United States Patent Oﬂ ice
Patented July 25, 1967
Harold Blumberg, Flushing, Irwin J. Pachter, Woodbury, and Zaven Matossian, Jamaica, N.Y., assignors to'Endo Laboratories, Inc., Garden City, N.Y., a corporation of
New York No Drawing. Filed Dec. 6, 1966, Ser. No. 599,379
7 Claims. (Cl. 260—285) This application is a continuation—in-part of our pend—
ing applications, Ser. No. 267,793 ﬁled Mar. 23, 1963, and Ser. No, 280,750, ﬁled May 15, 1963.
This invention relates to new and useful derivatives of morphine bearing selected substituents on the nitrogen atom, the effect of which is to confer narcotic antagonist properties to the molecules while at the same time con- ferring useful analgetic activity.
For many years attempts have been made to prepare new derivatives of morphine which are not addicting, retain analgetic potency and yet are relatively free of side effects, such as respiratory depression. For the most part, these efforts have not been rewarding.
It has been observed in recent years that when suitable substituents are introduced on the nitrogen atom of a normorphine derivative, the resulting compounds are not addicting and, indeed, are actually narcotic antagonists.
Occasionally, such narcotic antagonists also have been found to have analgetic properties. However, such anal- gesia, when present, has generally been characterized by decreased potency, hallucinogenic side effects and respira— tory depression.
Among the narcotic antagonists, the N-allyl and N-
propargyl derivatives of 14-hydroxydihydronormorphi- none described in British Patent 939,287 have been out- standing in that they are potent reversers of nareosis without inducing hallucinations or the respiratory depres- sion characteristic of other narcotic antagonists. Unfor- tunately, tests in experimental animals have shown that these compounds are devoid of analgetic properties.
In studying other derivatives of 14-hydroxydihydronor—
morphinone which Von Braun (Ber. 59, 1081 (1926)) has taught could also be expected to show narcotic an— tagonist activity, we made the surprising discovery that
N-(3’-methyl-2’-butenyl) - 14 - hydroxydihydronormor-
phinone, N-cy-clopropylmethyl ~ 14 - hydroxydihydronor-
morphinone and N—cyclobutylmethyl-l4-hydroxydihydro-
normorphinone of Formula I below, unlike the N-allyl and N—propargyl derivatives, are analgetics as well as narcotic antagonists. Furthermore, their analgetic action " is not accompanied by undesirable side effects charac- teristic of previously known analgetic narcotic antago- nists.
The compounds of this invention have Formula I
Formula I wherein R is 3’—methyl-2’-butenyl, cyclopropylmethylvor cyclobutylmethyl.
The preparation of the compounds of this invention may be exempliﬁed by the ﬂow sheet which illustrates the preparation of N-cyclobutylmethyl-l4-hydr0xydihy— dronormorphinone. Related procedures afford the other compounds of this invention.
When the substituting reagent is in the oxidized form, powerful reducing agents such as lithium aluminum hy- dride, potassium borohydride in the presence of lithium chloride, aluminum hydride in the presence of lithium chloride, sodium borohydride in the presence of alumi- num chloride, diborane and the like must be employed to reduce the amide carbonyl of the intermediate prod—
uct. Such reducing agents also reduce ketone carbonyl groups to alcohols. In order to retain the ketone car- . bony] in the ‘ﬁnal product, it may either be protected during the reduction step by temporary conversion into an acetal such as the cyclic ethylene acetal, the cyclic tri- methylene acetal, a lower alkyl acetyl such as the dimethyl acetal or the dipropyl acetal, a lower alkyl eno] ether, such as the methyl ether, the ethyl ether or the butyl ether, or like group resistant to hydride reduction, or it may be permitted to undergo reduction to the alcohol and later be reoxidized to the ketone by Oppenauer oxi- dation using potassium t-butoxide and benzoPhenone, aluminum isoprOpoxide and l-tetralone or related reagent pair, or by other oxidative process involving reagents such as chromic acid, chromium trioxide in pyridine or the like.
