Nitrogen Or Divalent Chalcogen Double Bonded Directly To Carbocyclic Ring Of The Pentacyclo Ring System (e.g., Morphinones, Etc.) Patents (Class 546/45)
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Patent number: 6090943Abstract: A process for the preparation of thebaine, its salts such as the bitartrate, and analogues thereof, together with a novel intermediate useful in said process are disclosed. Thebaine bitartrate is itself useful in the preparation of oxycodone; analogues are useful in the preparation of analogous 14-hydroxymorphinones.Type: GrantFiled: June 30, 1998Date of Patent: July 18, 2000Assignee: Johnson Matthey Public Limited CompanyInventors: Bogdan Mudryk, Chester Sapino, Jen-Sen Dung, Alice Sebastian
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Patent number: 6013796Abstract: For the synthesis of 3-methylnaltrexone from codeine in this invention, codeine is converted to 6-acetylcodeine, which is N-demethylated to 6-acetylcodeine hydrochloride, followed by alkylating the nitrogen to form 17-cyclopropylmethylnorcodeine. The latter is oxidized to 17-cyclopropylmethylnorcodeinone. For the synthesis of naltrexone from morphine in this invention, morphine is converted to 3-benzylnormorphine as described above in the synthesis of noroxymorphone. 3-Benzylnormorphine is reacted with cyclopropylmethyl halide to produce 3-benzyl-17cyclopropylmethylnormorphine, a novel compound, which is oxidized to 3-benzyl-17-cyclopropylmethyl-normorphinone, a novel compound, by Swern oxidation.Type: GrantFiled: July 16, 1998Date of Patent: January 11, 2000Assignee: Penick CorporationInventors: Bao-Shan Huang, Yansong Lu, Ben-Yi Ji, Aris P Christodoulou
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Patent number: 6008355Abstract: A process is provided for preparing oxycodone from codeine comprising either:(A) the steps of(1) oxidizing codeine so as to form codeinone;(2) converting codeinone to oxycodone in a two-step-one-pot reaction: first reacting codeinone with hydrogen peroxide in water in the presence of an acid at from about 15.degree. to about 70.degree. C. to form 14-hydroxycodeinone and then catalytically hydrogenating 14-hydroxycodeinone in its original reaction mixture to form oxycodone; or(B) the steps of(1) oxydizing codeine so as to form codeinone;(2) reacting codeinone with an acylating agent so as to form codeinone dienol acylate;(3) oxidizing codeinone dienol acylate with an oxidation agent in water or a solubilizing solvent mixture in the presence of an acid at from about 15.degree. to about 70.degree. C. to form 14-hydroxycodeinone;(4) hydrogenating 14-hydroxycodeinone in its original reaction mixture to form oxycodone.Type: GrantFiled: July 16, 1998Date of Patent: December 28, 1999Assignee: Penick CorporationInventors: Bao-Shan Huang, Yansong Lu, Ben-Yi Ji, Aris P Christodoulou
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Patent number: 6008354Abstract: The invention provides processes for the conversion of normorphinone and its derivatives, which can be synthesized from morphine, to the corresponding 14-hydroxynormorphinone and its derivatives including oxycodone, oxymorphone, noroxymorphone and naltrexone. Noroxymorphone is a key intermediate for the production of important narcotic analgesics and antagonists. The invention also provides certain novel intermediates.Type: GrantFiled: July 16, 1998Date of Patent: December 28, 1999Assignee: Penick CorporationInventors: Bao-Shan Huang, Yansong Lu, Ben-Yi Ji, Aris P. Christodoulou
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Patent number: 5981751Abstract: A method for removing residual organic solvents from a bulk substance, for example from a pharmaceutical drug substance, comprises drying the bulk substance in the presence of water vapor, such that the residual organic solvent molecules are displaced with water vapor molecules.Type: GrantFiled: August 21, 1998Date of Patent: November 9, 1999Assignee: Johnson Matthey Public Limited CompanyInventors: Bogdan Mudryk, Jen-Sen Dung, Chester Sapino, James Guro
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Patent number: 5977326Type: GrantFiled: April 14, 1997Date of Patent: November 2, 1999Assignee: Salford Ultrafine Chemicals and Research LimitedInventors: Feodor Scheinmann, Simon Joel, Andrew V. Stachulski
