PSMA-binding agents and uses thereof

Patent metadata

Field	Value
Publication number	US-12070513-B2
Application number	US-202117237850-A
Country	US
Kind code	B2
Filing date	Apr 22, 2021
Priority date	Aug 1, 2008
Publication date	Aug 27, 2024
Grant date	Aug 27, 2024

Abstract

Prostate-specific membrane antigen (PSMA) binding compounds having radioisotope substituents are described, as well as chemical precursors thereof. Compounds include pyridine containing compounds, compounds having phenylhydrazine structures, and acylated lysine compounds. The compounds allow ready incorporation of radionuclides for single photon emission computed tomography (SPECT) and positron emission tomography (PET) for imaging, for example, prostate cancer cells and angiogenesis.

First claim

We claim:

1. A composition comprising a pharmaceutically acceptable carrier and a compound having the structure

wherein
Z is tetrazole or CO 2 Q; each Q is independently selected from hydrogen or a protecting group;
and wherein
m is 0, 1, 2, 3, 4, 5, or 6;
R is a pyridine ring selected from the group consisting of

wherein X is fluorine, iodine, a radioisotope of fluorine, a radioisotope of iodine, chlorine, bromine, a radioisotope of bromine, a radioisotope of astatine, NO 2 NH 2 , N + (R 2 ) 3 , Sn(R 2 ) 3 , Si(R 2 ) 3 , Hg(R 2 ), B(OH) 2 , —NHNH 2 , —NHN═CHR 3 , —NHNH—CH 2 R 3 , n is 1, 2, 3, 4, or 5;
Y is O, S, N(R′), C(O), NR′C(O), C(O)N(R′), OC(O), C(O)(O), NR′C(O)NR′, NR′C(S)NR′, NR'S(O) 2 , S(CH 2 ) p , NR′(CH 2 )p, O(CH 2 ) p , OC(O)CHR 8 NHC(O), NHC(O) CHR 8 NHC(O), or a covalent bond; wherein p is 1, 2, or 3, R′is H or C 1 -C 6 alkyl, and R 8 is hydrogen, alkyl, aryl, or heteroaryl, each of which may be substituted;
R 2 is a C 1 -C 6 alkyl; and
R 3 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl each of which is substituted by fluorine, iodine, a radioisotope of fluorine, a radioisotope of iodine, chlorine, bromine, a radioisotope of bromine, or a radioisotope of astatine, NO 2 , NH 2 , N + (R 2 ) 3 , Sn(R 2 ) 3 , Si(R 2 ) 3 , Hg(R 2 ), or B(OH) 2 ; OR
m is 0, 1, 2, 3, 4, 5, or 6;
Y is O, S, N(R′), C(O), NR′C(O), C(O)N(R′), OC(O), C(O)(O), NR′C(O)NR′, NR′C(S)NR′, NR′, NR'S(O) 2 , S(CH 2 ) P , NR′—(CH 2 ) P , O(CH 2 ) P , OC(O)CHR 8 NHC(O), NHC(O) CHR 8 NHC(O), or a covalent bond; wherein p is 1, 2, or 3,R′ is H or C 1 -C 6 alkyl, R 8 is hydrogen, alkyl, aryl, or heteroaryl, each of which may be substituted;

R is
X′ is selected from the group consisting of NHNH 2 , —NHN═CHR 3 , —NHNH—CH 2 R 3 ; R 3 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl each of which is substituted by fluorine, iodine, a radioisotope of fluorine, a radioisotope of iodine, chlorine, bromine, a radioisotope of bromine, or a radioisotope of astatine, NO 2 , NH 2 , N + (R 2 ) 3 , Sn(R 2 ) 3 , Si(R 2 ) 3 , Hg(R 2 ), or B(OH) 2 ;
R 2 is C 1 -C 6 alkyl, n is 1, 2, 3, 4, or 5;

OR
m is 4,
Y is NR′, and

R is

wherein
G is O, NR′ or a covalent bond;
R′is H or C 1 -C 6 alkyl; p is 1, 2, 3, or 4, and
R 7 is selected from the group consisting of NH 2 , N═CHR 3 , NH—CH 2 R 3 , wherein R 3 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl each of which is substituted by fluorine, iodine, a radioisotope of fluorine, a radioisotope of iodine, chlorine, bromine, a radioisotope of bromine, or a radioisotope of astatine, NO 2 , NH 2 , N + (R 2 ) 3 , Sn(R 2 ) 3 , Si(R 2 ) 3 , Hg(R 2 ), or B(OH) 2 ; and R 2 is C 1 -C 6 alkyl.