In accord with the freedom from side effects, the com- pounds of this invention have very low toxicity, the sub‘ cutaneous LD50 (dose killing 50% of the animals) being between 400 and 600 mg. per kg. in mice.
To demonstrate the analgetic potency of the com-
pounds of this invention and thus to indicate use of these agents as non-addicting analgetics in their own right it animals and man, N-(3’-methyl-2’-butenyl)-14-hydroxyi dihydronormorphinone, in the form of its hydrochloridt salt, was injected by the intramuscular route post-opera tively in man. The analgetic effect produced .by a 35 mg dose was approximately the same as that produced by a dose of 15 mg. of: morphine sulfate or by a d-Ose 0 100—200 mg. of meperidine hydrochloride. More impor tantly the compound was found to be free of side effect that have hampered all prior non—addicting analgetics To demonstrate the narcotic antagonist potency of th compounds of this invention, and thus to indicate use 0 these agents in counteracting narcotic overdosage, in thw detection of narcotic addition, and post-operatively t: hasten recovery from surgery or labor after narcoti analgesia (veterinary and human), rats were narcotizel with 0.4 mg. per kg. of oxymorphone. The animals, whicl fell on their sides, were then injected subcutaneously witl as little as 0.005 mg. per kg. of N-cyclopropylmethyl
14-hydroxydihydronormorphinone. Rapidly, they wer roused from their stupor and restored to normal alertnes: activity and locomotion.
Narcotic antagonist potency is not directly related t analgetic potency, for N-cyclopropylmethyl-14-hydrox3
dihydronormorphinone, which has analgetic propertic in the rat is approximately twice as potent as an antagt nist as N—allyl—14—hydroxydihydronormorphinone, whic
has none. '
Although a compound such as N-allyl—14-hydroxydihj
IPR of Patent No. 7,919,499
H + y, EH50
LiAlI-I4 HQ’ mormorphinone is closely related in structure to the npounds of our invention, we made the further re- ,rkable discovery that the analgetic eﬁects produced our new compounds may be antagOnized by N—allyl- hydroxydihydronormorphinone. Clearly then, the new npounds, though chemically related, are biologically tinct from their previously described relative.
Fhe non-addicting nature of the compounds of this ention was demonstrated through negative test results 75 in monkeys that were physically dependent upon nar- cotics. Furthermore, the compounds of this invention fail to produce narcosis in rats -or the excitation (including the Straub tail phenomenon) in mice which are charac- teristic of all addicting lanalgetics. ' A portion of the animal pharmacology accumulated during the course of our studies is summarized in the Tables I, II and III. The writhing test for analgesia as described by Blumberg et al. (Proc. Soc. Exp. Biol. Med., IPR of Patent No. 7,919,499 118, 763 (1965)), Was employed to evaluate the cem- pounds.
Doses required to produce a 50% analgetic effect in the .
N - allyl-l4~hydroxydihydronormorphinone __ 100
N — propargyl - 14 - hydroxydihydronormor-
phinone ______________________________ 100
N - cyclopropylmethyl—14—hydroxydihydronor-
morphinone ___________________________ 100
N - cyclobutylmethyl - 14-hydroxydihydronor-
morphinOne ___________________________ 0.40
N - (3’—methyl—2—butenyl)—14-hydroxydihydro-
normorphinone ________________________ 8.3
Doses required to produce a 50% analgetic effect in the Mg./kg.
