US2008193381A1PendingUtilityA1
Heterodimers of glutamic acid
Est. expiryNov 8, 2026(~0.3 yrs left)· nominal 20-yr term from priority
A61P 35/00A61P 25/00A61P 25/18A61P 25/04A61P 29/00A61P 25/28A61P 25/02A61P 21/02A61P 21/00C07C 311/19C07C 275/24C07B 59/001C07D 213/38C07C 275/16C07C 275/30C07D 213/36A61K 51/0455C07F 13/005C07F 1/005C07B 59/002A61K 39/385
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Claims
Abstract
Compounds of Formula (Ia) wherein R is a C 6 -C 12 substituted or unsubstituted aryl, a C 6 -C 12 substituted or unsubstituted heteroaryl, a C 1 -C 6 substituted or unsubstituted alkyl or —NR′R′, Q is C(O), O, NR′, S, S(O) 2 , C(O) 2 (CH2)p Y is C(O), O, NR′, S, S(O) 2 , C(O) 2 (CH2) p Z is H or C 1 -C 4 alkyl, R′ is H, C(O), S(O) 2 , C(O) 2 , a C 6 -C 12 substituted or unsubstituted aryl, a C 6 -C 12 substituted or unsubstituted heteroaryl or a C 1 -C 6 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C 6 -C 12 heteroaryl, —NR′R′ or COOZ, which have diagnostic and therapeutic properties, such as the treatment and management of prostate cancer and other diseases related to NAALADase inhibition. Radiolabels can be incorporated into the structure through a variety of prosthetic groups attached at the X amino acid side chain via a carbon or hetero atom linkage.
Claims
exact text as granted — not AI-modified1 . A compound of Formula (I)
wherein R is a C 6 -C 12 substituted or unsubstituted aryl, a C 6 -C 2 substituted or unsubstituted heteroaryl, a C 1 -C 6 substituted or unsubstituted alkyl or —NR′R′,
Q is C(O), O, NR′, S, S(O) 2 , C(O) 2 (CH2)p
Y is C(O), O, NR′, S, S(O) 2 , C(O) 2 (CH2)p
Z is H or C 1 -C 4 alkyl,
m is 0, 1, 2, 3, 4 or 5
n is 0, 1, 2, 3, 4, 5 or 6
p is 0, 1, 2, 3, 4, 5 or 6
R′ is H, C(O), S(O) 2 , C(O) 2 , a C 6 -C 12 substituted or unsubstituted aryl, a C 6 -C 12 substituted or unsubstituted heteroaryl or a C 1 -C 6 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C 6 -C 12 heteroaryl, —NR′R′ or COOZ
further wherein
(i) at least one of R or R′ is a C 6 -C 12 aryl or C 6 -C 12 heteroaryl substituted with a halogen or
(ii) at least one of R or R′ is a C 6 -C 12 heteroaryl
or a pharmaceutically acceptable salt of the compound of Formula (I).
2 . The compound of claim 1 , wherein the halogen is a radiohalogen, I-123, I-125, I-131, I-124, Br-75, Br-77, or F-18.
3 . The compound of claim 1 , wherein
n is 0 or 1 m is 0, 1, 2, 3 or 4 Q is NR′ Y is C(O) or CH 2 and R is a C 6 -C 12 substituted or substituted aryl.
4 . The compound of claim 3 , wherein R is a phenyl moiety substituted with a halogen.
5 . The compound of claim 4 , wherein the compound is:
wherein the carboxy groups of any of the above compounds can be substituted with C 1 -C 4 alkyl and
X is selected from the group consisting of halogen, radiohalogen, I-123, I-125, I-131, I-124, Br-75, Br-77, and F-18.
6 . The compound of claim 4 , wherein the compound is:
7 . The compound of claim 1 , wherein
n is 0 or 1 m is 0, 1, 2, 3 or 4 Q is NR′ Y is C(O) or CH 2 and R is a —CH 2 (CH 2 ) 1-4 CHNR′R′ and R′ is a C 1 -C 2 alkyl substituted with a pyridine or carboxy group.
