Carbohydrate-mediated tumor targeting

Patent metadata

Field	Value
Publication number	US-9624255-B2
Application number	US-201013382581-A
Country	US
Kind code	B2
Filing date	May 5, 2010
Priority date	Aug 11, 2009
Publication date	Apr 18, 2017
Grant date	Apr 18, 2017

Abstract

Tumors can be selectively targeted via compounds provided herein according to the formula, or a pharmaceutically acceptable salt thereof, wherein R A and R B are as defined herein. Tumors can be imaged or targeted for therapeutic treatment using compounds described herein where at least one R A or at least one R B group comprises a imaging agent, a therapeutic agent, or a member of a specific binding pair which can be associated with a secondary imaging agent, such as a microbubble for ultrasonic imaging.

First claim

We claim:

1. A compound according to the formula,

an epimer thereof, or a pharmaceutically acceptable salt thereof, wherein
each R A is independently hydrogen, —OR 1 , —N(H)(R 1 ), or —R 4 , wherein each R 1 is independently hydrogen, a protecting group, —R 3 , —R 4 , or —R 5a , wherein
R 5a is

each R B is independently hydrogen, —OR 2 , —N(H)(R 2 ), or —R 4 , wherein each R 2 is independently hydrogen, a protecting group, —R 3 , —R 4 , or —R 5b , wherein
R 5b is

R 3 is —C(O)OR 30 , —C(O)N(H)(R 30 ), —S(O)OR 30 , —S(O) 2 OR 30 , —S(O)N(H)(R 30 ), —S(O) 2 N(H)(R 30 ), or —P(O)(OR 30 ) 2 , wherein
R 30 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, or heterocyclyl, wherein R 30 is optionally substituted with one to four groups which are each independently C 1 -C 6 alkyl, cyano, nitro,
halogen, —OR 31 , —N(R 31 ) 2 , —SR 31 , —C(O)R 31 , —C(O)OR 31 , —C(O)N(R 31 ) 2 , —OC(O)OR 31 , —OC(O)N (R 31 ) 2 , —N(R 31 )C(O)OR 31 , —N(R 31 )C(O)N(R 31 ) 2 , —S(O)R 31 , —S(O) 2 R 31 , —S(O)N(R 31 ) 2 ,
or —S(O) 2 N(R 31 ) 2 , wherein each R 31 is independently hydrogen or C 1 -C 6 alkyl;

each R 4 is independently -L-(R 40 ) q , wherein
each q is independently one or greater;
each L is independently —C 1 -C 20 alkyl-, —C 2 -C 20 alkenyl-, —C 2 -C 20 alkynyl-, -aryl-, -heteroaryl-, -heterocyclyl-, —C 3 -C 8 cycloalkyl-, an oligoalkylene glycol, an oligopeptide, a dendrimer, or -(L 1 -Y) n -L 2 -X—,
wherein Y is —O—, —S—, or —N(R Y )—, wherein R Y is hydrogen or C 1 -C 6 alkyl; n is an integer selected from 1 to 250; L 1 is —C 2 -C 6 alkyl-; L 2 is —C 1 -C 20 alkyl-, —C 2 -C 20 alkenyl-, —C 2 -C 20 alkynyl-, -aryl-, -heteroaryl-, -heterocyclyl-, —C 3 -C 8 cycloalkyl-; and X is a bond, —O—, —N(R X ), —S—, —C(O)—, —S(O)—, —S(O) 2 —, —OC(O)—, —N(R X )C(O)—,
—N(R X )S(O)—, —N(R X )S(O) 2 —, —C(O)O—, —C(O)N(R X )—, —S(O)N(R X )—, —S(O) 2 N(R X )—, —OC(O)O—, —OC(O)N(R X )—, —N(R X )C(O)O—, —N(R X )C(O)N(R X )—, or —N(R X )S(O) 2 N(R X )—, wherein each R X is independently hydrogen or C 1 -C 6 alkyl, provided that when L is a bond, then q is 1; and

each R 40 is independently an imaging agent, a member of a specific binding pair, a chemotherapeutic agent, or —R 41 , wherein
R 41 is —OH, —NH(R 42 ), —SH, —C(O)H, —C(O)OR 42 , —C(O)NH(R 42 ), —OC(O)OR 42 , —OC(O)N(R 42 ) 2 , —N(R 42 )C(O)OR 42 , —N(R 42 )C(O)N(R 42 ) 2 , —S(O)N(R 42 ) 2 , or —S(O) 2 N(R 42 ) 2 , wherein each R 42 is independently hydrogen, C 1 -C 6 alkyl, or benzyl; and

provided that
(i) no more than one R 1 is R 5a and no more than one R 2 is R 5b ;
(ii) when one R 1 group is R 5a , then R 2 is not R 5b ; and when one R 2 group is R 5b , then R 1 is not R 5a ;
(iii) no more than one R 3 group is present;
(iv) at least one R 4 is present;
(v) no more than one R A , and no more than one R B comprises R 4 ;
(vi) no more than two R A groups and no more than two R B groups are hydrogen;
(vii) R 40 is not (a) R 41 when L is a bond; and (b) bleomycin; and
(viii) the compound of formula (I) or (I′) is not bleomycin.

