Quinone reductase 2 inhibitors for use as neuroprotective agents

Abstract

According to some embodiments, provided herein is a method for treating acute neurological injury in a subject in need thereof, comprising administering to the subject a compound of Formula I or Formula II. Also provided is a method for treating vascular dementia in a subject in need thereof, comprising administering to the subject a compound of Formula I or Formula II. Further provided is a method for treating CNS lupus in a subject in need thereof, comprising administering to the subject a compound of Formula I or Formula II.

Description

[Background Technology]

[0001] Aminoquinolines, the prototypes of which are chloroquine (CQ) and hydroxychloroquine (HQ), are quinone reductase 2 (QR2) inhibitors originally developed to treat malaria but have since been found to have therapeutic efficacy in other indications, including autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), among others. Singer et al., “Update on immunosuppressive therapy,” Curr. Opin. Rheumatol. 1998, 10:169-173; Wallace, “The use of chloroquine and hydroxychloroquine for non-infectious conditions other than rheumatoid arthritis or lupus: a crucial review,” Lupus 1996, 5 Suppl 1:S59-64. In SLE and RA, aminoquinolines are the mainstay of first-line therapy, often in combination with other drugs. Aminoquinolines not only improve the signs and symptoms of SLE and RA, but also have beneficial effects on lipid metabolism and reduce the incidence of thrombosis. Similar benefits have been observed in patients with inflammatory or erosive osteoarthritis. They have also been shown to be effective as adjuvant therapy for graft-versus-host disease, cancer, and HIV.Savarino et al.,“Effects of chloroquine on viral infections:an old drug against today’s diseases?” Lancet Infect.Dis.2003,3(11):722-7;Savarino et al.,“Risks and benefits of chloroquine use in anticancer strategies,”Lancet Oncol.2006,7(10):792-3;Sotelo et al.,“Adding chloroquine to conventional treatment for glioblastoma multiforme:a randomized,double-blind,placebo-controlled trial,”Ann.Intern.Med.2006,144(5):337-43。

[0002] The neuroprotective potential of chloroquine (CQ) has been investigated in preclinical models of stroke, excitotoxicity, and traumatic injury, but the therapeutic mechanism remains elusive. CQ dramatically limits microglia and PMN migration to the brain injury site, reduces reactive astrogliosis and angiogenesis, and reduces infarct volume by 60% in a permanent MCA occlusion model. Giulian et al., "The role of mononuclear phagocytes in wound healing after traumatic injury to adult mammalian brain," J. Neurosci. 1989, 9:4416-4429; Ivanova et al., "Cerebral ischemia enhances polyamine oxidation: identification of enzymatically formed 3-aminopropanal as an endogenous mediator of neuronal and glial cell death," J. Exp. Med. 1998, 188:327-340. CQ also reduces cytokine production in microglial cells in vitro in response to various stimuli. Giulian, “Microglia and the immune pathology of Alzheimer's disease,” Am. J. Hum. Genet. 1999, 65:13-18.

[0003] Because some malaria are resistant to CQ, derivative compounds are also being explored. For example, US2006 / 0074105 to Ware et al. describes certain quinoline and quinazoline derivatives that may be useful in the treatment of malaria and autoimmune diseases.

[0004] CQ and HQ are often used clinically as first-line therapies for autoimmune disorders, but their effectiveness is limited by severe side effects. The most significant and well-characterized toxicity is retinal, and unless dosing is limited, long-term use can lead to "target maculopathy" and blindness. Cardiac toxicity, although rare, can also occur, manifesting as cardiomyopathy associated with conduction disturbances (e.g., bundle branch block) and / or congestive heart failure. Electron microscopy of cardiac and retinal biopsies after long-term CQ or HQ therapy reveals pathognomonic cytoplasmic inclusions, understood to be a direct result of high drug accumulation in lysosomes (and melanosomes in the retina and skin). Notably, CQ can accumulate to mM concentrations in skin, retinal, kidney, and liver cells during therapeutic dosing, while maintaining plasma concentrations below 1 μM.

[0005] In particular, there remains a need to develop additional aminoquinoline quinone reductase 2 (QR2) inhibitors that also have reduced lysosomal accumulation to reduce toxicity. Summary of the Invention

[0006] According to some embodiments, there is provided a method of treating acute nerve injury in a subject in need thereof, comprising administering to the subject a compound of Formula I: JPEG0007805620000001.jpg47170 (In the formula, W is N or N + O - and; X is CR 14 or N; R1 is H or trifluoromethyl; R2 is NR7R8, OR 11 , S.R. 12 or alkyl; R3 is H or OR 13 and; R4 is H or methoxy; R5 is H, Cl, or trifluoromethyl; R6 is H, NR9R 10or trifluoromethyl; R7 is H or C 1~5 C optionally substituted with alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heteroaryl, alkenyl, alkynyl, amido, alkoxy, alkylamino, alkylhydroxy, halo, hydroxyl, carboxylate, alkylcarboxylate, acyl azide, sulfonamido, or alkylhalo; 1~5 alkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, heterocyclo, aryl, heteroaryl, ureido, thioureido, alkenyl, alkynyl, amido, amino, alkoxy, alkylamino, alkylphosphonate, alkylnitrile, alkylhalo, or alkylhalo; R8 is H or C 1~5 C optionally substituted with alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heteroaryl, alkenyl, alkynyl, amido, alkoxy, alkylhydroxy, halo, hydroxyl, carboxylate, alkylcarboxylate, acyl azide, sulfonamido, or alkylhalo; 1~5 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ureido, thioureido, alkenyl, alkynyl, amido, amino, alkoxy, alkylamino, alkylphosphonate, alkylnitrile, alkylhalo, or alkylhalo; R9 is H, O, or C 1~5 C optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or alkylamino; 1~5 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylamino, alkylnitrile, or alkylphosphonate; R 10 is H, O, or C 1~5 C optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or alkylamino; 1~5alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylamino, alkylnitrile, or alkylphosphonate; R 11 is alkyl, aryl, or heteroaryl optionally substituted with alkyl, haloalkyl, aryl, or heteroaryl; R 12 is alkyl, aryl, or heteroaryl optionally substituted with alkyl, haloalkyl, aryl, or heteroaryl; R 13 is alkyl or aryl optionally substituted with alkyl or haloalkyl; R 14 is H or aryl) or a pharmaceutically acceptable salt or prodrug thereof.

[0007] In some embodiments, W is N. In some embodiments, X is CR 14 In some embodiments, R1 is H. In some embodiments, R2 is NR7R8. In some embodiments, R3 is H. In some embodiments, R4 is H. In some embodiments, R5 is Cl. In some embodiments, R6 is H. In some embodiments, R7 is H. In some embodiments, R8 is a C substituted with heteroaryl. 1~5 In some embodiments, R 14 is H.

[0008] In some embodiments, the compound has a positive logD value at about pH 4-5.

