US3814768A - 6-methylene-6-desoxy dihydro morphine and codeine derivatives and pharmaceutically acceptable salts - Google Patents

6-methylene-6-desoxy dihydro morphine and codeine derivatives and pharmaceutically acceptable salts Download PDF

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US3814768A
US3814768A US00202575A US20257571A US3814768A US 3814768 A US3814768 A US 3814768A US 00202575 A US00202575 A US 00202575A US 20257571 A US20257571 A US 20257571A US 3814768 A US3814768 A US 3814768A
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methylene
desoxy
pharmaceutically acceptable
allyl
acceptable salts
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J Fishman
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LEWENSTEIN E
LEWENSTEIN E US
LEWENSTEIN M
LEWENSTEIN M US
Teva Branded Pharmaceutical Products R&D Inc
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LEWENSTEIN E
LEWENSTEIN M
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Priority to FR7241464A priority patent/FR2160957B1/fr
Priority to CA157,312A priority patent/CA974235A/en
Priority to GB5421372A priority patent/GB1411129A/en
Priority to DE2257715A priority patent/DE2257715C2/en
Priority to JP11849472A priority patent/JPS5653556B2/ja
Priority to CH1715072A priority patent/CH578568A5/xx
Priority to US446498A priority patent/US3896226A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
    • C07D489/08—Oxygen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:

