Sugar-linker-drug conjugates

Patent metadata

Field	Value
Publication number	US-9919055-B2
Application number	US-201414776396-A
Country	US
Kind code	B2
Filing date	Mar 14, 2014
Priority date	Mar 15, 2013
Publication date	Mar 20, 2018
Grant date	Mar 20, 2018

Abstract

The present disclosure relates to sugar-linker-drug conjugates, of the formula [A-B-]n-L-D, wherein A is a saccharide; B is a spacer, n is an integer selected from 1 to 3; L is a linker group and D is a drug having a chemically reactive functional group selected from the group consisting of a primary or secondary amine, hydroxyl, sulfhydryl, carboxyl, aldehyde and ketone. Pharmaceutical compositions comprising the conjugates and methods of using them are also provided.

First claim

What is claimed is:

1. A sugar-linker-drug conjugate of formula (I)

or a pharmaceutically acceptable salt thereof,
wherein A is:

R 1 is selected from the group consisting of H, OH, SH, NH 2 , OR 4 , OC(O)R 4 , OC(O)NHR 4 , OC(O)NR 4 R 5 , OC(S)NHR 4 , OC(S)NR 4 R 5 , SC(O)NHR 4 , SC(O)NR 4 R 5 , NHC(O)NHR 4 , NHC(O)NR 4 R 5 , NHC(S)NHR 4 , NHC(S)NR 4 R 5 , NHC(N)NHR 4 , NHC(N)NR 4 R 5 , OCH 2 C(O)NHR 4 , OCH 2 C(O)NR 4 R 5 , OCH 2 C(S)NHR 4 , OCH 2 C(S)NR 4 R 5 , SCH 2 C(O)NHR 4 , SCH 2 C(O)NR 4 R 5 , NHCH 2 C(O)NHR 4 , NHCH 2 C(O)NR 4 R 5 , NHCH 2 C(S)NHR 4 and NHCH 2 C(S)NR 4 R 5 ;
each R 4 is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl;
each R 5 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 2 -C 6 alkynyl;

R 2 is selected from the group consisting of H, OH, SH, NH 2 , OR 4 , OC(O)R 4 , OC(O)NHR 4 , OC(O)NR 4 R 5 , OC(S)NHR 4 , OC(S)NR 4 R 5 , SC(O)NHR 4 , SC(O)NR 4 R 5 , NHC(O)NHR 4 , NHC(O)NR 4 R 5 , NHC(S)NHR 4 , NHC(S)NR 4 R 5 , NHC(N)NHR 4 , NHC(N)NR 4 R 5 , OCH 2 C(O)NHR 4 , OCH 2 C(O)NR 4 R 5 , OCH 2 C(S)NHR 4 , OCH 2 C(S)NR 4 R 5 , SCH 2 C(O)NHR 4 , SCH 2 C(O)NR 4 R 5 , NHCH 2 C(O)NHR 4 , NHCH 2 C(O)NR 4 R 5 , NHCH 2 C(S)NHR 4 and NHCH 2 C(S)NR 4 R 5 ;
R 3 is selected from the group consisting of H, OH, SH, NH 2 , OR 4 , OC(O)R 4 , OC(O)NHR 4 , OC(O)NR 4 R 5 , OC(S)NHR 4 , OC(S)NR 4 R 5 , SC(O)NHR 4 , SC(O)NR 4 R 5 , NHC(O)NHR 4 , NHC(O)NR 4 R 5 , NHC(S)NHR 4 , NHC(S)NR 4 R 5 , NHC(N)NHR 4 , NHC(N)NR 4 R 5 , OCH 2 C(O)NHR 4 , OCH 2 C(O)NR 4 R 5 , OCH 2 C(S)NHR 4 , OCH 2 C(S)NR 4 R 5 , SCH 2 C(O)NHR 4 , SCH 2 C(O)NR 4 R 5 , NHCH 2 C(O)NHR 4 , NHCH 2 C(O)NR 4 R 5 , NHCH 2 C(S)NHR 4 and NHCH 2 C(S)NR 4 R 5 ;
R′ is selected from the group consisting of H, OH and NHR 4 ;
B is X-(L 1 -Y) m -L 2 -Z,
wherein X is CH 2 or O;
L 1 is C 2 -C 6 alkyl;
Y is O, S, or NR y , wherein R y is hydrogen or C 1 -C 6 alkyl;
m is an integer selected from 1 to 10;
L 2 is C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, aryl, heteroaryl, heterocyclyl, C 3 -C 5 cycloalkyl; and
Z is absent, O, NR 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;

n is an integer selected from 1 to 3;
L is (E-L 3 -F-L 4 ) p -G,
wherein each E is bond, O, NR 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 );
each L 3 is C 2 -C 6 alkyl;
each F is bond, O, NR 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 );
each L 4 is C 0 -C 6 alkyl;
p is 1 or 2; and
G is a bond, O, NR 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 ); and