N - allyl-14—hydroxydihydronormorphinone __ 100
N - propargyl — 14 — hydroxydihydronormor-
phinone ______________________________ 100
N - cyclopropylmethyl - 14 - hydroxydihy-
7 dronormorphinone _____________________ 0.5
N - cyclobutylmethyl~ 14 — hydroxydihydro—
normorphinone ________________________ 0.06
N - (3’ - methyl—2’-butenyl)—l4-hydroxydihy-
- dronormorphinone _____________________ 0.7
TABLE III—ANTAGONISM OF THE ANALGE’I‘IC EFFECT
OF DOSES OF N-(3’-METHYL-2’-BUTENYL)»14—HYDROXY-
DIHYDRONORMORPHINONE BY DOSES OF N-ALLYL—14—
3’—methyl-2’butenyl Allyl compound, Analgesia, percent
compound, ngkg. m ./ g. , , The compounds are particularly useful in the form of addition salts thereof with pharmaceutically acceptable acids, as for example, hydrochloric, sulfuric, citric and the other acids, of which there are many, customarily em— ployed in the pharmaceutical ﬁeld in connection with the administration of nitrogen-containing compounds.
The dosages of the compounds are: for narcotic an— tagonismwabout 0.1 to 10 mg.; and for analgesia—about 0.5 to 50 mg.
These new compounds in the form of their pharma- ceutically acceptable acid addition salts can be admini— stered for narcotic antagonism, from ampoules or vials.
For analgesia, these compounds in the form of the men- tioned salts or the free base, may be put up, in addition to the vials or ampoules mentioned, as tablets (hypo- dermic, sublingual or oral, compounded according to known pharmaceutical methods), or as liquids, e.g., syrups and elixirs, or as rectal suppositories, etc. in short, in dosage or dispensible forms as combinations of the
active compound and an acceptable vehicle.
Details of suitable preparative procedures are disclosed in the following examples.
N - (3 ’—methyl~2’—butenyl ) -] 4 -hydr0xydihydronor-
A solution of 14.4 g. of 14-hydroxydihydronormor-
phinone, 14.9 g. of 1—bromo—3-methyl-2-butene and 550 ml. of dimethylformamide was heated at 65° for six days. The solvent was removed under reduced pressure and the residue was dissolved in 270 ml. of water. The resulting solution was clariﬁed with charcoal and adjusted to pH 9. There was obtained 11.9‘ g. of crude product, MP. 248—250". Recrystallization from chloroform and methanol raised the M.P. to 265.5°.
The hydrochloride salt, prepared by passing hydrogen chloride into a chloroform solution of the base, melted EXAMPLE 2
N-cyclo propy [methyl-1 4-hydr0arydz'hydronor-
Method a.—A solution of 14.4 g. of 14-hydroxydihy-
dronormorphinone, 13.5 g. of cyclopropylmethyl bro- mide and 550 ml. of dimethylformamide was heated at 70° for one week. The solvent was removed by distillation under reduced pressure and the residue was dissolved in water. The resulting solution was clariﬁed with charcoal and adjusted to pH 9. The product precipitated. It was collected and recrystallized from acetone. There was ob-
tained 10.0 g. of product, M.P. 168—170°; 1 The hydrochloride salt, prepared by treating the base with excess six normal hydrochloric acid, melted at 274— 276° after recrystallization from methanol.
Method b.——A mixture of 28.7 g. of 14-hydroxydihy-
dronormorphinone, 31.1 g. of ethylene glycol, 20.0 g. of p-toluenesulfonic acid and 250‘ ml. of benzene was heated under reﬂux with stirring for 35 hours. After cooling, the benzene layer was decanted and the glycol layer was di- luted with 500 ml. of water and 10 m1. of concentrated aqueous ammonia. The cyclic ethylene acetal crystallized.
It was collected, washed with methanol and recrystallized from 1:1 methanol—chloroform to give 23.8 g., M.P.
To a mixture of 15.0 g. of the acetal in 200 ml. 01 methylene chloride and 64 g. of triethylamine was added 16 g. of cyclopropane carboxylic acid chloride in 100 m1.
of methylene chloride over a period of 25 minutes. The resulting mixture was then heated under reﬂux for ﬁve hours and cooled. Triethylamine hydrochloride was re moved by ﬁltration. The ﬁltrate was evaporated to dry ness and diluted with water. The N,O-dicyclopropylcari bonyl derivative separated; M.P. 219—220° after re
crystallization from acetone.
