oxodecahydroquinoline formed in the above 
reaction. The oil was dissolved in chloroform and the chloroform solution 
chromatographed over florisil using chloroform containing increasing 
amounts (0-4%) methanol as the eluant. Fractions shown by TLC to contain 
the N-methyl derivative were combined to yield 1.6 g. (73.1% yield) of a 
colorless viscous oil comprising 
trans-(.+-.)-1-methyl-6-oxodecahydroquinoline; mass spectrum=167 (M+); 
single spot by TLC. 
The above material (1.6 g.) was dissolved in 20 ml. of glacial acetic acid. 
2.3 ml. of a 31% hydrogen bromide solution in glacial acetic acid was 
added followed by the dropwise addition of 0.8 ml. of bromine in 5 ml. of 
acetic acid. The reaction mixture was stirred at ambient temperature under 
ultra-violet illumination for one-half hour after which time the solvent 
was removed in vacuo, leaving as a residue 
trans-(.+-.)-1-methyl-6-oxo-7-bromodecahydroquinoline hydrobromide. 
About 10.8 millimole of the above hydrobromide salt were dissolved in 30 
ml. of anhydrous ethanol to which had been added 1.03 g. of thiourea. The 
reaction was carried out and the product isolated according to the 
procedure of Example 1. 
Trans-(.+-.)-2-amino-5-methyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]qu 
inoline, dihydrobromide salt thus prepared was twice crystallized from 
methanol to yield 0.61 g. of a colorless crystalline solid melting above 
235.degree. C. TLC using 4:1 chloroform-methanol with a trace of aqueous 
ammonium hydroxide as the solvent system gave a single spot; R.sub.f 
=0.30. 
Analysis Calculated: C, 34.30; H, 4.97; N, 10.91; Br, 41.49. Found: C, 
34.58; H, 5.21; N, 10.67; Br, 41.30. 
EXAMPLE 11 
Preparation of 
4aS,8aS-2-Amino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[3,4-g]quino 
line 
A solution was prepared from 1.95 g. of 
4aS,8aS-1-n-propyl-6-oxodecahydroquinoline in 25 ml. of glacial acetic 
acid. Two and three tenths milliliters of 31% hydrogen bromide in glacial 
acetic acid followed by 0.6 ml. of bromine in 5 ml. of glacial acetic acid 
were added in dropwise fashion under illumination. The bromine color was 
discharged immediately. After the addition had been completed, the 
reaction mixture was stirred for one-half hour at ambient temperature at 
which time the solvent was removed in vacuo. The viscous orange residue 
comprising 4aS,8aS-1-n-propyl-6-oxo-7-bromodecahydroquinoline 
dihydrobromide, formed in the above reaction, was used as such without 
further purification. 
The orange residue was dissolved in 30 ml. of anhydrous ethanol to which 
solution was added 0.84 g. of thiourea. The reaction mixture was heated to 
refluxing temperature for about 20 hours after which time it was cooled, 
and the solid which had formed separated by filtration. The filter cake 
was washed with ethanol and ether and was then dried. Recrystallization of 
the filter cake from a methanol/ether solvent mixture yielded 1.17 g. of 
colorless crystalline 
4aS,8aS-2-amino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[3,4-g]quino 
line dihydrobromide melting above 200.degree. C.; molecular ion by mass 
spectrum=251; [.alpha.].sub.D.sup.25 (water)=+88.4.degree., 
[.alpha.].sub.365.sup.25 (water)=+312.8.degree.; ultraviolet spectrum 
(ethanol), maxima at 262 nm (.epsilon.=5725.9), 326 nm (.epsilon.=58.8). 
Analysis Calculated: C, 37.79; H, 5.61; N, 10.17. Found: C, 37.70; H, 5.81; 
N, 10.13. 
The 4aR,8aR-1-substituted-6-oxodecahydroquinoline used to prepare the 
7-bromo starting material of Example 1 is itself prepared as follows. (The 
preparation of the 1-n-propyl derivative is described for purposes of 
exemplification only. Other 1-alkyl derivatives can be resolved in similar 
fashion). 
