5,6-Dihydro-11-methylenemorphanthridin-6-ones, their preparation and drugs containing these compounds

5,6-Dihydro-11-methylenemorphanthridin-6-ones of the formula I ##STR1## where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the meanings given in the description, and their preparation and use. The novel substances are particularly useful for treating gastric and duodenal ulcers.

The present invention relates to 
5,6-dihydro-11-methylenemorphanthridin-6-ones, processes for their 
preparation, therapeutic agents containing these compounds, and the use of 
these agents as drugs. 
It has been disclosed that tricyclic ring systems of the 
5,11-dihydro-6H-pyrido[2.3-b] [1.4]benzodiazepin-6-one type possess useful 
properties (Arzneim.Forsch. 27 (1977), 356; and German Laid-Open 
Applications DOS 2,724,501 and DOS 2,724,478), which enable them to be 
employed for the treatment of gastric and duodenal ulcers. 
We have found that 5,6-dihydro-11-methylenemorphanthridin-6-ones of the 
formula I 
##STR2## 
where R.sup.1 and R.sup.2 are each hydrogen, halogen, alkyl of 1 to 3 
carbon atoms or trifluoromethyl, R.sup.3 is aminoalkyl, where alkyl is of 
1 to 3 carbon atoms, and the amine nitrogen atom can be substituted by 1 
or 2 alkyl radicals of 1 to 3 carbon atoms or can form part of a 
5-membered, 6-membered or 7-membered saturated ring which can contain a 
nitrogen, oxygen or sulfur atom as a further hetero atom or can contain a 
carbonyl group, and any nitrogen atom present can be substituted by alkyl 
of 1 to 3 carbon atoms or hydroxyalkyl of 2 or 3 carbon atoms or by phenyl 
which may be substituted by fluorine, chlorine, methoxy or methyl, and 
R.sup.4 is hydrogen, or R.sup.3 and R.sup.4 together form a 5-membered, 
6-membered or 7-membered saturated ring which can be substituted by one or 
more alkyl radicals of 1 to 3 carbon atoms, or can be converted to a 
bicyclic structure by an intramolecular methylene or bismethylene bridge 
and can contain a further nitrogen atom which can be substituted by alkyl 
of 1 to 3 carbon atoms or can be present in the form of the N-oxide, and 
their physiologically tolerated addition salts with acids, possess useful 
pharmacological properties. 
The novel compounds of the formula I can occur as cis/trans isomers Ia and 
Ib: 
##STR3## 
R.sup.1 and R.sup.2 are each preferably hydrogen, chlorine or methyl. 
Specific examples of R.sup.3 are aminomethyl, methylaminomethyl, 
dimethylaminomethyl, 2-dimethylaminoethyl, 4-methylpiperazin-1-ylmethyl, 
morpholin-1-ylmethyl, 3,5-dimethylmorpholin-1-ylmethyl, 
2-morpholin-1-ylethyl, 1-methylmorpholin-3-yl, 1-benzylmorpholin-3-yl and 
1-benzylmorpholin-6-on-3-yl, morpholin-1-ylmethyl being particularly 
preferred. 
Cyclic structures R.sup.3 and R.sup.4 are, in particular, 
1-methylpiperidin-4-yl and N-methyl-8-azabicyclo[3.2.1]octan-3-yl. 
Compounds which are particularly active include 
cis,trans-11-(2-morpholin-1-yl)-ethoxycarbonylmethylene-5,6-dihydromorphan 
thridin-6-one, 
cis-11-(2-morpholin-1-yl)-ethoxycarbonylmethylene-5,6-dihydromorphanthridi 
n-6-one, 
trans-11-(2-morpholin-1-yl)-ethoxycarbonylmethylene-5,6-dihydromorphanthri 
din-6-one, cis, 
trans-11-(2-dimethylamino)-ethoxycarbonylmethylene-5,6-dihydromorphanthrid 
in-6-one and 
cis,trans-11-(3-morpholin-1-yl)-propoxycarbonylmethylene-5,6-dihydromorpha 
nthridin-6-one. 