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Patent number: 5972953Abstract: The present invention relates to a novel brain cell protective agent having for its active ingredient a morphinan derivative represented with Compound 1 ##STR1## or pharmacologically acceptable acid addition salt thereof. The compounds used in the present invention were found to have excellent defensive effects against brain nerve cell necrosis in both in vitro and in vivo pharmacological evaluations, and can be used as useful preventive and therapeutic agents of ischemic brain disorders, brain nerve cell disorders and dementia.Type: GrantFiled: November 7, 1996Date of Patent: October 26, 1999Assignee: Toray Industries, Ltd.Inventors: Hiroshi Nagase, Yoshifumi Imamura, Takashi Endo, Susumu Matsuda, Yasushi Miyauchi
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Patent number: 5952495Abstract: A process is provided for preparing 14-hydroxynormorphinones having the formula: ##STR1## which comprises reacting normorphinones having the formula: ##STR2## wherein R is selected from the group consisting of lower alkyl of 1 to 7 carbon atoms, cycloalkyl-lower alkyl with 3-6 ring carbon atoms, benzyl and a substituted-benzyl having the formula: ##STR3## wherein Q and Q.sup.1 are individually selected from the group consisting of hydrogen, lower alkyl, trifluoromethyl, nitro, dialkylamino and cyano;R' is selected from the group consisting of R, 2-(4-morpholinyl)ethyl, benzyloxy carbonyl and R"C(O)-- wherein R" is lower alkyl of 1-4 carbon atoms;with hydrogen peroxide at a temperature of from about 15.degree. C. to about 70.degree. C. in the presence of an acid and an aqueous solvent system to solubilize the reactant for a period of time so as to form the 14-hydroxynormorphinones.Type: GrantFiled: July 16, 1998Date of Patent: September 14, 1999Assignee: Penick CorporationInventors: Bao-Shan Huang, Yansong Lu, Ben-Yi Ji, Aris P Christodoulou
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Patent number: 5948788Abstract: Normorphine and normorphinone derivatives are provided as compositions of matter.Type: GrantFiled: July 17, 1998Date of Patent: September 7, 1999Assignee: Penick CorporationInventors: Bao-Shan Huang, Yansong Lu, Ben-Yi Ji, Aris P Christodoulou
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Patent number: 5922876Abstract: A process is provided for preparing oxymorphone from morphine by: (a) reacting morphine with an acyl halide or anhydride to form 3-acylmorphine, or (b) reacting morphine with benzyl-halide to form 3-benzylmorphine, and thereafter either by (3a) or (3b):(3a) introducing a .beta.-oriented hydroxy group at the 14-position of the 3-acyl- or 3-benzyl-morphinone with aqueous hydrogen peroxide and an acid at at temperature of about 15.degree. to about 70.degree. C. to form the 3-acyl or 3-benzyl-14-hydroxymorphinone;(3b) acylating the 3-acyl or 3-benzyl-morphinone with an acylating agent so as to form the dienol acylate followed by oxidizing the dienol acetate to the corresponding 3-acyl or 3-benzyl-14-hydroxymorphinone;(4) hydrogenating the 3-acyl-14-hydroxymorphinone with a catalyst so as to form the 3-acyloxymorphone;(5) hydrolyzing the 3-acyl-oxymorphone with aqueous acidic or basic solution to form oxymorphone;(6) hydrogenating the 3-benzyl-14-hydroxymorphinone with a catalyst so as to form oxymorphone.Type: GrantFiled: July 16, 1998Date of Patent: July 13, 1999Assignee: Penick CorporationInventors: Bao-Shan Huang, Yansong Lu, Ben-Yi Ji, Aris P Christodoulou
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Patent number: 5886001Abstract: New morphinane derivatives of the formula (I) ##STR1## their pharmaceutically acceptable salts, a process for their preparation and their use in therapy. The variables in the above structure are as follows: R.sub.1 is selected from the group consisting of C.sub.1 -C.sub.6 alkyl and hydrogen;R.sub.2 is selected from the group consisting of hydrogen; hydroxy; C.sub.1 -C.sub.6 alkoxy; C.sub.7 -C.sub.16 arylalkyloxy, wherein the aryl is C.sub.6 -C.sub.10 aryl and the alkyloxy is C.sub.1 -C.sub.6 alkyloxy;R.sub.3 is a C.sub.1 -C.sub.6 alkyl;R.sub.4 is a hydrogen; hydroxy; or a C.sub.1 -C.sub.6 alkoxy;R.sub.5 and R.sub.6 each and independently are selected from the group consisting of hydrogen; and C.sub.1 -C.sub.6 alkyl;X is NR.sub.9, wherein R.sub.9 is selected from the group consisting of hydrogen; and C.sub.1 -C.sub.6 alkyl;and wherein any aryl group in the compound may be unsubstituted or mono-, di-, or tri-substituted independently with hydroxy; halo; nitro; cyano; thiocyanato; trifluoromethyl; C.sub.1 -C.Type: GrantFiled: August 22, 1995Date of Patent: March 23, 1999Assignee: Astra ABInventor: Helmut Schmidhammer
