10-halo-E-homoeburnane derivatives, a process for the preparation thereof, a process for the use thereof as vasodilators, and vasodilating compositions thereof

The invention relates to new 10-halo-E-homoeburnane derivatives of the general formula (I), ##STR1## wherein R.sup.2 is a C.sub.1-6 alkyl group and X is halogen, and epimers, optically active derivatives and pharmaceutically acceptable acid addition salts thereof. These substances exert vasodilating effects and can be applied to advantage in the therapy. The new compounds are prepared so that a racemic or optically active 9-halo-octahydroindoloquinolisine derivative of the general formula (II), ##STR2## wherein R.sup.2 and X are as defined above and R.sup.1 is a C.sub.1-6 alkyl group, or an acid addition salt thereof is treated with a strong base, and, if desired, the 15-epimers of the resulting compound having the general formula (I) are separated from each other, and/or, if desired, the resulting substance is converted into its pharmaceutically acceptable acid addition salt and/or resolved.

The invention relates to new 10-halo-E-homoeburnane derivatives of the 
formula (I), 
##STR3## 
wherein R.sup.2 is a C.sub.1-6 alkyl group and X is a halogen, and 
pharmaceutically acceptable acid addition salts, epimers and optically 
active derivatives thereof. 
The invention also relates to pharmaceutical compositions which contain at 
least one of the new compounds defined above, and to a process for the 
preparation of the new compounds and the pharmaceutical compositions. 
The new compounds defined above are prepared according to the invention in 
that a racemic or optically active 9-halo-octahydroindoloquinolizine 
derivative of the general formula (II), 
##STR4## 
wherein R.sup.2 and X are as defined above and R.sup.1 is a C.sub.1-6 
alkyl group, or an acid addition salt thereof is treated with a strong 
base, and, if desired, the 15-epimers of the resulting compound having the 
formula (I) are separated from each other, and/or, if desired, the 
resulting substance is converted into its pharmaceutically acceptable acid 
addition salt and/or resolved. 
The new compounds according to the invention possess valuable vasodilating 
effects, and they can also be utilized as intermediates in the preparation 
of other pharmaceutically active compounds, such as 10-halovincaminic acid 
esters. 
In the compounds of the formulae (I) and (II) R.sup.1 and R.sup.2 can 
represent a straight-chain or branched C.sub.1-6 alkyl group, such as 
methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, 
n-pentyl, isopentyl, n-hexyl or isohexyl group. R.sup.2 represents 
preferably an ethyl or n-butyl group. 
X may represent all the four halogens, i.e. fluorine, chlorine, bromine and 
iodine, preferably bromine. 
The starting substances of the formula (II), where X, R.sup.1 and R.sup.2 
are as defined above, can be prepared as follows; a 
9-halo-1,2,3,4,6,7-hexahydroindolo[2,3-a]quinolizine derivative is reacted 
with a 2-acyloxy-acrylic acid ester, and the resulting 
1-(2'-acyloxy-2'-alkoxycarbonylethyl)-9-halo-1,2,3,4,6,7-hexahydroindolo[2 
,3-a]quinolizine derivative is first reduced and then deacylated, or first 
deacylated and then reduced. 
Of the strong bases applicable in the process of the invention for 
converting the starting substances into the compounds of the formula (I), 
e.g. the following are to be mentioned: alkali metal hydrides, such as 
sodium hydride, alkali metal alcoholates, such as sodium methoxide, sodium 
ethoxide, sodium tert.-butoxide and potassium tert.-butoxide, alkali metal 
amides, such as sodium amide and potassium amide, alkali metal 
dialkylamides, such as lithium diisopropylamide. 
This treatment can be performed in an inert aprotic non-polar organic 
solvent, such as an aromatic hydrocarbon (e.g. benzene, toluene or 
xylene). The starting substance is treated with the alkali preferably at 
or close to the boiling point of the solvent used. 
The above reaction yields the compounds of the formula (I) as mixtures of 
15-epimers. If desired, the individual epimers can be separated from each 
other preferably by preparative layer chromatography. When, however, the 
compounds of the formula (I) are to be converted later into 
10-halovincaminic acid esters, the epimers need not be separated, since 
the subsequent reactions involve the elimination of the center of 
asymmetry in position 15. 
It is preferred to use Merck PF.sub.254+366 grade silica gel plates in the 
preparative layer chromatography. Various solvent combinations can be 
utilized as running and eluting agents. 
