The invention relates to new 1-[6-(2'-substituted-5', 6', 7', 8'-tetrahydro-4'-oxo-quinazolino)]-3,4-dihydro-6,7-disubstituted-isoquinol ine derivatives of the formula (I) ##STR1## wherein R.sup.1 and R.sup.2 each independently represents hdyroxyl or alkoxy having from 1 to 6 carbon atoms, PA1 R.sup.3 is alky having from 1 to 6 carbon atoms, optionally substituted phenyl, optionally substituted alkylphenyl having from 1 to 4 carbon atoms in the alkyl moiety or an optionally substiutted heterocyclic group, and acid addition and quaternary salts thereof. Compounds of the formula (I) are pharmaceutically active, in particular show spasmolytic, analgesic, antipyretic activity and have a protecting effect in acute alcoholic intoxication.

The invention relates to new 
1-[6-(2'-substituted-5',6',7',8'-tetrahydro-4'-oxo-quinazolino)]-3,4-dihyd 
ro-6,7-disubstituted-isoquinoline derivatives of the formula (I) 
##STR2## 
wherein R.sup.1 and R.sup.2 each independently represents hydroxyl or 
alkoxy having from 1 to 6 carbon atoms, 
R.sup.3 is alkyl having from 1 to 6 carbon atoms, optionally substituted 
phenyl, optionally substituted alkylphenyl having from 1 to 4 carbon atoms 
in the alkyl moiety or an optionally substituted heterocyclic group, 
and acid addition and quaternary salts thereof. 
Compounds of the formula (I) are pharmaceutically active, in particular 
show spasmolytic, analgesic, antipyretic activity and have a protecting 
effect in acute alcoholic intoxication. 
In the compounds of formula (I) the alkyl groups as such or as parts of 
other groups are straight-chained or branched saturated hydrocarbon groups 
having from 1 to 6 and 1 to 4 carbon atoms, respectively, e.g. methyl, 
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, n-pentyl, 
isopentyl, n-hexyl or isohexyl groups, taking into account the restriction 
given for the number of carbon atoms. 
R.sup.3 as an alkylphenyl group having from 1 to 4 carbon atoms in the 
alkyl moiety preferably stands for benzyl. 
The phenyl and benzyl groups may optionally be substituted by one or more, 
identical or different substitutents, preferably selected from the group 
consisting of halogen, e.g. fluorine, chlorine, bromine or iodine, 
preferably chlorine; alkoxy having from 1 to 6, preferably 1 to 4 carbon 
atoms, e.g. methoxy; alkyl having from 1 to 6, preferably 1 to 4 carbon 
atoms, e.g. methyl; and trifluoromethyl. 
R.sup.3 as a heterocyclic group represents a saturated or unsaturated 
carbocyclic group containing one or more identical or different 
heteroatoms. As a heteroatom for example nitrogen, oxygen or sulfur may be 
incorporated into the carbon chain, and the heterocyclic ring preferably 
is 5- or 6-membered. Particularly preferred are the saturated or 
unsaturated, 6-membered heterocyclic groups containing one or more 
nitrogen and/or oxygen atoms, e.g. pyridyl, 1,2,5,6-tetrahydro-pyridinyl, 
morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, etc. The heterocyclic 
groups may be substituted by one or more, identical or different 
substituents, e.g. by a further heterocyclic, e.g. piperidinyl group, 
C.sub.1-4 -alkyl, phenyl, hydroxyl or carbamoyl. 
According to the invention compounds of the formula (I), wherein R.sup.1, 
R.sup.2 and R.sup.3 are as defined above, and acid addition or quaternary 
salts are prepared by condensing an acid of the formula (II), 
##STR3## 
wherein R.sup.1 and R.sup.2 are as defined above, 
X is oxygen or an .dbd.NH group, 
or a reactive derivative thereof, with a compound of the formula (III), 
##STR4## 
wherein R.sup.3 is as defined above, or a salt thereof formed with an 
inorganic or organic acid, in an alkaline medium, and, if desired, 
converting a compound of the formula (I) obtained into an acid addition or 
quaternary salt thereof. 