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Patent number: 5869669Abstract: The invention provides processes for the conversion of normorphinone and its derivatives, which can be synthesized from morphine, to the corresponding 14-hydroxynormorphinone and its derivatives including oxycodone, oxymorphone, noroxymorphone and naltrexone. Noroxymorphone is a key intermediate for the production of important narcotic analgesics and antagonists. The invention also provides certain novel intermediates.Type: GrantFiled: July 11, 1997Date of Patent: February 9, 1999Assignee: Penick CorporationInventors: Bao-Shan Huang, Yansong Lu, Ben-Yi Ji, Aris P. Christodoulou
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Patent number: 5847142Abstract: A novel process for preparing narcotic analgesics such as hydrocodone and hydromorphone using catalytic amounts of homogeneous organometallic complexes is disclosed.Type: GrantFiled: April 3, 1997Date of Patent: December 8, 1998Assignee: Johnson Matthey Public Limited CompanyInventors: Bogdan Mudryk, Joydeep Kant, Chester Sapino
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Patent number: 5783583Abstract: Methods whereby the narcotic antagonist 17-(cyclopropylmethyl)-4,5alpha-6-methylenemorphinan-3,14-diol,hydrochlori de salt and other narcotic antagonists are used for chemically precipitating a withdrawal response in human beings addicted to exogenous narcotics and who are currently using exogenous narcotics.Type: GrantFiled: April 12, 1996Date of Patent: July 21, 1998Inventor: David Lew Simon
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Patent number: 5736573Abstract: Amine compound derivatives enhancing the transdermal delivery (skin penetration) of pharmacologically active substances (drugs). In order to pass through the skin more effectively, the present invention provides derivatives that are soluble or miscible, or compatible with both lipids and water. These derivatives are formed by combining a drug of the amine class (to which most drugs belong) with a lipid-soluble long-chain acid such as oleic, linoleic, stearic, myristic, or palmitic acid.Type: GrantFiled: July 31, 1996Date of Patent: April 7, 1998Inventor: Alexander Galat
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Patent number: 5648359Abstract: There is provided a composition for inhibiting the production or secretion of tumor necrosis factor effective for the treatment of cachexia, septic shock, multiple organ failure, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, osteoarthritis, Behcet disease, systemic lupus erythematosus (SLE), graft versus host disease (GvHD), malaria, acquired immune deficiency syndrome (AIDS), meningitis, hepatitis and Type II diabetes mellitus. The composition comprises a pharmaceutically effective amount of a compound of formula (1).Type: GrantFiled: December 28, 1994Date of Patent: July 15, 1997Assignee: Sumitomo Pharmaceuticals Company, LimitedInventors: Naohito Ohashi, Norio Fujiwara, Yutaka Ueda
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Patent number: 5607940Abstract: A morphine formulation for use by electromotive administration comprising morphine citrate salts of the formula:M.sub.np Ct.sub.(3-n)p (C.sub.6 H.sub.5 O.sub.7).sub.pwherein M is protonated morphine, Ct is a physiologically acceptable cation, n is an integer or fractional number greater than 0 and less than or equal to 3, and p is an integer from 1 to 3.Type: GrantFiled: July 18, 1994Date of Patent: March 4, 1997Inventors: Robert L. Stephen, Cesare Bonezzi, Cino Rossi, Silvio Eruzzi
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Patent number: 5525727Abstract: The subject compounds, which are adapted for the site-specific/sustained delivery of centrally acting drug species to the brain, are:(a) compounds of the formula[D-DHC] (I)wherein [D] is a centrally acting drug species, and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating lipoidal form of a dihydropyridine .revreaction. pyridinium salt redox carrier, with the proviso that when [DHC] is ##STR1## wherein R is lower alkyl or benzyl and [D] is a drug species containing a single NH.sub.2 or OH functional group, the single OH group when present being a primary or secondary OH group, said drug species being linked directly through said NH.sub.2 or OH functional group to the carbonyl function of [DHC], then [D] must be other than a sympathetic-stimulant, steroid sex hormone or long chain alkanol; and(b) non-toxic pharmaceutically acceptable salts of compounds of formula (I). The corresponding ionic pyridinium salt type drug/carrier entities [D-QC].sup.+ X.sup.- are also disclosed.Type: GrantFiled: October 28, 1992Date of Patent: June 11, 1996Assignee: University of FloridaInventor: Nicholas S. Bodor
