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Publication numberUS3896226 A
Publication typeGrant
Publication dateJul 22, 1975
Filing dateFeb 27, 1974
Priority dateNov 26, 1971
Publication numberUS 3896226 A, US 3896226A, US-A-3896226, US3896226 A, US3896226A
InventorsJack Fishman
Original AssigneeLewinstein Evalina
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
6-methylene-6-desoxy dihydro morphine and codeine derivatives and pharmaceutically acceptable salts thereof, and use of the same as a narcotic antagonist
US 3896226 A
Abstract  available in
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Description  (OCR text may contain errors)

United States Patent [1 1 Fishman 1 6-METHYLENE-6-DESOXY DIHYDRO MORPHINE AND CODEINE DERIVATIVES AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, AND USE OF THE SAME AS A NARCOTIC ANTAGONIST [75] Inventor: Jack Fishman, New York, N.Y.

[73] Assignees: Evalina Lewinstein; Henry Hirsch;

Stanley Rothschild, all of New York, N.Y.

[22] Filed: Feb. 27, 1974 21 Appl. No.: 446,498

Related U.S. Application Data [63] Continuation-impart of Ser. No. 202,575, Nov. 26,

1971, Pat. No. 3,814,768.

[ 51 July 22,1975

3,322,771 5/1967 Bartels-Keith 260/285 3,332,950 7/1967 Blumberg 3,773,955 11/1973 Pacter et al 424/260 FOREIGN PATENTS OR APPLICATIONS 101,153 10/1963 Japan 260/285 OTHER PUBLICATIONS Gates et al., J. Med. Chem., Vol. 7, pp. 127-131, (1964).

Martin et al., Long Acting Narcotic Antagonists, N.I.M.I-l., pp. 21-29.

Primary Examiner-Albert T. Meyers Assistant Examiner-Norman A. Drezin Attorney, Agent, or Firm-Kirschstein, Kirschstein, Ottinger, & Frank [57] ABSTRACT A narcotic antagonist selected from the group 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.

19 Claims, No Drawings 1 6-METHYLENE-6-DESOXY DIHYDRO MORPHINE AND CODEINE DERIVATIVES AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, AND USE OF THE SAME AS A NARCOTIC ANTAGONIST CROSS REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of application Ser. No. 202,575 filed Nov. 26, 1971 now US. Pat. No. 3,814,768 for 6-METHYLENE-6-DESOXY Dl- HYDRO MORPHINE AND CODEINE DERIVA- TIVES AND PHARMACEUTICALLY ACCEPT- ABLE SALTS THEREOF.

BACKGROUND OF THE INVENTION l. Field of the Invention 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 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 difficult 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 addicts'whichpresent-day' society unfortunately has produced.

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 where R, is selected from the group consisting of ally] 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, 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 sugar and/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-allyll 4-hydroxydihydronormorphine. b. 6-methylene-6-desoxy-N-cyclopropylmethyll 4- hydroxydihydronormorphine. c. 6-methylene-6-desoxy-N-cyclopropylmethyl dihydronormorphine.

6-methylene-6-desoxy-N-allyl-dihydronormorphine. e. 6-methylene-6-desoxyl 4-hydroxydihydronormorphine f. 6-methylene-6-desoxy-dihydronormorphine. g. 6-methylene-6-desoxy-N-allyl-dihydronorcodeine. h. 6-methylene-6-desoxy-N-cyclopropylmethy]-l4- hydroxydihydronorcodeine. i. 6-methylene-6-desoxy-N-allyl- 1 4- hydroxydihydronorcodeine. 6-methylene-6-desoxyl 4-hydroxydihydronorcodeine.

PREPARATION EXAMPLE l 30 grams of l4-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 14- hydroxydihydronormorphinone-3-methoxymethyl ether thus obtained was crystallized from benzene.

grams of l4-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 60C. 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 c.c.

of chloroform and 100 c.c. vof water. The water layer was discarded and the chloroform was washed once with 100 c.c. of 5%NaOH andthen extracted three times with 100 c.c. of 2N sulfuric acid. The acid extract 5 was quickly neutralized and adjusted to pH 9 with concentrated ammonium hydroxide and the basic solution was extracted with four 100 c.c. 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 ethanol-ether to give 3.9 grams of 6- methylene-6-desoxyl 4-hydroxydihydronormorphine- 3-methoxymethy] ether. l5 1 gram of 6-methylene-6-desoxy-l4- hydroxydihydronormorphine-3-methoxymethyl ether was dissolved in c.c. of 1N HC] and allowed to stand for four hours at room temperature. The addition of 100 c.c. of water was followed by adjusting the pH to 9 with ammonium hydroxide. The basic mixture was extracted three times with 100 c.c. of chloroform which was dried and evaporated. Crystallization from dilute methanol gave 6-methylene-6-desoxy-l4- hydroxydihydronormorphine with a melting point of 246-250C.

