Azidoethylmorphine, a new 7,8-dihydroisomorphine derivative, has excellent antitussive effects without respiration depression.

FIELD OF THE INVENTION 
This invention relates to a new 7,8-dihydroisomorphine derivative and 
pharmaceutical products containing the same, as well as to a process for 
the preparation thereof and a method of treatment. 
More particularly, this invention relates to the new compound azidoethyl 
morphine and pharmaceutically acceptable salts of this compound. 
DESCRIPTION OF THE INVENTION 
The compound can be prepared according to the invention as follows: the 
hydroxy groups attached to positions 3 and 6 of the 7,8-dihydromorphine 
are blocked by appropriate protecting groups, the obtained compound is 
reacted with a metal azide or a substance furnishing azido groups under 
the reaction conditions and, if desired, the O-blocking group attached to 
position 3 of the obtained substance is split off, and/or, if desired, the 
product is converted into its salt, or the free base is liberated from the 
salt. 
The new compound according to the invention can be used in human therapy 
primarily as an analgesic agent. It can be administered either alone or 
together with other morphine derivatives or other biologically active 
substances. 
3-O-ethyl-7,8-dihydromorphine, used as a starting substance in the process 
according to the invention, is a known compound. The hydroxy groups 
attached to positions 3 and 6 of the molecules can be protected, prior to 
azidolysis, by several methods. The hydroxy group in position 3 is 
protected preferably with an acyl, tetrahydropyranyl or methylenemethoxy 
group; these groups can be removed either during or after azidolysis. 
If 3-substituted derivatives are to be prepared, the hydroxy group attached 
to position 3 of 7,8-dihydromorphine and of 14-hydroxy-7,8-dihydromorphine 
is protected with an acyl, alkyl, aralkyl or aryl group, and the 
protecting group is not removed during or after azidolysis, either. 
According to a preferred method of the invention the hydroxy group attached 
to position 3 is protected by subjecting the dihydroxy compounds to 
partial acylation, particularly acetylation, formylation or benzoylation. 
As esterifying agents, preferably the corresponding anhydrides are used, 
but other esterifying agents can be applied as well. 
The hydroxy group attached to position 6 can also be blocked with an acyl 
group. If more severe acylating conditions are used, the acylation of the 
hydroxy groups attached to position 3 and 6 takes place simultaneously, 
and 3,6-diacyl derivatives are formed. 
Particularly preferred intermediates for the azidolysis step can be formed 
by esterifying the hydroxy group in position 6 with an arylsulfonyl or 
alkylsulfonyl group, among which tosyl, mesyl, brosyl, nosyl and mesityl 
groups are the most preferred. 
If, for example, the hydroxy group in position 3 is blocked by partial 
esterification using acetic anhydride, and subsequently the hydroxy group 
in position 6 is esterified with p-toluenesulfonyl chloride, to yield an 
intermediate compound, the azidolysis is achieved with an excellent yield. 
Azidolysis is an important step of the synthesis according to the 
invention. In this step the substituted hydroxy group in position 6 is 
replaced by an azido group; this reaction is carried out by contacting the 
blocked compound with a substance furnishing azido groups. As reagents, 
metal azides, e.g. sodium or potassium or lithium azide, or substances 
furnishing azido groups during their decomposition can be used. 
The relatively unstable blocking groups attached to position 3 split off 
easily under the conditions of azidolysis, thus the hydroxy group in 
position 3 can be unblocked simultaneously with the introduction of the 
azido group. In this way e.g. a 3-O-acetyl derivative can be converted 
easily into the corresponding 3-hydroxy compound. 
The compounds prepared as described above can be isolated from the reaction 
mixture either as free bases or in the form of their salts. 
The salts obtained in the above reaction can be converted into other salts 
having greater pharmacological value or more favorable physicochemical 
properties. Of the salts the tartarates, acetates, salicylates, benzoates, 
hydrochlorides and formates are to be mentioned. 
The new compounds according to the invention can be converted into 
pharmaceutical compositions suitable for oral, parenteral or rectal 
administration. The pharmaceutical compositions can be prepared by known 
techniques, using conventional carriers and/or auxiliary agents. 
Azidoethylmorphine possesses outstanding therapeutical properties. When 
comparing this compound with the most important narcotics and analgesics 
we have found that it is more effective than any of the known substances 
with similar biological activities. A further advantage of the new 
compounds is that addiction occurs less frequently than with other 
analgesics, which where morphine derivatives are concerned, is an 
essential factor in judging therapeutic value. 