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Patent number: 5387264Abstract: The invention discloses a method for dyeing a hydrophobic fiber, in particular, a polyester fiber in an extremely brilliant yellow or orange with fluorescence, a method for coloring, for example, a polystyrene resin or a polyacrylate resin in a brilliant yellow or orange, and a coloring material therefore.A method for dyeing a hydrophobic fiber and a method for coloring an organic macromolecular substance characterized by using a coumarin compound represented by the general formula: ##STR1## wherein R.sub.1 and R.sub.2 independently represent each a hydrogen atom or an alkyl group having 1 to 4 carbon atoms;and a coloring material containing the coumarin compound are disclosed.Type: GrantFiled: March 31, 1994Date of Patent: February 7, 1995Assignee: Nippon Kayaku Kabushiki KaishaInventors: Yasuo Murakami, Ryuzo Orita, Tadaaki Sugimoto, Masao Ohnishi
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Patent number: 5260441Abstract: The present invention is directed to a fluorescence polarization assay for opiate alkaloids and their metabolites, to the various components needed for preparing and carrying out such an assay and to methods of making these components. Specifically, tracers, immunogens and antibodies are disclosed, as well as methods for making them. The tracers and the immunogens are made from substituted opiate alkaloids. A fluorescein moiety is included in the tracers, while a poly(amino acid) forms a part of the immunogens. The assay is conducted by measuring the degree of polarization retention of the fluorescence resulting when a sample mixed with antiserum and tracer is irradiated with plane-polarized light.Type: GrantFiled: February 28, 1989Date of Patent: November 9, 1993Assignee: Abbott LaboratoriesInventors: Daniel F. Heiman, Daniel S. Raden, Robert E. Dubler
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Patent number: 5258512Abstract: The present invention is directed to a fluorescence polarization assay for opiate alkaloids and their metabolites, to the various components needed for preparing and carrying out such an assay and to methods of making these components. Specifically, tracers, immunogens and antibodies are disclosed, as well as methods for making them. The tracers and the immunogens are made from substituted opiate alkaloids. A fluorescein moiety is included in the tracers, while a poly(amino acid) forms a part of the immunogens. The assay is conducted by measuring the degree of polarization retention of the fluorescence resulting when a sample mixed with antiserum and tracer is irradiated with plane-polarized light.Type: GrantFiled: September 4, 1992Date of Patent: November 2, 1993Assignee: Abbott LaboratoriesInventors: Daniel F. Heiman, Daniel S. Raden, Robert E. Dubler
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Patent number: 5232926Abstract: The present invention relates to novel morphinane-skeletoned compounds of the formula (I) ##STR1## wherein Y in-NH phenyl or --NH dintro phenyl, Z is --CH.sub.2 -- CH.sub.2, R.sub.2 is hydroxyl and R.sub.3 is H or methyl, the steric isomers and the pharmaceutically acceptable salts thereof, a novel process for producing the same and pharmaceutical compositions comprising the same as active ingredients.The novel compounds can be used in the therapy as analgetic or morphine-antagonistic agents.Type: GrantFiled: October 6, 1992Date of Patent: August 3, 1993Assignee: Alkaloida Vegyeszeti Gyar Rt.Inventors: Sandor Hosztafi, Sandor Makleit, Laszlo Szilagyi, Kalmany Zsupan
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Patent number: 5112975Abstract: 3,17-(diethoxycarbonyl)normorphine, which may be prepared by reaction of morphine with ethyl chloroformate, is converted to 3,17-(diethoxycarbonyl)normorphinone, a novel compound, by oxidation. The novel normorphinone derivative is converted to 3,17-(diethoxycarbonyl)normorphinone enol acetate, a second novel compound, by esterification with acetic anhydride or acetyl halide.A 14-hydroxy group is introduced into the novel dienol ester by oxidation with peracid. The resultant 14-hydroxy-3,17-(diethoxycarbonyl)normorphinone, a third novel compound, may be catalytically hydrogenated to produce 3,17-(diethoxycarbonyl)noroxymorphone. The latter intermediate may be converted to noroxymorphone by hydrolysis.Type: GrantFiled: September 14, 1989Date of Patent: May 12, 1992Assignee: Mallinckrodt Specialty Chemicals CompanyInventor: Rebecca A. Wallace
