Albumin binding probes and drug conjugates thereof

Patent metadata

Field	Value
Publication number	US-9480751-B2
Application number	US-201214111347-A
Country	US
Kind code	B2
Filing date	Apr 4, 2012
Priority date	Apr 11, 2011
Publication date	Nov 1, 2016
Grant date	Nov 1, 2016

Abstract

The present invention provides a long chain fatty acid (LCFA)-like albumin-binding probe/ligand containing no hydrolysable bond and having an enhanced associating affinity with human serum albumin, which upon conjugation with an amino- or mercapto-containing short-lived drug and administration of the conjugate, significantly prolongs the life time of said drug without substantially interfering with its pharmacological activity. The invention further provides conjugates of said probe with amino- or mercapto-containing drugs, as well as pharmaceutical compositions and uses thereof.

First claim

The invention claimed is:

1. A compound of the general formula I:
HO 3 S—R 1 —R 2 —R 3 —R 4   I

wherein:
R 1 is selected from the group consisting of (C 9 -C 25 )alkylene, (C 9 -C 25 )alkenylene, and (C 9 -C 25 ) alkynylene, optionally substituted by one or more groups each independently selected from the group consisting of halogen, —COR 5 , —COOR 5 , —OCOOR 5 , —OCON(R 5 ) 2 , —NO 2 , —SR 5 , —OR 5 , —N(R 5 ) 2 , —CON(R 5 ) 2 , —SO 2 R 5 , —SO 3 H, —S(═O)R 5 , (C 6 -C 10 )aryl, (C 1 -C 4 )alkylene-(C 6 -C 10 )aryl, heteroaryl, and (C 1 -C 4 )alkylene-heteroaryl, wherein said (C 9 -C 25 )alkylene is optionally further interrupted by one or more groups each independently selected from the group consisting of —S—, —NH—CO—, —CO—NH—, —N(C 6 -C 10 aryl)-, (C 6 -C 10 )arylene-diyl, and heteroarylenediyl, and said (C 9 -C 25 )alkenylene and (C 9 -C 25 )alkynylene is optionally further interrupted by one or more groups each independently selected from the group consisting of —S—, —O—, —N—, —NH—CO—, —CO—NH—, —N(C 1 -C 8 alkyl)-, —N(C 6 -C 10 aryl)-, (C 6 -C 10 )arylene-diyl, and heteroarylenediyl;
R 2 is —CO— or —S—;
R 3 is absent or selected from the group consisting of —NH—R 6 -maleimido, and -maleimido-R 6 -maleimido;
R 4 is absent or a leaving group;
R 5 each independently is H or (C 1 -C 8 )alkyl; and
R 6 is selected from the group consisting of (C 1 -C 12 )alkylene, (C 2 -C 12 )alkenylene, and (C 2 -C 12 )alkynylene, optionally substituted by one or more groups each independently selected from the group consisting of halogen, —COR 5 , —COOR 5 , —OCOOR 5 , —OCON(R 5 ) 2 , —CN, —NO 2 , —SR 5 , —OR 5 , —N(R 5 ) 2 , —CON(R 5 ) 2 , —SO 2 R 5 , and —S(═O)R 5 , and further optionally interrupted by one or more identical or different heteroatoms selected from the group consisting of S, O and N, and/or at least one group each independently selected from the group consisting of —NH—CO—, —CO—NH—, —N(C 1 -C 8 alkyl)-, and —N(C 6 -C 10 aryl)-,
provided that (i) when R 2 is —CO—, R 3 is absent and R 4 is a leaving group, or R 3 is —NH—R 6 -maleimido and R 4 is absent; and (ii) when R 2 is —S—, R 3 is absent and R 4 is a leaving group, or R 3 is -maleimido-R 6 -maleimido and R 4 is absent.

