Compounds for the prevention and treatment of cognitive dysfunction and impairment after intensive care due to respiratory distress - Patent Application 20070122993

Abstract

In certain embodiments, provided herein are methods for preventing, reducing, delaying, and treating post-intensive care cognitive dysfunction (PICCD) by administering a compound disclosed herein to a subject before, during, or after an ICU stay, intubation, or mechanical ventilation. Also provided herein are methods for treating, preventing, inhibiting, reducing the severity of, or delaying the onset of cognitive dysfunction or impairment resulting from or caused by respiratory distress.

Description

[Technical Field]

[0001] Provided herein, in certain embodiments, are methods for treating and / or preventing post-intensive care cognitive dysfunction (PICCD), comprising administering a compound disclosed herein to a subject before, during, or after an ICU stay, intubation, or mechanical ventilation. Also provided herein, in certain embodiments, are methods for treating or preventing cognitive impairment resulting from or caused by respiratory distress, comprising administering a compound disclosed herein to a subject before, during, or after respiratory distress. [Background technology]

[0002] Post-intensive care cognitive dysfunction (PICCD) is the impairment or decline in cognitive function observed in subjects after staying in an intensive care unit (ICU), after intubation, and / or after connecting to a ventilator. Patients who experience respiratory distress, such as acute respiratory distress syndrome (ARDS), also experience cognitive impairment or decline during or after respiratory distress. The compounds disclosed herein can be used to treat and / or prevent cognitive impairment associated with PICCD and respiratory distress. Summary of the Invention

[0003] In certain aspects, provided herein are methods for preventing, alleviating, delaying, or treating post-intensive care cognitive dysfunction (PICCD) in a subject, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein. In certain embodiments, PICCD includes the onset or worsening of delirium, memory loss, confusion, decreased consciousness, impaired executive function, speech impairment, language impairment, communication impairment, loss of attention, depression, anxiety, post-traumatic stress disorder, and / or impaired visuospatial ability. In certain embodiments, PICCD results from, is associated with, or is precipitated by a) a subject's stay or admission to an intensive care unit, b) a subject's intubation, and / or c) a subject's operative connection to a ventilator.

[0004] In certain aspects, provided herein are methods for treating, preventing, suppressing, reducing the severity of, or delaying the onset of cognitive impairment or impairment resulting from or caused by dyspnea in a subject, the methods comprising administering a therapeutically effective amount of a compound disclosed herein to a subject at risk of, suffering from, or experiencing, dyspnea, or who has previously experienced dyspnea.

[0005] In certain aspects, provided herein are methods for preventing or inhibiting the decline or worsening of existing cognitive impairment or impairment resulting from or caused by dyspnea in a subject, the methods comprising administering a therapeutically effective amount of a compound disclosed herein to a subject at risk of, suffering from or experiencing dyspnea, or who has previously experienced dyspnea.

[0006] In certain aspects, provided herein are methods of treating a subject at risk for, suffering from, experiencing, or who has previously experienced dyspnea, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, wherein cognitive impairment or impairment resulting from or caused by dyspnea is prevented, ameliorated, inhibited, reduced in severity, or delayed.

[0007] In certain aspects, provided herein are methods of treating a subject at risk for, suffering from, experiencing, or who has previously experienced dyspnea, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, wherein a pre-existing cognitive impairment, pre-existing cognitive disorder, or pre-existing neurodegenerative disease is prevented from worsening, prevented from increasing in severity, or inhibited.

[0008] In some embodiments, the subject has, is suspected of having, has been diagnosed with, or is at risk of having acute respiratory syndrome, acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome, asthma, pneumonia, or an infection.

[0009] In some embodiments, the subject is infected with a coronavirus, hi some embodiments, the subject has or is suspected of having COVID-19.

[0010] In some embodiments, the compounds disclosed herein are compounds of Formula I, II, III, or IV. In some embodiments, the compounds have the structure of Formula IV:

[0011] [ka]

[0012] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. [Brief explanation of the drawings]

[0013] [Figure 1] FIG. 1 shows the experimental design of Example 3, in which mice were subjected to ischemia and 45 minutes of hypoxia. [Figure 2] Figure 1 shows 2,3,5-triphenyltetrazolium chloride (TTC) staining of mouse hippocampus 24 hours after HI injury in a representative coronal brain section (white area indicates the damaged area (left)), and MRI image measurements of infarct volume as a percentage of the contralateral hemisphere volume for SH (sham control mice), HI (untreated hypoxic-ischemic mice), and HIJ (hypoxic-ischemic mice treated with J147) in Example 3. This figure demonstrates that J147 significantly reduces the area of ​​brain damage caused by hypoxia-ischemia. [Figure 3]Figure 10 shows the effect of treatment with J147 on magnetic resonance imaging measurements of ipsilateral hemispheric volume as a percentage of contralateral hemispheric volume by degree of reduction from 100%, reflecting the size of infarct volume 50 days after hypoxic-ischemic injury in Example 3. This figure shows that J147 almost completely reduces the area of ​​hypoxic-ischemic brain damage 50 days after injury. [Figure 4] FIG. 1 shows an analysis of the dose-dependence of J147 treatment on reducing apoptotic neuronal death in the hippocampus 4 days after injury in a neonatal hypoxic-ischemic encephalopathy mouse model in Example 3. [Figure 5] FIG. 1 shows the reduction of apoptotic cell death damage by J147 treatment after 4 days, as measured by NeuN-positive area and counting the number of TUNEL-positive cells in the hippocampus of sham-treated, HI, and J147-treated HI mice, in Example 3. [Figure 6] FIG. 1 shows functional recovery of HI mice induced by J147 treatment in the open field test, rotarod test, and Y-maze test in Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0014] In some embodiments, compounds are provided herein for treating and / or preventing PICCD. Post-intensive care cognitive dysfunction (PICCD) is the impairment or decline in cognitive function observed in a subject after a stay in an intensive care unit (ICU), after intubation, and / or after connection to a ventilator. In some embodiments, compounds are provided herein for treating and / or preventing cognitive impairment or decline observed in a subject during or after respiratory distress.

[0015] compound In some embodiments, provided herein are compounds for use in the prevention or treatment of PICCD. In some embodiments, the compounds used herein have the structure of Formula I:

[0016] [ka]

[0017] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. In some embodiments of Formula I, R 2 is hydrogen (H) or methyl; R 3 is methyl, fluorine-substituted alkyl (e.g., fluoromethyl, difluoromethyl, or trifluoromethyl), or bromine-substituted alkyl (e.g., bromomethyl, dibromomethyl, tribromomethyl); L 3 is carbonyl; R 6 is independently for each occurrence alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, hydroxyl, methoxy, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, mercapto, alkylthio, arylthio, carbonyl, carboxyl, aryl, substituted aryl, substituted heterocyclic, halogen, cyano, cyanoalkyl, amine, methylamine, dimethylamine, nitro, amino, amidino, carbamate, CF3, OCF3, S(O) n R 7 , and C(O)R 8 or two R6 at adjacent positions are joined to form an optionally substituted heteroaryl or heteroalkyl ring fused to adjacent phenyl moieties; 7 H, R 9 , NH2, HNR 9 , and NR 9 R 10 Selected from;R 8 OH, OR 9 , NH2, NHR 9 , and NR 9 R 10 where R is selected from 9 and R 10 is independently at each occurrence optionally substituted alkyl; and n is 1 or 2.

[0018] In certain embodiments of Formula I, R 6is independently at each occurrence alkyl, substituted alkyl, alkenyl, substituted alkenyl, hydroxyl, alkoxy, methoxy, substituted alkoxy, halogen, carbonyl, carboxyl, or C(O)R 8 In certain such embodiments, R 6 Each occurrence is methyl, methoxy, perfluoromethyl, perfluoromethoxy, hydroxyl, Cl, F, or I. In some embodiments of Formula I, L 3 is carbonyl and R 3 CF 3 and R 2 is H and R 6 Each occurrence is null or H. In some embodiments of Formula I, L 3 is carbonyl and R 3 is CF3 and R 2 is H and R 6 Each occurrence is independently selected from methyl or methoxy. In some embodiments of Formula I, L 3 is carbonyl and R 3 is CF3 and R 2 is methyl and R 6 is, at each occurrence, independently selected from methyl or methoxy.

[0019] In some embodiments, the compounds used herein have the structure of Formula II:

[0020] [ka]

[0021] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: (i)R A2 , R A4 , R A5 , and R A6 is H and R A3 is methoxy and R B2 is methyl and R B4 is methyl; (ii)R A2 , RA3 , R A5 , and R A6 is H and R A4 is methoxy and R B2 is methyl and R B4 is methyl; (iii)R A2 , R A3 , R A4 , R A5 , and R A6 is H and R B2 is H and R B4 is H; (iv)R A2 , R A3 , R A4 , R A5 , and R A6 is H and R B2 is methyl and R B4 is methyl; (v)R A2 , R A4 , R A5 , and R A6 is H and R A3 is methoxy and R B2 is H and R B4 is H; (vi)R A2 , R A3 , R A4 , R A5 , and R A6 is H and R B2 is H and R B4 is methyl; (vii)R A2 , R A4 , R A5 , and R A6 is H and R A3 is methoxy and R B2 is H and R B4 is methyl; (viii)R A2 , R A3 , R A4 , R A5 , and R A6 is H and R B2 is methyl and R B4 is H; (ix)RA2 , R A4 , R A5 , and R A6 is H and R A3 is methoxy and R B2 is methyl and R B4 is H; (x)R A2 , R A3 , R A5 , and R A6 is H and R A4 is COOH and R B2 is methyl and R B4 is methyl; (xi)R A2 , R A4 , and R A5 is H and R A3 and R A6 is hydroxyl and R B2 is methyl and R B4 is methyl; (xii)R A2 , R A4 , and R A6 is H and R A3 and R A5 is hydroxyl and R B2 is methyl and R B4 is methyl; (xiii)R A2 , R A4 , and R A5 is H and R A3 is methoxy and R A6 is F and R B2 is H and R B4 is Cl; (xiv)R A3 and R A5 is H and R A2 and R A6 is F and R A4 is hydroxyl and R A6 is F and R B2 is H and R B4 is F; (xv)R A2 , R A4 , and R A6 is H and R A3is hydroxyl and R A5 is F and R B2 is H and R B4 is F; or (xvi)R A2 , R A5 , and R A6 is H and R A3 and R A4 Together they form -O-CH2-O-, and R A5 is F and R B2 is H and R B4 is F.

[0022] In some embodiments of the compound of Formula II, R A2 , R A5 , and R A6 is H and R A3 is methoxy and R B2 and R B4 is methyl and R A4 is selected from H, NO, OH, methoxy, phenol, methyl, fluorine (F), N(CH), CHC(CN), and O-tert-butyldimethylsilyl (OTBDMS). In some embodiments of the compound of Formula II, R A2 , R A4 , R A5 , and R A6 is H and R A3 is methoxy and R B2 is methyl and R B4 is methyl. In some embodiments of the compound of Formula II, R A2 , R A3 , R A5 , and R A6 is H and R A4 is methoxy and R B2 is methyl and R B4 is methyl. In some embodiments of the compound of Formula II, R A2 , R A3 , R A4 , R A5 , and R A6 is H and R B2 is methyl and R B4 is methyl. In some embodiments of the compound of Formula II, RA2 , R A4 , R A5 , and R A6 is H and R A3 is methoxy and R B2 is H and R B4 is H. In some embodiments of the compound of Formula II, R A2 , R A3 , R A4 , R A5 , and R A6 is H and R B2 is H and R B4 is methyl. In some embodiments of the compound of Formula II, R A2 , R A3 , R A4 , R A5 , and R A6 is H and R B2 is H and R B4 is methyl. In some embodiments of the compound of Formula II, R A2 , R A4 , R A5 and R A6 is H and R A3 is methoxy and R B2 is H and R B4 is methyl. In some embodiments of the compound of Formula II, R A2 , R A4 , R A5 and R A6 is H and R A3 is methoxy and R B2 is methyl and R B4 is H. In some embodiments of the compound of Formula II, R A2 , R A3 , R A4 , R A5 and R A6 is H and R B2 is methyl and R B4 is H. In some embodiments of the compound of Formula II, R A2 , R A3 , R A5 and R A6 is H and R A4 is carboxyl and R B2 is methyl and R B4is methyl. In some embodiments of the compound of Formula II, R A2 , R A4 , R A5 and R A6 is H and R A3 is carboxyl and R B2 is methyl and R B4 is methyl.

[0023] In some embodiments, the compounds used herein have the structure of Formula VI:

[0024] [ka]

[0025] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1 is methyl, fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, dibromomethyl, or tribromomethyl; R2 is methyl, methoxy, hydroxyl, halogen, CF3, OCH3, OCF3, or OCBr3; and R3 and R4 are independently selected from hydrogen, hydroxyl, halogen (e.g., Cl, F, or Br), methyl, methoxy, and amine. In some embodiments of Formula III, R1 is CF3 (trifluoromethyl), R2 is OCH3, and R3 and R4 are methyl. In some embodiments of Formula III, R1 is CF3 (trifluoromethyl), R2 is OCF3, and R3 and R4 are methyl.

[0026] In some embodiments, the compounds used herein have the structure of Formula IV: or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0027] [ka]

[0028] The structure of formula IV is sometimes referred to herein as "J147."

[0029] The following terms have their respective definitions set forth below.

[0030] "Alkyl" refers to a straight- or branched-chain alkyl radical having in the range of about 1 up to about 12 carbon atoms (e.g., methyl, ethyl, propyl, butyl, etc.). "Substituted alkyl" refers to an alkyl further bearing one or more substituents (e.g., 1, 2, 3, 4, or even 5) as described herein. "Optionally substituted alkyl" refers to an alkyl or substituted alkyl.