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Patent number: 5071985Abstract: The invention relates to a process for the preparation of morphinane derivatives of general formula: ##STR1## by demethylation of 3-methoxylated compound with a sulfonic acid selected from methanesulfonic acid and trifluoromethanesulfonic acid in the presence of a sulfide.Type: GrantFiled: September 12, 1989Date of Patent: December 10, 1991Assignee: SanofiInventors: Jean-Daniel Andre, Jean-Robert Dormoy, Alain Heymes
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Patent number: 4939264Abstract: The present invention is directed to a fluorescence polarization assay for opiate alkaloids and their metabolites, to the various components needed for preparing and carrying out such an assay and to methods of making these components. Specifically, tracers, immunogens and antibodies are disclosed, as well as methods for making them. The tracers and the immunogens are made from substituted opiate alkaloids. A fluorescein moiety is included in the tracers, while a poly(amino acid) forms a part of the immunogens. The assay is conducted by measuring the degree of polarization retention of the fluorescence resulting when a sample mixed with antiserum and tracer is irradiated with plane-polarized light.Type: GrantFiled: July 14, 1986Date of Patent: July 3, 1990Assignee: Abbott LaboratoriesInventors: Daniel F. Heiman, Daniel S. Raden, Robert E. Dubler
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Patent number: 4925848Abstract: A compound of the formula: ##STR1## A process for its preparation and pharmaceutical compositions comprising the compound or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable diluent or carrier. The compound exhibits analgesic activity.Type: GrantFiled: April 28, 1988Date of Patent: May 15, 1990Assignee: Reckitt & Colman Products LimitedInventors: John W. Lewis, Colin F. C. Smith
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Patent number: 4912114Abstract: Compounds of formula I ##STR1## wherein X and Y each denotes hydrogen or together denote -0-,R.sub.1 denotes allyl optionally substituted by 1 to 3 alkyl groups, the substituent or substituents having in total a maximum of 3 carbon atoms, cyclopropyl-methyl or 3-furylmethyl,R.sub.2 denotes hydrogen, alkyl with 1 to 10 C-atoms, cycloalkyl with 5 or 6 carbon atoms, optionally substituted phenyl or optionally substituted phenyl-alkyl with 7 to 12 C-atoms,R.sub.3 denotes hydrogen, alkyl with 1 to 10 C-atoms or phenyl,R.sub.4 denotes hydrogen, OH, NR.sub.6 R.sub.7, NHCOR, NHSO.sub.2 R' or NHCOOR",R.sub.6 and R.sub.7, independently of one another, denote hydrogen or alkyl with 1 to 3 C-atoms,R denotes alkyl with 1 to 6 C-atoms, phenyl or --A--COOR",A denotes alkylene or alkenylene each with 2 to 4 C-atoms,R' denotes alkyl with 1 to 6 C-atoms or phenyl,R" denotes methyl or ethyland wherein either R.sub.3 is in the .alpha.-positionand R.sub.4 is in the .beta.-position, or R.sub.3 is in the .beta.position and R.sub.Type: GrantFiled: April 14, 1989Date of Patent: March 27, 1990Assignee: Sandoz Ltd.Inventor: Laszlo Revesz
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Patent number: 4889860Abstract: A potent, selective opioid receptor agonist or antagonist exhibiting properties useful for a longacting analgesic or opiate abuse treatment agent or appetite suppressant having the general formula: ##STR1## wherein R is methyl, cyclopropylmethyl or allyl, and R.sub.1 is an unsubstituted or substituted aryl, aralkyl, heteroaryl, heteroaralkyl or a cycloalkyl group with or without a heteroatom like S,O,N; and the pharmaceutically acceptable salts thereof.Type: GrantFiled: April 6, 1987Date of Patent: December 26, 1989Assignee: Nova Pharmaceutical CorporationInventors: Waclaw J. Rzeszotarski, Babu J. Mavunkel
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Patent number: 4806556Abstract: Gut-selective agonist or antagonist opiates of the formula: ##STR1## wherein R is (C.sub.1 -C.sub.5) alkyl, C.sub.3 -C.sub.6 (cycloalkyl)alkyl, aryl, aralkyl or trans-(C.sub.2 -C.sub.5)alkenyl; Z is H or OH, R' is (C.dbd.O)-A(B)(C) wherein A is selected from the group consisting of (C.sub.1 -C.sub.5)alkyl, (C.sub.2 -C.sub.5)alkenyl and (C.sub.2 -C.sub.6)alkoxy (alkyl); B is selected from the group consisting of H, amino and a (C.sub.1 -C.sub.5)alkyl group optionally substituted with CO.sub.2 H, OH or phenyl and C is CO.sub.2 H, SO.sub.3 H, amino or guanidino; and R" is selected from the group consisting of NH-A(B) (C) or is guanidino; and the pharmaceutically-acceptable salts thereof.Type: GrantFiled: December 24, 1987Date of Patent: February 21, 1989Assignee: Regents of the University of MinnesotaInventor: Philip S. Portoghese
