Migrastatin analog compositions and uses thereof

1. A method for treating breast tumor metastasis in a subject comprising:

administering to a subject in need thereof a therapeutically effective amount of a composition comprising a compound having one of the following structures:

or pharmaceutically acceptable salt thereof;

wherein R 1 and R 2 are hydrogen or lower alkyl;

R 3 , R 5 and R 6 are C 1-6 alkyl;

the bond  is a single bond or a double bond;

R 4 is halogen, —OR 4A , —OC(═O)R 4A or —NR 4A R 4B ; wherein R 4A and R 4B are independently hydrogen; a nitrogen protecting group selected from a carbamate, an amide, a cyclic imide derivative, an N-alkyl amine, an N-aryl amine, an imine derivative or an enamine derivative or an oxygen protecting group selected from a substituted methyl ether, a substituted ethyl ether, a substituted benzyl ether, a silyl ether, an ester, a carbonate, a cyclic acetal or a ketal; or R 4A and R 4B , taken together with the nitrogen atom to which they are attached, form a C 3-20 heterocyclic or C 3-14 heteroaryl moiety; or R 4 , taken together with the carbon atom to which it is attached forms a moiety having the structure

or R 4A and R 4B are independently a C 1-16 alkyl group optionally substituted with one or more of C 1-20 aliphatic; C 3-14 aryl; C 3-14 heteroaryl; C 1-20 alkylC 3-14 aryl; C 1-20 alkylC 3-14 heteroaryl, C 3-14 aryloxy; C 1-20 heteroalkoxy, C 3-14 heteroaryloxy; C 1-20 alkylthio; C 3-14 arylthio; heteroC 1-20 alkylthio; heteroC 3-14 arylthio; F; Cl; Br; I; —OH; —NO 2 ; —CN; —CF 3 ; —CH 2 CF 3 ; —CHCl 2 ; —CH 2 OH; —CH 2 CH 2 OH; —CH 2 NH 2 ; —CH 2 SO 2 CH 3 ; —C(O)R x ; —CO 2 (R x ); —CON(R x ) 2 ; —OC(O)R x ; —OCO 1 R x ; —OCON(R x ) 2 ; —N(R x ) 2 ; S(O) 2 R x ; —NR x (CO)R x wherein each occurrence of R x is independently C 1-20 aliphatic, heteroC 1-20 aliphatic, C 3-14 aryl, C 3-14 heteroaryl, C 1-20 alkylC 3-14 aryl or C 1-20 alkylC 3-14 heteroaryl;

X 1 is O, S, NR X1 or CR X1 R X2 ; wherein R X1 and R X2 are independently hydrogen, halogen, or a substituted or unsubstituted C 1-20 alkyl, heteroC 1-20 alkyl, cycloC 3-10 alkyl, heterocyclo C 3-10 alkyl, C 3-14 aryl or C 3-14 heteroaryl, or a nitrogen protecting group selected from a carbamate, an amide, a cyclic imide derivative, an N-alkyl amine, an N-aryl amine, an imine derivative or an enamine derivative;

Q is hydrogen, halogen, —CN, —S(O) 1-2 R Q1 , —NO 2 , —COR Q1 , —CO 2 R Q1 , —NR Q1 C(═O)R Q2 , —NR Q1 C(═O)OR Q2 , —CONR Q1 R Q2 , or a substituted or unsubstituted C 1-20 aliphatic, heteroC 1-20 aliphatic, C 3-20 alicyclic, heteroC 3-20 alicyclic, C 3-14 aryl or C 3-14 heteroaryl moiety, or —WR Q1 ; wherein W is independently O, S or NR Q3 and each occurrence of R Q1 , R Q2 and R Q3 is independently hydrogen, or a substituted or unsubstituted C 1-20 aliphatic, heteroC 1-20 aliphatic, C 3-20 alicyclic, heteroC 3-20 alicyclic, C 3-14 aryl or C 3-14 heteroaryl moiety;