Definitions

  • a narcotic antagonist selected from the class consisting of 6-methylene-6-desoxy dihydro morphine and codeine derivatives and pharmaceutically acceptable salts thereof which are particularly effective by the oral route and which are also effective when administered parenterally.
  • Narcotic antagonists are now entering into approved use for treatment of narcotic addiction.
  • One such narcotic antagonist whose use has become popular is cyclazocine.
  • a more effective narcotic antagonist is N-allyl-noroxymorphone known as naloxone.
  • Naloxone has been a, very effective narcotic antagonist when administered by a parenteral route at a dosage level of approximately 0.01 milligrams per kilogram of patient body weight. When so administered its narcotic antagonistic effect persists for approximately six hours. Naloxone is not as effective as a narcotic antagonist when administered orally.
  • narcotic antagonists are not satisfactory when given in oral doses because of the large amounts required, the necessity for concealing the taste of such large amounts and the short period of time between dosages. It would be highly desirable to supply a narcotic antagonist which could be administered orally in comparatively small dosages and which would have an appreciably longer lasting effect than either cyclazocine or naloxone.
  • EEG cyclopropylmethyl
  • R is selected from the group consisting of hydrogen and hydroxy (OH)
  • R is selected from the group consisting of hydroxy (OH) and methoxy (OCH and the pharmaceutically acceptable salts thereof.
  • the present invention principally resides in a new compound of matter constituting a 6- methylene-6-desoxy dihydro morphine or codeine derivative of the formula i H a o a where R is selected from the group consisting of, allyl and cyclopro'pylmethyl, R is selected from the group consisting of hydrogen and hydroxy, and R is selected from the group consisting of hydroxy and methoxy, and the pharmaceutically acceptable salts thereof.
  • the aforesaid novel compounds due to their high potency in small dosages, are preferably combined with a pharmaceutically acceptable inert carrier.
  • Suitable inert carriers for oral administration are water, milk optionally with sugarand/ or starch, natural and synthetic fruit juices, such as orange juice, grapefruit juice, grape juice, pineapple juice, lemon juice and prune juice, and sweetened beverages such, for instance, as flavored water with or without carbonation.
  • natural and synthetic fruit juices such as orange juice, grapefruit juice, grape juice, pineapple juice, lemon juice and prune juice
  • sweetened beverages such, for instance, as flavored water with or without carbonation.
  • the acid extract was quickly neutralized and adjusted to pH 9 with concentrated ammonium hydroxide and the basic solution was extracted with four 100 cc. portions of chloroform.
  • the ketonic materials were removed from the organic layer by washing with sodium bisulfite-sodium sulfite solution, and the chloroform was .dried over sodium sulfate and evaporated. The residue was crystallized from ethanolether to give 3.9 grams of 6-methylene-6-desoxy-14-hydroxydihydronormorphine-S-methoxymethyl ether.
  • Example II 50 grams of 6-methylene-6-desoxy-14-hydroxydihydronormorphine was reacted as above except that cyclopropylmethyl chloride was used instead of allyl bromide to give 6-methylene 6 desoxy-N-cyclopropylmethyl-14 hydroxydihydronormorphine.
  • Example III 10 grams of N-allyl-dihydronormorphinone-3-methoxymethyl ether was dissolved in cc. of tetrahydrofuran and three equivalents of triphenylphosphomethylene reagent in 100 cc. of tetrahydrofuran was added and the mixture was refluxed for three days. The reaction mixture was then cooled and the solvent was removed under reduced pressure. The residue was taken up in 300 cc. of chloroform and filtered and the organic layer was extracted three times with 100 cc. of 10% aqueous HCl. The acid extract was quickly adjusted to pH 9 with concentrated ammonium hydroxide and extracted four times with 100 cc.
  • 6-methylene-6-desoxy-N-allyl-dihydronormorphine-3-methoxymethyl ether was allowed to stand in 5% sulfuric acid (aq.) for four hours at room temperature, and the solution was then adjusted to pH 9 with dilute NaOH.
