(+)-morphinanium N-oxides and processes for their production
View Patent ↗The present invention provides (+)-morphinanium N-oxide compounds or pharmaceutically acceptable salts thereof. The invention also provides processes for producing (+)-morphinanium N-oxides or pharmaceutically acceptable salts thereof from the corresponding tertiary N-substituted (+)-morphinan compound or pharmaceutically acceptable salt thereof.
1. A compound of Formula (IV) or a pharmaceutically acceptable salt thereof:
wherein:
A is chosen from {—}C(O){—}, {—}C(═CH 2 ){—}, {—}(CH 2 ){—}, {—}(CH(A 1 ){—}, and {—}C(A 1 ){═};
A 1 is chosen from hydroxy, alkoxy, acyloxy, amido, hydrocarbyl, and substituted hydrocarbyl;
R 1 and R 7 are independently chosen from hydrocarbyl and substituted hydrocarbyl;
R 3 and R 4 are independently chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl;
R 5 and R 6 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, {—}OH, and {—}OR 7 ;
R 8 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl;
Y, if present, is chosen from hydrogen, hydroxy, protected hydroxy, alkoxy, and acyloxy;
Z is chosen from hydroxy, protected hydroxy, alkoxy, and acyloxy;
Z′ is chosen from hydrogen, hydroxy, protected hydroxy, alkoxy, and acyloxy; and
the dashed lines between the carbon atoms at positions 6 and 7, 7 and 8, and 8 and 14 represent carbon to carbon bonds selected from the group consisting of (a) single bonds between all carbon atoms; (b) single bonds between the carbons at both positions 6 and 7 and 8 and 14, and a double bond between the carbons at positions 7 and 8, wherein A is not {—}C(O){—} if there is a double bond between the carbons at positions 7 and 8; and (c) double bonds between the carbons at both positions 6 and 7 and 8 and 14, and a single bond between the carbons at positions 7 and 8, wherein Y is not present if there is a double bond between the carbons at positions 8 and 14.
2. The compound of claim 1 , wherein the compound is Formula (IVa) or a pharmaceutically acceptable salt thereof:
wherein:
A is chosen from {—}C(O){—}, {—}C(═CH 2 ){—}, {—}(CH 2 ){—}, and {—}(CH(A 1 ){—};
A 1 is chosen from hydroxy, alkoxy, acyloxy, amido, hydrocarbyl, and substituted hydrocarbyl;
R 1 is chosen from hydrocarbyl and substituted hydrocarbyl;
R 8 is chosen from hydrogen, hydroxy, alkyl, substituted alkyl, alkoxy, hydrocarbyl, and substituted hydrocarbyl;
Y is chosen from hydrogen, hydroxy, protected hydroxy, alkoxy, and acyloxy;
Z is chosen from hydroxy, protected hydroxy, alkoxy, and acyloxy; and
Z′ is chosen from hydrogen, hydroxy, protected hydroxy, alkoxy, and acyloxy.
3. The compound of claim 2 , wherein the compound or the pharmaceutically acceptable salt thereof is an N-oxide of a compound chosen from (+)-dextrorphan, (+)-dextromethorphan and (+)-dihydrosinomenine.
4. The compound of claim 1 , wherein the compound is Formula (IVb) or a pharmaceutically acceptable salt thereof:
wherein:
A is chosen from {—}C(═CH 2 ){—}, {—}(CH 2 ){—}, and {—}CH(A 1 ){—};
A 1 is chosen from hydroxy, alkoxy, acyloxy, amido, hydrocarbyl, and substituted hydrocarbyl;
R 1 is chosen from hydrocarbyl and substituted hydrocarbyl;
R 8 is chosen from hydrogen, hydroxy, alkyl, substituted alkyl, alkoxy, hydrocarbyl, and substituted hydrocarbyl;
Y is chosen from hydrogen, hydroxy, protected hydroxy, alkoxy, and acyloxy;
Z is chosen from hydroxy, protected hydroxy, alkoxy, and acyloxy; and
Z′ is chosen from hydrogen, hydroxy, protected hydroxy, alkoxy, and acyloxy.
