Hexahydro-1,4-oxazepines, their preparation, and drugs containing these compounds

Novel hexahydro-1,4-oxazepines of the general formula I ##STR1## where R.sup.1 is hydrogen, or alkyl or acyl each of 1 to 4 carbon atoms, PA1 R.sup.2 is alkyl of 1 to 4 carbon atoms and PA1 R.sup.3 and R.sup.4 are identical or different and each is hydrogen or methyl, and their salts with physiologically acceptable acids, processes for their preparation, drugs which contain these compounds, and their use in therapy. The compounds may be used for the pharmacotherapy of pain of various geneses.

It is known that certain nitrogen-containing heterocyclics with 7-membered 
and 8-membered rings possess an analgesic action. For example, amongst the 
group of the azepines, meptazinol 
(3-(3-ethyl-hexahydro-1-methyl-1H-azepin-3-yl)-phenol, disclosed in German 
laid-open application DOS Nos. 1,941,534), and amongst the group of the 
benzoxazepines, nefopam 
(5-methyl-1-phenyl-3,4,5,6-tetrahydro-1H-benz[f]-2,5-oxacine, disclosed in 
German Pat. No. 1,620,198) are known analgesics. 
We have found novel oxazepine derivatives which exhibit a stronger 
analgesic action. 
The present invention relates to hexahydro-1,4-oxazepines of the general 
formula I 
##STR2## 
where R.sup.1 is hydrogen, or alkyl or acyl each of 1 to 4 carbon atoms, 
R.sup.2 is alkyl of 1 to 4 carbon atoms and 
R.sup.3 and R.sup.4 are identical or different and each is hydrogen or 
methyl, 
and their salts with physiologically acceptable acids. 
The invention further relates to a process for the preparation of a 
hexahydro-1,4-oxazepine of the general formula I, wherein a compound of 
the general formula II 
##STR3## 
where R.sup.5 is alkyl of 1 to 4 carbon atoms and 
R.sup.2, R.sup.3 and R.sup.4 have the above meanings, is reduced and 
thereafter, if desired, the alkyl group R.sup.5 is replaced by hydrogen or 
acyl, and the compound obtained is converted, if desired, to a salt with a 
physiologically acceptable acid. 
Finally, the invention also relates to drugs which contain 
hexahydro-1,4-oxazepines of the general formula I. 
The compounds I contain from 1 to 3 asymmetric carbon atoms, so that they 
can be prepared in the form of racemates or of stereoisomers. The latter 
may be obtained in the pure form either by asymmetric synthesis or by 
separation of the racemates. 
The reduction of a compound II requires a powerful reducing agent, such as 
diborane or, preferably, lithium aluminum hydride, particularly suitable 
solvents being tetrahydrofuran, dioxane or diethyl ether. The reduction is 
carried out at an elevated temperature, preferably at the boiling point of 
the solvent. 
The replacement of an alkoxy group on the phenyl ring by a hydroxyl group 
can be effected, for example, with a basic ether-cleaving compound, such 
as sodium methylmercaptide, in a dipolar aprotic solvent, for example 
hexamethylphosphorotriamide, dimethylsulfoxide or dimethylformamide, at 
from 50.degree. to 200.degree. C., preferably at from 100.degree. to 
150.degree. C. 
Virtually all conventional processes may be employed for acylating the free 
hydroxyl group. The simplest is the reaction with an acid anhydride or an 
acid halide at an elevated temperature. 
The starting materials of the general formula II required for the 
preparation of the novel compounds have not previously been described. 
They may be prepared as follows: 
Reaction of a ketone III with N-benzyl-N-methyl-methyleneimonium chloride 
IV gives a Mannich compound V (cf. Angew. Chem. 88 (1976), 261): 
##STR4## 
The compound V reacts with an alkyl-Grignard compound to give a compound VI 
(cf. J. Amer. Chem. Soc. 71 (1949), 2050) 
##STR5## 
from which the benzyl radical is removed by hydrogenation. 
Reaction of the debenzylated compound with chloroacetyl chloride or 
.alpha.-chloropropionyl chloride in the presence of dilute sodium 
hydroxide solution or triethylamine gives the compound 
##STR6## 
from which the compounds II may be prepared by heating with a base, such 
as potassium tert.-butanolate, in dimethylsulfoxide (cf. German laid-open 
application DOS No. 1,944,468). 
The compounds according to the invention are distinguished by a pronounced 
analgesic action. They are therefore suitable for the pharmacotherapy of 
pain of different geneses. 