  • the precipitate so obtained was filtered, dried in air and recrystallized from methanol to give 6- methylene 6 desoxy-N-allyl-dihydronormorphine with a melting point of 235-24l C.
  • salts of the compounds embodying the present invention include hydrochloride, hydrobromide, neutral and acid sulfate, phosphates, nitrate, acetate, benzoate, salicylate, neutral and acid fu-marate and maleate, terephthalate, ethanesulfonate, the bitartrate and others.
  • Water-soluble salts with volatile acids can be prepared by adding an aqueous solution of slightly more than one equivalent of the acid to an aqueous dispersion of the base and evaporating the solution thus formed under reduced pressure. The residue can then be recrystallized.
  • Salts of non-volatile inorganic acids e.g. orthophosphoric acid
  • Salts of organic acids which are difiicultly soluble in water can be prepared by reacting the acid and the base in equivalent amounts in ethyl alcoholic medium and evaporating the solution.
  • Example V 100 mg. of 6-methylene-6-desoxy-N-allyl-l4-hydroxydihydronormorphine was dissolved in 20 cc. of dilute ethanol. Excess dilute hydrochloric acid -(10 cc.) was added, and the mixture was evaporated to dryness under reduced pressure on a steam bath. The white hydrochloride salt was crystalliezd from ethanol-ether.
  • Example VI 100 mg. of fi-methylene-6-desoxy-N-allyl-14-hydroxydihydronormorphine was dissolved in 20 ml. of ethanol. A solution of 39 mg. of benzoic acid in 5 cc. of ethanol was added and the solvent was evaporated under reduced pressure on a steam bath. The white benzoate was crystallized from ethanol-ether.
  • novel compounds can be combined to form metal salts thereof as, for example, combined with alkali metal and alkaline earth metal salts, sodium salts being the preferred form.
  • a highly effective oral dosage of 6-methylene-6-desoxy dihydro morphine and codeine derivatives and pharmaceutically acceptable salts thereof constitutes 0.1 milligrams to 10.0 milligrams per kilogram of patient body weight at which rate the duration of the narcotic antagonist effect persists for approximately eight to twelve hours.
  • the dilution of the aforesaid novel compound in any one of the carriers mentioned above can vary as desired, a typical dilution being 0.5% to 5.0% by weight of the compound in any of the aforesaid inert carriers.
  • novel compounds are believed to find their most effective use when employed orally, they also can be administered parenterally and, in this event, a dilution which obtains satisfactory results is 0.5 to 2% by weight of the compound in distilled water. Excellent narcotic antagonist effects are observed with dosages in the order of 0.02 to 2.0 milligram of the compound per kilogram of patient body weight.
  • the compounds also can be administered rectally by incorporating the same in a suppository, e.g. of the petrolatum or wax type.
  • compositions and methods for narcotic antagonists which accomplish the various objects of the invention and are well adapted to meet the conditions of practical use.
  • a compound as set forth in claim 1 constituting 6- methylene 6 desoxy-N-allyl-14-hydroxydihydronormorphine.
  • a compound as set forth in claim 1 constituting 6- methylene 6-desoxy-N-cyclopropylmethyl-l4-hydroxydihydronormorphine.
  • a compound as set forth in claim 1 constituting 6- methylene-6-desoxy-N-cyclopropylmethyl dihydronormorphine.
  • a compound as set forth in claim 1 constituting 6- methylene-6-desoxy-N-allyl-dihydronormorphine.
  • a compound as set forth in claim 1 constituting 6- methylene-fi-desoxy-l4-hydroxydihydronormorphine.
  • a compound as set forth in claim 1 constituting 6- methylene-6-desoxy-dihydronormorphine.
  • a compound as set forth in claim 1 constituting 6- methylene-6-desoxy-N-allyl-dihydronorcodeine.
  • a compound as set forth in claim 1 constituting 6- methylene 6-desoxy-N-cyclopropylmethyl-14-hydroxydihyronorcodeine.
  • a compound as set forth in claim 1 constituting 6- methylene 6 desoxy N allyl-l4-hydroxydihydronorcodeine.
  • a compound as set forth in claim 1 constituting 6- methylene-6-desoxy-14-hydroxydihydronorcodeine.

