Blood pressure lowering benzoquinolizines

The invention concerns novel benzoquinolizines of formula (I) ##STR1## and their pharmaceutically acceptable acid addition salts. In formula (I) R.sup.1 and R.sup.2 which may be the same or different, each represent hydrogen, lower alkyl, lower alkoxy or halogen, R.sup.3 and R.sup.4 which may be the same or different each represent hydrogen, lower alkyl, aryl or aryl(lower)alkyl or R.sup.3 and R.sup.4 together represent a tetra- or penta-methylene chain. The novel compounds of the invention lower blood pressure in warm-blooded animals.

The invention relates to novel heterocyclic compounds, more particularly to 
novel benzoquinolizines, to processes for preparing the compounds and to 
pharmaceutical compositions containing them. 
The present invention provides novel benzoquinolizines of the general 
formula (I) 
##STR2## 
and the pharmaceutically acceptable acid addition salts thereof, wherein 
R.sup.1 and R.sup.2 which may be the same or different, each represent 
hydrogen, lower alkyl, lower alkoxy or halogen, R.sup.3 and R.sup.4 which 
may be the same or different each represent hydrogen, lower alkyl, aryl or 
aryl(lower)alkyl or R.sup.3 and R.sup.4 together represent a a tetra- or 
pentamethylene chain. 
The term "lower" as used herein means that the radical referred to contains 
1 to 6 carbon atoms. Preferably the radical contains 1 to 4 carbon atoms. 
When a radical, or part of a radical, is referred to as "aryl" that radical 
or part of radical is preferably a phenyl or substituted phenyl group, The 
substituted phenyl group can be a phenyl group substituted by one or more 
substituents chosen from, for example, halogen (e.g. chlorine, fluorine or 
bromine), alkoxy (e.g. lower alkoxy such as methoxy or ethoxy), lower 
alkyl (e.g. methyl, ethyl, propyl or butyl), alkylenedioxy (e.g. 
methylenedioxy or ethylenedioxy), amino, lower alkylamino, 
diloweralkylamino or trifluoromethyl. 
Examples of R.sup.1 and R.sup.2 are hydrogen, lower alkyl such as methyl, 
ethyl, propyl or butyl, lower alkoxy such as methoxy, ethoxy, propoxy or 
butoxy or halogen such as chlorine, fluorine or bromine. R.sup.1 and 
R.sup.2 can be different or the same, e.g. they both can be lower alkoxy 
or preferably hydrogen. 
Examples of R.sup.3 and R.sup.4 are hydrogen, lower alkyl (e.g. methyl, 
ethyl, propyl or butyl), aryl (e.g. phenyl or substituted phenyl as 
mentioned above) or aryl(lower)alkyl (e.g. benzyl or phenethyl in which 
the phenyl ring can be substituted as mentioned above). When R.sup.3 and 
R.sup.4 together represent a tera- or pentamethylene chain the group 
--NR.sup.3 R.sup.4 represents respectively a pyrrolidino or piperidino 
ring. Preferably R.sup.3 and R.sup.4 are both hydrogen. 
The compounds of the invention may be prepared by a process in which an 
amine of general formula (II) 
##STR3## 
or an acid addition salt thereof (where R.sup.1 and R.sup.2 have the 
meanings given above) is reacted with a sulphonamide derivative of general 
formula (III) 
EQU NR.sup.3 R.sup.4 SO.sub.2 X (III) 
where R.sup.3 and R.sup.4 are as defined above and X is amino or halo, 
preferably chloro. In a preferred process the amine of general formula 
(II) is reacted with a compound of formula (III) in which R.sup.3 and 
R.sup.4 are both hydrogen and X is amino. The latter compound is 
sulphamide. Starting compounds of formula (III) in which R.sup.3 and 
R.sup.4 are other than hydrogen can be prepared by reacting sulphamide 
with an appropriate amine of formula NHR.sup.3' R.sup.4' [where R.sup.3' 
and R.sup.4' are lower alkyl, aryl or aryl(lower)alkyl or together 
represent a a tetra- or pentamethylene chain]. Compounds of formula (III) 
in which X is halo are known or can be made by methods known for analogous 
compounds. For example an isocyanate of general formula R.sup.3' NCO 
[where R.sup.3' is lower alkyl, aryl or aryl(lower)alkyl] may be reacted 
with fuming sulphuric acid to give an acid of formula R.sup.3 NHSO.sub.3 H 
which may be halogenated with, for example, phosphorus trichloride, 
phosphorus pentachloride or thionyl chloride to the corresponding compound 
of general formula (III) in which X is halo. 