A 10 g. sample of the dicyclopropylcarbonyl compounc in 300 ml. of tetrahydrofuran was stirred for 24 hour: with 3.0 g. of lithium aluminum hydride. The resulting , mixture was then heated under reﬂux for one hour, cooled diluted with 31 ml. of ethyl acetate and then with 304
ml. of saturated aqueous ammonium chloride. Inorganit material was removed by ﬁltration. The tetrahydrofurai layer was evaporated todryness and the residue was re crystallized from acetonebenzene. The N-cyclopropyl
methyl-14-hydroxydihydronormorphinone cyclic ethylent acetal thus produced melted at 220—221".
Heating a 2 g. portion of the resulting N-cyclopropyl methyl acetal with 20 ml. of 1 N hydrochloric acid fo , two hours on a steam bath resulted in hydrolysis of th
acetal to produce N-cyclopropylmethyl-14-hydroxydihy
dronormorphinone hydrochloride, M.P. 274—276°.
N-cyclobutylmethyl—I4—hydroxydihydronormorphinone Method a.—-—The compound was prepared from 1’4-hy droxydihydronormorphinone and cyclobutylmethyl brc mide by the method of Example 2a. It melted at 151—152 upon recrystallization from ether. The hydrochloride sa‘.
melted at 256—258°.
Method b.—To a slurry of 110.5 g. of 14-hydroxyd
hydronormorphinone in 2.5 l. of methylene chloride an
IPR of Patent No. 7,919,499 580 ml. of triethylamine was added a solution of 106 g.
if cyclobutanecarboxylic acid chloride in 500 ml. of
methylene chloride. The temperature of the reaction mix- ure was maintained at 20‘ to 25° during the addition.
kfter ﬁve minutes, the reaction mixture was brought to eﬂux and heated thusly for ﬁve hours. It was then cooled, vashed with water, dried over sodium sulfate and evapo- ated to dryness. The residue was crystallized from ben- ene and pentane to give 138.5 g. of the dicyclobutane- arbonyl derivative, M.P. about 112° (dec.).
The dicyclobutanecarbonyl derivative (136.7 g.) was issolved in 200 ml. of tetrahydrofuran and added drop- Iise to a suspension of 34.2 g. of lithium aluminum hy- ride in one liter of tetrahydrofuran. The temperature of re mixture rose to reﬂux during the addition. Reﬂux was raintained for two hours after the addition was com— leted. After cooling, 110 ml. of ethyl acetate was added ropwise, followed by 30 ml. of water, followed by a )lution of 53 g. of ammonium chloride in 125 ml. of Men The resulting mixture was ﬁltered and the in— rganic precipitate was washed with methanol. Evapora- on of the combined ﬁltrates gave 66 g. of N—cyclobutyl—
lethyl - 14 - hydroxydihydronormorphine, M.P. 229— A suspension of freshly prepared potassium t-butoxide made from 5 g. of potassium metal) in anhydrous ben- ane was heated under reﬂux for 2.5 hours with 13 g.
EN—cyclobutylmethyl - 14 - hydroxydihydronormorphine 1d 82 g. of benzophenonc. The resulting mixture was (tracted with three 80 ml. portions of three normal hy- rochloric acid. The acid extracts were combined, ad- sted to pH 9 and extracted with chloroform. The chloro- u‘m extract was evaporated to dryness and the dark ‘oduct was extracted with ether. The ethereal solution as separated from insoluble tarry material and concen- ated. The product, M.P. 151—152“, proved to be the
:me as that produced by Method a.