8 . The compound of claim 1 , wherein the compound is
wherein the carboxy groups of any of the above compounds can be substituted with C 1 -C 4 alkyl.
9 . The compound of claim 1 , wherein
n is 0 or 1 m is 0 Q is CH 2 Y is CH 2 and R is —NR′R′ and R′ is a C 1 -C 2 alkyl substituted with a pyridine or carboxy group.
10 . The compound of claim 9 , wherein the compound is
wherein the carboxy groups of any of the above compounds can be substituted with C 1 -C 4 alkyl.
11 . A compound of claim 1 , wherein the compound is:
wherein the carboxy groups of the above compounds can be substituted with C 1 -C 4 alkyl.
12 . The compound of claim 1 , wherein the compounds is of the Formula (II):
13 . A radionuclide chelate complex comprising the compound or salt of claim 1 .
14 . The radionuclide chelate complex of claim 13 , wherein the radionuclide is an imaging radionuclide.
15 . The radionuclide chelate complex of claim 13 , wherein the radionuclide is a therapeutic radionuclide.
16 . The radionuclide chelate complex of claim 14 , wherein the radionuclide is a (technetium-99m)Tc(CO) 3 chelate complex or (rhenium-186/188)Re(CO) 3 chelate complex.
17 . The radionuclide chelate complex of claim 16 , wherein the radionuclide is
wherein the carboxy groups of any of the above compounds can be substituted with C 1 -C 4 alkyl.
18 . A glutamate-urea-lysine PSMA-binding whose IC 50 inhibition of PSMA is less than 20 nM, wherein the glutamate-urea-lysine PSMA-binding moiety is a glutamate-urea-α or β-amino acid heterodimer coupled through the α-NH 2 or β-NH 2 groups.
19 . The compound of claim 18 in which the PSMA-binding moiety and the radio-imaging moiety are conjugated via an amide, ester, amine, or ether linkage.
20 . A method of imaging one or more organs or tissues or both of a mammal comprising administering to a mammal an effective amount of a glutamate-urea-lysine PSMA-binding moiety conjugated to a radio-imaging moiety and obtaining an image of one or more organs or tissues or both of the mammal, wherein the glutamate-urea-lysine PSMA-binding moiety is a glutamate-urea-α or β-amino acid heterodimer coupled through the α-NH 2 or β-NH 2 groups.
21 . The method of claim 20 , wherein the one or more organs or tissues or both includes prostate tissue, kidney tissue, brain tissue, vascular tissue, or tumor tissue.
22 . A kit comprising: (i) compound comprising a glutamate-urea-lysine PSMA-binding moiety conjugated to a metal chelating moiety, and (ii) radionuclide.
23 . The kit of claim 21 , wherein the radionuclide is selected from technetium-99m, rhenium-186, rhenium-188 or combinations thereof.
24 . A method of staging a pathological condition associated with one or more organs or tissues or both of a mammal comprising: (i) administering to a mammal an effective amount of a compound comprising a glutamate-urea-lysine PSMA-binding moiety conjugated to a radio-imaging moiety, (ii) obtaining an image of the one or more organs or tissues or both of said mammal; (iii) determining from said image the amount of PSMA which is present in the one or more organs or tissues or both of said mammal, and (iv) utilizing the amount determined and a control amount to arrive at a stage of the pathological condition, wherein the glutamate-urea-lysine PSMA-binding moiety is a glutamate-urea-α or β-amino acid heterodimer coupled through the α-NH 2 or β-NH 2 groups.
25 . The method of claim 24 , wherein the pathological condition is selected from the group consisting of cancer, prostate cancer, angiogenesis, heart failure, cardiomyopathy, lung disease, kidney dysfunction, renal failure, inflammation, atherosclerosis, vulnerable arterial plaques or neoplasm.
