United States Patent Office
`
`3,332,950
`Patented July 25, 1967
`
`1.
`
`10
`
`15
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`20
`
`2
`wherein R is 3'-methyl-2'-butenyl, cyclopropylmethyl or
`cyclobutylmethyl.
`The preparation of the compounds of this invention
`may be exemplified by the flow sheet which illustrates
`the preparation of N-cyclobutylmethyl-14-hydroxydihy
`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
`bonyl 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 enol 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
`25 and later be reoxidized to the ketone by Oppenauer oxi
`dation using potassium t-butoxide and benzophenone,
`aluminum isopropoxide and 1-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 ir
`animals and man, N-(3'-methyl-2'-butenyl)-14-hydroxy.
`dihydronormorphinone, in the form of its hydrochloride
`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 dose o
`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 o
`these agents in counteracting narcotic Overdosage, in th
`detection of narcotic addition, and post-operatively t
`hasten recovery from surgery or labor after narcoti
`analgesia (veterinary and human), rats were narcotize
`with 0.4 mg. per kg. of oxymorphone. The animals, whic
`fell on their sides, were then injected subcutaneously wit
`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-hydroxy
`dihydronormorphinone, which has analgetic propertie
`in the rat is approximately twice as potent as an antage
`nist as N-allyl-14-hydroxydihydronormorphinone, whic
`has none.
`-
`Although a compound such as N-allyl-14-hydroxydihy
`
`3,332,950
`14-HYDROXYDHYDRONORMORPHENONE
`OERVATIVES
`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. (C. 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 narcosis
`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-cyclopropylmethyl - 14 - hydroxydihydronor
`morphinone and N-cyclobutylmethyl-14-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
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`30
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`40
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`60
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`Formula I
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`APOTEX EXHIBIT 1042
`Apotex v. Alkermes
`IPR2025-00514
`
`

`

`
`
`3,332,950
`
`{ 2 COC
`Etan
`
`HO
`
`
`
`HO
`
`Yo
`
`HO
`
`
`
`
`
`Oppenauer
`oxidation
`
`iAlH4.
`
`G>
`
`in monkeys that were physically dependent upon nar
`normorphinone is closely related in structure to the
`cotics. Furthermore, the compounds of this invention fail
`mpounds of our invention, we made the further re-
`to produce narcosis in rats or the excitation (including
`rkable discovery that the analgetic effects produced
`our new compounds may be antagonized by N-allyl- 70 the Straub tail phenomenon) in mice which are charac
`hydroxydihydronormorphinone. Clearly then, the new
`teristic of all addicting analgetics.
`mpounds, though chemically related, are biologically
`A portion of the animal pharmacology accumulated
`tinct from their previously described relative.
`during the course of our studies is summarized in the
`the non-addicting nature of the compounds of this
`Tables I, II and III. The writhing test for analgesia as
`ention was demonstrated through negative test results 75 described by Blumberg et al. (Proc. Soc. Exp. Biol. Med.,
`
`