The tail flick test of D'AMOUR and SMITH (J. Pharmacol. 72 (1941), 74-79) 
was used as a model for testing the analgesic action. In this experiment, 
the compounds to be tested (in the form of aqueous solutions, the volume 
injected being 10 ml/kg) were administered intraperitoneally or orally to 
groups of 10 female mice (NMRI strain) each weighing 19-23 g. 
Pain reactions were caused by thermal irritation (focused radiation of heat 
from a halogen lamp onto the tail for a maximum of 30 seconds) before, and 
30 minutes after, the administration of the compound. 
The time which elapses before the tail is retracted, by reflex action from 
the irradiation zone is measured as the reaction time. In the case of 670 
untreated animals it averages 6.5.+-.0.29 sec. Analgesic compounds 
lengthen the reaction time, the effects depending on the dose. There is a 
linear relationship between the logarithms of the doses (mg/kg) and the 
relative increase in the reaction time (.DELTA.%), from which the ED 100%, 
i.e. the dose which doubles the reaction time, can be calculated by 
regression analysis. With an irradiation period of at most 30 seconds, the 
maximum possible increase in the reaction time is about 360%. 
The analgesic action of the compounds according to the invention in the 
tail flick test manifests itself particularly on oral administration, ie. 
the form of administration which is clinically important (Table 1). The 
activity of the compounds is from 2 to 28 times greater than that of 
nefopam. The quotient of the effective dose (ED 100%) for intraperitoneal 
and for oral administration (0.41-0.83), which is a measure of the enteral 
activity, is very high. It indicates that the doses of the compounds 
according to the invention which are orally active are only slightly above 
those which are intraperitoneally active. The enteral activity is from 2.4 
to 4.9 times greater than that of nefopam. 
In the tail flick test, non-toxic doses of nefopam can, regardless of the 
route of administration, only achieve partial analgesia (192% increase in 
the reaction time on intraperitoneal administration, or 93% on oral 
administration). At higher doses, nefopam is toxic and produces a high 
mortality rate. In contrast, with the compounds according to the invention 
the reaction time can be lengthened to substantially higher maximum values 
(by 276-435% on intraperitoneal administration and by 223-419% on oral 
administration), without producing toxic effects. 
TABLE 1 
__________________________________________________________________________ 
Analgesic action on mice in the tail flick test 
Com- 
pound Intraperitoneal administration 
Oral administration 
of Ex. 
ED Relative 
Maximum action.sup.2 
ED Relative 
Maximum action 
No. 100%.sup.1 
activity 
mg/kg 
% 100% 
activity 
mg/kg 
% Q.sup.3 
__________________________________________________________________________ 
2 12.7 
0.64 
46.4 332 22.4 
2.07 
100 333 0.57 
1 1.71 
4.73 
10.0 276 2.07 
22.42 
10.0 387 0.83 
6 6.83 
1.18 
46.4 326 8.71 
5.33 
46.4 419 0.78 
7 0.675 
11.97 
4.64 382 1.66 
27.95 
4.64 300 0.41 
3 6.58 
1.23 
21.5 351 15.3 
3.03 
46.4 223 0.43 
4 4.43 
1.82 
21.5 319 6.27 
7.40 
100 397 0.71 
5 5.66 
1.43 
46.4 435 7.01 
6.62 
21.5 318 0.81 
9 (+) 
2.08 
3.89 
10.0 339 2.76 
16.81 
10.0 310 0.75 
Nefopam 
8.08 
.ident.1.00 
21.5.sup.4 
192 about 
.ident.1.00 
46.4.sup.5 
93 0.17 
46.4 
__________________________________________________________________________ 
.sup.1 Dose (mg/kg) which lengthens the reaction time by 100% 
##STR7## 
.sup.3 Q = enteral activity = ED 100% for intraperitoneal 
administration/ED 100% for oral administration 
.sup.4 Toxic at 46.4 mg/kg (6 out of 10 animals die) 
.sup.5 Toxic at 100 mg/kg (6 out of 10 animals die) 
The compounds according to the invention can be administered in a 
conventional manner, orally or parenterally (subcutaneously, 
intravenously, intramuscularly or intraperitoneally). 
The dosage depends on the age, condition and weight of the patients and on 
the route of administration. As a rule, the daily dose of active compound 
is from about 0.01 to 1.0 mg/kg on intravenous, subcutaneous, 
intramuscular or oral administration. This dose is administered in from 1 
to 3 portions over the course of the day. In severe cases, administration 
may be even more frequent. 
The novel compounds may be employed in the conventional solid or liquid 
pharmaceutical forms for administration, for example as tablets, capsules, 
powders, granules, dragees, solutions or suppositories. These are produced 
in a conventional manner. 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. L. G. Goodman and A. Gilman: The 
Pharmacological Basis of Therapeutics). 
