Quaternary derivatives of noroxymorphone which relieve intestinal immobility

Compounds of the formula ##STR1## wherein R is allyl or a related radical such as chloroallyl, cyclopropyl-methyl or propargyl, and PA1 X is the anion of an acid, especially a chloride, bromide, iodide or methylsulfate anion; the compounds prevent or relieve the intestinal mobility inhibiting side-effects of narcotic analgesics without interfering with the analgesic activity of the latter.

This invention relates to novel quaternary derivatives of noroxymorphone, 
and to methods of preparing and using these compounds. 
More particularly, the present invention relates to a novel class of 
quaternary noroxymorphones represented by the formula 
##STR2## 
wherein R is allyl, chloroallyl, cyclopropyl-methyl or propargyl, and 
X is the anion of an acid, especially a chloride, bromide, iodide or 
methylsulfate anion. 
The compound are referred to as N-substituted noroxymorphone methosalts. 
The compounds embraced by formula I may be prepared by various methods 
involving known chemical synthesis principles, among which the following 
are preferred: 
Method A 
By quaternizing a tertiary N-substituted noroxymorphone of the formula 
##STR3## 
wherein R has the same meanings as in formula I, with a methylating agent 
of the formula 
EQU CH.sub.3 --X (III) 
wherein X is chlorine, bromine, iodine or --CH.sub.3 OSO.sub.3. For 
practical and economic reasons, methyl bromide, methyl iodide or 
dimethylsulfate are preferred as methylating agents. 
At least equimolar amounts of II and III are required for complete 
conversion of II into I. However, with a view toward a smooth and rapid 
reaction, it is advantageous to provide the methylating agent III in 
excess, preferably in an amount of 3 to 10 mols per mol of compound II, 
and the excess methylating agent may simultaneously serve as the solvent 
medium for the reaction. 
The reaction, may, however, also be preformed in another solvent medium, 
preferably in an inert solvent or mixture of inert solvents in which the 
starting compound II is sufficiently soluble, the rate of reaction is 
sufficiently rapid, and the formation of side-products is at a minimum. 
Examples of suitable such solvents are methanol, ethanol, or other 
alcohols, methylene chloride, chloroform, tetrahydrofuran, dioxane, 
dimethylformamide, dimethylsulfoxide, acetonitrile, nitromethane or 
hexamethylphosphoric triamide. Especially preferred is acetone from which 
the reaction product precipitates during the reaction in very pure 
crystalline form. 
The reaction temperature can be varied within wide limits, but most 
advantageous is a temperature range in which, on the one hand, the 
reaction still proceeds sufficiently rapidly and, on the other hand, side 
reactions are not yet predominant. Reaction temperature between 
-10.degree. and +150.degree. C. are advantageous, and the range between 
0.degree. and 100.degree. C. is preferred. 
Method B 
By quaternizing an O-substituted tertiary noroxymorphone of the formula 
##STR4## 
wherein R has the same meanings as in formula I, and 
R' is a substituent which can be introduced into compound II by known 
chemical methods and then removed again without altering the molecular 
structure, primarily methoxymethyl or acyl, especially acetyl, 
with a methylating agent of the formula III to form an O-substituted 
noroxymorphone methosalt of the formula 
##STR5## 
wherein R, R' and X have the meanings previously defined, and subsequently 
removing the substituent R' from the methosalt V by conventional methods, 
preferably by hydrolysis, to restore the phenolic hydroxyl group and form 
the desired end product of the formula I. This method has an advantage 
over method A in those cases where an undesirable O-methylation may take 
place besides the desired N-quaternization. 
The quaternization of compound IV is carried out in analogy to and under 
the same reaction conditions as described in method A. It is particularly 
advantageous to perform method B as a continuous, single-step procedure, 
that is, without isolation of the intermediate V. 
The end products of the formula I obtained by method A or B may be isolated 
from the reaction mixture and purified by conventional laboratory methods. 
If desired, a given anion in such an end product may be exchanged for 
another anion, which can also be done by conventional methods. 
The starting compounds of the formula II are either known compounds or may 
be prepared by known methods, for instance by alkylation of 
noroxymorphone, as illustrated in Example 11(a) below. 
Likewise, the starting compounds of the formula IV are either known or may 
be prepared by known methods, as illustrated in Example 9(a) below.

The following examples illustrate the present invention and will enable 
others skilled in the art to understand it more completely. It should be 
understood, however, that the invention is not limited solely to the 
particular examples given below. 