Y 2 is hydrogen, or a substituted or unsubstituted C 1-20 alkyl, heteroC 1-20 alkyl, cyclo C 3-10 alkyl, heterocycloC 3-10 alkyl, C 3-14 aryl, or C 3-14 heteroaryl moiety; or —WR Y1 ;

W is O or NH; and

R Y1 and R Y2 are independently hydrogen, or a substituted or unsubstituted C 1-20 aliphatic, heteroC 1-20 aliphatic, C 3-20 alicyclic, heteroC 3-20 alicyclic, C 3-14 aryl or C 3-14 heteroaryl moiety;

wherein for the compound of formula (a), when X 1 is O and the bond  is a double bond, Q is hydrogen, halogen, —CN, —S(O) 1-2 R Q1 , —NO 2 , —COR Q1 , —CO 2 R Q1 , —NR Q1 C(═O)R Q2 , —NR Q1 C(═O)OR Q2 , —CONR Q1 R Q2 , or —WR Q1 ; wherein W is independently O, S or NR Q3 and each occurrence of R Q1 , R Q2 and R Q3 is independently hydrogen, or a substituted or unsubstituted C 1-20 aliphatic, heteroC 1-20 aliphatic, C 3-20 alicyclic, heteroC 3-20 alicyclic, C 3-14 aryl or C 3-14 heteroaryl moiety;

wherein the composition is administered at a dose corresponding to a dose in a mouse that is between about 10 mg/kg and about 20 mg/kg.

2. The method of claim 1 wherein in the composition, the compound has one of the following structures:

3. The method of claim 1 , further comprising administering a cytotoxic agent.

4. The method of claim 3 , wherein the cytotoxic agent is an anticancer agent.

5. The method of claim 1 , further comprising administering a palliative agent.

6. The method of claim 1 , wherein in the composition the compound has one of the following structures:

or pharmaceutically acceptable salt thereof.

7. The method of claim 6 , wherein in the compound of the composition R 1 and R 2 are each hydrogen.

8. The method of claim 6 , wherein in the compound of the composition R 5 and R 6 are each methyl.

9. The method of claim 6 , wherein in the compound of the composition R 3 is lower alkyl.

10. The method of claim 9 , wherein in the compound of the composition R 3 is methyl.

11. The method of claim 6 , wherein in the compound of the composition R 4 is OH.

12. The method of claim 6 , wherein in the compound of the composition Y 2 is lower alkyl and R Y1 is hydrogen or lower alkyl.

13. The method of claim 6 , wherein in the compound of the composition R Y1 is hydrogen and Y 2 is CF 3 .

14. The method of claim 6 , wherein in the composition the compound has the structure:

or a pharmaceutically acceptable salt thereof, wherein n is 3; Y 2 is lower alkyl substituted with one or more halogen atoms selected from F, Cl, Br and I, and R Y1 is hydrogen or lower alkyl.

15. The method of claim 14 , wherein R Y1 is hydrogen and Y 2 is CF 3 .

16. The method of claim 6 , wherein in the composition the compound has one of the following structures:

or a pharmaceutically acceptable salt thereof, wherein Y 2 is lower alkyl substituted with one or more halogen atoms selected from F, Cl, Br and I, and R Y1 is hydrogen or lower alkyl.

17. The method of claim 16 , wherein R Y1 is hydrogen and Y 2 is CF 3 .

18. A method for treating breast tumor metastasis in a subject comprising:

administering to a subject in need thereof a therapeutically effective amount of a composition comprising a compound having the following structure:

or a pharmaceutically acceptable salt thereof;

wherein X 1 is CH 2 , NH or O;

Y 1 and Y 2 are independently OH, C(R Y ) 3 or Y 1 and Y 2 taken together with the carbon atom to which they are attached are —C═O, wherein R Y is halo;

the bond is a single bond or a double bond;

R 6 is H or lower alkyl;

R 5 is H or lower alkyl;

R 4 is OH; and

R 3 is lower alkyl;

wherein the composition is administered at a dose corresponding to a dose in a mouse that is between about 10 mg/kg and about 20 mg/kg.