[0001] The present application claims priority to U.S. Provisional Pat. Appl. No. 62/524,758, filed on June 26, 2017, and U.S. Provisional Pat. Appl. No. 62/574,635, filed on October 19, 2017, which applications are incorporated herein by reference in their entirety. FIELD OF THE INVENTION

[0002] The present invention is directed to the fields of traumatic brain injur}', biology, and medicine, including traumatic brain injury therapeutics. Specifically, the present invention regards methods of reducing symptoms of traumatic brain injury in patients by administering a therapeutically effective amount of a benzothiazole amphiphile compound to a patient suffering from a traumatic brain injury within 0 to 72 hours of incurring the injury.

BACKGROUND OF THE INVENTION

[0003] Traumatic brain injury (TBI) is a major cause of death and disability in the United States, contributing to about 30% of all injur}' deaths. Every day, 138 people in the United States die from injuries that include TBI. Those who survive a TBI can face effects lasting a few days to disabilities which may last the rest of their lives. Most TBIs that occur each year are mild, commonly called concussions. The effects of a mild traumatic brain injury (mTBI) can include impairments in movement, sensation (e.g., vision or hearing), emotional functioning (e.g., personality changes, depression), thinking, or memory. A TBI is caused by a bump, blow, jolt to the head, a sudden acceleration, deceleration or twisting of the head or a penetrating head injury that disrupts the normal function of the brain. Not all blows or jolts to the head result in a TBI. The severity of a TBI may range from "mild" (i.e., a brief change in mental status or

consciousness) to "severe" (i.e., an extended period of unconsciousness or memory loss after the injury). [0004] In 2010, more than 2.5 million injuries were associated with TBI— either alone or in combination with other injuries— in the United States. More specifically, TBI contributed to the deaths of more than 50,000 people, and was the diagnosis for more than 280,000 hospitalized patients and 2.2 million patients who visited the emergency department. Overall, it is estimated that the cost of traumatic brain injuries in the United States is $48.3 billion annually,

[0005] The effects of most (70-80%) mTB!s or concussions resolve within two to three weeks, while in the remainder of cases, effects may persist for months. These persistent symptoms may include difficulty thinking clearly, feeling slowed down, difficulty concentrating, difficulty remembering new information, increased frequency of headaches, fuzzy or blurry vision, dizziness, sensitivity to noise or light, balance problems, feeling tired or S ack of energy, irritability, sadness, nervousness or anxiety increased emotional response, sleeping more or less than usual and/or difficulty falling asleep. The effects from moderate and severe TBI may include any of the above and are usually much more prolonged and more severe.

[0006] There are numerous interventions that are employed after TBI, depending on the severity and the state of consciousness of the patient, including hypothermia, surgery, steroids, and the like, to manage the immediate damage to the brain. For example, drugs have been approved for the some post- TBI symptoms, such as difficulty with sleeping. However, there are no drugs approved for the treatment of the post-TBI symptoms per se. As such, what is needed is a new class of compounds and new methods for the treatment of traumatic brain injury in patients. The present invention addresses these needs.

BRIEF SUMMARY OF THE INVENTION

[0007] In one embodiment, the present invention provides a method of reducing the symptoms of traumatic brain injury in a patient suffering from traumatic brain injury. The method of reduci ng the symptoms of traumatic brain injury in a patient includes administering a

therapeutically effective amount of a benzothiazole amphiphile compound of formula (I):

The symbols R ¹ , R ² , R ^J , R ⁴ , R ³ , R ⁶ , R ^; , and R ^s are independently selected from the group consisting of hydrogen, halogen, -CXs, -CITX2, -CTI2X, -OCX, -OCHX2, -OCH2X, -CN, -OH, - ΝΙ-Ϊ2, -COO! !, -CONH2, - O2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, - HC(0)NHNH2, -NHC(0)NH ₂ , -NHSO2H, -NHC(0)H, -NHC(0)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroal ky) , substituted or unsubstituted cycioalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. The symbol X is halogen and the symbol Y is N or S. The symbol Z is absent, hydrogen, or substituted or unsubstituted C1-C0 alkyl. The symbol n is an integer from 1 to 15. The benzothiazole amphiphile compound of formula (I) is administered within about 0 to 72 hours of the traumatic brain injur ', and the therapeutically effective amount of the benzothiazole amphiphile compound of formula (I) is an amount sufficient to reduce the symptoms of traumatic brain injury.

[0008] In an aspect of the method described above, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroal ky] , substituted or unsubstituted cycioalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl . In a further aspect of the method described above, R ¹ , R , R ³ , R ⁴ , R ⁵ , R ⁶ , R', and R ⁸ are independently hydrogen or substituted or unsubstituted alkyl.

[0009] In another aspect of the method described above, the benzothiazole amphiphile compound is a compound of formula (II):

The symbol R ³ is hydrogen or substituted or unsubstituted alkyl and the symbol Y is N or S. The symbol Z absent, hydrogen, or substituted or unsubstituted Ci-C ₆ alkyl and the symbol n is an integer from 3 to 8.

[ 0010] In a preferred aspect of the method described above, R ³ is hydrogen or -CH ₃ . In a further preferred aspect of the method described above, Z is absent or hydrogen or -CH ₃ . [0011] In a further preferred aspect of the method described above, the compound has the formula:

[0012] In another preferred aspect of the method described above, the compound has the formula:

[0013] In another aspect of the method of reducing the symptoms of traumatic brain injury in a patient, as described above, the patient has suffered from a concussion, and/or a blunt force impact to the head, and/or a blast-induced traumatic brain injury.

[0014] In an aspect of the method described above, the reduction of the symptoms of trauma is measured by an improvement in the performance of one or more functional domains by at least 20% to 30% within about 7 days of treatment as compared to the performance of the one or more functional domains measured prior to treatment but after injury. [0015] In a further aspect of the method described above, the therapeutically effective amount of benzothiazole amphiphile compound is administered within 0 to 24 hours of the traumatic brain injur}'. In another aspect of the method described above, the therapeutically effective amount of benzothiazole amphiphile compound is administered within 18 hours of the traumatic brain injury. In another aspect of the method described above, the therapeutically effective amount of benzothiazole amphiphile compound is administered within no more than 18 hours of the traumatic brain injury. In another aspect of the method described above, the therapeutically effective amount of benzothiazole amphiphile compound is administered within 4 hours of the traumatic brain injury. In a preferred aspect of the method described above, the therapeutically effective amount of benzothiazole amphiphile compound is administered within 1 hour of the traumatic brain injury. [0016] Further aspects and embodiments of the invention are described in detail below.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 . Synthetic scheme for the preparation of exemplary benzothiazole amphiphile compounds, BAM 1-3. Abbreviations for all synthetic steps are as follows: potassium carbonate (K2CO3), potassium iodide (ΚΓ), potassium hydroxide (KOI I ), ionic liquid or l-pentyl-3- methyiimidazolium bromide ([pmimJBr), microwave (MW), tetrahvdroturan (THF), meta- chloroperoxybenzoic acid (mCPBA), dichlorom ethane (DCM), trifluoroacetic anhydride (TFAA), sodium hydroxide (NaOH), methanol (MeOH), sodium hydride (NaH),

dimethylformamide (DMF), and 17-iodo-3, 6,9, 12, 1.5-pentaoxaheptadecan-l-ol (EGe-I). [0018] FIG. 2. Weight gain of rats having TBI treated with BTA-EG4 ("BTA-EG4") compared to untreated rats having TBI ("DMSO") at day 0 (preinjury), day I, day 7, day 14, day 21 and day 35 after TBI.

[0019] FIG. 3. Sensorimotor recovery measured by the forelimb footfault test for rats having TBI treated with BTA-EG4 ("BTA-EG4") compared to untreated rats having TBI ("DMSO") at day 0 (preinjury), day 1, day 7, day 14, day 21 and day 35 after TBI.

[0020] FIG. 4. Sensorimotor recovery measured by the hindlimb footfault test for rats having TBI treated with BTA-EG4 ("BTA-EG4") compared to untreated rats having TBI ("DMSO") at day 0 (preinjury), day 1, day 7, day 14, day 21 and day 35 after TBI.

[0021] FIG. 5. Sensorimotor recovery measured by the adhesive patch removal test for rats having TBI treated with BTA-EG4 ("BTA-EG4") compared to untreated rats having TBI ("DMSO") at day 0 (preinjury), day 1, day 7, day 14, day 21 and day 35 after TBI.

[0022] FIG. 6. Neurological function measured by the modified neurological severity score (mNSS) test for rats having TBI treated with BTA-EG4 ("BTA-EG4") compared to untreated rats having TBI ("DMSO") at day 0 (preinjury), day 1 , day 7, day 14, day 21 and day 35 after TBI.

[0023] FIG. 7. Spatial memory and learning measured by latency time of the Morris water maze (MWM) test for rats having TBI treated with BTA-EG4 ("BTA-EG4") compared to untreated rats having TBI ("DMSO") at day 31 , day 32, day 33, day 34, and day 35 after TBI. [0024] FIG. 8. Spatial memory and learning measured by time spent in the correct quadrant of the Morris water maze (MWM) test for rats having TBI treated with BTA-EG4 ("BTA-EG4") compared to untreated rats having TBI ("DMSO") at day 31, day 32, day 33, day 34, and day 35 after TBI. [0025] FIG, 9. Spatial memory and learning measured by the swim speed of the Morris water maze (MWM) test for rats having TBI treated with BTA-EG4 ("BTA-EG4") compared to untreated rats having TBI ("DMSO") at day 31, day 32, day 33, day 34, and day 35 after TBI.

[0026] FIG. 10. Novel object recognition (NOR) test for rats having TBI treated with BTA~ EG4 ("BTA-EG4") compared to untreated rats having TBI ("DMSO") at day 14 and day 35 after TBI.

[0027] FIG. 1 1. Sociability and social novelty measured by the three-chambered social interaction test for rats having TBI treated with BTA-EG4 ("BTA-EG4") compared to untreated rats having TBI ("DMSO") at day 14 after TBI.

[0028] FIG. 12. Sociability and social novelty measured by the three-chambered social interaction test for rats having TBI treated with BTA-EG4 ("BTA-EG4") compared to untreated rats having TBI ("DMSO") at day 35 after TBI.

