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 one or more compounds of the formula I
wherein:
n is 1-3;
V is H, OR 2 , or halo, and W is H, OR 2 , or alkyl, where R 2 is independently selected in each instance from H, alkyl, and C(O)R 5 , where R 5 is independently selected in each instance from the group consisting of alkyl, cycloalkyl, alkenyl, arylalkyl and aryl; providing that R 2 is not H when both V and W are OR 2 ; 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, where R 4 is alkyl, CF 3 , or aryl;
R 1 is H, or R 1 represents 1 to 3 substituents independently selected in each instance from the group consisting of halo, nitro, carboxylate or a derivative thereof, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, and OR 6 , where R 6 is an optionally substituted aryl, C(O)R 7 , P(O)(OR 8 ) 2 , SO 3 R 8 , a phenol protecting group, or a prodrug moiety, where R 7 and R 8 are independently selected in each instance from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted, or R 8 is a metal cation;
R is OH or a leaving group, or R forms a carboxylic acid derivative; and
R 10 is independently selected in each instance from the group consisting of alkyl and alkenyl, each of which is optionally substituted; and where if there is a plurality of compounds of formula I, the plurality of compounds differ from each other in R 10 ;
into substantially a single compound of the formula II
wherein
n, V, W, Z, Y, R 1 and R are as defined in Formula I; and
X is CH 2 QR 9 ; where Q is —N(R 9 )— or —S—, and each R 9 is independently hydrogen, C 1-4 alkyl, alkenyl, aryl, each of which is optionally substituted, or C(O)R 11 , where R 11 is C 1-6 alkyl, alkenyl, aryl, or heteroaryl, each of which is optionally substituted; or Q is —O—, and R 9 is C(O)R 11 or C 5 alkyl;
the process comprising the steps of (a) mixing the one or more of compounds of formula I with an acid under substantially anhydrous conditions to form an intermediate; and
(b) reacting the intermediate with a nucleophile.
2. The process of claim 1 for converting substantially one compound of formula I.
3. The process of claim 1 for converting a plurality of compounds of formula I.
4. The process of claim 1 wherein n is 2 and R is OH.
5. The process of claim 1 wherein V is H and W is OR 2 .
6. The process of claim 4 wherein the nucleophile is a compound of the formula R 11 CO 2 H.
7. The process of claim 4 wherein the nucleophile is a compound of formula R 9 QH or an anion thereof.
8. The process of claim 4 wherein the nucleophile is a compound of the formula R 21 CN, wherein R 21 is alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl, each of which is optionally substituted.
9. The process of claim 1 wherein each Z is alkyl; and each Y is absent.
10. The process of claim 1 wherein each n is 1.
11. The process of claim 1 wherein each n is 2.
12. The process of claim 1 wherein each R 10 is alkyl.
13. The process of claim 1 wherein each V is H; and each W is OR 2 ; where R 2 is C(O)R 5 .
14. The process of claim 13 wherein R 5 is alkyl.
15. The process of claim 1 wherein each R 1 is H.
16. The process of claim 1 wherein each R 1 is OH.
17. The process of claim 1 wherein each R is OH.
18. The process of claim 1 wherein Q is —O—; and R 9 is C(O)R 11 .
19. The process of claim 18 wherein R 11 is C 1-6 alkyl.
20. The process of claim 18 wherein R 11 is C 1-6 alkenyl.
21. The process of claim 1 wherein Q is —NH—.
22. The process of claim 1 wherein Q is —S—.
23. The process of claim 1 wherein the one or more compounds of the formula I are of the formula.
24. The process of claim 1 wherein the compound of the formula II is of the formula.
25. The process of claim 1 wherein the one or more compounds of the formula I are of the formula
wherein R 1 is OH and R 10 is (CH 3 ) 2 CHCH 2 ; R 1 is OH and R 10 is CH 3 (CH 2 ) 2 ; R 1 is OH and R 10 is CH 3 CH 2 ; R 1 is H and R 10 is (CH 3 ) 2 CHCH 2 ; R 1 is H and R 10 is CH 3 (CH 2 ) 2 ; R 1 is H and R 10 is CH 2 CH 3 ; R 1 is OH and R 10 is (CH 3 ) 2 C=CH; R 1 is H and R 10 is CH 3 ; or R 1 is H and R 10 is CH 3 .
26. The process of claim 1 wherein the compound of the formula II is of the formula
wherein R 1 is OH and R 11 is (CH 3 ) 2 CHCH 2 ; R 1 is OH and R 11 is CH 3 (CH 2 ) 2 ; R 1 is OH and R 11 is CH 3 CH 2 ; R 1 is H and R 11 is (CH 3 ) 2 CHCH 2 ; R 1 is H and R 11 is CH 3 (CH 2 ) 2 ; R 1 is H and R 11 is CH 2 CH 3 ; R 1 is OH and R 11 is (CH 3 ) 2 C=CH; R 1 is H and R 11 is CH 3 ; or R 1 is H and R 11 is CH 3 .
27. The process of claim 1 wherein the compound of the formula II is tubulysin B.
28. The process of claim 1 wherein the compound of the formula II is selected from the group consisting of
29. A process for converting one or more compounds of the formula III
wherein:
n is 1-3;
V is H, OR 2 , or halo, and W is H, OR 2 , or alkyl, where R 2 is independently selected in each instance from H, alkyl, and C(O)R 5 , where R 5 is independently selected in each instance from the group consisting of alkyl, cycloalkyl, alkenyl, arylalkyl and aryl; providing that R 2 is not H when both V and W are OR 2 ; 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, where R 4 is alkyl, CF 3 , or aryl;
R 1 is H, or R 1 represents 1 to 3 substituents independently selected in each instance from the group consisting of halo, nitro, carboxylate or a derivative thereof, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, and OR 6 , where R 6 is an optionally substituted aryl, C(O)R 7 , P(O)(OR 8 ) 2 , SO 3 R 8 , a phenol protecting group, or a prodrug moiety, where R 7 and R 8 are independently selected in each instance from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted, or R 8 is a metal cation;
R is OH or a leaving group, or R forms a carboxylic acid derivative; and
R 10 is independently selected in each instance from the group consisting of alkyl and alkenyl, each of which is optionally substituted; and where if there is a plurality of compounds of formula I, the plurality of compounds differ from each other in R 10 ;
into substantially a single compound of the formula IV
wherein
n, V, W, Z, Y, R 1 and R are as defined in Formula I; and
X is CH 2 QR 9 ; where Q is -N(R 9 )- or -S-, and each R 9 is independently hydrogen, C 1-4 alkyl, alkenyl, aryl, each of which is optionally substituted, or C(O)R 11 , where R 11 is C 1-6 alkyl, alkenyl, aryl, or heteroaryl, each of which is optionally substituted; or Q is -O-, and R 9 is C(O)R 11 ;
the process comprising the steps of (a) mixing the one or more of compounds of formula I with an acid under substantially anhydrous conditions to form an iminium intermediate; and
(b) reacting the intermediate with a nucleophile.