US2005201933A1PendingUtilityA1
Macrocyclic chelants for metallopharmaceuticals
Assignee: BRISTOL MYERS SQUIBB PHARMA COPriority: Sep 13, 1999Filed: May 6, 2005Published: Sep 15, 2005
Est. expirySep 13, 2019(expired)· nominal 20-yr term from priority
Inventors:Shuang Liu
C07F 9/6584A61K 51/0482A61K 51/04C07F 9/6587
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Claims
Abstract
This invention relates to macrocyclic chelants comprised of one or two heteroatom-containing bridges, compositions containing them and their use in medicine, particularly in diagnostic imaging and radiotherapy. This invention relates especially to the use of metal chelates of the macrocyclic chelants as metallopharmaceuticals in Magnetic Resonance Imaging (MRI) and radiopharmaceuticals. This invention also relates to macrocyclic chelants as bifunctional chelating agents (BFC's) for the labeling of biologically active targeting molecules such as proteins, peptides, peptidomimetics, and non-peptide receptor ligands, with metal ions and radioisotopes.
Claims
exact text as granted — not AI-modified1 . A compound of formulae (I) or (II):
and pharmaceutically acceptable salts thereof wherein:
R 1 , R 2 , R 3 and R 4 are independently selected at each occurrence from the group: C 1 -C 10 alkyl substituted with 0-5 R 5 , C 2 -C 10 alkenyl substituted with 0-5 R 5 and aryl substituted with 0-5 R 5 ;
R 5 is independently elected at each occurrence from the group: H, C(═O)OR 18 , C 1 -C 10 alkyl substituted with 0-5 R 13 , C 2 -C 10 alkenyl substituted with 0-5 R 13 , aryl substituted with 0-5 R 13 and heterocycle substituted with 0-5 R 13 ;
X is selected from the group: BR 6 R 7 , C(═O), SiR 6 R 7 , GeR 6 R 7 , SnR 6 R 7 , NR 8 , PR 9 , P(═O)R 9 , P(═S)R 9 , AsR 9 and As(═O)R 9 ;
A is selected from the group: CH 2 , NR 10 and O;
Q 1 , Q 2 , and Q 3 are independently —(CR 11 R 12 ) n —, wherein: n is 2-5;
R 6 and R 7 are independently selected from the group: C 1 -C 10 alkyl substituted with 0-5 R 13 , C 2 -C 10 alkenyl substituted with 0-5 R 13 and aryl substituted with 0-5 R 13 ;
or alternatively, R 6 and R 7 may be taken together to form a transannular bridge, said bridge selected from the group: C 3 -C 10 alkyl substituted with 0-5 R 13 and ortho-aryl substituted with 0-3 R 13 ;
R 8 is selected from the group: OR 14 , C(═O)R 14 , S(═O) 2 R 14 and P(═O)(OR 14 );
R 9 is selected from the group: OR 14 , NR 15 R 16 and CH 2 NR 15 R 16 ;
R 10 , R 11 and R 12 are independently selected from the group: H, C 1 -C 10 alkyl substituted with 0-5 R 17 , C 2 -C 10 alkenyl substituted with 0-5 R 17 and aryl substituted with 0-3 R 17 ;
R 13 is independently selected at each occurrence from the group: H, OH, NHR 18 , C(═O)R 18 , OC(═O)R 18 , OC(═O)OR 18 , C(═O)OR 18 , C(═O)NR 2 18 , PO 3 R 2 18 , SR 18 , SOR 18 , SO 2 R 18 , NHC(═O)R 18 , NHC(═O)NHR 18 , CH 2 OR 18 , CH 3 and NHC(═S)NHR 18 ;
R 14 , R 15 and R 16 are independently selected from the group: hydrogen, C 1 -C 10 alkyl substituted with 0-5 R 13 , C 2 -C 10 alkenyl substituted with 0-5 R 13 and aryl substituted with 0-5 R 13 ;
or, alternatively, two R 14 or R 15 and R 16 may be taken together to form a transannular bridge, said bridge selected from the group: C 3 -C 10 alkyl substituted with 0-5 R 13 and ortho-aryl substituted with 0-3 R 13 ;
R 17 is independently selected at each occurrence from the group: H, OH, NHR 18 , C(═O)R 18 , OC(═O)R 18 , OC(═O)OR 18 , C(═O)OR 18 , C(═O)NR 2 18 , PO 3 R 2 18 , SR 18 , SOR 18 , SO 2 R 18 , NHC(═O)R 18 , NHC(═O)NHR 18 and NHC(═S)NHR 18 ; and
R 18 is independently selected at each occurrence from the group: H, C 1 -C 6 alkyl, benzyl and phenyl;
with the proviso that when X is P(═O)R 9 , A is not CH 2 .
2 . A compound of claim 1 , wherein:
X is selected from the group: NR 8 , PR 9 and P(═O)R 9 ; R 8 is selected from the group: OR 14 , C(═O)R 14 and S(═O) 2 R 14 ; and R 9 is CH 2 NR 15 R 16 .
3 . A compound of claim 1 , wherein:
Q 1 , Q 2 , and Q 3 are independently —(CR 11 R 12 ) n —, wherein: n is 2 or 3; R 11 and R 12 are independently selected from the group: H, C 1 -C 5 alkyl substituted with 0-3 R 17 and aryl substituted with 0-1 R 17 ; R 17 is independently selected at each occurrence from the group: H, OH, NHR 18 , C(═O)R 18 , OC(═O)R 18 , OC(═O)OR 18 , C(═O)OR 18 , C(═O)NR 2 , PO 3 R 2 , SO 2 R 18 , NHC(═O)R 18 , NHC(═O)NHR 18 and NHC(═S)NHR 18 ; and R 18 is independently selected at each occurrence from the group: H and C 1 -C 3 alkyl.
4 . A compound of claim 3 , wherein:
R 1 , R 2 , R 3 and R 4 are independently selected at each occurrence from the group: H, CH 2 COOH, CH 2 PO 3 H 2 and CH 2 -heterocycle substituted with 0-3 R 13 ; and R 13 is independently selected at each occurrence from the group: H, OH, NH 2 , COOH, PO 3 H 2 , CH 2 OH, CH 3 and SO 3 H.
5 . A radiopharmaceutical of formulae (III) or (IV):
and pharmaceutically acceptable salts thereof, wherein:
M is selected from the group: 64 Cu, 67 Cu, 67 Ga, 68 Ga, 99m Tc, 111 In 90 Y, 149 Pr, 153 Sm, 159 Gd, 166 Ho, 169 Yb, 177 Lu, 186 Re and 188 Re;
R 1 , R 2 , R 3 and R 4 are independently selected at each occurrence from: C 1 -C 10 alkyl substituted with 0-5 R 5 , C 2 -C 10 alkenyl substituted with 0-5 R 5 and aryl substituted with 0-5 R 5 ;
R 5 is independently elected at each occurrence from: H, C(═O)OR 18 , C(═O)OR 23 , C 1 -C 10 alkyl substituted with 0-5 R 13 , C 2 -C 10 alkenyl substituted with 0-5 R 13 , aryl substituted with 0-5 R 13 and heterocycle substituted with 0-5 R 13 ;
X is selected from the group: BR 6 R 7 , C(═O), SiR 6 R 7 , GeR 6 R 7 , SnR 6 R 7 , NR 8 , PR 9 , P(═O)R 9 , P(═S)R 9 , AsR 9 and As(═O)R 9 ;
A is selected from the group: CH 2 , NR 10 and O;
Q 1 , Q 2 , and Q 3 are independently —(CR 11 R 12 ) n —, wherein: n is 2-5;
R 6 and R 7 are independently selected from the group: C 1 -C 10 alkyl substituted with 0-5 R 13 , C 2 -C 10 alkenyl substituted with 0-5 R 13 and aryl substituted with 0-5 R 13 ;
or alternatively, R 6 and R 7 may be taken together to form a transannular bridge, said bridge selected from the group: C 3 -C 10 alkyl substituted with 0-5 R 13 and ortho-aryl substituted with 0-3 R 13 ;
R 8 is selected from the group: OR 23 , OR 14 , C(═O)R 14 , S(═O) 2 R 14 and P(═O)(OR 14 );
R 9 is selected from the group: OR 14 , NR 15 R 16 and CH 2 NR 15 R 16 ;
R 10 , R 11 and R 12 are independently selected from the group: H, C 1 -C 10 alkyl substituted with 0-5 R 17 , C 2 -C 10 alkenyl substituted with 0-5 R 17 and aryl substituted with 0-3 R 17 ;
R 13 is independently selected at each occurrence from the group: H, OH, OR 23 , NHR 18 , C(═O)R 18 , OC(═O)R 18 , OC(═O)OR 18 , OC(═O)OR 23 , C(═O)OR 18 , C(═O)OR 23 , C(═O)NR 2 18 , PO 3 R 2 18 , PO 3 R 18 R 23 , SR 18 , SR 23 , SOR 18 , SO 2 R 18 , SOR 23 , SO 2 R 23 , NHC(═O)R 18 , NHC(═O)NHR 18 , CH 2 OR 18 , CH 2 OR 23 , CH 3 and NHC(═S)NHR 18 ;
R 14 , R 15 and R 16 are independently selected from the group: C 1 -C 10 alkyl substituted with 0-5 R 13 , C 2 -C 10 alkenyl substituted with 0-5 R 13 and aryl substituted with 0-5 R 13 ;
or, alternatively, two R 14 or R 15 and R 16 may be taken together to form a transannular bridge, said bridge selected from the group: C 3 -C 10 alkyl substituted with 0-5 R 13 and ortho-aryl substituted with 0-3 R 13 ;
R 17 is independently selected at each occurrence from the group: H, OH, NHR 18 , C(═O)R 18 , OC(═O)R 18 , OC(═O)OR 18 , C(═O)OR 18 , C(═O)NR 2 18 , PO 3 R 2 18 , SR 18 , SOR 18 , SO 2 R 18 , NHC(═O)R 18 , NHC(═O)NHR 18 and NHC(═S)NHR 18 ;
R 18 is independently selected at each occurrence from the group: H, C 1 -C 6 alkyl, benzyl and phenyl; and
R 23 is a bond to the metal M;
with the proviso that when X is P(═O)R 9 , A is not CH 2 .
6 . A radiopharmaceutical of claim 5 , wherein:
X is selected from the group: NR 8 , PR 9 and P(═O)R 9 ; R 8 is selected from the group: OR 23 , OR 14 , C(═O)R 14 and S(═O) 2 R 14 ; and R 9 is CH 2 NR 15 R 16 .
7 . A radiopharmaceutical of claim 5 , wherein:
Q 1 , Q 2 , and Q 3 are independently —(CR 11 R 12 ) n —, wherein: n is 2 or 3; R 11 and R 12 are independently selected from the group: H, C 1 -C 5 alkyl substituted with 0-3 R 17 and aryl substituted with 0-1 R 17 ; R 17 is independently selected at each occurrence from the group: H, OH, NHR 18 , C(═O)R 18 , OC(═O)R 18 , OC(═O)OR 18 , C(═O)OR 18 , C(═O)NR 2 18 , PO 3 R 2 18 , SO 2 R 18 , NHC(═O)R 18 , NHC(═O)NHR 18 and NHC(═S)NHR 18 ; and R 18 is independently selected at each occurrence from the group: H and C 1 -C 3 alkyl.
8 . A radiopharmaceutical of claim 7 , wherein:
R 1 , R 2 , R 3 and R 4 are independently selected at each occurrence from the group: H, CH 2 COOH, CH 2 PO 3 H 2 and CH 2 -heterocycle substituted with 0-3 R 13 ; and R 13 is independently selected at each occurrence from the group: H, OR 23 , OC(═O)OR 23 , C(═O)OR 23 , PO 3 18 R 23 , SR 23 , SOR 23 , SO 2 R 23 , CH 2 OR 23 , OH, NH 2 , COOH, PO 3 H 2 , CH 2 OH, CH 3 and SO 3 H.
9 . A MRI contrast agent of the formulae (V) or (VI):
and pharmaceutically acceptable salts thereof, wherein:
M is a paramagnetic metal ion of atomic number selected from the group: 21-29, 42-44 and 58-70;
R 1 , R 2 , R 3 and R 4 are independently selected at each occurrence from: C 1 -C 10 alkyl substituted with 0-5 R 5 , C 2 -C 10 alkenyl substituted with 0-5 R 5 and aryl substituted with 0-5 R 5 ;
R 5 is independently elected at each occurrence from: H, C(═O)OR 18 , C(═O)OR 23 , C 1 -C 10 alkyl substituted with 0-5 R 13 , C 2 -C 10 alkenyl substituted with 0-5 R 13 , aryl substituted with 0-5 R 13 and heterocycle substituted with 0-5 R 13 ;
X is selected from the group: BR 6 R 7 , C(═O), SiR 6 R 7 , GeR 6 R 7 , SnR 6 R 7 , NR 8 , PR 9 , P(═O)R 9 , P(═S)R 9 , AsR 9 and As(═O)R 9 ;
A is selected from the group: CH 2 , NR 10 and O;
Q 1 , Q 2 , and Q 3 are independently —(CR 11 R 12 ) n —, wherein: n is 2-5;
R 6 and R 7 are independently selected from the group: C 1 -C 10 alkyl substituted with 0-5 R 13 , C 2 -C 10 alkenyl substituted with 0-5 R 13 and aryl substituted with 0-5 R 13 ;
or alternatively, R 6 and R 7 may be taken together to form a transannular bridge, said bridge selected from the group: C 3 -C 10 alkyl substituted with 0-5 R 13 and ortho-aryl substituted with 0-3 R 13 ;
R 8 is selected from the group: OR 23 , OR 14 , C(═O)R 14 , S(═O) 2 R 14 and P(═O)(OR 14 );
R 9 is selected from the group: OR 14 , NR 15 R 16 and CH 2 NR 15 R 16 ;
R 10 , R 11 and R 12 are independently selected from the group: H, C 1 -C 10 alkyl substituted with 0-5 R 17 , C 2 -C 10 alkenyl substituted with 0-5 R 17 and aryl substituted with 0-3 R 17 ;
R 13 is independently selected at each occurrence from the group: H, OH, OR 23 , NHR 18 , C(═O)R 18 , OC(═O)R 18 , OC(═O)OR 18 , OC(═O)OR 23 , C(═O)OR 18 , C(═O)OR 23 , C(═O)NR 2 18 , PO 3 R 2 18 , PO 3 R 18 R 23 , SR 18 , SR 23 , SOR 18 , SO 2 R 18 , SOR 23 , SO 2 R 23 , NHC(═O)R 18 , NHC(═O)NHR 18 , CH 2 OR 18 , CH 2 OR 23 , CH 2 OR 23 , CH 3 and NHC(═S)NHR 18 ;
R 14 , R 15 and R 16 are independently selected from the group: C 1 -C 10 alkyl substituted with 0-5 R 13 , C 2 -C 10 alkenyl substituted with 0-5 R 13 and aryl substituted with 0-5 R 13 ;
or, alternatively, two R 14 or R 15 and R 16 may be taken together to form a transannular bridge, said bridge selected from the group: C 3 -C 10 alkyl substituted with 0-5 R 13 and ortho-aryl substituted with 0-3 R 13 ;
R 17 is independently selected at each occurrence from the group: H, OH, NHR 18 , C(═O)R 18 , OC(═O)R 18 , OC(═O)OR 18 , C(═O)OR 18 , C(═O)NR 2 18 , PO 3 R 2 18 , SR 18 , SOR 18 , SO 2 R 18 , NHC(═O)R 18 , NHC(═O)NHR 18 and NHC(═S)NHR 18 ;
R 18 is independently selected at each occurrence from the group: H, C 1 -C 6 alkyl, benzyl and phenyl; and
R 23 is a bond to the metal M;
with the proviso that when X is P(═O)R 9 , A is not CH 2 .
10 . A MRI contrast agent of claim 9 , wherein:
X is selected from the group: NR 8 , PR 9 and P(═O)R 9 ; R 8 is selected from the group: OR 23 , OR 14 , C(═O)R 14 and S(═O) 2 R ; and R 9 is CH 2 NR 15 R 16 .
11 . A MRI contrast agent of claim 9 wherein:
Q 1 , Q 2 , and Q 3 are independently —(CR 11 R 12 ) n —, wherein: n is 2 or 3; R 11 and R 12 are independently selected from the group: H, C 1 -C 5 alkyl substituted with 0-3 R 17 and aryl substituted with 0-1 R 17 ; R 17 is independently selected at each occurrence from the group: H, OH, NHR 18 , C(═O)R 18 , OC(═O)R 18 , OC(═O)OR 18 , C(═O)OR 18 , C(═O)NR 2 18 , PO 3 R 2 18 , SO 2 R 18 , NHC(═O)R 18 , NHC(═O)NHR 18 and NHC(═S)NHR 18 ; and R 18 is independently selected at each occurrence from the group: H and C 1 -C 3 alkyl.
12 . A MRI contrast agent of claim 11 , wherein:
R 1 , R 2 , R 3 and R 4 are independently selected at each occurrence from the group: H, CH 2 COOH, CH 2 PO 3 H 2 and CH 2 -heterocycle substituted with 0-3 R 13 ; and R 13 is independently selected at each occurrence from the group: H, OR 23 , OC(═O)OR 23 , C(═O)OR 23 , PO 3 R 18 R 23 , SR 23 , SOR 23 , SO 2 R 23 , CH 2 OR 23 , OH, NH 2 , COOH, PO 3 H 2 , CH 2 OH, CH 3 and SO 3 H.
13 . A conjugate of the formula:
C h -L n -W,
and pharmaceutically acceptable salts thereof,
wherein:
C h is a chelator of formulae (VII) or (VIII):
wherein:
R 1 , R 2 , R 3 and R 4 are independently selected at each occurrence from the group: C 1 -C 10 alkyl substituted with 0-5 R 5 , C 2 -C 10 alkenyl substituted with 0-5 R 5 and aryl substituted with 0-5 R 5 ;
R 5 is independently elected at each occurrence from the group: H, C(═O)OR 18 , C 1 -C 10 alkyl substituted with 0-5 R 13 , C 2 -C 10 alkenyl substituted with 0-5 R 13 , aryl substituted with 0-5 R 13 and heterocycle substituted with 0-5 R 13 ;
X is selected from the group: BR 6 R 7 , C(═O), SiR 6 R 7 , GeR 6 R 7 , SnR 6 R 7 , NR 18 , PR 9 , P(═O)R 9 , P(═S)R 9 , AsR 9 and As(═O)R 9 ;
A is selected from the group: CH 2 , NR 10 and O;
Q 1 , Q 2 , and Q 3 are independently —(CR 11 R 12 ) n —, wherein: n is 2-5;
R 6 and R 7 are independently selected from the group: C 1 -C 10 alkyl substituted with 0-5 R 13 C 2 -C 10 alkenyl substituted with 0-5 R 13 and aryl substituted with 0-5 R 13 ;
or alternatively, R 6 and R 7 may be taken together to form a transannular bridge, said bridge selected from the group: C 3 -C 10 alkyl substituted with 0-5 R 13 and ortho-aryl substituted with 0-3 R 13 ;
R 8 is selected from the group: OR 14 , C(═O)R 14 , S(═O) 2 R 14 and P(═O)(OR 14 );
R 9 is selected from the group: OR 14 , NR 15 R 16 and CH 2 NR 15 R 16 ;
R 10 , R 11 and R 12 are independently selected from the group: H, C 1 -C 10 alkyl substituted with 0-5 R 17 , C 2 -C 10 alkenyl substituted with 0-5 R 17 and aryl substituted with 0-3 R 17 ;
R 13 is independently selected at each occurrence from the group: H, OH, NHR 18 , C(═O)R 18 , OC(═O)R 18 , OC(═O)OR 18 , C(═O)OR 18 , C(═O)NR 2 18 , PO 3 R 2 18 , SR 18 , SOR 18 , SO 2 R 18 , NHC(═O)R 18 , NHC(═O)NHR 18 , CH 2 OR 18 , CH 3 , NHC(═S)NHR 18 and a bond to L n ;
R 14 , R 15 and R 16 are independently selected from the group: hydrogen, C 1 -C 10 alkyl substituted with 0-5 R 13 C 2 -C 10 alkenyl substituted with 0-5 R 13 and aryl substituted with 0-5 R 13 ;
or, alternatively, two R 14 or R 15 and R 16 may be taken together to form a transannular bridge, said bridge selected from the group: C 3 -C 10 alkyl substituted with 0-5 R 13 and ortho-aryl substituted with 0-3 R 13 ;
R 17 is independently selected at each occurrence from the group: H, OH, NHR 18 , C(═O)R 18 , OC(═O)R 18 , OC(═O)OR 18 , C(═O)OR 18 , C(═O)NR 2 18 , PO 3 R 2 18 , SR 18 , SOR 18 , SO 2 R 18 , NHC(═O)R 18 , NHC(═O)NHR 18 , NHC(═S)NHR 18 and a bond to L n ;
R 18 is independently selected at each occurrence from the group: H, C 1 -C 6 alkyl, benzyl, phenyl and a bond to L n ;
L n is a linking group of formula:
L 1 -[Y 1 (CR 19 R 20 ) f (Z 1 ) f″ Y 2 ] f -L 2 ,
wherein:
L 1 is —[(CH 2 ) g Z 1 ] g′ —(CR 19 R 20 ) g″ —;
L 2 is —(CR 19 R 20 ) g″ -[Z 1 (CH 2 ) g ] g′ —;
g is independently 0-10;
g′ is independently 0-1;
g″ is independently 0-10;
f is independently 0-10;
f′ is independently 0-10;
f″ is independently 0-1;
Y 1 and Y 2 , at each occurrence, are independently selected from the group: a bond, O, NR 20 , C═O, C(═O)O, OC(═O)O, C(═O)NH—, C═NR 20 , S, SO, SO 2 , NHC(═O), (NH) 2 C(═O) and (NH) 2 C═S;
R 19 and R 20 are independently selected at each occurrence from the group: H, C 1 -C 10 alkyl substituted with 0-5 R 21 and alkaryl wherein the aryl is substituted with 0-5 R 21 ;
R 21 is independently selected at each occurrence from the group: NHR 22 , C(═O)R 22 , OC(═O)R 22 , OC(═O)OR 22 , C(═O)OR 22 , C(═O)NR 2 22 , —CN, SR 22 , SOR 22 , SO 2 R 22 , NHC(═O)R 22 , NHC(═O)NHR 22 , NHC(═S)NHR 22 and a bond to W;
R 22 is independently selected at each occurrence from the group: H, C 1 -C 6 alkyl, benzyl, phenyl and a bond to W; and
W is a biologically active molecule selected from the group: IIb/IIIa receptor ligands, fibrin binding peptides, leukocyte binding peptides, chemotactic peptides, somatostain analogs, selectin binding peptides, vitronectin receptor antagonists and tyrosine kinase inhibitors;
with the proviso that when X is P(═O)R 9 , A is not CH 2 .
14 . A conjugate of claim 13 , wherein:
X is selected from the group: NR 8 , PR 9 and P(═O)R 9 ; R 8 is selected from the group: OR 23 , OR 14 , C(═O)R 14 and S(═O) 2 R 14 ; R 9 is CH 2 NR 15 R 16 ; g is independently 0-5; g″ is independently 0-5; f is independently 0-5; f′ independently 0-5; Y 1 and Y 2 , at each occurrence, are independently selected from the group: a bond, O, NR 20 , C═O, C(═O)O, OC(═O)O, C(═O)NH—, SO, SO 2 , NHC(═O), (NH) 2 C(═O) and (NH) 2 C═S; and R 21 is independently selected at each occurrence from the group: NHR 22 , C(═O)R 22 , OC(═O)R 22 , OC(═O)OR 22 , C(═O)OR 22 , C(═O)NR 2 22 , SO 2 R 22 , NHC(═O)R 22 , NHC(═O)NHR 22 , NHC(═S)NHR 22 and a bond to W.
15 . A conjugate of claim 13 wherein:
Q 1 , Q 2 , and Q 3 are independently —(CR 11 R 12 ) n —, wherein: n is 2 or 3; R 11 and R 12 are independently selected from the group: H, C 1 -C 5 alkyl substituted with 0-3 R 17 and aryl substituted with 0-1 R 17 ; R 17 is independently selected at each occurrence from the group: H, OH, NHR 18 , C(═O)R 18 , OC(═O)R 18 , OC(═O)OR 18 , C(═O)OR 18 , C(═O)NR 2 18 , PO 3 R 2 18 , SO 2 R 18 , NHC(═O)R 18 , NHC(═O)NHR 18 and NHC(═S)NHR 18 ; and R 18 is independently selected at each occurrence from the group: H and C 1 -C 3 alkyl.
16 . A conjugate of claim 15 , wherein:
R 1 , R 2 , R 3 and R 4 are independently selected at each occurrence from the group: H, CH 2 COOH, CH 2 PO 3 H 2 and CH 2 -heterocycle substituted with 0-3 R 13 ; and R 13 is independently selected at each occurrence from the group: H, OH, NH 2 , COOH, PO 3 H 2 , CH 2 OH, CH 3 and SO 3 H.
17 . A radiopharmaceutical of the formula:
M-C h -L n -W,
and pharmaceutically acceptable salts thereof,
wherein,
M is selected from the group: 64 Cu, 67 Cu, 67 Ga, 68 Ga, 99m Tc, 111 In, 90 Y, 149 Pr, 153 Sm, 159 Gd, 166 Ho, 169 Yb, 177 Lu, 116 Re and 188 Re;
C h is a chelator of formulae (IX) or (X):
wherein:
R 1 , R 2 , R 3 and R 4 are independently selected at each occurrence from the group: C 1 -C 10 alkyl substituted with 0-5 R 5 , C 2 -C 10 alkenyl substituted with 0-5 R 5 and aryl substituted with 0-5 R 5 ;
R 5 is independently elected at each occurrence from the group: H, C(═O)OR 18 , C(═O)OR 23 , C 1 -C 10 alkyl substituted with 0-5 R 13 , C 2 -C 10 alkenyl substituted with 0-5 R 13 , aryl substituted with 0-5 R 13 and heterocycle substituted with 0-5 R 13 ;
X is selected from the group: BR 6 R 7 , C(═O), SiR 6 R 7 , GeR 6 R 7 , SnR 6 R 7 , NR 8 , PR 9 , P(═O)R 9 , P(═S)R 9 , AsR 9 and As(═O)R 9 ;
A is selected from the group: CH 2 , NR 10 and O;
Q 1 , Q 2 , and Q 3 are independently —(CR 11 R 12 ) n —, wherein: n is 2-5;
R 6 and R 7 are independently selected from the group: C 1 -C 10 alkyl substituted with 0-5 R 13 , C 2 -C 10 alkenyl substituted with 0-5 R 13 and aryl substituted with 0-5 R 13 ;
or alternatively, R 6 and R 7 may be taken together to form a transannular bridge, said bridge selected from the group: C 3 -C 10 alkyl substituted with 0-5 R 13 and ortho-aryl substituted with 0-3 R 13 ;
R 8 is selected from the group: OR 23 , OR 14 , C(═O)R 14 , S(═O) 2 R 14 and P(═O)(OR 14 );
R 9 is selected from the group: OR 14 , NR 15 R 16 and CH 2 NR 15 R 16 ;
R 10 , R 11 and R 12 are independently selected from the group: H, C 1 -C 10 alkyl substituted with 0-5 R 17 , C 2 -C 10 alkenyl substituted with 0-5 R 17 and aryl substituted with 0-3 R 17 ;
R 13 is independently selected at each occurrence from the group: H, OH, OR 23 , NHR 18 , C(═O)R 18 , OC(═O)OR 23 , OC(═O)R 18 , C(═O)OR 23 , OC(═O)OR 18 , C(═O)OR 18 , C(═O)NR 2 18 , PO 3 R 2 18 , PO 3 R 18 , R 23 , SR 18 , SR 23 , SOR 18 , SO 2 R 18 , SOR 23 , SO 2 R 23 , NHC(═O)R 18 , NHC(═O)NHR 18 , CH 2 OR 18 , CH 2 OR 23 , CH 3 , NHC(═S)NHR 18 and a bond to L n ;
R 14 , R 15 and R 16 are independently selected from the group: C 1 -C 10 alkyl substituted with 0-5 R 13 , C 2 -C 10 alkenyl substituted with 0-5 R 13 and aryl substituted with 0-5 R 13 ;
or, alternatively, two R 14 or R 15 and R 16 may be taken together to form a transannular bridge, said bridge selected from the group: C 3 -C 10 alkyl substituted with 0-5 R 13 and ortho-aryl substituted with 0-3 R 13 ;
R 17 is independently selected at each occurrence from the group: H, OH, NHR 18 , C(═O)R 18 , OC(═O)R 18 , OC(═O)OR 18 , C(═O)OR 18 , C(═O)NR 2 18 , PO 3 R 2 18 , SR 18 , SOR 18 , SO 2 R 18 , NHC(═O)R 18 , NHC(═O)NHR 18 , NHC(═S)NHR 18 and a bond to L n ;
R 18 is independently selected at each occurrence from the group: H, C 1 -C 6 alkyl, benzyl, phenyl and a bond to L n ;
R 23 is a bond to the metal M;
L n is a linking group of formula:
L 1 -[Y 1 (CR 19 R 20 ) f (Z 1 ) f″ Y 2 ] f -L 2 ,
wherein:
L 1 is —[(CH 2 ) g Z 1 ] g′ —(CR 19 R 20 ) g″ —;
L 2 is —(CR 19 R 20 ) g″ -[Z 1 (CH 2 ) g ] g′ —;
g is independently 0-10;
g′ is independently 0-1;
g″ is independently 0-10;
f is independently 0-10;
f′ is independently 0-10;
f″ is independently 0-1;
Y 1 and Y 2 , at each occurrence, are independently selected from the group: a bond, O, NR 20 , C═O, C(═O)O, OC(═O)O, C(═O)NH—, C═NR 20 , S, SO, SO 2 , NHC(═O), (NH) 2 C(═O) and (NH) 2 C═S;
R 19 and R 20 are independently selected at each occurrence from the group: H, C 1 -C 10 alkyl substituted with 0-5 R 21 and alkaryl wherein the aryl is substituted with 0-5 R 21 ;
R 21 is independently selected at each occurrence from the group: NHR 22 , C(═O)R 22 , OC(═O)R 22 , OC(═O)OR 22 , C(═O)OR 22 , C(═O)NR 2 22 , —CN, SR 22 , SOR 22 , SO 2 R 22 , NHC(═O)R 22 , NHC(═O)NHR 22 , NHC(═S)NHR 22 and a bond to W;
R 22 is independently selected at each occurrence from the group: H, C 1 -C 6 alkyl, benzyl, phenyl and a bond to W; and
W is a biologically active molecule selected from the group: IIb/IIIa receptor ligands, fibrin binding peptides, leukocyte binding peptides, chemotactic peptides, somatostatin analogs, selectin binding peptides, vitronectin receptor antagonists and tyrosine kinase inhibitors;
with the proviso that when X is P(═O)R 9 , A is not CH 2 .
18 . A radiopharmaceutical of claim 17 , wherein:
X is selected from the group: NR 8 , PR 9 and P(═O)R 9 ; R 8 is selected from the group: OR 23 , OR 14 , C(═O)R 14 and S(═O) 2 R 14 ; R 9 is CH 2 NR 15 R 16 ; g is independently 0-5; g″ is independently 0-5; f is independently 0-5; f′ is independently 0-5; Y 1 and Y 2 , at each occurrence, are independently selected from the group: a bond, O, NR 20 , C═O, C(═O)O, OC(═O)O, C(═O)NH—, SO, SO 2 , NHC(═O), (NH) 2 C(═O) and (NH) 2 C═S; and R 21 is independently selected at each occurrence from the group: NHR 22 , C(═O)R 22 , OC(═O)R 22 , OC(═O)OR 22 , C(═O)OR 22 , C(═O)NR 2 22 , SO 2 R 22 , NHC(═O)R 22 , NHC(═O)NHR 22 , NHC(═S)NHR 22 and a bond to W.
19 . A radiopharmaceutical of claim 17 , wherein:
Q 1 , Q 2 , and Q 3 are independently —(CR 11 R 12 ) n —, wherein: n is 2 or 3; R 11 and R 12 are independently selected from the group: H, C 1 -C 5 alkyl substituted with 0-3 R 17 and aryl substituted with 0-1 R 17 ; R 17 is independently selected at each occurrence from the group: H, OH, NHR 18 , C(═O)R 18 , OC(═O)R 18 , OC(═O)OR 18 , C(═O)OR 18 , C(═O)NR 2 18 , PO 3 R 2 18 , SO 18 , NHC(═O)R 18 , NHC(═O)NHR 18 and NHC(═S)NHR 18 ; and R 18 is independently selected at each occurrence from the group: H and C 1 -C 3 alkyl.
20 . A radiopharmaceutical of claim 19 , wherein:
R 1 , R 2 , R 3 and R 4 are independently selected at each occurrence from the group: H, CH 2 COOH, CH 2 PO 3 H 2 and CH 2 -heterocycle substituted with 0-3 R 13 ; and R 13 is independently selected at each occurrence from the group: H, OR 23 , OC(═O)OR 23 , C(═O)OR 23 , PO 3 R 18 R 23 , SR 23 , SOR 23 , SO 2 R 23 , CH 2 R 23 , OH, NH 2 , COOH, PO 3 H 2 , CH 2 OH, CH3 and SO 3 H.
21 . A MRI contrast agent of the formula:
M-C h -L n -W,
and pharmaceutically acceptable salt thereof,
wherein:
M is a paramagnetic metal ion of atomic number selected from the group: 21-29, 42-44 and 58-70;
C h is a chelator of formulae (XI) or (XII):
wherein:
R 1 , R 2 , R 3 and R 4 are independently selected at each occurrence from the group: C 1 -C 10 alkyl substituted with 0-5 R 5 , C 2 -C 10 alkenyl substituted with 0-5 R 5 and aryl substituted with 0-5 R 5 ;
R 5 is independently elected at each occurrence from the group: H, C(═O)OR 18 , C(═O)OR 23 , C 1 -C 10 alkyl substituted with 0-5 R 13 , C 2 -C 10 alkenyl substituted with 0-5 R 13 , aryl substituted with 0-5 R 13 and heterocycle substituted with 0-5 R 13 ;
X is selected from the group: BR 6 R 7 , C(═O), SiR 6 R 7 , GeR 6 R 7 , SnR 6 R 7 , NR 8 , PR 9 , P(═O)R 9 , P(═S)R 9 , AsR 9 and As(═O)R 9 ;
A is selected from the group: CH 2 , NR 10 and O;
Q 1 , Q 2 , and Q 3 are independently —(CR 11 R 12 ) n —, wherein: n is 2-5;
R 6 and R 7 are independently selected from the group: C 1 -C 10 alkyl substituted with 0-5 R 13 , C 2 -C 10 alkenyl substituted with 0-5 R 13 and aryl substituted with 0-5 R 13 ;
or alternatively, R 6 and R 7 may be taken together to form a transannular bridge, said bridge selected from the group: C 3 -C 10 alkyl substituted with 0-5 R 13 and ortho-aryl substituted with 0-3 R 13 ;
R 8 is selected from the group: OR 23 , OR 14 , C(═O)R 14 , S(═O) 2 R 14 and P(═O)(OR 14 );
R 9 is selected from the group: OR 14 , NR 15 R 16 and CH 2 NR 15 R 16 ;
R 10 , R 11 and R 12 are independently selected from the group: H, C 1 -C 10 alkyl substituted with 0-5 R 17 , C 2 -C 10 alkenyl substituted with 0-5 R 17 and aryl substituted with 0-3 R 17 ;
R 13 is independently selected at each occurrence from the group: H, OH, OR 23 , NHR 18 , C(═O)R 18 , OC(═O)R 18 , OC(═O)OR 18 , OC(═O)OR 23 , C(═O)OR 18 , C(═O)OR 23 , C(═O)NR 2 18 , PO 3 R 2 18 , PO 3 R 18 R 23 , SR 18 , SR 23 , SOR 18 , SO 2 R 18 , SOR 23 , SO 2 R 23 , NHC(═O)R 18 , NHC(═O)NHR 18 , CH 2 OR 18 , CH 2 OR 23 , CH 3 , NHC(═S)NHR 18 and a bond to L n ;
R 14 , R 15 and R 16 are independently selected from the group: C 1 -C 10 alkyl substituted with 0-5 R 13 , C 2 -C 10 alkenyl substituted with 0-5 R 13 and aryl substituted with 0-5 R 13 ;