50 grams of 6-methyIene-6-desoxy-l4-hydroxydihydronormorphine was dissolved in 200 c.c. of ethanol, half its weight of sodium bicarbonate and half its weight of allyl bromide was added and the mixture was refluxed at about 75C 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 c.c. of chloroform and filtered; the solvent was removed under reduced pressure and the residue was crystallized from benzene-hexane to give 6- methylene-6-desoxy-N-allyl-14-hydroxydihydronormorphine.

EXAMPLE I] 50 grams of 6-methylene-6-desoxy-l4-hydroxydihydronormorphine was reacted as above except that cyclopropylmethyl chloride was used instead of allyl bromide to give 6methylene-6-desoxy-N- cyclopropylmethyll 4-hydroxydihydronormorphine.

EXAMPLE ll] 2 grams of 6-methylene-6-desoxy-N-allyl-l4- hydroxydihydronormorphine was dissolved in 75 c.c. of ethanol and allowed to stand with excess diazomethane in ether for 48 hours at 5C. The solvents and excess reagent were then evaporated and the residue was crystallized from ethanol to give 6-methylene-6-desoxy-N- allyl-l4-hydroxydihydronorcodeine with a melting point of l72-l78C.

EXAMPLE IV 10 grams of N-allyl-dihydronormorphinone-3- methoxymethyl ether was dissolved in 100 c.c. of tetrahydrofuran and three. equivalents of triphenylphosphomethylene reagent in 100 c.c. of-tetrahydrofuran was added and the mixture was refluxed for three days. The reaction mixture was then cooled and the solvent was removedunder reduced pressure The residue was taken up in 300 c.c. of chloroform and filtered and the organic layer. was extracted three times with 100 c.c. of 10% aqueousHCl. The acidextract was quickly adjusted to pH 9 with concentrated ammonium hydroxide and extracted four times with 100 c.c. 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 allyldihydronormorphine-3-methoxymethyl ether with a melting point of l9720lC.

5 grams of 6-methylene-6-desoxy-N-allyldihydronormorphine-3-methoxymethyl ether was allowed to stand in 5% sulfuric acid (aq.) for 4 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 methano] to give 6-methylene-6-desoxy-N-allyl-dihydronormorphine with a melting point of 235-24lC 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 fumarate 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 difficultly 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 c.c. of dilute ethanol. Excess dilute hydrochloric acid (10 c.c.) was added, and the mixture was evaporated to dryness under reduced pressure on a steam bath. The white hydrochloride salt was crystallized from ethanolether.

EXAMPLE VI 100 mg. of 6-methylene-6-desoxy-N-allyl-14- hydroxydihydronormorphine was dissolved in ml. of ethanol. A solution of 39 mg. of benzoic acid in 5 c.c. 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 changesmight 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 narcotic antagonist composition comprising a. an effective amount of a compound selected from the group consisting of those having the formula and pharmaceutically acceptable salts thereof 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, and

b. a pharmaceutically acceptable inert carrier.

2. A narcotic antagonist composition as set forth in claim 1 wherein the compound is 6-methylene-6- desoxy-N-allyll 4-hydroxydihydronormorphine.

3. A narcotic antagonist composition as set forth in claim 1 wherein the compound is 6-methylene-6- desoxy-N-cyclopropylmethyl- 1 4-hydroxydihy dronormorphine.

4. A narcotic antagonist composition as set forth in claim 1 wherein the compound is 6-methylene-6- desoxy-N-cyclopropylmethyl-dihydronormorphine.

5. A narcotic antagonist composition as set forth in claim 1 wherein the compound is 6-methylene-6- desoxy-N-allyl-dihydronormorphine.

6. A narcotic antagonist composition as set forth in claim 1 wherein the compound is 6-methylene-6- desoxy- 1 4-hydroxydihydronormorphine.

7. a narcotic antagonist composition as set forth in claim 1 wherein the compound is 6-methylene-6- desoxydihydronormorphine.