There are numerous pharmaceutically active isoquinoline derivatives known 
in the art (see e.g. Ehrhart-Ruschig, Arzneimittel, S. Ebel: Synthetische 
Arzneimittel; Verlag Chemie). Pharmaceutically active quinazolinone 
derivatives are known, too (Armarego, E. L. F.: Quinazolines-Fused 
Pyrimidines, Part I, Interscience Publishers, New York, 1967). There is 
not known, however, any publication which would disclose a combination of 
these two ring systems. 
The keto-esters of the formula (II) used as starting materials in the 
process according to the invention, in which R.sup.1, R.sup.2 and X are as 
defined above, may be prepared according to our co-pending U.S. patent 
application Ser. No. 721,880, filed Apr. 10, 1985, now U.S. Pat. No. 
4,622,329, for example from the corresponding diesters by ring closure. 
The diesters used in this procedure are either new compounds or can be 
prepared in a known manner, e.g. from the corresponding known diesters 
(which are unsubstituted in the 6,7-positions) or from the corresponding 
disubstituted 1-methyl-3,4-dihydroisoquinoline derivatives, which are 
known in the art. 
As reactive derivatives of the compounds of formula (II) e.g. their esters 
or acid amides, preferably esters may be used. 
Compounds of the formula (III), wherein R.sup.3 is as defined above, are 
known and can be prepared by methods known in the organic chemistry, e.g. 
by reacting the corresponding iminoethers or salts thereof with ammonia. 
The reaction of the acids of the formula (II) or reactive derivatives 
thereof with the compounds of the formula (III) or their salts formed with 
inorganic or organic acids proceeds in an alkaline medium smoothly already 
at room temperature, if desired, however, the reaction can be accelerated 
by increasing the temperature. 
As alkaline catalysts for example alkali metal hydroxides, e.g. sodium or 
potassium hydroxide; alkali metal carbonates, e.g. sodium or potassium 
carbonate; alkali metal alcoholates, e.g. sodium or potassium alcoholate, 
can be used in the process according to the invention. 
The reaction is carried out in an aqueous or organic medium. As organic 
solvent for example alcohols, e.g. methanol, ethanol; aromatic solvents, 
e.g. benzene; ethers, e.g. tetrahydrofurane, are employed. 
In the compounds of formula (I) the substituents R.sup.1 and/or R.sup.2 
and/or R.sup.3 may be converted into other groups within the definition of 
R.sup.1, R.sup.2 and R.sup.3, respectively. For example from the 
compounds, in which R.sup.1 and/or R.sup.2 is alkoxy having from 1 to 6 
carbon atoms, the corresponding compounds containing hydroxyl groups as 
R.sup.1 and/or R.sup.2 can be prepared by desalkylation. Desalkylation can 
be performed in a known manner, e.g. by heating the alkoxy compound with 
hydrogen bromide or iodide, or by means of anhydrous aluminium chloride. 
On the other hand, the compounds of the formula (I), in which R.sup.1 
and/or R.sup.2 stands for hydroxyl, can be converted into the 
corresponding alkoxy derivatives in a known manner. Methylation is 
preferably carried out with diazomethane or dimethyl sulfate, while the 
higher ethers can be prepared for example by the Williamson synthesis, 
using alkyl iodides. 
Compounds of the formula (I) can be converted into their acid addition 
salts by reaction with suitable acids. 
Salt formation can be carried out, for example, in an inert organic 
solvent, such as a C.sub.1-6 aliphatic alcohol, by suspending or 
dissolving the compound of the formula (I) in the solvent and adding the 
selected acid or a solution thereof formed with the same solvent to the 
first solution until it becomes slightly acidic. Thereafter the acid 
addition salt separates and can be removed from the reaction mixture e.g. 
by filtration. 
