Salts and prodrugs of 1-methyl-D-tryptophan

1. A crystalline form of a salt of 1-methyl-D-tryptophan.

2. The crystalline form of claim 1 , wherein the crystalline form is substantially pure.

3. The crystalline form of claim 1 , wherein the salt of 1-methyl-D-tryptophan is a salt selected from the group consisting of a PO 4 H 3 (phosphoric acid) salt, SO 4 H 2 (sulfuric acid) salt, HCl (hydrochloric acid) salt, HSO 3 CH 3 (methyl sulfonic acid) salt, C 6 H 5 SO 3 H (benzyl sulfonic acid) salt, acetic acid salt, ascorbic acid salt, aspartic acid salt, glutamic acid salt, glutaric acid salt, maleic acid salt, malonic acid salt, oxalic acid salt, succinic acid salt, fumaric acid salt, tartaric acid salt, citric acid salt, Li salt, K salt, Mg salt, and Ca salt.

4. The crystalline form of claim 1 , wherein the salt of 1-methyl-D-tryptophan is a HCl (hydrochloric acid) salt.

5. The crystalline form of claim 4 , wherein the salt is anhydrous.

6. The crystalline form of claim 4 , wherein the crystalline form is 1-methyl-D-tryptophan HCl salt Form 1.

7. The crystalline form of claim 1 , wherein the salt of 1-methyl-D-tryptophan is a PO 4 H 3 (phosphoric acid) salt or a HSO 3 CH 3 (methyl sulfonic acid) salt.

8. A pharmaceutical composition comprising the crystalline form of claim 1 .

9. The pharmaceutical composition of claim 8 , wherein the salt of 1-methyl-D-tryptophan is a HCl (hydrochloric acid) salt.

10. The pharmaceutical composition of claim 9 , wherein the salt is anhydrous.

11. The pharmaceutical composition of claim 9 , wherein the crystalline form is 1-methyl-D-tryptophan HCl salt Form 1.

12. The pharmaceutical composition of claim 8 , wherein the composition is a capsule or a tablet.

13. A method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of the crystalline form of claim 1 , wherein the cancer is selected from melanoma, colon cancer, lung cancer, or breast cancer.

14. The method of claim 13 , wherein the cancer is melanoma.

15. The method of claim 14 , wherein the wherein the salt of 1-methyl-D-tryptophan is a HCl (hydrochloric acid) salt.

16. A method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula 2:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is —OH, —OC 2-3 alkyl, —OCH 2 CH(OH)CH 2 OH, —O(CH 2 ) 2 N(CH 3 ) 2 , —OC 1-3 alkyl-R 3 , —NHC (S) HR 4 (COOH), —NHC (R) HR 4 (COOH), —OC 1-6 alkylR 6 , —OC 1-2 alkyl-C (S) H(NH 2 )(COOH), or —OC 1-2 alkyl-C (R) H(NH 2 )(COOH);

R 2 is H, —C(O)C (S) H(NH 2 )R 4 , —C(O)C (R) H(NH 2 )R 4 , —C(O)CH 2 C (S) H(NH 2 ), —C(O)OCH 3 , —C(O)OR 5 , or —C(O)NHR 5 ;

R 3 is tetrahydropyran or

R 4 is H, —C 1-5 alkyl, —(CH 2 ) 1-2 SH, C 1-5 alkylSC 1-5 alkyl, C 1-5 alkylOC 1-5 alkyl, —CH 2 —R 6 , —CH 2 OH, —CH(OH)CH 3 , —(CH 2 ) 1-2 C(O)NH 2 , —(CH 2 ) 1-3 C(O)OH, —(CH 2 ) 1-4 NH 2 , or —(CH 2 ) 1-3 NC(═NH 2 )NH 2 ;

C (S) and C (R) are carbons with the S or R stereochemistry, respectively, when R 4 is not H;

R 5 is H, C 1-6 alkylR 6 , or R 6 ;

