Sterling Drug Inc.

Robert L Clarke

Sol J Daum

Philip E Shaw

Aminocyclitol analogs of gentamicin C.sub.1, C.sub.2 and C.sub.1a and the corresponding compounds acylated on the 1-, 3- and 2'-amino groups with an .omega.-amino-.alpha.-hydroxy-lower-alkanoyl group are prepared by culturing a nutrient medium containing carbohydrates, a source of assimilable nitrogen, essential salts and an added aminocyclitol with a mutant of Micromonospora purpurea and acylating the product with an ester of an .omega.-(N-benzyloxycarbonyl)amino-.alpha.-hydroxy-lower-alkanoic acid followed by catalytic hydrogenolysis of the benzyloxycarbonyl group.

Aminocyclitol antibiotics, pharmaceutical compositions and method of

3.alpha.-Benzoylamino-2.beta.-hydroxy-nortropanes substituted in the 8-position by an alkoxycarbonyl or alkanoyl group, useful as analgesics, are prepared by reacting the corresponding 2.beta.,3.beta.-epoxy-nortropane with benzylamine in the presence of phenol.

Nortropane derivatives

3.alpha.-Benzylamino-2.beta.-hydroxy-nortropanes substituted in the 8-position by an alkoxycarbonyl or alkanoyl group, useful as analgesics, are prepared by reacting the corresponding 2.beta.,3.beta.-epoxy-nortropane with enzylamine in the presence of phenol.

Tropane derivatives

Compounds of tropane (8-azabicyclo[3.2.1]octane) series having an aromatic substituent in the 2-position and a carboalkoxy group in the 3-position are prepared by reacting a tropane-3-carboxylate having a double bond in the 2,3-position with an aryl Grignard reagent. Transformations of the substituent on nitrogen are subsequently effected. Compounds where the 3-carboalkoxy group is in the exo configuration possess hypoglycemic activity, and those where the 3-carboalkoxy group is in the endo configuration possess narcotic antagonist activity.

Lower-alkyl

Compounds of the tropane (8-azabicyclo[3.2.1]octane) series having an aromatic substitutent in the 2-position and a carboalkoxy group in the 3-position are prepared by reacting a tropane-3-carboxylate having a double bond in the 2,3-position with an aryl Grignard reagent. Transformations of the substituent on nitrogen are subsequently effected. Compounds where the 3-carboalkoxy group is in the exo configuration possess hypoglycemic activity, and those where the 3-carboalkoxy group is in the endo configuration possess narcotic antagonist activity.

1-(8-Methyl-2-phenyl(or thienyl)-8-azabicyclo[3.2.1]octan-3-yl) ethanone

3-Methoxycarbonyl-2-(2-thienyl)-8-azabicyclo[3.2.1]octane-8-acetamide

Compounds of the tropane (8-azabicyclo[3.2.1]octane) series having an aromatic substituent in the 2-position and a carboalkoxy group in the 3-position are prepared by reacting a tropane-3-carboxylate having a double bond in the 2,3-position with an aryl Grignard reagent. Transformations of the substituent on nitrogen are subsequently effected. Compounds where the 3-carboalkoxy group is in the exo configuration possess hypoglycemic activity, and those where the 3-carboalkoxy group is in the endo configuration possess narcotic antagonist activity.

Ethanopyrrolo[1,2-b]isoquinolines

Compounds of the tropane (8-azabicyclo[3.2.1]octane) series having an aromatic substiutent in the 2-position and a carboalkoxy group in the 3-position are prepared by reacting a tropane-3-carboxylate having a double bond in the 2,3-position with an aryl Grignard reagent. Transformations of the substituent on nitrogen are subsequently effected. Compounds where the 3-carboalkoxy group is in the exo configuration possess hypoglycemic activity, and those where the 3-carboalkoxy group is in the endo configuration possess narcotic antagonist activity.

2-Aryltropane compounds

Aminocyclitol antibiotics

Alkyl polyhydro-2-phenanthrylideneacetates are prepared by interacting the corresponding 2-oxopolyhydrophenanthrenes with a tri-lower-alkyl .alpha.-phosphono-lower-alkanoate. Said alkyl polyhydro-2-phenanthrylideneacetates are hydrolyzed to the free acid, and then reesterified via the acid chloride with a tertiaryamino-lower-alkanol to give basic esters having cardiotonic activity.

Polyhydrophenanthrene derivatives

Aminocyclitol antibiotics of the streptamine, deoxystreptamine or dideoxystreptamine type are prepared by culturing a nutrient medium containing carbohydrates, a source of assimilable nitrogen, essential salts and a non-nitrogen containing cyclitol with a mutant of an aminocyclitol antibiotic producing organism.

Process for preparing aminocyclitol antibiotics

Alkyl polyhydro-2-phenanthrylideneacetates are prepared by interacting the corresponding 2-oxopolyhydrophenanthrenes with a tri-lower-alkyl .alpha.-phosphono-lower-alkanoate. Said alkyl polyhydro-2-phenanthrylideneacetates are hydrolyzed to the free acid, and then reesterified via the acid chloride with a tertiary-amino-lower-alkanol to give basic esters having cardiotonic activity.

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Bethlehem, NY, United States of America

Robert L Clarke