2. The compound of claim 1 , wherein the leaving group is selected from the group consisting of —O—(CH 2 ) 2 —CN, —Cl, N-hydroxysuccinimide (—OSu), 2-nitrophenoxy, 4-nitrophenoxy, 2,3,4,5,6-pentachloro phenoxy, isoindoline-1,3-dione-2-oxy, benzenesulfanyl, nitrobenzenesulfanyl, pyridine-2-sulfanyl, pyridine-3-sulfanyl, and pyridine-4-sulfanyl.

3. The compound of claim 1 , wherein R 1 is (C 9 -C 25 )alkylene, optionally substituted by one or more groups each independently selected from the group consisting of halogen, —COH, —COOH, —OCOOH, —OCONH 2 , —CN, —NO 2 , —SH, —OH, —NH 2 , —CONH 2 , —SO 2 H, —SO 3 H, —S(═O)H, (C 1 -C 2 )alkylene-(C 6 -C 10 )aryl, and (C 1 -C 2 )alkylene-heteroaryl, and further optionally interrupted by one or more groups each independently selected from the group consisting of —S—, —NH—CO—, and —CO—NH—.

4. The compound of claim 3 , wherein R 1 is (C 10 -C 20 )alkylene, optionally substituted by one or more groups each independently is —CH 2 —(C 6 -C 10 )aryl, and further interrupted by at least one group each independently is —NH—CO—, or —CO—NH—.

5. The compound of claim 3 , wherein said (C 6 -C 10 )aryl is phenyl, hydroxyphenyl, carboxyphenyl, nitrophenyl, cianophenyl, mercaptophenyl, aminocarbonylphenyl, fluorophenyl, chlorophenyl, or bromophenyl; and said heteroaryl is 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 2-imidazolyl, 4-imidazolyl, or 5-imidazolyl.

6. The compound of claim 4 , wherein R 1 is —(CH 2 ) 10 —, —(CH 2 ) 15 —, —(CH 2 ) 10 —CO—NH—CH(CH 2 -phenyl)-, or —(CH 2 ) 15 —CO—NH—CH(CH 2 -phenyl)-.

7. The compound of claim 1 , wherein:
(i) R 2 is —CO—; R 3 is absent; and R 4 is —O—(CH) 2 —CN, —Cl, N-hydroxysuccinimide (—OSu), 2-nitrophenoxy, 4-nitrophenoxy, 2,3,4,5,6-pentachlorophenoxy, isoindoline-1,3-dione-2-oxy, benzenesulfanyl, nitrobenzenesulfanyl, pyridine-2-sulfanyl, pyridine-3-sulfanyl, or pyridine-4-sulfanyl;
(ii) R 2 is —CO—; R 3 is —NH—R 6 -maleimido; and R 4 is absent;
(iii) R 2 is —S—; R 3 is absent; and R 4 is benzenesulfanyl, nitrobenzenesulfanyl, pyridine-2-sulfanyl, pyridine-3-sulfanyl, or pyridine-4-sulfanyl, preferably pyridine-2-sulfanyl, or pyridine-4-sulfanyl; or
(iv) R 2 is —S—; R 3 is -maleimido-R 6 -maleimido; and R 4 is absent.

8. The compound of claim 7 , wherein R 6 is (C 1 -C 12 )alkylene, optionally substituted by one or more groups each independently selected from the group consisting of halogen, —COH, —COOH, —OCOOH, —OCONH 2 , —CN, —NO 2 , —SH, —OH, —NH 2 , —CONH 2 , —SO 2 H, and —S(═O)H, and further optionally interrupted by one or more identical or different heteroatoms selected from the group consisting of S, O and N, and/or at least one group each independently is —NH—CO—, or —CO—NH—.

9. The compound of claim 8 , wherein R 6 is (C 1 -C 10 )alkylene, optionally interrupted by one or more groups each independently is —NH—CO—, or —CO—NH—.

10. The compound of claim 9 , wherein R 6 is —CH 2 —, —(CH 2 ) 3 —, —(CH 2 ) 3 —NH—CO—(CH 2 ) 3 —, or —(CH 2 ) 2 —NH—CO—(CH 2 ) 5 —.