The novel compounds may also be administered in the form of their salts 
with physiologically acceptable acids. Examples of such acids are 
hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, citric 
acid, fumaric acid, acetic acid, formic acid, succinic acid, maleic acid, 
lactic acid and amidosulfonic acid. 
Preparation of the starting materials 
(a) .beta.-(N-Benzyl-N-methyl)-amino-3-methoxypropiophenone hydrochloride. 
60 g of 3-methoxyacetophenone (0.4 mole) and 70 g of 
N-benzyl-N-methyl-methyleneimonium chloride (0.4 mole) (prepared from 
bis-(benzylmethylamino)-methane and acetyl chloride) in 500 ml of dry 
acetonitrile are heated, whilst stirring, for 60 minutes at 75.degree. C. 
and then for 15 minutes at 80.degree. C. The solution is cooled and 
introduced into 2 liters of ether, the product is filtered off and 88 g 
(69% of theory) of a compound of melting point 134.degree.-138.degree. C. 
are obtained; this can be recrystallized from isopropanol or can be used 
in the crude form for the subsequent reaction. 
Melting point, after recrystallization from isopropanol: 
140.degree.-142.degree. C. 
.beta.-(N-Benzyl-N-methyl)-amino-.alpha.-methyl-3-methoxypropiophenone 
hydrochloride is prepared similarly from 3-methoxypropiophenone. Melting 
point 125.degree. C. 
(b) 1-(N-Benzyl-N-methyl)-amino-3-hydroxy-3-(3-methoxyphenyl)-pentane 
170 g (0.53 mole) of 
.beta.-(N-benzyl-N-methyl)-amino-3-methoxypropiophenone hydrochloride 
(obtained as described in (a)) are introduced, whilst stirring and cooling 
with an icebath, into a Grignard solution which has been prepared from 218 
g (2.0 moles) of ethyl bromide, 48 g (2.0 moles) of magnesium and 1.5 
liters of dry ether; the mixture is refluxed for 2-3 hours and is then 
stirred overnight at room temperature, after which the batch is decomposed 
with ammonium chloride solution. The ether phase is separated off and 
dried with sodium sulfate, the ether is distilled off and the residue is 
fractionated under reduced pressure. 
Yield 134 g (81% of theory). Boiling point 180.degree.-190.degree. C./0.01 
mbar. 
The following are obtained by a similar method: 
1-(N-Benzyl-N-methyl)-amino-3-hydroxy-3-(3-methoxyphenyl)-butane, boiling 
point 175.degree.-180.degree. C./0.01 mbar, 
1-(N-benzyl-N-methyl)-amino-3-hydroxy-3-(3-methoxyphenyl)-hexane, boiling 
point 185.degree.-195.degree. C./0.01 mbar and 
1-(N-benzyl-N-methyl)-amino-2-methyl-3-hydroxy-3-(3-methoxyphenyl)-pentane, 
boiling point 180.degree.-185.degree. C./0.01 mbar. 
(c) 1-Methylamino-3-hydroxy-3-(3-methoxyphenyl)-pentane 
78.6 g (0.25 mole) of 
1-(N-benzyl-N-methyl)-amino-3-hydroxy-3-(3-methoxyphenyl)-pentane 
(prepared as described in (b)) are dissolved in 400 ml of methanol and are 
hydrogenated in the presence of 8 g of 10% strength palladium-on-charcoal 
catalyst under atmospheric pressure at room temperature. After the 
absorption of hydrogen has ended, the catalyst is filtered off, the 
solution is evaporated and the product is obtained as an oil which 
crystallizes. 
Yield: 53 g (94% of theory). Melting point, after recrystallization from 
hexane: 52.degree.-54.degree. C. 
The following are obtained by similar methods: 
1-Methylamino-3-hydroxy-3-(3-methoxyphenyl)-butane (used in the crude form 
for further conversion), 
1-methylamino-3-hydroxy-3-(3-methoxyphenyl)-hexane, melting point, after 
recrystallization from hexane: 70.degree.-72.degree. C., and 
1-methylamino-2-methyl-3-hydroxy-3-(3-methoxyphenyl)-pentane (used in the 
crude form for further conversion). 
(d) 1-(N-Chloroacetyl)-methylamino-3-hydroxy-3-(3-methoxyphenyl)-pentane 
100 ml of 2 N sodium hydroxide solution are added to a solution of 35 g 
(0.16 mole) of 1-(methylamino-3-hydroxy-3-(3-methoxyphenyl)-pentane 
(obtained as described in (c)) in 250 ml of ether, and 18 g (0.16 mole) of 
chloroacetyl chloride are then added dropwise in the course of 30 minutes, 
whilst stirring. The mixture is then heated for 90 minutes, the ether 
layer is separated off and dried with sodium sulfate, and the solvent is 
distilled off. The residue is used in the crude form for further 
conversion. 