The starting amines of general formula (II) are known compounds or they may 
be made by methods known for analogous compounds as, for example, 
described in our U.K. Specification No. 1,513,824. 
The compounds of the invention may be prepared by an alternative process in 
which a compound of general formula (IV) 
##STR4## 
or an acid addition salt thereof, (wherein R.sup.1 and R.sup.2 have the 
meanings given above) and Y is chloro or bromo (preferably chloro) is 
reacted with a compound of general formula NHR.sup.3 R.sup.4 (where 
R.sup.3 and R.sup.4 have the meanings given above). When R.sup.3 and 
R.sup.4 are both hydrogen the compound NHR.sup.3 R.sup.4 is ammonia and 
when at least one of the groups R.sup.3 R.sup.4 is other than hydrogen the 
compound is a primary or secondary amine. The starting compounds of 
general formula (IV) may be prepared by halogenating the corresponding 
acid of general formula (V) 
##STR5## 
(where R.sup.1 and R.sup.2 have the meanings given above). The acid may be 
halogenated with a halogenating agent such as, for example, phosphorus 
trichloride, phosphorus pentachloride or thionyl chloride. The acid of 
general formula (V) may be prepared from an isocyanate of general formula 
(VI) 
##STR6## 
(where R.sup.1 and R.sup.2 have the meanings given above) by treating it 
with fuming sulphuric acid. The isocyanate of general formula (VI) may be 
prepared from the amino of general formula (II), by for example, the 
methods disclosed in our U.K. Specification No. 1,513,824. 
In a further process compounds of general formula (I) in which at least one 
of R.sup.3 and R.sup.4 is other than hydrogen may be prepared by reacting 
a compound of general formula (I) in which both R.sup.3 and R.sup.4 are 
hydrogen with a secondary or tertiary amine of general formula NHR.sup.3 
R.sup.4 (where R.sup.3 and R.sup.4 have the meanings given in connection 
with formula I except that at least one of R.sup.3 and R.sup.4 is other 
than hydrogen). 
If necessary in the reactions hereinbefore described, reactive substituent 
groups may be protected during a reaction and the protecting group removed 
at a later stage. Once the compound of general formula (I) has been 
prepared then if necessary a substituent in the molecule may be converted 
into another substituent specified in connection with general formula (I). 
If in the processes described above the compound of the invention is 
obtained as an acid addition salt, the free base can be obtained by 
basifying a solution of the acid addition salt. Conversely, if the product 
of the process is a free base, an acid addition salt, particularly a 
pharmaceutically acceptable acid addition salt may be obtained by 
dissolving the free base in a suitable organic solvent and treating the 
solution with an acid, in accordance with conventional procedures for 
preparing acid addition salts from base compounds. 
Examples of acid addition salts are those formed from inorganic and organic 
acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, 
fumaric, maleic, citric, acetic, formic, methanesulphonic and 
p-toluenesulphonic acids. 