DETAILED DESCRIPTION OF THE INVENTION

L Introduction

[0029] Recently, a class of benzothiazole amphiphiles (B AMs) were discovered to prevent the toxic interaction of amyloid beta peptide with neurons and macromolecules (including catalase), reducing the peptide's toxicity. BAMs have been suggested for treatment of a host of neurodegenerative disorders which result in a progressive loss of memory, cognition, attention and mood; but, there have been no suggestion that such compounds can be used to treat TBI. TBI produces immediate effects on memory, cognition, attention, motor coordination, and mood, which typically improve over time. Unlike neurodegenerative disorders, TBI involves a physical tearing and shearing of axons and dendrites, resulting in a loss of synapses. Surprisingly, in vitro and in vivo experiments have shown that dramatic improvements across a variety of TBI symptoms can be achieved by administering benzothiazole amphiphile compounds. Herein are methods for the use of benzothiazole amphiphiles (BAMs) for the reduction of symptoms in humans caused by traumatic brain injuries.

II. Definitions [0030] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0031] The terms "a" or "an" as used in herein means one or more. In addition, the phrase "substituted with a[n]," as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryf group, is "substituted with an unsubstituted Ci-Cio alkyl, or unsubstituted 2 to 20 membered heteroalkyl," the group may contain one or more unsubstituted Ci-Ciio alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls. Moreover, where a moiety is substituted with an R substituent, the group may be referred to as "R-substituted.'' Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different.

[0032] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-. [0033] "Alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono-or polyunsaturated and can include mono-, di-, and multivalent radicals, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbons). Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl; homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2- isopentenyi, 2-butadienyl, 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1 -and 3-propynyi, 3- butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the mol ecule via an oxygen linker (-0-).

[0034] "Alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. [0035] "Heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized). The heteroatom(s) (e.g., N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule,

Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -Π I2-O Ϊ2·Ν(( Ί ί ^: }-( ^' ! ί ^■ . -CH2-S-CH2-CH3, -CH2-CH2, -S(0)-CH ₃ , -CH2- CH2-S(0)2-CH ₃ , ~CH OM-O-CH ^; , -SHC i hK -< Ί Ι -( Ί Ι VOC! k ~C! i (Ί I )-( ^' ] U, -()-

CH ^' 3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH^-NH-OCEb and -CH ₂ -0-Si(CH ₃ ) ₃ . A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two, three, four, or five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to eight optionally different heteroatoms (e.g., O, N, S, Si, or P).

[0036] "Heteroalkyiene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2- S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkyiene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyl eneamino, al kylenediamino, and the like). Sti ll further, for alkylene and heteroalkyiene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(0) ₂ R'- represents both -C(0) ₂ R'- and -R'C(0) ₂ -. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(0)R', -C(0) R', -NR'R", -OR', - SR', and/or -SO2R'. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R" or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R" or the like.

[0037] "Cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of "aikyi" and "heteroalkyl," respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. An example of a cycloalkyl is a spirocyclic cycloalkyl, wherein the spirocyclic rings are cycloalkyl rings. A cycloalkyl can be a fused ring cycloalkyl, wherein the fused rings are cycloalkyl rings. A cycloalkyl can be a bridged ring cycloalkyl, wherein the bridged rings are cycloalkyl rings. A cycloalkyl can be monocyclic. A cycloalkyl can be two, three, four, or five rings. A cycloalkyl can be poly cyclic. An example of a heterocycloalkyl is a spirocyclic heterocycloalkyl, wherein the spirocyclic rings are one or more heterocycloalkyl rings and optionally one or more cycloalkyl rings. A heterocycloalkyl can be a fused ring

heterocycloalkyl, wherein the fused rings are one or more heterocycloalkyl rings and optionally one or more cycloalkyl rings. A heterocycloalkyl can be a bridged ring heterocycloalkyl, wherein the bridged rings are one or more heterocycloalkyl rings and optionally one or more cycloalkyl rings. The rings of a spirocyclic, fused ring, or bridged ring heterocycloalkyl can be heterocyclic rings. A heterocycloalkyl can be monocyclic. A heterocycloalkyl can be two, three, four, or five rings. A heterocycloalkyl can be polycyclic. Examples of cycloalkyl include, but are not limited to, cyciopropyi, cyciobutyi, cyciopentyl, cyclohexyl, 1-cyciohexenyi, 3- cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1 -(1,2,5, 6-tetrahydropyridyl), 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A "cycloalkylene" and a

"heterocycloalkylene," alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. [0038] "Halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(Ci-C4)alkyl" includes, but is not limited to, fluoromethyi, difluoromethyi, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0039] "Aryl" means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term "heteroaryl" refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term "heteroaryl" includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6- fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. An aryl can be a fused ring aryl, wherein the fused rings are one or more aryl rings and optionally one or more cycloalkyl and/or heterocycloalkyl rings. An aryl can be a bridged ring aryl, wherein the bridged rings are one or more aryl rings and optionally one or more cycloalkyl and/or heterocycloalkyl rings. The rings of a fused ring aryl or bridged ring aryl can be aryl rings. An aryl can be monocyclic or polycyclic. An aryl can have two, three, four, or five rings. A heteroaryl can be a fused ring heteroaryl, wherein the fused rings are one or more heteroaryl rings and optionally one or more cycloalkyl, heterocycloalkyl, and/or aryl rings. A heteroaryl can be a bridged ring heteroaryl, wherein the bridged rings are one or more heteroaryl rings and optionally one or more cycloalkyl, heterocycloalkyl, and/or aryl rings. The rings of a fused ring heteroaryl or bridged ring heteroaryl can be heteroaryl rings. A heteroaryl can be monocyclic or polycyclic. A heteroaryl can have two, three, four, or five rings. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazoiyl, isoxazolyl, thiazolyl, furyi, thienyl, pyridyl, pyrimidyl, benzothiazolvl, benzoxazoyl benziniidazolyi, benzofuran, isobeiizofuranyl, indolyl, isoiiidolyl, benzothiophenyl, isoquinolyl, quinoxaiinyl, quinolyl, 1 -naphthyl, 2-naphthyl, 4-biphenyl, 1- pyrrolyl, 2-pyrrolyl, 3 -pyrrolyl, 3 -pyrazolyl, 2-iriiidazolyl, 4-iriiidazolyl, pyrazinyl, 2-oxazolyi, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazoiyl, 5-isoxazolyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2 -pyridyl, 3 -pyridyl, 4- pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5 -benzothiazolvl, purinyl, 2 -benziniidazolyi, 5-indolyl, 1- isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl.

Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An "arylene" and a "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.

[0040] "Spirocyclic rings" are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different.

Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g. substituents for cycloalkyl or heterocycloalkyl rings).

Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkyl ene. Individual rings within a spirocyclic ring group may be any of the immediately previous list, including having ail rings of one type (e.g. all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted

heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different,

[0041] "Oxo" means an oxygen that is double bonded to a carbon atom. |Ό042| "Alkylarylene" is an aryiene moiety covalentiy bonded to an aikyiene moiety (also referred to herein as an aikyiene linker). An alkylarylene moiety may be substituted (e.g. with a substituent group) on the aikyiene moiety or the arylene linker (e.g. at carbons 2, 3, 4, or 6) with halogen, oxo, -N ₃ , -( VCCk -CBn, -CI3, -CN, -CHO, -OH, - H2, -COOH,•COM ! -. -NO2, - SH, -SO2CH3 -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(0)NHNH ₂ , substituted or unsubstituted Cj-Cs alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl. The alkylarylene can be unsubstituted.

[0043] Each of the above terms (e.g., "alkyl," " ^• heteroalkyl," "cycloalkyl," "heterocycloalkyi," "aryl," and "heteroaryl") includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0044] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as aikyiene, aikenyl, heteroalkylene, heteroaikenyl, aikynyl, cycloalkyl,

heterocycloalkyi, cycloalkenyl, and heterocy cl oalkeny 1) can be one or more of a variety of groups selected from, but not limited to -OR', =0, =NR', =N-OR', -NR'R", -SR ^! , -halogen, - SiR'R"R'", -OC(0)R', -C(0)R', -CO2R, -CONR'R", -OC(0)NR'R", -NR"C(0)R', ~NR'~

C(0)NR"R"', -NR"C(0) ₂ R', - R-C(NR¾."R" ^, )= R" -NR-C(NR'R")=NR" ^! , -S(0)R', -S(0) _? .R', -S(0)2 R ^! R", -NRS0 ₂ R ^! , -NR'NR"R"', -ONR'R", -NR'C(Q)NR"NR"'R"", -CN, -NO2, - NR'SChR", -NR'C(0)R" -NR'C(0)-OR", -NR'OR", in a number ranging from zero to (2m'+ 1), where m' is the total number of carbon atoms in such radical. R, R', R", R'", and R"" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyi, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'", and R"" group when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyi. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF ₃ and -CH2CF3) and acyl (e.g., -C(0)CH ₃ , -C(0)CF ₃ , -C(0}0 bOCl I ·, and the like).

[0045] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R", -SR.', -halogen, - SiR'R"R"', -OC(0)R', -C(0)R', -CO2R, -CONR'R", -OC(0)NR'R", -NR"C(0)R', -NR-

C(0)NR"R"\ -NR"C(0)2R', ~\ R~C( \ R'R ^'' R" ^' ) \ R" ", ~\ R-C( N R'R ^" ) NR"\ -S(0)R', -S(0) ₂ R',- S(0) ₂ R ^! R", -NRSO2R, -NR'NR"R"', -ONR'R", ~NR'C(0)NR"NR"'R'''', -CN, -NO2, -R', -N ₃ ,~ CH(Ph) ₂ , fluoro(Ci-C4)alkoxy, and fluoro(Ci-C ₄ )alkyl, -NR'SC R", - R'C(0)R", -NR'C(O)- OR", -NR'OR", in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R", R'", and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R"', and R" " groups when more than one of these groups is present.

[0046] Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl ene, heterocycloalkylene, arylene, or heteroaryl ene) may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings, bridged rings, or spirocyclic rings, a substituent depicted as associated with one member of the fused rings, bridged rings, or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused ri ngs, bridged rings, or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different bridged rings, or different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of fused rings, bridged rings, or spirocyclic rings, any atom of any of the fused rings, bridged rings, or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, bridged rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, bridged rings, or spirocyclic rings are shown with one or more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.