[0031] "Cycloalkyl" refers to a cyclic ring-containing group containing in the range of about 3 up to about 12 carbon atoms. "Substituted cycloalkyl" refers to a cycloalkyl further bearing one or more substituents (e.g., 1, 2, 3, 4, or even 5) selected from alkyl, substituted alkyl, and any of the substituents described herein. "Optionally substituted cycloalkyl" refers to a cycloalkyl or substituted cycloalkyl.

[0032] Terms such as "heterocycle," "heterocyclic," and the like refer to cyclic (i.e., ring-containing) groups that contain one or more heteroatoms (e.g., N, O, S, etc.) as part of the ring and have in the range of 1 up to about 14 carbon atoms. Terms such as "substituted heterocyclic" refer to heterocycles that further have one or more substituents (e.g., 1, 2, 3, 4, or even 5) as described herein. Exemplary heterocyclic moieties include saturated rings, unsaturated rings, and aromatic heteroatom-containing ring systems, such as epoxy, tetrahydrofuran, oxazoline, pyrrole, pyridine, furan, and the like. Terms such as "optionally substituted heterocycle" refer to heterocycles or substituted heterocycles.

[0033] References to "optionally substituted bicyclic ring" refer to bicyclic ring structures known in the art, optionally containing substitutions as defined herein.

[0034] "Alkenyl" refers to a straight-chain, branched-chain, or cyclic hydrocarbyl group containing 2 to about 20 carbon atoms and having at least one, 1 to 3, 1 to 2, or 1 carbon-carbon double bond. "Substituted alkenyl" refers to an alkenyl substituted at one or more positions, e.g., 1, 2, 3, 4, or even 5, with substitution as described herein. "Optionally substituted alkenyl" refers to an alkenyl or a substituted alkenyl. In some embodiments, the alkenyl is ethylenyl or propylenyl. In certain embodiments, the substituted alkenyl is substituted ethylenyl or substituted propylenyl. In some embodiments, the ethylenyl or propylenyl is substituted with one or more CN moieties. For example, in some embodiments, the substituted ethylenyl comprises (CN)C=CH-.

[0035] "Aryl" refers to an aromatic group having ranging from 6 up to about 14 carbon atoms. "Substituted aryl" refers to an aryl radical further bearing one or more substituents (e.g., 1, 2, 3, 4, or even 5) selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyl, alkoxy, aryloxy, mercapto, alkylthio, arylthio, carbonyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, halogen, trifluoromethyl, pentafluoroethyl, cyano, cyanoalkyl, nitro, amino, amido, amidino, carboxyl, carbamate, SO2X (where X is H, R, NH2, NHR, or NR2, SO3Y, where Y is H, NH2, NHR, or NR2, or C(O)Z, where Z is OH, OR, NH2, NHR, or NR2, etc.). "Optionally substituted aryl" refers to an aryl or substituted aryl.

[0036] "Aralkyl" refers to an alkyl group substituted with an aryl group. "Substituted aralkyl" refers to an aralkyl further bearing one or more substituents (e.g., 1, 2, 3, 4, or even 5) selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and any of the substituents described herein. Thus, aralkyl groups include, among others, benzyl, diphenylmethyl, and 1-phenylethyl (-CH(CH)(CH)). "Optionally substituted aralkyl" refers to an aralkyl or substituted aralkyl.

[0037] "Heteroaryl" refers to an aromatic group containing one or more heteroatoms (e.g., N, O, S, etc.) as part of the aromatic ring, typically having in the range of 2 up to about 14 carbon atoms, and "substituted heteroaryl" refers to a heteroaryl radical further bearing one or more substituents (e.g., 1, 2, 3, 4, or even 5) selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, as well as any of the above substituents.

[0038] "Heteroaralkyl" and "heteroarylalkyl" refer to an alkyl group substituted with one or more heteroaryl groups. "Substituted heteroaralkyl" refers to a heteroaralkyl further bearing one or more substituents (e.g., 1, 2, 3, 4, or even 5) selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and any of the substituents described herein. "Optionally substituted heteroaralkyl" refers to a heteroaralkyl or substituted heteroaralkyl.

[0039] "Halogen" and "halo" refer to fluorine, chlorine, bromine, or iodine.

[0040] "Hydroxyl" and "hydroxy" refer to the functionality --OH.

[0041] "Alkoxy" refers to the group -OR where R is alkyl. "Substituted alkoxy" refers to the group -OR where R is substituted alkyl. "Optionally substituted alkoxy" refers to alkoxy or substituted alkoxy.

[0042] "Aryloxy" refers to the group -OR where R is aryl. "Substituted aryloxy" refers to the group -OR where R is substituted aryl. "Optionally substituted aryloxy" refers to aryloxy or substituted aryloxy.

[0043] "Mercapto" and "thiol" refer to the functionality -SH.

[0044] "Alkylthio" and "thioalkoxy" refer to the groups -SR, -S(0) n=1-2 "Substituted alkylthio" and "substituted thioalkoxy" refer to the groups -SR, -S(O) n=1-2 -R, where R is substituted alkyl. "Optionally substituted alkylthio" and "optionally substituted thioalkoxy" refer to alkylthio or substituted alkylthio.

[0045] "Arylthio" refers to the group -SR where R is aryl. "Substituted arylthio" refers to the group -SR where R is substituted aryl. "Optionally substituted arylthio" refers to arylthio or substituted arylthio.

[0046] "Amino" refers to unsubstituted, monosubstituted, and disubstituted amino groups, including the substituent -NH; "monoalkylamino" refers to a substituent having the structure -NHR, where R is alkyl or substituted alkyl; and "dialkylamino" refers to a substituent of the structure -NR, where each R is independently alkyl or substituted alkyl.

[0047] "Amidino" is the group -C(=NR q )NR r R s where Rq , R r. , and R s is independently hydrogen or optionally substituted alkyl.

[0048] Reference to an "amide group" includes a substituent of the structure -C(O)-NR, where each R is independently H, alkyl, substituted alkyl, aryl, or substituted aryl, as defined above. When each R is H, the substituent is also referred to as a "carbamoyl" (i.e., a substituent having the structure -C(O)-NH). When only one of the R groups is H, the substituent is also referred to as a "monoalkylcarbamoyl" (i.e., a substituent having the structure -C(O)-NHR, where R is alkyl or substituted alkyl, as defined above) or an "arylcarbamoyl" (i.e., a substituent having the structure -C(O)-NH(aryl), where aryl is as defined above, including substituted aryl). When neither R group is H, the substituent is also referred to as a "dialkylcarbamoyl" (i.e., a substituent having the structure -C(O)-NR, where each R is independently alkyl or substituted alkyl, as defined above).

[0049] Reference to a "carbamate" includes a substituent of the structure -OC(O)-NR2, where each R is independently H, alkyl, substituted alkyl, aryl, or substituted aryl.

[0050] Reference to an "ester group" includes substituents of the structure --O--C(O)--R, where each R is independently alkyl, substituted alkyl, aryl, or substituted aryl.

[0051] "Acyl" refers to a group having the structure -C(O)R, where R is hydrogen, alkyl, aryl, etc., as defined herein. "Substituted acyl" refers to acyl in which the substituent R is substituted as defined herein. "Optionally substituted acyl" refers to acyl and substituted acyl.

[0052] "Cyanoalkyl" refers to the group -R≡N, where R is an optionally substituted alkylenyl.

[0053] As used herein, "substituted" refers to an atom or group of atoms replaced with another atom or group of atoms (i.e., a substituent), and includes all levels of chemically permissible substitution, such as mono-, di-, tri-, tetra-, penta-, or even hexa-substitution. Substitutions can occur at any chemically accessible position and at any atom, including substitutions at carbon and heteroatoms such as oxygen, nitrogen, and sulfur. For example, substituted moieties include those in which one or more bonds to hydrogen or carbon atom(s) contained therein are replaced with a bond to a non-hydrogen and / or non-carbon atom(s). Substitutions may include, but are not limited to, halogen atoms such as F, Cl, Br, and I; oxygen atoms in groups such as hydroxyl, alkoxy, aryloxy, and ester groups; sulfur atoms in groups such as thiol, alkyl and aryl sulfide, sulfone, sulfonyl, and sulfoxide groups; nitrogen atoms in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; silicon atoms in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl groups; and heteroatoms in other groups well known in the art.

[0054] Non-limiting examples of substituents include, but are not limited to, halogen, -OH, -NH, -NO, -CN, -C(O)OH, -C(S)OH, -C(O)NH, -C(S)NH, -S(O)NH, -NHC(O)NH, -NHC(S)NH, -NHS(O)NH, -C(NH)NH, -OR, -SR, -OC(O)R, -OC(S)R, -C(O)R, -C(S)R, -C(O)OR, -C(S)OR, -S(O)R, -S(O)2R, -C(O)NHR, -C(S)NHR, -C( O)NRR, -C(S)NRR, -S(O)2NHR, -S(O)2NRR, -C(NR)NHR, -C(NH)NRR, -NHC(O)R, -NHC(S)R, - and optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, wherein R is independently at each occurrence H, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.Substitution with optionally substituted hydrocarbyl moieties containing one or more of the following chemical functional groups is also contemplated: -O-, -S-, -NR-, -OC(O)-, -OC(O)-O-, -OC(O)-NR-, -NR-C(O)-, -NR-C(O)-O-, -NR-C(O)-NR-, -SC(O)-, -SC(O)-O-, -SC(O)-NR-, -S(O)-, -S(O)2-, -OS(O)2-, -O S(O)2-O, -OS(O)2-NR-, -OS(O)-, -OS(O)-O-, -OS(O)-NR-, -O-NR-C(O)-, -O-NR-C(O)-O-, -O-NR-C(O)-NR-, -NR -OC(O)-, -NR-OC(O)-O-, -NR-OC(O)-NR-, -O-NR-C(S)-, -O-NR-C(S)-O-, -O-NR-C(S)-NR-, -NR-OC(S)-, -NR-OC( S)-O-, -NR-OC(S)-NR-, -OC(S)-, -OC(S)-O-, -OC(S)-NR-, -NR-C(S)-, -NR-C(S)-O-, -NR-C(S)-NR-, -SS(O)2-, -SS(O)2-O-, -SS(O)2-NR-, -NR-OS(O)-, -NR-OS(O)-O-, -NR-OS(O)-NR-, -NR-OS(O)2-, -NR-OS(O)2-NR-, -O-NR- S(O)-, -O-NR-S(O)-O-, -O-NR-S(O)-NR-, -O-NR-S(O)-O-, -O-NR-S(O)-NR-, -O-NR-S(O)-, -OP(O)R-, -SP(O)R-, or -NR-P(O)R-, where R is independently for each occurrence H, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0055] In some embodiments, the compounds used herein include isomers, including stereoisomers (e.g., optical isomers and diastereomers), structural isomers, tautomers, conformational isomers, and geometric isomers of the compounds disclosed herein.

[0056] Exemplary structural isomers include, but are not limited to, isomers resulting from different connectivity of the functionalities forming the compounds disclosed herein, such as, for example, 1-propyl substitution versus 2-propyl substitution. Structural isomers combined with tautomerization further encompass bond rearrangements, including double bond and substituent migration. For example, tautomerization combined with multifaceted hydrogen shifts from 1 to 3 can result in structural isomerism.

[0057] Exemplary conformational isomers include, for example, but are not limited to, isomers resulting from rotation about a bond where rotation is hindered to an extent that separable isomers result, as is well known in the art.

[0058] Exemplary geometric isomers include, for example, double bonds in the "E" or "Z" configuration, as are well known in the art.

[0059] The compounds disclosed herein can be easily prepared using suitable synthetic methods. For example, curcumin can be condensed with phenylhydrazine by heating under reflux overnight in toluene. Optionally, a catalytic amount of acid (HCl) can be used. In some embodiments, pure curcumin (for technical use) and freshly distilled phenylhydrazine can be used.

[0060] As another example, 3-methoxybenzaldehyde can be condensed with 2,4-dimethylphenylhydrazine in methanol using standard hydrazone preparation conditions (e.g., microwave heating to shorten reaction times). The free NH is then acylated with TFAA (trifluoroacetic anhydride) and a catalytic (0.1%) amount of DMAP (dimethylaminopyridine), THE (tetrahydrofuran), or DCM (dichloromethane).

[0061] In some embodiments, CF3-substituted triazoles can be prepared by 1,3-dipolar cycloaddition between an appropriate aryl trifluoromethyl acetylene and an aryl azide. Regioselectivity can be achieved by utilizing appropriate click chemistry (see, for example, Huisgen R. (1984) 1,3-Dipolar Cycloaddition Chemistry, pp. 1-176, London: Wiley; Padwa (1991) Comprehensive Organic Synthesis, Vol. 4: pp. 1069-1109, Oxford: Pergamon; and Fan & Katritzky (1996) Comprehensive Heterocyclic Chemistry II, Vol. 4: pp. 101-126, Oxford: Pergamon). Further methods for producing the compounds disclosed herein can be found in Lima et al., (2015) Chem. Commun. 51:10784-10796, and Kim et al., (2015) Org. Biomol. Chem. 13:9564-9569.

[0062] In some embodiments, the compounds used herein are provided in the form of pharmaceutically acceptable salts. The compounds used herein can be complexed with any suitable inorganic or organic salt using a suitable method. In some embodiments, the salts of the compounds used herein are prepared by reacting the compounds with a suitable organic or inorganic acid or base. Non-limiting examples of organic salts contemplated for use herein include methanesulfonate, acetate, oxalate, adipate, alginate, aspartate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate (tosylate), citrate, malate, maleate, fumarate, succinate, tartrate, napsylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, benzenesulfonate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, glucoheptanoate, glycerophosphate, heptanoate, hexanoate, undecanoate, 2-hydroxyethanesulfonate, ethanesulfonate, and the like. In some embodiments, inorganic salts can be formed from inorganic acids such as sulfates, bisulfates, hemisulfates, hydrochlorides, chlorates, perchlorates, hydrobromides, hydroiodides, etc. Non-limiting examples of basic salts include ammonium salts, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, phenylethylamine, and salts with amino acids such as arginine and lysine.