The compounds of the invention possess two asymmetric carbon atoms and 
hence they can exist in various stereochemical forms. In addition they can 
exist as cis or trans isomers. It will be realised that if the starting 
material of formula (II) is a mixture of isomers the product of formula 
(I) will also be a mixture of isomers which can be separated, if required, 
by standard procedures. The preferred compounds of the invention are the 
trans isomers in which the --NHSO.sub.2 NR.sup.3 R.sup.4 group is in the 
equatorial position i.e. compounds of the general formula (VI) 
##STR7## 
and the pharmaceutically acceptable acid addition salts thereof (wherein 
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined above). These 
compounds can be prepared by the methods described above starting from the 
corresponding trans isomer of general formula (II). 
The compounds of the invention have blood pressure lowering activity. For 
example, the compounds exhibit antihypertensive activity upon 
administration to warm-blooded animals according to a standard 
pharmacological procedure. One such pharmacological test procedure is 
described below: 
Female rats are rendered hypertensive by implanting subcutaneously two wax 
pellets (30 mg) containing desoxycorticosterone acetate (15 mg) followed 
immediately by uninephrectomy. The drinking water is replaced by normal 
saline ad lib for 4 weeks. Blood pressure stabilises at a hypertensive 
level after six weeks. Systolic pressure is measured indirectly before 
dosing with a test compound using an E and M pneumatic pulse transducer 
and a Devices MX2 recorder. Groups of 4 rats are dosed orally with 
suspensions or solution of the test compound in 0.5% 
hydroxypropylmethylcellulose 0.9% saline vehicle. Blood pressures are 
recorded again at 2, 6 and 24 hours and the results, expressed as a 
percentage of the pre-dose values compared with those of a similar group 
of rats receiving vehicle alone. 
In the aforementioned test 
2.beta.-sulphonamido-1,2,3,4,6,7,11b.alpha.-hexahydro-2H-benzo[a]quinolizi 
ne, a representative compound of the present invention, was found to lower 
blood pressure by 47.7% 2 hours after dosing and by 50.3% 6 hours after 
dosing when administered at 50 mg/kg. 
The invention further provides a pharmaceutical composition which comprises 
a compound of formula (I) or a pharmaceutically acceptable acid addition 
salt thereof, in association with a pharmaceutically acceptable carrier. 
In such a composition, the carrier may be a solid, liquid or mixture of a 
solid and a liquid. Solid form composition includes powders, tablets and 
capsules. A solid carrier can be one or more substances which may also act 
as flavouring agents, lubricants, solubilisers, suspending agents, binders 
or tablet disintegrating agents; it can also be an encapsulating material. 
In powders the carrier is a finely divided solid which is in admixture 
with the finely divided active ingredients. In tablets the active 
ingredient is mixed with a carrier having the necessary binding properties 
in suitable proportions and compacted in the shape and size desired. The 
powders and tablets preferably contain from 5 to 99, preferably 10-80% of 
the active ingredient. Suitable solid carriers are magnesium carbonate, 
magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, 
gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a 
low melting wax and cocoa butter. The term "composition" is intended to 
include the formulation of an active ingredient with encapsulating 
material as carrier to give a capsule in which the active ingredient (with 
or without other carriers) is surrounded by carrier, which is thus in 
association with it. Similarly cachets are included. 
Sterile liquid form compositions include sterile solutions, suspensions, 
emulsions, syrups and elixirs. The active ingredient can be dissolved or 
suspended in a pharmaceutically acceptable sterile liquid carrier, such as 
sterile water, sterile organic solvent or a mixture of both. Preferably a 
liquid carrier is one suitable for parenteral injection. Where the active 
ingredient is sufficiently soluble it can be dissolved in normal saline as 
a carrier; if it is too insoluble for this it can be dissolved in a 
suitable organic solvent, for instance aqueous propylene glycol containing 
from 10 to 75% of the glycol by weight is generally suitable. 
In other instances compositions can be made by dispersing the 
finely-divided active ingredient in aqueous starch or sodium carboxymethyl 
cellulose solution, or in a suitable oil, for instance arachis oil. Liquid 
pharmaceutical compositions which are sterile solutions or suspensions can 
be utilised by intramuscular, intraperitoneal or subcutaneous injection. 