[0047] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. The ring-forming substituents can be attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. The ring- forming substituents can be attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base stmcture create a spirocyclic structure. The ring-forming substituents can be attached to non-adjacent members of the base structure and form a bridged ring structure.

[0048] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(0)-(CRR')q-U-, wherein T and U are independently - R-, -0-, - CRR'~, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A~(CH2)r-B-, wherein A and B are independently -CRR'-, -0-, -NR-, -S-, -S(O)-, - S(0) ₂ -, -S(Q)?.NR ^! -, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR ^! )s-X'-(C"R"R'")d-, where s and d are independently integers of from 0 to 3, and X ^* is -0-, -NR ^* -, -S-, -S(0k -S« )).-.-. or ~S(0) ₂ NR'~. The substituents R, R', R", and R'" are preferably independently selected from hydrogen, substituted or unsubstituted aikyi, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkvl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl ,

[0049] "Heteroatom" or "ring heteroatom" are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si). [0050] "Substituent group" means a group selected from the following moieties: oxo, halogen, -CF ₃ , -CHF2, -( ] ! :!' . -CN, -OH, -NH ₂ , -COOH, -CO H2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, •N l 1 M b. -OM k ·Μ ί( ^' (())·{)1 L - Xf lOI I. -OCF3, -OCHF ₂ , -OCH2F, -NHSO2CFI3, -N3, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl , or unsubstituted heteroaryl. A substituent group can also be an alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, substituted by any suitable number and any type of substituent defined herein.

[0051] "Size-limited substituent" and "size-limited substituent group" mean a group selected from all of the substituents described above for a "substituent group," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 rnembered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C ₃ -Cs cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 rnembered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted Ce-C io aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 rnembered heteroaryl.

[0052] "Lower substituent" and "lower substituent group" mean a group selected from all of the substituents described above for a "substituent group," wherein each substituted or

unsubstituted al kyl is a substituted or unsubstituted Ci-Cs alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 rnembered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 rnembered

heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted Ce-Cio aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 rnembered heteroaryl. [0053] "Salt" refers to acid or base salts of the benzothiazole amphiphile compounds used in the methods of the present invention. Il lustrative examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.

[0054] "Pharmaceutically acceptable salts" are salts of the active benzothiazole amphiphile compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a suffi cient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,

monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as alginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge et al., Journal of

Pharmaceutical Science 66: 1 -19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for the present invention. Salts tend to be more soluble in aqueous or other protonic solvents that are the corresponding free base forms. In other cases, the preparation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5, that is combined with buffer prior to use. It is understood that the

pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0055] "Base" refers to a compound capable of accepting a proton (ΕΓ) under the Bronsted- Lowry definition, or is an electron-pair donor under the Lewis definition. Bases useful in the present invention that are Bronsted-Lowry bases include hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, magnesium hydroxide, strontium hydroxide, barium hydroxide, and others. Lewis bases include, but are not limited to, amines such as ammonia, trimethyl amine, triethylamine, diisopropylethylamine (DIPEA or Hunig's Base), l,8-diazabicycloundec-7-ene (DBU), 2,6-di-tert-butylpyridine, quinuclidine, and lithium di-isopropylamine (LDA), and nucleophilic bases such as butyl- lithium. Other bases are known to one of skill in the art.

[0056] "Acid" refers to a compound that is capable of donating a proton (EF) under the Bronsted-Lowry definition, or is an electron pair acceptor under the Lewis definition. Acids useful in the present invention are Bronsted-Lowry acids that include, but are not limited to, alkanoic acids or carboxylic acids (formic acid, acetic acid, citric acid, lactic acid, oxalic acid, etc.), sulfonic acids and mineral acids, as defined herein. Mineral acids are inorganic acids such as hydrogen halides (hydrofluoric acid, hydrochloric acid, hydrobromice acid, etc.), halogen oxoacids (hypochlorous acid, perchloric acid, etc.), as well as sulfuric acid, nitric acid, phosphoric acid, chromic acid and boric acid. Sulfonic acids include methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifiouromethanesulfonic acid, camphorsulfonic acid, among others.

[0057] "Isomers" refer to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms. [0058] "Tautomer" refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.

[0059] "Patient" or "subject in need thereof refers to a living organism suffering from or prone to a condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals and other non- mammalian animals.

[0060] "Effective amount" is an amount sufficient to accomplish a stated purpose (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce one or more symptoms of a disease or condition). An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a "therapeutically effective amount," A "reduction" of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A "prophylactically effective amount" of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage

Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0061] "Treat", "treating" and "treatment" refer to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. Examples of treatment include the administration of a benzothiazole amphiphile compound to a patient having a traumatic brain injury, in which the administration of said compound leads to the amelioration and/or reduction in the symptoms of trauma in the patient.

[0062] "Disorder" or "condition" refer to a state of being or health status of a patient or subject capable of being treated with the benzothiazole amphiphile compounds of the present invention. Examples of disorders or conditions include, but are not limited to traumatic brain injury.

[0063] "Traumatic brain injury" or "TBI" refer to an acquired brain injury or a head injury, when a trauma causes damage to the brain. Trauma includes, e.g., post-head trauma, impact trauma, and other traumas to the head such as, for example, traumas caused by accidents and/or sports injuries, eoneussive injuries, penetrating head wounds, brain tumors, stroke, heart attack, meningitis, viral encephalitis, and other conditions that deprive the brain of oxygen. In a particular embodiment, the trauma is an external, physical force. In another embodiment, the trauma is a "blast-induced traumatic brain injury," which refers to a TBI caused by the direct or indirect exposure to an explosion.

[0064] "Blunt force impact" refers to a brain injury when the head suddenly and violently hits an obj ect but the obj ect does not break through the skul 1.

[0065] "Concussion" refers to a mild form of traumatic brain injury resulting in temporary impairment of neurological function which quickly resolves by itself, and where there are generally no gross structural changes to the brain as the result of the condition. A concussion is generally considered to occur when there is a blow to the head or other forceful event, resulting in loss of consciousness for less than 30 minutes.

[0066] "Assessment" and "test" refer to an evaluation used to determine the severity of a traumatic brain injury, the details of which are described herein.

[0067] "An amount sufficient to reduce the symptoms" refers to the quantity of a

benzothiazole amphiphile compound administered to a patient suffering from a traumatic brain injury necessary to observe a reduction of the symptoms of traumatic brain injur}' in a patient. "Symptoms" of a traumatic brain injury include elevated levels of biomarkers in a patient's blood. Examples of biomarkers that become elevated in the blood of a patient suffering from a traumatic brain injur are GFAP and UCH-L1. Other symptoms of a traumatic brain injury are the deficits of the following functional domains: physical, visual, auditor}', neurobehavioral, cognitive-communication, and sleep. The details of biomarkers and each functional domain are described herein. A sufficient amount of a benzothiazole compound administered to a patient having traumatic brain injury symptoms will cause at least a 20% to 30% reduction in the symptoms compared to a statistically significant cohort of patients with a traumatic brain injury who are not administered a sufficient amount of benzothiazole amphiphile compounds.

III. Methods of Diagnosis

[0068] Traumatic brain injury may occur as a result of a head injur}'. A head injury can include any of the following: a bump to the head, a blow to the head, a jolt to the head, a sudden acceleration, a sudden deceleration, a sudden twisting of the head, a compression of the brain as a result of a nearby explosion or a penetrating head injury, and/or any type of force applied to the head which disrupts the normal function of the brain. In some embodiments of the invention, a TBI can be the result of a head injur)', wherein the head injury can be caused by, for example, blunt trauma to the head or a blow to the head.

[0069] In some embodiments of the invention, a traumatic brain injury can be a mild, moderate, or severe traumatic brain injury. In other embodiments, a TBI can be a mild TBI

(mTBI). In some embodiments, the mildest form of TBI (mTBI) can also be called a concussion, and is characterized by a temporary loss of brain function. As an example, a concussed patient can temporarily lose consciousness from a few seconds up to 30 minutes. When assessing whether or not a patient should receive treatment for a traumatic brain injury (i.e., treatment for the reduction in the symptoms of traumatic brain injury), it is necessary to confirm whether or not the patient has acquired a traumatic brain injury. Described herein are several methods and assessments that can be used to diagnostically determine the initial and subsequent level of neurologic damage of a patient with TBI.

[0070] In some embodiments of the invention, a patient having experienced a head injury can be diagnosed as having a mTBI by observing the patient and subsequently recognizing that the patient is experiencing symptoms of a traumatic brain injury. For example, a patient having a head injury can be diagnosed as having a mTBI if the patient experiences one or more of the following conditions: (1) observed or self-reported contusion, disorientation, or impaired consciousness, dysfunction of memory at the time of the injury, loss of consciousness lasting less than 30 minutes; and, (2) symptoms such as headache, dizziness, fatigue, irritability, impaired memory and poor concentration soon after the injury.

[0071] In other embodiments of the invention, a patient having a head injur}' can be diagnosed as having a TBI by evaluating the severity of the head injury using a test or a combination of tests. For example, a patient can be diagnosed as having a TBI by using the Glasgow Coma

Scale (GCS). The GCS is an assessment that can measure and score the eye opening, verbal, and motor responses of a patient that has experienced a head injury. The GCS score is the sum total score of each measured response. A GCS score may increase or decrease over time. The general definition of the scores is Severe (3-8), Moderate (9-12) and Mild (13-15). The GCS can be implemented to evaluate the response of patients having experienced a serious traumatic brain injury (i.e., unconscious patients). The Glasgow Coma Scale is a commonly used method of diagnosing traumatic brain injuries in patients and is known to those skilled in the art

(http :/7www . gl asgowcomascal e . org) .

