18/19F-labelled compounds which target the prostate specific membrane antigen

Patent metadata

Field	Value
Publication number	US-10882871-B2
Application number	US-201716068992-A
Country	US
Kind code	B2
Filing date	Jan 10, 2017
Priority date	Jan 10, 2016
Publication date	Jan 5, 2021
Grant date	Jan 5, 2021

Abstract

This disclosure relates to novel compounds comprising a zwitterionic trifluoroborate prosthetic group which target prostate-specific membrane antigen (PSMA), e.g. in prostate cancer. The compounds have Formula I, wherein each R1 is an anionic group, L is a linker and R2B-F3 is —N(R 3 ) 2 CH 2 BF 3 , a pyridinium group substituted with BF 3 or methyl BF 3 , or an azole group substituted with methyl BF3. Methods and uses of imaging and treating PSMA-expressing cancers are also disclosed.

First claim

What is claimed is:

1. A compound, the compound having Formula I or being a salt or solvate of Formula I

wherein:
each R 1 is independently CO 2 H, PO 3 H 2 , SO 2 H, SO 3 H, SO 4 H or OPO 3 H 2 ;
R 2 BF 3 :
is —N(R 3 ) 2 CH 2 BF 3 wherein each R 3 is independently: H, methyl, X 2 -X 15 akyl, X 2 -X 15 heteroalkyl, X 3 -X 15 aryl or X 3 -X 15 heteroaryl; wherein the X 2 -X 15 akyl or the X 2 -X 15 heteroalkyl is one or more of: branched or linear; acyclic, cyclic or multi-cyclic; saturated or unsaturated; and optionally substituted with one or more of halide, amide, oxo, hydroxyl, thiol, phosphate and sulfate; wherein the X 3 -X 15 aryl or the X 3 -X 15 heteroaryl is one or more of: cyclic or multi-cyclic; aromatic or nonaromatic; and optionally substituted with one or more of halide, amide, oxo, hydroxyl, thiol, phosphate and sulfate; wherein each X is independently C, N, O, P, S or Se; and wherein the N in the —N(R 3 ) 2 CH 2 BF 3 is linked to the X 2 -X 15 akyl, the X 2 -X 15 heteroalkyl, the X 3 -X 15 aryl or the X 3 -X 15 heteroaryl through at least two C atoms in the X 2 -X 15 akyl, the X 2 -X 15 heteroalkyl, the X 3 -X 15 aryl or the X 3 -X 15 heteroaryl;
forms a pyridinium group that is C-substituted with —B − F 3 or N-substituted with CH 2 B − F 3 , and which is optionally substituted with one or more halogens, methyl groups, aryl groups, branched or linear alkyl groups, hydroxyls, esters, thiols, thioethers, amines, ketones, carboxaldehyde, carboxylates, carboxamides, nitriles, monohalomethyl groups, dihalomethyl groups and trihalomethyl groups; or

forms:

in which R is alkyl or aryl;

in which R is alkyl or aryl;

wherein the azole ring is optionally further substituted with one or more halogens, alkyls, ketones, carboxaldehyde, carboxylates, carboxamides, nitriles, monohalomethyl groups, dihalomethyl groups and trihalomethyl groups; and
L is ether, ester, thioether, disulfide, thioester, amide, carbamate, ureido, phosphodiester, polyethylene glycol (PEG), peptide, polypeptide or R 4 R 5 R 6 in which R 4 , R 5 and R 6 together form X 1 -X 100 alkyl, X 1 -X 100 heteroalkyl, X 3 -X 100 aryl or X 3 -X 100 heteroaryl, wherein the X 1 -X 100 alkyl or the X 1 -X 100 heteroalkyl of R 4 R 5 R 6 is one or more of: branched or linear; acyclic, cyclic or multi-cyclic; saturated or unsaturated; and optionally substituted with one or more of halide, amide, oxo, hydroxyl, thiol, phosphate and sulfate; wherein the X 3 -X 15 aryl or the X 3 -X 15 heteroaryl is one or more of: cyclic or multi-cyclic; aromatic or nonaromatic; and optionally substituted with one or more of halide, amide, oxo, hydroxyl, thiol, phosphate and sulfate; and wherein each X is independently C, N, O, P, S or Se.