D is a Drug Unit selected from the group consisting of mitomycin-C, mitomycin-A, daunorubicin, doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, aminopterin, actinomycin, bleomycin, 9-amino camptothecin, N8-acetyl spermidine, 1-(2 chloroethyl)-1,2-dimethanesulfonyl hydrazide, tallysomycin, methotrexate, amsacrin, cis-platin, mercaptopurine, etoposide, camptothecin, taxol, esperamicin, 1,8-dihydroxy-bicyclo[7.3.1]trideca-4,9-diene-2,6-diyne-13-one, anguidine, doxorubicin, morpholino-doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, vincristine, vinblastine, bleomycin, teniposide, podophyllotoxin, esperamicin, 6-mercaptopurine, methotrexate, camptothecin (ring-opened form of the lactone), butyric acid, retinoic acid, nitrogen mustard drugs, chlorambucil, melphalan, cinnamaldehyde, inosine dialdehyde, diglycoaldehyde, anthracycline and epothilone.

2. The conjugate according to claim 1 , wherein A is

3. The conjugate according to claim 1 , wherein A is selected from the group consisting of:

4. The conjugate according to claim 1 , wherein R 1 is selected from the group consisting of H, OH, OR 4 , OC(O)R 4 , NHC(N)NHR 4 , NHC(N)NR 4 R 5 , OC(O)R 4 , OCONHR 4 , and OCONR 4 R 5 .

5. The conjugate according to claim 1 , wherein R 2 is selected from the group consisting of H, OH, OR 4 , OC(O)R 4 ,NHC(N)NHR 4 , NHC(N)NR 4 R 5 , OC(O)R 4 , OCONHR 4 , OCONR 4 R 5 , OCSNHR 4 , NHCONHR 4 , OCH 2 CONHR 4 , and OCH 2 CONR 4 R 5 .

6. The conjugate according to claim 1 , wherein R 3 is selected from the group consisting of H, OH, OR 4 , OC(O)R 4 ,NHC(N)NHR 4 , NHC(N)NR 4 R 5 , OC(O)R 4 , and OCONHR 4 .

7. The conjugate according to claim 1 , wherein R′ is H or OH.

8. The conjugate according to claim 1 , wherein each R 4 is selected from the group consisting of H, methyl and ethyl.

9. The conjugate according to claim 1 , wherein each R 5 is selected from the group consisting of methyl, ethyl, and isobutyl.

10. The conjugate according to claim 1 , wherein A is selected from the group consisting of:

11. The conjugate according to claim 1 , wherein E is NR x or C(O);
L 3 is C 4 -C 6 alkyl;
L 4 is C 0 -C 2 alkyl;
p is 1 or 2;
F is a bond, NR x , N(R x )C(O), OC(O), C(O)O or C(O)N(R x ); and
G is O, S, C(O) or NR x .

12. The conjugate according to claim 1 , wherein D is a drug selected from the group consisting of a cytotoxic drug, a cytostatic drug, antiproliferative drug, antitumor agent, an inhibitor of a cellular metabolic event and is an enzyme or protein inhibitor.

13. A pharmaceutical composition comprising a conjugate of formula (I) according to claim 1 , and a pharmaceutically acceptable carrier.

14. A method of treating cancer in a patient comprising administering to a patient in need thereof a conjugate according to claim 1 , or a pharmaceutical composition according to claim 13 .

15. A method of reducing the toxic side effects of administering a drug to treat cancer, comprising administering to a patient an effective amount of a conjugate according to claim 1 , or a pharmaceutical composition according to claim 13 .

16. A conjugate represented by formula:

17. A conjugate represented by formula:

or a pharmaceutically acceptable salt thereof.

Assignees

• Hecht Sidney
• Paul Rakesh
• Tang Chenhong
• Madathil Manikandadas Mathilakathu
• Bhattacharya Chandrabali
• Univ Arizona State

Inventors

• Hecht Sidney
• Paul Rakesh
• Tang Chenhong
• Madathil Manikandadas Mathilakathu
• Bhattacharya Chandrabali

Classifications

• A61K31/4745

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K47/549 Primary

  Sugars, nucleosides, nucleotides or nucleic acids · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/7042 Primary

  Compounds having saccharide radicals and heterocyclic rings · CPC title