2. The compound of claim 1 according to the formula,

3. The compound of claim 2 , wherein one R A group is —N(H)(R 1 ); each of the remaining R A groups is —OR 1 ; and each R B is —OR 2 .

4. The compound of claim 2 , wherein one R A group is —N(H)(R 1 ); each of the remaining R A groups is —OR 1 ; and each R B is —OR 2 .

5. The compound of claim 2 , wherein one R B group is —N(H)(R 2 ); each of the remaining R B groups is —OR 2 ; and each R A is —OR 1 .

6. The compound of claim 2 , wherein one R A group is hydrogen; each of the remaining R A groups is —OR 1 ; and each R B is —OR 2 .

7. The compound of claim 2 , wherein one R B group is hydrogen; each of the remaining R B group is —OR 2 ; and each R A is —OR 1 .

8. The compound of claim 1 according to the formula,

9. The compound of claim 1 according to the formula,

10. The compound of claim 1 , wherein each R 1 and R 2 is independently a protecting group.

11. The compound of claim 1 , wherein each R 1 and R 2 is independently a protecting group, wherein each protecting group is independently —C(O)R A0 or benzyl, wherein R A0 is C 1 -C 6 alkyl, halomethyl, dihalomethyl, trihalomethyl, or C 1 -C 4 alkoxymethyl.

12. The compound of claim 1 , wherein each R 1 and R 2 is hydrogen.

13. The compound of claim 1 , wherein R 3 is —C(O)OR 30 or —C(O)N(H)(R 30 ).

14. The compound of claim 1 , wherein R 3 is —C(O)N(H)(R 30 ), wherein R 30 is hydrogen or C 1 -C 6 alkyl.

15. The compound of claim 1 , wherein R 3 is —C(O)NH 2 .

16. The compound of claim 1 , wherein q is 1.

17. The compound of claim 16 , wherein L 1 is —C 2 -C 4 alkyl-; L 2 is —C 1 -C 6 alkyl-; and X is a bond, —O—, —N(R X ), —S—, —C(O)—, —S(O)—, or —S(O) 2 —.

18. The compound of claim 17 , wherein L is —(CH 2 CH 2 —O) n —CH 2 CH 2 —X—, wherein X is —O—, —N(H), or —S— and n is an integer selected from 1 to 20.

19. The compound of claim 17 , wherein L is —(CH 2 CH 2 —O) n —CH 2 CH 2 —X—, wherein X is —C(O)— or —S(O) 2 — and n is an integer selected from 1 to 20.

20. The compound of claim 1 , wherein R 40 is —R 41 .

21. The compound of claim 1 , wherein R 40 is an imaging agent.

22. The compound of claim 1 , wherein R 40 is a fluorescent imaging agent.

23. The compound of claim 1 , wherein R 40 is an imaging agent comprising a chelating group coordinated to a radioactive imaging moiety.

24. The compound of claim 1 , wherein R 40 is a member of a specific binding pair.

25. The compound of claim 24 , wherein R 40 is a member of a specific binding pair, selected from biotin-streptavidin and biotin-avidin.

26. The compound of claim 1 , wherein R 40 is a chemotherapeutic agent.

27. The compound of claim 1 which is
(2R,3R,4S,5S,6R)-2-(acetoxymethyl)-4-(carbamoyloxy)-6-((2R,3S,4S,5R,6S)-4,5-diacetoxy-6-(acetoxymethyl)-2-(2-(2-(benzyloxycarbonylamino)ethoxy)ethoxy)tetrahydro-2H-pyran-3-yloxy)tetrahydro-2H-pyran-3,5-diyl diacetate;
(2R,3R,4S,5S,6R)-2-(acetoxymethyl)-4-(carbamoyloxy)-6-((2R,3S,4S,5R,6S)-4,5-diacetoxy-6-(acetoxymethyl)-2-(2-(2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)ethoxy)ethoxy)tetrahydro-2H-pyran-3-yloxy)tetrahydro-2H-pyran-3,5-diyl diacetate; or
(2R,3S,4S,5R,6R)-2-((2R,3S,4S,5S,6S)-4,5-dihydroxy-6-(hydroxymethyl)-2-(2-(2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)ethoxy)ethoxy)tetrahydro-2H-pyran-3-yloxy)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl carbamate,
(2R,3S,4S,5R,6R)-24(2R,3S,4S,5S,6S)-2-(2-(2-Benzyloxycarbonylaminoethoxy)ethoxy)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yloxy)-3,5-dihydroxy-6-(hy

Assignees

• Hecht Sidney
• Schmaltz Ryan
• Tsosie Krystal
• Univ Arizona

Inventors

• Hecht Sidney
• Schmaltz Ryan
• Tsosie Krystal

Classifications

• C07H13/12

  by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid · CPC title

• C07H15/26 Primary

  Acyclic or carbocyclic radicals, substituted by hetero rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/6925

  the form being a microcapsule, nanocapsule, microbubble or nanobubble · CPC title

• C07H15/18

  Acyclic radicals, substituted by carbocyclic rings · CPC title