EXAMPLE 1 
N-Allyl-noroxymorphone methoiodide by method A 
An excess of concentrated ammonia was added to a concentrated aqueous 
solution of 18.2 gm (0.05 mol) of N-allyl-noroxymorphone hydrochloride, 
whereupon the free base precipitated, which was separated by extraction 
with chloroform. The combined chloroform extracts were dried with sodium 
sulfate and evaporated in vacuo. The residue was dissolved in 150 ml of 
absolute acetone, the resulting solution was admixed with 18 ml (0.29 mol) 
of methyl iodide in a pressure vessel, the vessel was sealed, and the 
reaction mixture contained therein was heated at 70.degree. C. for three 
days. Thereafter, the reaction product which had separated out in 
crystalline form was collected by suction filtration, washed first with 
absolute acetone and then with absolute ether, and dried at 80.degree. C. 
16.6 gm (70.5% of theory) of the compound of the formula 
##STR6## 
having a melting point of 217.degree.-218.degree. C. were obtained. 
Additional crystalline reaction product was obtained by evaporation of the 
mother liquor. 
EXAMPLE 2 
N-allyl-noroxymorphone methobromide by method A 
36.4 gm (0.1 mol) of N-allyl-noroxymorphone hydrochloride were converted 
into the free base as described in Example 1. The free base was dissolved 
in 180 ml of absolute acetone, the solution was admixed with 33.0 ml (0.6 
mol) of methyl bromide in a pressure vessel, the vessel was sealed, and 
its contents were heated at 70.degree. C. for seven days. Thereafter, the 
reaction mixture was cooled, and the reaction product which had separated 
out in crystalline form was collected by suction filtration, washed first 
with a little absolute acetone and then with absolute ether, and dried at 
80.degree. C. 35 gm (85.5% of theory) of N-allyl-noroxymorphone 
methobromide, m.p. 246.degree. C., were obtained. The melting point of a 
sample recrystallized from methanol remained unchanged at 246.degree. C. 
EXAMPLE 3 
N-Allyl-noroxymorphone methomethylsulfate by method A 
3.64 gm (0.01 mol) of N-allyl-noroxymorphone hydrochloride were converted 
into the free base, as described in Example 1. The free base was dissolved 
in 40 ml of absolute acetone, 3.8 gm (0.03 mol) of dimethyl sulfate were 
added to the solution, and the mixture was refluxed for 48 hours, during 
which time an oil gradually separated out. Thereafter, the oil was 
isolated by decanting the supernatent liquid, crystallized from 
methanol/ether, and the crystallizate was collected by suction filtration, 
washed first with absolute methanol/ether and then with absolute ether, 
and dried at 80.degree. C. 0.9 gm of N-allyl-noroxymorphone 
methomethylsulfate, m.p. 219.degree.-222.degree. C., were obtained. 
EXAMPLE 4 
N-allyl-noroxymorphone methobromide by anion exchange 
12.0 gm (0.0256 mol) of N-allyl-noroxymorphone methoiodide, prepared in 
accordance with Example 1, were dissolved in 500 ml of water, and the 
solution was filtered through a column charged with a strongly basic anion 
exchanger (bromide-loaded anion exchanger, 171 gm, with an exchange 
capacity of 0.513 Val). The column was subsequently rinsed with 1.5 liters 
of water, and the filtrates were combined and evaporated in vacuo at 
70.degree. C. The residue was dissolved in 100 ml of methanol, and 100 ml 
of ether were added to the solution, whereupon 9.65 gm (92% of theory) of 
the methobromide, m.p. 245.degree. C., separated out. After 
recrystallization from methanol it had a melting point of 246.degree. C. 
EXAMPLE 5 
N-Cyclopropylmethyl-noroxymorphone methobromide by method A 
2.5 gm (7.35 millimols) of N-cyclopropylmethylnoroxymorphone were dissolved 
in a mixture consisting of 50 ml of absolute acetone and 0.5 ml of 
dimethylformamide, and the resulting solution was admixed with 4.25 gm 
(44.8 millimols) of methyl bromide. The reaction mixture was then allowed 
to stand for three weeks at room temperature in a sealed pressure vessel. 
Thereafter, the contents of the vessel were evaporated, and the residue 
was crystallized from methanol and recrystallized from methanol/ether, 
yielding 1.0 gm of the methobromide which had a melting point of 
253.degree. C. 