The following are obtained by similar methods: 
1-(N-Chloroacetyl)-methylamino-3-hydroxy-3-(3-methoxyphenyl)-butane, 
1-(N-chloroacetyl)-methylamino-3-hydroxy-3-(3-methoxyphenyl)-hexane and 
1-(N-chloroacetyl)-methylamino-2-methyl-3-hydroxy-3-(3-methoxyphenyl)-penta 
ne. 
If .alpha.-chloropropionyl chloride is used, 
1-(N-.alpha.-chloropropionyl)-methylamino-3-hydroxy-3-(3-methoxyphenyl)-pe 
ntane is obtained. 
(e) 7-Ethyl-7-(3-methoxyphenyl)-4-methyl-hexahydro-1,4-oxazepin-3-one 
41.4 g (0.14 mole) of 
1-(N-chloroacetyl)-methylamino-3-hydroxy-3-(3-methoxyphenyl)-pentane, 
obtained as described in (d), are dissolved in 200 ml of dimethylsulfoxide 
and 33.6 g of potassium tert.-butanolate are added in portions at 
20.degree. C. whilst stirring and gently cooling the mixture. The mixture 
is then heated at 50.degree. C. for 30-120 minutes, after which it is 
stirred overnight at room temperature. The mixture is worked up either by 
distilling off the solvent under reduced pressure at as low a temperature 
as possible, or by diluting the batch with 1.5 liters of water and 
extracting it with 3.times.250 ml of methylene chloride. The solvent is 
removed after drying over sodium sulfate, giving a crude product which is 
used, as obtained, for further processing. 
The following are obtained by similar methods: 
4,7-Dimethyl-7-(3-methoxyphenyl)-hexahydro-1,4-oxazepin-3-one; the compound 
crystallizes, melting point 88.degree.-94.degree. C., 
7-(3-methoxyphenyl)-4-methyl-7-propyl-hexahydro-1,4-oxazepin-3-one, 
4,6-dimethyl-7-ethyl-7-(3-methoxyphenyl)-hexahydro-1,4-oxazepin-3-one and 
2,4-dimethyl-7-ethyl-7-(3-methoxyphenyl)-hexahydro-1,4-oxazepin-3-one. 
Preparation of the end products

EXAMPLE 1 
7-Ethyl-7-(3-methoxyphenyl)-4-methyl-hexahydro-1,4-oxazepine 
36 g (0.14 mole) of crude 
7-ethyl-7-(3-methoxyphenyl)-4-methyl-hexahydro-1,4-oxazepine (cf. e) are 
dissolved in 100 ml of absolute tetrahydrofuran and the solution is added 
dropwise to a suspension of 15 g of lithium aluminum hydride in 500 ml of 
absolute tetrahydrofuran, at the boil. The mixture is then boiled for 6 
hours, cooled and decomposed with water in a conventional manner; after 
filtering off the inorganic residue, drying the filtrate and distilling 
off the solvent, the crude base is obtained, which is converted to its 
hydrochloride by means of a solution of hydrochloric acid in isopropanol. 
Yield of hydrochloride 15 g (38% of theory), melting point 
181.degree.-183.degree. C. 
The compounds tabulated below are obtained by similar methods: 
______________________________________ 
##STR8## 
Hydrochloride 
Example Melting point, 
Yield, 
No. R.sup.2 R.sup.3 R.sup.4 
.degree.C. % 
______________________________________ 
2 CH.sub.3 
H H 207-208 32 
3 C.sub.3 H.sub.7 
H H 199-201 33 
4 C.sub.2 H.sub.5 
CH.sub.3 
H 185-187 28 
5 C.sub.2 H.sub.5 
H CH.sub.3 
202-203 47 
______________________________________ 
EXAMPLE 6 
4,7-Dimethyl-7-(3-hydroxyphenyl)-hexahydro-1,4-oxazepine 
A solution of sodium methylmercaptide in ethanol is prepared from 2.3 g 
(0.1 mole) of sodium, 100 ml of absolute ethanol and 6.2 g (0.1 mole) of 
ethylmercaptan, the alcohol is distilled off under reduced pressure, 50 ml 
of dry dimethylformamide and 5.1 g (0.02 mole) of 
4,7-dimethyl-7-(3-methoxyphenyl)-hexahydro-1,4-oxazepine (base) (obtained 
as described in Example 1) are added and the batch is heated at 
140.degree. C. for 3 hours. It is then diluted with 500 ml of water and 
neutralized with acetic acid, and the solution is repeatedly extracted 
with methylene chloride. After removing the solvent from the extract, the 
residue is taken up in 100 ml of ether and the product is precipitated as 
the hydrochloride by introducing hydrogen chloride gas into the solution. 