26 . A method of monitoring a mammal's response to therapy for a pathological condition associated with one or more organs or tissues or both of the mammal comprising (i) administering to a mammal an effective amount of a compound comprising a glutamate-urea-lysine PSMA-binding moiety conjugated to a radio-imaging moiety, (ii) obtaining an image of the one or more organs or tissues or both of the mammal, (iii) determining from said image the amount of peptidase which is present in the one or more organs or tissues or both of the mammal, and (iv) utilizing the amount determined and a control amount to gauge the mammal's response, if any, to a therapy, wherein the glutamate-urea-lysine PSMA-binding moiety is a glutamate-urea-α or β-amino acid heterodimer coupled through the α-NH 2 or β-NH 2 groups.
27 . The method of claim 26 , wherein the control amount is obtained from an amount found in a group of normal subjects.
28 . The method of claim 26 , wherein the control amount is obtained from a baseline amount found in the one or more organs of said mammal.
29 . A method of quantifying expression of a peptidase in one or more organs or tissues or both of a mammal comprising administering to a mammal an effective amount of a compound including a peptidase-binding moiety conjugated to a radio-imaging moiety, obtaining an image of the one or more organs or tissues or both of the mammal; quantifying from the image and a series of standard images an amount of expression of the peptidase in the one or more organs or tissues or both of the mammal.
30 . A method of treating a patient with painful and sensory diabetic neuropathy, neuronal damage and prostate cancer, schizophrenia, colorectal cancer, inflammation, amyotrophic lateral schlerosis, or diabetic neuropathy comprising administering to the patient a therapeutically effective amount of a glutamate-urea-lysine PSMA-binding moiety, wherein the glutamate-urea-lysine PSMA-binding moiety is a glutamate-urea-α or β-amino acid heterodimer coupled through the α-NH 2 or β-NH 2 groups.
31 . A method of treating a patient in need of an analgesic comprising administering to the patient a therapeutically effective amount of a glutamate-urea-lysine PSMA-binding moiety, wherein the glutamate-urea-lysine PSMA-binding moiety is a glutamate-urea-α or β-amino acid heterodimer coupled through the α-NH 2 or β-NH 2 groups.
32 . A compound of Formula (Ia)
wherein R is a C 6 -C 12 substituted or unsubstituted aryl, a C 6 -C 12 substituted or unsubstituted heteroaryl, a C 1 -C 6 substituted or unsubstituted alkyl or —NR′R′,
Q is C(O), O, NR′, S, S(O) 2 , C(O) 2 (CH2)p
Y is C(O), O, NR′, S, S(O) 2 , C(O) 2 (CH2)p
Z is H or C 1 -C 4 alkyl,
m is 0, 1, 2, 3, 4 or 5
n is 0, 1, 2, 3, 4, 5 or 6
n′ is 0, 1, 2, 3, 4, 5 or 6
p is 0, 1, 2, 3, 4, 5 or 6
R′ is H, C(O), S(O) 2 , C(O) 2 , a C 6 -C 12 substituted or unsubstituted aryl, a C 6 -C 12 substituted or unsubstituted heteroaryl or a C 1 -C 6 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C 6 -C 12 heteroaryl, —NR′R′ or COOZ
further wherein
(i) at least one of R or R′ is a C 6 -C 12 aryl or C 6 -C 12 heteroaryl substituted with at least a halogen or
(ii) at least one of R or R′ is a substituted or unsubstituted C 6 -C 12 heteroaryl
or a pharmaceutically acceptable salt of the compound of Formula (I).
33 . The compound of claim 32 , wherein the halogen is a radiohalogen, I-123, I-125, I-131, I-124, Br-75, Br-77, or F-18.
34 . The compound of claim 32 , wherein
n is 0 or 1 n′ is 0 or 1 m is 0, 1, 2, 3 or 4 Q is NR′ Y is C(O) or CH 2 and R is a C 6 -C 12 substituted or substituted aryl.