[0009] In some embodiments, the compound has formula I(a): JPEG0007805620000002.jpg45170 (wherein R7 and R8 are each independently H or C 1~5alkyl, 1~5 Alkyl can be cycloalkyl, heterocycloalkyl, heterocyclo, aryl, or heteroaryl (each of which can be optionally substituted with any suitable substituent, e.g., C 1~5 and optionally substituted with alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heteroaryl, alkenyl, alkynyl, amido, alkoxy, alkylamino, alkylhydroxy, halo, hydroxyl, carboxylate, alkylcarboxylate, acyl azide, sulfonamido, or alkylhalo. is a compound of

[0010] In some embodiments, one of R7 and R8 is hydrogen and the other is C 1~5 alkyl, 1~5 Alkyl can be cycloalkyl, heterocycloalkyl, heterocyclo, aryl, or heteroaryl (each of which can be optionally substituted with any suitable substituent, e.g., C 1~5 and optionally substituted with alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heteroaryl, alkenyl, alkynyl, amido, alkoxy, alkylamino, alkylhydroxy, halo, hydroxyl, carboxylate, alkylcarboxylate, acyl azide, sulfonamido, or alkylhalo.

[0011] In some embodiments, the compound has a positive logD value at about pH 4-5.

[0012] 1. A method of treating acute nerve injury in a subject in need thereof, comprising administering to the subject a compound of formula II: JPEG0007805620000003.jpg39170 wherein R' is selected from the group consisting of pyridin-2-ylmethyl, pyridin-3-ylmethyl, 1-benzylpiperidin-4-yl, 4-cyano-2,2-diethylbutyl, 2-chlorocyclopentyl, 4-(diethylamino)butan-2-yl, 1-(furan-2-yl)ethyl, 1-cyclopropylethyl, 1-ethylpiperidin-4-yl, 5-amino-2,2-diethylpentyl, and 2-(diethylphosphoryl)-1-methylethyl. or a pharmaceutically acceptable salt or prodrug thereof.

[0013] In some embodiments, the compound has a positive logD value at about pH 4-5.

[0014] In some embodiments, the acute neurological injury comprises traumatic brain injury. In some embodiments, the acute neurological injury comprises subarachnoid hemorrhage. In some embodiments, the acute neurological injury comprises postoperative cognitive impairment. In some embodiments, the acute neurological injury comprises hypoxic brain injury. In some embodiments, the acute neurological injury comprises ischemic brain injury.

[0015] Also provided is an active compound taught herein for use in a method for treating acute neurological injury. Further provided is a use of an active compound taught herein for preparing a medicament for treating acute neurological injury. In some embodiments, the acute neurological injury comprises traumatic brain injury. In some embodiments, the acute neurological injury comprises subarachnoid hemorrhage. In some embodiments, the acute neurological injury comprises postoperative cognitive impairment. In some embodiments, the acute neurological injury comprises hypoxic brain injury. In some embodiments, the acute neurological injury comprises ischemic brain injury.

[0016] 1. A method of treating vascular dementia in a subject in need thereof, comprising administering to the subject a compound of Formula I: JPEG0007805620000004.jpg47170 (In the formula, W is N or N + O - and; X is CR14 or N; R1 is H or trifluoromethyl; R2 is NR7R8, OR 11 , S.R. 12 or alkyl; R3 is H or OR 13 and; R4 is H or methoxy; R5 is H, Cl, or trifluoromethyl; R6 is H, NR9R 10 or trifluoromethyl; R7 is H or C 1~5 C optionally substituted with alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heteroaryl, alkenyl, alkynyl, amido, alkoxy, alkylamino, alkylhydroxy, halo, hydroxyl, carboxylate, alkylcarboxylate, acyl azide, sulfonamido, or alkylhalo; 1~5 alkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclo, heteroaryl, ureido, thioureido, alkenyl, alkynyl, amido, amino, alkoxy, alkylamino, alkylphosphonate, alkylnitrile, alkylhalo, or alkylhalo; R8 is H or C 1~5 C optionally substituted with alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heteroaryl, alkenyl, alkynyl, amido, alkoxy, alkylhydroxy, halo, hydroxyl, carboxylate, alkylcarboxylate, acyl azide, sulfonamido, or alkylhalo; 1~5 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ureido, thioureido, alkenyl, alkynyl, amido, amino, alkoxy, alkylamino, alkylphosphonate, alkylnitrile, alkylhalo, or alkylhalo; R9 is H, O, or C 1~5C optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or alkylamino; 1~5 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylamino, alkylnitrile, or alkylphosphonate; R 10 is H, O, or C 1~5 C optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or alkylamino; 1~5 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylamino, alkylnitrile, or alkylphosphonate; R 11 is alkyl, aryl, or heteroaryl optionally substituted with alkyl, haloalkyl, aryl, or heteroaryl; R 12 is alkyl, aryl, or heteroaryl optionally substituted with alkyl, haloalkyl, aryl, or heteroaryl; R 13 is alkyl or aryl optionally substituted with alkyl or haloalkyl; R 14 is H or aryl) or a pharmaceutically acceptable salt or prodrug thereof.

[0017] In some embodiments, W is N. In some embodiments, X is CR 14 In some embodiments, R1 is H. In some embodiments, R2 is NR7R8. In some embodiments, R3 is H. In some embodiments, R4 is H. In some embodiments, R5 is Cl. In some embodiments, R6 is H. In some embodiments, R7 is H. In some embodiments, R8 is a C substituted with heteroaryl. 1~5 In some embodiments, R14 is H.

[0018] In some embodiments, the compound has a positive logD value at about pH 4-5.

[0019] In some embodiments, the compound has formula I(a): JPEG0007805620000005.jpg45170 (wherein R7 and R8 are each independently H or C 1~5 alkyl, 1~5 Alkyl can be cycloalkyl, heterocycloalkyl, heterocyclo, aryl, or heteroaryl (each of which can be optionally substituted with any suitable substituent, e.g., C 1~5 and optionally substituted with alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heteroaryl, alkenyl, alkynyl, amido, alkoxy, alkylamino, alkylhydroxy, halo, hydroxyl, carboxylate, alkylcarboxylate, acyl azide, sulfonamido, or alkylhalo. is a compound of

[0020] In some embodiments, one of R7 and R8 is hydrogen and the other is C 1~5 alkyl, 1~5 Alkyl can be cycloalkyl, heterocycloalkyl, heterocyclo, aryl, or heteroaryl (each of which can be optionally substituted with any suitable substituent, e.g., C 1~5 and optionally substituted with alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heteroaryl, alkenyl, alkynyl, amido, alkoxy, alkylamino, alkylhydroxy, halo, hydroxyl, carboxylate, alkylcarboxylate, acyl azide, sulfonamido, or alkylhalo.

[0021] In some embodiments, the compound has a positive logD value at about pH 4-5.

[0022] 1. A method of treating vascular dementia in a subject in need thereof, comprising administering to the subject a compound of Formula II: JPEG0007805620000006.jpg40170 wherein R' is selected from the group consisting of pyridin-2-ylmethyl, pyridin-3-ylmethyl, 1-benzylpiperidin-4-yl, 4-cyano-2,2-diethylbutyl, 2-chlorocyclopentyl, 4-(diethylamino)butan-2-yl, 1-(furan-2-yl)ethyl, 1-cyclopropylethyl, 1-ethylpiperidin-4-yl, 5-amino-2,2-diethylpentyl, and 2-(diethylphosphoryl)-1-methylethyl. or a pharmaceutically acceptable salt or prodrug thereof.

[0023] In some embodiments, the compound has a positive logD value at about pH 4-5.

[0024] Also provided is the use of an active compound taught herein for use in a method for treating vascular dementia. Further provided is the use of an active compound taught herein for the preparation of a medicament for treating vascular dementia.