In many instances a compound is orally active and can be administered 
orally either in liquid or solid composition form. 
Preferably the pharmaceutical composition is in unit dosage form. In such 
form, the composition is sub-divided in unit doses containing appropriate 
quantities of the active ingredient; the unit dosage form can be a 
packaged composition, the package containing specific quantities of 
compositions, for example packeted powders or vials or ampoules. The unit 
dosage form can be a capsule or tablet itself, or it can be the 
appropriate number of any of these in packaged form. The quantity of 
active ingredient in a unit dose of composition may be varied or adjusted 
from about 5 mg. to 500 mg., according to the particular need and the 
activity of the active ingredient. The invention also includes the 
compounds in the absence of carrier where the compounds are in unit dosage 
form.

The following Examples illustrated the invention. 
EXAMPLE 1 
2.beta.-Sulphamamido-1,3,4,6,7,11b.alpha.-hexhydro-1H-benzo[a]quinolizine 
To a solution of 
2.beta.-amino-1,3,4,6,7,11b.alpha.-hexahydro-2H-benzo[a]quinolizine (2.26 
g.) in 1,2-dimethoxyethane (50 ml) was added sulphamide (1.344 g.) and the 
mixture was heated to reflux for 21 hours. The clear supernatent solution 
was decanted from a black tar and evaporated in vacuo. The residue was 
taken up in dichloromethane (25 ml) and quickly washed with water 
(2.times.15 ml). On standing for 0.5 hour, a precipitate formed from the 
organic layer, this was collected by filtration, washed with ice-cold 
dichloromethane and dried to give crude title compound (0.8 g.), m.p. 
192.degree.-193.degree. C. A second crop of 0.1 g. was combined with the 
first. 
A suspension of the title compound in ethanol was treated with ethanolic 
hydrogen chloride and shaken to solution. The solvent was evaporated and 
the product recrystallised from water to give the pure title compound as 
the hydrochloride, (0.71 g.), pale-brown plates, m.p. 
205.degree.-205.5.degree. (dec). (C.sub.13 H.sub.19 N.sub.3 O.sub.2 S. HCl 
requires C, 48.14; H, 6.46; N, 13.47:. Found C, 48.48; H, 6.56; N, 
13.28%). 
EXAMPLE 2 
9,10-Dimethoxy-2.beta.-sulphamamido-1,3,4,6,7,11b.alpha.-hexahydro-2H-benzo 
[a]quinolizine 
A slurry of 
9,10-dimethoxy-2.beta.-amino-1,3,4,6,7,11b.alpha.-hexahydro-2H-benzo[a]qui 
nolizine (2.05 g.) in 1,2-dimethoxyethane (50 cm.sup.3) with sulphamide 
(0.94 g) was stirred and heated to reflux for 21h. The clear solution was 
decanted from a small amount of red tar and evaporated in vacuo to an 
off-white glass-like solid. Crude title product was isolated as the 
hydrochloride, a very gummy yellow solid, re-converted to the free-base 
with aq.NaHCO.sub.3, and extracted with CH.sub.2 Cl.sub.2. Evaporation 
gave the crude base (1.22 g) as a yellow, glass-like solid. This was 
crystallised from a small volume of isopropanol overnight to give 
9,10-dimethoxy-2.beta.-sulphamamido-1,3,4,6,7,11b.alpha.-hexahydro-2H-benz 
o[a]quinolizine (0.48 g) as off-white micro-needles, m.p. 
168.degree.-172.degree. C. (dec). 