`

`0
`
`5
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`20
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`30
`
`TABLE II
`Doses required to produce a 50% analgetic effect in the
`rat:
`Mg/kg.
`N - allyl-14-hydroxydihydronormorphinone -
`100
`N - propargyl - 14 - hydroxydihydronormor
`phinone ------------------------------ 100
`N - cyclopropylmethyl - 14 - hydroxydihy
`dronormorphinone --------------------- 0.5
`N - cyclobutylmethyl - 14 - hydroxydihydro
`normorphinone ------------------------ 0.06
`N - (3' - methyl-2'-butenyl)-14-hydroxydihy
`- dronormorphinone ---------------------
`0.7
`
`TABLE II. ANTAGONISM OF THE ANALGETIC EFFECT
`OF DOSES OF N-(3'-METHYL-2'-BUTENYL)-14-HYDROXY
`DIHYDRONORMORPHINONE BY DOSES OF NALLYL-14
`HYDROXYEHYDRONORMORPHINONE
`3'-methyl-2'butenyl
`Allyl compound,
`Analgesia, percent
`compound, mg/kg.
`mg/kg.
`
`35
`
`3,332,950
`6
`ml. of dimethylformamide was heated at 65" for six
`118, 763 (1965)), was employed to evaluate the com
`days. The solvent was removed under reduced pressure
`pounds.
`and the residue was dissolved in 270 ml. of water. The
`TABLE I
`resulting solution was clarified with charcoal and adjusted
`Doses required to produce a 50% analgetic effect in the
`to pH 9. There was obtained 11.9 g, of crude product,
`M.P. 248-250. Recrystallization from chloroform and
`.
`OSC:
`Mg/kg.
`methanol raised the M.P. to 265.5.
`N - allyl-14-hydroxydihydronormorphinone - 100
`The hydrochloride salt, prepared by passing hydrogen
`N - propargyl - 14 - hydroxydihydronormor
`chloride into a chloroform solution of the base, melted
`phinone ------------------------------ 100
`at 264-265.
`N - cyclopropylmethyl-14-hydroxydihydronor
`EXAMPLE 2
`morphinone --------------------------- 100
`N-cyclopropylmethyl-14-hydroxydihydronor
`N - cyclobutylmethyl - 14-hydroxydihydronor
`morphinone
`morphinone --------------------------- 0.40
`N - (3'-methyl-2-butenyl)-14-hydroxydihydro
`Method a.-A solution of 14.4 g. of 14-hydroxydihy
`normorphinone ------------------------ 8.3
`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.
`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 ml. 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.
`311-313.
`To a mixture of 15.0 g of the acetal in 200 ml. of
`methylene chloride and 64 g. of triethylamine was added
`16 g. of cyclopropane carboxylic acid chloride in 100 ml,
`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-dicyclopropylcar.
`bonyl derivative separated; M.P. 219–220
`after re.
`crystallization from acetone.
`A 10 g. sample of the dicyclopropylcarbonyl compound
`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 30
`ml. of Saturated aqueous ammonium chloride. Inorgani
`material was removed by filtration. The tetrahydrofural
`layer was evaporated to dryness and the residue was re
`crystallized from acetonebenzene. The N-cyclopropyl
`methyl-14-hydroxydihydronormorphinone cyclic ethylen
`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.
`EXAMPLE 3
`N-cyclobutylmethyl-1 4-hydroxydihydronomorphinone
`Method a.-The compound was prepared from 14-hy,
`droxydihydronormorphinone and cyclobutylmethyl bro
`70
`mide by the method of Example 2a. It melted at 151-152
`upon recrystallization from ether. The hydrochloride sa
`melted at 256-2.58.
`Method b.--To a slurry of 110.5 g. of 14-hydroxyd
`hydronormorphinone in 2.5 1. of methylene chloride an
`
`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
`50
`ployed in the pharmaceutical field in connection with the
`administration of nitrogen-containing compounds.
`The dosages of the compounds are: for narcotic an
`tagonism-about 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.
`EXAMPLE 1.
`N-(3'-methyl-2'-butenyl)-14-hydroxydihydronor
`morphinone
`A solution of 14.4 g. of 14-hydroxydihydronormor
`phinone, 14.9 g of 1-bromo-3-methyl-2-butene and 550
`
`20
`20
`20
`20
`20
`
`0.0
`0.1
`0.2
`0.4
`0, 8
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`87
`70
`40
`10
`0
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`40
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`45
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`55
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`60
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`65
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`75
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`

`

`3,332,950
`7
`80 ml. of triethylamine was added a solution of 106 g.
`f cyclobutanecarboxylic acid chloride in 500 ml. of
`nethylene chloride. The temperature of the reaction mix
`ure was maintained at 20 to 25 during the addition.
`After 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
`ise to a suspension of 34.2 g. of lithium aluminum hy
`ride in one liter of tetrahydrofuran. The temperature of
`he mixture rose to reflux during the addition. Reflux was
`laintained 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
`olution of 53 g. of ammonium chloride in 125 ml. of
`'ater. 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
`ethyl - 14 - hydroxydihydronormorphine, M.P. 229
`31.
`A suspension of freshly prepared potassium t-butoxide
`made from 5 g. of potassium metal) in anhydrous ben
`2ne was heated under reflux for 2.5 hours with 13 g.
`f N-cyclobutylmethyl - 14 - hydroxydihydronormorphine
`ld 82 g. of benzophenone. The resulting mixture was
`ktracted with three 80 ml. portions of three normal hy
`cochloric acid. The acid extracts were combined, ad
`sted to pH 9 and extracted with chloroform. The chloro
`irm extract was evaporated to dryness and the dark
`roduct 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 b,
`- hydroxydihydronormorphinone cyclic ethylene acetal
`as converted into the dicyclobutanecarbonyl compound
`40
`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
`loride of the product, M.P. 257-258, identical with
`e hydrochloride made by Method a.
`Examples of dosage forms of the compounds
`EXAMPLE 4
`Parenteral form
`Mg/cc.
`ydrochloride salt of N-cyclopropylmethyldihydro
`14-hydroxynormorphinone -------------------- 0.5
`dium chloride ------------------------------ 9.0
`ethyl paraben ------------------------------- 1.8
`opyl paraben ------------------------------- 0.2
`ater for injection ---------------------------- C.S.
`
`45
`
`55
`
`60
`
`te 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
`2n 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,
`
`35
`
`IO)
`
`20
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`25
`
`30
`
`35
`
`3.
`EXAMPLE 5
`Oral form
`Mg/tablet
`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 142'' punch with a hardness of 4 kg.
`These tablets will disintegrate within a half hour accord
`ing to the method described in USP XVI.
`EXAMPLE 6
`Suppositories
`Percent
`Hydrochloride salt of N-(3'-methyl-2'-butenyl)-di
`hydro-14-hydroxynormorphinone ------------ 1.66
`Polyoxyethylene 1000 (approx. M 1000) ------- 80.14
`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 polyoxyethylenes
`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
`(1) N - substituted 14 - hydroxydihydronormorphinone
`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,
`
`