[0072] In some embodiments of the invention, a patient having a head injury can be diagnosed as having a TBI using the Rivermead Post-Concussion Questionnaire (RPQ). The RPQ is useful in determining the severity of several symptoms and functional deficits in a patient having been observed as having a concussion (niTBI). Patients can be asked to rate the severity of symptoms that they experience. The symptoms that are evaluated using the RPQ include: headaches, dizziness, nausea and/or vomiting, hyperacusis, sleep disturbance, fatigue, blurred vision, double vision, light sensitivity, restlessness, irritability, frustration, depression, memory loss, poor concentration, and taking a longer time to think. These symptoms can be evaluated within 24 hours of a patient having experienced a head injur . The RPQ is a commonly used method of diagnosing traumatic brain injuries in patients and is known to those skilled in the art (King, N.; Crawford, S., Wenden, F,; Moss, N.; and Wade, D. (1995) Journal of Neurology 242: 587-592), [0073] Several other tests used to diagnose a patient with a TBI include: Military Acute Concussion Evaluation (MACE) (Kennedy, C. H.; Moore, J. L. Military Neuropsychology (2010), Immediate Post-Concussion Assessment and Cognitive Test (ImPACT)

(https://www.impacttest.com), Sports Concussion Assessment Tool (SCAT)

(http://physicians.cattonline.COm/scat/); Automated Neuropsychological Assessment Metrics (AN AM) (Archives of Clinical Neuropsychology (2007), 22, Suppl. 1, S1 -S144); and Cogstate (https://cogstate.com). The assessments described herein are commonly used methods to diagnose patients with a TBI and are known to those skilled in the art.

[0074] A patient can be diagnosed as having a traumatic brain injury by monitoring the level of particular biomarkers in the patient's blood. Specifically, the glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase LI (UCH-L1) are the biomarkers that can be measured at multiple time points in patients with mild to moderate TBI (i.e., a GCS 9-15). The blood test results measuring the levels of GFAP and UCH-L1 in the patients at multiple time points indicate whether or not a TBI has occurred. For example, the levels of GFAP and UCH- Ll are both elevated very soon after a TBI, but then decline within a week to substantially lower levels. It is known to one skilled in the art how to diagnose a TBI using biomarkers (Papa, !,. JAMA Neurol. (2016) 73 (5), 551-560).

[0075] In some cases, a patient can be diagnosed as having a traumatic brain injury using methods of neuroimaging, such as computerized axial tomography (CAT or CT) and magnetic resonance imaging (MRI). CT and MRI scans can be used to identify the severity of a brain injury. For example CT and MRI scans are often used in hospitals to identify brain injuries, though they are often not useful at detecting mTBI in which there is no obvious damage to the brain. In some embodiments, patients having a mTBI with a normal CT or MRI scan can be distinguished from patients having a moderate TBI with bleeding in the brain and an abnormal CT or MRI scan. A CT scan may be implemented within the first 24 hours of a brain injury, and can be useful at detecting bony pathology and some types of early brain bleeds. An MRI scan is considered more valuable when performed 48 to 72 hours after a brain injury, and can be useful at hemorrhagic cortical contusions, petechiae, axonal injury, and subtle neuronal damage. In general, the methods of neuroimaging can be most useful to patients having experienced a moderate to serious traumatic brain injury. It is known to one skilled in the art how to diagnose a TBI using neuroimaging methods (Lee, B. NeuroRX. (2005) 2 (2), 372-383, International application number PCT/US2015/024739).

[0076] In some embodiments of the invention, a patient can be di agnosed as having a traumatic brain injury by any one of the methods described above or known in the art, or any combination of the methods described above or known in the art. In other embodiments, the patient having a head injury is diagnosed with a TBI by observation and recognition of TBI symptoms, in addition to implementing an assessment, such as the GCS or the RPQ. In other embodiments, the patient having a head injur}' is diagnosed with a TBI by observation and recognition of TBI symptoms, in addition to monitoring biomarkers. In other embodiments, the patient having a head injury is diagnosed with a TBI using multiple assessments, such as the GCS, RPQ, and MACE. In other embodiments, the patient having a head injury is diagnosed with a TBI using neuroimaging methods, in addition to monitoring biomarkers and performing an assessment, such as the GCS or the RPQ. In other embodiments, the patient having a head injury is diagnosed with a TBI using neuroimaging methods, in addition to monitoring biomarkers. In other embodiments, the patient having a head injury is diagnosed with a TBI using neuroimaging methods, in addition to performing an assessment, such as the GCS or the RPQ. In some other embodiments, the patient having a head injur}' is diagnosed with a TBI using neuroimaging methods, such as MRI and CT scans. In some embodiments, the patient having a head injur}' is diagnosed with a TBI by monitoring the levels of biomarkers. In other embodiments, the patient having a head injury is diagnosed with a TBI by observation and recognition of TBI symptoms. In other embodiments, the patient having a head injury is diagnosed with a TBI using one assessment, such as the GCS or RPQ. In some embodiments, the patient having a head injury is diagnosed with a TBI using the RPQ assessment.

[0077] In further embodiments of the invention, a patient having a head injury is diagnosed with a TBI using any of the methods and assessments described herein immediately after receiving the head injury, i.e. within 0 hours of receiving a head injury. In some embodiments, the patient having a head injury is diagnosed with a TBI within about 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 4 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 42 hours or 48 hours of receiving a head injury. In some embodiments, a patient having a head injury is diagnosed with a TBI within about 0 to about 48 hours of receiving a head injury, or about 5 minutes to about 42 hours, or about 10 minutes to about 36 hours, or about 15 minutes to about 30 hours, or about 20 minutes to about 24 hours, or about 30 minutes to about 18 hours, or about 45 minutes to about 12 hours, or about 1 to about 4 hours of receiving a head injury. In some embodiments, a patient having a head injury is diagnosed with a TBI within about 0 hours to about 1 hour of receiving a head injury. In another embodiment, a patient having a head injur}'- is diagnosed with a TBI within about 30 minutes of receiving a head injury. [0078] In some cases, patients diagnosed with a concussion/mTBI and more serious TBIs can experience neurologi cal effects caused by altered levels of neurochemicals, and subsequent neuron damage. The neurological effects can linger for days, weeks, months or years. These neurological effects cause deficits in the following functional domains: physical, visual, auditory, neurobehavioral, cognitive-communication, and sleep. Deficits of the physical domain can induce any of the following symptoms: nausea, vomiting, dizziness, headaches, seizures, changes in consciousness, fatigue, weakened muscles, impaired balance, and/or impaired coordination. Deficits of the visual domain can induce any of the following symptoms: light sensitivity, double vision, decreased visual acuity, visual neglect, and/or changes in the accommodation-convergence reflex. Deficits of the auditor}- domain can induce any of the following symptoms: hyperacusis, tinnitus, hearing loss, and/or central auditory dysfunction. Deficits of the neurobehavioral domain can induce any of the following symptoms: agitation, anxiety, depression, mood swings, restlessness, disorientation, impulsivity, irritability, impatience, and/or stress disorders Deficits of the cognitive-communication domain can induce any of the following symptoms: attention deficits, executive function deficits, information processing impairments, memory deficits, learning deficits, impaired metacognition, impaired spatial cognition, aphasia, and/or motor speech deficits. Deficits of the sleep domain can induce any of the following symptoms: insomnia, hypersomnia, and/or sleep disturbance.

[0079] In some embodiments, a patient diagnosed with a TBI can have a deficit in one or more functional domains. A patient diagnosed with a TBI having a deficit in one or more functional domains can receive a therapeutically effective amount of a benzothiazole amphiphi!e compound. The benzothiazole amphiphile compounds of the invention are described herein.

IV. Benzothiazole Amphiphile Compounds

[0080] The present invention provides a series of benzothiazole amphiphile compounds that are useful for treating traumatic brain injury in a patient. In some embodiments, the present invention provides a compound having the formula (I):

wherein R ¹ , R ² , R ^J , R ⁴ , R ³ , R ⁶ , R ^; , and R ⁸ of formula (I) are independently selected from the group consisting of hydrogen, halogen, -CX3, -CHX2, -CH2X, -OCX, -OCHX2, -OCH2X, -CN, - OI L - H2, -COO] ! -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, - NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO2H, -NHC(0)H, -NHC(0)OH, -NHOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroal kyl , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocvcloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroarvl. Each X can be independently a halogen. The Y of formula (I) can be N or S. The Z of formula (I) can be absent, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocvcloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroarvl. The n of formula (I) can be an integer from 1 to 15. The benzothiazoie amphiphiie compound of formula (I) can be administered within about 0 to 72 hours of the traumatic brain injury, and can be used in an amount sufficient to reduce the symptoms of traumatic brain injury.

[0081] In some embodiments of the invention, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ of formula (I) are independently selected from the group consisting of hydrogen, halogen, -CX3, -CHX2, - CH2X, -OCX, -OCHX2, -OCH2X, -CN, -OH, -NH2, -COO! !, -CONH2, -NO2, -SH, -SO3H, - SO4H, -SO2NH2, -\ i I M f % -ONH2, -NHC(0)NHNH ₂ , -NHC(0)NH2, -NHSO2H, -NHC(0)H, - NHC(0)OH, -NHOH, substituted or unsubstituted alkyl (e.g. Ci-Ce, C1-C0, Ci-C¾, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or Cs-Ce.), substituted or unsubstituted heterocvcloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In some

embodiments, R ¹ , R ² , R ^J , R , R ⁵ , R ⁶ , R ⁷ , and R ⁸ of formula (I) is hydrogen or an unsubstituted Ci-C& alkyl. In other embodiments, R ^! , R ² , R ³ , R ⁴ , R ⁵ , R°, R ⁷ , and R ⁸ of formula (I) is hydrogen or -CH3. In some embodiments, R ³ of formula (I) is -CH3 and R ^l , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ of formula (I) are hydrogen.