The product was slurried with hot ethanol (5 cm.sup.3), acidified with 
ethanolic hydrogen chloride (1 cm.sup.3), to give a clear solution and 
allowed to cool overnight. Filtration gave the title compound 
hydrochloride as a sticky pink solid which was triturated with hot 
MeOH-EtOH (1:1) with stirring, filtered and washed with ethanol to give 
title compound as hydrochloride hemihydrate (0.39 g), off-white spikes, 
m.p. 215.degree.-217.degree. C. (dec). (C.sub.15 H.sub.23 N.sub.3 O.sub.4 
S.HCl. 0.5H.sub.2 O requires C, 46.57; H, 6.25; N, 10.86% Found: C, 46.40; 
H, 6.23; N, 10.63%) 
EXAMPLE 3 
N-[1,3,4,6,7,11b.alpha.-Hexahydro-2H-benzo[a]quinolizin-2.beta.-yl]-N'-meth 
ylsulphamamide 
Methyl isocyanate was converted to methanesulphamic acid with oleum and 
thence with PCl.sub.5 to methanesulphamyl chloride by the method of J. A. 
Kloek and K. L. Leschinsky, J. Org. Chem. 41 (1976) 4028-9. 
A slurry of the 
2.beta.-amino-1,3,4,6,7,11b.alpha.-hexahydro-2H-benzo[a]quinolizine 
dihydrochloride (2.75 g) and triethylamine (3.60 g) in dichloromethane (30 
cm.sup.3) was cooled to 0.degree. C. and treated dropwise, with stirring, 
with a solution of methanesulphamyl chloride (95% pure; 1.30 g) in 
dichloromethane (10 cm.sup.3). The mixture was stirred at room temperature 
for 10 hours and allowed to stand over the weekend. It was then washed 
with water (2.times.25 cm.sup.3) and dried (MgSO.sub.4). Filtration and 
evaporation afforded a brown, glass-like solid (2.24 g). The free base was 
chromatographed on silica and eluted with 10% ethanol in ethyl acetate to 
give the title compound as a pale-yellow solid (1.15 g). This was treated 
with ethanolic hydrogen chloride to give the hydrochloride of the title 
compound (0.82 g) as colourless crystals, m.p. 206.5.degree.-208.degree. 
C. (dec). 
EXAMPLE 4 
N,N-Dimethyl-N'-(1,3,4,6,7,11b.alpha.-hexahydro-2H-benzo[a]-quinolizin-2.be 
ta.-yl)sulphamamide 
A solution of dimethylsulphamyl chloride (1.44 g) in dichloromethane (15 
cm.sup.3) was added dropwise with stirring to an ice-cold solution of 
2.beta.-amino-1,3,4,6,7,11b.alpha.-hexahydro-2H-benzo[a]quinolizine (2.02 
g) and triethylamine (1.01 g) in dichloromethane (15 cm.sup.3). The 
mixture was allowed to stand at room temperature for 19 hours, then washed 
with water (2.times.25 cm.sup.3) and dried (MgSO.sub.4). Filtration and 
evaporation afforded an oil which was taken up in ethanol and acidified 
with ethanolic hydrogen chloride. The mixture was allowed to stand in the 
refrigerator over the weekend, then stirred at room temperature to break 
up the precipitated crystals, filtered, and washed with ethanol to give 
the title compound as the hydrochloride (1.60 g) cream crystals, m.p. 
201.5.degree.-202.5.degree. C. (dec). 
EXAMPLE 5 
N-(1,3,4,6,7,11b.alpha.-Hexahydro-2H-benzo[a]quinolizin-2.beta.-yl)-N'-phen 
ylsulphamamide 
A solution of phenylsulphamoyl chloride (prepared in two steps from aniline 
by method of J. A. Kloek & K. L. Leschinsky, J. O. C., (1976), 41, 
4028-9); (1.12 g) in dichloromethane (10 cm.sup.3) was added to a stirred 
ice-cold solution of 
2.beta.-amino-1,3,4,6,7,11b.alpha.-hexahydro-2H-benzo[a]quinolizine (1.25 
g) and triethylamine (3 g) in dichloromethane (20 cm.sup.3). The mixture 
was allowed to stand at room temperature for 90 hours, then washed with 
water (2.times.25 cm.sup.3) and dried (MgSO.sub.4). Filtration and 
evaporation afforded a glass-like solid (2.32 g). Repeated solution and 
evaporation in a variety of solvents converted this into a pale-brown 
crystalline solid, which was triturated with benzene (10 cm.sup.3) and 
filtered to give the crude product as its base (2.0 g). This was dissolved 
in ethanol (6 cm.sup.3), acidified with ethanolic hydrogen chloride, the 
solvent evaporated and the residue crystallised overnight from methanol. 