[0063] Thus, in certain embodiments, the methods herein comprise administering to a subject a therapeutically effective amount of a compound of Formula I, II, III, or IV.

[0064] difficulty breathing Acute respiratory distress syndrome (ARDS) is a life-threatening condition associated with fluid accumulation in the lungs (pulmonary edema) and the resulting inability to maintain adequate blood oxygen levels (hypoxia or hypoxemia). ARDS can have a variety of potential causes, non-limiting examples of which include pneumonia, sepsis, viral infections, and trauma. Before the COVID-19 pandemic, an estimated 3 million cases of ARDS occurred annually worldwide, accounting for 10% of all ICU patients. The primary treatment option available for ARDS is mechanical ventilation, in which breathing is assisted by a ventilator that forces air into the lungs.

[0065] Patients who recover from ARDS typically experience some form of cognitive impairment (Hopkins et al. (1999) American Journal of Respiratory and Critical Care Medicine 160(1):50-56; Sasannejad et al. (2019) Critical Care 23(1):1-12). Some studies suggest that 56-80% of patients suffer from impairments in memory, attention, concentration, and / or processing speed after one year and 20% after five years. Some patients with long-term impairment show significant declines in performance on standardized tests of intelligence, falling below the 6th percentile of the normal distribution (Hopkins et al. (2005) American Journal of Respiratory and Critical Care Medicine 171(4):340-347). Additionally, ARDS survivors are prone to anxiety and depression (Mikkelsen et al. (2009) Respirology 14(1):76-82; Mikkelsen et al. (2012) American Journal of Respiratory and Critical Care Medicine 185(12):1307-1315), and a large proportion exhibit symptoms of post-traumatic stress disorder (Kapfhammer et al. (2004) The American Journal of Psychiatry 161(1):45-52; Mikkelsen et al., 2012).

[0066] Imaging studies have shown significant brain atrophy and ventricular hypertrophy in ARDS survivors compared with matched controls (Hopkins et al., (2006) Brain Injury 20(3):263-271). Patients with pre-existing cognitive decline or brain injury are at increased risk (Sasannejad et al., 2019), but there is no clear association with age or disease severity (Herridge et al., 2016). Duration of hypoxemia during acute illness has also been associated with increased risk (Mikkelsen et al., 2012), but experiments in a porcine model of ARDS suggest that cytokine-mediated brain damage resulting from lung injury, rather than hypoxemia, contributes significantly to hippocampal damage. Many other clear risk factors have been identified, including duration of hypotension, reduced central venous pressure, hyperglycemia, and glycemic variability (Herridge et al. (2016) Intensive Care Medicine 42(5):725-738). The occurrence and duration of delirium, which commonly occurs during and after treatment for ARDS, is also a risk factor for long-term cognitive decline ( Mikkelsen et al., 2012 ; Sasannejad et al., 2019 ).

[0067] The physiological mechanisms responsible for the cognitive effects of ARDS are unclear. Several possible mechanisms have been suggested. For example, cytokine-induced breakdown of the blood-brain barrier has been suggested as a central event in the process, potentially interfering with amyloid-β clearance and causing further neurological damage. Cytokine production in the hippocampus has been implicated in the depletion of brain-derived neurotrophic factor (BDNF), which is essential for neuroplasticity, learning, and memory.

[0068] Mechanical ventilation, used to treat ARDS, has significant risks associated with its use (Wolthius et al. (2009) Critical Care (London, England) 13(1):1-11; Matthay et al. (2019) Nature Reviews. Disease Primers 5(1):18) and may be an independent cause of cognitive impairment experienced by patients after recovery (Bilotta et al. (2019) Critical Care 23(1):1-3).

[0069] There are no established preventive measures or treatments to minimize ARDS-related cognitive impairment. Current recommendations focus on sedation and minimizing tidal volume during mechanical ventilation. Currently, no medications are recommended for preventing or minimizing ARDS-related cognitive decline. Clinical trials of statin medications for delirium during treatment and subsequent cognitive impairment have failed to demonstrate efficacy (Needham et al. (2016) The Lancet Respiratory Medicine 4(3):203-212; Clinical Trial IDs NCT00979121 and NCT00719446).

[0070] As demonstrated herein, pharmaceutical agents with neurotrophic effects, such as those of Formulas I, II, III, and IV, can help minimize the neurological damage resulting from ARDS and its treatment.

[0071] In some embodiments, provided herein are methods for treating, inhibiting, reducing the severity of, delaying the onset of, or preventing cognitive impairment or impairment resulting from or caused by dyspnea in a subject, the methods comprising administering a therapeutically effective amount of a compound having the structure of Formula I, II, III, or IV to a subject at risk of, suffering from, or experiencing dyspnea, or who has previously experienced dyspnea. A subject who has previously experienced dyspnea is a subject who has experienced or been diagnosed with dyspnea within 1 day to 10 years of performing the methods herein. In some embodiments, administering a therapeutically effective amount of a compound disclosed herein to a subject who has previously experienced dyspnea comprises administering a compound disclosed herein to the subject within 1 day to 10 years of the subject suffering from or being diagnosed with dyspnea. In certain embodiments, the method includes preventing or inhibiting the decline and / or worsening of existing cognitive impairment, existing cognitive disorder, or existing neurodegenerative disease, the method comprising administering a therapeutically effective amount of a compound having the structure of Formula I, II, III, or IV to a subject at risk of, suffering from, or experiencing, dyspnea, or who has previously experienced dyspnea. The term "existing" in the context of dyspnea means before the subject experiences or suffers from dyspnea. In some embodiments, the method includes treating a subject at risk of, suffering from, or experiencing, dyspnea, or who has previously experienced dyspnea, comprising administering a therapeutically effective amount of a compound having the structure of Formula I, II, III, or IV to the subject, wherein cognitive impairment or cognitive impairment resulting from, caused by, or exacerbated by dyspnea is prevented, ameliorated, suppressed, reduced in severity, or delayed.In certain embodiments, the method comprises treating a subject at risk for, suffering from, experiencing, or having previously experienced dyspnea, comprising administering to the subject a therapeutically effective amount of a compound having the structure of Formula I, II, III, or IV, wherein a pre-existing cognitive impairment, pre-existing cognitive disorder, or pre-existing neurodegenerative disease is prevented from worsening or an increase in severity is prevented or inhibited.

[0072] Non-limiting examples of respiratory distress include acute respiratory distress, acute respiratory distress syndrome (ARDS), and severe acute respiratory syndrome (SARS). In certain embodiments, the respiratory distress is associated with hypoxia. In some embodiments, the ARDS is associated with or caused by sepsis, pneumonia, a lung infection (e.g., a fungal infection, a viral infection (e.g., influenza or coronavirus infection), or a bacterial infection), pancreatitis, physical trauma (e.g., head trauma, chest trauma, or lung trauma), aspiration, smoke inhalation, inhalation of toxic substances, idiopathic pulmonary fibrosis, blood transfusion, massive transfusion, burns, drowning, a drug reaction, a drug overdose, shock, lung surgery, cardiopulmonary bypass surgery, disseminated intravascular coagulation, or tick-borne relapsing fever. In some embodiments, the coronavirus is SARS-associated coronavirus or SARS-associated coronavirus-2. Thus, in certain embodiments, the methods herein include treating, inhibiting, reducing the severity of, delaying the onset of, or preventing cognitive impairment or impairment resulting from or caused by ARDS, where ARDS is caused by or associated with sepsis, pneumonia, a lung infection (e.g., a fungal infection, a viral infection (e.g., influenza or coronavirus infection), or a bacterial infection), pancreatitis, physical trauma (e.g., head trauma, chest trauma, or lung trauma), aspiration, smoke inhalation, inhalation of harmful substances, idiopathic pulmonary fibrosis, blood transfusion, massive transfusion, burns, drowning, a reaction to a drug, a drug overdose, shock, lung surgery, cardiopulmonary bypass surgery, disseminated intravascular coagulation, or tick-borne relapsing fever.

[0073] Non-limiting examples of cognitive impairment and disorders precipitated by, worsened by, or associated with dyspnea include loss of memory (short-term and long-term), loss of concentration, difficulty concentrating, loss of attention, delirium, confusion, decreased consciousness, difficulty completing familiar or routine tasks; confusion in space and time; impaired vision, loss of color or symbol recognition, loss or impairment of communication skills (e.g., difficulty speaking (e.g., slurred, slurred, or irregular speech), difficulty writing, loss of reading comprehension, loss of vocabulary, etc., or combinations thereof), loss of judgment, irritability, bad mood, unusual or frequent reactivity to stimuli, loss or impairment of executive function, depression, anxiety, post-traumatic stress disorder, etc., and combinations thereof. Additional non-limiting examples of cognitive impairment and cognitive disorders caused by, worsened by, or associated with dyspnea include fatigue (e.g., excessive fatigue); passivity; lethargy; lethargy; tremor; ataxia; spasms, shrinkage, or weakness; shortness of breath; difficulty breathing; loss of depth perception; unusual or frequent aggression; paranoia; delusions; withdrawal from social engagements; unusual or frequent stiffness or rigidity; loss of fine or gross motor control; slowed movements; impaired balance; physical instability; posture or gait abnormalities (e.g., shuffling, unsteady, or irregular gait); decreased coordination; motor dysfunction; Jerky or involuntary body movements; slow and saccadic eye movements; seizures; dysphagia; difficulty chewing, eating, or swallowing; decreased cognitive / mental abilities; dementia; irregular sleep; insomnia; sleep disorders; diagnosed behavioral or psychiatric abnormalities; impaired regulation of social behavior; social withdrawal; hyperactivity; pacing; wandering; impaired balance; lunging forward when mobilized; fast gait; ataxia; falls; personality changes; loss of inhibitions or ability to organize information; ophthalmoplegia or impaired eye movement; eyelid dysfunction; involuntary facial muscle contractures; parkinsonism; and the like, and combinations thereof.Thus, in some embodiments, methods include preventing, reducing the severity of, delaying the onset of, and / or treating one or more cognitive impairments or cognitive dysfunctions caused by, worsened by, or associated with dyspnea, the methods comprising administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein, to a subject suffering from, suspected of having, or at risk of having dyspnea.

[0074] In some embodiments, the methods include treating, inhibiting, reducing the severity of, delaying the onset of, or preventing memory loss resulting from or caused by respiratory distress in a subject.

[0075] In some embodiments, the methods include treating, inhibiting, reducing the severity of, delaying the onset of, or preventing impairment or loss of attention or concentration resulting from or caused by dyspnea in a subject.

[0076] In some embodiments, the methods include treating, inhibiting, reducing the severity of, delaying the onset of, or preventing the reduction or worsening of delirium resulting from or caused by respiratory distress in a subject.

[0077] In some embodiments, the methods include treating, inhibiting, reducing the severity of, delaying the onset of, or preventing the reduction or worsening of depression, anxiety, and / or post-traumatic stress disorder resulting from or caused by dyspnea in a subject.

[0078] In some embodiments, the methods include treating, inhibiting, reducing the severity of, delaying the onset of, or preventing impairment or loss of executive function, speech, language, or communication skills resulting from or caused by dyspnea in a subject.

[0079] In some embodiments, the methods include treating, inhibiting, reducing the severity of, delaying the onset of, or preventing impairment or loss of visual and spatial abilities resulting from or caused by respiratory distress in a subject.

[0080] In some embodiments, the methods include treating, inhibiting, reducing the severity of, delaying the onset of, or preventing an akinetic crisis resulting from or caused by dyspnea in a subject.

[0081] In some embodiments, cognitive impairment or loss due to dyspnea is detected and / or diagnosed by a medical professional. Cognitive impairment, impairment, or loss of cognitive function due to dyspnea can be detected and / or diagnosed by comparing the results of appropriate cognitive testing (e.g., psychological testing) administered before and / or after the onset of dyspnea. The appropriate cognitive testing can be administered before and / or at least one day, or at least one week after the onset of dyspnea. In some embodiments, the cognitive testing is administered 1 to 30 days, 1 to 15 days, or 1 to 7 days after the onset of dyspnea in the ICU. In some embodiments, the cognitive testing is administered 1 to 6 months, 1 to 30 days, 1 to 15 days, or 1 to 7 days before the onset of dyspnea.

[0082] In certain embodiments, the subject has not been diagnosed with a cognitive impairment or a neurodegenerative disease prior to the dyspnea, hi certain embodiments, the subject has not been diagnosed with and / or does not suffer from cancer, diabetes, arthritis, insulinoma, stroke, or ischemia (e.g., cardiac ischemia) prior to the dyspnea.

[0083] In certain embodiments, the subject has been diagnosed with a cognitive impairment or a neurodegenerative disease during or before the dyspnea. In certain embodiments, the subject has been previously diagnosed with, is suffering from, or is suspected of having, cancer, diabetes, hyperglycemia, hypoglycemia, serum glucose fluctuations, acute hospital stress syndrome, delirium, arthritis, pancreatitis, and / or insulinoma during or before the dyspnea. In certain embodiments, the subject has or has been diagnosed with asthma during or before the dyspnea. In certain embodiments, the subject has or has been diagnosed with pneumonia during or before the dyspnea.

[0084] PICCD Presented herein are methods for preventing, reducing the severity of, delaying the onset of, and / or treating PICCD, which, in certain embodiments, comprise administering a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein to a subject suffering from, suspected of suffering from, or at risk of suffering from PICCD. In some embodiments, the method comprises treating a subject suffering from, suspected of suffering from, or at risk of suffering from PICCD, comprising administering to the subject (e.g., a subject in need thereof) a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein.