35 . The compound of claim 34 , wherein R is a phenyl moiety substituted with a halogen.
36 . The compound of claim 32 , wherein
n is 0 or 1 n′ is 0 or 1 m is 0, 1, 2, 3 or 4 Q is NR′ Y is C(O) or CH 2 and R is a —CH 2 (CH 2 ) 1-4 CHNR′R′ and R′ is a C 1 -C 2 alkyl substituted with a pyridine or carboxy group.
37 . The compound of claim 36 , wherein the compound is
wherein the carboxy groups of any of the above compounds can be substituted with C 1 -C 4 alkyl.
38 . The compound of claim 32 , wherein
n is 0 or 1 n′ is 0 or 1 m is 0, 1, 2, 3 or 4 Q is CH 2 Y is CH 2 and R is —NR′R′ and R′ is a C 1 -C 2 alkyl substituted with a pyridine or carboxy group.
39 . The compound of claim 38 , wherein the compound is
wherein the carboxy groups of any of the above compounds can be substituted with C 1 -C 4 alkyl.
40 . The compound of claim 32 , wherein the compounds is of the Formula (Iia):
41 . A radionuclide chelate complex comprising the compound or salt of claim 31 .
42 . The radionuclide chelate complex of claim 44 , wherein the radionuclide is an imaging radionuclide.
43 . The radionuclide chelate complex of claim 44 , wherein the radionuclide is a therapeutic radionuclide.
44 . The radionuclide chelate complex of claim 45 , wherein the radionuclide is a (technetium-99m)Tc(CO) 3 chelate complex or (rhenium-186/188)Re(CO) 3 chelate complex.
45 . The compound of claim 1 , wherein the compound is of Formula Iib:
wherein -Y-R is selected from the group consisting of:
and H;
wherein X is selected from the group consisting of: I, Br, Cl, F, and H.
46 . The compound of claim 45 , wherein the compound is of the following structure:
wherein X is selected from the group consisting of:
47 . The compound of claim 45 , wherein the compound is of the following structure:
wherein X is selected from the group consisting of:
48 . The compound of claim 45 selected from the group consisting of:
(S)-2-(3-((S)-5-amino-1-carboxypentyl)ureido)pentanedioic acid,
(S,S)-2-{3-[1-Carboxy-5-(2-chloro-benzylamino)-pentyl]-ureido}-pentanedioic acid,
(S,S)-2-{3-[1-Carboxy-5-(3-chloro-benzylamino)-pentyl]-ureido}-pentanedioic acid,
(S,S)-2-{3-[1-Carboxy-5-(4-chloro-benzylamino)-pentyl]-ureido}-pentanedioic acid,
(S)-2-(3-((R)-5-(benzylamino)-1-carboxypentyl)ureido)pentanedioic acid,
2-(3-{1-Carboxy-5-[3-(phenyl)-ureido]-pentyl}-ureido)-pentanedioic acid,
2-(3-{1-Carboxy-5-[3-(4-bromo-phenyl)-ureido]-pentyl}-ureido)-pentanedioic acid;
2-(3-{1-Carboxy-5-[3-(4-chloro-phenyl)-ureido]-pentyl}-ureido)-pentanedioic acid;
(S)-2-(3-((R)-1-carboxy-5-(□pyridine-1-ylmethylamino)pentyl)ureido)pentanedioic acid; and
2-(3-{1-Carboxy-5-[3-(3-iodo-benzyl)-ureido]-pentyl}-ureido)-pentanedioic acid.
49 . The compound according to claim 1 , selected from the group consisting of:
50 . The compound according to claim 32 , selected from the group consisting of:
51 . A radionuclide chelate complex comprising the compound or salt of claim 45 .
52 . The radionuclide chelate complex of claim 57 , wherein the radionuclide is an imaging radionuclide.