[0025] 1. A method of treating CNS lupus in a subject in need thereof, comprising administering to the subject a compound of Formula I: JPEG0007805620000007.jpg47170 (In the formula, W is N or N + O - and; X is CR 14 or N; R1 is H or trifluoromethyl; R2 is NR7R8, OR 11 , S.R. 12 or alkyl; R3 is H or OR 13 and; R4 is H or methoxy; R5 is H, Cl, or trifluoromethyl; R6 is H, NR9R 10 or trifluoromethyl; R7 is H or C 1~5 C optionally substituted with alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heteroaryl, alkenyl, alkynyl, amido, alkoxy, alkylamino, alkylhydroxy, halo, hydroxyl, carboxylate, alkylcarboxylate, acyl azide, sulfonamido, or alkylhalo; 1~5 alkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, heterocyclo, aryl, heteroaryl, ureido, thioureido, alkenyl, alkynyl, amido, amino, alkoxy, alkylamino, alkylphosphonate, alkylnitrile, alkylhalo, or alkylhalo; R8 is H or C 1~5 C optionally substituted with alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heteroaryl, alkenyl, alkynyl, amido, alkoxy, alkylhydroxy, halo, hydroxyl, carboxylate, alkylcarboxylate, acyl azide, sulfonamido, or alkylhalo; 1~5 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ureido, thioureido, alkenyl, alkynyl, amido, amino, alkoxy, alkylamino, alkylphosphonate, alkylnitrile, alkylhalo, or alkylhalo; R9 is H, O, or C 1~5 C optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or alkylamino; 1~5 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylamino, alkylnitrile, or alkylphosphonate; R 10 is H, O, or C1~5 C optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or alkylamino; 1~5 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylamino, alkylnitrile, or alkylphosphonate; R 11 is alkyl, aryl, or heteroaryl optionally substituted with alkyl, haloalkyl, aryl, or heteroaryl; R 12 is alkyl, aryl, or heteroaryl optionally substituted with alkyl, haloalkyl, aryl, or heteroaryl; R 13 is alkyl or aryl optionally substituted with alkyl or haloalkyl; R 14 is H or aryl) or a pharmaceutically acceptable salt or prodrug thereof.

[0026] In some embodiments, W is N. In some embodiments, X is CR 14 In some embodiments, R1 is H. In some embodiments, R2 is NR7R8. In some embodiments, R3 is H. In some embodiments, R4 is H. In some embodiments, R6 is H. In some embodiments, R7 is H. In some embodiments, R8 is a C substituted with heteroaryl. 1~5 In some embodiments, R 14 is H.

[0027] In some embodiments, the compound has a positive logD value at about pH 4-5.

[0028] In some embodiments, the compound has formula I(a): JPEG0007805620000008.jpg44170 (wherein R7 and R8 are each independently H or C 1~5 alkyl, 1~5 Alkyl can be cycloalkyl, heterocycloalkyl, heterocyclo, aryl, or heteroaryl (each of which can be optionally substituted with any suitable substituent, e.g., C 1~5 and optionally substituted with alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heteroaryl, alkenyl, alkynyl, amido, alkoxy, alkylamino, alkylhydroxy, halo, hydroxyl, carboxylate, alkylcarboxylate, acyl azide, sulfonamido, or alkylhalo. is a compound of

[0029] In some embodiments, one of R7 and R8 is hydrogen and the other is C 1~5 alkyl, 1~5 Alkyl can be cycloalkyl, heterocycloalkyl, heterocyclo, aryl, or heteroaryl (each of which can be optionally substituted with any suitable substituent, e.g., C 1~5 and optionally substituted with alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heteroaryl, alkenyl, alkynyl, amido, alkoxy, alkylamino, alkylhydroxy, halo, hydroxyl, carboxylate, alkylcarboxylate, acyl azide, sulfonamido, or alkylhalo.

[0030] In some embodiments, the compound has a positive logD value at about pH 4-5.

[0031] 1. A method of treating CNS lupus in a subject in need thereof, comprising administering to the subject a compound of Formula II: JPEG0007805620000009.jpg39170 wherein R' is selected from the group consisting of pyridin-2-ylmethyl, pyridin-3-ylmethyl, 1-benzylpiperidin-4-yl, 4-cyano-2,2-diethylbutyl, 2-chlorocyclopentyl, 4-(diethylamino)butan-2-yl, 1-(furan-2-yl)ethyl, 1-cyclopropylethyl, 1-ethylpiperidin-4-yl, 5-amino-2,2-diethylpentyl, and 2-(diethylphosphoryl)-1-methylethyl. or a pharmaceutically acceptable salt or prodrug thereof.

[0032] In some embodiments, the compound has a positive logD value at about pH 4-5.

[0033] Also provided is the use of the active compounds taught herein for use in a method for treating CNS lupus. Further provided is the use of the active compounds taught herein for the preparation of a medicament for treating CNS lupus. [Brief explanation of the drawings]

