US 10,519,160 B2Granted

Imaging agents for neural flux

AssigneeThe General Hospital Corporation

InventorsGenevieve Van de Bittner, Jacob M. Hooker

Life of this patent

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Abstract

Provided herein are radiolabeled compounds useful for non-invasive imaging techniques. An exemplary radiolabeled compound provided herein is useful as a radiotracer for positron emission tomography. The present application also provides unlabeled compounds useful in methods of treating diseases of the central nervous system or disease of the peripheral nervous system. Methods for preparing radiolabeled compounds, preparing unlabeled compounds, and diagnostic methods using labeled or unlabeled compounds are also provided.

Claims12

Dependent claims

A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:
represents a single- or double-bond;
X1 is CRA or NRB;
X2 is CRA or NRB;
wherein
one of X1 and X2 is CRA and the other is NRB;
RA is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, 4-10 membered heterocycloalkyl, —(C1-6 alkylene)-Cy2, ORa2, C(═O)Rb2, C(═O)ORb2, NRc2Rd2, C(═O)NRc2Rd2, NRc2C(═O)Rb2, NRc2C(═O)ORb2, NRc2C(═O)NRc2Rd2, NRc2S(═O)2Rb2, NRc2S(═O)2NRc2Rd2, S(O)Ra2, S(O)2Ra2, S(O)NRc2Rd2, and S(O)2NRc2Rd2, wherein the C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R4 groups;
RB is absent;
or
RB is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, 4-10 membered heterocycloalkyl, —(C1-6 alkylene)-Cy2, ORa2, C(═O)Rb2, C(═O)ORb2, NRc2Rd2, C(═O)NRc2Rd2, NRc2C(═O)Rb2, NRc2C(═O)ORb2, NRc2C(═O)NRc2Rd2, NRc2S(═O)2Rb2, NRc2S(═O)2NRc2Rd2, S(O)Ra2, S(O)2Ra2, S(O)NRc2Rd2, and S(O)2NRc2Rd2, wherein the C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R4 groups;
R1 is NRNRN′;
RN is selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl;
RN′ is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, 4-10 membered heterocycloalkyl, and —(C1-6 alkylene)-Cy1, wherein the C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R4 groups;
R2 is absent;
or
R2 is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, 4-10 membered heterocycloalkyl, —(C1-6 alkylene)-Cy2, ORa2, C(═O)Rb2, C(═O)Rb2, NRc2Rd2, C(═O)NRc2Rd2, NRc2C(═O)Rb2, NRc2C(═O)ORb2, NRc2C(═O)NRc2Rd2, NRc2S(═O)2Rb2, NRc2S(═O)2NRc2Rd2, S(O)Ra2, S(O)2Ra2, S(O)NRc2Rd2, and S(O)2NRc2Rd2, wherein the C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R4 groups;
wherein at least two of RA, RB, and R2 are independently H or absent;
R3 is selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, NRc3Rd3 and NO2, wherein the C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R4 groups;
each Ra2, Rb2, Rc2, and Rd2 is independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
Rc3 and Rd3 are each independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C(═O)ORa2, wherein the C1-6 alkyl is optionally substituted by 1, 2, 3, or 4 independently selected R4 groups;
each Cy is independently selected from the group consisting of C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 independently selected R4 groups;
each Cy1 is independently selected from the group consisting of C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 independently selected R4 groups;
each Cyt is independently selected from the group consisting of C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 independently selected R4 groups;
and
each R4 is independently selected from the group consisting of OH, SH, CN, NO2, halo, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, —(C1-6 alkoxy)-(C1-6 alkoxy), C1-6 haloalkoxy, C3-10 cycloalkyl, phenyl, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, —(C1-6 alkylene)-amino, —(C1-6 alkylene)-C1-6 alkylamino, —(C1-6 alkylene)-di(C1-6 alkyl)amino, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, —(C1-6 alkylene)-C1-6 alkyoxycarbamyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C6-10 arylcarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino;
wherein the compound of Formula (II) comprises at least one radioisotope.