Preparation 1 
Ten g. of (-)-di-p-toluoyltartaric acid were dissolved in 75 ml. of warm 
methanol. The solution was added to a solution of 5.05 g. of 
trans-dl-1-n-propyl-6-oxodecahydroquinoline in 15 ml. of methanol. The 
reaction mixture was brought to a boil and was then allowed to cool to 
ambient temperature. After remaining at ambient temperature overnight, 
crystallization was induced by the addition of seed crystals previously 
obtained. The crystalline tartarate salt was isolated by filtration and 
the filter cake washed with methanol; yield=2.813 g. (18.7%) of a white 
crystalline solid comprising the (-)-di-p-toluoyltartrate of 
4aR,8aR-1-n-propyl-6-oxodecahydroquinoline; [.alpha.].sub.D.sup.25.degree. 
=-107.49.degree.(MeOH, c=1). Recrystallization of the salt from methanol 
gave 1.943 g. of the optically pure salt, [.alpha.].sub.D.sup.25.degree. 
=-108.29.degree.(MeOH, c=1). The (-)-di-p-toluoyltartrate salt thus 
obtained was treated with dilute aqueous sodium hydroxide and the 
resulting alkaline solution extracted with methylene dichloride. The 
methylene dichloride extract was dried and concentrated, and the solvent 
removed therefrom in vacuo. The resulting residue was distilled to yield a 
colorless oil comprising purified 
4aR,8aR-1-n-propyl-6-oxodecahydroquinoline; [.alpha.].sub.D.sup.25.degree. 
=-88.51.degree.(MeOH, c-1). 
The 4aS, 8aS derivative can be prepared in similar fashion by reacting 
(+)-di-p-toluoyltartaric acid with the racemate. 
The preparation of pharmaceutically-acceptable acid addition salts of the 
compounds of this invention, particularly the hydrohalide and maleate 
salts, is illustrated in the above examples. Generally speaking, a 
solution of an equivalent of the free base represented by I, III or IIIa 
in a lower alkanol is mixed with an equivalent of the acid, also in 
solution in a lower alkanol. The salt is recovered by evaporation of the 
solvent and purified by recrystallization. Alternatively, an equivalent of 
the free base in a nonpolar organic solvent such as ether can be mixed 
with an equivalent of the acid, also in ether. In this procedure, the salt 
is usually insoluble in the solvent system and is recovered by filtration. 
The compounds represented by I, III or IIIa have at least two basic amine 
groups, the more basic group being the octahydroquinoline ring nitrogen. 
Disalts can be formed with these compounds by using at least two 
equivalents of the acid per equivalent of base. In general, only the 
stronger organic and inorganic acids will form disalts; the mineral acids, 
toluenesulfonic acid, methanesulfonic acid etc. Dihydrochloride salts are 
conveniently prepared by dissolving the free base in ether, saturating the 
ethereal solution with gaseous HCl, and recovering the dihydrochloride 
salt by filtration. 
As previously stated, the drugs of this invention as represented by 
formulas I and III above are D-2 dopamine agonists. One of such D-2 
dopamine agonist activities is the inhibition of prolactin secretion, as 
demonstrated by the following procedure. 
Adult male rats of the Sprague-Dawley strain weighing about 200 g. were 
housed in an air-conditioned room with controlled lighting (lights on 6 
a.m.-8 p.m.) and fed lab chow and water ad libitum. Each rat received an 
intraperitoneal injection of 2.0 mg. of reserpine in aqueous suspension 18 
hours before administration of the test drug. The purpose of the reserpine 
was to keep the rat prolactin levels uniformly elevated. The compound was 
dissolved in 10 percent ethanol, and injected intraperitoneally at doses 
of 0.017, 0.03, 0.17 and 0.3.mu. moles/kg. The compound was administered 
at each dose level to a group of 10 rats, and a control group of 10 intact 
males received an equivalent amount of 10 percent ethanol. One hour after 
treatment, all rats were killed by decapitation, and 150 .mu.l aliquots of 
serum were assayed for prolactin. 