2. A composition according to claim 1 , wherein Z is CO 2 Q.

3. A composition according to claim 1 , wherein Q is hydrogen.

4. A composition according to claim 1 , wherein m is 1, 2, 3, or 4.

5. A composition according to claim 1 , having the structure

wherein m is 0, 1, 2, 3, 4, 5, or 6;
R is a pyridine ring selected from the group consisting of

wherein X is fluorine, iodine, a radioisotope of fluorine, a radioisotope of iodine, chlorine, bromine, a radioisotope of bromine, a radioisotope of astatine NO 2 , NH 2 , N + (R 2 ) 3 , Sn(R 2 ) 3 , Si(R 2 ) 3 , Hg(R 2 ), B(OH) 2 , —NHNH 2 , —NHN═CHR 3 , —NHNH—CH 2 R 3 , each Q is independently selected from hydrogen or a protecting group;
Y is O, S, N(R′), C(O), NR′C(O), C(O)N(R′), OC(O), C(O)(O), NR′C(O)NR′, NR′C(S)NR′, NR′, NR′S(O) 2 , S(CH 2 ) p , NR′—(CH 2 ) p , O(CH 2 ) p , OC(O)CHR 8 NHC(O), NHC(O) CHR 8 NHC(O), or a covalent bond; wherein p is 1, 2, or 3, R′is H or C 1 -C 6 alkyl, and R 8 is hydrogen, alkyl, aryl, or heteroaryl, each of which may be substituted;
Z is tetrazole or CO 2 Q;
R 2 is C 1 -C 6 alkyl; and
R 3 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl each of which is substituted by fluorine, iodine, a radioisotope of fluorine, a radioisotope of iodine, chlorine, bromine, a radioisotope of bromine, or a radioisotope of astatine, NO 2 , NH 2 , N + (R 2 ) 3 , Sn(R 2 ) 3 , Si(R 2 ) 3, Hg(R 2 ), or B(OH) 2 .

6. A composition according to claim 5 , having the structure

wherein m is not 0.

7. A composition A compound according to claim 6 , whereine Z is CO 2 Q, Q is hydrogen, and m is 4.

8. A composition according to claim 5 , having the structure

wherein m is not 0.

9. A composition according to claim 8 , wherein Z is CO 2 Q, Q is hydrogen, and m is 1, 2, or 3.

10. A composition according to claim 1 , wherein m is 0, 1, 2, 3, 4, 5, or 6;
Y is O, S, N(R′), C(O), NR′C(O), C(O)N(R′), OC(O), C(O)(O), NR′C(O)NR′, NR′C(S)NR′, NR′, NR'S(O) 2 , S(CH 2 ) p , NR′—(CH 2 ) p , O(CH 2 ) p , OC(O)CHR 8 NHC(O), NHC(O) CHR 8 NHC(O), or a covalent bond; wherein p is 1, 2, or 3, R′is H or C 1 -C 6 alkyl, and R 8 is hydrogen, alkyl, aryl, or heteroaryl, each of which may be substituted;
R is

wherein X′ is selected from the group consisting of NHNH 2 , —NHN═CHR 3 , —NHNH—CH 2 R 3 wherein R 3 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl each of which is substituted by fluorine, iodine, a radioisotope of fluorine, a radioisotope of iodine, bromine, a radioisotope of bromine, or a radioisotope of astatine, NO 2 , NH 2 , N + (R 2 ) 3 , Sn(R 2 ) 3 , Si(R 2 ) 3 , Hg(R 2 ), and B(OH) 2 where R 2 is C 1 -C 6 alkyl, n is 1, 2, 3, 4, or 5.

11. A composition according to claim 1 , wherein n is 1.

12. A composition according to claim 1 , wherein X or X′is fluorine, iodine, or a radioisotope of fluorine or iodine, bromine, a radioisotope of bromine, or a radioisotope of astatine.

13. A composition according to claim 1 , wherein X or X′ is fluorine, iodine, or a radioisotope of fluorine or iodine.

14. A composition according to claim 1 , wherein m is 4, Y is NR′, and R is

wherein G is O, NR′ or a covalent bond; p is 1, 2, 3, or 4, and
R 7 is selected from the group consisting of NH 2 , N═CHR 3 , NH—CH 2 R 3 , wherein R 3 is alkyl, alkenyl, alkynyl, aryl, heteroaryl each of which is substituted by fluorine, iodine, a radioisotope of fluorine, a radioisotope of iodine, chlorine, bromine, a radioisotope of bromine, or a radioisotope of astatine, NO 2 , NH 2 , N + (R 2 ) 3 , Sn(R 2 ) 3 , Si(R 2 ) 3 , Hg(R 2 ), or B(OH), wherein R 2 is C 1 -C 6 alkyl.

15. A composition according to claim 14 , wherein G is O or NR′.

16. A composition according to claim 1 , wherein the radioisotope of fluorine is 18 F, the radioisotope of iodine is selected from the group consisting of 123 I, 124 I, 125 I, 12

Assignees

• Univ Johns Hopkins
• The Johns Hopkins Universty

Inventors

• Pomper Martin G
• Mease Ronnie Charles
• Chen Ying

Classifications

• C07C275/18

  of a saturated carbon skeleton containing rings · CPC title

• A61K51/0402

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

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C07D213/82

  in position 3 · CPC title

• C07D213/74

  Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals · CPC title