[0082] In some embodiments of the invention, R ¹ , R ² , R", R ⁴ , R ³ , R ⁶ , R ^; , and II ^s of formula (Γ) are independently selected from the group consisting of hydrogen, halogen, -CX3, -C IX2, - CH2X, -OCX, -OCHX2, -OCH2X, -CN, -OH, -NI-I2, -COOH, -CONH2, -NO2, -SH, -SO3H, - SO4H, -SO2NH2, - HNH2, -O H2, -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO2H, -NHC(0)H, - NHC(0)OH, -NHOH, substituted (e.g., sub tituted with substituent group(s), size-limited substituent group(s), or lower substituent group(s)) or unsubstituted alkyl, substituted (e.g., substituted with substituent group(s), size-limited substituent group(s), or lower substituent group(s)) or unsubstituted heteroalkyl, substituted (e.g., substituted with substituent group(s), size-limited substituent group(s), or lower substituent group(s)) or unsubstituted cycloalkyl, substituted (e.g., substituted with substituent group(s), size-limited substituent group(s), or lower substituent groupis )) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with substituent group(s), size-limited substituent group(s), or lower substituent group(s)) or unsubstituted aryl, or substituted (e.g., substituted with substituent group(s), size-limited substituent group(s), or lower substituent group(s)) or unsubstituted heteroaryl. In embodiments, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ of formula (Γ) are substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments, R ¹ , R ² , R ^J , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ of formula (I) are substituted or unsubstituted alkyl ,

[0083] In some embodiments of the invention, R ¹ , R ² , R", R ⁴ , R ³ , R ⁶ , R ^; , and R ⁸ of formula (Γ) are independently selected from the group consisting of hydrogen, halogen, -CX3, -C IX2, - CH2X, -OCX, -OCHX2, -OCH2X, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -

SO4H, -SO2NH2, - HNH2, -O H2, -NHC(0)NHNH ₂ , -NHC(0)NH ₂ , -NHSO2H, -NHC(0)H, - NHC(0)OH, -NHOH, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

[0084] In some embodiments of the invention, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ of formula (I) are independently substituted (e.g., substituted with substituent group(s), size-limited substituent group(s), or lower substituent group(s)) or unsubstituted alkyl. In embodiments, R ¹ , R ² , R ^J , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are independently substituted (e.g., substituted with substituent group(s), size- limited substituent groupfs), or lower substituent group(s)) alkyl. In some embodiments, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ^s are independently unsubstituted alkyl. In embodiments, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are independently substituted or unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C , or Ci-Cii). In embodiments, R ¹ , R ² , R ^J , R ⁴ , R ³ , R ⁶ , R ^; , and R ^s are independently substituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2). In other embodiments, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are independently unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, Ci-C ₄ , or C1-C2). In embodiments, R ¹ , R ² , R ^J , R ⁴ , R ³ , R ⁶ , R', and R ⁸ are independently unsubstituted C1-C2 alkyl. In some

embodiments, R ³ of formula (I) is Ci-C ₂ alkyl and R ¹ , R ² , R ⁴ , R ³ , R ⁶ , R ⁷ , and R ⁸ of formula (I) are hydrogen.

[0085] In some embodiments, R ¹ , R , R ³ , R ⁴ , R ³ , R ⁶ , R', and R ⁸ are independently substituted (e.g., substituted with substituent group(s), size-limited substituent group(s), or lower substituent group(s)) or unsubstituted heteroalkyl. In other embodiments, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ^s can be substituted (e.g., substituted with substituent group(s), size-limited substituent group(s), or lower substituent group(s)) heteroalkyl. In embodiments, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R°, R ⁷ , and R ⁸ can be unsubstituted heteroalkyl. In other embodiments, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R', and R ⁸ can be substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In still other embodiments, R ¹ , R , R ³ , R ⁴ , R ⁵ , R ⁶ , R' ^' , and R ⁸ can be substituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In some embodiments, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ can be an unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered).

[0086] In embodiments, R ¹ , R ² , R ^J , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ can be substituted (e.g., substituted with substituent group(s), size-limited substituent group(s), or lower substituent group(s)) or unsubstituted cycioalkyl. In other embodiments, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ can be substituted (e.g., substituted with substituent group(s), size-limited substituent group! s), or lower substituent group(s)) cycioalkyl. In some embodiments, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R', and R ⁸ can be an unsubstituted cycioalkyl. In other embodiments, R ¹ , R ² , R ^J , R ⁴ , R ⁵ , R ^b , R ⁷ , and R ⁸ can be substituted or unsubstituted cycioalkyl (e.g., C ₃ -Cs, C ₃ -C ₆ , C ₄ -C ₆ , or Cs-Ce). In another embodiment, R ^! , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ can be substituted cycloaikyi (e.g., Cs-Cg, Cs-Ce, C4-C6, or C5-C0). In some embodiments, R ^l , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ can be unsubstituted cycloaikyi (e.g., Cs-Cs, C ₃ -Ce, C ₄ -C ₆ , or Cs-Ce).

[0087] In embodiments, R ¹ , R ² , R ³ , R ⁴ , R ³ , R ⁶ , R ⁷ , and R ^s can be substituted (e.g., substituted with substituent group(s), size-limited substituent group(s), or lower substituent group(s)) or unsubstituted heterocy cloalkyl. In other embodiments, R ¹ , R\ R ³ , R ⁴ , R ⁵ , R ^b , R ⁷ , and R ⁸ can be substituted (e.g., substituted with substituent group(s), size-limited substituent group(s), or lower substituent group(s)) heterocycloalkyl. In some embodiments, R\ R ² , R ³ , R ⁴ , R ³ , R ⁶ , R ⁷ , and R ⁸ can be an unsubstituted heterocycloalkyl. In still other embodiments, R ¹ , R ² , R ³ , R ⁴ , R ³ , R ⁶ , R', and R ⁸ can be substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments of the invention, R ¹ , R ² , R ^J , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ can be substituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R°, R ', and R ⁸ can be an unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).

[0088] In another embodiment, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ can be substituted (e.g., substituted with substituent group(s), size-limited substituent group(s), or lower substituent group(s)) or unsubstituted aryl. In other embodiments, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ can be substituted (e.g., substituted with substituent group(s), size-limited substituent group(s), or lower substituent group(s)) aryl. In some embodiments, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ can be an unsubstituted aryl. In other embodiments, R ¹ , R ² , R ³ , R ⁴ , R\ R°, R ^? , and R ⁸ can be substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl). In embodiments, R ¹ , R ² , R ^J , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ can be substituted aryl (e.g., Ce-Oo or phenyl). In another embodiment, R ¹ , R ² , R R ⁴ , R ³ , R ⁶ , R ⁷ , and R ⁸ can be an unsubstituted aryl (e.g., Ce-Cio or phenyl). [0089] In one embodiment, R ¹ , R ² , R R R ⁵ , R ⁶ , R ⁷ , and R ⁸ can be substituted (e.g., substituted with substituent group(s), size-limited substituent group(s), or lower substituent group(s)) or unsubstituted heteroaryl. In other embodiments, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ can be substituted (e.g., substituted with substituent group(s), size-limited substituent group(s), or lower substituent group(s)) heteroaryl. In embodiments, R ^l , R ² , R ³ , R ⁴ , R ³ , R ⁶ , R', and R ⁸ can be unsubstituted heteroaryl. In some embodiments, R\ R ² , R ³ , R ⁴ , R ³ , R ⁶ , R ⁷ , and R ⁸ can be substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R ¹ , R ² , R ^J , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ can be substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In still other embodiments, R ¹ , R ² , R ³ , R ⁴ , R ³ , R ⁶ , R ⁷ , and R ⁸ can be an unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

[0090] In some embodiments of the invention, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ of formula (I) are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some other embodiments, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R°, R ', and R ⁸ of formula (I) can be independently substituted or unsubstituted alkyl (e.g. Ci-Cs, Ci-Ce, C1-C4, or C1-C2), substituted or

unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl (e.g., CB-CS, C3-C&, C ₄ - Ce, or Cs-Ce), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g., Ce-Cio or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In some other embodiments, R ¹ , R ² , R ^J , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are independently hydrogen or substituted or unsubstituted alkyl. In some embodiments, R ¹ , R ² , R ^J , R ⁴ , R ⁵ , R ⁶ , R', and R ⁸ of formula (I) can be independently hydrogen or substituted or unsubstituted alkyl (e.g. Ci-Cg, Ci-Ce, C1-C4, or C1-C2). In some embodiments, R ³ of formula (I) is Ci-C? alkyl and R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ of formula (I) are hydrogen.

[0091] In embodiments, X of formula (I) is F, CI, Br, or I. In other embodiments, X can be F. In embodiments, X can be CI. In some embodiments, X can be Br. In other embodiments, X can be I. [0092] In some embodiments, the Z of formula (I) can be absent, hydrogen, or substituted

(e.g., substituted with substituent group(s), size-limited substituent group(s), or lower substituent group(s)) or unsubstituted alkyl. In some embodiments, Z is substituted (e.g., substituted with substituent group(s), size-limited substituent group(s), or lower substituent group(s)) alkyl . In other embodiments, Z is unsubstituted alkyl. In other embodiments, Z can be substituted or unsubstituted alkyl (e.g. , Ci-Cs, Ci-Ce, C1-C4, or C1-C2), In embodiments, Z can be substituted alkyl (e.g., Ci-Cs, Ci-C&, C1-C4, or C1-C2). In other embodiments Z can be unsubstituted alkyl (e.g., Ci-Cs, Ci-Ce, C1-C4, or C1-C2). In some embodiments, Z can be unsubstituted C1-C2 alkyl. In some embodiments, Z can be absent, hydrogen, or substituted or unsubstituted Ci-Ce alkyl. In some embodiments, Z is an unsubstituted Ci-C ₄ alkyl. The Z of formula (I) can be unsubstituted C1-C2 alkyl. In other embodiments, Z can be -CH3. In some embodiments, Z can be hydrogen. In other embodiments, Z can be absent.

[0093] In some embodiments, n of formula (I) is an integer from 1 to 20. In embodiments, n is an integer from 1 to 15, 1 to 14, 1 to 13, or 1 to 12. In some embodiments, n can be an integer from 3 to 12, 3 to 10, 3 to 8, 3 to 6, or 3 to 5. In other embodiments, n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, n is 3 to 5.

[0094] In one aspect of the invention, the benzothiazole amp hip hi le compounds that are useful for treating traumatic brain injury in a patient are compounds having the formula (II):

wherein R ³ , X, Y, Z, and n are as described herein. The benzothiazole amphiphile compound of formula (II) can be administered within about 0 to 72 hours of the traumatic brain injur}' and can be used in an amount sufficient to reduce the symptoms of traumatic brain injury. In some embodiments, R ⁵ of formula (II) is hydrogen or substituted or unsubstituted alkyl. In other embodiments of the invention, Y of formula (II) is N or S. In other embodiments, the Z of formula (II) can be absent, hydrogen or substituted or unsubstituted Ci-Ce alkyl. The n of formula (II) can be an integer from 3 to 8.