11. The compound of claim 7 , wherein (i) R 1 is —(CH 2 ) 10 —, —(CH 2 ) 15 —, —(CH 2 ) 10 —CO—NH—CH(CH 2 -phenyl)-, or —(CH 2 ) 15 —CO—NH—CH(CH 2 -phenyl)-; R 2 is —CO—; R 3 is absent; and R 4 is —Osu; (ii) R 1 is —(CH 2 ) 10 —, or —(CH 2 ) 15 —; R 2 is —CO—; R 3 is —NH—R 6 -maleimido; R 4 is absent; and R 6 is —CH 2 —, —(CH 2 ) 3 —, —(CH 2 ) 3 —NH—CO—(CH 2 ) 3 —, or —(CH 2 ) 2 —NH—CO—(CH 2 ) 5 —; or (iii) R 1 is —(CH 2 ) 15 —; R 2 is —S—; R 3 is absent; and R 4 is pyridine-2-sulfanyl, or pyridine-4-sulfanyl.

12. A conjugate of the general formula II:
HO 3 S—R 1 —R 2 —R 3 —Y  II

Y is a moiety of a drug containing at least one amino or mercapto group, linked through said at least one amino or mercapto group;
R 1 is selected from the group consisting of (C 9 -C 25 )alkylene, (C 9 -C 25 )alkenylene, and (C 9 -C 25 ) alkynylene, optionally substituted by one or more groups each independently selected from the group consisting of halogen, —COR 5 , —COOR 5 , —OCOOR 5 , —OCON(R 5 ) 2 , —CN, —NO 2 , —SR 5 , —OR 5 , —N(R 5 ) 2 , —CON(R 5 ) 2 , —SO 2 R 5 , —SO 3 H, —S(═O)R 5 , (C 6 -C 10 )aryl, (C 1 -C 4 )alkylene-(C 6 -C 10 )aryl, heteroaryl, and (C 1 -C 4 )alkylene-heteroaryl, wherein said (C 9 -C 25 )alkylene is optionally further interrupted by one or more groups each independently selected from the group consisting of —S—, —NH—CO—, —CO—NH—, —N(C 6 -C 10 aryl)-, (C 6 -C 10 )arylene-diyl, and heteroarylenediyl, and said (C 9 -C 25 )alkenylene and (C 9 -C 25 )alkynylene is optionally further interrupted by one or more groups each independently selected from the group consisting of —S—, —O—, —N—, —NH—CO—, —CO—NH—, —N(C 1 -C 8 alkyl)-, —N(C 6 -C 10 aryl)-, (C 6 -C 10 )arylene-diyl, and heteroarylenediyl;
R 2 is —CO— or —S—;
R 3 is absent or selected from the group consisting of —NH—R 6 -maleimido, and -maleimido-R 6 -maleimido;
R 5 each independently is H or (C 1 -C 8 )alkyl; and
R 6 is selected from the group consisting of (C 1 -C 12 )alkylene, (C 2 -C 12 )alkenylene, and (C 2 -C 12 )alkynylene, optionally substituted by one or more groups each independently selected from the group consisting of halogen, —COR 5 , —COOR 5 , —OCOOR 5 , —OCON(R 5 ) 2 , —CN, —NO 2 , —SR 5 , —OR 5 , —N(R 5 ) 2 , —CON(R 5 ) 2 , —SO 2 R 5 , and —S(═O)R 5 , and further optionally interrupted by one or more identical or different heteroatoms selected from the group consisting of S, O and N, and/or at least one group each ind

Assignees

• Shechter Yoram
• Fridkin Matityahu
• Yeda Res & Dev

Inventors

• Shechter Yoram
• Fridkin Matityahu

Classifications

• C07C309/17 Primary

  containing carboxyl groups bound to the carbon skeleton · CPC title

• A61K47/48038 Primary

  Human Necessities · mapped topic

• A61K38/28

  Insulins · CPC title

• A61K38/4846

  Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38) · CPC title

• C12Y304/21021

  Coagulation factor VIIa (3.4.21.21) · CPC title