EXAMPLE 6 
N-Cyclopropylmethyl-noroxymorphone methoiodide by method A 
8.0 gm (0.0211 mol) of N-cyclopropylmethyl-noroxymorphone hydrochloride 
were converted into the free base, as described for N-allyl-noroxymorphone 
hydrochloride in Example 1. The free base was dissolved in 50 ml of 
absolute acetone in a pressure vessel, the solution was admixed with 8 ml 
(0.128 mol) of methyl iodide, the vessel was sealed, and the reaction 
mixture was heated at 70.degree. C. for four days, during which time a 
viscous oil separated out. After cooling, the solvent was decanted, and 
the reside was crystallized from ethanol/ether, yielding 5.8 gm (57% of 
theory) of the methoiodide. 
EXAMPLE 7 
N-Cyclopropylmethyl-noroxymorphone methobromide by anion exchange 
5.8 gm of N-cyclopropylmethyl-noroxymorphone methoiodide (see Example 6) 
were converted by anion exchange analogous to Example 4 into the 
methobromide 4.8 gm (94.7% of theory) of the methobromide, m.p. 
253.degree. C., were obtained. The melting point remained unchanged after 
recrystallization from methanol/ether. 
EXAMPLE 8 
N-Propargyl-noroxymorphone methobromide by method A 
4.0 gm (12.29 millimols) of N-propargyl-noroxymorphone were dissolved in a 
mixture consisting of 30 ml of methanol and 20 ml of dimethylformamide, 
the solution was admixed with 6.8 gm (71.6 millimols) of methyl bromide, 
and the mixture was heated at 70.degree. C. in a sealed pressure vessel 
for five days. Thereafter, the contents of the vessel were cooled and 
evaporated in vacuo. The residue was crystallized from ethanol/ether, 
recrystallized from water and dried at 80.degree. C., yielding 1.1 gm 
(21.3% of theory) of the pure methobromide with a melting point of 
220.degree. C. 
EXAMPLE 9 
N-Allyl-noroxymorphone methobromide by method B 
(a) 10.9 gm (0.03 mol) of N-allyl-noroxoymorphone hydrochloride were 
converted into the free base, as described in Example 1. The evaporation 
residue of the combined chloroform extracts was dissolved in 70 ml of 
absolute methylene chloride, 3.4 gm (0.033 mol) of triethylamine were 
added and, while cooling the mixture on an ice bath, a solution of 2.6 gm 
(0.033 mol) of acetyl chloride in absolute methylene chloride was admixed 
therewith. The ice bath was then removed, and the reaction mixture was 
slowly allowed to warm to room temperature and was subsequently refluxed 
for one hour. Thereafter, the reaction solution was cooled, washed twice 
with ice water, dried with sodium sulfate and evaporated in vacuo, leaving 
as the residue O.sup.3 -acetyl-N-allyl-noroxymorphone. 
(b) The evaporation residue obtained in step (a) was quaternized with 
methyl bromide in analogy to the procedure of Example 2. After a reaction 
time of seven days at 70.degree. C., the reaction solution was evaporated 
in vacuo, leaving as the residue O.sup.3 -acetyl-N-allyl-noroxymorphone 
methobromide. 
(c) The evaporation residue obtained in step (c) was dissolved in 1 N 
hydrobromic acid, and the solution was evaporated in vacuo on a water bath 
at 60.degree. C. The residue was crystallized as described in Example 2, 
yielding 5.3 gm (41.7% of theory, based on the N-allyl-noroxymorphone 
hydrochloride starting material) of N-allyl-noroxymorphone methobromide, 
m.p. 247.degree. C. 
EXAMPLE 10 
N-Allyl-noroxymorphone methobromide by method B 
3.64 gm (0.01 mol) of N-allyl-noroxymorphone were converted into O.sup.3 
-acetyl-N-allyl-noroxymorphone, as described in Example 9(a), and the 
evaporation residue was dissolved in 60 ml of absolute methylene chloride. 
While stirring and cooling it on an ice bath, the resulting solution was 
admixed with 2.22 gm (0.015 mol) of trimethyloxonium fluoroborate. After 1 
hour the ice bath was removed, and the mixture was stirred for sixteen 
hours at room temperature. Thereafter, the reaction solution was 
evaporated, the residual quaternary fluoroborate was dissolved in 150 ml 
of water, and the solution was filtered, in analogy to Example 2, through 
a strong basic anion exchange column (175 gm, OH-form, about 0.25 Val), 
and the column was rinsed with about 1 liter of water. The combined 
aqueous solutions were then acidified with concentrated hydrobrmic acid 
(pH about 3) and subsequently evaporated in vacuo on a water bath at 
60.degree. C. The residue was crystallized from 75 ml of methanol and 30 
ml of ether, yielding 1.5 gm (36.7% of theory) of N-allyl-noroxymorphone 
methobromide having a melting point of 246.degree.-247.degree. C. An 
additional amount of the methobromide was recovered from the mother 
liquor. 