[0085] PICCD is a cognitive condition that is precipitated, caused, or worsened by an intensive care unit (ICU) stay, intubation, and / or mechanical ventilation. In certain embodiments, PICCD is a cognitive impairment, cognitive impairment, and / or decline, loss, or impairment of one or more cognitive functions that occurs during or after an intensive care unit (ICU) stay, during or after intubation, and / or during or after mechanical ventilation. In some embodiments, PICCD is a new cognitive impairment or impairment detected or diagnosed after an ICU stay, after intubation, or after mechanical ventilation. Thus, in certain embodiments, PICCD is a cognitive impairment or impairment that was not present before an ICU stay, before intubation, or before mechanical ventilation, but is present after an ICU stay, after intubation, and / or after the subject is attached to a mechanical ventilation. In some embodiments, PICCD comprises or consists of post-intensive care syndrome (Inoue, et al. (2019) Acute Medicine & Surgery 6:233-246).

[0086] In some embodiments, PICCD is a chronic condition. In some embodiments, chronic PICCD can last for 6 months or more, 12 months or more, or 1 year or more, or may last for 5 years or more if untreated. Thus, in some embodiments, methods include preventing or treating chronic PICCD in a subject, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein.

[0087] In some embodiments, PICCD is an acute condition. In some embodiments, acute PICCD can last up to 6 months, up to 12 months, up to 20 months, or up to 36 months after an ICU stay, intubation, or mechanical ventilation. Thus, in some embodiments, methods include preventing or treating acute PICCD in a subject, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein.

[0088] Non-limiting examples of cognitive impairments and disorders associated with PICCD include memory loss (short-term and long-term), loss of concentration, difficulty concentrating, loss of attention, delirium, confusion, decreased awareness, difficulty completing familiar or routine tasks; confusion in space and time; impaired vision, loss of color or symbol recognition, loss or impairment of communication skills (e.g., difficulty speaking (e.g., slurred, slurred, or irregular speech), difficulty writing, loss of reading comprehension, loss of vocabulary, etc., or combinations thereof), loss of judgment, irritability, unusual or frequent reactivity to stimuli, loss or impairment of executive function, depression, anxiety, post-traumatic stress disorder, etc., and combinations thereof. Additional non-limiting examples of cognitive impairment and disorders associated with PICCD include fatigue (e.g., excessive fatigue); passivity; lethargy; lethargy; tremor; ataxia; twitching, shrinking, or weakness; shortness of breath; difficulty breathing; loss of depth perception; unusual or frequent aggression; paranoia; delusions; withdrawal from social engagements; unusual or frequent stiffness or rigidity; loss of fine or gross motor control; slowed movements; impaired balance; physical instability; posture or gait abnormalities (e.g., shuffling, unsteady, or irregular gait); decreased coordination; motor dysfunction; jerky or irregular movements. These include: involuntary body movements; slow and saccadic eye movements; seizures; dysphagia; difficulty chewing, eating, or swallowing; decreased cognitive / mental abilities; dementia; irregular sleep; insomnia; sleep disorders; diagnosed behavioral or psychiatric abnormalities; impaired regulation of social behavior; social withdrawal; hyperactivity; pacing; wandering; impaired balance; lunging forward when mobilizing; fast gait; ataxia; falls; personality changes; loss of inhibition or ability to organize information; ophthalmoplegia or impaired eye movement; eyelid dysfunction; involuntary facial muscle contractures; parkinsonism; and the like, and combinations thereof. Thus, in some embodiments, methods include preventing, reducing the severity of, delaying the onset of, and / or treating one or more cognitive impairments or cognitive dysfunctions of PICCD, the methods comprising administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein, to a subject suffering from, suspected of suffering from, or at risk of suffering from PICCD.

[0089] In some embodiments, methods of treating or preventing PICCD include treating or preventing, delaying the onset of, reducing the severity of, reducing the frequency of, and / or inhibiting memory impairment or loss.

[0090] In some embodiments, methods of treating or preventing PICCD include treating or preventing, delaying the onset of, reducing the severity of, reducing the frequency of, and / or inhibiting impairment or loss of attention or concentration (e.g., a subject's ability to concentrate).

[0091] In some embodiments, methods of treating or preventing PICCD include treating or preventing the reduction or worsening of delirium, delaying its onset, reducing its severity, reducing its frequency, and / or inhibiting it. Non-limiting examples of symptoms of delirium include decreased awareness of a subject's environment, decreased ability to focus attention, disorientation to time, place, and people, speech disturbances (e.g., inability to name objects, inability to write, and indistinct speech), perceptual disturbances (e.g., hallucinations, illusions, or misunderstandings), and the like, and combinations thereof.

[0092] In some embodiments, methods of treating or preventing PICCD include treating or preventing, delaying the onset of, reducing the severity of, reducing the frequency of, and / or inhibiting the worsening of depression, anxiety, and / or post-traumatic stress disorder.

[0093] In some embodiments, methods of treating or preventing PICCD include treating or preventing, delaying the onset of, reducing the severity of, reducing the frequency of, and / or inhibiting impairment or loss of executive function, speech, language, or communication skills.

[0094] In some embodiments, methods of treating or preventing PICCD include treating or preventing, delaying the onset of, reducing the severity of, reducing the frequency of, and / or inhibiting impairment or loss of visual and spatial abilities.

[0095] In some embodiments, methods of treating or preventing PICCD include preventing, alleviating the symptoms of, delaying the onset of, or treating an akinetic crisis that occurs during or after an intensive care unit (ICU) stay, intubation, and / or mechanical ventilation. An akinetic crisis (also known as acute akinesia) refers to a situation in which the motor symptoms of Parkinson's disease (PD) suddenly worsen to the point where the patient is almost completely akinetic. Non-limiting examples of symptoms of an akinetic crisis include a worsening of or symptoms of problems such as dysphagia, hyperthermia, autonomic imbalance, tremor, bradykinesia, muscle rigidity, loss of movement, difficulty with physical movements, slow movements, impaired posture and balance, changes in speech, changes in writing, micrographia, muscle stiffness, difficulty standing, difficulty walking, involuntary movements, coordination problems, rhythmic muscle contractions, elevated serum muscle enzyme levels, and combinations thereof.

[0096] In certain embodiments, PICCD is an exacerbation or worsening of a pre-existing cognitive disorder, pre-existing cognitive impairment, or pre-existing neurodegenerative disease that occurs during or after a stay in an intensive care unit (ICU), during or after intubation, and / or during or after mechanical ventilation. In some embodiments, PICCD is a pre-existing cognitive disorder or neurodegenerative disease that is exacerbated, increases in severity, or worsens as a result of a stay in an ICU, intubation, or mechanical ventilation. The term "pre-existing" in the context of PICCD means before admission to the ICU, before intubation, and / or before mechanical ventilation. Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, glaucoma, retinal degeneration, macular degeneration, presbycusis, mild cognitive impairment, dementia, delirium, depression, anxiety, progressive supranuclear palsy, spinocerebellar ataxia, retinal neuropathy, peripheral neuropathy, diabetic neuropathy, background neuropathy, familial amyloid polyneuropathy, senile systemic amyloidosis, prion diseases, scrapie, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, amyloidosis, and the like, and combinations thereof.

[0097] In some embodiments, PICCD is detected and / or diagnosed by a medical professional. PICCD can be detected and / or diagnosed by comparing the results of appropriate cognitive testing (e.g., psychological testing) administered before and / or after an intensive care unit (ICU) stay or admission, intubation, and / or mechanical ventilation. Suitable cognitive testing can be administered before and / or at least one day, or at least one week after an ICU stay, intubation, and / or mechanical ventilation. In some embodiments, cognitive testing can be administered 1 to 30 days, 1 to 15 days, or 1 to 7 days after an ICU stay, intubation, and / or mechanical ventilation. In some embodiments, cognitive testing can be administered 1 to 6 months, 1 to 30 days, 1 to 15 days, or 1 to 7 days before an ICU stay, intubation, and / or mechanical ventilation.

[0098] Multiple cognitive domains can be tested to determine the presence or severity of cognitive impairment or disorder, non-limiting examples of which include tests of learning, memory, attention, and concentration. Non-limiting examples of cognitive tests that can be administered to diagnose the presence, absence, severity, onset, or amount of cognitive impairment or disorder include the Mini-Mental State Examination (MMSE) (see, e.g., Saczynski et al., (2012) N. Engl. J. Med. 367:30-39); the Confidence Change Index (see, e.g., Lewis et al., (2006) Acta Anaesthesiol Scand. 50:50-57; and Berger et al., (2015) Anesthesiol Clin. 33(3):517-50); Rey Auditory Verbal Learning Test; Trail Making Test, Parts A and B; Grooved Pegboard Test; Digit Span Test; Stroop Test, Four Fields Test, Erzigkeit Short-Term Cognitive Performance Test; patient self-assessment; and various tests disclosed in various clinical trials (see, e.g., ClinicalTrials.gov numbers: NCT0361019, NCT03540433, NCT02265263, NCT02650687, NCT02848599, NCT03084393, NCT03029676, and NCT03635229).

[0099] PICCD has not been clearly linked to a pathological process, and its etiology has not been precisely identified. Inflammation may be involved in PICCD. However, several immunosuppressants / anti-inflammatory drugs have failed to prevent or treat cognitive impairment thought to be induced, caused, or exacerbated by surgery. For example, intravenous magnesium (considered an immunosuppressant) administered during cardiac surgery failed to alleviate postoperative cognitive impairment in clinical trials (see, e.g., ClinicalTrials.gov number: NCT00041392). As another example, pexelizumab, a humanized monoclonal antibody used as an immunosuppressant, did not affect postoperative cognitive impairment after coronary artery bypass graft surgery (see, e.g., Mathew et al. (2004) Stroke 35:2335-239). As yet another example, minocycline, an antibiotic that has been shown to have anti-inflammatory and neuroprotective effects, exacerbated postoperative cognitive impairment (Li W, et al., (2018) J Int Med Res.46(4):1404-1413). Therefore, it cannot be predicted with reasonable certainty that PICCD is a disorder caused by inflammation or that specific drugs with anti-inflammatory or immunosuppressive properties can be used to prevent or treat PICCD.

[0100] Additionally, some drugs used to treat neurodegenerative diseases have failed to prevent or treat postoperative cognitive impairment. For example, donepezil (Aricept), used to treat dementia, memory loss, and Alzheimer's disease, did not affect the overall cognitive scores of patients with cognitive decline one year after cardiac surgery (Doraiswamy et al., (2007) Psychopharmacol Bull. 40:54-62). Dexmedetomidine, a sedative suggested for use in the treatment of delirium (MacLaren, et al. (2015) Journal of Intensive Care Medicine. 30 (3): 167-175), also failed to demonstrate efficacy against postoperative cognitive impairment (Skvarc et al., (2018) Neurosci. Biobehav. Rev. 84, 116-133). A clinical investigation testing the use of rivastigmine (Exelon), an AD / Parkinson's disease drug, to treat postoperative cognitive impairment was terminated because it proved too dangerous for critically ill patients after surgery, and no efficacy was observed at the time of termination (NCT00835159). Therefore, it cannot be predicted with reasonable certainty that drugs used successfully to treat neurological disorders can also be used to prevent or treat PICCD.

[0101] subject The term "subject" refers to a mammal. Any suitable mammal can be treated by the methods or compositions described herein. Non-limiting examples of mammals include humans, non-human primates (e.g., apes, gibbons, chimpanzees, orangutans, monkeys, macaques, etc.), livestock (e.g., dogs and cats), farm animals (e.g., horses, cows, goats, sheep, pigs), and laboratory animals (e.g., mice, rats, rabbits, guinea pigs). In some embodiments, the subject is a non-human primate or a human. In some embodiments, the subject is a human. The subject can be of any age or at any stage of development (e.g., an adult, teenager, child, infant, or mammal in utero). The subject can be male or female.

[0102] In some embodiments, the subject is one who exhibits stable cognitive function (e.g., before respiratory distress, before ICU stay, before intubation, and / or before being placed on a ventilator). In some embodiments, the subject has not previously been diagnosed with a cognitive impairment or neurodegenerative disease (e.g., before respiratory distress, before ICU stay, before intubation, and / or before being placed on a ventilator). In some embodiments, the subject has not previously been diagnosed with cancer, diabetes, arthritis, insulinoma, stroke, or ischemia (e.g., cardiac ischemia). In some embodiments, the subject has not previously been administered a compound selected from any one of Formula I, Formula II, Formula III, and Formula IV. In certain embodiments, the subject is about to, will be, has been, and / or recently (e.g., within hours to days) placed on an ICU, intubated, or placed on a ventilator.

[0103] In certain embodiments, a subject is at risk of developing PICCD. In some embodiments, a subject at risk of developing PICCD is 45 years of age or older, 50 years of age or older, 55 years of age or older, 60 years of age or older, 65 years of age or older, 70 years of age or older, or 75 years of age or older. In some embodiments, a subject at risk of developing PICCD is 45 to 100 years of age, 50 to 100 years of age, 55 to 100 years of age, 60 to 100 years of age, 65 to 100 years of age, 70 to 100 years of age, or 75 to 100 years of age. In some embodiments, a subject at risk of developing PICCD is a pediatric subject or patient. In some embodiments, a subject at risk of developing PICCD is 18 years of age or younger, 16 years of age or younger, 13 years of age or younger, 10 years of age or younger, 8 years of age or younger, or 5 years of age or younger. In some embodiments, subjects at risk of developing PICCD are in the age range of 18 years to 1 week, 18 years to 1 month, 18 years to 6 months, 18 years to 1 year, 16 years to 1 year, or 13 years to 1 year.