[0034] [Figure 1A] The log D graph for chloroquine is shown. The shaded area represents the likely range of lysosomal pH reached in vivo. At lysosomal pH, the log D of both chloroquine and hydroxychloroquine is substantially negative, reflecting the accumulated charge of these molecules and their loss of membrane permeability. [Figure 1B] The log D graph for hydroxychloroquine is shown. The shaded area represents the likely range of lysosomal pH reached in vivo. At lysosomal pH, the log D of both chloroquine and hydroxychloroquine is substantially negative, reflecting the accumulated charge of these molecules and their loss of membrane permeability. [Figure 2A] Figure 1 shows the logD graph for Example Compound A. Note that for Example Compound A, the logD value remains positive at lysosomal pH (pH 4-5). [Figure 2B]Figure 1 shows the logD graph for Example Compound B. Note that for Example Compound B, the logD value remains positive at lysosomal pH (pH 4-5). [Figure 2C] Figure 1 shows the logD graph for Example Compound C. Note that for Example Compound C, the logD value remains positive at lysosomal pH (pH 4-5). [Figure 2D] Figure 1 shows the logD graph for Example Compound D. Note that for Example Compound D, the logD value remains positive at lysosomal pH (pH 4-5). [Figure 2E] Figure 1 shows the logD graph for Example Compound E. Note that for Example Compound E, the logD value remains positive at lysosomal pH (pH 4-5). [Figure 3A] Diffusion-weighted magnetic resonance imaging (DW-MRI) images of transient middle cerebral artery occlusion (MCAO) infarct evolution in mice at 4 hours (left) and 24 hours (right). [Figure 3B] Neurological scores (left) and rotarod assessment (right) with chloroquine (CQ) versus vehicle after MCAO are provided. [Figure 3C] Cortical (left) and subcortical infarct volumes after 3 days are shown in comparison to Example Compound E (7C-4MAQ), chloroquine (CQ), QRII null mice, QRII null mouse littermates, and vehicle. [Figure 4] Results of rotarod (left) and Morris water maze (right) performance after TBI are shown comparing Example Compound E (7C-4MAQ) with chloroquine (CQ) and vehicle. [Figure 5] T2-weighted and susceptibility-weighted images (SWI) of hemorrhage in the right basal ganglia of an intracranial hemorrhage model are shown. [Figure 6]Neuronal apoptosis after deep hypothermic circulatory arrest (DHCA) is shown. TUNEL analysis in the cortex and hippocampus 48 hours after DHCA in rats treated with CQ (25 mg / kg, horizontally shaded bars), PBS (equal volume, black bars), the QR2 inhibitor 7C-4MAQ (25 mg / kg, vertically shaded bars), or vehicle (50% DMSO, open bars). [Figure 7] Acid fuchsin-celestin blue staining in the cortex and hippocampus 48 hours after DHCA in rats treated with CQ (25 mg / kg, horizontally shaded bars), PBS (equal volume, black bars), the QR2 inhibitor 7C-4MAQ (25 mg / kg, vertically shaded bars), or vehicle (50% DMSO, open bars) shows neuronal necrosis after DHCA. [Figure 8] Neurological outcomes analyzed by neuroscore on postoperative days (POD) 1 and 2 are shown in rats treated with the QR2 inhibitor 7C-4MAQ (25 mg / kg, open bars) or 50% DMSO (filled bars) 2 h before CPOB / DHCA. [Figure 9] Whole-brain perfusion measured by MRI ADC-perfusion is shown. (A) ADC-perfusion intensity comparing sham-operated mice with a pooled group of all mice with BCAS on days 3 and 32. 100% perfusion was defined as the mean ADC-perfusion intensity for the sham-operated group. On day 3, perfusion in BCAS mice (n = 17) was significantly lower than that in sham-operated mice (n = 5) (**p < 0.01), but by day 32, perfusion had returned to normal levels. (B) Representative colorized ADC-perfusion MR sequence overlaid on a grayscale coronal T2-weighted sequence 3 days after BCAS surgery. Note the increased perfusion (increased ADC-perfusion signal intensity) in the sham-operated brain compared to the other treatment groups. (C) ADC-perfusion on days 3 and 32 by treatment group. On day 3, perfusion in the sham-operated group (n = 5) was significantly higher than in all other groups (p < 0.05, group effect; sham × N-MCQ, n = 4, p < 0.01; sham × CQ, n = 5, p < 0.01; sham × vehicle, n = 9, p < 0.05). Values ​​represent mean ± SEM. *p < 0.05, **p < 0.01. [Figure 10] Morris water maze (MWM) learning performance is shown. A, Escape latency. Mice (n = 10) administered 7C-4MAQ ("N-MCQ") showed reduced escape latency compared to vehicle controls (vehicle, n = 10; p < 0.05, group effect; p < 0.01, N-MCQ x vehicle) and were indistinguishable from sham-operated mice (sham, n = 14). After MWM testing on day 5, making the submerged platform visible eliminated all differences between groups. B, Escape latency. Animals administered CQ (n = 10) had a performance profile similar to their N-MCQ counterparts (p < 0.05, group effect; p < 0.001, CQ x vehicle). C, Probe test. Mice treated with N-MCQ stayed in the goal quadrant significantly longer than all other treatment groups (p<0.05, group effect). D, Swimming speed. No differences in swimming speed between treatment groups were observed. Values ​​represent mean ± SEM. *p<0.05, **p<0.01, ***p<0.001.5, p<0.01; Sham x Vehicle, n=9, p<0.05). Values ​​represent mean ± SEM. *p<0.05, **p<0.01. [Figure 11] Figure 1 shows that aminoquinolines reduce microgliosis and astrocytosis in the WM tracts of BCAS mice. (A) Representative Iba-1 and GFAP staining of the central CC (bregma = 0 mm) on day 3. (B) Iba-1 immunopositive cell density in multiple WM tracts on days 3 and 32. Vehicle controls (n = 9) had a significantly higher density of Iba-1 positive cells in multiple WM tracts on days 3 and 32 compared with other treatment groups (n = 5). (C) GFAP immunopositive cell density. Vehicle controls had a significantly higher density of GFAP positive cells in the CC on days 3 and 32 compared with all other treatment groups. Values ​​represent mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001. Positive cells in the CC on days 3 and 32 compared with all other treatment groups. Values ​​represent mean ± SEM. *p<0.05, **p<0.01, ***p<0.001. [Figure 12]These results demonstrate that inhibition of QR2 reduces oxidative stress in the WM tract of BCAS mice. The vehicle group (n = 9) exhibited significantly higher 8-OHdG staining density in the IC than all other treatment groups (CQ, n = 8; N-MCQ, n = 7; vehicle, n = 9) at day 32, and higher density in the CC than the sham-operated and N-MCQ groups at day 3. Values ​​represent mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001. DETAILED DESCRIPTION OF THE INVENTION

[0035] Provided herein are methods for treating acute neurological injury, vascular dementia, or CNS lupus. In some embodiments, quinoline and quinazoline derivatives useful for inhibiting quinone reductase 2 (QR2) are provided for such treatment.

[0036] The disclosures of all patent references cited herein are hereby incorporated by reference to the extent consistent with the disclosure set forth herein. As used herein in describing the invention and in the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms unless the context clearly dictates otherwise. As used herein in describing the invention and in the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms unless the context clearly dictates otherwise. Furthermore, the terms "about" and "approximately," when used herein in reference to measurable values, such as the amount of a compound, dosage, time, temperature, etc., are intended to encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% from the specified amount. Also, as used herein, "and / or" and " / " refer to and include all possible combinations of one or more of the associated listed items, and no combinations when interpreted in the alternative ("or").

[0037] [I. Definition] The following definitions are used herein:

[0038] As known in the art, "H" refers to a hydrogen atom; "C" refers to a carbon atom; "N" refers to a nitrogen atom; and "O" refers to an oxygen atom.

[0039] "Halo" refers to F, Cl, Br, or I. "Cl" is chlorine, "I" is iodine, "F" is fluorine, and "Br" is bromine.

[0040] "Acyl" is the group --C(O)R, where R is a suitable substituent (e.g., acetyl, propionyl, butyroyl, benzoyl, or alkylbenzoyl).

[0041] "Alkyl," as used herein, refers to a straight-chain or branched-chain saturated hydrocarbon containing 1 or 2 to 10 or 20 or more carbon atoms (e.g., C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, etc.). Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. In some embodiments, alkyl is a "lower alkyl" having 1 to 3, 4, or 5 carbon atoms.

[0042] "Alkenyl," as used herein, is a straight-chain or branched-chain unsaturated hydrocarbon group having one or more double bonds.

[0043] "Alkynyl," as used herein, is a straight-chain or branched-chain unsaturated hydrocarbon group having one or more triple bonds.

[0044] "Amino" is the group -NH2. "Amide" or "amido," as used herein, refers to an organic functional group having a carbonyl group (C=O) attached to a nitrogen atom (N). "Alkylamino" refers to an alkyl group, as defined herein, appended to the parent molecule through a nitrogen atom (-NH-).

[0045] "Alkoxy," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecule through an oxygen atom (-O-). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

[0046] "Aryl," as used herein, refers to a ring system having one or more aromatic rings. Representative examples of aryl include azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like. The aryl groups of the present invention can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, aryl, aryloxy, azido, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, formyl, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, mercapto, nitro, sulfamyl, sulfo, sulfonate, NR'R" (where R' and R" are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl), and -C(O)NR'R" (where R' and R" are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl).

[0047] "Cycloalkyl" refers to a monocyclic or fused polycyclic C3-C10 saturated hydrocarbon group. "Heterocycloalkyl" refers to a cycloalkyl group in which one or more carbon atoms are replaced with an atom independently selected from the group consisting of O, N, and S.