Ethanol was added, and the methanol evaporated on the rotary evaporator. 
Three crops of the crude hydrochloride were collected by filtration over a 
period of three days. These were combined, dissolved in methanol, diluted 
with ethanol, the methanol evaporated on the rotary evaporator, and the 
residual suspension in ethanol stirred and heated to reflux for 2 hours. 
After cooling in ice, the precipitate was collected by filtration. 
Concentration of the mother-liquors gave a second crop and, after standing 
three days, a large third crop. All crops (possessing similar melting 
points) were combined and washed with ice-cold ethanol, to give pure title 
compound as the hydrochloride hemihydrate (0.41 g), cream crystals, m.p. 
210.degree.-213.degree. C. (dec.). 
EXAMPLE 6 
N-(1,3,4,6,7,11b.alpha.-Hexahydro-2H-benzo[a]quinolizin-2.beta.-aminosulpho 
nyl)pyrrollidine 
A solution of pyrollidinesulphonyl chloride (2.0 g) in dichloromethane (5 
cm.sup.3) was added dropwise, with stirring, to an ice-cold solution of 
2.beta.-amino-1,3,4,6,7,11b.alpha.-hexahydro-2H-benzo[a]quinolizine (2.02 
g) and triethylamine (1.25 g) in dichloromethane (20 cm.sup.3). The clear 
solution was stirred for a further 1/4 hour, then allowed to stand at room 
temperature for 45 hours. The turbid mixture was washed with water 
(2.times.25 cm.sup.3) and dried (MgSO.sub.4). Filtration and evaporation 
afforded a brown gum (3.67 g), which was dissolved in hot ethanol (10 
cm.sup.3), acidified with ethanolic hydrogen chloride, evaporated, the 
residue taken up in a small volume of ethanol and scratched, to give the 
crude product as its hydrochloride. This was recrystallised twice from 
ethanol to give pure title compound as the hydrochloride hemihydrate (1.30 
g), very pale yellow rods, m.p. 206.degree.-207.degree. C. (dec). 
EXAMPLE 7 
N,N-Diethyl-N'-(1,3,4,6,7,11b.alpha.-hexahydro-2H-benzo[a]quinolizin-2.beta 
.-yl)sulphamamide 
A solution of diethylaminesulphonyl chloride (prepared from diethylamine 
and thionyl chloride; 2.0 g) in dichloromethane (5 cm.sup.3) was added 
dropwise, with stirring, to an ice-cold solution of 
2.beta.-amino-1,3,4,6,7,11b.alpha.-hexahydro2H-benzo[a]quinolizine (2.02 
g) and triethylamine (1.25 g) in dichloromethane (20 cm.sup.3). The clear 
solution was stirred for 15 min., then allowed to stand at room 
temperature for 45 hours, during which time precipitation occurred. The 
mixture was washed with water (2.times.25 cm.sup.3) and the clear organic 
layer dried (MgSO.sub.4). Filtration and evaporation afforded a brown gum 
(3.38 g), which was chromatographed on silica eluted with 10% ethanol in 
ethyl acetate to give the crude product as its base, a brown oil (2.01 g). 
This was converted to the hydrochloride with ethanolic hydrogen chloride. 
Very slow precipitation (several days) from iso-propanol gave, in three 
crops, pure title compound as the hydrochloride quaterhydrate (0.80 g), 
colourless glass, m.p. 120.degree.-140.degree. C.