IP Library › Patent Application 15527637
Patent Application
App. No. 15/527,637

METHOD OF MAKING PRODRUGS AND TARGETED THERAPEUTIC COMPOUNDS

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Quick Facts
Patent No.
US None
App. No.
15/527,637
Abstract

Provided is a method for making the compound of Formula 1. Various compounds utilized in that method are also provided, as are methods of making those compounds. Also provided is a compound having the formula XO—CO—(CH 2 ) n NH 2 , where n is an integer greater than 2. A method of making that compound is additionally provided. Further provided is a method of making a prodrug of a bioactive compound.

Claims (42)

1 . A method for making the compound of Formula 1:

the method comprising

(a) reacting the compound of Formula 2:

with X—OH in the presence of an acid catalyst to produce the compound of Formula 3a

wherein X is a substituent that forms an ester that can be cleaved from the compound of Formula 5a

to produce the compound of Formula 6:

(b) reacting the compound of Formula 3a with the compound of Formula 4:

to produce the compound of Formula 5a;

(c) removing the X group from the compound of Formula 5a to produce the compound of Formula 6:

(d) reacting the compound of Formula 6 with the compound of Formula 7:

to produce the compound of Formula 8:

 and

(e) converting the compound of Formula 8 into the compound of Formula 1.

2 . The method of claim 1 , wherein the compound of Formula 7 is made by reacting the compound of Formula 9:

with a base in an alcohol.

3 . The method of claim 2 , wherein the base in the alcohol are sodium ethoxide in ethanol.

4 . The method of claim 1 , wherein step (b) is performed using ethyl-(dimethylaminopropyl)carbodiimide (EDC), diisopropylethylamine (iPr2NEt), hydroxybenzotriazole (HOBt), and dimethylformamide (DMF).

5 . The method of claim 1 , wherein step (c) is performed using a palladium on carbon (Pd/C) catalyst and triethylsilane.

6 . The method of claim 1 , wherein step (d) is performed using 4-dimethylaminopyridine (4-DMAP) and diisopropylcarbodiimide (DIC) in dichloromethane.

7 . The method of claim 1 , wherein step (e) is performed using triethylsilane and trifluoroacetic acid in dichloromethane.

8 - 11 . (canceled)

12 . A compound having the formula of Formula 3, Formula 3a, Formula 5, Formula 5a or Formula 6.

13 - 20 . (canceled)

21 . A compound having the formula XO—CO—(CH 2 ) n NH 2 , wherein X is a substituent that forms an ester that can be cleaved from the compound of Formula 5a,

and wherein n is an integer greater than 2.

22 . The compound of claim 21 , wherein X is benzyl.

23 . The compound of claim 21 , wherein n=11.

24 - 26 . (canceled)

27 . A method of making a prodrug of a bioactive compound, the method comprising

(a) reacting the compound of Formula 3a with a masking moiety (MM) to form the compound X-linker-MM;

(b) removing an X group from the X-linker-MM compound to produce the compound OH-linker-MM; and

(c) reacting a bioactive compound with the compound OH-linker-MM to produce the prodrug of the bioactive compound.

28 . The method of claim 27 , wherein the MM is a peptide.

29 . The method of claim 27 , wherein the MM can be cleaved by prostate specific membrane antigen.

30 . The method of claim 27 , wherein X is benzyl.

31 . The method of claim 27 , wherein n=11.

32 . The method of claim 27 , wherein the linker compound is the compound of Formula 3.

33 . (canceled)

34 . The method of claim 27 , wherein the bioactive compound is a thapsigargin.

35 . The method of claim 27 , wherein the bioactive compound is modified before step (c).

36 . (canceled)

37 . The method of claim 1 , wherein X is benzyl and the compound of Formula 3a is Benzyl 12-AD having Formula 3: