US 5,859,050 A · Method for the preparation of (+)-calanolide A and analogues thereof

Abstract

A method of preparing (+)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. According to the disclosed method, chromene 4 intermediate was subjected to a chlorotitanium-mediated aldol reaction with acetaldehyde to selectively produce (.+-.)-8a. Separation and enzyme-mediated resolution of (.+-.)-8a produced (+)-8a. Cyclization of (+)-8a under neutral Mitsunobu conditions followed by Luche reduction of (+)-7 produced (+)-calanolide A in high yield and enantiomeric purity. The method of the invention has been extended to produce potent antiviral calanolide A analogues.

A method of preventing or treating a viral infection comprising administering to a mammal an antiviral effective, non-toxic amount of at least one compound of the formula I, II, III, IV, V, or VI:

##STR7## wherein R.sub.1 is H, halogen, hydroxyl, amino, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy, amino-C.sub.1-8 alkyl, C.sub.1-6 alkylamino, di(C.sub.1-6 alkyl)amino, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alkyl)amino-C.sub.1-8 alkyl, cyclohexyl, aryl, or heterocycle, wherein aryl or heterocycle may each be unsubstituted or substituted with one or more of the following:
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy-C.sub.1-4 alkyl, hydroxyl, amino, C.sub.1-6 alkylamino, di(C.sub.1-6 alkyl)amino, amino-C.sub.1-8 alkyl, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alkyl)-amino-C.sub.1-8 alkyl, nitro, azido or halogen;
R.sub.2 is H, halogen, hydroxyl, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, aryl or heterocycles;
R.sub.3 and R.sub.4 are independently selected from the group consisting of H, halogen, hydroxyl, amino, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, hydroxy-C.sub.1-6 alkyl, amino-C.sub.1-8 alkyl, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alkyl)amino-C.sub.1-8 alkyl, cyclohexyl, aryl or heterocycle;
and R.sub.3 and R.sub.4 can be taken together to form a 5-7 membered saturated cycle ring or heterocyclic ring;
R.sub.5 and R.sub.6 are independently selected from the group consisting of H, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, aryl or heterocycle;
R.sub.5 and R.sub.6 can be taken together to form a 5-7 membered saturated cycle ring or heterocycle ring;
R.sub.7 is H, halogen, methyl, or ethyl;
R.sub.8 and R.sub.9 are independently selected from the group consisting of H, halogen C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, hydroxy-C.sub.1-6 alkyl, amino-C.sub.1-8 alkyl, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alkyl)amino-C.sub.1-8 alkyl, cyclohexyl, aryl or heterocycle;
and R.sub.8 and R.sub.9 can be taken together to form a 5-7 membered saturated cycle ring or heterocyclic ring;
or a pharmaceutically acceptable salt thereof;
##STR8## wherein R.sub.1 is H, halogen, hydroxyl, amino, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy, amino-C.sub.1-8 alkyl, C.sub.1-6 alkylamino, di(C.sub.1-6 alkyl)amino, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alkyl)amino-C.sub.1-8 alkyl, cyclohexyl, aryl or heterocycle, wherein aryl or heterocycle may each be unsubstituted or substituted with one or more of the following:
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy-C.sub.1-4 alkyl, hydroxyl, amino, C.sub.1-6 alkylamino, di(C.sub.1-6 alkyl)amino, amino-C.sub.1-8 alkyl, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alkyl)amino-C.sub.1-8 alkyl, nitro, azido or halogen;
R.sub.2 is H, halogen, hydroxyl, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, aryl or heterocycle;
R.sub.3 and R.sub.4 are independently selected from the group consisting of H, halogen, hydroxyl, amino, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, hydroxy-C.sub.1-6 alkyl, amino-C.sub.1-8 alkyl, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alkyl)amino-C.sub.1-8 alkyl, cyclohexyl, aryl or heterocycle;