[0104] In certain embodiments, a subject with PICCD or at risk for PICCD is a subject suffering from, suspected of, or previously diagnosed (e.g., prior to intubation, admission to an ICU, or connection to a ventilator) with a cognitive impairment or neurodegenerative disease. In certain embodiments, a subject with PICCD or at risk for PICCD is a subject suffering from, suspected of, or previously diagnosed with symptoms of dementia, delirium, depression, anxiety, and / or acute hospital stress.

[0105] In certain embodiments, a subject with PICCD or at risk for PICCD is a subject suffering from, suspected of, or previously diagnosed with diabetes, hyperglycemia, hypoglycemia, serum glucose fluctuations, and / or pancreatitis. In certain embodiments, a subject with PICCD or at risk for PICCD is a subject suffering from, suspected of, or previously diagnosed with cancer.

[0106] Certain studies suggest that female subjects are significantly more likely to develop PICCD, and therefore, in some embodiments, the at-risk subject is female.

[0107] Certain studies suggest that patients with secondary health conditions, non-limiting examples of which include organ dysfunction, pulmonary dysfunction, and asthma, are at increased risk for developing PICCD. Thus, in certain embodiments, a subject with or at risk for PICCD is one who has, is suspected of having, or has previously been diagnosed with organ dysfunction, pulmonary dysfunction, or asthma.

[0108] In certain embodiments, subjects at risk for PICCD are those with an education level of 12th grade (GED or high school diploma) or less.

[0109] In certain embodiments, a subject with PICCD or at risk for PICCD is a subject suffering from, suspected of, or previously diagnosed with acute respiratory syndrome, severe acute respiratory syndrome, asthma, pneumonia, or an infectious disease. In certain embodiments, a subject with PICCD or at risk for PICCD is a subject suffering from, suspected of, or previously diagnosed with an infection by a pathogen, non-limiting examples of which include bacteria, viruses, or fungi. In certain embodiments, a subject with PICCD or at risk for PICCD is a subject infected with a coronavirus, non-limiting examples of which include SARS-associated coronavirus (SARS-CoV) and SARS-associated coronavirus-2 (SARS-CoV-2). In certain embodiments, a subject with PICCD or at risk for PICCD is a subject suffering from or suspected of suffering from COVID-19.

[0110] Pharmaceutical Composition In some embodiments, a composition or pharmaceutical composition comprises a compound disclosed herein. In some embodiments, a composition or pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein. In some embodiments, a composition or pharmaceutical composition comprises a compound disclosed herein in an amount ranging from 1 μg to 100 mg, or from 10 μg to 100 μg. In some embodiments, provided herein are pharmaceutical compositions comprising a compound disclosed herein for use in practicing the methods described herein. In some embodiments, the pharmaceutical composition comprises a compound disclosed herein and a pharmaceutically acceptable excipient, diluent, additive, or carrier.

[0111] Pharmaceutical compositions can be formulated for an appropriate route of administration. In some embodiments, pharmaceutical compositions are formulated for oral, subcutaneous (sc), intradermal, intramuscular, intraperitoneal, and / or intravenous (iv) administration. In certain embodiments, pharmaceutical compositions include formulation materials to modify, maintain, or preserve, for example, the pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption or penetration of the composition. In certain embodiments, suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine, or lysine); antimicrobial agents; antioxidants (such as ascorbic acid, sodium sulfite, or sodium bisulfite); buffers (such as borate, bicarbonate, Tris-HCl, citrate, phosphate (e.g., phosphate buffered saline), or suitable organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediaminetetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, β-cyclodextrin, or hydroxypropyl-β-cyclodextrin); proteins (such as serum albumin, gelatin, or immunoglobulins); colorants, flavorings, and diluents; emulsifiers; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight polypeptides; salt-forming counterions (such as sodium); solvents (such as glycerin, propylene glycol, or polyethylene glycol); diluents; excipients and / or pharmaceutical adjuvants. In particular, the pharmaceutical compositions may include any suitable carrier, agent, or ingredient, or combination thereof, listed in "Remington: The Science And Practice Of Pharmacy" Mack Publishing Co., Easton, PA, 19th Edition, (1995) (hereinafter Remington '95), or "Remington: The Science And Practice Of Pharmacy", Pharmaceutical Press, Easton, PA, 22nd Edition, (2013) (hereinafter Remington 2013), the entire contents of which are incorporated herein by reference.

[0112] In certain embodiments, the pharmaceutical composition comprises suitable excipients, non-limiting examples of which include anti-adherents (e.g., magnesium stearate), binders, fillers, monosaccharides, disaccharides, other carbohydrates (e.g., glucose, mannose, or dextrin), sugar alcohols (e.g., mannitol or sorbitol), coatings (e.g., cellulose, hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, synthetic polymers, shellac, gelatin, corn protein zein, enterobacteriaceae, or other polysaccharides), starches (e.g., potato, corn, or wheat starch), silica, and the like. Examples of suitable binders include colorants, disintegrants, flavoring agents, lubricants, preservatives, adsorbents, sweeteners, vehicles, suspending agents, surfactants, and / or wetting agents (such as Pluronic®, PEG, sorbitan esters, polysorbates such as Polysorbate 20, Polysorbate 80, Triton, tromethamine, lecithin, cholesterol, tyloxapal, etc.), stability enhancers (such as sucrose or sorbitol), and tonicity enhancers (such as alkali metal halides, sodium or potassium chloride, mannitol, sorbitol, etc.), and / or any excipients disclosed in Remington '95 or Remington 2013. As used herein, the term "binder" refers to a compound or ingredient that helps hold a pharmaceutical mixture together. Suitable binders for manufacturing pharmaceutical formulations, often used in the preparation of pharmaceutical tablets, capsules, and granules, are known to those skilled in the art.

[0113] In some embodiments, the pharmaceutical composition comprises a suitable pharmaceutically acceptable excipient and / or carrier. Non-limiting examples of suitable excipients include suitable pH adjusters, soothing agents, buffers, sulfur-containing reducing agents, antioxidants, etc. Non-limiting examples of sulfur-containing reducing agents include those having a sulfhydryl group (e.g., thiol), such as N-acetylcysteine, N-acetylhomocysteine, thioctic acid, thiodiglycol, thioethanolamine, thioglycerol, thiosorbitol, thioglycolic acid and its salts, sodium thiosulfate, glutathione, and C1-C7 thioalkanoic acids. Non-limiting examples of antioxidants include erythorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, α-tocopherol, tocopherol acetate, L-ascorbic acid and its salts, L-ascorbyl palmitate, L-ascorbyl stearate, sodium bisulfite, sodium sulfite, triamyl gallate, and propyl gallate, as well as chelating agents such as ethylenediaminetetraacetic acid (EDTA), sodium pyrophosphate, and sodium metaphosphate. Additionally, diluents, additives, and excipients may contain other commonly used ingredients, for example, inorganic salts such as sodium chloride, potassium chloride, calcium chloride, sodium phosphate, potassium phosphate, and sodium bicarbonate, and organic salts such as sodium citrate, potassium citrate, and sodium acetate.

[0114] The pharmaceutical compositions used herein may be stable for extended periods of time, for example, months or years. In some embodiments, the pharmaceutical compositions contain one or more suitable preservatives. Non-limiting examples of preservatives include benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, hydrogen peroxide, and / or combinations thereof. Preservatives can include quaternary ammonium compounds such as benzalkonium chloride, benzoxonium chloride, benzethonium chloride, cetrimide, sepazonium chloride, cetylpyridinium chloride, or domiphen bromide (BRADOSOL®). Preservatives can include alkylmercury salts of thiosalicylic acid, such as thimerosal, phenylmercuric nitrate, phenylmercuric acetate, or phenylmercuric borate. Preservatives can include parabens, such as methylparaben or propylparaben. Preservatives can include alcohols, such as chlorobutanol, benzyl alcohol, or phenylethyl alcohol. Preservatives can include biguanide derivatives such as chlorhexidine or polyhexamethylene biguanide. Preservatives can include sodium perborate, imidazolidinyl urea, and / or sorbic acid. Preservatives can include stabilized oxychloro complexes, such as those commercially available under the trade name PURITE®. Preservatives can include polyglycol-polyamine condensation resins, such as those commercially available under the trade name POLYQUART® from Henkel KGaA. Preservatives can include stabilized hydrogen peroxide. The preservative can be benzalkonium chloride. In some embodiments, the pharmaceutical composition is preservative-free.

[0115] In some embodiments, the compositions, pharmaceutical compositions, or compounds disclosed herein are substantially free of contaminants (e.g., blood cells, platelets, polypeptides, minerals, blood-derived compounds or chemicals, viruses, bacteria, other pathogens, toxins, etc.). In some embodiments, the compositions, pharmaceutical compositions, or compounds disclosed herein are substantially free of serum and serum contaminants (e.g., serum proteins, serum lipids, serum carbohydrates, serum antigens, etc.). In some embodiments, the compositions, pharmaceutical compositions, or compounds disclosed herein are substantially free of pathogens (e.g., viruses, parasites, or bacteria). In some embodiments, the compositions, pharmaceutical compositions, or compounds disclosed herein are substantially free of endotoxins. In some embodiments, the compositions, pharmaceutical compositions, or compounds disclosed herein are sterile. In certain embodiments, the compositions or pharmaceutical compositions disclosed herein comprise a compound of Formula I, II, III, or IV.

[0116] The pharmaceutical compositions described herein can be configured to be administered to a subject in any suitable form and / or amount according to the therapeutic method for which they are used. For example, pharmaceutical compositions configured for parenteral administration (e.g., by injection or infusion) can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, which may include formulating agents, excipients, additives, and / or diluents such as aqueous or non-aqueous solvents, cosolvents, suspending solutions, preservatives, stabilizers, and / or dispersing agents. In some embodiments, pharmaceutical compositions suitable for parenteral administration may include one or more excipients. In some embodiments, the pharmaceutical composition is lyophilized into a dry powder form. In some embodiments, the pharmaceutical composition is lyophilized into a dry powder form suitable for reconstitution with an appropriate pharmaceutical solvent (e.g., water, saline, isotonic buffer (e.g., PBS), DMSO, combinations thereof, etc.). In certain embodiments, the reconstituted form of the lyophilized pharmaceutical composition is suitable for parenteral administration (e.g., intravenous administration) to a mammal.

[0117] In certain embodiments, the pharmaceutical composition is adapted for oral administration and can be formulated as a tablet, microtablet, minitablet, micropellet, powder, granule, capsule (e.g., capsule filled with microtablets, micropellets, powder, or granules), emulsion, solution, etc., or combinations thereof. Pharmaceutical compositions adapted for oral administration can include a suitable coating to delay or sustain the release of the active ingredient, non-limiting examples of which include enteric coatings such as fatty acids, waxes, shellac, plastics, methyl acrylate-methacrylic acid copolymer, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer, cellulose acetate trimellitate, sodium alginate, zein, vegetable fibers, etc., and combinations thereof.

[0118] In some embodiments, the pharmaceutical compositions described herein can be configured for topical administration and can include one or more of the following: binders and / or lubricants, polymeric glycols, gelatin, cocoa butter, or other suitable waxes or fats. In some embodiments, the pharmaceutical compositions described herein are incorporated into a topical formulation containing a topical carrier, which is generally suitable for topical drug administration and includes any suitable material known to those skilled in the art. In certain embodiments, the topical formulation of the pharmaceutical composition is formulated to administer the compound using a topical patch.

[0119] In certain embodiments, the optimal pharmaceutical composition will be determined by one of skill in the art depending, for example, on the intended route of administration, delivery format, and desired dosage (see, e.g., Remington '95 or Remington 2013, supra.) Pharmaceutical compositions can be manufactured by any suitable method, including, for example, conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or tabletting processes (see, e.g., methods described in Remington '95 or Remington 2013).

[0120] Route of administration Any suitable method of administering the compositions, pharmaceutical compositions, or compounds disclosed herein to a subject can be used. Any suitable formulation and / or administration route can be used to administer the compounds disclosed herein or the compositions disclosed herein (see, for example, Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics," which is incorporated herein by reference in its entirety). The appropriate formulation and / or administration route can be selected by a medical professional (e.g., a physician) taking into account, for example, the risk, age, and / or condition of the subject. Non-limiting examples of routes of administration include topical or local (e.g., transdermal or dermal (e.g., on the skin or epidermis), intraocular or supraocular, intranasal, transmucosal, otic, intraaural (e.g., behind the tympanic membrane)), enteral (e.g., delivered via the gastrointestinal tract, e.g., orally (e.g., as a tablet, capsule, granule, liquid, emulsion, lozenge, or combination thereof), sublingually, by gastric feeding tube, rectally, etc.), parenteral administration (e.g., parenterally, e.g., intravenously, intraarterially, intramuscularly, intraperitoneally, intradermally, subcutaneously, intracavitary, intracranially, intra-articularly, into a joint cavity, intracardially, (into the heart), intracavernously, intralesionally (into a lesion), intraosseous infusion (into bone marrow), intraspinal (into the spinal canal), intrauterinely, intravaginally, intravesically, intravitreal), etc., or combinations thereof.

[0121] In some embodiments, a compound disclosed herein or a pharmaceutical composition described herein is administered to the lungs, bronchi, trachea, esophagus, paranasal sinuses, or nasal cavity using a suitable method, non-limiting examples of which include intranasal administration, intratracheal instillation, and oral inhalation administration (e.g., by use of an inhaler, e.g., a single / multiple dose dry powder inhaler, a nebulizer, etc.).