The invention is represented by the following non-limiting Examples.

EXAMPLES 
EXAMPLE I 
14.85 g. of 3-O-ethyl-7,8-dihydromorphine are dissolved in 60 ml. of 
absolute pyridine, and a solution of 6.014 g. (4.06 ml.) of 
methanesulfonyl chloride in 60 ml. of absolute pyridine are added dropwise 
to the stirred solution within about 20 minutes. During the addition the 
temperature of the mixture is kept between 0.degree. and 5.degree. C. The 
mixture is stirred for an additional 2 hours, thereafter allowed to stand 
at room temperature overnight. The reaction mixture is poured onto 1.5 l. 
of saturated aqueous sodium hydrocarbonate solution, and extracted with 
3.times.200 ml. of chloroform. The chloroform solutions are combined, 
washed with 2.times.100 ml. of water, and dried over magnesium sulfate. 
The solvents, including pyridine, are removed by distillation, and the 
obtained resinous substance is dissolved in warm absolute ether. The 
substance starts soon to crystallize. This way 11.86 g. (64%) of 
6-O-mesyl-dihydro-dionine are obtained; m.p.: 135.degree.-136.degree. C., 
(.alpha.).sub.D =-96.1.degree. (c=0.52, in chloroform). 
EXAMPLE II 
11.0 g. of 6-O-mesyl-dihydro-dionine are dissolved in 330 ml. of 
dimethylformamide, and a solution of 18.19 g. of sodium azide in 51.2 ml. 
of water is added. The homogeneous reaction mixture is warmed at 
100.degree. C. for 24 hours, thereafter cooled and poured onto 1.65 l. of 
water. The aqueous solution is extracted with 4.times.200 ml. of 
chloroform. The chloroform solutions are combined, washed with 2.times.110 
ml. of saturated aqueous sodium chloride solution, dried over magnesium 
sulfate, filtered, and the filtrate is evaporated at a temperature not 
exceeding 50.degree. C. The obtained resinous product is dissolved in 
absolute ether. The separated fluffy substance is filtered off, and the 
filtrate is evaporated to dryness. 6.8 g. of a pure, resinous substance 
are obtained. This substance is dissolved in 102 ml. of dry ethanol, and a 
hot solution of 3 g. of D-tartaric acid in 30 ml. of ethanol is added. The 
tartrate separates as yellow crystal plates. The product is recrystallized 
twice from water. This way 
3-O-ethyl-6-deoxy-6-azido-7,8-dihydroisomorphine (azidoethyl morphine) 
bitartrate, melting at 55.degree.-56.degree. C., is obtained. 
(.alpha.).sub.D =-192.degree. (c=0.5, in chloroform). 
The bitartrate is dissolved in water, and the solution is rendered alkaline 
with sodium carbonate, to yield crystalline 
3-O-ethyl-6-deoxy-6-azido-7,8-dihydroisomorphine (azidoethyl morphine). 
Antitussive activity. The antitussive activity in rats was tested by the 
method of Gosswald (1). Wistar rats weighing 130-180 g were placed in a 
plexi box (23.times.22.times.11 cm) and cough responses were elicited by 
citric acid aerosol (10%). The latency period of cough was measured before 
and after drug administration. The control latency was determined 18 hours 
before the drug administration. Animals with less than 60 sec control 
latency were used for the experiments. The average control latency was 
found to be 29.41.+-.9.61 sec. Each animal was exposed to citric acid 
aerosol for a 3 min period 30 and 60 min after drug administration. The 
dose of a drug which inhibited coughing over 90 sec was considered 
effective. Ten animals were used at each dose level. The antitussive dose 
(AtD.sub.50) was calculated according to Litchfield and Wilcoxon (2). The 
drugs were administered by subcutaneous and oral routes. 
Antitussive activity in cats was determined by the method of Domenjoz (3). 
Cats weighing 2.5-3.5 kg were anaesthetized with an i.p. dose of 30 mg per 
kg of sodium pentobarbitone. The superior laryngral nerve was exposed and 
cough was induced by electrical stimulation of the nerve (1 msec, 10 Hz, 
5-10 V for 10 sec) through bipolar platinum electrodes every five minutes. 
