Nuclear imaging and radiotherapeutics agents targeting carbonic anhydrase IX and uses thereof

Patent metadata

Field	Value
Publication number	US-10857246-B2
Application number	US-201615578473-A
Country	US
Kind code	B2
Filing date	Jun 1, 2016
Priority date	Jun 1, 2015
Publication date	Dec 8, 2020
Grant date	Dec 8, 2020

Abstract

Highly potent and selective radionuclide-based imaging and therapy agents targeting carbonic anhydrase IX with minimum non-specific organ uptake are disclosed. Methods of imaging and/or treating carbonic anhydrase IX-expressing cells or tumors also are disclosed.

First claim

That which is claimed:

1. A compound of formula (I):

wherein:
B is a metal chelating moiety optionally comprising a metal or a radiometal, or a halogenated or radio-halogenated prosthetic group;
L 1 , L 2 , L 3 , and L 4 are —C 1 -C 24 alkyl-, wherein each alkyl group is optionally substituted with one to four groups selected from the group consisting of ═O, ═S, and —COOR and one to six of the methylene groups in each alkyl group is optionally replaced by —O—, —S—, or —(NR′)—, provided that no two adjacent methylene groups are both replaced by —O—, —S—, or —(NR′)—;
each R and R′ is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 12 aryl, and C 4 -C 16 alkyl aryl;
Tz is a triazole group selected from the group consisting of

S is a sulfonamide selected from the group consisting of:

each R 1 is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl;
each R 2 is selected from the group consisting of hydrogen, halogen, hydroxyl, alkoxyl, —CN, —CF 3 , substituted or unsubstituted amine, nitro, sulfonyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkylaryl substituted or unsubstituted arylalkyl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heteroalkylaryl, and substituted or unsubstituted naphthyl, substituted or unsubstituted biphenyl;
m is an integer selected from the group consisting of 1, 2, 3, and 4;
n is an integer selected from the group consisting of 1, 2, and 3;
each Z 1 is independently selected from the group consisting of CR 3 , and N;
each Z 2 is independently selected from the group consisting of CR 3 , and S;
each R 3 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkoxyl, —CN, —CF 3 , amino, nitro, sulfonyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkylaryl substituted or unsubstituted arylalkyl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heteroalkylaryl, and substituted or unsubstituted naphthyl, substituted or unsubstituted biphenyl;
A is

R 4 is independently selected from the group consisting of hydrogen, hydroxyl, alkoxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, and substituted or unsubstituted alkynyl;
R 5 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkoxyl, —CN, —CF 3 , substituted or unsubstituted amine, nitro, sulfonyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkylaryl substituted or unsubstituted arylalkyl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heteroalkylaryl, and substituted or unsubstituted naphthyl, substituted or unsubstituted biphenyl;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (II):

wherein:
p is an integer selected from the group consisting of 0, 1, 2, 3, and 4;
q is an integer selected from the group consisting of 1, 2, 3, and 4;
each R 6 is independently selected from the group consisting of H and COOR;
wherein R is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 6 -C 12 aryl, and C 4 -C 16 alkyl aryl
or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , wherein the compound of formula (II) is a compound of formula (III):

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein S is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein B is a metal chelating moiety optionally comprising a metal or a radiometal selected from the group of:

or wherein B is a halogenated or radio-halogenated prosthetic group selected from the group consisting of:

wherein:
X is a halogen or a radio-halogen;
n is an integer selected from the group consisting of 1, 2, 3, 4, 5 and 6;
t is an integer selected from the group consisting of 1, 2, and 3;
Z 1 is independently selected from the group consisting of CR 3 , and N;
each R 3 and R 7 is selected from the group consisting of hydrogen, halogen, hydroxyl, alkoxyl, —CN, —CF 3 , substituted or unsubstituted amine, nitro, sulfonyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkylaryl substituted or unsubstituted arylalkyl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heteroalkylaryl, and substituted or unsubstituted naphthyl, substituted or unsubstituted biphenyl;
or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 , wherein the metal chelating agent comprises a metal selected from the group consisting of: Y, Lu, Tc, Zr, In, Sm, Re, Cu, Pb, Ac, Bi, Al, Ga, Re, Ho and Sc.

7. The compound of claim 5 , wherein the metal is a radiometal and is selected from the group consisting of: 67 Ga, 68 Ga, 64 Cu, 67 Cu, Al- 18 F, 86 Y, 90 Y, 89 Zr, 111 In, 99m Tc, 177 Lu, 153 Sm, 186 Re, 188 Re, 203 Pb, 212 Pb, 225 Ac, 212 Bi, 213 Bi, 47 Sc, and 166 Ho.

8. The compound of claim 5 , wherein the halogen is selected from the group consisting of: F, Br, I, and At.

9. The compound of claim 5 , wherein the radio-halogen is selected from the group consisting of: 18 F, 76 Br, 77 Br, 80m Br, 125 I, 124 I, 131 I, and 211 At.

10. The compound of claim 1 , wherein the compound of formula (I) is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , wherein the compound of formula (I) is selected from the group consisting of:

Assignees

• Univ Johns Hopkins

Inventors

• Yang Xing
• Minn Il
• Rowe Steven
• Ray Sangeeta
• Mease Ronnie C
• Gorin Michael
• Allaf Mohamad
• Pomper Martin G

Classifications

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K51/0497 Primary

  conjugates with a carrier being an organic compounds · CPC title