[0095] In some embodiments of the invention, the R" of formula (II) is a hydrogen or -CH ₃ . In other embodiments, Z of formula (II) is absent. In an embodiment of the invention, Z of formula (II) can be hydrogen or -CH ₃ .

[0096] In an aspect of the invention, the benzothiazole amphiphile compound has the formula:

In some embodiments, the compound has the formula:

In other embodiments, the compound has the formula:

[0099] In one aspect of the invention, the benzothiazole amphiphile compound has the formula:

In some embodiments, the compound has the formula:

In other embodiments, the compound has the formula:

In another embodiment, the compound has the formula:

[0103] In certain embodiments, the compounds described herein are non-toxic. In other embodiments, the compounds described herein are not harmful to cells. Methods for measuring toxicity may be found in Prangkio et al,, PLoS ONE, 7(10): e47261 , 2012 and P. Prangkio et al., Biochimica et Biophysica Acta 1808: 2877-2885, 2011, and are incorporated in their entirety, for all purposes. In embodiments, the therapeutically effective concentration for treating a disease (e.g., a neuronal disease) is below the lethal concentration (e.g., LDso). [0104] In certain embodiments, the compounds have a solvent accessible surface area (SASA) from about 950 to about 990 A ² , or from about 960 to about 990, or from about 960 to about 985 A ² . In other embodiments, the SASA measurements are determined using PyMOL. In some embodiments, the compounds have a SASA of less than about 990 A ² . In other embodiments, the compounds have a SASA of less than about 985 A ² ,

[0105] In some embodiments, the present invention provides compositions comprising the benzothiazole amphiphile compounds as described herein. The compositions can also include salts and isomers of the benzothiazole amphiphile compounds of the present invention.

[0106] In some embodiments, the compounds of the present invention may exist as salts, such as with pharmaceutically acceptable acids. The present invention includes such salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maieates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in the art. The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0107] It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, ail such tautomeric forms of the compounds being within the scope of the invention.

[0108] Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds: the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute

stereochemistry, as (R)-or (S)-or, as (D)-or (L)-for amino acids, and individual isomers are encompassed within the scope of the present invention. The compounds of the present invention do not include those which are known in art to be too unstable to synthesize and/or isolate. The present invention is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers,

[0109] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the staicture; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention,

[0110] Unless otherwise stated, structures depicted herein are also meant to include

compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ⁱ³ C- or ¹⁴ C-enriched carbon, are within the scope of this invention. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0111] Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0112] The present invention also provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. In some embodiments, the prodrug form may include a phosphate derivative or a sugar (e.g. ribose) derivative. For example prodrugs moieties used in HCV nucleoside and nucleotide prodrugs may be added to the compounds described herein or the compounds used in methods described herein. In some embodiments, prodrug moieties described in: Murakami et al. J. Med ( ^' hem.. 2011, 54, 5902; Sofia et al., J. Med Chem. 2010, 53, 7202; Lam et al. A CC, 2010, 54, 3187; Chang et al. , ACS Med Chem Lett , 201 1, 2, 130; Furman et al, Antiviral Res., 2011, 91, 120; Vemachio et al, ACC, 2011, 55, 1843; Zhou et al, AAC, 2011, 44, 76; Reddy et al, BMCL, 2010, 20, 7376; Lam et al, J. Virol,, 2011, 85, 12334; Sofia et al, J. Med. Chem., 2012, 55, 2481, Hecker et al., J. Med. Chem., 2008, 51 , 2328; or Rautio et al, Nature Rev. Drug. Discov., 2008, 7, 255, all of which are incorporated herein by reference in their entirety for all purposes, may be added to compounds described herein or used in methods described herein.

[0113] It should be noted that throughout the application that alternatives are written in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit.

[0114] Descriptions of compounds of the present invention are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.

Synthesis of Benzoihiazole Amphiphile Compounds

[01.15] The compounds of the invention can be synthesized by a variety of methods known to one of skill in the art (see Comprehensive Organic Transformations by Richard C. Larock, 1989) or by an appropriate combination of generally well known synthetic methods. [0116] The benzothiazole amphiphile compounds of the present invention can be synthesized by an appropriate combination of generally well known synthetic methods. Techniques useful in synthesizing the compounds of the invention are both readily apparent and accessible to those of skill in the relevant art. The discussion below is offered to illustrate certain of the diverse methods available for use in assembling the compounds of the invention. However, the discussion is not intended to define the scope of reactions or reaction sequences that are useful in preparing the compounds of the present invention. Exemplary syntheses of the compounds of formula (I) and formula (II) can be found in U.S. patent application Ser. No, 11/487,224, now U.S. Pat. No. 7,666,886; U.S. patent application Ser. No. 14/771,1 18; International application number PCT/US2017/012139; J. Biol Chem., 291 , 1 1981-1 1992, 2016; and J. Neurosci,, 33(22): 9306-9318, 2013.

[0117] Compound s of formula (I) and formula (II) are prepared as described in Scheme 1 :

Scheme a

[0118] Compounds of formula (I) and formula (II) are prepared as described in Scheme 1. Unless indicated otherwise, R ¹ , R , R ³ , R ⁴ , R ⁵ , R ⁶ , R', R ⁸ , X, Y, Z, and n are as described herein. In Scheme la, benzothiazole amphiphile compounds, wherein Y is N, are synthesized by first alkylating a 4-hydroxy benzaldehyde 17 with a 2-chl oro-N-acetamide 18 by an Finkel stein reaction (step i(a)). Step i(a) involves treatment of 17 and 18 with a suitable halide salt (e.g. sodium or potassium iodide) in the presence of a weak base (e.g. potassium carbonate, cesium carbonate, or sodium carbonate) in a suitable polar, aprotic solvent (e.g. acetone or acetonitrile) at a reflux temperature. The resulting aryl ether 19 will undergo a rearrangement in step u(a) in the presence of a strong base (e.g. potassium hydroxide, lithium hydroxide, or sodium

hydroxide) in a suitable non-polar solvent (e.g. toluene, benzene, or 1,4-dioxane) at a reflux temperature to form the 4-N-amino benzaldehvde 20.

[0119] Compound 20 and a 2-aminothiophenol 21 are exposed to microwave irradiation in step iii(a) in the presence of a suitable ionic liquid (e.g. l-pentyl-3-methylimidazolium bromide or 1- butyl-3-methylimidazolium hexafluorophosphate) to afford a benzothiazole 22. Compound 22 is converted to 24, the benzothiazole amphiphile compound of formula (I) and formula (II), wherein Y is N, in step iv(a). Step iv(a) involves a nucleophilic substitution reaction between compound 22 and an iodo-poly ethylene glycol compound 23, in which the compounds are exposed to microwave irradiation in the presence of a suitable weak base (e.g. potassium carbonate) and a polar aprotic solvent (e.g. tetrahydrofuran or dimethylformamide).

[0120] Alternatively, benzothiazole amphiphile compounds, wherein Y is S, can be synthesized as described in Scheme lb. A 4-methylthio benzaldehvde 25 is combined with 2- aminothiophenol 21 in step i( ) under conditions similar to that of step iii(a) (microwave irradiation in the presence of a suitable ionic liquid). The resulting methvlthio benzothiazole compound 26 is oxidized to the methylsufinyl benzothiazole 27 in step ii(b) using a suitable peroxy acid (e.g. /wet -chloroperoxybenzoic acid) in a suitable inert solvent (e.g. toluene, dichloromethane, 1,2-dichloroethane or dioxane). Step iu(b) of Scheme lb involves a

Pummerer rearrangement of compound 27 in the presence of trifluoroacetic anhydride in a suitable inert solvent (e.g. toluene, dichloromethane, 1,2-dichloroethane or dioxane) forms an a- acyloxy-thioether compound 28. Other suitable anhydrides can be used to perform step iii(b), such as acetic anhydride or trifluoromethanesulfonic anhydride.

[0121] Treatment of oc-acyloxy-thioether compounds such as 28 with a suitable strong base (e.g. potassium or sodium hydroxide) in a suitable polar protic solvent (e.g. methanol, ethanol, or water) will convert the thioether derivative 28 into a thiol 29, as in step iv(b). The thiol benzothiazole compound 29 undergoes a nucleophilic substitution reaction in step v(b) with iodo-polyethylene glycol compound 23, in which the compounds are exposed to a strong base (e.g. sodium or lithium hydride) in a suitable polar aprotic solvent (e.g. dimethylferm amide, tetrahydrofuran, or acetonitrile) at a reflux temperature. Step v(b) of Scheme lb results in the formation of a 30, a benzothiazole amphiphile compound of formula (I) and formula (II), wherein Y is S.

V. Formulation

[0122] The compositions of the present invention can be prepared in a wide variety of oral and parenteral forms. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. The compositions of the present invention can also be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneousiy, intraduodenally,

intraperitoneal!}', or intrathecally. Also, the compositions described herein can be administered by inhalation, for example, intranasaily (for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35: 1187-1 193, 1995, Tjwa, Ann. Allergy Asthma Immunol ^' . 75: 107-1 11, 1995). Accordingly, the present invention also provides pharmaceutical compositions including a pharmaceutically acceptable carrier or excipient and the benzothiazole amphiphile compound.

[0123] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors, and the like. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention. [0124] For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Co, Easton Pa, ("Remington's").

[0125] In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component, i.e. a benzothiazole amphiphile compound. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets can contain from 5% or 10% to 70% of the benzothiazole amphiphile compound.

[0126] Suitable solid excipients include, but are not limited to, magnesium carbonate;

magnesium stearate; talc; pectin; dextrin; starch; tragacanth; a low melting wax; cocoa butter; carbohydrates, sugars including, but not limited to, lactose, sucrose, mannitol, or sorbitol, starch from com, wheat, rice, potato, or other plants; cellulose such as methyl cellulose,

hydroxypropylmethyl -cellulose, or sodium carboxymethylcellulose; and gums including arabie and tragacanth; as well as proteins including, but not limited to, gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.