Abstract

A NARCOTIC ANTAGONIST SELECTED FROM THE CLASS CONSISTING OF 6-METHYLENE-6-DESOXY DIHYDRO MORPJINE AND CODEINE DERIVATIVES AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF WHICH ARE PARTICULARLY EFFECTIVE BY THE ORAL ROUTE AND WITH ALSO EFFECTIVE WHEN ADMINISTERED PARENTERALLY.

Description

3,814,768 G-METHYLENE-fi-DESOXY DIHYDRO MORPHINE AND CODEINE DERIVATIVES AND PHARMA- CEUTICALLY ACCEPTABLE SALTS Jack Fishman, New York, N.Y., assignor to Evalina Lewenstein, executrix of the estate of Mozes J. Lewenstein, deceased, New York, N.Y. No Drawing. Filed Nov. 26, 1971, Ser. No. 202,575 Int. Cl. C07d 43/28 US. Cl. 260-285 11 Claims ABSTRACT OF THE DISCLOSURE A narcotic antagonist selected from the class consisting of 6-methylene-6-desoxy dihydro morphine and codeine derivatives and pharmaceutically acceptable salts thereof which are particularly effective by the oral route and which are also effective when administered parenterally.
BACKGROUND OF THE INVENTION (1) Field of the invention 7 Narcotic antagonists.
(2) Description of the prior art Narcotic antagonists are now entering into approved use for treatment of narcotic addiction. One such narcotic antagonist whose use has become popular is cyclazocine. A more effective narcotic antagonist is N-allyl-noroxymorphone known as naloxone. Naloxone has been a, very effective narcotic antagonist when administered by a parenteral route at a dosage level of approximately 0.01 milligrams per kilogram of patient body weight. When so administered its narcotic antagonistic effect persists for approximately six hours. Naloxone is not as effective as a narcotic antagonist when administered orally. By the latter route larger doses are required, for example 25.0 milligrams per kilogram of patient body weight, and the duration of the effect is less than when administered parenterally, for example, about four hours. It is undesirable to administer a narcotic antagonist parenterally for psychological reasons. On the other hand, current narcotic antagonists are not satisfactory when given in oral doses because of the large amounts required, the necessity for concealing the taste of such large amounts and the short period of time between dosages. It would be highly desirable to supply a narcotic antagonist which could be administered orally in comparatively small dosages and which would have an appreciably longer lasting effect than either cyclazocine or naloxone.
SUMMARY OF THE INVENTION (1) Purposes of the invention It is an object of the invention to provide a narcotic antagonist which is more effective than cyclazocine and United States Patent naloxone when administered orally and which will have a longer lasting effect when so administered.
It is another object of the invention to provide a narcotic antagonist of the character described which is also capable of administration parenterally.
It is another object of the invention to provide a narcotic antagonist of the character described which is no more expensive or difiicult to make than cyclazocine or naloxone and which is, therefore, less expensive to administer because of the lower dosages needed and the longer periods of effectiveness.
It is another object of the invention to provide a narcotic antagonist of the character described which may be made simply and quickly and on a large scale production basis so as to be able to administer the same to the many 3,814,768 Patented June 4, 1974 addicts which present-day society unfortunately has produced.
Other objects of the invention in part will be obvious and in part will be pointed out hereinafter.
(2) Brief description of the invention i. \0/ CH.
where R, is selected from the group consisting of allyl H H H (0-o=o and cyclopropylmethyl (EEG)- R is selected from the group consisting of hydrogen and hydroxy (OH), and R is selected from the group consisting of hydroxy (OH) and methoxy (OCH and the pharmaceutically acceptable salts thereof. The said compound is combined (mixed) with a pharmaceutically acceptable inert carrier for easy ingestion. Any typical carrier well known in the art can be used, examples thereof being water, milk with or without sugar and/or starch, natural and synthetic fruit juice and beverages. If the compound is to be administered parenterally, distilled water is a desirable carrier. The narcotic antagonistic also may be administered rectally by incorporation in a standard suppository.
The invention consists in the compositions of matter and series of steps which will hereinafter be described and of which the scope of application will be indicated in the appended claims.
PREFERRED EMBODIMENTS OF THE INVENTION As indicated above, the present invention principally resides in a new compound of matter constituting a 6- methylene-6-desoxy dihydro morphine or codeine derivative of the formula i H a o a where R is selected from the group consisting of, allyl and cyclopro'pylmethyl, R is selected from the group consisting of hydrogen and hydroxy, and R is selected from the group consisting of hydroxy and methoxy, and the pharmaceutically acceptable salts thereof. The aforesaid novel compounds, due to their high potency in small dosages, are preferably combined with a pharmaceutically acceptable inert carrier. Suitable inert carriers for oral administration are water, milk optionally with sugarand/ or starch, natural and synthetic fruit juices, such as orange juice, grapefruit juice, grape juice, pineapple juice, lemon juice and prune juice, and sweetened beverages such, for instance, as flavored water with or without carbonation.