Method c.—By the procedure of Example 2, Method 1), l - hydroxydihydronormorphinone cyclic ethylene acetal as converted into the dieyclobutanecarbonyl compound ith cyclobutanecarboxylic acid chloride and thence re- lced with lithium aluminum hydride to crystalline N-
'clobutylmethyl - 14 - hydroxydihydronormorphinone
'clic ethylene acetal, M.P. 167—168°. Hydrolysis of the :etal with dilute hydrochloric acid afforded the hydro- Lloride of the product, M.P. 257—258", identical with e hydrochloride made by Method a.
Examples of dosage forms of the compounds
vdrochloride salt of N-cyclopropylmethyldihydro-
14-hydroxynormorphinone ____________________ 0.5
dium chloride ______________________________ 9.0
ethyl paraben _______________________________ 1.8
opyl paraben _______________________________ 0.2
ater for injection ____________________________ q.s.
16 solution is prepared by ﬁrst dissolving the parabens hot water for injection, cooling to room temperature d dissolving the compound and sodium chloride. It is in ﬁltered, using sterile technique, through a bacterio- gical ﬁlter (0.6 micron or smaller porosity), after which is ﬁlled with .ampoules or multiple-dose vials with : equipment commonly used in the pharmaceutical in- stry.
Hydrochloride salt of N-cyclobutylmethyldihydro—14-
hydroxynormorphine _________________________ 50
Starch _______________________________________ 50
Lactose ______________________________________ 75
Magnesium stearate ____________________________ 2
Stearic acid ___________________________________ 5
The compound, a portion of the starch, and the lactose are combined and wet granulated with starch paste. The wet granulation is placed on trays and allowed to dry overnight at a temperature of 45° C. The dried granula- tion is comminuted in a comminutor to a particle size of approximately 20 mesh. Magnesium stearate, stearic acid. and the balance of the starch are added and the entire mix blended prior to compression on a suitable tablet press. The tablets are compressed at a weight of 232 mg. using a 11/32” punch with a hardness of 4 kg.
These tablets will disintegrate within a half 'hour accord- ing to the method described in USP XVI.
Hydrochloride salt of N-(3’-methyl-2’-butenyl)-di-
hydro-14-hydroxynormorphinone ____________ 1.66
Polyoxyethylene 10010 (approx. M 1000) _______ 801.14
Polyoxyethylene 4000 (approx. M 4000) _______ 15.0
Methyl paraben _____________________________ .15
Propyl paraben _____________________________ .05
Puriﬁed water USP __________________________ 3.0 The HCl salt of the compound is dissolved in the water and added to a melted mixture of the polyoxyethylcnes which already were combined with the parabens. This mol- ten mixture is poured into suppository molds and cast into suppositories weighing 3 grams each. They are frozen to solidify and packaged into foil. These suppositories liquefy in the rectal area due to a combination of body heat and moisture thus releasing the active substance which is rapidly absorbed. This provides a concentration of 50 mg./suppository.
We claim: 1. A compound selected from the group consisting of (l) N - substituted 14 - hydroxydihydronor-morphinone wherein the N-substituent is 3’-methyl-2’~butenyl, cyclo- propylmethyl or cyclobutylmethyl, and (2) the addition salts of (1) with pharmaceutically acceptable acids.
2. A compound in accordance with claim 1 wherein ( 1) is N-(3’-methyl-2‘-butenyl) - 14 — hydroxydihydronor- morphinone.
3. A compound in accordance with claim 1 wherein (1) is N—cyclopropylmethyl - 14 - hydroxydihydronormor- phinone.
4. A compound in accordance with claim 1 wherein ( 1) is N-cyclobutylmethyl - 14 ~ hydroxydihydroxynor- morphinone.
5. A pharmaceutically acceptable acid addition salt of
the base in accordance with claim 2.
6, A pharmaceutically acceptable acid addition salt of
the base in accordance with claim 3.
7. A pharmaceutically acceptable acid addition salt of
the base in accordance with claim 4.
No references cited.
ALEX MAZEL, Primary Examiner.
D. DAUS, Assistant Examiner.
IPR of Patent No.