The cough responses were measured by means of a Marey-tambour connected to 
a face mask, and recorded on a smoked paper. Drugs were given 
intravenously in increasing doees. The effect of each dose was measured on 
at least five cats. Effects of the drugs were calculated from the changes 
in amplitude of cough curves. If no coughing was produced by two 
successive stimulations, the dose was taken as the effective antitussive 
dose (AtD.sub.100). The antitussive dose (AtD.sub.50) which reduces the 
control response by 50 percent was calculated by the method of Litchfield 
and Wilcoxon (3). 
Respiratory effects. Effects on respiration were determined by means of 
Krogh-equipment. Respiratory frequency, depth and minute volume were 
calculated from the Krogh curves. Changes in respiration were determined 
before drug administration and after injecting doses at the AtD.sub.100 
level. Five animals were used for each substance. 
Circulatory effects. Blood pressure changes were studied in cats 
anaesthetized with pentobarbitone sodium (35 mg/kg.sup.-1, i.p). The 
substances were injected into the right femoral vein, responses to drugs 
were measured by means of a mercury manometer and recorded on a smoked 
cylinder. Since the hypotensive effects or morphine decrease on repeated 
administration (4), the blood pressure changes were calculated from the 
responses to the very first injections of the substances. 
Compounds. Codeine HCl, azidocodeine bitartrate, 14-OH-azidocodeine 
bitartrate, hydrocodone base, oxycodone base, morphine HCl, azidomorphine 
bitartrate, 14-OH-azidomorphine bitartrate, hydromorphone base, 
oxymorphone base, ethylmorphine HCl, azidoethylmorphine bitartrate, 
pholcodine base, azidopholcodine base (Alkaloida Pharmaceutical Works, 
Hungary). 
Antitussive effects. Tables I and II show the results of antitussive 
testing in cats and rats. The antitussive effect of azidomorphine in the 
cat was formed to be dose-dependent. An i.v. dose of 0.25-0.50 
mg.kg.sup.-1 of nalorphine antagonized the antitussive effects of all 
investigated drugs. 
The data in Tables I and II demonstrate that azidomorphines are the most 
potent antitussives among the semisynthetic morphine derivatives hitherto 
known. 
Effects on respiration. Table III shows the effect of the alkaloids on 
respiration in the cat expressed by the ratios of different breathing 
parameters (respiratory frequency, depth and minute volume) measured 
before and after administration of the AtD.sub.100 of the test compound. 
The azidomorphines (except 14-hydroxy-azidocodeine) did not influence 
respiration, but 5 out of the 8 non-azids depressed significantly at least 
one of the respiratory parameters. 
TABLE I 
__________________________________________________________________________ 
Inhibitory activity of azidomorphine derivatives and reference 
antitussives on citric acid aerosol induced cough in rats 
AtD.sub.50 Ratio 
AtD.sub.50 Ratio 
mg. kg..sup.-1 codeine/ 
mg. kg..sup.-1 codeine/ 
Compounds s.c. drug oral drug 
__________________________________________________________________________ 
Codeine 19.0(15.08-23.94) 
1.00 100.0(66.67-150.00 
1.00 
Hydrocodone 
0.90(0.61-1.37) 
21.11 
16.0(8.89-28.80) 6.25 
Oxycodone 1.40(1.15-1.71) 
13.57 
3.5(2.08-5.88) 28.57 
Azidocodeine 
1.57(1.29-2.41) 
12.10 
2.5(1.69-3.70) 40.00 
14-OH-azidocodeine 
0.82(0.71-0.95) 
23.17 
3.2(2.00-5.12) 31.25 
Morphine 3.00(1.84-4.25) 
6.33 74.0(51.03-107.30) 
1.35 
Hydromorphone 
0.26(0.22-0.30) 
73.07 
17.5(13.46-22.75 5.71 
Oxymorphone 
0.058(0.052-0.065) 
327.58 
14.0(11.45-15.38) 
7.14 
Azidomorphine 
0.034(0.023-0.049) 
558.82 
9.0(4.74-17.01) 11.11 
14-OH-azidomorphine 
0.021(0.013-0.035) 
904.76 
10.0(7.40-13.50) 10.00 
Ethylmorphine 
34.4(27.31-43.34) 
0.55 103.2(92.14-152.22) 
0.97 
Azidoethylmorphine 
3.5(2.37-5.18) 5.42 1.67(1.14-2.44) 59.88 
Pholcodine 30.00(20.00-45.00) 
0.63 -- -- 
Azidopholcodine 
4.5(3.04-6.66) 4.22 460.0(396.60-533.60) 
0.22 
Oxymethebanol 
7.0(4.93-9.94) 2.71 24.0(17.8-32.4) 4.16 
__________________________________________________________________________ 
Values in brackets indicate 95% confidence limits. 