and R.sub.3 and R.sub.4 can be taken together to form a 5-7 membered saturated cycle ring or heterocyclic ring;
R.sub.5 and R.sub.6 are independently selected from the group consisting of H, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, aryl or heterocycle;
and R.sub.5 and R.sub.6 can be taken together to form a 5-7 membered saturated cycle ring or heterocyclic ring;
R.sub.7 is H, halogen, methyl, or ethyl;
R.sub.8 and R.sub.9 are independently selected from the group consisting of H, halogen, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, hydroxy-C.sub.1-6 alkyl, amino-C.sub.1-8 alkyl, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alkyl)amino-C.sub.1-8 alkyl, cyclohexyl, aryl or heterocycle;
and R.sub.8 and R.sub.9 can be taken together to form a 5-7 membered saturated cycle ring or heterocyclic ring;
R.sub.10 is H, acyl, P(O)(OH).sub.2, S(O)(OH).sub.2, CO(C.sub.1-10 alkyl)CO.sub.2 H, (C.sub.1-8 alkyl)CO.sub.2 H, CO(C.sub.1-10 alkyl)NR.sub.11 R.sub.12, (C.sub.1-8 alkyl)NR.sub.11 R.sub.12 ;
wherein R.sub.11 and R.sub.12 are independently selected from the group consisting of H, C.sub.1-6 alkyl;
and R.sub.11 and R.sub.12 can be taken together to form a 5-7 membered saturated heterocyclic ring containing said nitrogen;
or a pharmaceutically acceptable salt thereof;
##STR9## wherein R.sub.1 is H, halogen, hydroxyl, amino, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy, amino-C.sub.1-8 alkyl, C.sub.1-6 alkylamino, di(C.sub.1-6 alkyl)amino, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alkyl)amino-C.sub.1-8 alkyl, cyclohexyl, aryl or heterocycle, wherein aryl or heterocycle may each be unsubstituted or substituted with one or more of the following:
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy-C.sub.1-4 alkyl, hydroxyl, amino, C.sub.1-6 alkylamino, di(C.sub.1-6 alkyl)amino, amino-C.sub.1-8 alkyl, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alyl)amino-C.sub.1-8 alkyl, nitro, azido or halogen;
R.sub.2 is H, halogen, hydroxyl, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, aryl or heterocycle;
R.sub.3 and R.sub.4 are independently selected from the group consisting of H, halogen, hydroxyl, amino, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, hydroxy-C.sub.1-6 alkyl, amino-C.sub.1-8 alkyl, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alkyl)amino-C.sub.1-8 alkyl, cyclohexyl, aryl or heterocycle;
and R.sub.3 and R.sub.4 can be taken together to form a 5-7 membered saturated cycle ring or heterocyclic ring;
R.sub.5 and R.sub.6 are independently selected from the group consisting of H, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, aryl or heterocycle;
R.sub.7 is H, halogen, methyl, or ethyl;
R.sub.8 and R.sub.9 are independently selected from the group consisting of H, halogen, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, hydroxy-C.sub.1-6 alkyl, amino-C.sub.1-8 alkyl, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alkyl)amino-C.sub.1-8 alkyl, cyclohexyl, aryl or heterocycle;
and R.sub.8 and R.sub.9 can be taken together to form a 5-7 membered saturated cycle ring or heterocyclic ring;
R.sub.10 is halogen, OR.sub.11, NHOR.sub.11, NHOR.sub.12, NR.sub.11 R.sub.12, NR.sub.12 R.sub.13 ;
wherein R.sub.11 is H, acyl, P(O)(OH).sub.2, S(O)OH).sub.2, CO(C.sub.1-10 alkyl)CO.sub.2 H, (C.sub.1-8 alkyl)CO.sub.2 H, CO(C.sub.1-10 alkyl)NR.sub.12 R.sub.13, (C.sub.1-8 alkyl)NR.sub.12 R.sub.13 ;
R.sub.12 and R.sub.13 are independently selected from the group consisting of H, C.sub.1-6 alkyl;
and R.sub.12 and R.sub.13 can be taken together to form a 5-7 membered saturated heterocyclic ring containing said nitrogen;
or a pharmaceutically acceptable salt thereof, with the proviso that:
when R.sub.1 is n-propyl or phenyl, R.sub.2, R.sub.7, and R.sub.8 are H, R.sub.5 and R.sub.6 and R.sub.9 are methyl, and R.sub.10 is OH, then R.sub.3 and R.sub.4 cannot both be H;
when R.sub.1 is n-propyl and phenyl, R.sub.2, R.sub.4, R.sub.7, and R.sub.8 are H, R.sub.5 and R.sub.6 and R.sub.9 are methyl, and R.sub.10 is OH, then R.sub.3 cannot be methyl;
when R.sub.1 is n-prophyl or phenyl, R.sub.2, R.sub.3, R.sub.7, and R.sub.9 are H, R.sub.5 and R.sub.8 are methyl, and R.sub.10 is OH, then R.sub.4 cannot be methyl;
##STR10## wherein R.sub.1 is H, halogen, hydroxyl, amino, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy, amino-C.sub.1-8 alkyl, C.sub.1-6 alkylamino, di(C.sub.1-6 alkyl)amino, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alkyl)amino-C.sub.1-8 alkyl, cyclohexyl, aryl or heterocycle, wherein aryl or heterocycle may each be unsubstituted or substituted with one or more of the following:
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy-C.sub.1-6 alkyl, hydroxyl, amino, C.sub.1-6 alkylamino, di(C.sub.1-6 alkyl)amino, amino-C.sub.1-8 alkyl, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alkyl)amino-C.sub.1-8 alkyl, nitro azido or halogen;
R.sub.2 is H, halogen, hydroxyl, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, aryl or heterocycle;
R.sub.3 and R.sub.4 are independently selected from the group consisting of H, halogen, hydroxyl, amino, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, hydroxy-C.sub.1-6 alkyl, amino-C.sub.1-8 alkyl, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alkyl)amino-C.sub.1-8 alkyl, cyclohexyl, aryl or heterocycle;
and R.sub.3 and R.sub.4 can be taken together to form a 5-7 membered saturated cycle ring or heterocyclic ring;
R.sub.5 and R.sub.6 are independently selected from the group consisting of H, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, aryl or heterocycle;
and R.sub.5 and R.sub.6 can be taken together to form a 5-7 membered saturated cycle ring or heterocyclic ring;
R.sub.7 is H, halogen, methyl, or ethyl;
R.sub.8 and R.sub.9 are independently selected from the group consisting of H, halogen, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, hydroxy-C.sub.1-6 alkyl amino-C.sub.1-8 alkyl, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alkyl)amino-C.sub.1-8 alkyl, cyclohexyl, aryl or heterocycle;
and R.sub.8 and R.sub.9 can be taken together to form a 5-7 membered saturated cycle ring or heterocyclic ring;
R.sub.10 is halogen, OR.sub.11, NHOR.sub.11, NHOR.sub.12, NR.sub.11 R.sub.12, NR.sub.12 R.sub.13 ;
wherein R.sub.11 is H, acyl, P(O)(OH).sub.2, S(O)(OH).sub.2, CO(C.sub.1-10 alkyl)CO.sub.2 H, (C.sub.1-8 alkyl)CO.sub.2 H, CO(C.sub.1-10 alkyl)NR.sub.12 R.sub.13, (C.sub.1-8 alkyl)NR.sub.12 R.sub.13 ;
R.sub.12 and R.sub.13 are independently selected from the group consisting of H, C.sub.1-6 alkyl;
and R.sub.12 and R.sub.13 can be taken together to form a 5-7 membered saturated heterocyclic ring containing said nitrogen;
or a pharmaceutically acceptable salt thereof, with the proviso that:
when R.sub.1 is n-propyl, R.sub.2, R.sub.4, R.sub.7, and R.sub.8 are H, R.sub.5 and R.sub.6 and R.sub.9 are methyl, and R.sub.10 is OH, then R.sub.3 cannot be methyl;
when R.sub.1 is n-propyl, R.sub.2, R.sub.3, R.sub.7, and R.sub.9 and H, R.sub.5 and R.sub.6 and R.sub.8 are methyl, and R.sub.10 is OH, then R.sub.4 cannot be methyl;
##STR11## wherein R.sub.1 is H, halogen, hydroxyl, amino, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy, amino-C.sub.1-8 alkyl, C.sub.1-6 alkylamino, di(C.sub.1-6 alkyl)amino, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alkyl)amino-C.sub.1-8 alkyl, cyclohexyl, aryl or heterocycle, wherein aryl or heterocycle may each be unsubstituted or substituted with one or more of the following:
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy-C.sub.1-4 alkyl, hydroxyl, amino, C.sub.1-6 alkylamino, di(C.sub.1-6 alkyl)amino, amino-C.sub.1-8 alkyl, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alkyl)amino-C.sub.1-8 alkyl, nitro, azido or halogen;
R.sub.2 is H, halogen, hydroxyl, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, aryl or heterocycle;
R.sub.3 and R.sub.4 are independently selected from the group consisting of H, halogen, hydroxyl, amino, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, hydroxy-C.sub.1-6 alkyl, amino-C.sub.1-8 alkyl, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alkyl)amino-C.sub.1-8 alkyl, cyclohexyl, aryl or heterocycle;
and R.sub.3 and R.sub.4 can be taken together to form a 5-7 membered saturated cycle ring or heterocyclic ring;
R.sub.5 and R.sub.6 are independently selected from the group consisting of H, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, aryl or heterocycle;
and R.sub.5 and R.sub.6 can be taken together to form a 5-7 membered saturated cycle ring or heterocyclic ring;
R.sub.7 is H, halogen, methyl, or ethyl;
R.sub.8 and R.sub.9 are independently selected from the group consisting of H, halogen, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, amino-C.sub.1-8 alkyl, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alkyl)amino-C.sub.1-8 alkyl, cyclohexyl, aryl or heterocycle;
and R.sub.8 and R.sub.9 can be taken together to form a 5-7 membered saturated cycle ring or heterocyclic ring;
or a pharmaceutically acceptable salt thereof;
##STR12## wherein R.sub.1 is H, halogen, hydroxyl, amino, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, hydroxy-C.sub.1-6 alkyl, C.sub.1-6 alkoxy, amino-C.sub.1-8 alkyl, C.sub.1-6 alkylamino, di(C.sub.1-6 alkyl)amino, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alkyl)amino-C.sub.1-8 alkyl, cyclohexyl, aryl or heterocycle, wherein aryl or heterocycle may each be unsubstituted or substituted with one or more of the following:
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy-C.sub.1-6 alkyl, hydroxyl, amino, C.sub.1-6 alkylamino, di(C.sub.1-6 alkyl)amino, amino-C.sub.1-6 alkyl, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alkyl)amino-C.sub.1-8 alkyl, nitro, azido or halogen;
R.sub.2 is H, halogen, hydroxyl, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl mono- or poly-fluorinated C.sub.1-6 alkyl, aryl or heterocycle;
R.sub.3 and R.sub.4 are independently selected from the group consisting of H, halogen, hydroxyl, amino, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, hydroxy-C.sub.1-6 alkyl, amino-C.sub.1-8 alkyl, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alkyl)amino-C.sub.1-8 alkyl, cyclohexyl, aryl or heterocycle;
and R.sub.3 and R.sub.4 can be taken together to form a 5-7 membered saturated cycle ring or heterocyclic ring;
R.sub.5 and R.sub.6 are independently selected from the group consisting of H, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, aryl or heterocycle;
and R.sub.5 and R.sub.6 can be taken together to form a 5-7 membered saturated cycle ring or heterocyclic ring;
R.sub.7 is H, halogen, methyl, or ethyl;
R.sub.8 and R.sub.9 are independently selected from the group consisting of H, halogen, C.sub.1-6 alkyl, aryl-C.sub.1-6 alkyl, mono- or poly-fluorinated C.sub.1-6 alkyl, hydroxy-C.sub.1-6 alkyl, amino-C.sub.1-8 alkyl, C.sub.1-8 alkylamino-C.sub.1-8 alkyl, di(C.sub.1-6 alkyl)amino-C.sub.1-8 alkyl, cyclohexyl, aryl or heterocycle;
and R.sub.8 and R.sub.9 can be taken together to form a 5-7 membered saturated cycle ring or heterocyclic ring;
R.sub.10 is H, C.sub.1-6 alkyl, aryl and aryl-C.sub.1-6 alkyl;
or a pharmaceutically acceptable salt thereof.

79 more elements

Method for the preparation of (+)-calanolide A and analogues thereof

Life of this patent

Method for the preparation of (+)-calanolide A and analogues thereof

Life of this patent

Abstract

Claims8