5. The compound of claim 1 , wherein the compound is Formula (IVc) or a pharmaceutically acceptable salt thereof:
wherein:
A 1 is chosen from hydrogen, hydroxy, alkoxy, acyloxy, amido, hydrocarbyl, and substituted hydrocarbyl;
R 1 is chosen from hydrocarbyl and substituted hydrocarbyl;
R 8 is chosen from hydrogen, hydroxy, alkyl, substituted alkyl, alkoxy, hydrocarbyl, and substituted hydrocarbyl;
Z is chosen from hydroxy, protected hydroxy, alkoxy, and acyloxy; and
Z′ is chosen from hydrogen, hydroxy, protected hydroxy, alkoxy, and acyloxy.
6. A process for the preparation of a compound of claim 1 , the process comprising contacting a (+)-morphinan comprising a tertiary amine at position 17 or a pharmaceutically acceptable salt thereof with an oxidizing agent to form the compound of claim 1 , wherein the (+)-morphinan comprising a tertiary amine at position 17 is a compound of Formula (III) or a pharmaceutically acceptable salt thereof; the compound of claim 1 is a compound of Formula (IV) or a pharmaceutically acceptable salt thereof, and the process proceeds according to the following reaction:
wherein:
A is chosen from {—}C(O){—}, {—}C(═CH 2 ){—}, {—}(CH 2 ){—}, {—}(CH(A 1 ){—}, and {—}C(A 1 ){═};
A 1 is chosen from hydroxy, alkoxy, acyloxy, amido, hydrocarbyl, and substituted hydrocarbyl;
R 1 and R 7 are independently chosen from hydrocarbyl and substituted hydrocarbyl;
R 3 and R 4 are independently chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl;
R 5 and R 6 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, {—}OH, and {—}OR 7 ;
R 3 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl;
Y, if present, is chosen from hydrogen, hydroxy, protected hydroxy, alkoxy, and acyloxy;
Z is chosen from hydroxy, protected hydroxy, alkoxy, and acyloxy;
Z′ is chosen from hydrogen, hydroxy, protected hydroxy, alkoxy, and acyloxy; and
the dashed lines between the carbon atoms at positions 6 and 7, 7 and 8, and 8 and 14 represent carbon to carbon bonds selected from the group consisting of (a) single bonds between all carbon atoms; (b) single bonds between the carbons at both positions 6 and 7 and 8 and 14, and a double bond between the carbons at positions 7 and 8, wherein A is not {—}C(O){—} if there is a double bond between the carbons at positions 7 and 8; and (c) double bonds between the carbons at both positions 6 and 7 and 8 and 14, and a single bond between the carbons at positions 7 and 8, wherein Y is not present if there is a double bond between the carbons at positions 8 and 14.
7. The process of claim 6 , wherein the oxidizing agent is chosen from a transition metal catalyst, hydrogen peroxide, peroxysulfate, peroxyacetic acid, 3-chloroperoxybenzoic acid, and RCO 3 H, wherein R is chosen from hydrogen, an alkyl, a substituted alkyl, an aryl, a substituted aryl, and combinations thereof.
8. The process of claim 6 , wherein the mole to mole ratio of (+)-morphinan to oxidizing agent is from about 1:1 to about 1:20 and the oxidation reaction is conducted at a temperature ranging from about −10° C. to about 80° C.
9. The process of claim 6 , wherein R 3 , R 4 , R 5 , and R 6 are hydrogen; the oxidizing agent is chosen from tungsten(VI) oxide, chromium oxide, dichromate, copper oxide, nickel oxide, cobalt oxide, silver oxide, oxides of mercury, oxides of lead, selenium oxide, ruthenium oxide, hydrogen peroxide, peroxysulfate, peroxyacetic acid, 3-chloroperoxybenzoic acid, and RCO 3 H, wherein R is chosen from hydrogen, an alkyl, a substituted alkyl, an aryl, a substituted aryl, and combinations thereof; the mole to mole ratio of the compound comprising Formula (III) or the pharmaceutically acceptable salt thereof to oxidizing agent is from about 1:1 to about 1:20, and the nitrogen at position 17 of the compound comprising Formula (IV) or the pharmaceutically acceptable salt thereof comprises an R or an S configuration.