23 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/326,890Filed 17 Jul 2015 · us provisional application
Priority: 18 Jul 2014
Published: US 2018/0258090 A113 Sep 2018
Granted: 31 Dec 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 473/40
Heterocyclic compounds containing purine ring systems: with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
A61K 51/0459
Having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins: having six-membered rings with two nitrogen atoms as the only ring hetero…
C07B 59/002
Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se: heterocyclic compounds
C07D 473/16
With oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6: two nitrogen atoms

Family

Application62/026,147Us provisional application · filed 18 Jul 2014
Application62/074,853Us provisional application · filed 4 Nov 2014
US 2018/0258090 A1Pre-grant publication · published 13 Sep 2018
US 10,519,160 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:
represents a single- or double-bond;
X1 is CRA or NRB;
X2 is CRA or NRB;
wherein
one of X1 and X2 is CRA and the other is NRB;
RA is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, 4-10 membered heterocycloalkyl, —(C1-6 alkylene)-Cy2, ORa2, C(═O)Rb2, C(═O)ORb2, NRc2Rd2, C(═O)NRc2Rd2, NRc2C(═O)Rb2, NRc2C(═O)ORb2, NRc2C(═O)NRc2Rd2, NRc2S(═O)2Rb2, NRc2S(═O)2NRc2Rd2, S(O)Ra2, S(O)2Ra2, S(O)NRc2Rd2, and S(O)2NRc2Rd2, wherein the C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R4 groups;
RB is absent;
or
RB is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, 4-10 membered heterocycloalkyl, —(C1-6 alkylene)-Cy2, ORa2, C(═O)Rb2, C(═O)ORb2, NRc2Rd2, C(═O)NRc2Rd2, NRc2C(═O)Rb2, NRc2C(═O)ORb2, NRc2C(═O)NRc2Rd2, NRc2S(═O)2Rb2, NRc2S(═O)2NRc2Rd2, S(O)Ra2, S(O)2Ra2, S(O)NRc2Rd2, and S(O)2NRc2Rd2, wherein the C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R4 groups;
R1 is NRNRN′;
RN is selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl;
RN′ is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, 4-10 membered heterocycloalkyl, and —(C1-6 alkylene)-Cy1, wherein the C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R4 groups;
R2 is absent;
or
R2 is selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, 4-10 membered heterocycloalkyl, —(C1-6 alkylene)-Cy2, ORa2, C(═O)Rb2, C(═O)Rb2, NRc2Rd2, C(═O)NRc2Rd2, NRc2C(═O)Rb2, NRc2C(═O)ORb2, NRc2C(═O)NRc2Rd2, NRc2S(═O)2Rb2, NRc2S(═O)2NRc2Rd2, S(O)Ra2, S(O)2Ra2, S(O)NRc2Rd2, and S(O)2NRc2Rd2, wherein the C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R4 groups;
wherein at least two of RA, RB, and R2 are independently H or absent;
R3 is selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, 4-10 membered heterocycloalkyl, halo, NRc3Rd3 and NO2, wherein the C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R4 groups;
each Ra2, Rb2, Rc2, and Rd2 is independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
Rc3 and Rd3 are each independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C(═O)ORa2, wherein the C1-6 alkyl is optionally substituted by 1, 2, 3, or 4 independently selected R4 groups;
each Cy is independently selected from the group consisting of C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 independently selected R4 groups;
each Cy1 is independently selected from the group consisting of C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 independently selected R4 groups;
each Cyt is independently selected from the group consisting of C3-10 cycloalkyl, C6-10 aryl, 4-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 independently selected R4 groups;
and
each R4 is independently selected from the group consisting of OH, SH, CN, NO2, halo, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, —(C1-6 alkoxy)-(C1-6 alkoxy), C1-6 haloalkoxy, C3-10 cycloalkyl, phenyl, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, —(C1-6 alkylene)-amino, —(C1-6 alkylene)-C1-6 alkylamino, —(C1-6 alkylene)-di(C1-6 alkyl)amino, carbamyl, C1-6 alkylcarbamyl, di(C1-6 alkyl)carbamyl, —(C1-6 alkylene)-C1-6 alkyoxycarbamyl, C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C6-10 arylcarbonyl, C1-6 alkylcarbonylamino, C1-6 alkylsulfonylamino, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6 alkyl)aminosulfonyl, aminosulfonylamino, C1-6 alkylaminosulfonylamino, di(C1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, and di(C1-6 alkyl)aminocarbonylamino;
wherein the compound of Formula (II) comprises at least one radioisotope.

23 more elements

Facts

Application

15/326,890Filed 17 Jul 2015 · us provisional application

Priority

18 Jul 2014

Published

US 2018/0258090 A113 Sep 2018

Granted

31 Dec 2019

Term ends

Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 473/40
Heterocyclic compounds containing purine ring systems: with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
A61K 51/0459
Having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins: having six-membered rings with two nitrogen atoms as the only ring hetero…
C07B 59/002
Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se: heterocyclic compounds
C07D 473/16
With oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6: two nitrogen atoms