The compounds of the formula (I) can be reacted with various acids to form 
the respective acid addition salts. Of the acids applicable in the salt 
formation step, e.g. the following are to be mentioned: mineral acids, 
such as hydrogen halides (e.g. hydrochloric acid or hydrogen bromide), 
sulfuric acid, phosphoric acid, nitric acid, perhaloic acids (such as 
perchloric acid), organic carboxylic acids, such as formic acid, acetic 
acid, propionic acid, glycolic acid, maleic acid, hydroxymaleic acid, 
fumaric acid, salicylic acid, lactic acid, cinnamic acid, benzoic acid, 
phenylacetic acid, p-aminosalicylic acid, p-aminobenzoic acid, 
p-hydroxybenzoic acid; alkylsulfonic acids, such as methanesulfonic acid; 
ethanesulfonic acid, cycloaliphatic sulfonic acids, such as 
cyclohexylsulfonic acid, arylsulfonic acids, such as p-toluenesulfonic 
acid, naphthylsulfonic acid, sulfanilic acid; amino acids, such as 
aspartic acid and glutamic acid. 
If desired, the racemic compounds of the general formula (I) can be 
resolved in a manner known per se to obtain the respective optically 
active derivatives. The optically active end-products can also be 
prepared, however, from the appropriate optically active starting 
substances. 
If desired, the racemic or optically active compounds of the formula (I) as 
well as the respective pure epimers and acid addition salts thereof can be 
subjected to further purification steps, such as recrystallization from an 
appropriately selected solvent or solvent mixture. The solvents or solvent 
mixtures utilized in this step are chosen in accordance with the 
solubility and crystallization characteristics of the substance to be 
purified. 
The process of the invention yields the end-products in forms easy to 
identify. The analytical data, IR spectra, NMR spectra and mass spectra of 
the compounds prepared are in harmony with the assigned structures. 
The compounds of the formula (I) were subjected to pharmacological tests in 
order to determine their effects on the circulation. 
The tests were performed on dogs narcotized with chloralose urethane, and 
the arterial blood pressure, heart rate, and the blood flows in the 
arteria femoralis and arteria carotis interna were measured. Vascular 
resistances were calculated for the latter two vascular beds by the 
formula 
##EQU1## 
The substances under examination were administered as aqueous solutions in 
intravenous dosages of 1 mg/kg body weight. The tests were repeated five 
or six times. The results of the tests are listed in Table 1, whereas the 
corresponding properties of vincamine (reference substance) are given in 
Table 2. 
The abbreviations used in the tables have the following meanings: 
MABP: mean arterial blood pressure (mmHg) 
HR: heart rate (min.sup.-1) 
CBF: blood flow in the carotis interna (ml.min.sup.-1) 
CVR: carotis vascular resistance (mm Hg.min.ml.sup.-1) 
FBF: femoral blood flow (ml.min.sup.-1) 
FVR: femoral vascular resistance (mm Hg.min.ml.sup.-1) 
TABLE 1 
______________________________________ 
Circular effects of 10-bromo-14-oxo-15-hydroxy-E-homoeburnane- 
(3.alpha.,17.alpha.) (mean values .+-. standard error) 
Percentage 
Control Treated difference 
______________________________________ 
MABP 146 .+-. 6.8 
132 .+-. 9.8 
-9.6 
HR 148 .+-. 16 139 .+-. 11 
-6.1 
CBF 61.2 .+-. 13 
74.0 .+-. 13 
+21 
CVR 2.38 .+-. 0.52 
1.78 .+-. 0.29 
-25 
FBF 37.0 .+-. 7.8 
37.2 .+-. 7.6 
+0.5 
FVR 3.94 .+-. 0.61 
3.55 .+-. 0.57 
-9.9 
______________________________________ 
TABLE 2 
______________________________________ 
Circular effects of vincamine (mean values .+-. standard error) 
Percentage 
Control Treated difference 
______________________________________ 
MABP 131 .+-. 5.2 
112 .+-. 6.1 
-15 
HR 181 .+-. 19 165 .+-. 15 
-9.1 
CBF 39.2 .+-. 8.6 
40.8 .+-. 8.5 
+4.1 
CVR 3.35 .+-. 0.56 
2.74 .+-. 0.52 
-18 
FBF 35.9 .+-. 7.2 
42.8 .+-. 7.4 
+19 
FVR 3.65 .+-. 0.58 
2.61 .+-. 0.53 
-28 
______________________________________ 
The data indicate that 
10-bromo-14-oxo-15-hydroxy-E-homoeburnane-(3.alpha.,17.alpha.) hardly 
affects the blood pressure and the heart rate when administered to 
narcotized dogs in an intravenous dosage of 1 mg/kg body weight, i.e. it 
exerts favorably weak effects on the systemic circulation. The main effect 
of 10-bromo-14-oxo-15-hydroxy-E-homoeburnane-(3.alpha.,17.alpha.) is the 
dilatation of arteria carotis, which may reach 25%, corresponding to a 21% 
increase in blood flow. It is particularly advantageous that this compound 
exerts practically no other effect on the circulation. 
Because of their favorable vasodilating effects, the compounds according to 
the invention can be applied to advantage in therapy. 