EXAMPLE 11 
N-(Trans-3-chloroallyl)-noroxymorphone methobromide by method B 
(a) A mixture consisting of 6.48 gm (0.02 mol) of noroxymorphone 
hydrochloride, 4.2 gm of sodium bicarbonate, 2.44 gm (0.022 mol) of 
trans-3-chloroallyl chloride and 70 ml of dimethylformamide was stirred 
for four hours at 90.degree. C. Thereafter, the reaction solution was 
evaporated in vacuo, and the residue was shaken with a mixture of 75 ml of 
chloroform and 75 ml of water. The chloroform phase was separated, and the 
aqueous phase was again extracted with 25 ml of chloroform. The combined 
chloroform extracts were washed with 50 ml of water, dried with sodium 
sulfate and evaporated in vacuo. The residue was crystallized from 
isopropanol, yielding 6.2 gm (86% of theory) of 
N-(trans-3-chloroallyl)-noroxymorphone, which was found by thin-layer 
chromatography to be not completely pure. Recrystallization from 450 ml of 
toluene yielded 4.0 gm of the pure product having a melting point of 
226.degree. C. An additional 1 gm of the pure substance having the same 
melting point was obtained by concentrating the mother liquor to 50 ml. 
The hydrochloride, m.p. 243.degree. C., was obtained by dissolving the base 
in methanolic hydrochloric acid and adding ether to the solution until it 
just turned cloudy. 
(b) 7.2 gm (0.02 mol) of N-trans-3-chloroallyl)noroxymorphone were 
converted into O.sup.3 -acetyl-N-(trans-3-chloroallyl)-noroxymorphone by 
the procedure described in Example 9(a), yielding 9 gm of the O.sup.3 
-acetylated derivative, which was dissolved in 50 ml of absolute methylene 
chloride and quaternized with 3.26 gm (0.022 mol) of trimethyloxomium 
fluoroborate in analogy to Example 10. The working up of the reaction 
mixture, accompanied by regeneration of the phenolic hydroxyl group and 
exchange of the fluoroborate anion for a bromide anion, was also effected 
in analogy to Example 10, yielding 1.2 gm of 
N-trans-3-chloroallyl)-noroxymorphone methobromide having a melting point 
of 200.degree. C. 
EXAMPLE 12 
N-(Cis-3-chloroallyl)-noroxymorphone methobromide by method B 
(a) 6.48 gm (0.02 mol) of noroxymorphone hydrochloride were reacted with 
the 2.44 gm (0.022 mol) of cis-3-chloroallyl chloride in analogy to 
Example 11(a), the reaction mixture was evaporated, and the residue was 
taken up in a mixture of chloroform and water. The chloroform phase was 
separated and evaporated, and the residue was crystallized from 30 ml of 
toluene, yielding 6.1 gm (84.5% of theory) of 
N-(cis-3-chloroallyl)-noroxymorphone containing 1/4 mol of toluene of 
crystallization; it first melted at 144.degree. C. and then, after 
re-solidifying, again at 186.degree. C. Its hydrochloride, m.p. 
202.degree. C., was obtained by dissolving the base in ethanolic 
hydrochloric acid and adding ether thereto until the solution just began 
to turn cloudy. 
(b) 8.0 gm (0.0207 mol) of N-(cis-3-chloroallyl)-noroxymorphone with 1/4 
mol of toluene of crystallization were converted into the O.sup.3 -acetyl 
derivative, the latter was quaternized with trimethyloxonium fluoroborate, 
and the quaternary compound was converted into the methobromide, was 
described in Example 11 (b). 2.5 gm of 
N-(cis-3-chloroallyl)-noroxymorphone methobromide, m.p. 220.degree. C., 
were obtained. 
The compounds embraced by formula I above have useful pharmacodynamic 
properties. More particularly, they prevent or relieve the intestinal 
mobility inhibiting side-effect of narcotic analgesics, such as morphine 
and related opiates, meperidine, methadone or the like, in warm-blooded 
animals such as dogs, rats, and monkeys, without impairing the analgesic 
activity of the narcotic analgesic. In other words, the compounds of the 
present invention are useful for the prophylactic as well as therapeutic 
treatment of intestinal immobility associated with narcotic analgesics. 
For pharmaceutical purposes the compounds of the present invention are 
administered to warm-blooded animals enterally or parenterally as active 
ingredients in customary dosage unit compositions, that is, compositions 
in dosage unit form consisting essentially of an inert pharmaceutical 
carrier and one effective dosage unit of the active ingredient, such as 
tablets, coated pills, capsules, wafers, powders, solutions, suspensions, 
emulsions, syrups, suppositories and the like. One effective dosage unit 
of the compounds according to the present invention is from 0.133 mgm/kg 
to 1.33 mgm/kg body weight, depending upon the expected or existing 
severity of the intestinal mobility inhibition. 