The hydrochloride is recrystallized from ethanol. 
Yield: 2.7 g (53% of theory). Melting point 248.degree. C. 
The following are obtained by similar methods: 
EXAMPLE 7 
7-Ethyl-7-(3-hydroxyphenyl)-4-methyl-hexahydro-1,4-oxazepine, melting point 
204.degree.-206.degree. C. 
EXAMPLE 8 
7-(3-Acetoxyphenyl)-7-ethyl-4-methyl-hexahydro-1,4-oxazepine 
2.7 g (0.01 mole) of the 
7-ethyl-7-(3-hydroxyphenyl)-4-methyl-hexahydro-1,4-oxazepine hydrochloride 
obtained as described in Example 2 are boiled with 25 ml of acetic 
anhydride for 3 hours. The excess acetic anhydride is then distilled off 
under reduced pressure and the residue is recrystallized from an 
isopropanol/ether mixture. 
Yield: 2.4 g of the hydrochloride (75% of theory). Melting point 
210.degree. C. 
EXAMPLE 9 
(+)- and (-)-7-Ethyl-7-(3-methoxyphenyl)-4-methyl-hexahydro-1,4-oxazepine 
(separation of the racemate) 
A solution of 12 g (0.05 mole) of racemic 
7-ethyl-7-(3-methoxyphenyl)-4-methyl-hexahydro-1,4-oxazepine (cf. Example 
1) and 17 g (0.05 mole) of L-(-)-0,0-dibenzoyltartaric acid monohydrate in 
50 ml of isopropanol and 10 ml of diisopropyl ether is prepared; after 
some time, the salt of the dextrorotatory base crystallizes out. After 
recrystallizing this 3 or 4 times from a 5-fold amount of isopropanol, 6 g 
(about 40% of theory) of a product of constant optical rotation are 
obtained. 
Specific rotation: [.alpha.].sub.589 nm.sup.20 =-45.degree. (c=10 mg/ml in 
ethanol). 
The base is obtained from the salt in a conventional manner and is 
converted to its hydrochloride. 
If D-(+)-0,0-dibenzoyltartaric acid is used for separating the racemate, 
the dibenzoyltartrate of the levorotatory base is obtained similarly. 
Specific rotations: 
bases: [.alpha.].sub.589.sup.20 =+/-35.degree. (c=28 mg/ml in ethanol) 
hydrochlorides: [.alpha.].sub.589.sup.20 =+/-44.degree. (c=10 mg/ml in 
ethanol) 
Melting point 202.degree.-203.degree. C. 
EXAMPLE 10 
Tablets of the following composition are produced in a conventional manner 
on a tableting press: 
10.00 mg of 7-ethyl-7-(3-methoxyphenyl)-4-methyl-hexahydro-1,4-oxazepine 
hydrochloride 
50.00 mg of corn starch 
4.50 mg of gelatin 
15.00 mg of lactose 
7.50 mg of talc 
0.75 mg of Aerosil.RTM. (chemically pure silica in a submicroscopic state 
of division) and 
2.25 mg of potato starch (as a 6% strength paste). cl EXAMPLE 11 
Dragees of the following composition are prepared in a conventional manner: 
10.00 mg of 7-ethyl-7-(3-methoxyphenyl)-4-methyl-hexahydro-1,4-oxazepine 
hydrochloride 
50.00 mg of core composition 
40.00 mg of sugar-coating composition. 
The core composition consists of 9 parts of corn starch, 3 parts of lactose 
and 1 part of Luviskol.RTM. VA 64 (a 60:40 vinylpyrrolidone/vinyl acetate 
copolymer, cf. Pharm. Ind. 1962, 586). The sugar-coating composition 
consists of 5 parts of cane sugar, 2 parts of corn starch, 2 parts of 
calcium carbonate and 1 part of talc. The dragees thus produced are then 
provided with a coating resistant to gastric juices. 
EXAMPLE 12 
5 g of 7 -ethyl-7-(3-methoxyphenyl)-4-methyl-hexahydro-1,4-oxazepine 
hydrochloride are dissolved in 2.0 liters of water, sodium chloride is 
added to make the solution isotonic, and the latter is sterile-packed in 
ampoules of 2 ml capacity.