The following are specific examples of compounds of the present invention:
(a) 6-methylene-6-desoxy-N-allyl-14-hydroxydihydronormorphine.
(b) 6-methylene-6-desoxy-N-cyclopropylmethyl-14- hydroxydihydronormorphine.
(c) 6-methylene-6-desoxy-N-cyclopropylmethyl dihydronormorphine.
(d) -6-methylene-6-desoxy-N-allyl-dihydronormorphine.
(e) 6-methylene-6-desoxy-l4-hydroxydihydronormorphine.
(f) 6-methylene-6-desoxy-dihydronormorphine.
(g) 6-methylene-6-desoxy-N-allyl-dihydronorcodeine.
(h) 6-methylene-6-desoxy-N-cyclopropylmethyl-14- hydroxydihydronorcodeine.
(i) 6-methylene-6-desoxy-N-allyl-14-hydroxydihydronorcodeine.
(i) 6-methylene-6-desoxy-14-hydroxydihydronorcodeine.
PREPARATION Example I 30 grams of 14-hydroxydihydronormorphinone was converted to its sodium salt and suspended in 200 cc. of chloroform. 8 grams of chloromethyl ether in 50 cc. of chloroform were added and the mixture was stirred in a nitrogen atmosphere for ten hours. The sOlutiOn was then Washed with dilute NaOH and water, dried and evaporated. The l4-hydroxydihydronormorphinone-3-methoxymethyl ether thus obtained was crystallized from benzene.
grams of 14-hydroxydihydronormorphinone-3-methoxymethyl ether dissolved in the minimum amount of tetrahydrofuran was added slowly to a stirred solution of four equivalents of triphenylphosphomethylene reagent in ethyl ether. The ether was fractionally distilled off with periodic additions of tetrahydrofuran until the reflux temperature reached 60 C. The solution was refluxed at this temperature for 40 hours, after which the solvent was removed under reduced pressure. The residue was taken up in 200 cc. of chloroform and 100 cc. of water. The water layer was discarded and the chloroform was washed once with 100 cc. of 5% NaOH and then extracted three times with 100 cc. of 2 N sulfuric acid. The acid extract was quickly neutralized and adjusted to pH 9 with concentrated ammonium hydroxide and the basic solution was extracted with four 100 cc. portions of chloroform. The ketonic materials were removed from the organic layer by washing with sodium bisulfite-sodium sulfite solution, and the chloroform was .dried over sodium sulfate and evaporated. The residue was crystallized from ethanolether to give 3.9 grams of 6-methylene-6-desoxy-14-hydroxydihydronormorphine-S-methoxymethyl ether.
1 gram of 6-methylene 6 desoxy-14-hydroxydihydronormorphine-3-methyoxymethyl ether was dissolved in cc. of 1 N HCl and allowed to stand for four hours at room temperature. The addition of 100 cc. of water was followed by adjusting the pH to 9 with ammonium hydroxide. The basic mixture was extracted three times with 100 cc. of chloroform which was dried and evaporated. Crystallization from dilute methanol gave 6-methylene-6- desoxy 14 hydroxydihydronormorphine with a melting point of 246250 C.
50' grams of 6-methylene-6-desoxy-l4-hydroxydihydronormorphine was dissolved in 200 cc. of ethanol, half its weight of sodium bicarbonate and half its weight of allyl bromide was added and the mixture was refluxed at about 75 C. for 50 hours. The solution was cooled to room temperature, filtered and the alcohol was removed under reduced pressure. The residue was taken up in 100 cc. of
chloroform and filtered; the solvent was removed under reduced pressure and the residue was crystallized from benzene-hexane to give 6-methylene-6-des0xy-N-allyl-14- hydroxydihydronormorphine.
Example II 50 grams of 6-methylene-6-desoxy-14-hydroxydihydronormorphine was reacted as above except that cyclopropylmethyl chloride was used instead of allyl bromide to give 6-methylene 6 desoxy-N-cyclopropylmethyl-14 hydroxydihydronormorphine.
Example III Example IV 10 grams of N-allyl-dihydronormorphinone-3-methoxymethyl ether was dissolved in cc. of tetrahydrofuran and three equivalents of triphenylphosphomethylene reagent in 100 cc. of tetrahydrofuran was added and the mixture was refluxed for three days. The reaction mixture was then cooled and the solvent was removed under reduced pressure. The residue was taken up in 300 cc. of chloroform and filtered and the organic layer was extracted three times with 100 cc. of 10% aqueous HCl. The acid extract was quickly adjusted to pH 9 with concentrated ammonium hydroxide and extracted four times with 100 cc. of chloroform, which was washed with water, dried and evaporated under reduced pressure. The residue was crystallized from ethanol to give 6-methylene-6-desoxy-N-allyl dihydronormorphine-3-methoxymethyl ether with a melting point of 197201 C.
5 grams of 6-methylene-6-desoxy-N-allyl-dihydronormorphine-3-methoxymethyl ether was allowed to stand in 5% sulfuric acid (aq.) for four hours at room temperature, and the solution was then adjusted to pH 9 with dilute NaOH. The precipitate so obtained was filtered, dried in air and recrystallized from methanol to give 6- methylene 6 desoxy-N-allyl-dihydronormorphine with a melting point of 235-24l C.
It has been found that a wide variety of salts of the compounds embodying the present invention can be prepared. They include hydrochloride, hydrobromide, neutral and acid sulfate, phosphates, nitrate, acetate, benzoate, salicylate, neutral and acid fu-marate and maleate, terephthalate, ethanesulfonate, the bitartrate and others.