[0122] In some embodiments, a compound disclosed herein or a pharmaceutical composition disclosed herein is provided to a subject. For example, the composition provided to a subject may be provided to the subject for self-administration or for administration to the subject by another person (e.g., a non-medical professional). As another example, the composition may be provided as written instructions (e.g., a prescription) by a medical practitioner authorizing the provision of a composition or treatment described herein to the patient. In yet another example, the composition may be provided to a subject where the subject self-administers the composition, for example, orally, intravenously, or using an inhaler.

[0123] Alternatively, the compounds or compositions disclosed herein can be administered locally rather than systemically, for example, by direct application to the skin, mucosa, or area of ​​interest for treatment, including the use of a depot or sustained release formulation.

[0124] In certain embodiments, a pharmaceutical composition comprising a compound disclosed herein is administered alone (e.g., as a single active ingredient (AI, or e.g., as a single active pharmaceutical ingredient (API)). In other embodiments, a pharmaceutical composition comprising a compound disclosed herein is administered in combination with one or more additional AIs / APIs, e.g., as two separate compositions or as a single composition in which the one or more additional AIs / APIs are mixed or formulated together with the compound disclosed herein in the pharmaceutical composition.

[0125] Dosage and Therapeutically Effective Amount In some embodiments, the amount of a compound disclosed herein (e.g., in a pharmaceutical composition) is a therapeutically effective amount. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein. In some embodiments, a therapeutically effective amount of a compound disclosed herein is administered to a subject. In some embodiments, a therapeutically effective amount of a compound disclosed herein is the amount necessary to achieve an effective therapeutic outcome. In certain embodiments, a therapeutically effective amount of a compound disclosed herein is an amount sufficient to treat or prevent cognitive impairment or cognitive impairment caused by dyspnea. In certain embodiments, a therapeutically effective amount of a compound disclosed herein is an amount sufficient to treat or prevent PICCD. Determination of a therapeutically effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0126] In certain embodiments, a therapeutically effective amount is an amount high enough to provide an effective therapeutic effect (e.g., a beneficial therapeutic effect) and low enough to minimize undesirable adverse effects. Thus, in certain embodiments, the therapeutically effective amount of a compound disclosed herein may vary from subject to subject, often depending on the age, weight, general health condition of the subject, the severity of the condition being treated, the length of stay in the ICU, the length of intubation, or the time the subject is connected to a ventilator. Thus, in some embodiments, the therapeutically effective amount is determined empirically. Thus, the therapeutically effective amount of a compound to be administered to a subject can be determined by those skilled in the art, for example, based on the amount found to be effective in animal or clinical studies, the physician's experience, and the recommended dosage range or dosing guidelines.

[0127] In certain embodiments, a therapeutically effective amount of a compound disclosed herein is administered at an appropriate dose (e.g., at an appropriate amount, frequency, and / or concentration, which often depends on the subject's body weight, age, and / or condition) to achieve an acceptable therapeutic outcome. In certain embodiments, a therapeutically effective amount of a compound includes one or more doses selected from at least 0.01 mg / kg (e.g., mg of compound of the invention per kg of subject body weight), at least 0.1 mg / kg, at least 0.5 mg / kg, at least 1 mg / kg, at least 10 mg / kg, or at least 100 mg / kg. In certain embodiments, a therapeutically effective amount of a compound is from about 0.001 mg / kg (e.g., mg of a compound of the invention per kg of subject body weight) to about 5000 mg / kg, 0.01 mg / kg to 1000 mg / kg, 0.01 mg / kg to 500 mg / kg, 0.1 mg / kg to 1000 mg / kg, 1 mg / kg to 1000 mg / kg, 10 mg / kg to 1000 mg / kg, 100 mg / kg to 1000 mg / kg, 0.1 mg / kg The dose is selected from one or more doses of 0.1 mg / kg to 500 mg / kg, 0.1 mg / kg to 250 mg / kg, 0.1 mg / kg to 150 mg / kg, 0.1 mg / kg to 100 mg / kg, 0.1 mg / kg to 75 mg / kg, 0.1 mg / kg to 50 mg / kg, 0.1 mg / kg to 25 mg / kg, 0.1 mg / kg to 10 mg / kg, 0.1 mg / kg to 5 mg / kg, 0.5 mg / kg to 5 mg / kg, and intervening doses and combinations thereof. In some aspects, the therapeutically effective amount of a compound administered to a subject comprises one or more doses of about 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 50 mg / kg, 100 mg / kg, 500 mg / kg, and intervening amounts and combinations thereof. In some embodiments, a therapeutically effective amount of a compound disclosed herein is between about 0.1 mg / kg and about 50 mg / kg.

[0128] In certain embodiments, a therapeutically effective amount of a compound comprises one or more doses, the dose being determined by reference to a dose selected from the effective doses for mice, as follows: A mouse dose of D μg / g = D mg / kg can be converted by a conversion factor known in the art, such as 3 / 37, which is a conversion factor that takes into account the difference in body surface area between mice and humans (see FASEB J. 22, 659-661 (2007)). Thus, in some embodiments, an appropriate dose for a human would be (3 / 37) * D mg / kg, based on the mouse dose of D μg / g. For example, a mouse dose of 5 μg / g would convert to 5 mg / kg × 3 / 37 = 0.40 mg / kg in humans, which would be a dose of 24 mg in a 60 kg human. Using this conversion, (i) a mouse dose of 10 μg / g would result in a human dose of 0.81 mg / kg, and (ii) a mouse dose of 25 μg / g would result in a human dose of 2.02 mg / kg.

[0129] In some aspects, the therapeutically effective amount of a compound administered to a subject comprises one or more doses of about 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2.0 mg / kg, and intervening amounts and combinations thereof. In some embodiments, a therapeutically effective amount of a compound disclosed herein is between about 0.4 mg / kg and about 2.0 mg / kg.

[0130] In some embodiments, administering a therapeutically effective amount of a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein includes administering a suitable dose at a frequency or interval needed to achieve an effective therapeutic result. In some embodiments, administering a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein includes administering a suitable dose hourly, every 2 hours, every 4 hours, every 6 hours, three times a day, twice a day, once a day, six times a week, five times a week, four times a week, three times a week, twice a week, once a week, combinations thereof, and / or at regular or irregular intervals thereof, and / or simply as needed or as recommended by a medical professional. In some embodiments, a therapeutically effective amount of a compound or pharmaceutical composition is administered continuously, for example, by intravenous administration.

[0131] In some embodiments, a therapeutically effective amount of a compound is administered to a subject before, during, or after an ICU stay, intubation, or mechanical ventilation. In some embodiments, a therapeutically effective amount of a compound is administered to a subject up to 3 days, up to 2 days, up to 1 day, up to 20 hours, up to 15 hours, up to 10 hours, up to 5 hours, up to 2 hours, or up to 1 hour before an ICU stay, intubation, or mechanical ventilation. In some embodiments, a therapeutically effective amount of a compound is administered to a subject 0 to 72 hours, 0 to 48 hours, 0 to 24 hours, 0 to 12 hours, 0 to 6 hours, 0 to 4 hours, or 0 to 2 hours before an ICU stay, intubation, or mechanical ventilation. In some embodiments, a therapeutically effective amount of a compound is administered during an ICU stay, intubation, and / or while the subject is mechanically ventilated. In some embodiments, a therapeutically effective amount of the compound is administered intermittently or continuously up to 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 2 days, 3 days, 1 week, 1 month, 3 months, 6 months, 12 months, 18 months, 24 months, or up to 36 months after ICU stay, intubation, or connection to a ventilator.

[0132] The term "connected" as used herein with respect to a ventilator means that the ventilator is "operably connected" to provide oxygen to the lungs of a subject or patient. Ventilators are known in the art and are often medical machines that actively move breathable air and / or oxygen into and out of a patient's lungs.

[0133] The phrase "intensive care unit (ICU)" refers to an intensive care unit, intensive care facility, intensive care department, and / or intensive care unit, which is a specialized department or branch of a hospital that provides intensive care medications to patients with severe or life-threatening illnesses or injuries, often requiring constant care and careful monitoring of life support systems and medications. ICUs, as known in the art, differ from standard hospital rooms. ICUs are often staffed by highly trained doctors, nurses, and therapists who specialize in the care of critically ill patients. ICUs are also distinguished from general hospital wards by their high staff-to-patient ratios and access to advanced medical resources and equipment that are not routinely available. The phrase "admitted to an intensive care unit" refers to a subject who is in, transported to, or transferred to a hospital's intensive care unit as a patient.

[0134] kit In some embodiments, kits are provided herein that include a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein. In some embodiments, the kit includes one or more doses of a pharmaceutical composition comprising a compound disclosed herein. In some embodiments, the kit includes one or more packs and / or one or more dispenser devices that can contain one or more doses of a compound disclosed herein or a pharmaceutical composition thereof, as described herein. Non-limiting examples of packs include metal, glass, or plastic containers, syringes, or blister packs that contain a compound disclosed herein or a composition described herein. In certain embodiments, the kit includes a dispensing device, such as a syringe or inhaler, that may or may not contain a compound disclosed herein or a composition described herein. The pack and / or dispenser device can be accompanied by instructions for administration. The pack or dispenser can also be accompanied by a notice associated with the container in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, reflecting the agency's approval of the drug dosage form for administration to humans or animals. Such notice, for example, may be in the form of labeling approved by the US Food and Drug Administration for prescription drugs or an approved product insert.

[0135] In some embodiments, the kit or pack contains an amount of a compound disclosed herein sufficient to treat a patient for 1 day to 1 year, 1 to 180 days, 1 to 120 days, 1 to 90 days, 1 to 60 days, 1 to 30 days, 1 to 24 hours, 1 to 12 hours, 1 to 4 hours, or any amount of time therebetween.

[0136] Kits optionally include a product label and / or one or more packaging inserts that provide a description of the components or instructions for in vitro, in vivo, or ex vivo use of the components in the kit. Exemplary instructions may include a description of a treatment protocol or treatment regimen. In certain embodiments, kits include packaging, which refers to the physical structure that houses the components of the kit. Packaging can maintain the sterility of the components and can be made of materials commonly used for such purposes (e.g., paper, cardboard, glass, plastic, foil, ampoules, vials, tubes, etc.). Product labels or inserts include "printed matter," such as paper or cardboard, or separate or affixed to a component, kit, packaging (e.g., a box), or attached to an ampoule, tube, or vial containing a component of the kit. The label or insert may further comprise a computer-readable medium, an optical disk such as a CD- or DVD-ROM / RAM, a DVD, an MP3, or an electrical storage medium such as a DVD, MP3, magnetic tape, or RAM and ROM, or a hybrid such as a magnetic / optical storage medium, flash media, or memory-type card. The product label or insert may include the identity of one or more components therein, dosage amounts, clinical pharmacology of the active ingredients, including mechanism of action, pharmacokinetics (PK), and pharmacodynamics (PD). The product label or insert may include manufacturer information, lot number, manufacturer's address, date, and information regarding the specific condition, disorder, disease, or symptom for which the kit components may be used. The product label or insert may include instructions for a clinician or subject to use one or more of the kit components in a method, treatment protocol, or treatment regimen. The instructions may include dosage, frequency, or duration, and instructions for practicing any of the methods, treatment protocols, or treatment regimes described herein. The kit may additionally include a label or instructions for practicing any of the methods described herein.Product labels or inserts may include information about possible adverse side effects and / or warnings. [Example]

[0137] Example 1 - Proactive Treatment A 60-year-old male subject is diagnosed with ARDS. The subject is administered J147 intravenously at a dose of 1 mg / kg, followed by daily intravenous administration of 1 mg / kg for 1 to 6 weeks. The subject is assessed for loss of cognitive function after recovery by administering one or more appropriate cognitive tests. After the final test, the subject is determined to have little or no loss of cognitive function.

[0138] Example 2 - Proactive Treatment A 60-year-old male subject is diagnosed with COVID-19 and severe acute respiratory syndrome coronavirus 1 (SARS-CoV-2). Prior to intubation and mechanical ventilation, J147 is administered intravenously at a dose of 1 mg / kg, followed by multiple daily doses while on the ventilator. Then, starting the day the subject is removed from the ventilator, a 1 mg / kg oral dose is administered daily for 1-6 weeks. The subject is assessed for PICCD by administering one or more appropriate cognitive tests beginning one week after removal from the ventilator. Following the final test, the subject is deemed to have little or no loss of cognitive function.

[0139] Example 3 - Demonstration of improved neurogenesis and structural and functional recovery in a mouse model of neonatal hypoxic-ischemic brain injury Approximately one million newborns suffer neonatal hypoxic-ischemic brain injury (HI) annually, resulting in a high rate of severe neurological damage among survivors. Hypothermic neuroprotection is the only proven alternative treatment, but it offers very limited benefit and often cannot be initiated in time to achieve benefit. The primary pathology of neonatal HI is neuronal death and dysfunction; therefore, enhancing neurogenesis to prevent neuronal death and promote repair is a desirable therapeutic strategy.

[0140] J147, a compound of Formula IV, is highly neuroprotective against a wide variety of neurotoxic insults and neurogenic through the endogenous production of brain-derived growth factor, a trophic factor that promotes neural stem cell proliferation and differentiation. This mouse model study demonstrated J147's ability to improve the outcome of neonatal HI by potently preventing neuronal cell death and significantly upregulating neurogenesis. The efficacy of J147 to treat HI in mice, in light of hypoxia associated with intubation or mechanical ventilation, respiratory distress, or other conditions or treatments that pose a risk of hypoxia during ICU stays, supports the use of J147 for the treatment and / or prevention of the consequences of hypoxia associated with ARDS or PICCD.

[0141] Ten-day-old mice were subjected to a modified Vanucci-Rice model of hypoxic-ischemic injury (permanent right common carotid artery ligation followed by exposure to 8% oxygen / balanced nitrogen), and then treatment was initiated the same day with J147 administered by oral gavage at 10 mg / kg / day for 2 weeks post-injury. Infarct volume, performance on functional tests of coordination, mobility, and memory, markers of neurogenesis, and apoptotic cell death were measured. The experimental design is summarized in Figure 1.

