Tubulysins and processes for preparing
Processes are described for the preparation of tubulysins. The processes are useful for preparing predetermined mixtures of tubulysins, preparing single tubulysins from mixtures of tubulysins, and for converting one tubulysin into a different tubulysin. The tubulysins described herein are useful in treating diseases and disease states that include pathogenic cell populations.
1. A process for converting a compound of the formula (I)
wherein:
n is an integer from 1 to 3;
V is selected from the group consisting of H, OR 2 , and halo, and W is selected from the group consisting of H, OR 2 , and alkyl; or V and W are taken together with the attached carbon to form a carbonyl;
Z is alkyl, and Y is O; or Z is alkyl or C(O)R 4 , and Y is absent;
R is OH or a leaving group; or R forms a carboxylic acid derivative selected from the group consisting of an ester, an amide, an imide, and an acylhydrazide;
R 1 is H; or R 1 represents 1 to 3 substituents each independently selected from the group consisting of halo, nitro, carboxylate, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, and OR 6 ;
each R 2 is independently selected from the group consisting of H, alkyl, and C(O)R 5 , provided that R 2 is not H when both V and W are OR 2 ;
R 4 is selected from the group consisting of alkyl, CF 3 , and aryl;
each R 5 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, arylalkyl and aryl;
R 6 is selected from the group consisting of aryl, C(O)R 7 , P(O)(OR 8 ) 2 , SO 3 R 8 , and a phenol protecting group;
each R 7 and R 8 is independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl; or R 8 is a metal cation;
and
R 10 is alkyl or alkenyl, each of which is optionally substituted;
into a compound of the formula (II)
wherein:
n, V, W, Z, Y, R, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 10 are as defined in formula I;
X is CH 2 QR 9 ;
Q is —NH— or —S—, and each R 9 is independently selected from the group consisting of hydrogen, C 1-4 alkyl, alkenyl, aryl, and C(O)R 11 ; or Q is —O—, and R 9 is C(O)R 11 or C 5 alkyl; and
each R 11 is independently selected from the group consisting of C 1-6 alkyl, alkenyl, aryl, and heteroaryl;
the process comprising
(a) mixing the compound of the formula (I) with an acid to form an intermediate; and
(b) reacting the intermediate with a nucleophile.
2. The process of claim 1 , wherein the nucleophile is selected from the group consisting of 3-methylbutanol, 1-propanethiol, 2-sulfanylethanol, 1,2-ethanedithiol, acetic acid, butyric acid, trans-4-chloro-2-butenoic acid, and isovaleronitrile.
3. The process of claim 1 , wherein the acid is trifluoroacetic acid.
4. A process for converting a compound of the formula (I)
wherein:
n is an integer from 1 to 3;
V is selected from the group consisting of H, OR 2 , and halo, and W is selected from the group consisting of H, OR 2 , and alkyl; or V and W are taken together with the attached carbon to form a carbonyl;
Z is alkyl, and Y is O; or Z is alkyl or C(O)R 4 , and Y is absent;
R is OH or a leaving group; or R forms a carboxylic acid derivative selected from the group consisting of an ester, an amide, an imide, and an acylhydrazide;
R 1 is H; or R 1 represents 1 to 3 substituents each independently selected from the group consisting of halo, nitro, carboxylate, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, and OR 6 ;
each R 2 is independently selected from the group consisting of H, alkyl, and C(O)R 5 , provided that R 2 is not H when both V and W are OR 2 ;
R 4 is selected from the group consisting of alkyl, CF 3 , and aryl;
each R 5 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, arylalkyl and aryl;
R 6 is selected from the group consisting of aryl, C(O)R 7 , P(O)(OR 8 ) 2 , SO 3 R 8 , and a phenol protecting group;
each R 7 and R 8 is independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl; or R 8 is a metal cation;
and
R 10 is alkyl or alkenyl;
into a compound of the formula (II)
wherein:
n, V, W, Z, Y, R, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 10 are as defined in formula I;
X is selected from the group consisting of C 1-4 alkyl, alkenyl, and CH 2 QR 9 ;
Q is selected from the group consisting of —NH—, —O—, and —S—;
each R 9 is independently selected from the group consisting of hydrogen, C 1-5 alkyl, alkenyl, aryl, and C(O)R 11 ; and
each R 11 is independently selected from the group consisting of C 1-6 alkyl, alkenyl, aryl, and heteroaryl;
the process comprising
(a) mixing the compound of the formula (I) with trifluoroacetic acid to form an intermediate and
(b) reacting the intermediate with a nucleophile.