or, alternatively, two R 14 or R 15 and R 16 may be taken together to form a transannular bridge, said bridge selected from the group: C 3 -C 10 alkyl substituted with 0-5 R 13 and ortho-aryl substituted with 0-3 R 13 ;
R 17 is independently selected at each occurrence from the group: H, OH, NHR 18 , C(═O)R 18 , OC(═O)R 18 , OC(═O)OR 18 , C(═O)OR 18 , C(═O)NR 2 18 , PO 3 R 2 18 , SR 18 , SOR 18 , SO 2 R 18 , NHC(═O)R 18 , NHC(═O)NHR 8 , NHC(═S)NHR 18 and a bond to L n ;
R 18 is independently selected at each occurrence from the group: H, C 1 -C 6 alkyl, benzyl, phenyl and a bond to L n ;
R 23 is a bond to the metal M;
L n is a linking group of formula:
L 1 -[Y 1 (CR 19 R 20 ) f (Z 1 ) f″ Y 2 ] f -L 2 ,
wherein:
L 1 is —[(CH 2 ) g Z 1 ] g′ -(CR 19 R 20 ) g″ —;
L 2 is —(CR 19 R 20 ) g″ -[Z 1 (CH 2 ) g ] g′ —;
g is independently 0-10;
g′ is independently 0-1;
g″ is independently 0-10;
f is independently 0-10;
f′ is independently 0-10;
f″ is independently 0-1;
Y 1 and Y 2 , at each occurrence, are independently selected from the group: a bond, O, NR 20 , C═O, C(═O)O, OC(═O)O, C(═O)NH—, C═NR 20 , S, SO, SO 2 , NHC(═O), (NH) 2 C(═O) and (NH) 2 C═S;
R 19 and R 20 are independently selected at each occurrence from: H, C 1 -C 10 alkyl substituted with 0-5 R 21 and alkaryl wherein the aryl is substituted with 0-5 R 21 ;
R 21 is independently selected at each occurrence from the group: NHR 22 , C(═O)R 22 , OC(═O)R 22 , OC(═O)OR 22 , C(═O)OR 22 , C(═O)NR 2 22 , —CN, SR 22 , SOR 22 , SO 2 R 22 , NHC(═O)R 22 , NHC(═O)NHR 22 , NHC(═S)NHR 22 and a bond to W;
R 22 is independently selected at each occurrence from the group: H, C 1 -C 6 alkyl, benzyl, phenyl and a bond to W; and
W is a biologically active molecule selected from the group: IIb/IIIa receptor ligands, fibrin binding peptides, leukocyte binding peptides, chemotactic peptides, somatostatin analogs, selectin binding peptides, vitronectin receptor antagonists and tyrosine kinase inhibitors
with the proviso that when X is P(═O)R 9 , A is not CH 2 .
22 . A MRI contrast agent of claim 21 , wherein:
X is selected from the group: NR 8 , PR 9 and P(═O)R 9 ; R 8 is selected from the group: OR 23 , OR 14 , C(═O)R 14 and S(═O) 2 R 14 ; R 9 is CH 2 NR 15 R 16 ; g is independently 0-5; g″ is independently 0-5; f is independently 0-5; f′ is independently 0-5; Y 1 and Y 2 , at each occurrence, are independently selected from the group: a bond, O, NR 20 , C═O, C(═O)O, OC(═O)O, C(═O)NH—, SO, SO 2 , NHC(═O), (NH) 2 C(═O) and (NH) 2 C═S; and R 21 is independently selected at each occurrence from the group selected from the group: NHR 22 , C(═O)R 22 , OC(═O)R 22 , OC(═O)OR 22 , C(═O)OR 22 , C(═O)NR 2 22 , SO 2 R 22 , NHC(═O)R 22 , NHC(═O)NHR 22 , NHC(═S)NHR 22 and a bond to W.
23 . A MRI contrast agent of claim 21 , wherein:
Q 1 , Q 2 , and Q 3 are independently —(CR 11 R 12 ) n —, wherein n: is 2 or 3; R 11 and R 12 are independently chosen from the group: H, C 1 -C 5 alkyl substituted with 0-3 R 17 and aryl substituted with 0-1 R 17 ; R 17 is independently selected at each occurrence from the group: H, OH, NHR 18 , C(═O)R 18 , OC(═O)R 18 , OC(═O)OR 18 , C(═O)OR 18 , C(═O)NR 2 18 , PO 3 R 2 18 , SO 2 R 18 , NHC(═O)R 18 , NHC(═O)NHR 18 and NHC(═S)NHR 18 ; and R 18 is independently selected at each occurrence from the group: H and C 1 -C 3 alkyl.
24 . A MRI contrast agent of claim 23 , wherein:
R 1 , R 2 , R 3 and R 4 are independently selected at each occurrence from the group: H, CH 2 COOH, CH 2 PO 3 H 2 , CH 2 -heterocycle substituted with 0-3 R 13 ; and R 13 is independently selected at each occurrence from the group: H, OR 23 , OC(═O)OR 23 , C(═O)OR 23 , PO 3 R 18 R 23 , SR 23 , SOR 23 , SO 2 R 23 , CH 2 OR 23 , OH, NH 2 , COOH, PO 3 H 2 , CH 2 OH, CH3 and SO 3 H.Join the waitlist — get patent alerts
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