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Patent number: 4803208Abstract: Dihydromorphinone compound of the general formulaHDM.dbd.N--Rwherein ##STR1## where * indicates binding carbon R1 is an optionally substituted alkyl, alkylene, cycloalkyl, or cycloalkyleneR2 is OH or HR3 is OH or OCH3 andR is N.dbd.R4, N--R4, ##STR2## R4 is an optionally substituted alkyl, alkylene, cycloalkyl, cycloalkylene, aryl, heterocycloalkyl, heterocycloalkylene, or alkenyl, andn is 1-10, and use thereof as an opiate receptor blocker.Type: GrantFiled: October 11, 1985Date of Patent: February 7, 1989Assignee: Sloan-Kettering Institute For Cancer ResearchInventor: Gavril W. Pasternak
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Patent number: 4795813Abstract: A 14-hydroxy group is introduced into a morphinan structure by singlet oxygen reaction with a novel dienol ester of an N-substituted-3-O-alkylnormorphinone. The resultant N-substituted-3-O-alkyl-141-hydroxynormorphinone is also a novel compound which may be catalytically hydrogenated to produce a novel N-substituted-3-O-alkylnoroxymorphone. The latter intermediate may be converted to a 3-O-alkylnoroxymorphone by hydrolytic removal of the N-substituent and to noroxymorphone by both hydrolysis and O-dealkylation.The dienol ester intermediate is prepared by N-demethylation of codeine or other 3-O-alkylmorphine by reaction with a cyanogen halide or haloformate ester, followed by oxidation of the resultant N-substituted-3-O-alkylnormorphine to an N-substituted-3-O-alkylnormorphinone and esterification of the latter with an acid anhydride or acid halide.Type: GrantFiled: December 24, 1986Date of Patent: January 3, 1989Assignee: The Florida Board of Regents on behalf of The Florida State UniversityInventor: Martin A. Schwartz
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Patent number: 4767718Abstract: Fluorescent reagents useful as opioid receptor probes. Opioids labeled at the 3 position with fluorescers are useful in various in vivo and in vitro methods for the detection and quantification of receptor sites in tissue cells and subcellular particles.Type: GrantFiled: June 18, 1984Date of Patent: August 30, 1988Assignee: Southern Illinois University FoundationInventor: Vera K. Meyers
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Patent number: 4760069Abstract: A potent, selective opioid receptor agonist or antagonist exhibiting properties useful for a long-acting analgesic or opiate abuse treatment agent or appetite suppressant having the general formula: ##STR1## wherein R is methyl, cyclopropylmethyl or allyl, and R.sub.1 is an unsubstituted or substituted aryl, aralkyl, heteroaryl, heteroaralkyl or a cycloalkyl group with or without a heteroatom like S,O,N; and the pharmaceutically acceptable salts thereof.Type: GrantFiled: September 23, 1985Date of Patent: July 26, 1988Assignee: Nova Pharmaceutical CorporationInventors: Waclaw J. Rzeszotarski, Babu J. Mavunkel
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Patent number: 4749706Abstract: Stereoisomerically pure forms of normorphine analogs which have superior analgesic and nonaddicting qualities are described. In addition, a method of separating diastereomeric forms of N-sec-alkyl-substituted analogs utilizes the hydrocarbyl(1-8C) diesters of the normorphine derivatives. A new method for preparing the N-methylalkylmethyl derivatives of normorphine and norcodeine and their conventional analogs is also disclosed. This method employs the corresponding methyl alkyl ketones and a reducing agent.Type: GrantFiled: March 24, 1986Date of Patent: June 7, 1988Assignee: SRI InternationalInventors: John A. Lawson, Joseph I. DeGraw, Gilda H. Loew
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Patent number: 4730048Abstract: Gut-selective agonist or antagonist opiates of the formula: ##STR1## wherein R is (C.sub.1 -C.sub.5)alkyl, C.sub.3 -C.sub.6 (cycloalkyl)alkyl, aryl, aralkyl or trans-(C.sub.2 -C.sub.5)alkenyl; Z is H or OH, R' is (C.dbd.O)-A(B)(C) wherein A is selected from the group consisting of (C.sub.1 -C.sub.5)alkyl, (C.sub.2 -C.sub.5)alkenyl and (C.sub.2 -C.sub.6)alkoxy (alkyl); B is selected from the group consisting of H, amino and a (C.sub.1 -C.sub.5)alkyl group optionally substituted with CO.sub.2 H, OH or phenyl and C is CO.sub.2 H, SO.sub.3 H, amino or guanidino; and R" is selected from the group consisting of NH-A(B)(C) or is guanidino; and the pharmaceutically-acceptable salts thereof.Type: GrantFiled: December 12, 1985Date of Patent: March 8, 1988Assignee: Regents of the University of MinnesotaInventor: Philip S. Portoghese