The compounds of the formula (I) or the salts thereof can be subjected, if 
desired, to further purification, e.g. recrystallization. The solvents 
used for recrystallization are selected depending on the solubility and 
crystallization properties of the compound to be crystallized. 
The new compounds of the formula (I) and their physiologically acceptable 
acid addition salts can be formulated for therapeutic purposes. The 
invention therefore relates also to pharmaceutical compositions comprising 
as active ingredient at least one compound of formula (I) or a 
physiologically acceptable salt thereof, in association with 
pharmaceutical carriers and/or excipients. Carriers conventional for this 
purpose and suitable for parenteral or enteral administration as well as 
other additives may be used. As carriers solid or liquid compounds, for 
example water, gelatine, lactose, starch, pectin, magnesium stearate, 
stearic acid, talc, vegetable oils, such as peanut oil, olive oil, arabic 
gum, polyalkylene glycols, and Vaseline (registered Trade Mark) can be 
used. The compounds can be formulated as conventional pharmaceutical 
formulations, for example in a solid (globular and angular pills, dragees, 
capsules, e.g. hard gelatine capsules) or liquid (injectable oily or 
aqueous solutions or suspensions) form. The quantity of the solid carrier 
can be caried within wide ranges, but preferably is between 25 mg and 1 g. 
The compositions optionally contain also conventional pharmaceutical 
additives, such as preserving agents, wetting agents, salts for adjusting 
the osmotic pressure, buffers, flavouring and aroma substances. 
The compositions according to the invention optionally contain the 
compounds of formula (I) in association with other known active 
ingredients. The unit doses are selected depending on the route of 
administration. The pharmaceutical compositions are prepared by 
conventional techniques including sieving, mixing, granulation, pressing 
or dissolution of the active ingredients. The formulations obtained are 
then subjected to additional conventional treatments, such as 
sterilization. 
For the pharmacological tests CFLP (LATI) mice of both sexes, weighing 18 
to 22 g each, and male Han. Wister (LATI) rats, weighing 160 to 180 g 
each, were used. The test materials were administered orally, in 30 mg/kg 
doses, in the form of a suspension containing 5% of Tween 80, one hour 
before the tests. 
TEST METHODS 
1. Metrazole spasm (MET), mice 
After pretreatment, the animals were subcutaneously administered 125 mg/kg 
of pentylenetetrazole. The animals which did not show a tonic extensoric 
spasm and survived the experiment were regarded protected. Observation 
time: one hour [Everett, L. M. and Richards, R. K.: J. Pharmacol. Exp. 
Ther. 81, 402 (1944)]. 
2. Strychnine spasm (STRY), mice 
One hour after pretreatment the animals were intraperitoneally administered 
2.5 mg/kg of strychnine nitrate to induce tonic extensoric spasm. The 
animals which showed no sign of spasm after treatment were considered 
protected [Kerley, T. L. et al.: J. Pharmacol. Exp. Ther. 132, 360 
(1961)]. 
3. Analgesic activity (ANAL), mice 
One hour after pretreatment, mice were administered 0.3 ml of a 0.6% acetic 
acid solution intraperitoneally, as a pain stimulus. The frequency of 
writhing syndrom was registered for 30 minutes. The changes observed as a 
result of treatment with the test compounds are related to the mean value 
of the frequency of writhing syndrom in the control group, and the 
difference is expressed in percentage [Koster, R. et al.: J. Pharmacol. 
Exp. Ther. 72, 74 (1941)]. 
