Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUS3814768 A
Publication typeGrant
Publication dateJun 4, 1974
Filing dateNov 26, 1971
Priority dateNov 26, 1971
Also published asCA974235A1, DE2257715A1, DE2257715C2
Publication numberUS 3814768 A, US 3814768A, US-A-3814768, US3814768 A, US3814768A
InventorsJ Fishman
Original AssigneeLewenstein E, Lewenstein M
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
6-methylene-6-desoxy dihydro morphine and codeine derivatives and pharmaceutically acceptable salts
US 3814768 A
Abstract  available in
Images(3)
Previous page
Next page
Claims  available in
Description  (OCR text may contain errors)

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

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4322426 *Apr 28, 1980Mar 30, 1982E. I. Du Pont De Nemours And Company17-Substituted-6-desoxy-7,8-dihydro-6α-methylnoroxymorphone narcotic antagonists
US4477457 *Oct 28, 1982Oct 16, 1984E. I. Du Pont De Nemours And CompanyMethod for inducing anorexia using nalmetrene
US4478840 *Oct 11, 1983Oct 23, 1984E. I. Du Pont De Nemours And CompanyAppetite suppressing compositions and methods
US4535157 *Nov 1, 1983Aug 13, 1985Key Pharmaceuticals, Inc.Process for making 6-desoxy-6-methylenenaloxone and 6-desoxy-6-methylenenaltrexone
US4639455 *Oct 2, 1984Jan 27, 1987Key Pharmaceuticals, Inc.Means of aiding in the prevention of sudden infant death syndrome
US4751307 *Feb 27, 1987Jun 14, 1988Mallinckrodt, Inc.Wittig-reaction processes
US5028612 *Mar 22, 1990Jul 2, 1991Hillel GloverMethod for treating emotional numbness
US7736665Jun 2, 2003Jun 15, 2010Titan Pharmaceuticals, Inc.Implantable polymeric device for sustained release of buprenorphine
US8841452Dec 6, 2012Sep 23, 2014H. Lundbeck A/SProcess for recovery of nalmefene hydrochloride
US8852623Jun 15, 2012Oct 7, 2014Titan Pharmaceuticals, Inc.Implantable polymeric device for sustained release of dopamine agonist
CN102584840A *Dec 28, 2011Jul 18, 2012南京优科生物医药有限公司Method for preparing nalmefene compound
EP0236477A1 *Sep 8, 1986Sep 16, 1987Key PharmaUse of 6-methylene-6-desoxy-N-cyclopropylmethyl-14-hydroxydihydronormorphine.
WO2013083685A1 *Dec 6, 2012Jun 13, 2013H. Lundbeck A/SProcess for recovery of nalmefene hydrochloride
Classifications
U.S. Classification546/46, 514/823
International ClassificationA61P25/30, A61K31/485, C07D489/00, C07D489/08
Cooperative ClassificationY10S514/823, C07D489/00, C07D489/08
European ClassificationC07D489/00, C07D489/08
Legal Events
DateCodeEventDescription
Jun 22, 1989ASAssignment
Owner name: BAKER CUMMINS PHARMACEUTICALS, INC., FLORIDA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:BAKER CUMMINS LABORATORIES, INC.;REEL/FRAME:005120/0430
Effective date: 19890606
Jun 22, 1989AS02Assignment of assignor's interest
Owner name: BAKER CUMMINS LABORATORIES, INC.
Effective date: 19890606
Owner name: BAKER CUMMINS PHARMACEUTICALS, INC., 8800 N.W. 36T
May 11, 1989AS01Change of name
Owner name: BAKER CUMMINS LABORATORIES, INC.
Owner name: BAKER CUMMINS PHARMACEUTICALS, INC.,
Effective date: 19881027
May 11, 1989ASAssignment
Owner name: BAKER CUMMINS LABORATORIES, INC.
Free format text: CHANGE OF NAME;ASSIGNOR:BAKER CUMMINS PHARMACEUTICALS, INC.,;REEL/FRAME:005080/0956
Effective date: 19881027
Owner name: BAKER CUMMINS PHARMACEUTICALS, INC.
Free format text: CHANGE OF NAME;ASSIGNOR:IVAX PHARMACEUTICALS, INC.;REEL/FRAME:005080/0953
Effective date: 19880812
Owner name: IVAX PHARMACEUTICALS, INC.
Free format text: CHANGE OF NAME;ASSIGNOR:PHARMEDIX, INC.;REEL/FRAME:005080/0950
Effective date: 19880203
Apr 10, 1989ASAssignment
Owner name: PHARMEDIX, INC., FLORIDA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:PHARMEDIX INTERNATIONAL, LTD.;REEL/FRAME:005043/0618
Effective date: 19871210
Apr 10, 1989AS02Assignment of assignor's interest
Owner name: PHARMEDIX INTERNATIONAL, LTD.
Owner name: PHARMEDIX, INC., 8800 N.W. 36TH STREET, MIAMI, FLO
Effective date: 19871210