[0048] "Haloalkyl," as used herein, refers to a straight or branched chain hydrocarbon containing 1 or 2 to 10 or 20 or more carbon atoms (e.g., C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, etc.) in which at least one of the hydrogen atoms has been replaced with halo (F, Cl, Br, or I). Representative examples of "haloalkyl" include, but are not limited to, fluoroalkyl (e.g., fluoromethyl (-CH2F), difluoromethyl (-CHF2), or trifluoromethyl (-CF3)).

[0049] "Heterocyclo," as used herein, refers to a monocyclic, bicyclic, or tricyclic ring system containing at least one heteroatom selected from O, N, and S. Monocyclic heterocyclic ring systems are exemplified by any 5- or 6-membered ring containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of O, N, and S. Five-membered rings have 0 to 2 double bonds, and six-membered rings have 0 to 3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine, tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazoline, thiazolidine, thiophene, thiomorpholine, thiomorpholine sulfone, sulfoxide, thiopyran, triazine, triazole, trithiane, and the like. Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group, as defined herein, a cycloalkyl group, as defined herein, or another monocyclic ring system, as defined herein. Representative examples of bicyclic ring systems include, but are not limited to, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxin, 1,3-benzodioxole, cinnoline, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, thiopyranopyridine, and the like.Examples of nitrogen-containing heterocycles include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like.

[0050] "Heteroaryl" refers to a cyclic aromatic hydrocarbon in which one or more carbon atoms are replaced by an atom independently selected from the group consisting of O, N, and S. Examples of heteroaryl groups include pyridyl, pyrimidinyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, indolyl, isoindolyl, indolizinyl, triazolyl, pyridazinyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, isothiazolyl, and benzo[b]thienyl. Preferred heteroaryl groups are 5- and 6-membered rings and contain 1 to 3 heteroatoms independently selected from the group consisting of O, N, and S. Heteroaryl groups, including each heteroatom, can be unsubstituted or, if chemically feasible, substituted with 1 to 4 suitable substituents. For example, the heteroatom S may be substituted with one or two oxo groups, which may be depicted as =0. Examples of nitrogen-containing heteroaryls include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrazolyl, thiazolyl, triazolyl, isothiazolyl, indolyl, benzimidazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, acridinyl, carbazole, azepinyl, 1,4-diazepinyl, purinyl, pteridinyl, phthalazinyl, and the like.

[0051] "Hydroxyl" and "hydroxy" refer to the group --OH.

[0052] "Nitrile" refers to the group --CN.

[0053] "Nitro" refers to the group -NO2.

[0054] "Sulfone" refers to the sulfonyl functional group -SO2R, where R is any covalently bonded atom or atoms.

[0055] "Sulfoxide" refers to the group -S(O)R, where R is any covalently bonded atom or atoms.

[0056] "Thiol" or "mercapto" refers to the group --SH or its tautomer, .dbd.S.

[0057] "Ureido" refers to the group -NHCONH2. "Thioureido" refers to the group -NHCSNH2.

[0058] A "pharmaceutically acceptable salt" is a salt that retains the biological effectiveness of the free acid and base of a particular compound and is not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, and benzoate. These include benzoate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.

[0059] A "prodrug," as known in the art, is a compound that can be converted under physiological conditions, by solvolysis, or metabolically into a specific pharmaceutically active compound. A complete discussion is provided in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, and Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties. See also U.S. Patent No. 6,680,299. Examples include prodrugs that are metabolized in vivo by a subject to an active compound described herein, where the prodrug is an ester of an alcohol or carboxylic acid group, if such groups are present in the compound; an acetal or ketal of an alcohol group, if such groups are present in the compound; an N-Mannich base or imine of an amine group, if such groups are present in the compound; or a Schiff base, oxime, acetal, enol ester, oxazolidine, or thiazolidine of a carbonyl group, if such groups are present in the compound, as described in U.S. Pat. Nos. 6,680,324 and 6,680,322.

[0060] As understood in the art, the term "optionally substituted" indicates that the particular group is unsubstituted or substituted with one or more suitable substituents. A "substituted" "substituent" is a group that replaces a hydrogen atom of a parent organic molecule.

[0061] [II. Active Compounds] Formula I: JPEG0007805620000010.jpg48170 (In the formula, W is N or N + O- and; X is CR 14 or N; R1 is H or trifluoromethyl; R2 is NR7R8, OR 11 , S.R. 12 or alkyl; R3 is H or OR 13 and; R4 is H or methoxy; R5 is H, Cl, or trifluoromethyl; R6 is H, NR9R 10 or trifluoromethyl; R7 is H or C 1~5 C optionally substituted with alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heteroaryl, alkenyl, alkynyl, amido, alkoxy, alkylamino, alkylhydroxy, halo, hydroxyl, carboxylate, alkylcarboxylate, acyl azide, sulfonamido, or alkylhalo. 1~5 alkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, heterocyclo, aryl, heteroaryl, ureido, thioureido, alkenyl, alkynyl, amido, amino, alkoxy, alkylamino, alkylphosphonate, alkylnitrile, alkylhalo, or alkylhalo; R8 is H or C 1~5 C optionally substituted with alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heteroaryl, alkenyl, alkynyl, amido, alkoxy, alkylhydroxy, halo, hydroxyl, carboxylate, alkylcarboxylate, acyl azide, sulfonamido, or alkylhalo; 1~5 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ureido, thioureido, alkenyl, alkynyl, amido, amino, alkoxy, alkylamino, alkylphosphonate, alkylnitrile, alkylhalo, or alkylhalo; R9 is H, O, or C1~5 C optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or alkylamino; 1~5 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylamino, alkylnitrile, or alkylphosphonate; R 10 is H, O, or C 1~5 C optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or alkylamino; 1~5 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylamino, alkylnitrile, or alkylphosphonate; R 11 is alkyl, aryl, or heteroaryl optionally substituted with alkyl, haloalkyl, aryl, or heteroaryl; R 12 is alkyl, aryl, or heteroaryl optionally substituted with alkyl, haloalkyl, aryl, or heteroaryl; R 13 is alkyl or aryl optionally substituted with alkyl or haloalkyl; R 14 is H or aryl) or a pharmaceutically acceptable salt or prodrug thereof is provided herein as an active compound according to some embodiments.

[0062] In some embodiments of Formula I, W is N. In some embodiments of Formula I, X is CR 14In some embodiments of Formula I, R1 is H. In some embodiments of Formula I, R2 is NR7R8. In some embodiments of Formula I, R3 is H. In some embodiments of Formula I, R4 is H. In some embodiments of Formula I, R5 is Cl. In some embodiments of Formula I, R6 is H. In some embodiments of Formula I, R7 is H. In some embodiments of Formula I, R8 is C substituted with heteroaryl. 1~5 In some embodiments of Formula I, R 14 is H.

[0063] In some embodiments of Formula I, the compound has Formula I(a): JPEG0007805620000011.jpg45170 (wherein R7 and R8 are each independently H or C 1~5 alkyl, 1~5 Alkyl can be cycloalkyl, heterocycloalkyl, heterocyclo, aryl, or heteroaryl (each of which can be optionally substituted with any suitable substituent, e.g., C 1~5 and optionally substituted with alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heteroaryl, alkenyl, alkynyl, amido, alkoxy, alkylamino, alkylhydroxy, halo, hydroxyl, carboxylate, alkylcarboxylate, acyl azide, sulfonamido, or alkylhalo. is a compound of

[0064] In some embodiments of Formula I(a), one of R7 and R8 is hydrogen and the other is C 1~5 alkyl, 1~5 Alkyl can be cycloalkyl, heterocycloalkyl, heterocyclo, aryl, or heteroaryl (each of which can be optionally substituted with any suitable substituent, e.g., C 1~5and optionally substituted with alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heteroaryl, alkenyl, alkynyl, amido, alkoxy, alkylamino, alkylhydroxy, halo, hydroxyl, carboxylate, alkylcarboxylate, acyl azide, sulfonamido, or alkylhalo.