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Patent number: 4727146Abstract: In a short total synthesis of morphinan compounds, derivatives of 1-benzyl-1,2,3,4-tetrahydroisoquinoline are produced. Certain of these compounds, although highly aromatic and functionalized, can be optically resolved. The optically active enantiomers can serve as important intermediates for both natural and unnatural opioids. As a special function of this invention, certain of the derivatives, namely 4'-6' and 7'-9', may be hydrogenated to 1'-3' derivative by asymmetric reduction either of the catalytic or chemical type.Type: GrantFiled: June 26, 1985Date of Patent: February 23, 1988Assignee: The United States of America as represented by the Department of Health and Human ServicesInventor: Kenner C. Rice
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Patent number: 4668685Abstract: Substituted benzoate ester prodrug derivatives of 3-hydroxymorphinans are useful as analgesics or narcotic antagonists and provide enhanced bioavailability of 3-hydroxymorphinans from orally administered doses.Type: GrantFiled: May 14, 1985Date of Patent: May 26, 1987Assignee: E.I. Du Pont de Nemours and CompanyInventor: Elie G. Shami
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Patent number: 4667037Abstract: An improved process for the dealkylation of alkyl aryl ethers to aryl phenols is provided. In this process, an alkyl aryl ether, such as a methyl ether of an opioid, is contacted with an aqueous acid selected from HBr, HCl, or HI which contains at least one equivalent weight, based on the ether, of boric acid or an inorganic salt of a metal selected from Li, Na, K, Al, Mg, Ca, Mn and Ni. MgBr.sub.2 in aqueous HBr is preferred in dealkylating an N-substituted 14-hydroxydihydronorcodeine.Type: GrantFiled: June 6, 1985Date of Patent: May 19, 1987Assignee: E. I. Du Pont de Nemours and CompanyInventor: Walter M. Bryant, III
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Patent number: 4639520Abstract: N-ethoxycarbonyl-14-hydroxynorcodeinone is prepared by contacting N-ethoxycarbonyl-norcodeinone enol acetate with an aromatic or aliphatic mono-basic or poly-basic peroxy-acid under reaction conditions effective for substituting an --OH group in the 14-position of the norcodeinone enol acetate.In a preferred embodiment the reaction conditions include effecting the contacting in the presence of (A) a moderately strong acid having a pK.sub.a of from about 0.3 to about 3.5, (B) an inert organic solvent, and (C) in the substantial absence of water.Codeine is converted to noroxymorphone by an improved process employing the above method for introducing the 14-hydroxy group into the codeine derivative.Type: GrantFiled: March 27, 1984Date of Patent: January 27, 1987Assignee: Mallinckrodt, Inc.Inventor: Frank Kavka
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Patent number: 4613668Abstract: There is disclosed herewith a method of producing morphinan compounds by total synthesis which incorporates utilization of N-cycloalkylcarbonyl compounds, which show certain advantages over the prior art which has been previously expressed in U.S. Pat. No. 4,368,326.Type: GrantFiled: December 22, 1983Date of Patent: September 23, 1986Assignee: The United States of America as represented by the Department of Health and Human ServicesInventor: Kenner C. Rice
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Patent number: 4608376Abstract: Dihydromorphinone compound of the general formulaHDM.dbd.N--RwhereinHDM is ##STR1## where * indicates binding carbonR1 is an optionally substituted alkyl, alkylene, cycloalkyl, or cycloalkyleneR2 is OH or HR3 is OH or OCH3 andR is N.dbd.R4, N--R4, ##STR2## R4 is an optionally substituted alkyl, alkylene, cycloalkyl, cycloalkylene, aryl, heterocycloalkyl, heterocycloalkylene, or alkenyl, andn is 1-10, and use thereof as an opiate receptor blocker.Type: GrantFiled: September 30, 1982Date of Patent: August 26, 1986Assignee: Carolyn McGinnisInventor: Gavril W. Pasternak
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Patent number: 4521601Abstract: This invention relates to compounds which may be described as the unnatural enantiomers of morphine agonists and antagonists, which are useful as antitussives. The synthesis utilized is capable of producing all of the unnatural enantiomers of medically important opium derivatives of the morphinan type, including thebaine.Type: GrantFiled: March 23, 1983Date of Patent: June 4, 1985Assignee: The United States of America as represented by the Department of Health & Human ServicesInventor: Kenner C. Rice