8. A narcotic antagonist composition as set forth in claim 1 wherein the compound is 6-methylene-6- desoxy-N-allyl-dihydronorcodeine.

9. A narcotic antagonist compositionasset forth in claim 1 wherein the' compound is 6-methy lene6- desoxy-N-cyclopropylmethylr14- hydroxydihydronorcodeine.

10. A narcotic antagonist composition asset forth in claim 1 wherein the compound is 6-methylene-6- desoxy-N-allyl-l 4-hydroxydihydronorcodeine.

11. A narcotic antagonist composition as set forth in claim 1 wherein the compound is 6-methylene-6- desoxyl 4-hydroxydihydronorcodeine.

12. A narcotic antagonist composition as set forth in claim 1 wherein the compound is from 0.5% to 2% by weight of the composition.

13. A narcotic antagonist composition as set forth in claim 12 wherein the inert carrier is water.

14. A method of antagonizing narcotics in a patient in need thereof which comprises administering to said patient an effective amount of the composition of claim 1, providing from 0.02 to 10.0 milligrams per kilogram of patient body weight of said compound.

15 A method as set forth in claim 14 wherein the composition is administered orally.

16. A method as set forth in claim 15 wherein the dosage is from 0.1 to 10.0 milligrams of the compound per kilogram of patient body weight.

17. A method as set forth in claim 14 wherein the composition is administered parenterally.

18. a method as set forth in claim 17 wherein the dosage is from 0.02 to 2.0 milligrams of the compound per kilogram of patient body weight.

19. A method as set forth in claim 14 wherein the composition is administered rectally.

Patent Citations
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Referenced by
Citing PatentFiling datePublication dateApplicantTitle
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
US4751307 *Feb 27, 1987Jun 14, 1988Mallinckrodt, Inc.Wittig-reaction processes
US4785000 *Nov 16, 1987Nov 15, 1988The Rockefeller UniversityMethod of treating patients suffering from chronic pain or chronic cough
US4946848 *Feb 21, 1989Aug 7, 1990Baker Cumins Dermatologicals, Inc.Method of treating pruritus with nalmefene and clonidine
US4972308 *Jan 16, 1990Nov 20, 1990Chen I MingInnovated lamp fitting set without welding
US4987136 *Feb 12, 1986Jan 22, 1991The Rockefeller UniversityOpioid antagonists
US5028612 *Mar 22, 1990Jul 2, 1991Hillel GloverMethod for treating emotional numbness
US5668285 *Mar 12, 1992Sep 16, 1997The United States Of America As Represented By The Department Of Health And Human ServicesTotal synthesis of northebaine, normophine, noroxymorphone enantiomers and derivatives via N-Nor intermediates
US5783583 *Apr 12, 1996Jul 21, 1998Simon; David LewNalmefene, withdrawal from drug dependence, side effect reduction
US5919760 *Jun 24, 1997Jul 6, 1999Intensive Narcotic Detoxification Centers Of America, LlcMethod for treating acute and severe diarrhea
US5922705 *Apr 13, 1998Jul 13, 1999Intensive Narcotic Detoxification Centers Of America, LlcRapid narcotic detoxification
US6087356 *May 25, 1999Jul 11, 2000Simon; David LewAnesthetizing the patient to produce a state of unconsciousness, administering dextromethorphan to reduce the feelings of withdrawal symptoms, administering an opioid antagonist to induce acute withdrawal
US6271240Sep 14, 1998Aug 7, 2001David Lew SimonProlonged, controlled administration of nalmefene, coadministered with bupropion, in steady state plasma concentration; achieved via sustained release delivery system (transdermal patch)
US7968119Jun 26, 2002Jun 28, 2011Farrell John JAdministering antagonist and antagonist removal drug
US8841452Dec 6, 2012Sep 23, 2014H. Lundbeck A/SProcess for recovery of nalmefene hydrochloride
WO1983003197A1Mar 14, 1983Sep 29, 1983Univ RockefellerMethod for controlling gastrointestinal dysmotility
WO1989010125A1 *Apr 7, 1989Nov 2, 1989Baker Cummins PharmaMethod of reversing the side effects of epidural analgesics
WO2013083685A1 *Dec 6, 2012Jun 13, 2013H. Lundbeck A/SProcess for recovery of nalmefene hydrochloride
Classifications
U.S. Classification514/282, 546/46
International ClassificationC07D489/00, C07D489/08
Cooperative ClassificationC07D489/00, C07D489/08
European ClassificationC07D489/00, C07D489/08
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