[0065] In some embodiments of Formula I, the compound is JPEG0007805620000012.jpg246170 or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments of Formula I, the compound is JPEG0007805620000013.jpg44170 or a pharmaceutically acceptable salt thereof.

[0067] Formula II: JPEG0007805620000014.jpg40170 wherein R' is selected from the group consisting of pyridin-2-ylmethyl, pyridin-3-ylmethyl, 1-benzylpiperidin-4-yl, 4-cyano-2,2-diethylbutyl, 2-chlorocyclopentyl, 4-(diethylamino)butan-2-yl, 1-(furan-2-yl)ethyl, 1-cyclopropylethyl, 1-ethylpiperidin-4-yl, 5-amino-2,2-diethylpentyl, and 2-(diethylphosphoryl)-1-methylethyl. or a pharmaceutically acceptable salt or prodrug thereof is further provided herein as an active compound.

[0068] In some embodiments of Formula II, the compound is JPEG0007805620000015.jpg129170 or a pharmaceutically acceptable salt thereof.

[0069] Additional active compounds can be found in U.S. Patent Application Publication No. 2006 / 0074105 to Ware, Jr. et al., which is incorporated herein by reference. The compounds can be prepared according to known methods, such as those described in Egan et al., J. Med. Chem. 2000, 43:283-291; Stocks et al., J. Med. Chem. 2002, 45:4975-4983, or by the methods described herein in the Examples below.

[0070] In some embodiments of the above compounds of Formula I or Formula II, the compounds have a positive logD value at about pH 4-5.

[0071] Unless otherwise stated, structures depicted herein are also intended to include all enantiomers, diastereomers, and geometric (or conformational) isomers of the structure, e.g., the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomers of the compounds of the invention are within the scope of the invention. Tautomers include keto-enol tautomers of the compounds. Furthermore, unless otherwise stated, all rotational isomeric forms of the compounds of the invention are within the scope of the invention. Unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, e.g., by replacing hydrogen with deuterium or tritium, or by 13 C or 14 Compounds having the present structure except for the replacement of a carbon with a C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0072] [III. How to use] As noted above, the active compounds taught herein may be useful in the treatment of acute neurological injury, vascular dementia, or CNS lupus.

[0073] Acute neurological injury includes, but is not limited to, traumatic brain injury and non-traumatic acute brain injury.Traumatic brain injury, as known in the art, is the brain damage and / or dysfunction caused by one or repeated external mechanical force, for example, blunt force or true force due to sudden acceleration or deceleration.Traumatic brain injury includes, but is not limited to, concussion, contusion, and hemorrhage, including parenchymal, subdural, epidural, and subarachnoid hemorrhage.Other acute neurological injury includes hypoxic or ischemic brain injury, for example, arterial stroke (localized, widespread), venous infarction, infection, perioperative brain injury, etc.

[0074] Vascular dementia is dementia or cognitive impairment caused by an acute cerebrovascular accident, often accompanied by multiple cerebrovascular events such as stroke.

[0075] Central nervous system lupus (CNS lupus) refers to a neurological and / or behavioral clinical syndrome in subjects with systemic lupus erythematosus (SLE). CNS lupus may manifest clinically as acute confusion, fatigue, headache, mild cognitive impairment, delirium, coma, dementia, sensory / motor / autonomic dysfunction, and / or seizures (which occur more frequently in lupus patients than in the general population). CNS lupus may also manifest as psychiatric disorders, such as depression, mania, and / or psychosis. More focal neurological disorders are also possible, which may occur secondary to lupus-related embolic, thrombotic, or vasculitic infarction of the brain and spinal cord and cranial neuropathy. The pathophysiological mechanisms of CNS lupus may include encephalitis, transverse myelitis, neuritis, and stroke (embolic, thrombotic, or vasculitic) of the brain or spinal cord.

[0076] The term "treating," as used herein, refers to any type of treatment that confers a benefit to a subject suffering from or at risk of an injury, disease, or disorder (e.g., improvement in or reduction in the risk of developing one or more symptoms, such as cognitive and / or motor dysfunction), slowing the progression of the injury or symptom, etc.

[0077] Although the present invention is primarily concerned with the treatment of human subjects, the invention may also be practiced in animal subjects, particularly mammalian subjects, such as mice, rats, dogs, cats, livestock, and horses, for veterinary purposes and / or drug screening and / or drug development purposes.

[0078] [IV. Formulations] In some embodiments, the active compound may be provided in a pharmaceutically acceptable carrier. The carrier should be acceptable in that it is compatible with any other components of the formulation and is not harmful to the recipient. In some embodiments, the pharmaceutically acceptable carrier is sterile (e.g., endotoxin-free or pyrogen-free water, or endotoxin-free or pyrogen-free saline).

[0079] Formulations of the present invention may include short-term, immediate-acting, rapid-offset, controlled-release, sustained-release, delayed-release, and pulsed-release formulations, provided that the formulation achieves administration of the compounds described herein. See Remington's Pharmaceutical Sciences (18th ed.; Mack Publishing Company, Eaton, Pa., 1990), which is incorporated herein by reference in its entirety.

[0080] Pharmaceutical formulations according to the present invention may be suitable for a variety of modes of delivery, including oral, parenteral (including intravenous, intramuscular, subcutaneous, intradermal, and transdermal), topical (including cutaneous, buccal, and sublingual), and rectal administration.

[0081] Examples of suitable unit dosage forms according to the present invention are tablets, capsules, liquid preparations for oral administration in a suitable liquid vehicle, sterile preparations in a suitable liquid vehicle for intramuscular and intravenous administration, suppositories, and sterile dry preparations for extemporaneous preparation of sterile injectable preparations in a suitable pharmaceutically acceptable carrier. Suitable solid diluents or carriers for solid oral pharmaceutical unit dosage forms can be selected from the group consisting of lipids, carbohydrates, proteins, and mineral solids, such as starch, sucrose, kaolin, dicalcium phosphate, gelatin, acacia, corn starch, talc, and the like. Both hard and soft capsules can be formulated with suitable diluents and excipients, such as edible oils, talc, calcium carbonate, and also calcium stearate. Liquid preparations for oral administration can be prepared in water or aqueous solutions containing suspending agents, such as sodium carboxymethylcellulose, methylcellulose, acacia, polyvinylpyrrolidone, polyvinyl alcohol, and the like. In some embodiments, preservatives, such as parabens, chlorobutanol, benzyl alcohol, phenol, and the like, can be included. See McCall, U.S. Patent No. 4,159,331.

[0082] The amount of active compound administered for therapeutic treatment may depend on the patient's age, weight, and condition, as determined by a physician. In some embodiments, the administration and / or pharmaceutical unit dosage form may provide from about 0.05 mg to about 100 mg of active compound per dose. In some embodiments, the active compound is provided in an amount of from about 1 microgram per kg of recipient body weight to about 1 g per kg of recipient body weight, or from 10 micrograms per kg to 100 mg per kg of body weight, or from 0.1 mg to 50 mg per kg of body weight.