Table II 
______________________________________ 
Inhibitory activity of azidomorphine derivatives and reference 
antitussives on electrical stimulation induced cough in cats 
Ratio Ratio 
AtD.sub.50 
Co- AtD.sub.50 
Co- 
mg. kg.sup.-1 
deine/ mg. kg.sup.-1 
deine/ 
Compounds i.v. drug i.v. drug 
______________________________________ 
Codeine 1.45 1.00 5.07 .+-. 1.87 
1.00 
Hydrocodone 0.20 7.25 0.56 .+-. 0.07 
9.05 
Oxycodone 0.20 7.25 0.44 .+-. 0.07 
11.52 
Azidocodeine 0.40 3.63 1.08 .+-. 0.04 
4.69 
14-OH-azidocodeine 
0.60 2.42 1.47 .+-. 0.07 
2.91 
Morphine 0.61 2.38 1.28 .+-. 0.32 
3.96 
Hydromorphone 
0.026 55.76 0.064 .+-. 0.001 
79.21 
Oxymorphone 0.016 80.55 0.032 .+-. 0.005 
158.43 
Azidomorphine 
0.006 241.66 0.018 .+-. 0.002 
281.66 
14-OH-azidomorphine 
0.012 120.83 0.020 .+-. 0.002 
253.50 
Ethylmorphine 
2.58 0.56 8.32 .+-. 1.56 
0.61 
Azidoethylmorphine 
0.54 2.69 0.84 .+-. 0.29 
6.03 
Pholcodine 8.8 0.16 12.7 .+-. 1.41 
0.40 
Azidopholcodine 
2.0 0.73 3.5 .+-. 0.48 
1.45 
______________________________________ 
Table III 
______________________________________ 
Respiratory changes due to various drugs given in doses 
producing total cough depression in cats 
Min. vol- 
ume after 
Frequency Depth after 
AtD.sub.100 
after AtD.sub.100 
AtD.sub.100 per 
per control 
per control 
control minute 
Compounds frequency depth volume 
______________________________________ 
Codeine 0.82 .+-. 0.03.sup.1 
0.83 .+-. 0.03.sup.1 
0.70 .+-. 0.04.sup.1 
Hydrocodone 0.90 .+-. 0.05.sup.1 
0.93 .+-. 0.03 
0.84 .+-. 0.05.sup.1 
Oxycodone 0.84 .+-. 0.05.sup.1 
0.91 .+-. 0.04 
0.78 .+-. 0.07.sup.1 
Azidocodeine 
0.82 .+-. 0.09 
0.97 .+-. 0.13 
0.81 .+-. 0.14 
14-OH-azido- 
0.88 .+-. 0.05.sup.1 
0.93 .+-. 0.08 
0.67 .+-. 0.07.sup.1 
codeine 
Morphine 0.78 .+-. 0.07.sup.1 
0.79 .+-. 0.06.sup.1 
0.62 .+-. 0.07.sup.1 
Hydromorphone 
1.09 .+-. 0.12 
0.80 .+-. 0.07.sup.1 
0.85 .+-. 0.08 
Oxymorphone 0.92 .+-. 0.10 
0.99 .+-. 0.23 
0.91 .+-. 0.12 
Azidomorphine 
0.94 .+-. 0.06 
0.97 .+-. 0.05 
0.93 .+-. 0.06 
14-OH-azido- 
0.91 .+-. 0.10 
1.02 .+-. 0.15 
0.88 .+-. 0.08 
morphine 
Ethylmorphine 
0.85 .+-. 0.02 
0.72 .+-. 0.24 
0.65 .+-. 0.14 
Azidoethyl- 0.95 .+-. 0.10 
0.91 .+-. 0.05 
0.88 .+-. 0.13 
morphine 
Pholcodine 1.17 .+-. 0.07 
0.90 .+-. 0.06 
1.05 .+-. 0.04 
Azidophol- 1.15 .+-. 0.13 
0.88 .+-. 0.06 
1.02 .+-. 0.16 
codine 
______________________________________ 
Means .+-. S.E.--n = 5.--.sup.1 P &lt; 0.05 (Student test).