Water-soluble salts with volatile acids (e.g. hydrochloric and acetic acid) can be prepared by adding an aqueous solution of slightly more than one equivalent of the acid to an aqueous dispersion of the base and evaporating the solution thus formed under reduced pressure. The residue can then be recrystallized. Salts of non-volatile inorganic acids (e.g. orthophosphoric acid) can be prepared by adding the stoichiometric amount of the acid to an aqueous dispersion of the base and treating the resulting solution in the manner described above. Salts of organic acids which are difiicultly soluble in water (e.g., the benzoate) can be prepared by reacting the acid and the base in equivalent amounts in ethyl alcoholic medium and evaporating the solution.
Example V 100 mg. of 6-methylene-6-desoxy-N-allyl-l4-hydroxydihydronormorphine was dissolved in 20 cc. of dilute ethanol. Excess dilute hydrochloric acid -(10 cc.) was added, and the mixture was evaporated to dryness under reduced pressure on a steam bath. The white hydrochloride salt was crystalliezd from ethanol-ether.
Example VI 100 mg. of fi-methylene-6-desoxy-N-allyl-14-hydroxydihydronormorphine was dissolved in 20 ml. of ethanol. A solution of 39 mg. of benzoic acid in 5 cc. of ethanol was added and the solvent was evaporated under reduced pressure on a steam bath. The white benzoate was crystallized from ethanol-ether.
Furthermore, the novel compounds can be combined to form metal salts thereof as, for example, combined with alkali metal and alkaline earth metal salts, sodium salts being the preferred form.
As indicated previously, a highly effective oral dosage of 6-methylene-6-desoxy dihydro morphine and codeine derivatives and pharmaceutically acceptable salts thereof constitutes 0.1 milligrams to 10.0 milligrams per kilogram of patient body weight at which rate the duration of the narcotic antagonist effect persists for approximately eight to twelve hours. The dilution of the aforesaid novel compound in any one of the carriers mentioned above can vary as desired, a typical dilution being 0.5% to 5.0% by weight of the compound in any of the aforesaid inert carriers. Although as mentioned above the novel compounds are believed to find their most effective use when employed orally, they also can be administered parenterally and, in this event, a dilution which obtains satisfactory results is 0.5 to 2% by weight of the compound in distilled water. Excellent narcotic antagonist effects are observed with dosages in the order of 0.02 to 2.0 milligram of the compound per kilogram of patient body weight. The compounds also can be administered rectally by incorporating the same in a suppository, e.g. of the petrolatum or wax type.
It thus will be seen that there have been provided compositions and methods for narcotic antagonists which accomplish the various objects of the invention and are well adapted to meet the conditions of practical use.
As various possible embodiments might be made of the above invention and as changes might be made in the embodiments above set forth, it is to be understood that all matter herein described is to be interpreted as illustrative and not in a limiting sense.
Having thus described the invention there is claimed as new and desired to be secured by Letters Patent:
1. A compound selected from the group consisting of a chemical having the following formula and pharmaceutically acceptable salts thereof 6 where R is selected from the group consisting of allyl and cyclopropylmethyl, R is selected from the group consisting of hydrogen and hydroxy, and R is selected from the group consisting of hydroxy and methoxy.
2. A compound as set forth in claim 1 constituting 6- methylene 6 desoxy-N-allyl-14-hydroxydihydronormorphine.
3. A compound as set forth in claim 1 constituting 6- methylene 6-desoxy-N-cyclopropylmethyl-l4-hydroxydihydronormorphine.
4. A compound as set forth in claim 1 constituting 6- methylene-6-desoxy-N-cyclopropylmethyl dihydronormorphine.
5. A compound as set forth in claim 1 constituting 6- methylene-6-desoxy-N-allyl-dihydronormorphine.
6. A compound as set forth in claim 1 constituting 6- methylene-fi-desoxy-l4-hydroxydihydronormorphine.
7. A compound as set forth in claim 1 constituting 6- methylene-6-desoxy-dihydronormorphine.
8. A compound as set forth in claim 1 constituting 6- methylene-6-desoxy-N-allyl-dihydronorcodeine.
9. A compound as set forth in claim 1 constituting 6- methylene 6-desoxy-N-cyclopropylmethyl-14-hydroxydihyronorcodeine.
10. A compound as set forth in claim 1 constituting 6- methylene 6 desoxy N allyl-l4-hydroxydihydronorcodeine.
11. A compound as set forth in claim 1 constituting 6- methylene-6-desoxy-14-hydroxydihydronorcodeine.
References Cited UNITED STATES PATENTS 3,153,042 10/ 1964 Fishman 260285 3,162,639 12/1964 Fishman 260285 3,332,950 7/1967 Blumberg 260285 3,322,771 5/ 1967 Bartels-Kcith 260-285 FOREIGN PATENTS 101,153 10/ 1963 Japan 260285 OTHER REFERENCES Gates et al.: Jour. Med. Chem., vol. 7, pp. 127-31 (1964).
Martin et al.: Long Acting Narcotic Antagonists, N.I.M.H., pp. 21-9.
DONALD G. DAUS, Primary Examiner US. Cl. X.R. 424-260
US00202575A 1971-11-26 1971-11-26 6-methylene-6-desoxy dihydro morphine and codeine derivatives and pharmaceutically acceptable salts Expired - Lifetime US3814768A (en)