[0083] The present invention is described in more detail in the following non-limiting examples. [Example]

[0084] Example 1: Development of non-lysosomotropic aminoquinoline inhibitors of QR2 Chloroquine and hydroxychloroquine are lysosomotropic drugs that preferentially accumulate in the lysosomes of cells. Their structures are: JPEG0007805620000016.jpg68170.

[0085] For chloroquine, the pKa of the tertiary amine nitrogen is 10.32, and the pKa of the quinoline nitrogen is 7.29. Thus, at the acidic lysosomal pH of 4-5.5, nearly 100% of chloroquine is doubly protonated, resulting in a molecule with a 2+ charge, which makes the molecule highly hydrophilic, membrane-impermeable, and therefore trapped in acidic organelles.

[0086] A quantitative treatment of this trapping phenomenon can be achieved by examining the octanol-water partition coefficient (logD) of a drug, which represents the relative partitioning properties of all forms of a compound at different pH levels. Compounds with a positive logD for a given pH are relatively lipophilic and highly membrane permeable, whereas compounds with a negative logD are hydrophilic and less membrane permeable.

[0087] Figure 1A shows the log D of chloroquine, and Figure 1B shows the log D of hydroxychloroquine. The shaded areas in the figures represent the likely range of lysosomal pH reached in vivo. At lysosomal pH, the log D of both chloroquine and hydroxychloroquine is substantially negative, reflecting the accumulated charge of these molecules and their loss of membrane permeability.

[0088] Using a chemoproteomic strategy, we generated a chemical library of 4-aminoquinoline scaffolds with selectivity for QR2. Using a suite of chemoinformatics tools, we mined this library in silico to identify aminoquinoline derivatives with nanomolar to micromolar inhibition of QR2 and chemical properties that also avoid lysosomal accumulation, thereby exploring the mechanisms responsible for the most common toxicity of CQ / HQ.

[0089] The example compounds listed below and their respective logD predictions are shown in Figures 2A-2E. Note that regardless of acidity, the logD values ​​remain positive (>0.5) for each compound, indicating that these molecules retain lipophilicity (and therefore membrane permeability) at lysosomal pH (pH 4-5).

[0090] Example Compound A (logD shown in Figure 2A):

[0091] JPEG0007805620000017.jpg57170

[0092] Example Compound B (logD shown in Figure 2B):

[0093] JPEG0007805620000018.jpg58170

[0094] Example Compound C (logD shown in Figure 2C):

[0095] JPEG0007805620000019.jpg58170

[0096] Example Compound D (logD shown in Figure 2D):

[0097] JPEG0007805620000020.jpg54170

[0098] Example Compound E (logD shown in Figure 2E):

[0099] JPEG0007805620000021.jpg43170

[0100] Example Compound F:

[0101] JPEG0007805620000022.jpg61170

[0102] Table 1 below shows further estimates of the druglikeness of non-lysosomotropic 4-aminoquinolines compared to chloroquine (CQ). Lipophilicity Efficiency, LiPE (also known as Ligand Lipophilicity Efficiency), is a drug design and discovery parameter that relates potency to lipophilicity. LiPE is a function of pIC 50 (-logIC 50 ) minus the calculated logP and clogP: LiPE=pIC 50 -clogP LiPE is used to estimate drug specificity in vivo, with higher values ​​predicting greater potency and a lower probability of undesired or off-target interactions. Many of the disclosed 4-aminoquinoline QR2 inhibitors have higher LiPEs than CQ, thus predicting a better toxicity profile than CQ, independent of the substantially reduced toxicity expected from elimination of lysosomotropism.

[0103] JPEG0007805620000023.jpg129170

[0104] Example 2: Synthesis and characterization of 7-chloro compounds

[0105] A suspension of 4,7-dichloroquinoline (2.0 g, 10.2 mmol) in aqueous methylamine (40%, 20 mL, 260 mmol, 26 equiv.) was heated in a microwave oven at 90 °C (initial power setting of 150 W) for 2 h. Analysis of the reaction mixture by TLC (2% MeOH in CHCl) indicated complete consumption of the starting material. The reaction mixture was diluted with H2O (100 mL), and the insoluble material was collected in vacuo. The filter cake was washed with H2O and dried in vacuo to give the pure product as a white microcrystalline solid (1.8 g, 92%). 1H NMR (DMSO-d6, 300 MHz) δ 8.40 (d, J = 5.1 Hz, 1H), 8.16 (d, J = 9.0 Hz, 1H), 7.77 (s, 1H), 6.38 (d, J = 5.4 Hz, 1H), 2.86 (d, J = 5.4 Hz, 3H). ESIMS: m / z = 193 [(M+H) + ].

[0106] JPEG0007805620000025.jpg22170

[0107] General procedure for 7-substituted-4-(pyridin-3-yl)-methylaminoquinolines. A mixture of 7-substituted-4-chloroquinoline (5.1 mmol), 3-aminomethylpyridine (0.70 g, 6.2 mmol, 1.2 equiv.), and 1-butanol (5 mL) was heated at 130 °C (bath temperature) for 24 h in a sealed, heavy-walled pressure vessel (12 mL). The vessel was cooled to room temperature, and the contents were diluted with EtO (150 mL). The insoluble material was removed in vacuo. The filter cake was dissolved in a minimum amount of MeOH, and the resulting solution was added to silica gel (approximately 3 g). The mixture was concentrated to dryness under reduced pressure. Flash column chromatography (RediSep®) was used to elucidate the elution. f SiO2 (40 g), 100% CH2Cl2 → 75% (90:10, CH2Cl2:MeOH with 10% NH3) gave the desired product. X = Cl (white solid, 0.92 g, 67%). 1 H NMR (DMSO-d6, 400 MHz) δ 8.61 (s, 1H), 8.42 (s, 1H), 8.27 (m, 2H), 8.00 (s, 1H), 7.75 (m, 2H), 7.46 (d, J = 8.8 Hz, 1H), 7.31 (m, 3H), 6.39 (d, J = 5.4 Hz, 1H), 4.55 (d, J = 5.4 Hz, 2H). ESIMS: m / z = 270 [(M+H) + ].

[0108] Example 3: Evidence for the protective role of QR2 inhibition in cerebral infarction and the therapeutic efficacy of non-lysosomally targeted inhibitors of QR2. The neuroprotective effects of chloroquine (CQ) were demonstrated in a mouse model of transient middle cerebral artery (MCA) occlusion. Postmortem histological evaluation at 72 hours shows that a single ip administration of CQ (25 mg / kg) 90 minutes after the onset of ischemia resulted in a 55% reduction in overall infarct volume, a corresponding reduction in infarct extension at 4 to 24 hours as measured by diffusion-weighted magnetic resonance imaging (DW-MRI), and improvements in neurological scores and motor function, as shown in Figures 3A-3C.

[0109] In the same model, the non-lysosomotropic QR2-selective 4-aminoquinoline, 7-chloro-N-methylquinolin-4-amine (7C-4MAQ, the example compound shown above) E The neuroprotective effects of 7-chloro-N-methylquinolin-4-amine were also examined. 7-Chloro-N-methylquinolin-4-amine provided striking neuroprotection in this animal model, resulting in a nearly 2-fold reduction in cortical infarct volume seen after CQ administration when compared with an equivalent single acute dose (25 mg / kg) (Figure 3C).