[0127] Dragee cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arable, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound (i .e., dosage of the

benzothiazole amphiphile compound). Pharmaceutical preparations of the invention can also be used orally using, for example, push-fit capsules made of gelatin, as wel l as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules can contain the benzothiazole amphiphile compound mixed with a filler or binders such as lactose or starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the benzothiazole amphiphile compound may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers. [0128] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0129] Aqueous solutions suitable for oral use can be prepared by dissolving the benzothiazoie amphiphile compound in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations can be adjusted for osmolality. [0130] Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. [0131] Oil suspensions can be formulated by suspending the benzothiazoie amphiphile compound in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin, or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281 :93-102, 1997. The pharmaceutical formulations of the invention can also be in the form of oil -in- water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono- oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a

preservative, or a coloring agent.

[0132] The compositions of the present invention can also be delivered as microspheres for slow release in the body. For example, microspheres can be formulated for administration via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Set Polym. Ed. 7:623-645, 1995); as biodegradable and injectable gel formulations (see, e.g., Gao, Pharm. Res. 12:857-863, 1995), or, as microspheres for oral administration (see, e.g., Eyles, J. Pharm,. Pharmacol. 49:669-674, 1997).

[0133] In another embodiment, the compositions of the present invention can be formulated for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or lumen of an organ. The formulations for administration will commonly comprise a solution of the compositions of the present invention dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can

conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter. These formulations may be sterilized by conventional, well known sterilization techniques. The formulations may contain

pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of the compositions of the present invention in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. For IV administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3-butanediol.

[0134] In another embodiment, the formulations of the compositions of the present invention can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing ligands attached to the liposome, or attached directly to the oligonucleotide, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present invention into the target cells in vivo, (See, e.g., Ai-Muhammed, J. Microencapsul. 13 :293-306, 1996; Chonn, Ctirr. Opin. BiotechnoL 6:698- 708, 1995; Ostro, Am. J. Hasp. Pharm. 46: 1576-1587, 1989). The compositions of the present invention can also be delivered as nanoparticles.

VL Administration [0135] The compositions of the present invention can be delivered by any suitable means, including oral, intravenous, and intranasal methods. The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the benzothiazole amphiphile compound. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0136] Pharmaceutical compositions provided by the present invention can include

compositions wherein the active ingredient can be a benzothiazole amphiphile compound described herein (including embodiments or examples). The pharmaceutical compositions can contain a therapeutically effective amount of the active ingredient. In some embodiments of the invention, a therapeutically effective amount of the active ingredient is an amount effective to achieve its intended purpose. In some embodiments of the invention, a therapeutically effective amount of the active ingredient can be an amount effective to reduce the symptoms of traumatic brain injury. The actual amount effective for a particular application can depend, inter alia, on the condition being treated (i.e., traumatic brain injury). When administered in methods to treat a condition or disease (i.e., traumatic brain injury) such compositions will contain an amount of active ingredient effective to achieve the desired result. Determination of a therapeutically effective amount of a compound of the invention is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure herein.

[0137] The dosage and frequency (single or multiple doses) of a therapeutically effective amount of the benzothiazole amphiphile compounds described herein administered to a mammal can vary depending upon a variety of factors, for example, whether the mammal suffers from another condition or disease; its route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated, kind of concurrent treatment, complications from the disease being treated or other health-related problems. Other therapeutic regimens or agents can be used in conjunction with the methods and compounds of the present invention. Adjustment and manipulation of established dosages (e.g., frequency and duration) are well within the ability of those skilled in the art.

[0138] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art. [0139] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animal s. The dosage in humans can be adjusted by monitoring compounds' effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.

[0140] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the patient over time. In some embodiments, the dose of the benzothiazole amphiphile compound administered to a patient can be sufficient to reduce the symptoms of traumatic brain injury in the patient. The size of the dose can be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.

[0141] Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the traumatic brain injury and state of the patient.

[0142] Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is effective to treat the clinical symptoms demonstrated by the particular patient. This planning can involve the careful choice of active compound by considering factors such as compound potency, relative bioavail bility, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent.

[0143] In some embodiments, suitable dosage ranges for the active agent (i.e. a benzothiazole amphiphile compound described herein) include from about 0.1 mg to about 10,000 mg, or about 1 mg to about 1000 mg, or about 10 mg to about 750 mg, or about 25 mg to about 500 mg, or about 50 mg to about 250 mg. Suitable dosages for the active agent include about I mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1200 mg.

[0144] In some embodiments, the dosage of a pharmaceutical composition for oral

administration of a benzothiazole amphiphile compound described herein can be about 0.1 mg/kg of body weight per patient, or 0.5, 1 , 5, 10, 25, 50, 100, 250, 500, 750, or 1000 mg/kg of body weight per patient. In other embodiments, the dosage of a pharmaceutical composition for oral administration of a benzothiazole amphiphile compound described herein can be from about 0.1 to 1000 mg/kg of body weight per patient, or from about 0.5 to 750, or from about 1 to 500, or from about 5 to 250, or from about 10 to 100, or from about 25 to 50 mg/kg of body weight per patient. In still another embodiment, the dosage can be between about 0.5 to about 25 mg/kg of body weight per patient, or between about 5 to 15 mg/kg of body weight per patient, or between about 8 to about 12 mg/kg of body weight per patient, or about 10 mg/kg of body weight per patient. Lower dosages can be used, particularly when the drug is administered to an anatomically secluded site, such as the cerebral spinal fluid (CSF) space, in contrast to administration orally, into the blood stream, into a body cavity or into a lumen of an organ. Actual methods for preparing parenterally administrable benzothiazole amphiphile compound formulations will be known or apparent to those skilled in the art and are described in more detail in such publications as Remington's, supra. See also ieman, In "Receptor Mediated Antisteroid Action," Agarwal, et al., eds., De Gruyter, New York, 1987.

[0145] The active agent can be present in the compositions of the present invention in any suitable weight ratio, such as from about 1 : 100 to about 100: 1 (w/w), or about 1 :50 to about 50: 1, or about 1 :25 to about 25: 1, or about 1 : 10 to about 10: 1, or about 1 :5 to about 5: 1 (w/w). The active agent can be present in any suitable weight ratio, such as about 1 : 100 (w/w), 1 :50, 1 :25, 1 : 10, 1 :5, 1 :4, 1 :3, 1 :2, 1 : 1, 2: 1, 3 : 1, 4: 1, 5: 1 , 10: 1, 25: 1, 50: 1 or 100: 1 (w w).

[0146] In certain embodiments of the invention, a patient having been diagnosed with a TBI can be administered a therapeutically effective amount of a benzothiazole amphiphile compound (including embodiments, examples, and/or pharmaceutical compositions thereof) in a dosage described above immediately after receiving the TBI, i.e. within 0 hours of receiving the TBI, In some embodiments, the patient having a TBI can be administered a therapeutically effective amount of a benzothiazole amphiphile compound within about 10 minutes of receiving the TBI, or within about 20 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 7 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours, 48 hours, or 72 hours of receiving the TBI. In some embodiments, a patient having a TBI can be administered a therapeutically effective amount of a benzothiazole amphiphile compound within about 0 to about 72 hours of receiving the TBI, or within about 10 minutes to about 48 hours, or within about 20 minutes to about 36 hours, or within about 30 minutes to about 30 hours, or within about 45 minutes to about 24 hours, or within about 1 to about 18 hours, or within about 2 to about 12 hours, or within about 4 to about 7 hours of receiving the TBI. In certain other embodiments of the invention, a patient having a TBI can be administered a therapeutically effective amount of a benzothiazole amphiphile compound within about 0 to 24 hours of receiving the TBI. In other embodiments of the invention, a patient having a TBI can be administered a therapeutically effective amount of a benzothiazole amphiphile compound within about 18 hours of receiving the TBI. In other embodiments of the invention, a patient having a TBI can be administered a therapeutically effective amount of a benzothiazole amphiphile compound within no more than 18 hours of receiving the TBI. In certain embodiments of the invention, a patient having a TBI can be administered a therapeutically effective amount of a benzothiazole amphiphile compound within 4 hours of receiving the TBI. In some other certain embodiments of the invention, a patient having a TBI can be administered a therapeutically effective amount of a benzothiazole amphiphile compound within 1 hour of receiving the TBI.

[0147] In some embodiments of the invention, a patient having a TBI can be administered a therapeutically effect amount in a dosage described above of a benzothiazole amphiphile compound (including embodiments, examples, and/or pharmaceutical compositions thereof) at least once per 30 minutes, or 1 hour, 2 hours, 3 hours, 4 hours, 6, hours, 8 hours, 12 hours, 18 hours, or 24 hours. In other embodiments, a patient having a TBI is administered a dose of a pharmaceutical composition of a benzothiazole amphiphile compound at least once per 30 minutes to 24 hours, or at least once per 1 hour to 18 hours, or at least once per 2 to 12 hours, or at least once per 3 to 8 hours, or at least once per 4 to 6 hours.

[0148] In some embodiments of the invention, a patient having a TBI can receive a treatment regimen as described above (i.e. dosage and dosage frequency of a therapeutically effective amount of benzothiazole amphiphile compound) for any suitable length of time. In other embodiments, a patient having a TBI can receive a treatment regimen for about 1 day, or 2, 3, 5, 7, 10, 14, 20, 25, 30, 35, 45, 60, or about 90 days. In some embodiments, a patient having a TBI can receive a treatment regimen for about 1 day to about 90 days, or about 2 to about 60, or about 3 to about 45, or about 5 to about 35, or about 7 to about 30, or about 10 to about 25, or about 14 to about 20 days. In another embodiment, a patient having a TBI can receive a treatment regimen for about 35 days.