53 . The radionuclide chelate complex of claim 57 , wherein the radionuclide is a therapeutic radionuclide.
54 . The radionuclide chelate complex of claim 51 , wherein the radionuclide is a (technetium-99m)Tc(CO) 3 chelate complex or (rhenium-186/188)Re(CO) 3 chelate complex.
55 . A compound of formula III:
wherein
L is a bond, an optionally substituted alkyl, alkenyl, or alkynyl of C 1 -C 15 , or —[(CH 2 ) q O] s —, wherein q and s are independently an integer of 1 to 10;
E is —NR′R′,
Q is C(O), O, NR′, S, S(O) 2 , C(O) 2 (CH 2 ) p
Y is C(O), O, NR′, S, S(O) 2 , C(O) 2 (CH 2 ) p
Z is H or C 1 -C 4 alkyl,
m is 0, 1, 2, 3, 4 or 5
n is 0, 1, 2, 3, 4, 5 or 6
n′ is 0, 1, 2, 3, 4, 5 or 6
p is 0, 1, 2, 3, 4, 5 or 6
R′ is independently H, C(O), S(O) 2 , C(O) 2 , a C 6 -C 12 substituted or unsubstituted aryl, a C 6 -C 12 substituted or unsubstituted heteroaryl or a C 1 -C 14 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C 6 -C 12 heteroaryl, —NR′R′ or COOZ.
or a pharmaceutically acceptable salt thereof.
56 . A radionuclide chelate complex comprising the compound or salt of claim 55 .
57 . The compound of claim 55 , wherein the compound is of the following structure:
wherein n is an integer of 0 to 9.
58 . The compound of claim 57 , wherein n is 9 and the compound is (19S,23S)-2-(4-iodobenzyl)-1-(4-iodophenyl)-13,21-dioxo-2,14,20,22-tetraazapentacosane-19,23,25-tricarboxylic acid.
59 . The compound of claim 55 , wherein the compound is of the following structure:
wherein n is 2, 4, or 8.
60 . A radionuclide chelate complex comprising the compound of claim 59 of the following structure:
wherein n is 2, 4 or 8 or a salt thereof.
61 . The radionuclide chelate complex of claim 60 of the following structure:
[Re(CO) 3 {(17R,21S)-11,19-dioxo-1-(ÿyridine-2-yl)-2-(ÿyridine-2-ylmethyl)-5,8-dioxa-2,12,18,20-tetraazatricosane-17,21,23-tricarboxylic acid}][Br];
[Re(CO) 3 {(23R,27S)-17,25-dioxo-1-(pyridin-2-yl)-2-(pyridin-2-ylmethyl)-5,8,11,14-tetraoxa-2,18,24,26-tetraazanonacosane-23,27,29-tricarboxylic acid}][Br]; and
[Re(CO) 3 {(35R,39S)-29,37-dioxo-1-(ÿyridine-2-yl)-2-(ÿyridine-2-ylmethyl)-5,8,11,14,17,20,23,26-octaoxa-2,30,36,38-tetraazahentetracontane-35,39,41-tricarboxylic acid}][Br] or a salt thereof.
62 . The compound of claim 55 of the following structure:
63 . A radionuclide chelate complex comprising a salt form of the compound of claim 62 of the following structure:
[Re(CO) 3 {(19R,23S)-13,21-dioxo-2-(ÿyridine-2-ylmethyl)-2,14,20,22-tetraazapentacosane-1,19,23,25-tetracarboxylic acid}].
64 . A radionuclide chelate complex of claim 13 , wherein the radionuclide is a radio copper.
65 . A radionuclide chelate complex of claim 41 , wherein the radionuclide is a radio copper.
66 . A radionuclide chelate complex of claim 51 , wherein the radionuclide is a radio copper.
67 . A radionuclide chelate complex comprising the compound or salt of claim 32 selected from the following structures:Join the waitlist — get patent alerts
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