R 6 is H, aryl, alkylaryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, alkylaryl, heteroaryl, cycloalkyl or heterocycloalkyl is optionally substituted with one, two or three R 7 groups;

each R 7 is independently halogen, cyano, nitro, —OR, —N(R) 2 , —SR, —C(O)OR, C 1-6 alkyl, C 1-6 haloalkyl, —C(O)N(R) 2 , —C(O)R, —S(O)R, —S(O)OR, —S(O)N(R) 2 , —S(O) 2 R, —S(O) 2 OR, —S(O) 2 N(R) 2 , —OC(O)R, —OC(O)OR, —OC(O)N(R) 2 , —N(R)C(O)R, —N(R)C(O)OR, or —N(R)C(O)N(R) 2 , wherein R is H or C 1-4 alkyl;

with the proviso that R 1 cannot be OH when R 2 is H, and the compound cannot be N α -tert-butoxycarbonyl-1-methyl-D-tryptophan, ethyl N α -benzyl-1-methyl-D-tryptophanate, or benzyl N α -(tert-butoxycarbonyl)-1-methyl-D-tryptophanate; and

wherein the cancer is selected from melanoma, colon cancer, lung cancer, or breast cancer.

17. The method of claim 16 , wherein:

R 1 is —OH, —OC 2-3 alkyl, —OCH 2 CH(OH)CH 2 OH, —O(CH 2 ) 2 N(CH 3 ) 2 , or —OC 1-3 alkyl-R 3 ;

R 2 is H or —C(O)C (S) H(NH 2 )R 4 ;

R 3 is tetrahydropyran, or

R 4 is —CH 2 CH(CH 3 ) 2 , —(CH 2 ) 2 SCH 3 , —C (S) H(CH 3 )CH 2 CH 3 , —CH 2 —R 6 , (CH 2 ) 2 C(O)NH 2 , —(CH 2 ) 3 C(O)OH, or —(CH 2 ) 4 NH 2 ;

C (S) is a carbon with the S stereochemistry;

R 6 is phenyl; and

with the proviso that R 1 cannot be OH when R 2 is H.

18. The method of claim 16 , wherein:

R 1 is —OC 2-3 alkyl or —OCH 2 CH(OH)CH 2 OH;

R 2 is H or —C(O)C (S) H(NH 2 )R 4 ;

R 4 is —CH 2 CH(CH 3 ) 2 , —(CH 2 ) 2 SCH 3 or —(CH 2 ) 2 C(O)NH 2 ;

C (S) is a carbon with the S stereochemistry; and

with the proviso that R 1 cannot be —OH when R 2 is H.

19. The method of claim 16 , wherein the compound of Formula 2 is selected from:

ethyl N α -(L-leucyl)-1-methyl-D-tryptophanate;

ethyl N α -(L-methionyl)-1-methyl-D-tryptophanate;

2,3-dihydroxypropyl 1-methyl-D-tryptophanate;

N α -(L-leucyl)-1-methyl-D-tryptophan;

N α -(L-methionyl)-1-methyl-D-tryptophan;

ethyl N α -(L-isoleucyl)-1-methyl-D-tryptophanate;

N α -(L-glycyl)-1-methyl-D-tryptophan;

(S)-5-amino-6-(((R)-1-carboxy-2-(1-methyl-1H-indol-3-yl)ethyl)amino)-6-oxohexanoic acid;

N α -(L-lysyl)-1-methyl-D-tryptophan;

N α -(L-phenylalanyl)-1-methyl-D-tryptophan;

ethyl N α -(L-glutaminyl)-1-methyl-D-tryptophanate;

2-(dimethylamino)ethyl 1-methyl-D-tryptophanate;

(2-ethoxy-2-oxido-1,3,2-dioxaphospholan-4-yl)methyl 1-methyl-D-tryptophanate;

2-(tetrahydro-2H-pyran-4-yl)ethyl 1-methyl-D-tryptophanate;

ethyl 1-methyl-D-tryptophanate; or

isopropyl 1-methyl-D-tryptophanate;

or a pharmaceutically acceptable salt thereof.

20. The method of claim 16 , wherein the compound of Formula 2 is ethyl N α -(L-leucyl)-1-methyl-D-tryptophan or a pharmaceutically acceptable salt thereof.

21. The method of claim 20 , wherein the compound is ethyl N α -(L-leucyl)-1-methyl-D-tryptophan HCl salt.

22. The method of claim 16 , wherein the cancer is melanoma.

23. An HCl salt of 1-methyl-D-tryptophan.

24. The salt of claim 23 , wherein the salt is anhydrous.

25. A pharmaceutical composition comprising the salt of claim 23 .

26. A method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of the salt of claim 23 , wherein the cancer is selected from melanoma, colon cancer, lung cancer, or breast cancer.

27. The method of claim 26 , wherein the cancer is melanoma.