The novel compounds of the formula I are prepared by a process wherein 
(a) a compound of the formula II 
##STR4## 
where R.sup.1 and R.sup.2 have the above meanings and Z is a nucleofugic 
leaving group, is reacted with an aminoalcohol of the formula III 
EQU HO--CHR.sup.3 R.sup.4 III, 
where R.sup.3 and R.sup.4 have the above meanings, 
or, where R.sup.4 is hydrogen, 
(b) a compound of the formula IV 
##STR5## 
where Hal is halogen and n is 1, 2 or 3, is reacted with an appropriate 
amine, with nucleophilic substitution of the halogen, and, if required, 
the product thus obtained is separated into the pure cis and trans isomers 
and/or, if desired, converted to an addition salt with a physiologically 
tolerated acid. 
A suitable nucleofugic leaving group Z is halogen, in particular chlorine. 
Reaction (a) is advantageously carried out in the presence of one mole 
equivalent of a tertiary amine, eg. triethylamine, in an inert solvent, 
such as a cyclic saturated ether, in particular tetrahydrofuran or 
dioxane, or in a polar aprotic solvent, preferably dimethylformamide, at 
from 0.degree. to 150.degree. C., preferably at room temperature, and is 
in general complete in the course of from 3 to 10 hours. 
If appropriate, the reaction can also be carried out in the presence of an 
excess of the aminoalcohol III employed, and this simultaneously serves as 
the solvent and, where relevant, as an acid acceptor. 
Suitable nucleofugic groups are chlorine, bromine, iodine and 
alkylcarbonyloxy. 
Reaction (b) is carried out in an excess of the appropriate amine, which 
simultaneously serves as the solvent, at from 50.degree. to 150.degree. 
C., preferably 110.degree. C., or in an inert organic solvent. 
The product is converted to the N-oxide in a conventional manner, 
advantageously with aqueous hydrogen peroxide in ethanolic solution. 
Conversion to an addition salt with a physiologically tolerated acid is 
likewise carried out in a conventional manner. 
The compounds of the formula I are obtained as a rule in crystalline form, 
and can be purified by recrystallization from a conventional organic 
solvent, preferably a lower alcohol, eg. ethanol, or a lower ester, 
preferably ethyl acetate, or by column chromatography. 
The resulting compounds according to the invention are, if desired, 
converted to addition salts with physiologically tolerated acids. Examples 
of suitable conventional physiologically tolerated organic or inorganic 
acids are hydrochloric acid, hydrobromic acid, phosphoric acid and 
sulfuric acid, and oxalic acid, maleic acid, fumaric acid, lactic acid, 
tartaric acid, malic acid, citric acid, salicylic acid, adipic acid and 
benzoic acid. Further acids can be found in, for example, J. Pharm. Sci. 
66 (1977), 1. 
The addition salts with acids are obtained as a rule in a conventional 
manner, by mixing the free base, or a solution thereof, with the 
appropriate acid, or a solution thereof, in an organic solvent, for 
example a lower alcohol, such as methanol, ethanol or propanol, a lower 
ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, or 
an ether, such as diethyl ether, tetrahydrofuran or dioxane. To achieve 
better precipitation of crystals, a mixture of any of the above solvents 
may also be used. 
The starting compounds of the formula II are obtained by reacting a 
cis,trans-11-carboxymethylene-5,6-dihydromorphanthridin-6-one of the 
formula V 
##STR6## 
where R.sup.1 and R.sup.2 have the above meanings, with excess thionyl 
chloride in a conventional manner at room temperature to give the acyl 
chloride. 
The compounds of the formula V are obtained by hydrolysis of the 
corresponding esters (German Laid-Open Application DOS 2,918,832) with 
alcoholic sodium hydroxide solution at from 40.degree. to 90.degree. C. 
The compounds IV are obtained by reacting a compound II with a haloalcohol 
of the formula Hal--(CH.sub.2 ).sub.n --OH, where Hal is halogen and n is 
2, 3 or 4. The reaction can be carried out in an inert organic solvent or 
an excess of the haloalcohol at from 20.degree. to 100.degree. C. 
To prepare the pure cis and trans isomers, the cis- and trans-carboxylic 
acid derivatives, respectively, of the formula V are preferably employed 
as starting materials. The isomer mixture is best separated by fractional 
crystallization, and the isomers are assigned on the basis of the NMR 
signals (270 MHz) of the 11-methylene proton at 6.12 and 6.18 ppm. 
The individual isomers are assigned to the cis or trans series by, for 
example, X-ray structure analysis. 
The novel compounds and their physiologically tolerated addition salts with 
acids are drugs which are useful for the treatment of disorders associated 
with pathologically increased gastric secretion, for example gastric and 
duodenal ulcers. 