The difference between the prolactin level of the treated rats and 
prolactin level of the control rats, divided by the prolactin level of the 
control rats, gives the percent inhibition of prolactin secretion 
attributable to the given dose. Inhibition percentages are given in Tables 
1 and 2 below for compounds according to I or III above respectively. In 
the tables, columns 1 and 2 give substitution patterns for the basic 
structures at the head of the Table, column 3 the form (salt or free 
base--FB), column 4, the stereochemistry trans-(.+-.) or trans-(-) 
(4aR,8aR) and columns 5, 6, 7 and 8, the percent prolactin inhibition at 
the specified dose levels. 
TABLE 1 
______________________________________ 
Percent Inhibition of Proclactin Secretion 
##STR12## 
Stereo- 
Dose in mcg/kg 
R R.sup.1 Form chemistry 
100 50 10 5 
______________________________________ 
n-Pr NH.sub.2 2HBr trans (.+-.) 
93 88 60 35 
" NHCH.sub.3 2HCl " -- 82 62 -- 
" N(CH.sub.3).sub.2 
" " -- 55 -- -- 
" NH.sub.2 " trans-(-) 
-- 89 69 67 
" NHbenzyl " trans-(.+-.) 
-- 67 -- -- 
" 1-pyrrolidinyl 
maleate " -- 41 -- -- 
" NHCOCH.sub.3 FB " -- 80 -- -- 
" H 2HCl " -- 76 35 14 
Me NH.sub.2 2HBr " -- 33 -- -- 
n-Pr H HI " -- 30 -- -- 
methio- 
dide 
" OH HCl " -- 27 -- -- 
______________________________________ 
The compounds represented by I and III are also active by the oral route, 
but at higher doses. 
Compounds according to I and III, dopamine D-2 agonists, have also been 
found to 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 Arbuthnott, Brain Res, 24, 
485 (1970). A compound having dopamine agonist activity causes the rats to 
turn in circles contralateral to the side of the lesion. After a latency 
period, which varies from compound to compound, the number of turns is 
counted over a 15-minute period. 
Results obtained from such testing are set forth in Table 2 below. In the 
table, columns 1 and 2 give the substitution pattern for the compound at 
the head of the table, column 3, salt or free base, column 4, 
stereochemistry, column 5, dose administered, column 6, percent of test 
animals exhibiting turning behavior, and column 7, average number of turns 
observed in first 15 minutes after end of latency period. 
TABLE 2 
__________________________________________________________________________ 
Turning Behaviour 
##STR13## 
dose in 
% Rats exhibiting 
Average No. of 
R R.sup.1 Form 
Stereochemistry 
mcg/kg 
turning behaviour 
turns per rat 
__________________________________________________________________________ 
n-Pr 
NH.sub.2 2HBr 
Trans-(.+-.) 
100 78 51 
20 0 
" NHCH.sub.3 
2HCl 
" 1000 100 100 
100 100 80 
20 75 27 
N(CH.sub.3).sub.2 
" " 1000 100 62 
" NH.sub.2 " Trans-(-) 
1000 100 109 
100 80 102 
20 100 37 
" 1-pyrrolidinyl 
FB Trans-(.+-.) 
1000 100 67 
" NHCOCH.sub.3 1000 100 91 
" H 2HCl 1000 100 100 
100 100 44 
20 25 16 
Br 2HCl 
Trans-(.+-.) 
1000 100 42 
__________________________________________________________________________ 
The compounds of this invention I, and III are effective in the treatment 
of hypertension. The compounds will demonstrate such activity in standard 
laboratory tests; ie., upon administration to SHR (spontaneously 
hypertensive rats) or in blocking NE (norepinephrine) release from 
sympathetic nerve terminals in pithed SHR. The compounds lack alpha 
adrenergic blocking activity. 
Activity in affecting sexual behavior by the compounds according to I or 
III is demonstrated by measuring mount latency, intromission latency, 
ejaculatory latency, postejaculatory interval, mount frequency and 
intromission frequency in male rats who required at least five minutes to 
achieve ejaculation when a sexually receptive female is introduced into 
the behavioral arena prior to drug treatment. Reduction in one or more of 
the above indicis indicates a positive effect on sexual behaviour in male 
mammals including but not limited to improving potency. Sexually 
unresponsive male rats can also be used in such tests. Positive effects 
upon the sexual behaviour of female mammals are found when drugs according 
to I or III are administered ovariectomized, estrogen-treated female rats 
and the lordosis to mount ratio measured. An increase indicates a positive 
effect to be expected in female mammals suffering from a sexual 
dysfunction. 