[0110] A dose of 25 mg / kg was determined to be the LD for this compound. 50 Finally, we compared QR2 null mice with their littermate controls in the same MCA occlusion / reperfusion model, as shown in Figure 3C.

[0111] Example 4: Traumatic Brain Injury (TBI) The neuroprotective potential of QR2 inhibition was investigated in a murine TBI model of diffuse closed head injury (Laskowitz et al., "Neuroprotective pentapeptide CN-105 is associated with reduced sterile inflammation and improved functional outcomes in a traumatic brain injury murine model." Sci. Rep. 2017 Apr 21;7:46461). As shown in Figure 4, significant improvements were observed after TBI in both neurocognitive and neuromotor functional assessments. 7-Chloro-N-methylquinolin-4-amine (7C-4MAQ, the example compound shown above) E A single 25 mg / kg dose of ) produced a 20% improvement over vehicle in rotarod latency (n=12 / gp) and, more significantly, a 62% improvement in Morris water maze performance (n=12 / gp), even 1 month after injury.

[0112] As in the stroke model, nearly identical trends are observed when comparing 7C-4MAQ with CQ and QR2 null mice with their littermate controls.

[0113] Example 5: Intracranial hemorrhage (ICH) QR2 inhibition was investigated in a mouse model of intracranial hemorrhage injury (Lei et al., "Neuroprotective pentapeptide CN-105 improves functional and histological outcomes in a murine model of intracerebral hemorrhage." Sci. Rep. 2016 Oct 7;6:34834). In this study, the inventors investigated 7C-4MAQ, chloroquine (CQ), and the 8-aminoquinoline, primaquine, to test the efficacy of example compounds while also further exploring the molecular mechanisms of their therapeutic action.

[0114] It has previously been reported that aminoquinolines such as CQ and hydroxychloroquine inhibit the second half of the QR2 response, while other quinolines, such as primaquine, inhibit the first half. In this particular ICH model (Figure 5), it is important to note that prior neuroprotective interventions only demonstrated statistically discernible therapeutic efficacy at the histological and molecular levels, but not at the behavioral level. In our experiments, CQ therapy also resulted in a non-significant 14% (p = 0.3) improvement in motor function (rotarod assessment). However, 7C-4MAQ administration resulted in a statistically significant 21% improvement in behavioral outcomes (p = 0.013, two-tailed t-test, n = 21) after a single 25 mg / kg ip dose (data not shown). It is also noteworthy that primaquine, which selectively inhibits only the first phase of the QR2 response, resulted in a 35% deterioration in motor function (p = 0.0001) after a comparable single ip dose (data not shown).

[0115] Example 6: Postoperative cognitive impairment Perioperative brain injury (PCI) after major cardiovascular surgery using cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) remains a significant cause of adverse cerebral outcomes. We compared the effects of QR2 inhibition with CQ and 7C-4MAQ on cerebral outcomes after cardiopulmonary bypass (CPB) / deep hypothermic circulatory arrest (DHCA) in a well-established rat model originally developed in Dr. Podgoreanu's laboratory at Duke University (de Lange et al., "A novel survival model of cardioplegic arrest and cardiopulmonary bypass in rats: a methodology paper," J Cardiothorac Surg. 2008 Aug 19;3:51). The results are shown in Figures 6, 7, and 8. For this model of CPB / DHCA, fasted adult male Sprague-Dawley rats (10–12 weeks old) were anesthetized with inhaled isoflurane at 2–2.5%, intubated, and mechanically ventilated. Cannulae were placed in the tail artery and right external jugular vein. The animals were then cooled on CPB for 30 minutes, and DHCA was initiated at a pericranial temperature of 16-18°C. After 60 minutes of DHCA, CPB was resumed, the animals were rewarmed for 30 minutes, and then weaned from CPB at a temperature above 35.5°C. MRI was performed on postoperative day 1, and neurological evaluations were performed on postoperative days 1 and 2. The animals were then sacrificed after day 2.

[0116] Primary outcome MRI analysis revealed a 3% reduction in postoperative blood-brain barrier permeability measured by gadolinium chelation in animals treated with chloroquine (CQ) or the example compound (7C-4MAQ) compared with their respective control groups (p<0.05). Animals treated with CQ or 7C-4MAQ also exhibited fewer apoptotic and necrotic neurons in the cortex and hippocampus (Figures 6 and 7). Finally, 7C-4MAQ-treated rats showed significantly improved neurological scores on postoperative days 1 and 2 (Figure 8).

[0117] Example 7: Dementia, vascular subtype Vascular dementia is caused by chronic cerebral hypoperfusion and is characterized clinically by white matter lesions on MRI and impaired executive function. Recent studies have demonstrated that hippocampal expression of quinone oxidoreductase 2 (QR2) is significantly increased in rat models and human patients with dementia, suggesting that QR2 is a potential therapeutic target. We investigated the neuroprotective effects of chloroquine and 7C-4MAQ in a mouse model of vascular dementia. Physiological, cellular, and functional outcomes were determined using a combination of quantitative immunochemistry, MRI, and behavioral tasks including the Morris water maze and rotarod.

[0118] As shown in Figures 9-12, both QR2 inhibitors improved Morris water maze performance while simultaneously reducing markers of astrocytosis, microgliosis, and oxidative stress. Note that in Figures 9-12, 7C-4MAQ is referred to using its previous name, "N-MCG." Despite improvements in functional outcomes and cellular inflammatory responses, structural markers of white matter damage were unchanged between treatment and control groups. These results provide evidence for the pathogenic role of QR2 in dementia and its potential as a therapeutic target. Furthermore, the results suggest that functionally relevant neuroprotection occurs through mechanisms unrelated to those responsible for dementia-associated white matter pathology, often characterized by MRI.

[0119] The foregoing is illustrative of the present invention, and is not to be construed as limiting thereof. The present invention is defined by the following claims, with equivalents of the claims to be included therein.

Claims

1. 1. A pharmaceutical composition for treating acute nerve injury in a subject in need thereof, comprising: 【Chemistry 1】 A pharmaceutical composition comprising 7-chloro-N-methylquinolin-4-amine or a pharmaceutically acceptable salt thereof.

2. 2. The pharmaceutical composition of claim 1, wherein the acute neurological injury comprises a traumatic brain injury.

3. 2. The pharmaceutical composition of claim 1, wherein the acute neurological injury comprises subarachnoid hemorrhage.

4. The pharmaceutical composition of claim 1 , wherein the acute neurological injury comprises postoperative cognitive impairment.

5. 2. The pharmaceutical composition of claim 1, wherein the acute neurological injury comprises hypoxic brain injury.

6. 2. The pharmaceutical composition of claim 1, wherein the acute neurological injury comprises an ischemic brain injury.

7. 1. A pharmaceutical composition for treating vascular dementia in a subject in need thereof, comprising: 【Chemistry 2】 A pharmaceutical composition comprising 7-chloro-N-methylquinolin-4-amine or a pharmaceutically acceptable salt thereof.

8. 1. A pharmaceutical composition for treating CNS lupus in a subject in need thereof, comprising: 【Transformation 3】 A pharmaceutical composition comprising 7-chloro-N-methylquinolin-4-amine or a pharmaceutically acceptable salt thereof.

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