To investigate the antiulcerogenic action, 1 mg/kg of reserpine is 
administered intraperitoneally to groups of 10 female Sprague-Dawley rats 
each weighing 160-180 g, and the rats then remain without food for 18 
hours (water ad libitum). This period is followed by intraperitoneal 
administration of 21.5 mg/kg of indometacin and oral administration of the 
test substance to the animals, which are then kept for 6 hours at 
8.degree. C., after which they are sacrificed. The stomachs are removed, 
and the area of ulcerous mucosal lesions is determined. The dose which 
reduces the ulcerous area by 50%, ie. the ED 50%, is determined from the 
linear regression between the logarithms of the doses administered and the 
relative reduction in the area of ulcerations, based on the control 
animals. 
Pirenzepine 
(5,11-dihydro-11-[(4-methylpiperazin-1-yl)-acetyl]-6H-pyrido[2,3-b][1,4]be 
nzodiazepin-6-one; German Pat. No. 1,795,183) is used as the reference 
substance. 
The compounds according to the invention inhibit the formation of gastric 
ulcers, to an extent dependent on the dose (Table 1). 
The actions of the compounds of Examples 3, 1, 2 and 15 are superior to the 
action of the known drug pirenzepine by a factor of from 3.4 to 10.2. 
TABLE 1 
______________________________________ 
Antiulcerogenic action on the rat 
ED 50% Relative 
Example No. mg/kg activity 
______________________________________ 
1, cis/trans 1.90 3.4 
1, cis 1.50 4.3 
1, trans 5.30 1.2 
2 0.64 10.2 
14 0.83 7.8 
pirenzipine 6.5 .ident.1.0 
______________________________________ 
The present invention therefore furthermore relates to drugs which contain 
a compound of the formula I or its physiologically tolerated addition salt 
with an acid, and to the use of the novel compounds in the treatment of 
disorders associated with pathologically increased gastric secretion. 
The novel compounds may be employed in the conventional solid or liquid 
pharmaceutical forms, such as tablets, film tablets, powders, granules, 
coated tablets, suppositories or solutions. These are prepared in a 
conventional manner, and to do so the active compounds can be mixed with 
the conventional pharmaceutical auxiliaries, such as tablet binders, 
fillers, preservatives, tablet disintegrating agents, flow regulators, 
plasticizers, wetting agents, dispersants, emulsifiers, solvents, 
retarders and/or antioxidants (cf. H. Sucker et al.: Pharmazeutische 
Technologie, Thieme-Verlag, Stuttgart 1978). The formulations thus 
obtained normally contain from 0.1 to 99% by weight of the active 
compound. 
The dosage of the compounds according to the invention depends on the age, 
condition and weight of the patient and on the route of administration. As 
a rule, the daily dose of active compound is from 5 to 100, preferably 
from 10 to 80, mg.

The Examples which follow illustrate the invention. The melting points of 
the cis/trans isomer mixtures can vary depending on the cis/trans ratio. 
EXAMPLE 1 
cis,trans-11-(2-Morpholin-1-yl)-ethoxycarbonylmethylene-5,6-dihydromorphant 
hridin-6-one 
a. Preparation of the starting material 
200 ml of 10% strength sodium hydroxide solution were added to 30.0 g (108 
millimoles) of 11-carbomethoxymethylene-5,6-dihydromorphanthridin-6-one in 
150 ml of ethanol, the reaction mixture was stirred under reflux for 2 
hours, then cooled and filtered, and the filtrate was evaporated down to 
about half its volume, under reduced pressure from a waterpump. The 
residue was acidified with concentrated hydrochloric acid, while cooling 
with ice, and the precipitated crystals were filtered off under suction 
and washed thoroughly with water. 27 g (94%) of 
cis,trans-11-carboxymethylene-5,6-dihydromorphanthridin-6-one of melting 
point 258.degree.-260.degree. C. were isolated. 