The new compounds according to the invention can be converted into 
pharmaceutical compositions for parenteral or enteral administration, 
utilizing conventional non-toxic, inert, solid or liquid pharmaceutical 
carriers, diluents and/or auxiliary agents. As carrier e.g. water, 
gelatine, lactose, starch, pectin, magnesium stearate, stearic acid, talc 
and vegetable oils such as peanut oil, olive oil, etc. can be applied. The 
pharmaceutical compositions can be presented in conventional forms, e.g. 
as solids (round or angular tablets, coated tablets, capsules, such as 
hard gelatine capsules, furthermore pills, suppositories, etc.) or liquids 
(such as oily or aqueous solutions, suspensions, emulsions syrups, soft 
gelatine capsules, injectable oily or aqueous solutions or suspensions, 
etc.). The amount of the solid carrier present may vary within wide 
limits; the solid compositions may contain preferably about 25 mg to 1 g 
of a carrier. If necessary, the pharmaceutical compositions may also 
contain conventional pharmaceutical additives, such as preservatives, 
wetting agents, emulsifying agents, salts for adjusting the osmotic 
pressure, buffers, flavoring agents, odorants, etc. If desired, the 
compositions may also contain other known pharmaceutically active 
substances in addition to the new compounds according to the invention. 
The pharmaceutical compositions are presented preferably in the form of 
unit dosages corresponding to the way of administration. The 
pharmaceutical compositions are prepared by methods well known in the 
pharmaceutical industry, such as sieving, mixing, granulating and pressing 
the components, dissolving the substances, etc. If desired, the 
compositions can also be subjected to other conventional pharmacotechnical 
operations, such as sterilization.

The invention is elucidated in detail by the aid of the following 
non-limiting Examples. 
EXAMPLE 1 
10-Bromo-14-oxo-15-hydroxy-E-homoeburnane-(3.alpha.,17.alpha.) 
0.30 g (2.7 mmoles) of potassium tert.-butoxide are added to a suspension 
of 3.0 g (6.9 mmoles) of 
9-bromo-1.alpha.-ethyl-1-(2-hydroxy-2-methoxycarbonyl-ethyl)-1,2,3,4,5,6,7 
,12-octahydro-12b.alpha.H-indolo[2,3-a]quinolisine in 200 ml of dry toluene 
and 2.8 ml (2.6 g) of acetophenone, and the mixture is stirred and 
refluxed in an argon atmosphere for 4 hours. When the reaction terminates 
the mixture is cooled to 0.degree. C. and shaken four times with 30 ml of 
cold 2.5% aqueous sulfuric acid, each. The aqueous acidic phases are 
combined, cooled, the pH of the solution is adjusted to 10 with 25% 
aqueous ammonia, and then extracted three times with 30 ml of 
dichloromethane, each. The organic phases are combined, dried over 
magnesium sulfate, filtered, and the filtrate is evaporated in vacuo. The 
residue is crystallized from 10 ml of methanol to obtain 1.85 g (66.6%) of 
the named compound as a mixture of epimers; m.p.: 206-208.degree. C. The 
empirical formula of the product is C.sub.20 H.sub.23 BrN.sub.2 O.sub.2 
(mol.wt.:403.33). 
The epimers are separated from the epimeric mixture by preparative thin 
layer chromatography. Kieselgel PF.sub.254+366 grade silica gel plates, 
20.times.20 cm in area and 1.5 mm in thickness, are applied as adsorbent, 
and a 14:3 mixture of benzene and methanol is utilized as solvent. The 
product is eluted with dichloromethane. The fast-moving epimer is termed 
as epimer "A", and the slow-moving epimer is termed as epimer "B". Epimer 
"A" is crystallized from 5 ml of methanol, and epimer "B" is crystallized 
from 10 ml of methanol. 
0.4 g of epimer "A" are isolated from the upper spot, which corresponds to 
a yield of 21.6%. The substance melts at 177.degree.-178.degree. C. 
IR spectrum (KBr): .upsilon..sub.max. 3400 cm.sup.-1 (--OH), 1660 cm.sup.-1 
(amide--CO). 
Mass spectrum (m/e): 404, 403, 402, 401, 376, 374, 360, 358, 347, 345, 332, 
330, 317, 315, 303, 301, 277, 275, 180, 167, 153, 140. 
1.25 g of epimer "B" are isolated from the lower spot; i.e. this epimer is 
obtained with a yield of 67.6%. The substance melts at 214-216.degree. C. 
IR spectrum (KBr): .upsilon..sub.max. 3400 cm.sup.-1 (--OH), 1685 cm.sup.-1 
(amide --CO). 
Mass spectrum (m/e): 404, 403, 402, 401, 376, 374, 360, 358, 347, 345, 332, 
330, 303, 301, 277, 275, 180, 167, 153, 140. 
NMR spectrum (deuterochloroform): .delta. 0.96 (t, 3H,--CH.sub.3), 
7.39-8.24 (m, 3H, aromatic protons) ppm. C.sub.9 --H=7.51 ppm, J.sub.12,9 
=0.2 Hz (para); C.sub.11 --H=7.39 ppm, J.sub.11,12 =8.7 Hz (ortho); 
C.sub.12 --H=8.24 ppm, J.sub.11,9 =2.8 Hz (meta).