Granted Patent B2

US 9,107,911 · App. 12/978,273 · Granted Aug 18, 2015

Abstract

Claims (49)

1. A prodrug compound

of Formula I;

or a pharmaceutically acceptable salt thereof, wherein:

X 1 is N;

X 2 is N;

X 3 is N;

X 4 is CR;

R is optionally substituted aliphatic, aromatic or heteroaromatic;

R 5 is selected from —C(R 8 )(R 9 )—OC(O)OR 10 , —C(R 8 )(R 9 )—OC(O)R 10 , and —C(R 8 )(R 9 )—OC(O)NR 11 R 12 ;

R 8 and R 9 are hydrogen;

R 10 is C 9 -C 24 -alkyl, substituted C 9 -C 24 -alkyl, C 9 -C 24 -alkenyl, substituted C 9 -C 24 -alkenyl, C 9 -C 24 -alkynyl, substituted C 9 -C 24 -alkynyl, aryl or substituted aryl;

R 11 and R 12 are each independently hydrogen, aliphatic or substituted aliphatic, provided that at least one of R 11 and R 12 is C 9 -C 24 -alkyl, substituted C 9 -C 24 -alkyl, C 9 -C 24 -alkenyl, substituted C 9 -C 24 -alkenyl, C 9 -C 24 -alkynyl, substituted C 9 -C 24 -alkynyl; or R 11 and R 12 together form a substituted or unsubstituted alkylene or alkenylene group which can optionally be interrupted by up to three heteroatoms independently selected from oxygen, nitrogen and sulfur.

2. The compound of claim 1 , wherein R 10 , or at least one of R 11 and R 12 , is optionally substituted aryl, C 9 -C 24 -alkyl, C 9 -C 24 -alkenyl, or C 9 -C 24 -alkynyl.

3. The compound of claim 1 , wherein R 10 , or at least one of R 11 and R 12 , is branched C 9 -C 24 -alkyl, -alkenyl or -alkynyl.

4. The compound of claim 3 , wherein R 10 , or at least one of R 11 and R 12 , is a secondary or tertiary C 9 -C 24 -alkyl, -alkenyl or -alkynyl group.

5. The compound of claim 3 , wherein R 10 , or at least one of R 11 and R 12 , is a β-branched C 9 -C 24 -alkyl, -alkenyl or -alkynyl group.

6. A method of sustained delivery of a heteroaryl NH-containing parent drug to a subject in need thereof, said method comprising the step of administering to the subject an effective amount of a prodrug compound produced by substituting a labile, hydrophobic aldehyde-linked prodrug moiety replacing the H of NH on the heteroaryl NH nitrogen atom wherein said prodrug compound is a compound of claim 1 .

7. The method of claim 6 , wherein the prodrug compound has decreased solubility under physiological conditions compared to the parent drug.

8. The method of claim 6 , wherein the heteroaryl NH-containing parent drug is represented by Formula II:

and the prodrug is represented by Formula I:

or a pharmaceutically acceptable salt thereof, wherein

X 1 is N;

X 2 is N;

X 3 is N;

X 4 is CR;

R is optionally substituted aliphatic, aromatic or heteroaromatic;

R 5 is selected from —C(R 8 )(R 9 )—OC(O)OR 10 , —C(R 8 )(R 9 )—OC(O)R 10 , and —C(R 8 )(R 9 )—OC(O)NR 11 R 12 ;

R 8 and R 9 are hydrogen;

R 10 is C 9 -C 24 -alkyl, substituted C 9 -C 24 -alkyl, C 9 -C 24 -alkenyl, substituted C 9 -C 24 -alkenyl, C 9 -C 24 -alkynyl, substituted C 9 -C 24 -alkynyl, aryl or substituted aryl;

R 11 and R 12 are each independently hydrogen, aliphatic or substituted aliphatic, provided that at least one of R 11 and R 12 is C 9 -C 24 -alkyl, substituted C 9 -C 24 -alkyl, C 9 -C 24 -alkenes substituted C 9 -C 24 -alkenyl, C 9 -C 24 -alkynyl, substituted C 9 -C 24 -alkynyl.

9. The method of claim 8 , wherein R 5 is selected from —CH(R 8 )—OC(O)OR 10 , and CH(R 8 )—OC(O)R 10 .

10. A method of producing a prodrug of a parent heteroaromatic NH-containing drug compound, wherein the prodrug has decreased solubility under physiological conditions and sustained activity upon dosing compared to the parent drug compound, said method comprising the step of modifying the parent drug by substituting a labile, hydrophobic aldehyde-linked prodrug moiety on the heteroaromatic NH nitrogen atom;

Wherein said parent heteroaromatic NH-containing drug compound is represented by Formula II,

the prodrug is represented by Formula I:

or a pharmaceutically acceptable salt thereof,

and the prodrug moiety is R 5 ;

X 1 is N;

X 2 is N;

X 3 is N;

X 4 is CR;

R is optionally substituted aliphatic, aromatic or heteroaromatic; and,

R 5 is selected from —C(R 8 )(R 9 )—OC(O)OR 10 , —C(R 8 )(R 9 )—OC(O)R 10 , and —C(R 8 )(R 9 )—OC(O)NR 11 R 12 ;

R 8 and R 9 are hydrogen;

R 10 is C 9 -C 24 -alkyl, substituted C 9 -C 24 -alkyl, C 9 -C 24 -alkenyl, substituted C 9 -C 24 -alkenyl, C 9 -C 24 -alkynyl, substituted C 9 -C 24 -alkynyl, aryl or substituted aryl;

R 11 and R 12 are each independently hydrogen, aliphatic or substituted aliphatic, provided that at least one of R 11 and R 12 is C 9 -C 24 -alkyl, substituted C 9 -C 24 -alkyl, C 9 -C 24 -alkenyl, substituted C 9 -C 24 -alkenyl, C 9 -C 24 -alkynyl, substituted C 9 -C 24 -alkynyl.

11. The method of claim 10 , wherein R 5 is selected from —CH(R 8 )—OC(O)OR 10 , and —CH(R 8 )—OC(O)R 10 .

12. A compound of claim 1 , having the formula:

Wherein n is 6, 14 or 18.

13. A compound having the formula:

Assignments (9)