200 ml of thionyl chloride were added to 31.0 g (124 millimoles) of the 
compound thus prepared, and the mixture was stirred at room temperature, a 
solution being obtained in the course of 1 hour. Stirring was continued 
for a further hour, after which the thionyl chloride was stripped off 
under reduced pressure from an oilpump, the residue was taken up with a 
little toluene and the solvent was once again stripped off completely. The 
cis,trans-11-chlorocarbonylmethylene-5,6-dihydromorphanthridin-6-dihydromo 
rphanthridin-6-one which remained (yield 99%) was sufficiently pure for 
further reaction. 
b. Preparation of the end product 
19.6 g (150 millimoles) of N-(2-hydroxyethyl)morpholine and 12.5 g (124 
millimoles) of triethylamine were added, a little at a time, to 35.1 g 
(124 millimoles) of 
11-chlorocarbonylmethylene-5,6-dihydromorphanthridin-6-one (cis/trans 
isomer mixture) in 220 ml of dimethylformamide, while stirring thoroughly. 
The mixture was stirred under a nitrogen atmosphere for 2 hours at room 
temperature and then left to stand overnight, after which the solvent was 
completely distilled off under reduced pressure, the residue was 
partitioned between methylene chloride and water, the aqueous phase was 
rendered slightly alkaline with dilute sodium hydroxide solution and 
extracted twice with methylene chloride, and the combined organic phases 
were washed thoroughly with water, dried and evaporated down to give 46 g 
of crude product. 
To prepare the pure cis/trans isomer mixture, the crude product was 
purified by column chromatography over silica gel, using a 95:5 mixture of 
methylene chloride and methanol. 31 g (66%) of colorless 
cis,trans-11-(2-morpholin-1-yl)-ethoxycarbonylmethylene-5,6-dihydromorphan 
thridin-6-one of melting point 92.degree.-94.degree. C. were isolated. 
c. Separation of the isomer mixture 
Separation of the mixture to give the cis and trans isomers is best carried 
out at the stage of 11-carboxymethylene-5,6-dihydromorphanthridin-6-one 
(cf. a): 
20 g of 
cis,trans-11-(2-morpholin-1-yl)rethoxycarbonylmethylene-5,6-dihydromorphan 
thridin-6-one were dissolved in 1,200 ml of boiling methanol, the solution 
was filtered and the filtrate was subjected to fractional crystallization. 
8.2 g of colorless crystals were isolated as the fraction of lowest 
solubility, and were shown by the 270 MHz NMR spectrum to be very rich in 
isomer A (methylene-H in the 11-position at 6.18 ppm in D.sub.6 -DMSO); 
this product was obtained in pure form (mp. 299.degree.-301.degree. C. 
(decomposition)) by a further recrystallization from methanol. X-ray 
structure analysis of isomer A established that the carboxylic acid group 
is trans to the carbonyl group of the acid amide structure in the 
7-membered ring. 
A mixed fraction followed by a 3rd or 4th fraction comprising 6.5 g of a 
product very rich in isomer B (methylene-H in the 11-position at 6.12 ppm 
in D.sub.6 -DMSO) crystallized out from the mother liquor. 
Isomer B was purified by a further recrystallization from methanol; mp.: 
297.degree.-299.degree. C. (decomposition). 
From isomers A and B isolated in this manner, the pure cis and trans 
isomers of the end product were then obtained by procedures similar to 
those described in a and b. 5.0 g of isomer A gave, after the product had 
been purified by column chromatography (cf. b), 3,6 g (51%) of 
trans-11-(2-morpholin-1-yl)-ethoxycarbonylmethylene-5,6-dihydromorphanthri 
din-6-one of melting point 88.degree.-90.degree. C., while 3.6 g of isomer 
B gave 2.7 g (53%) of the corresponding cis-isomer of melting point 
98.degree.-100.degree. C. 
The following compounds were prepared by a procedure similar to that 
described in Example 1: 
2. 
cis,trans-11-(2-Dimethylamino)-ethoxycarbonylmethylene-5,6-dihydromorphant 
hridin-6-one. H.sub.2 O, mp. 78.degree.-80.degree. C. 
3. 
cis,trans-11-(3-Dimethylamino)-propoxycarbonylmethylene-5,6-dihydromorphan 
thridin-6-one.0.5 H.sub.2 O, mp. 74.degree.-76.degree. C. 
4. 
cis,trans-11-[2-(4-Methylpiperazin-1-yl)]-ethoxycarbonylmethylene-5,6-dihy 
dromorphanthridin-6-one.0.5 H.sub.2 O), mp. 87.degree.-90.degree. C. 
5. 
cis,trans-11-(1-Methylmorpholin-3-yl)-methoxycarbonylmethylene-5,6-dihydro 
morphanthridin-6-one, mp. 103.degree.-105.degree. C. 