The following examples illustrate a few pharmaceutical dosage unit 
compositions comprising a compound of the present invention as an active 
ingredient and represent the best modes contemplated of using the 
invention. The parts are parts by weight unless otherwise specified. 
EXAMPLE 13 
Tablets 
The tablet compositions is compounded from the following ingredients: 
______________________________________ 
N-Allyl-noroxymorphone methobromide 
50 parts 
Lactose 95 parts 
Corn starch 45 parts 
Colloidal silicic acid 2 parts 
Magnesium stearate 3 parts 
Soluble starch 5 parts 
Total 200 parts 
______________________________________ 
Preparation 
The active ingredient is intimately admixed with a portion of the inert 
excipients, and the mixture is granulated in conventional manner with the 
aid of an aqueous solution of the soluble starch. The granulate is then 
dried and admixed with the remainder of the inert excipients, and the 
composition is compressed into 200 mgm-tablets. Each table is an oral 
dosage unit composition containing 50 mgm of the active ingredient. 
EXAMPLE 14 
Coated pills 
The pill core composition is compounded from the following ingredients: 
______________________________________ 
N-Allyl-noroxymorphone methobromide 
75 parts 
Lactose 100 parts 
Corn starch 65 oarts 
Colloidal silicic acid 2 parts 
Magnesium stearate 3 parts 
Soluble starch 5 parts 
Total 250 parts 
______________________________________ 
Preparation 
The ingredients are compounded as described in the preceding example, and 
the composition is compressed into 250-mgm-pill cores which are 
subsequently coated with a thin shell consisting essentially of a mixture 
of sugar, talcum and gum arabic, and polished with beeswax. Each coated 
pill is an oral dosage unit composition containing 75 mgm of the active 
ingredient. 
EXAMPLE 15 
Suppositories 
The supporting composition is compounded from the following ingredients: 
______________________________________ 
N-Allyl-noroxymorphone methoiodide 
50 parts 
Lactose 200 parts 
Supporting base(e.g. coca butter) 
1450 parts 
Total 1700 parts 
______________________________________ 
Preparation 
The active ingredient and the lactose are initimately admixed with each 
other, and the mixture is homogeneously blended into the molten supporting 
base. 1700 mgm-portions of the composition are poured into cooled 
supporting molds and allowed to harden therein. Each suppository is a 
rectal dosage unit composition containing 50 mgm of the active ingredient. 
EXAMPLE 16 
Hypodermic solution 
The solution is compounded from the following ingredients: 
______________________________________ 
N-Allyl-noroxymorphone methobromide 
10 parts 
Sodium chloride 5 parts 
Double-distilled water q.s.ad 
500 parts by 
volume 
______________________________________ 
Preparation 
The active ingredient and the sodium chloride are dissolved in the 
distilled water, the solution is filtered until free from suspended 
particles, and the filtrate is filled into 5 cc-ampules which are 
sterilized and sealed. The contents of each ampules are an injectable 
dosage unit composition containing 10 mgm of the active ingredient. 
EXAMPLE 17 
Drop solution 
The solution is compounded from the following ingredients: 
______________________________________ 
N-Allyl-noroxymorphone methochloride 
1.0 parts 
Methyl p-hydroxy-benzoate 
0.07 parts 
Propyl p-hydroxy-benzoate 
0.03 parts 
De-mineralized water q.s.ad. 
100.00 parts by 
volume 
______________________________________ 
Preparation 
The active ingredient and the p-hydroxy-benzoates (preservatives) are 
dissolved in the de-mineralized water, the solution is filtered, and the 
filtrate is filled into 100 ml-bottles. 5 ml of the solution are an oral 
dosage unit composition containing 50 mgm of the active ingredient. 
Any one of the other compounds embraced by the formula I may be substituted 
for the particular quaternary noroxymorphone in Examples 13 through 17. 
Likewise, the amount of active ingredient in these illustrative examples 
may be varied to achieve the dosage unit range set forth above, and the 
amounts and nature of the inert pharmaceutical carrier ingredients may be 
varied to meet particular requirements. 
While the present invention has been illustrated with the aid of certain 
specific embodiments thereof, it will be readily apparent to others 
skilled in the art that the invention is not limited to these particular 
embodiments, and that various changes and modifications may be made 
without departing from the spirit of the invention or the scope of the 
appended claims.