5. The process of claim 4 , wherein the nucleophile is a compound of the formula R 11 CO 2 H or an anion thereof, wherein R 11 is as defined in formula II; or the nucleophile is a compound of the formula R 9 OH or an anion thereof, wherein R 9 is as defined in formula II; or the nucleophile is a compound of the formula R 21 CN, wherein R 21 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl.
6. The process of claim 4 , wherein the nucleophile is selected from the group consisting of methanol, 1-propanol, ethylene glycol, 3-methylbutanol, 1-propanethiol, 2-sulfanylethanol, 1,2-ethanedithiol, acetic acid, butyric acid, trans-4-chloro-2-butenoic acid, isovaleronitrile, and allyltrimethylsilane.
7. The process of claim 4 , wherein the second compound is tubulysin B and the nucleophile is butyric acid.
8. A process for converting a compound of the formula (I)
wherein:
n is an integer from 1 to 3;
V is selected from the group consisting of H, OR 2 , and halo, and W is selected from the group consisting of H, OR 2 , and alkyl; or V and W are taken together with the attached carbon to form a carbonyl;
Z is alkyl, and Y is O; or Z is alkyl or C(O)R 4 , and Y is absent;
R is OH or a leaving group; or R forms a carboxylic acid derivative selected from the group consisting of an ester, an amide, an imide, and an acylhydrazide;
R 1 is H; or R 1 represents 1 to 3 substituents each independently selected from the group consisting of halo, nitro, carboxylate, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, and OR 6 ;
each R 2 is independently selected from the group consisting of H, alkyl, and C(O)R 5 , provided that R 2 is not H when both V and W are OR 2 ;
R 4 is selected from the group consisting of alkyl, CF 3 , and aryl;
each R 5 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, arylalkyl and aryl;
R 6 is selected from the group consisting of aryl, C(O)R 7 , P(O)(OR 8 ) 2 , SO 3 R 8 , and a phenol protecting group;
each R 7 and R 8 is independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl; or R 8 is a metal cation;
and
R 10 is alkyl or alkenyl;
into a compound of the formula (II)
wherein:
n, V, W, Z, Y, R, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 10 are as defined in formula I;
X is CH 2 OR 9 ;
each R 9 is independently selected from the group consisting of C 1-5 alkyl, alkenyl, aryl, and C(O)R 11 ; and
each R 11 is independently selected from the group consisting of C 1-6 alkyl, alkenyl, aryl, or heteroaryl;
the process comprising
(a) mixing the compound of the formula (I) with trifluoroacetic acid to form an intermediate; and
(b) reacting the intermediate with a nucleophile.
9. The process of claim 8 , wherein the nucleophile is a compound of the formula R 11 CO 2 H or an anion thereof, wherein R 11 is as defined in formula II; or the nucleophile is a compound of the formula R 9 OH or an anion thereof, wherein R 9 is as defined in formula II.
10. The process of claim 8 , wherein the nucleophile is selected from the group consisting of methanol, 1-propanol, ethylene glycol, 3-methylbutanol, acetic acid, and butyric acid.
11. The process of claim 8 , wherein R 9 is C 1-5 alkyl.
12. The process of claim 8 , wherein R 9 is C(O)R 11 , and R 11 is C 1-6 alkyl.
13. The process of claim 8 , wherein R 9 is C(O)R 11 , R 11 is —CH 2 CH 2 CH 3 , and the nucleophile is butyric acid.
14. The process of claim 8 , wherein the first compound is mixed with trifluoroacetic acid under substantially anhydrous conditions.
15. The process of claim 8 , wherein R is OH or forms an acylhydrazide.
16. The process of claim 8 , wherein n is 2.
17. The process of claim 8 , wherein V is H, W is OR 2 , R 2 is C(O)R 5 , and R 5 is alkyl.
18. The process of claim 8 , wherein Z is alkyl, and Y is absent.
19. The process of claim 10 , wherein R 1 represents 1 substituent that is OH, or R 1 is H.
20. The process of claim 10 , wherein the compound of the formula I is of the formula (III)
wherein:
R, R 1 , R 6 , R 7 , R 8 , and R 10 are as defined in formula I.