6. 
cis,trans-11-(1-Benzylmorpholin-3-yl)-methoxycarbonylmethylene-5,6-dihydro 
morphanthridin-6-one.0.5 H.sub.2 O, mp. 81.degree.-84.degree. C. 
7. 
cis,trans-11-(1-Benzylmorpholin-6-on-3-yl)-methoxycarbonylmethylene-5,6-di 
hydromorphanthridin-6-one.0.5 H.sub.2 O, mp. 91.degree.-94.degree. C. 
8. 
cis,trans-11-(1-Methylpiperidin-4-yl)-oxycarbonylmethylene-5,6-dihydromorp 
hanthridin-6-one, mp. 114.degree.-116.degree. C. 
9. 
cis,trans-11-(N-Methyl-8-azabicyclo[3.2.1]octan-3-yloxycarbonylmethylene-5 
,6-dihydromorphanthridin-6-one.1.5 H.sub.2 O, mp. 133.degree.-136.degree. 
C. (column chromatography, 70:30 mixture of CH.sub.2 Cl.sub.2 and 
methanol). 
10. cis,trans-2-Chloro-11-(2-morpholin-1-yl)-ethoxycarbonylmethylene-5,6- 
dihydromorphanthridin-6-one, mp. 88.degree.-90.degree. C. 
11. 
cis-trans-3-Methyl-11-(2-morpholin-1-yl)-ethoxycarbonylmethylene-5,6-dihyd 
romorphanthridin-6-one, mp. 85.degree.-87.degree. C. 
EXAMPLE 12 
cis,trans-11-[2-(3,5-cis-dimethylmorpholin-1yl)]ethoxycarbonylmethylene-5,6 
-dihydromorphanthridin-6-one 
a. Preparation of the starting material 
cis,trans-11-(2-chloro)-ethoxycarbonylmethylene-5,6-dihydromorphanthridin- 
6-one 
7.0 g (25 millimoles) of 
11-chlorocarbonylmethylene-5,6-dihydromorphanthridin-6-one (cis/trans 
isomer mixture) were introduced, a little at a time, into 24 ml of 
2-chloroethanol at room temperature, while stirring, and a slightly 
exothermic reaction took place. The reaction mixture was stirred for a 
further 3 hours, and was then poured onto ice water. The simi-crystalline 
precipitate was filtered off under suction and washed thoroughly with 
water. The crude product was then dissolved in 500 ml of methylene 
chloride, and the solution was washed with water and 0.5N sodium hydroxide 
solution. The organic phase was dried and evaporated down to give 7.6 g 
(92%) of a crude product in the form of an oil, which was sufficiently 
pure for the subsequent reaction. 
b. Preparation of the end product 
3.5 g (10.7 millimoles) of 
cis,trans-11-(2-chloro)-ethoxycarbonylmethylene-5,6-dihydromorphanthridin- 
6-one were stirred with 8 ml of cis-3,5-dimethylmorpholine for 3 hours at 
110.degree. C., and the mixture was cooled. The dark reaction mixture was 
then dissolved in about 200 ml of methylene chloride, and the solution was 
washed three times with water, the pH of the aqueous phase being brought 
to 8-9 during washing. The organic phase was dried and evaporated down to 
give a crude product in the form of a dark oil, which was purified by 
column chromatography on silica gel, using a 95:5 mixture of methylene 
chloride and methanol as the mobile phase. 2.4 g (55%) of colorless 
crystals of melting point 75.degree.-78.degree. C. were isolated. 
The following compounds were obtained by a similar procedure: 
13. 
cis,trans-11-[2-(3,5-trans-Dimethylmorpholin-1-yl)]ethoxycarbonylmethylene 
-5,6-dihydromorphanthridin-6-one, mp. 67.degree.-69.degree. C. 
14. 
cis,trans-11-(3-Morpholin-1-yl)-propoxycarbonylmethylene-5,6-dihydromorpha 
nthridin-6-one, mp. 79.degree.-81.degree. C. 
15. 
cis,trans-11-(2-Methylmorpholin-1-yl)-ethoxycarbonylmethylene-5,6-dihydrom 
orphanthridin-6-one, mp. 76.degree.-78.degree. C. 
16. 
cis,trans-11-(Thiamorpholin-1-yl)-ethoxycarbonylmethylene-5,6-dihydromorph 
anthridin-6-one, mp. 83.degree.-85.degree. C.