This disclosure relates to crystalline forms of 3-acyl-buprenorphine derivatives and sustained release injectable pharmaceutical compositions for treatment of opioid dependence, pain or depression, including an aqueous suspension of crystalline 3-acyl-buprenoprhine, or a pharmaceutically acceptable salt thereof, wherein the composition does not include an organic solvent, a polylactide polymer, a polyglycolide polymer, or a copolymer of polylactide and polyglycolide. This disclosure also includes 3-acyl-buprenoprhine or a pharmaceutically acceptable salt thereof prepared in a controlled release matrix, including poly(lactide-co-glycolide), sucrose acetoisobutyrate, lecithin, diolein and a combination of two or more thereof.

This disclosure relates to crystalline forms of 3-acyl-buprenorphine derivatives and sustained release injectable pharmaceutical compositions for treatment of opioid dependence, pain or depression, including an aqueous suspension of crystalline 3-acyl-buprenoprhine, or a pharmaceutically acceptable salt thereof, wherein the composition does not include an organic solvent, a polylactide polymer, a polyglycolide polymer, or a copolymer of polylactide and polyglycolide. This disclosure also includes 3-acyl-buprenoprhine or a pharmaceutically acceptable salt thereof prepared in a controlled release matrix, including poly(lactide-co-glycolide), sucrose acetoisobutyrate, lecithin, diolein and a combination of two or more thereof.

The present invention relates to a novel route of synthesis for the opioid receptor antagonist Buprenorphine or a pharmaceutically acceptable salt thereof, starting from thebaine, wherein the route comprises the reaction of thebaine with a dienophile; forming an alkylated reaction product by reaction with a Grignard-reagent; formation of an cyanamide; deprotection of the cyanamide- and the phenolic-oxygen-moiety, wherein the cleavage of one or both groups is performed in the presence of an alkali or alkaline earth sulfide; followed by derivatization with a cyclopropyl-halogen and hydrogenation to yield Buprenorphine.

The present invention relates to a novel route of synthesis for the opioid receptor antagonist Buprenorphine or a pharmaceutically acceptable salt thereof, starting from thebaine, wherein the route comprises the reaction of thebaine with a dienophile; forming an alkylated reaction product by reaction with a Grignard-reagent; formation of an cyanamide; deprotection of the cyanamide- and the phenolic-oxygen-moiety, wherein the cleavage of one or both groups is performed in the presence of an alkali or alkaline earth sulfide; followed by derivatization with a cyclopropyl-halogen and hydrogenation to yield Buprenorphine.

The application is directed to a process for increasing the proportion of 7β-epimer in an 7α/7β-epimer mixture of a 7-substituted 6α,14α-ethenomorphinan or a 7-substituted 6α,14α-ethanomorphinan, and specifically of compounds of Formula (I), wherein G, R.sup.2-R.sup.4, and are defined as set forth in the specification. The application is also directed to a process for purifying the 7β-epimer from an 7α/7β-epimer mixture of a 7-substituted 6α,14α-ethenomorphinan or a 7-substituted 6α,14α-ethanomorphinan. The application is also directed to a process for preparing 7β-substituted compounds of Formula V.sup.b wherein G and R.sup.2-R.sup.5 are defined as set forth in the specification. ##STR00001##

The application is directed to a process for increasing the proportion of 7β-epimer in an 7α/7β-epimer mixture of a 7-substituted 6α,14α-ethenomorphinan or a 7-substituted 6α,14α-ethanomorphinan, and specifically of compounds of Formula (I), wherein G, R.sup.2-R.sup.4, and are defined as set forth in the specification. The application is also directed to a process for purifying the 7β-epimer from an 7α/7β-epimer mixture of a 7-substituted 6α,14α-ethenomorphinan or a 7-substituted 6α,14α-ethanomorphinan. The application is also directed to a process for preparing 7β-substituted compounds of Formula V.sup.b wherein G and R.sup.2-R.sup.5 are defined as set forth in the specification. ##STR00001##

8-Substituted-2,6-methano-3-benzazocines of general structure I in which A is —CH.sub.2—OH, —CH.sub.2NH.sub.2, —NHSO.sub.2CH.sub.3,

##STR00001##

and Y is O, S or NOH are useful as analgesics, anti-diarrheal agents, anticonvulsants, antitussives and anti-addiction medications.

##STR00002##

8-Carboxamides, thiocarboxamides, hydroxyamidines and formamides are preferred.

8-Substituted-2,6-methano-3-benzazocines of general structure I in which A is —CH.sub.2—OH, —CH.sub.2NH.sub.2, —NHSO.sub.2CH.sub.3,

##STR00001##

and Y is O, S or NOH are useful as analgesics, anti-diarrheal agents, anticonvulsants, antitussives and anti-addiction medications.

##STR00002##

8-Carboxamides, thiocarboxamides, hydroxyamidines and formamides are preferred.

The present invention provides a process for the preparation of a compound of formula (VI), or a salt or derivative thereof,

##STR00001##

wherein R.sup.1 and R.sup.2 are independently C.sub.1-8 alkyl and * represents a stereocentre.

The present invention provides a process for the preparation of a compound of formula (VI), or a salt or derivative thereof,

##STR00001##

wherein R.sup.1 and R.sup.2 are independently C.sub.1-8 alkyl and * represents a stereocentre.