[0142] Hypoxic-ischemic (HI) injury and J147 treatment To induce HI injury, p10 C57BL6 mice underwent permanent right common carotid artery ligation followed by 45 min of exposure to 8% oxygen / balance nitrogen in a hypoxic chamber at 37°C. From the day of HI injury, either J147 (10 mg / kg / day) or vehicle (corn oil, equal volume) was administered by oral gavage once daily for 2 weeks.

[0143] TTC staining Twenty-four hours after HI injury, 2 mm coronal brain sections were immersed in 1% 2,3,5-triphenyltetrazolium chloride (TTC) for 30 minutes at 37°C. Images of individual sections were digitized, and the infarct area was measured using ImageJ software. The lesion volume was calculated using the formula: [contralateral hemisphere volume - (ipsilateral hemisphere volume - lesion volume)] / contralateral hemisphere volume × 100.

[0144] Magnetic Resonance Imaging (MRI) Postmortem high-resolution T2-weighted MRI of mouse brains at p60 was performed on a 9.4 Tesla vertical-bore NMR spectrometer using a 15 mm diameter volume coil as the radiofrequency transmitter and receiver. A 3D rapid acquisition with a refocused echo sequence was used (TE / TR = 40 / 2000 ms, RARE factor = 8, 4-signal averaging, FOV = 16.0 mm x 9.0 mm x 18.0 mm, matrix size = 128 x 72 x 144, native resolution ≈ 125 x 125 x 125 μm3, time = 3 h). Volumetric measurements were performed using ROI editor software.

[0145] Behavioral testing Three different tests were employed to analyze different neurological domains: i) the open field test, measuring general locomotor activity, was performed on p14 by measuring the escape latency from a 13 cm circle; ii) the rotarod test, measuring motor coordination, was performed on p45 by measuring the endurance time on a rotating rod (9.3 cm wide, 3 cm diameter) accelerated at 0.3 rpm / s from 4 to 99 rpm for up to 3 min; iii) the Y-maze, measuring spatial learning, was performed on p60 by measuring the spontaneous alternation of three arm entries (successive triplets of different arm choices) for 5 min.

[0146] J147 administration reduced infarct volume in both acute and chronic conditions. As shown in Figures 2 and 3, J147-treated mice showed reduced hippocampal lesion size by histological measurement at 24 hours and magnetic resonance imaging measurement at 50 days.

[0147] Figure 2 shows 2,3,5-triphenyltetrazolium chloride (TTC) staining of mouse hippocampus (white indicates damaged area) 24 hours after HI injury in representative coronal brain sections from Example 3. Sham-treated (SH) sections showed no damage, HI sections showed substantial damage, and HIJ sections from mice treated with J147 showed a reduced regional extent of damage. MRI measurements at 50 days showed no infarct volume in SH mice and approximately a 50% reduction in infarct volume in HIJ mice compared to untreated HI mice.

[0148] Figure 3 shows the effect of treatment with J147 in Example 3, as measured by the ipsilateral hemisphere volume as a percentage of the contralateral hemisphere volume by the degree of reduction from 100%, which reflects the size of the infarct volume. SH shows no effect. HIJ shows a significantly reduced effect compared to HI.

[0149] J147 demonstrated a dose-dependent reduction in apoptotic cell death in the hippocampus in a neonatal hypoxic-ischemic encephalopathy (HIE) mouse model. C57BL6 mice were subjected to complete unilateral carotid artery blockage using a cautery at P10, followed by exposure to hypoxia at 8% O2 for 45 minutes. This was followed by daily oral gavage of a range of doses of J147 or vehicle from P10 to P14. Animals were then sacrificed and processed for TUNEL staining. In the sham group, almost no TUNEL-positive cells were observed in the dentate gyrus (DG, 4.7 ± 4.1, respectively). HIE dramatically increased apoptotic cells (141.7 ± 56.6; p < 0.0001), and J147 treatment dose-dependently reduced this number. 123.2 ± 51.5 TUNEL-positive cells were detected in the 0.5 μg / g / day group and 107.8 ± 42.7 cells in the 1 μg / g / day group (p > 0.05). 5 μg / g / day J147 significantly reduced these numbers (55 ± 23.6; p < 0.01). 42.2 ± 23 (p < 0.001) and 31.7 ± 21.4 (p < 0.001) cells were observed in the DG in the 10 μg / g / day and 25 μg / g / day groups (one-way ANOVA; n = 6). The results are shown in Figure 4.

[0150] J147 treatment resulted in a decrease in apoptotic cell death, as shown in Figure 5, by measuring the NeuN-positive area and counting the number of TUNEL-positive cells in the hippocampus in sham-treated, HI, and J147-treated HI mice. Neonatal hypoxia-ischemia (HI) was performed at P10, and 10 μg / g J147 was administered by oral gavage daily from P10 to P14. HI resulted in a decrease in the NeuN-positive area (0.52 mm / section (SH) vs. 0.32 mm / section (HI); p = 0.0025), while J147 administration increased the area (0.45 mm / section (HI + J147); p = 0.0433), returning it to near the level of sham-treated mice. HI induced TUNEL-positive apoptotic cells (36.33 / section (SH) vs. 372.67 / section (HI); p<0.0001), and J147 reduced this number (208.17 / section (HI+J147); p=0.0092).

[0151] Figure 6 shows the functional recovery of HI mice induced by J147 treatment in the open field test, rotarod test, and Y-maze test in Example 3. J147-treated mice showed significant improvements in performance in the open field test 4 days after HI, the rotarod test 5 weeks after HI, and the dentate gyrus-dependent Y-maze spatial learning task 50 days after HI (33%, p<0.001 compared to the untreated HI group). In all cases, HI mice performed worse than sham-treated mice, and the performance of J147-treated mice was comparable to that of sham-treated mice. Thus, J147-treated mice demonstrated substantial functional recovery from the performance decline associated with HI injury in behavioral tests. Four days after HI injury, mice were administered the open field test to assess locomotion and rotation behavior. Five weeks after HI injury, mice were administered the rotarod test to assess motor coordination. 50 days after HI injury, mice were administered the spontaneous alternation test in the Y-maze test to assess working memory.

[0152] overviewAs measured by TTC staining, infarct size was reduced by 48% with 1 day of J147 treatment compared with HI controls (p<0.001), and MRI images showed an 88% reduction in lesion size in adult mice with 2 weeks of J147 treatment. Consistent with this effect, J147 treatment resulted in a 50% reduction in apoptotic cell death in the hippocampus. Furthermore, behavioral tests suggested improvements with J147 treatment. Acute performance in the open field test on day 4 and chronic performance in the rotarod test were significantly improved by approximately 25% in the J147-treated group, while performance in the Y-maze spatial learning task showed a 33% improvement compared with HI controls. Collectively, these findings strongly suggest that J147 promotes neurological recovery after neonatal HI through neuroprotection and upregulation of neurogenesis. Fluorescent staining of neural progenitor markers revealed an increase in nestin-positive cells 1 day and 1 week after injury with J147 treatment. At 1 week, there was a significant increase in Tbr2-positive cells, suggesting rapid proliferation of intermediate neuronal precursors. These results support the conclusion that treatment with J147 is protective against and promotes recovery from hypoxia-induced injury, and therefore may be effective in treating PICCD and ARDS, as described in certain embodiments of the present invention.

[0153] References :1.Patel SD, et al. Biochem Soc Trans. 2014 Apr;42(2):564-8; 2. Lai M, et al. J Biomed Biotechnol. 2011: 609813; 3. Prior M, et al. Alzheimers Res Ther. 2013 May 14;5(3):25; 4. Chen Q, et al. PLoS One. 2011;6(12):e27865; 5. Nicola Z, et al. Front Neuroanat. 2015 May 7;9:53.

[0154] Example 4 - Certain Non-Limiting Embodiments Example 4 consists of the following embodiments A1-A5, B1, C1-C27, D1-D2, described below in this paragraph: A1. A therapeutically effective amount of a compound having the structure of Formula I:

[0155] [ka]

[0156] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof EP 1 237 299 A1 2 Description

[0001] A method for treating or preventing post-intensive care cognitive dysfunction (PICCD) in a subject in need thereof, comprising administering [In the formula, R 2 is selected from the group consisting of H and methyl; R 3 is trifluoromethyl or other fluoro-substituted alkyl; L 3 is a carbonyl; and R 6 is independently for each occurrence alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, mercapto, alkylthio, arylthio, carbonyl, aryl, substituted aryl, substituted heterocyclic, halogen, cyano, cyanoalkyl, nitro, amino, amidino, carbamate, S(O) n R 7 , and C(O)R 8 or two R6 at adjacent positions are joined to form an optionally substituted heteroaryl or heteroalkyl ring fused to adjacent phenyl moieties; R 7 H, R 9 , NH2, HNR 9 , or NR 9 R 10 and; R 8 OH, OR 9 , NH2, NHR 9 , or NR 9 R10 and; R 9 and R 10 is, independently at each occurrence, optionally substituted alkyl; and n=1 or 2].

[0157] A2.R 6 is, for each occurrence, alkyl, substituted alkyl, hydroxyl, alkoxy, substituted alkoxy, halogen, and C(O)R 8 The method of embodiment A1, selected from the group consisting of:

[0158] A3.R 6 The method of embodiment A2, wherein each occurrence is selected from the group consisting of methyl, methoxy, perfluoromethyl, perfluoromethoxy, hydroxyl, Cl, F, and I.

[0159] A4. The compound has the structure of Formula II:

[0160] [ka]

[0161] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof The method of embodiment A1, comprising: [In the formula, (i)R A2 , R A4 , R A5 , and R A6 is H and R A3 is methoxy and R B2 is methyl and R B4 is methyl; or (ii)R A2 , R A3 , R A5 , and R A6 is H and R A4 is methoxy and R B2 is methyl and R B4 is methyl; or (iii)R A2, R A3 , R A4 , R A5 , and R A6 is H and R B2 is H and R B4 is H; or (iv)R A2 , R A3 , R A4 , R A5 , and R A6 is H and R B2 is methyl and R B4 is methyl; or (v)R A2 , R A4 , R A5 , and R A6 is H and R A3 is methoxy and R B2 is H and R B4 is H; or (vi)R A2 , R A3 , R A4 , R A5 , and R A6 is H and R B2 is H and R B4 is methyl; or (vii)R A2 , R A4 , R A5 , and R A6 is H and R A3 is methoxy and R B2 is H and R B4 is methyl; or (viii)R A2 , R A3 , R A4 , R A5 , and R A6 is H and R B2 is methyl and R B4 is H; or (ix)R A2 , R A4 , R A5 , and R A6 is H and R A3 is methoxy and R B2 is methyl and R B4 is H; or (x)R A2 , R A3 , R A5 , and R A6 is H and R A4 is COOH and R B2 is methyl and R B4 is methyl; or (xi)R A2 , R A4 , and R A5 is H and R A3 and R A6 is hydroxyl and R B2 is methyl and R B4 is methyl; or (xii)R A2 , R A4 , and R A6 is H and R A3 and R A5 is hydroxyl and R B2 is methyl and R B4 is methyl; or (xiii)R A2 , R A4 , and R A5 is H and R A3 is methoxy and R A6 is F and R B2 is H and R B4 is Cl; or (xiv)R A3 and R A5 is H and R A2 and R A6 is F and R A4 is hydroxyl and R A6 is F and R B2 is H and R B4 is F; or (xv)R A2 , R A4 , and R A6 is H and R A3 is hydroxyl and R A5 is F and R B2 is H and R B4 is F; or (xvi)R A2 , RA5 , and R A6 is H and R A3 and R A4 Together they form -O-CH2-O-, and R A5 is F and R B2 is H and R B4 is F].

[0162] A5.R A2 , R A4 , R A5 , and R A6 is H and R A3 is methoxy and R B2 is methyl and R B4 The method of embodiment A4, wherein is methyl.

[0163] B1. A compound comprising the structure of Formula IV:

[0164] [ka]

[0165] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof to the subject.

[0166] C1. A method for preventing or treating PICCD in a subject, comprising administering to the subject a therapeutically effective amount of a compound comprising a structure selected from any of Formulas I-IV.

[0167] The method of any one of embodiments A1 to C1, wherein the PICCD comprises a cognitive disorder and / or a psychiatric disorder.

[0168] C1.2. The method of any of embodiments A1 to C1.1, wherein PICCD is post-critical care syndrome.

[0169] C1.3. The method of any of embodiments A1 to C1.2, wherein the PICCD comprises delirium, memory loss, confusion, decreased consciousness, impaired executive function, impaired language, loss of attention, and / or impaired visuospatial abilities.

[0170] C1.4. The method of any of embodiments A1 to C1.3, wherein the PICCD is acute, transient, or temporary.

[0171] C1.5. The method of any of embodiments A1 to C1.4, wherein the PICCD is chronic.

[0172] C2. The method of any one of embodiments A1 to C1.5, wherein the subject is a human.

[0173] C2.1. The method of any one of embodiments A1 to C2, wherein the subject is elderly or at least 60 years old.

[0174] C2.2. The method of any one of embodiments A1 to C2.1, wherein the subject is a pediatric patient or under 13 years of age.

[0175] C2.3. The method of any one of embodiments A1 to C2.2, wherein the subject is female.

[0176] C2.4. The method of any of embodiments A1 to C2.3, wherein the subject is at risk of being intubated and / or at risk of being operably connected to a ventilator.

[0177] C2.5. The method of any of embodiments A1 to C2.4, wherein the subject is intubated and / or operably connected to a ventilator.

