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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Publication number
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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United States
Prior art keywords
methylene
desoxy
pharmaceutically acceptable
allyl
acceptable salts
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Expired - Lifetime
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US00202575A
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English (en)
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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 US00202575A priority Critical patent/US3814768A/en
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/de
Priority to CH1715072A priority patent/CH578568A5/xx
Priority to JP11849472A priority patent/JPS5653556B2/ja
Priority to US446498A priority patent/US3896226A/en
Application granted granted Critical
Publication of US3814768A publication Critical patent/US3814768A/en
Assigned to PHARMEDIX, INC. reassignment PHARMEDIX, INC. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: PHARMEDIX INTERNATIONAL, LTD.
Assigned to BAKER CUMMINS PHARMACEUTICALS, INC. reassignment BAKER CUMMINS PHARMACEUTICALS, INC. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). FILED AUGUST 17, 1988. DELAWARE Assignors: IVAX PHARMACEUTICALS, INC.
Assigned to BAKER CUMMINS LABORATORIES, INC. reassignment BAKER CUMMINS LABORATORIES, INC. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). FILED NOVEMBER 10, 1988. DELAWARE Assignors: BAKER CUMMINS PHARMACEUTICALS, INC.,
Assigned to IVAX PHARMACEUTICALS, INC. reassignment IVAX PHARMACEUTICALS, INC. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). FILED FEBRUARY 16, 1988 Assignors: PHARMEDIX, INC.
Assigned to BAKER CUMMINS PHARMACEUTICALS, INC. reassignment BAKER CUMMINS PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: BAKER CUMMINS LABORATORIES, INC.
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Addiction (AREA)
  • Psychiatry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US00202575A 1971-11-26 1971-11-26 6-methylene-6-desoxy dihydro morphine and codeine derivatives and pharmaceutically acceptable salts Expired - Lifetime US3814768A (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
US00202575A US3814768A (en) 1971-11-26 1971-11-26 6-methylene-6-desoxy dihydro morphine and codeine derivatives and pharmaceutically acceptable salts
FR7241464A FR2160957B1 (de) 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
CH1715072A CH578568A5 (de) 1971-11-26 1972-11-24
JP11849472A JPS5653556B2 (de) 1971-11-26 1972-11-24
DE2257715A DE2257715C2 (de) 1971-11-26 1972-11-24 N-substituierte 6-Methylen-6-desoxy-14-hydroxydihydronormorphinderivate
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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US00202575A US3814768A (en) 1971-11-26 1971-11-26 6-methylene-6-desoxy dihydro morphine and codeine derivatives and pharmaceutically acceptable salts

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US (1) US3814768A (de)
JP (1) JPS5653556B2 (de)
CA (1) CA974235A (de)
CH (1) CH578568A5 (de)
DE (1) DE2257715C2 (de)
FR (1) FR2160957B1 (de)
GB (1) GB1411129A (de)

Cited By (18)

* 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
US5028612A (en) * 1990-03-22 1991-07-02 Hillel Glover Method for treating emotional numbness
EP0236477B1 (de) * 1985-09-06 1993-01-20 Baker Norton Pharmaceuticals, Inc. Verwendung von 6-Methylen-6-desoxy-N-cyclopropylmethyl-14-hydroxydihydronormorphin
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 (zh) * 2011-12-28 2012-07-18 南京优科生物医药有限公司 一种制备纳美芬化合物的方法
CN103012416A (zh) * 2011-09-28 2013-04-03 辽宁海思科制药有限公司 一种高纯度盐酸纳美芬的制备方法
WO2013083685A1 (en) * 2011-12-06 2013-06-13 H. Lundbeck A/S Process for recovery of nalmefene hydrochloride
CN103204859A (zh) * 2013-04-25 2013-07-17 四川海思科制药有限公司 一种盐酸纳美芬化合物及其制备方法
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

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5855258A (ja) * 1981-09-30 1983-04-01 Ricoh Co Ltd 熱転写型カラープリンタ
JPS5889377A (ja) * 1981-11-20 1983-05-27 Canon Inc ドツトプリンタ

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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 (de) * 1985-09-06 1993-01-20 Baker Norton Pharmaceuticals, Inc. Verwendung von 6-Methylen-6-desoxy-N-cyclopropylmethyl-14-hydroxydihydronormorphin
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 (zh) * 2011-09-28 2013-04-03 辽宁海思科制药有限公司 一种高纯度盐酸纳美芬的制备方法
CN103012416B (zh) * 2011-09-28 2015-07-01 辽宁海思科制药有限公司 一种盐酸纳美芬的制备方法
RU2631652C2 (ru) * 2011-12-06 2017-09-26 Х. Лундбекк А/С Способ извлечения налмефена гидрохлорида
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 (zh) * 2011-12-06 2014-10-08 H.隆德贝克有限公司 用于回收盐酸纳美芬的方法
CN104093721B (zh) * 2011-12-06 2016-05-18 H.隆德贝克有限公司 用于回收盐酸纳美芬的方法
CN102584840A (zh) * 2011-12-28 2012-07-18 南京优科生物医药有限公司 一种制备纳美芬化合物的方法
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 (zh) * 2013-04-25 2015-12-02 四川海思科制药有限公司 一种盐酸纳美芬化合物及其制备方法
CN103204859A (zh) * 2013-04-25 2013-07-17 四川海思科制药有限公司 一种盐酸纳美芬化合物及其制备方法
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

Also Published As

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

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