Penick Corporation

Anaquest, Inc.

The Boc Group, Inc.

Bao-Shan Huang

Yansong Lu

Aris P Christodoulou

Ben-Yi Ji

Nhora L Lalinde

H Kenneth Spencer

Ross C Terrell

Linas V Kudzma

Jerome R Bagley

Danging D Feng

Suzanne M Evans

Vidyadhar M Paradkar

Tamara B Latham

Raghunathan V Nair

Martin Gall

Kirsten H Deutsche

Methods are provided which include converting oripavine to other opiates, including converting oripavine to naltrexone, buprenorphine, 14-hydroxymorphinone and/or converting 14-hydroxymorphinone to oxymorphone. Purification and salt formation are optionally included.

Process for preparing oxymorphone, naltrexone, and buprenorphine

Process for preparing oxymorphone

Methods are provided which include converting oripavine to other opiates, including converting oripavine to 14-hydroxymorphinone and/or converting 14-hydroxymorphinone to oxymorphone. Purification and salt formation are optionally included.

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.

Preparation of naltrexone from codeine and 3-benzylmorphine

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.

Preparation of noroxymorphone from morphine

A process is provided for preparing oxycodone from codeine comprising either: (A) the steps of

Preparation of oxycodone from codeine

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;

Preparation of 14-hydroxynormorphinones from normorphinones

Normorphine and normorphinone derivatives are provided as compositions of matter.

Normorphine and normorphinone derivatives

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):

Preparation of oxymorphone from morphine

Preparation of 14-hydroxynormorphinones from normorphinone dienol

This invention pertains to a method for treating a condition of nausea and vomiting in a mammal which comprises administering a therapeutically effective amount of a 4,5,6,7-tetrahydroimidazo[4,5-c]pyridinyl-6-carboxylic acid derivative represented by the formula: ##STR1## wherein R.sub.1 and R.sub.2 are hydrogen or lower-alkyl; R.sub.3 is selected from the group consisting of hydrogen, lower-alkyl, nitro, amino, cyano, and alkylmercapto; R.sub.4 and R.sub.5 are selected from the group consisting of hydrogen, lower-alkyl, aryl, and aryl lower-alkyl, or R.sub.4 and R.sub.5 together with the carbon atom to which they are attached form a 5- or 6-member saturated hydrocarbon ring; R.sub.6 is selected from the group consisting of hydrogen, lower-alkyl, aryl lower-alkyl, formyl, lower-alkyl carbonyl, and aryl carbonyl; R.sub.7 is selected from the group consisting of phenyl, thienyl, indolyl, indazolyl, benzo[b]furanyl, benzo[b]thiophenyl, and R.sub.8 R.sub.9 --N--; R.sub.8 is selected from the group consisting of 8-[1,2,3,4,-tetrahydroquinolinyl], pyridinyl, 3-quinolinyl, 2-naphthalinyl, 2-thiazolyl, 2-benzothiazolyl, 4-[2,1,3]benzothiadiazolyl, 2-(4,5,6,7-tetrahydrobenzo)thiazolyl, 7-(2,2-dimethyl-2,3-dihydrobenzo)furanyl, and phenyl; R.sub.9 is hydrogen or lower-alkyl; R.sub.8 R.sub.9 --N-- is selected from the group consisting of 1-indolinyl, 1-(3,3-dimethylindolinyl), and 1-(1,2,3,4-tetrahydroquinolinyl); wherein the groups represented by R.sub.7 other than R.sub.8 R.sub.9 N-- may be unsubstituted or substituted with one or more substituents selected from the group consisting of lower-alkyl, lower-alkoxy, di-lower-alkylamino, and aryloxy, and the groups represented by R.sub.8 and the radical R.sub.8 R.sub.9 N-- may have one or more substituents selected from the group consisting of hydroxy, halogen, lower-alkyl, lower-alkoxy, amino, mono- or di-lower-alkylamino, lower-alkyl carbonyl, lower-alkoxy carbonyl, and aryloxy; wherein each aryloxy group may be unsubstituted or substituted with substituents independently selected from the group consisting of lower-alkyl, lower-alkoxy, halogen, and trifluoromethyl with the proviso that, when R.sub.8 is phenyl, said phenyl group contains at least one substituent.

Derivatives of 4,5,6,7-tetrahydroimidazo-[4,5-c]pyridinyl-6-carboxylic

This invention pertains to novel substituted N-aryl-N-[4-(1-heterocyclicalkyl)piperidinyl]amides useful as analgesics, and methods of administering analgesia, which comprises the systemic administration to mammals of such compounds, and pharmaceutical compositions containing such compounds, wherein the novel compounds have the general formula: ##STR1## including optically active isomeric forms, and the pharmaceutically acceptable acid addition salts thereof, wherein R, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are defined in the disclosure.

N-aryl-N-[4-(1-heterocyclicalkyl)piperidinyl]amides and pharmaceutical

Compounds are disclosed of the formula ##STR1## optically active isomeric forms thereof, and/or pharmaceutically acceptable acid addition salts thereof, in which formula: R is defined in the disclosure.

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Bao-Shan Huang