[0178] C2.6. The method of any of embodiments A1 to C2.5, wherein the subject is intubated and / or operably connected to a ventilator.

[0179] C3. The compound has the structure of Formula III:

[0180] [ka]

[0181] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R1 is methyl, fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, dibromomethyl, or tribromomethyl; R2 is OCH3, OCF3, or OCBr3; and R3 and R4 are independently selected from hydrogen, hydroxyl, halogen (e.g., Cl, F, or Br), methyl, methoxy, or amine.

[0182] C4. The compound has the structure of Formula IV:

[0183] [ka]

[0184] The method of embodiment C3, comprising:

[0185] C5. The method of any of embodiments A1 to C4, wherein the PICCD results from or is precipitated by a stay in an intensive care unit.

[0186] C6. The method of any of embodiments A1 to C5, wherein the PICCD results from or is precipitated by intubation of the subject.

[0187] C7. The method of any of embodiments A1 to C6, wherein the subject exhibits stable cognitive function prior to intubation, prior to ICU stay, or prior to being operably connected to a ventilator.

[0188] C8. The method of any of embodiments A1 to C7, wherein the subject had not been diagnosed with a cognitive impairment or neurodegenerative disease before being intubated or operably connected to a ventilator.

[0189] C9. The method of any one of embodiments A1 to C7, wherein the subject is diagnosed with a cognitive impairment or neurodegenerative disease before being intubated or operably connected to a ventilator.

[0190] C10. The method of embodiment C8 or C9, wherein the cognitive impairment or neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, glaucoma, retinal degeneration, macular degeneration, presbycusis, mild cognitive impairment, dementia, delirium, progressive supranuclear palsy, spinocerebellar ataxia, retinal neuropathy, peripheral neuropathy, diabetic neuropathy, background neuropathy, familial amyloid polyneuropathy, senile systemic amyloidosis, prion disease, scrapie, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, and amyloidosis.

[0191] C11. The method of any of embodiments A1 to C10, wherein the subject has not been previously diagnosed with and / or does not suffer from cancer, diabetes, arthritis, insulinoma, stroke, ischemia (e.g., cardiac ischemia), or cardiovascular disease.

[0192] C12. The method of any of embodiments A1 to C10, wherein the subject has been previously diagnosed with, is suffering from, or is suspected of suffering from cancer, diabetes, hyperglycemia, hypoglycemia, serum glucose fluctuations, hospital acute stress syndrome, delirium, arthritis, pancreatitis, and / or insulinoma.

[0193] C13. The method of any one of embodiments A1 to C12, wherein the subject has or is at risk of having acute respiratory syndrome.

[0194] C14. The method of any one of embodiments A1 to C13, wherein the subject has or has been diagnosed as having asthma.

[0195] C15. The method of any one of embodiments A1 to C14, wherein the subject has or has been diagnosed with pneumonia.

[0196] C16. The method of any one of embodiments A1 to C15, wherein the subject is infected with a pathogen.

[0197] C17. The method of any one of embodiments A1 to C16, wherein the pathogen is a virus, fungus, or bacterium.

[0198] C18. The method of embodiment C17, wherein the virus is a coronavirus.

[0199] C19. The method of embodiment C18, wherein the coronavirus is COVID19.

[0200] C20. The method of any of embodiments A1 to C19, wherein the subject has previously been diagnosed with or is prone to depression.

[0201] C21. The method of embodiment A1 or C20, wherein the subject has not previously (e.g., before staying in an ICU or before intubation) been administered a compound selected from any one of Formula I, Formula II, Formula III, and Formula IV.

[0202] C22. The method of embodiment A1 or C21, wherein the compound is administered to the subject before, during, and / or after the subject is intubated or operably connected to a ventilator.

[0203] C23. The method of embodiment A1 or C22, wherein the compound is administered to the subject before, during, and / or after the subject is in or admitted to an intensive care unit.

[0204] C24. The method of any of embodiments A1 to C23, wherein the compound is administered at least 24 hours, at least 12 hours, or at least 4 hours before intubation, operative connection to a ventilator, or ICU stay or admission.

[0205] C25. The method of any of embodiments A1 to C24, wherein the compound is administered at once or twice daily intervals.

[0206] C26. The method of any of embodiments A1 to C25, wherein the compound is administered at a dose of 0.5 mg / kg to 100 mg / kg, or 10 mg / kg to 50 mg / kg.

[0207] C27. The method of any of embodiments A1 to C26, wherein the compound is administered orally or intravenously.

[0208] D1. A compound comprising a structure selected from any of Formula I, Formula II, Formula III, and Formula IV for use in practicing the method of any of embodiments A1 to C27.

[0209] D2. A pharmaceutical composition comprising a compound comprising a structure selected from any of Formula I, Formula II, Formula III, and Formula IV for use in practicing the method of any of embodiments A1 to C27.

[0210] The entirety of each patent, patent application, publication, or any other reference or document cited herein is hereby incorporated by reference. In case of conflict, the present specification, including definitions, will control.

[0211] Citation of any patent, patent application, publication, or any other document is not an admission that any of the foregoing is pertinent prior art, nor does it constitute any admission as to the contents or date of such publication or document.

[0212] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described herein.

[0213] All features disclosed herein can be combined in any combination. Each feature disclosed herein can be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless otherwise specified, a disclosed feature (e.g., an antibody) is an example of a genus of equivalent or similar features.

[0214] As used herein, all numerical values ​​or ranges include integers within such ranges and fractions of values ​​or integers within such ranges, unless the context clearly dictates otherwise. Furthermore, when a list of values ​​is set forth herein (e.g., about 50%, 60%, 70%, 80%, 85%, or 86%), the list also includes all intermediate and subvalues ​​therein (e.g., 54%, 85.4%). Thus, for purposes of illustration, reference to 80% or greater identity includes 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, etc., as well as 81.1%, 81.2%, 81.3%, 81.4%, 81.5%, etc., 82.1%, 82.2%, 82.3%, 82.4%, 82.5%, etc.

[0215] Reference to a greater or smaller integer includes any number greater or less than the referenced number, respectively. Thus, for example, reference to less than 100 includes 99, 98, 97, etc. up to 1, and reference to less than 10 includes 9, 8, 7, etc. up to 1.

[0216] As used herein, all numerical values ​​or ranges include values ​​and integer fractions within such ranges, and integer fractions within such ranges, unless the context clearly indicates otherwise. Thus, for purposes of illustration, a reference to a numerical range such as 1 to 10 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, as well as 1.1, 1.2, 1.3, 1.4, 1.5, etc. Thus, a reference to a range of 1 to 50 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc., up to and including 50, as well as 1.1, 1.2, 1.3, 1.4, 1.5, etc., 2.1, 2.2, 2.3, 2.4, 2.5, etc.

[0217] Reference to a series of ranges includes ranges combining the limits of different ranges within that series. Thus, for purposes of illustration, for example, 1 to 10, 10 to 20, 20 to 30, 30 to 40, 40 to 50, 50 to 60, 60 to 75, 75 to 100, 100 to 150, 150 to 200, 200 to 250, 250 to 300, 300 to 400, 400 to 500, 500 to 750, 750 to 1,000, 1,000 to 1,500, 1,500 to 2,000, 2,000 to 2,500, 2,500 to References to a series of ranges such as 3,000, 3,000-3,500, 3,500-4,000, 4,000-4,500, 4,500-5,000, 5,500-6,000, 6,000-7,000, 7,000-8,000, or 8,000-9,000 include ranges such as 10-50, 50-100, 100-1,000, 1,000-3,000, 2,000-4,000, etc.

[0218] Modifications to the foregoing can be made without departing from the fundamental aspects of the technology. Although the technology has been described in substantial detail with reference to one or more specific embodiments, those skilled in the art will recognize that changes can be made to the embodiments specifically disclosed in this application, and that these changes and improvements are within the scope and spirit of the technology.

[0219] The present invention is generally disclosed herein using affirmative language to describe many embodiments and aspects. The present invention also specifically includes embodiments in which certain subject matter, such as substances or materials, method steps and conditions, protocols, or procedures, is completely or partially excluded. For example, in some embodiments or aspects of the methods disclosed herein, certain materials and / or method steps are excluded. Thus, even if the present invention is generally not expressed herein in terms of what is not included herein, aspects of the present invention that are not explicitly excluded are nonetheless disclosed herein.

[0220] Some embodiments of the technology described herein can be suitably practiced without elements not specifically disclosed herein. Thus, in some embodiments, the terms "comprising" or "comprises" can be replaced with "consisting essentially of" or "consisting of," or grammatical variations thereof. The terms "a" or "an" can refer to the element or elements that it modifies, unless the context clearly indicates that either one element or multiple elements are being described (e.g., "reagent" can refer to one or more reagents). As used herein, the term "about" refers to a value within 10% (i.e., ±10%) of the underlying parameter, and the use of the word "about" at the beginning of a value string modifies the respective value (e.g., "about 1, 2, and 3" refers to about 1, about 2, and about 3). For example, a weight of "about 100 grams" can include weights between 90 grams and 110 grams. As used herein, the term "substantially" refers to a modifier of a value meaning "at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, and can include 100%. For example, a composition that is substantially free of X can contain less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% X, and / or X may be absent or undetectable in the composition.

Claims

1. A pharmaceutical composition for use in preventing, reducing the severity of, delaying the onset of, or treating Post-Intensive Care Cognitive Disorder (PICCD) in a subject having hypoxia-induced injury or at risk of developing PICCD, comprising a therapeutically effective amount of N-(2,4-dimethylphenyl)-2,2,2-trifluoro-N'-[(E)-(3-methoxyphenyl)methylene]acetohydrazide (also known as J147), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

2. 10. The pharmaceutical composition of claim 1, wherein the subject or at-risk subject is at risk of, during, or after a) admission to an intensive care unit, b) intubation, or c) operably connected to a ventilator.

3. 10. The pharmaceutical composition of claim 1, wherein the subject or at-risk subject has previously been diagnosed with, is suffering from, or is suspected of suffering from hyperglycemia, hypoglycemia, serum glucose fluctuations, pancreatitis, acute hospital stress syndrome, depression, anxiety, and / or delirium.

4. 10. The pharmaceutical composition of claim 1, wherein the subject or at-risk subject has, is suspected of having, or is at risk of having acute respiratory syndrome, acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), asthma, pneumonia, or an infectious disease.

5. 10. The pharmaceutical composition of claim 1, wherein the subject or at-risk subject is infected with a pathogen selected from a virus, a fungus, and a bacterium.

6. The pharmaceutical composition of claim 5, wherein the virus is SARS-associated coronavirus or SARS-associated coronavirus-2.

7. 2. The pharmaceutical composition of claim 1, wherein the PICCD comprises the onset or worsening of delirium, memory loss, confusion, decreased consciousness, impaired executive function, speech impairment, language impairment, communication impairment, loss of attention, depression, anxiety, post-traumatic stress disorder, and / or impaired visuospatial ability.

8. The pharmaceutical composition of claim 1, wherein the subject or at-risk subject is 60 years of age or older.

9. A pharmaceutical composition for use in treating, preventing, suppressing, reducing the severity of, or delaying the onset of cognitive impairment or impairment resulting from hypoxia-related respiratory distress in a subject, comprising a therapeutically effective amount of N-(2,4-dimethylphenyl)-2,2,2-trifluoro-N'-[(E)-(3-methoxyphenyl)methylene]acetohydrazide (also known as J147), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

10. 10. The pharmaceutical composition of claim 9, wherein the respiratory distress is selected from acute respiratory distress, acute respiratory distress syndrome (ARDS), and severe acute respiratory syndrome (SARS).

11. 11. The pharmaceutical composition of claim 10, wherein the respiratory distress is acute respiratory distress syndrome (ARDS).

12. 12. The pharmaceutical composition of claim 11, wherein the ARDS is associated with or caused by sepsis, pneumonia, lung infection, pancreatitis, physical trauma, aspiration, smoke inhalation, inhalation of toxic substances, idiopathic pulmonary fibrosis, blood transfusion, massive transfusion, burns, drowning, a reaction to a drug, a drug overdose, shock, lung surgery, cardiopulmonary bypass surgery, disseminated intravascular coagulation, or tick-borne relapsing fever.

13. 10. The pharmaceutical composition of claim 9, wherein the cognitive impairment comprises delirium, memory loss, confusion, decreased consciousness, impaired executive function, language impairment, loss of attention, and / or impaired visuospatial ability.

14. 10. The pharmaceutical composition of claim 9, wherein the subject is 60 years of age or older.

15. 10. The pharmaceutical composition of claim 9, wherein the subject has previously been diagnosed with, is suffering from, or is suspected of suffering from cancer, diabetes, hyperglycemia, hypoglycemia, serum glucose fluctuations, hospital acute stress syndrome, delirium, arthritis, pancreatitis, and / or insulinoma.

16. 10. The pharmaceutical composition of claim 9, wherein the subject has or has been diagnosed as having asthma.

17. 10. The pharmaceutical composition of claim 9, wherein the subject has or has been diagnosed with pneumonia.

18. 10. The pharmaceutical composition of claim 9, wherein the subject is infected with a pathogen selected from a virus, a fungus, and a bacterium.

19. 19. The pharmaceutical composition of claim 18, wherein the virus is SARS-associated coronavirus or SARS-associated coronavirus-2.

20. A pharmaceutical composition comprising a therapeutically effective amount of N-(2,4-dimethylphenyl)-2,2,2-trifluoro-N'-[(E)-(3-methoxyphenyl)methylene]acetohydrazide (also known as J147), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, for use in preventing, ameliorating, inhibiting, reducing the severity of, or delaying cognitive impairment or impairment caused by hypoxia-related dyspnea in a subject at risk of, suffering from, or experiencing, or who has previously experienced such dyspnea.

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