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US00202575A US3814768A (en) 1971-11-26 1971-11-26 6-methylene-6-desoxy dihydro morphine and codeine derivatives and pharmaceutically acceptable salts
FR7241464A FR2160957B1 (en) 1971-11-26 1972-11-22
GB5421372A GB1411129A (en) 1971-11-26 1972-11-23 Morphine and codeine derivatives suitable as nacotic antagonists
CA157,312A CA974235A (en) 1971-11-26 1972-11-23 Morphine derivatives
JP11849472A JPS5653556B2 (en) 1971-11-26 1972-11-24
CH1715072A CH578568A5 (en) 1971-11-26 1972-11-24
DE2257715A DE2257715C2 (en) 1971-11-26 1972-11-24 N-substituted 6-methylene-6-deoxy-14-hydroxydihydronormorphine derivatives
US446498A US3896226A (en) 1971-11-26 1974-02-27 6-methylene-6-desoxy dihydro morphine and codeine derivatives and pharmaceutically acceptable salts thereof, and use of the same as a narcotic antagonist

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GB (1) GB1411129A (en)

Cited By (18)

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US4322426A (en) * 1980-04-28 1982-03-30 E. I. Du Pont De Nemours And Company 17-Substituted-6-desoxy-7,8-dihydro-6α-methylnoroxymorphone narcotic antagonists
US4477457A (en) * 1982-10-28 1984-10-16 E. I. Du Pont De Nemours And Company Method for inducing anorexia using nalmetrene
US4478840A (en) * 1983-10-11 1984-10-23 E. I. Du Pont De Nemours And Company Appetite suppressing compositions and methods
US4535157A (en) * 1983-11-01 1985-08-13 Key Pharmaceuticals, Inc. Process for making 6-desoxy-6-methylenenaloxone and 6-desoxy-6-methylenenaltrexone
US4639455A (en) * 1984-10-02 1987-01-27 Key Pharmaceuticals, Inc. Means of aiding in the prevention of sudden infant death syndrome
US4751307A (en) * 1985-01-17 1988-06-14 Mallinckrodt, Inc. Wittig-reaction processes
US5028612A (en) * 1990-03-22 1991-07-02 Hillel Glover Method for treating emotional numbness
EP0236477B1 (en) * 1985-09-06 1993-01-20 Baker Norton Pharmaceuticals, Inc. Use of 6-methylene-6-desoxy-n-cyclopropylmethyl-14-hydroxydihydronormorphine
US20040033250A1 (en) * 2002-05-31 2004-02-19 Patel Rajesh A. Implantable polymeric device for sustained release of buprenorphine
US20070015138A1 (en) * 2005-07-08 2007-01-18 Braincells, Inc. Methods for identifying agents and conditions that modulate neurogenesis
US20080311171A1 (en) * 2003-03-31 2008-12-18 Patel Rajesh A Implantable polymeric device for sustained release of dopamine agonist
CN102584840A (en) * 2011-12-28 2012-07-18 南京优科生物医药有限公司 Method for preparing nalmefene compound
CN103012416A (en) * 2011-09-28 2013-04-03 辽宁海思科制药有限公司 Method for preparing high-purity nalmefene hydrochloride
WO2013083685A1 (en) * 2011-12-06 2013-06-13 H. Lundbeck A/S Process for recovery of nalmefene hydrochloride
CN103204859A (en) * 2013-04-25 2013-07-17 四川海思科制药有限公司 Nalmefene hydrochloride compound and preparation method thereof
WO2014170704A1 (en) 2013-04-15 2014-10-23 Szegedi Tudományegyetem Deuterated morphine derivatives
WO2015163486A1 (en) 2014-04-22 2015-10-29 Otsuka Pharmaceutical Co., Ltd. Combination of brexpiprazole and nalmefene and use thereof for treating substance-related disorders
US9642849B2 (en) 2012-06-27 2017-05-09 H. Lundbeck A/S Nalmefene for reduction of alcohol consumption in specific target populations

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JPS5855258A (en) * 1981-09-30 1983-04-01 Ricoh Co Ltd Heat transfer type color printer
JPS5889377A (en) * 1981-11-20 1983-05-27 Canon Inc Dot printer

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US3162639A (en) * 1964-12-22 G-desoxy-ix-hydroxy-dihydromorphine