4. Antipyretic activity (PYR), mice 
On rats hyperthermia was induced by a brewer's yeast suspension (0.5% of 
brewer's yeast, 1% of arabic gum made up to 0.3 ml with water) 
administered subcutaneously. After 4 hours, the animals were treated with 
the test materials, and the tracheal temperature was registered with an 
ELAB thermometer (Type TE-3) every hour, altogether for 4 hours. The 
antipyretic activity is expressed in percentage of the animals which had a 
1.degree. C. lower temperature after treatment than the mean temperature 
of the control group, treated with solvent alone [Nimegeers, C. J. E. et 
al.: Arzneim. Forsch. 25, 1591 (1975)]. 
5. Acute alcoholic intoxication (ETA), rats 
One hour after pretreatment the animals were intraperitoneally administered 
3.5 g/kg of ethyl alcohol. The narcosis time was registered and the mean 
times of the individual test groups were related to the narcosis time of 
the control group. The difference is expressed in percentage. 
The results of pharmacological tests are set forth in Table I below. 
Test compounds: 
Compound "A": 
1-[6'-(2'-piperidino-5',6',7',8'-tetrahydro-4'-oxo-quinazolinyl)]-3,4-dihy 
dro-6,7-dimethoxy-isoquinoline; 
Compound "B": 
1-{6'-[2'-(4"-p-chlorophenyl-piperidino-4"-ol)-5',6',7',8'-tetrahydro-4'-o 
xo-quinazolinyl]}-3,4-dihydro-6,7-dimethoxy-isoquinoline; 
Compound "C": 
1-[6'-(2'-piperidino-4"-carboxamide)-5',6',7',8'-tetrahydro-4'-oxo-quinazo 
linyl]-3,4-dihydro-6,7-dimethoxy-isoquinoline; 
Compound "D": 
1-{6'-[2'-(3",4",5"-trimethoxyphenyl)-5',6',7',8'-tetrahydro-4'-oxo-quinaz 
olinyl]}-3,4-dihydro-6,7-dimethoxy-isoquinoline; 
Compound "E": 
1-{6'-[2'-(1",2",5",6"-tetrahydro-4"-phenyl-pyridino)-5',6',7',8'-tetrahyd 
ro-4'-oxo-quinazolinyl]}-3,4-dihydro-6,7-dimethoxy-isoquinoline 
Compound "F": 
1-{6'-[2'-N-(2"-chlorophenyl)-piperizino-5',6',7'8'-tetrahydro-4'-oxo-quin 
azolinyl]}-3,4-dihydro-6,7-dimethoxy-isoquinoline; 
Compound "G": 
1-{6'-[2'-(3"-methyl)-phenyl-5',6',7',8'-tetrahydro-4'-oxo-quinazolinyl]}- 
3,4-dihydro-6,7-dimethoxy-isoquinoline; 
Compound "H": 
1-{6'-[2'-(3"-pyridine)-5',6',7',8'-tetrahydro-4'-oxo-quinazolinyl]}-3,4-d 
ihydro-6,7-dimethoxy-isoquinoline; 
Compound "I": 
1-[6'-(2'-pyrrolidino-5',6',7',8'-tetrahydro-4'-oxo-quinazolinyl)]-3,4-dih 
ydro-6,7-dimethoxy-isoquinoline 
TABLE I 
______________________________________ 
Anticonvulsive activity (%) 
Compound 
MET STRY ANAL PYR ETA 
______________________________________ 
"A" -40 
"B" -40% -45% 
"C" -58% 
"D" 40 
"E" 40 
"F" 40 
"G" ED.sub.50 = 21.2 
mg/kg 
"H" -40% 
"I" 40 40 ED.sub.50 = 
-40% 
19.3 mg/kg 
______________________________________ 
The results show that especially compound "G" shows a remarkable 
anticonvulsive activity, having an ED.sub.50 -value of 21.2 mg/kg. As to 
the analgesic activity of the test compounds, Compound "I" is the most 
effective, with an ED.sub.50 -value of 19.3 mg/kg. Compounds "B" and "I" 
show a substantial antipyretic activity, while compounds "B", "C" and "H" 
have a remarkable protecting effect in acute alcoholic intoxication.