The compounds of this invention according to IIIa above are dopamine D-1 
agonists. The compounds are tested for this activity by their ability to 
stimulate cyclic AMP formation in rat striatal membrane or in increasing 
cyclic AMP efflux in striatal tissue slices--see Stoof and Kebabian, Brain 
Research, 250, 263 (1982). 
The compounds of this invention are usually administered for therapeutic 
purposes in a variety of oral formulations as illustrated below. 
Hard gelatin capsules are prepared using the following ingredients: 
______________________________________ 
Quantity (mg./capsule) 
______________________________________ 
Active compound 
.1-2 mg 
Starch dried 200 
Magnesium stearate 
10 
______________________________________ 
The above ingredients are mixed and filled into hard gelatin capsules. 
A tablet formulation is prepared using the ingredients below: 
______________________________________ 
Quantity (mg./tablet) 
______________________________________ 
Active compound .1-2 mg 
Cellulose, microcrystalline 
400 
Silicon dioxide, fumed 
10 
Stearic acid 5 
______________________________________ 
The components are blended and compressed to form tablets. 
Alternatively, tablets each containing 0.1-2 mg. of active ingredient are 
made up as follows: 
Active ingredient: 0.1-2 mg. 
Starch: 45 mg. 
Microcrystalline cellulose: 35 mg. 
Polyvinylpyrrolidone (as 10% solution in water): 4 mg. 
Sodium carboxymethyl starch: 4.5 mg. 
Magnesium stearate: 0.5 mg. 
Talc: 1 mg. 
The active ingredient, starch and cellulose are passed through a No. 45 
mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone 
is mixed with the resultant powders which are then passed through a No. 14 
mesh U.S. sieve. The granules so produced are dried at 
50.degree.-60.degree. C. and passed through a No. 18 mesh U.S. sieve. The 
sodium carboxymethyl starch, magnesium stearate and talc, previously 
passed through a No. 60 mesh U.S. sieve, are then added to the granules 
which, after mixing, are compressed with a tablet machine to yield 
tablets. 
Capsules each containing 0.1-2 mg. of medicament are made as follows: 
Active ingredient: 0.1-2 mg. 
Starch: 59 mg. 
Microcrystalline cellulose: 59 mg. 
Magnesium stearate: 2 mg. 
The active ingredient, cellulose, starch and magnesium stearate are 
blended, passed through a No. 45 mesh U.S. sieve, and filled into hard 
gelatin capsules. 
Suspensions each containing 0.1-2 mg. of medicament per 5 ml. dose are made 
as follows: 
Active ingredient: 0.1-2 mg. 
Sodium carboxymethyl cellulose: 50 mg. 
Syrup: 1.25 ml. 
Benzoic acid solution: 0.10 ml. 
Flavor: q.v. 
Color: q.v. 
Purified water to: 5 ml. 
The medicament is passed through a No. 45 mesh U.S. sieve and mixed with 
the sodium carboxymethylcellulose and syrup to form a smooth paste. The 
benzoic acid solution, flavor and color are diluted with some of the water 
and added with stirring. Sufficient water is then added to produce the 
required volume. 
For oral administration, for treating sexual dysfunction, improving 
potency, lowering blood pressure (either thru a D-2 or D-1 mechanism), for 
increasing renal vascular flow, treating depression or anxiety, 
alleviating the symptoms of Parkinsonism or inhibiting prolactin release, 
tablets, capsules or suspensions containing from about 0.1 to about 2 mg. 
of active drug per dose are given 3-4 times a day, giving a daily dosage 
of 0.3 to 8 mgs. or, for a 75 kg. person, about 2.25 to about 600 mg./per 
day. The intravenous dose is in the range from about 0.1 to about 100 
mcg./kg.