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4322426A (en) * 1980-04-28 1982-03-30 E. I. Du Pont De Nemours And Company 17-Substituted-6-desoxy-7,8-dihydro-6α-methylnoroxymorphone narcotic antagonists
US4477457A (en) * 1982-10-28 1984-10-16 E. I. Du Pont De Nemours And Company Method for inducing anorexia using nalmetrene
US4478840A (en) * 1983-10-11 1984-10-23 E. I. Du Pont De Nemours And Company Appetite suppressing compositions and methods
US4535157A (en) * 1983-11-01 1985-08-13 Key Pharmaceuticals, Inc. Process for making 6-desoxy-6-methylenenaloxone and 6-desoxy-6-methylenenaltrexone
US4639455A (en) * 1984-10-02 1987-01-27 Key Pharmaceuticals, Inc. Means of aiding in the prevention of sudden infant death syndrome
US4751307A (en) * 1985-01-17 1988-06-14 Mallinckrodt, Inc. Wittig-reaction processes
EP0236477B1 (en) * 1985-09-06 1993-01-20 Baker Norton Pharmaceuticals, Inc. Use of 6-methylene-6-desoxy-n-cyclopropylmethyl-14-hydroxydihydronormorphine
US5028612A (en) * 1990-03-22 1991-07-02 Hillel Glover Method for treating emotional numbness
US20080026031A1 (en) * 2002-05-31 2008-01-31 Titan Pharmaceuticals, Inc. Implantable polymeric device for sustained release of buprenorphine
US7736665B2 (en) 2002-05-31 2010-06-15 Titan Pharmaceuticals, Inc. Implantable polymeric device for sustained release of buprenorphine
US20040033250A1 (en) * 2002-05-31 2004-02-19 Patel Rajesh A. Implantable polymeric device for sustained release of buprenorphine
US8852623B2 (en) 2003-03-31 2014-10-07 Titan Pharmaceuticals, Inc. Implantable polymeric device for sustained release of dopamine agonist
US9278163B2 (en) 2003-03-31 2016-03-08 Titan Pharmaceuticals, Inc. Implantable polymeric device for sustained release of dopamine agonist
US20080311171A1 (en) * 2003-03-31 2008-12-18 Patel Rajesh A Implantable polymeric device for sustained release of dopamine agonist
US20090162412A1 (en) * 2003-03-31 2009-06-25 Patel Rajesh A Implantable polymeric device for sustained release of dopamine agonist
US20070015138A1 (en) * 2005-07-08 2007-01-18 Braincells, Inc. Methods for identifying agents and conditions that modulate neurogenesis
CN103012416A (en) * 2011-09-28 2013-04-03 辽宁海思科制药有限公司 Method for preparing high-purity nalmefene hydrochloride
CN103012416B (en) * 2011-09-28 2015-07-01 辽宁海思科制药有限公司 Method for preparing high-purity nalmefene hydrochloride
RU2631652C2 (en) * 2011-12-06 2017-09-26 Х. Лундбекк А/С Method for extracting nalmephene hydrochloride
US8841452B1 (en) 2011-12-06 2014-09-23 H. Lundbeck A/S Process for recovery of nalmefene hydrochloride
WO2013083685A1 (en) * 2011-12-06 2013-06-13 H. Lundbeck A/S Process for recovery of nalmefene hydrochloride
CN104093721A (en) * 2011-12-06 2014-10-08 H.隆德贝克有限公司 Process for recovery of nalmefene hydrochloride
CN104093721B (en) * 2011-12-06 2016-05-18 H.隆德贝克有限公司 For reclaiming the method for nalmefene hydrochloride
CN102584840A (en) * 2011-12-28 2012-07-18 南京优科生物医药有限公司 Method for preparing nalmefene compound
US9642849B2 (en) 2012-06-27 2017-05-09 H. Lundbeck A/S Nalmefene for reduction of alcohol consumption in specific target populations
US10034874B2 (en) 2012-06-27 2018-07-31 H. Lundbeck A/S Nalmefene for reduction of alcohol consumption in specific target populations
WO2014170704A1 (en) 2013-04-15 2014-10-23 Szegedi Tudományegyetem Deuterated morphine derivatives
CN103204859B (en) * 2013-04-25 2015-12-02 四川海思科制药有限公司 A kind of Nalmefene hydrochloride compound and preparation method thereof
CN103204859A (en) * 2013-04-25 2013-07-17 四川海思科制药有限公司 Nalmefene hydrochloride compound and preparation method thereof
WO2015163486A1 (en) 2014-04-22 2015-10-29 Otsuka Pharmaceutical Co., Ltd. Combination of brexpiprazole and nalmefene and use thereof for treating substance-related disorders

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GB1411129A (en) 1975-10-22
CH578568A5 (en) 1976-08-13
DE2257715C2 (en) 1985-06-05
FR2160957A1 (en) 1973-07-06
CA974235A (en) 1975-09-09
JPS4858000A (en) 1973-08-14
FR2160957B1 (en) 1975-11-28
JPS5653556B2 (en) 1981-12-19
DE2257715A1 (en) 1973-05-30

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