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Patent number: 4477456Abstract: Novel bridged benzofuroisoquinoline compounds having analgesic, narcotic antagonist and anorexigenic properties.Type: GrantFiled: April 22, 1982Date of Patent: October 16, 1984Assignee: E. I. Du Pont de Nemours and CompanyInventor: Engelbert Ciganek
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N-(2-methoxyethyl)-noroxymorphone and pharmaceutical compositions for relieving pain containing same
Patent number: 4473573Abstract: The invention relates to N-(2-methoxyethyl)-noroxymorphone and pharmacologically acceptable acid addition salts thereof. These compounds are analgesically effective and can be used for controlling pain.Type: GrantFiled: May 17, 1983Date of Patent: September 25, 1984Assignee: Boehringer Ingelheim KGInventors: Herbert Merz, Adolf Langbein, Klaus Stockhaus -
Patent number: 4472253Abstract: A 14-hydroxy group is introduced into a morphinan structure by singlet oxygen reaction with a novel dienol ester of an N-substituted-3-O-alkylnormorphinone. To carry out the singlet oxygen reaction, the enolate substrate may be contacted with molecular oxygen in the presence of light and a light sensitizing agent or in the presence of a chemical reagent for forming singlet oxygen from molecular oxygen.Type: GrantFiled: August 17, 1981Date of Patent: September 18, 1984Assignee: The Florida Board of Regents on behalf of the Florida State UniversityInventor: Martin A. Schwartz
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Patent number: 4464378Abstract: The invention provides a novel method of administering narcotic antagonists, narcotic analgesics and related compounds, and novel dosage forms containing those compounds which are adapted for nasal administration. The nasal dosage forms disclosed include solutions, suspensions, gels and ointments. Especially preferred compounds which can be advantageously administered in accordance with the invention include naloxone, naltrexone, nalbuphine, levorphanol, buprenorphine, butorphanol, .DELTA..sup.9 -tetrahydrocannabinol (THC), cannabidiol (CBD) and levonantradol.Type: GrantFiled: April 28, 1981Date of Patent: August 7, 1984Assignee: University of Kentucky Research FoundationInventor: Anwar A. Hussain
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Patent number: 4451470Abstract: 14-Fluoromorphinans such as 17-cyclopropylmethyl-4,5-epoxy-14-fluoro-3-hydroxymorphinan-6-one are useful as analgesics, narcotic antagonists, and/or anorexigenic agents.Type: GrantFiled: July 6, 1982Date of Patent: May 29, 1984Assignee: E. I. Du Pont de Nemours and CompanyInventor: Venkat Ganti
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Patent number: 4440931Abstract: Disclosed are 7.beta.-alkyl or arylalkyl-3-methoxy or hydroxy-4,5.alpha.-epoxy-6.beta.-hydroxy-7.alpha.-hydroxymethyl-17-methyl or cycloalkylmethylmorphinans of the formula: ##STR1## In the above formula, R is H or methyl, R.sub.1 is methyl, cyclopropylmethyl or cyclobutylmethyl, n is 2 to 4 and Y is H or phenyl. These compounds are useful as narcotic analgesics.Type: GrantFiled: September 9, 1982Date of Patent: April 3, 1984Assignee: Miles Laboratories, Inc.Inventors: Michael P. Kotick, David L. Leland, Joseph O. Polazzi
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Patent number: 4440932Abstract: Disclosed are 7.beta.-arylalkyl-7.alpha.-methyl-6-oxo or 6.alpha.-hydroxy-3-methoxy or 3-hydroxy-4,5.alpha.-epoxy-17-methyl or 17-cycloalkylmethyl-morphinans of the formula: ##STR1## wherein R is H or methyl, X is oxo or .alpha.-hydroxy, n is 2 to 4 and R.sub.1 is methyl, cyclopropylmethyl or cyclobutylmethyl. These compounds are useful as strong analgesics.Type: GrantFiled: September 9, 1982Date of Patent: April 3, 1984Assignee: Miles Laboratories, Inc.Inventors: Michael P. Kotick, David L. Leland
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Patent number: 4390699Abstract: 6-Keto-hydroxymorphinans having at the 4 position a substituent which is R.sub.1 =H, O lower alkyl, or O lower acyl, and N may be substituted by R.sub.2, which for agonist properties may be lower alkyl, lower alkenyl, cyclopropylmethyl, or phenyl lower alkyl, etc. Additionally, the nitrogen may be substituted by R.sub.2, which is allyl, cyclopropylmethyl, cyclobutylmethyl, dimethylallyl, etc., which function as antagonists to the morphine-like activity of the compound. Such activity is known as antinociceptive.Type: GrantFiled: July 16, 1981Date of Patent: June 28, 1983Assignee: The United States of America as represented by the Secretary of the Department of Health and Human ServicesInventors: Arnold Brossi, Helmut Schmidhammer, Arthur E. Jacobson