2. The compound of claim 1 , having Formula II or a salt or solvate thereof

3. The compound of claim 1 , wherein R 1 is CO 2 H.

4. The compound of claim 1 , wherein R 2 BF 3 forms

in which R in the pyridine substituted —OR, —SR, —NHR, —NR— or —NR 2 is aryl or branched or linear alkyl, and in which the pyridinium ring is optionally further substituted with one or more of halogens, aryls, branched or linear alkyls, ketones, carboxaldehydes, carboxylates, carboxamides, nitriles, monohalomethyl groups, dihalomethyl groups and trihalomethyl groups.

5. The compound of claim 1 , wherein R 2 BF 3 forms

in which R in the pyridine substituted —OR, —SR, —NR— or —NR 2 is aryl or branched or linear alkyl, and in which the pyridinium ring is optionally further substituted with one or more of halogens, aryls, branched or linear alkyls, ketones, carboxaldehydes, carboxylates, carboxamides, nitriles, monohalomethyl groups, dihalomethyl groups and trihalomethyl groups.

6. The compound of claim 1 ,
wherein R 2 BF 3 is

7. The compound of claim 1 , wherein R 4 is absent, —CH 2 —, —CH 2 CH 2 — or —CH 2 CH 2 CH 2 .

8. The compound claim 1 , wherein R 5 is —S—, —NHC(O)—, —C(O)—, —C(O)O— or —OC(O)—.

9. The compound of claim 1 , wherein R 6 is (phenyl)CH 2 R 7 , (pyridyl)CH 2 R 7 , or

wherein R 7 is absent or

wherein R 8 is a an aliphatic or aromatic hydrophobic side chain of a natural or artificial amino acid, and wherein R 9 is an X 1 -X 30 alkyl or X 1 -X 30 heteroalkyl that is one or more of: branched or linear; acyclic, cyclic or multi-cyclic; saturated or unsaturated; and optionally substituted with one or more of halide, amide, oxo, hydroxyl, thiol, phosphate and sulfate; wherein each X is independently C, N, O, P, S or Se.

10. The compound of claim 9 , wherein R 6 is

11. The compound of claim 9 , wherein R 8 is:

which is unsubstituted or substituted with one or more of halogen, nitro, carboxy, carboxamide, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, thiol, thioether or cyano groups at any or multiple positions on the ring.

12. A compound, which:

or a salt or solvate thereof.

13. The compound of claim 1 , in which at least one fluorine in the —BF 3 moiety is 18 F.

14. A method of imaging prostate specific membrane antigen (PSMA)-expressing cancer in a subject, the method comprising:
administering to the subject a composition comprising the compound of claim 13 and a pharmaceutically acceptable excipient; and
imaging tissue of the subject using positron emission tomography (PET).

15. A method of treating prostate specific membrane antigen (PSMA)-expressing cancer in a subject, the method comprising: administering to the subject a composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

16. The method of claim 14 , wherein the cancer is prostate cancer, renal cancer, breast cancer, thyroid cancer, gastric cancer, colorectal cancer, bladder cancer, pancreatic cancer, lung cancer, liver cancer, brain tumor, melanoma, neur

Assignees

• British Columbia Cancer Agency Branch
• Univ British Columbia

Inventors

• Benard Francois
• Lin Kuo-Shyan
• Perrin David
• Liu Zhibo
• Kuo Hsiou-Ting
• Pan Jinhe
• Roxin Aron
• Lepage Mathieu

Classifications

• A61K51/0497 Primary

  conjugates with a carrier being an organic compounds · CPC title

• C07F5/003

  without C-Metal linkages · CPC title

• A61K51/0402

  carboxylic acid carriers, fatty acids (amino acids A61K51/0406) · CPC title

• C07B59/004

  Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium · CPC title

• A61K51/0453

  having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole · CPC title