VII. Measuring Treatment Efficacy

[0149] A patient diagnosed with a traumatic brain injur}' who has received treatment for reducing the symptoms of the traumatic brain injury as described above (i.e., a patient being administered a therapeutically effective amount of a benzothiazole amphiphiie compound) will be evaluated periodically throughout the patient's treatment regimen to determine the treatment's efficacy. A patient being administered a therapeutically effective amount of the benzothiazole amphiphiie compound can be evaluated for an improvement in the performance of one or more functional domains (i.e., physical, visual, auditory, neurobehavioral, cognitive-communication, and sleep). In some embodiments, a patient being treated for a TBI can be evaluated for an improvement in one or more of the functional domains using any one of the methods used to diagnose the patient with a TBI (as described herein or known in the art), or any combination of such methods. For example, a TBI patient receiving a treatment regimen described above can be evaluated for an improvement in one or more of the functional domains by monitoring the level of GFAP and UCH-L1 biomarkers in the patient's blood and/or using any of the following assessments: GCS, RPQ, MACE, ImPACT, SCAT, ANAM, and/or Cogstate. In some embodiments of the invention, a TBI patient receiving a treatment regimen can be evaluated for an improvement in one or more of the functional domains using GCS, RPQ, and/or MACE, In other embodiments of the invention, a TBI patient receiving a treatment regimen can be evaluated for an improvement in one or more of the functional domains using GCS and RPQ. In certain embodiments of the invention, TBI patient receiving a treatment regimen can be evaluated for an improvement in one or more of the functional domains using RPQ.

[0150] In certain embodiments of the inventi on, a TBI patient recei ving treatment can be evaluated for an improvement in the performance of one or more functional domains for any suitable number of times during the span of a TBI treatment regimen. In some embodiments of the invention, a TBI patient receiving treatment can be evaluated for an improvement in the performance of one or more functional domains at least 1 time per treatment regimen, or about 2, 3, 6, 12, 15, 18, 20, 25, 30, 40, 50, 60, 80, 100, or 150 times per treatment regimen. In other embodiments of the invention, a TBI patient receiving treatment can be evaluated for an improvement in the performance of one or more functional domains about 1 to about 150 times per treatment regimen, or about 2 to about 100, or about 3 to about 80, or about 6 to about 60, or about 12 to about 50, or about 15 to about 40, or about 18 to about 30, or about 20 to about 25 times per treatment regimen. In certain embodiments, a TBI patient receiving treatment can be evaluated for an improvement in the performance of one or more functional domains about 3 to about 80 times per treatment regimen. For example, a TBI patient receiving a treatment regimen for about 35 days can be evaluated for an improvement in the performance of one or more functional domains anywhere between 3 and 80 times during the 35 day span of treatment regimen.

[0151] In embodiments of the invention, the reduction of the symptoms of traumatic brain injur}' in a TBI patient can be observed as an improvement in the performance of one or more functional domains in the TBI patient. Alternatively, an improvement in the performance of one or more functional domains in a TBI patient can be observed as a reduction of the symptoms of traumatic brain injur}' in the TBI patient.

[0152] After receiving treatment for a TBI, the measured performance of one or more functional domains in a patient will improve by a percentage (%) compared to the performance of the one or more functional domains measured prior to treatment but after injury. In some embodiments of the invention, the performance of one or more functional domains can improve by at least 1% compared to the performance of the one or more functional domains measured prior to treatment but after injury, or by at least 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 70 or 80% compared to the performance of the one or more functional domains measured prior to treatment but after injury. In other embodiments, the measured performance of one or more functional domains in a patient can improve by at least 1% to 80% compared to the performance of the one or more functional domains measured prior to treatment but after injury, or by at least 1% to 80%, or by at least 5% to 70%, or by at least 10% to 60%, or by at least 15% to 50%, or by at least 20% to 40%, or by at least 25% to 35% compared to the performance of the one or more functional domains measured prior to treatment but after injury. In certain embodiments, the performance of one or more functional domains can improve by at least 20% to 30% compared to the performance of the one or more functional domains measured prior to treatment but after injur}'.

[0153] In some embodiments of the invention, the performance of one or more functional domains can improve within any suitable amount of time of treatment. In other embodiments, the performance of one or more functional domains can improve within about 24 hours of treatment, or within about 48 hours, 72 hours, 5 days, 7 days, 14 days, 4 weeks, 6 weeks, 8 weeks, 12 weeks, 16 weeks, or 20 weeks of treatment. In some embodiments of the invention, the performance of one or more functional domains can improve within about 24 hours to about 20 weeks of treatment, or within about 48 hours to about 16 weeks, or within about 72 hours to about 12 weeks, or within about 5 days to about 8 weeks, or within about 7 days to about 6 weeks, or within about 14 days to about 4 weeks of treatment. In certain embodiments, the performance of one or more functional domains can improve within about 7 days to about 4 weeks of treatment. In other particular embodiments, the performance of one or more functional domains can improve within about 7 days of treatment. VOL Examples

[0154] The following examples are offered to illustrate, but not to limit the claimed invention. Example 1. Synthesis of benzothiazole amphiphile compounds

[0155] The general synthetic procedures used to prepare benzothiazole amphiphiies (BAMs 1- 3) are outlined in FIG. 1. For the synthesis of the benzothiazole core for B AM2, commercially available 4-hydroxy benzaldehyde (4) was alkylated with and 2-chloro-N-methylacetamide (5) via an in situ Finklestein reaction [1]. The aryl ether (6) underwent a reaiTangement under basic conditions to yield 4-N-(methylamino) benzaldehyde (7) [2], Microwave irradiation in ionic liquid ([pmimjBr) [3] of 2-aminothiophenol (8) with benzaldehyde (7) afforded benzothiazole 9. An analogous microwave-assisted reaction [4] between 8 and 12 gave 2-(4- (methylthio)phenyl)benzo[d]thiazole (13) in good yield. The methylthiol group on 13 was then oxidized to the sulfoxide via mCPBA oxidation to yield 2-(4-(methylsulfinyl)phenyl) benzo[d]thiazole (14). Pummerer rearrangement [5, 6] of compound 14 gave the a-acyloxy- thioether (15), which was converted to the thiol (16). Compounds 9, 10 (commercially available), and 16 were then reacted with EGe-Iodide (11) [7] under standard nucleophilic substitution conditions to yield BAMl-EGe (1), BAM2-EGe (2), and BAM3-EGe (3), respectively,

[0156] Aikyiation of 4-hydroxy benzaldehyde (6). 4-Hydroxy benzaldehyde 4 (2g, 16.5 mmole, 1.1 equiv.) and anhydrous potassium carbonate (K2CO3) (4.14 g, 29.9 rnrnole, 2 equiv.) were dissolved in acetone (30 niL) and let stir under nitrogen (N2) for 30 min . Then 2-chloro-N- methylacetamide 5 (1.61 g, 15 mmole, 1 equiv.) and potassium iodide (KI) (249 mg, 1.5 mmole, 0, 1 equiv,) were added and let reflux for 24 h . After cooling to room temperature (RT), solids were filtered off and the solvent was removed and replaced with dichloromethane (DCM).

Extraction was done with 10% sodium hydroxide (NaOH) followed by column chromatography purification (95% DCM/ methanol ( MeOl I }) to yield compound 6 as a white solid (2.4 g, 83% yield). ¾ NMR (500 MHz, CDCh): δ 9.91 (s, IH), 7.88 (d, 2H), 7,04 (d, 2H), 6.50 (b, I H), 4.57 (s, 2H), 2.93 (s, 3H), ESI-MS (m/z) 194.12 | \ 1 · I I ] .

[0157] Synthesis of 4-N-(methylamino) benzaldehyde (7). To a round bottom with dry toluene, compound 6 (300 mg, 1 .55 mmole, 1 equiv.) and potassium hydroxide (KOH) pellets (174 mg, 3 , 10 mmole, 2 equiv.) were added and let reflux for 24 h. After cooling to RT, the reaction was put on ice and water was added. The organic layer was washed 3x with water, dried, and concentrated. Column chromatography (50% ethyl acetate (EtOAc)/Hexanes) yielded compound 7 as a red solid (64 mg, 30% yield). ¾ NMR (500 MHz, CDCh): δ 9.72 (s, IH), 7.71 (d, 2H), 6.61 i d, 2H), 4.41 (b, IH), 2.91 (s, 3 H). ESI-MS (m/z): 136.19 [M+ 1 1 ) .

[0158] Synthesis of Benzothiazoie (9) [4]. A microwave vial was charged with 2- aminothiophenoi 7 (45 mg, 0.36 mmole, 1 equiv.), followed by l-pentyl-3-methylimidazolium bromide ([pmIm]Br) [3] (29 mg, 0.18 mmole, 0.5 equiv.) and then 4-(methylamino)

benzaldehyde 8 (49mg, 0.36 mmole, 1 equiv.). The mixture was irradiated under microwave (MW) conditions (1 50 °C, 4 min). The reaction mixture was extracted with ether/TfcO (4x). The ether was evaporated and the compound was purified by column chromatography (25%DCM/ 70%Hexanes/ 5%EtO Ac), affording compound 9 as a light orange solid (55 mg, 64% yield). ¾ NMR (500 MHz, CDCh): δ 8.02 (d, IH), 7.96 (d, 2H), 7.84 (d, I H), 7.44 (t, IH), 7.32 (t, IH), 6.66 (d, 2H), 2.92 (s, 3H). ¹³ CNMR (400 MHz, CDCh): δ 169.05, 154.53, 151.82, 134.73, 129.32 (2C), 126.25, 124.50, 122.68, 122.53, 121.60, 112.24 (2C), 30.54. ESI-MS im/z): 241.0 | \i · ! f | .

[0159] General protocol for (ethylene glycol)e (EGe) addition. Synthesis of 17~iodo-3,6,9, 12, 15-pentaoxaheptadecan-l-ol (11) (EGe-I) was prepared as previously described [7]. A

microwave vial was charged with EGe-I (11) (1 equiv.), benzothiazole aniline 9 or 10 (2 equiv.), potassium carbonate (3 equiv.) and tetrahydrofuran (THF). The mixture was irradiated under MW (125 °C, 2 h). The mixture was filtered, concentrated and normal phase column

chromatography (4% MeOH/EtOAc) followed by reverse phase column chromatography (3 : 1 MeOH/H?G) yielded compound 1 (285 mg, 48% yield) or compound 2 (13 mg, 30% yield [0160] B AMI -EG, (1). ¾ NMR (500 MHz, CDCb): δ 7.99 (d, 1H), 7.92 (d, 2H), 7.84 (d, 1H), 7.43 (t, IH), 7.30 (t, 1H), 6.76 (d, 2H), 4.97 (b, 1H), 3.73-3.58 (m, 22H), 3.39 (t, 2H). ^l3 C NMR (500 MHz, CDCb): δ 168.92, 154,51, 151.38, 134.74, 129, 13 (2C), 126.24, 124.54, 123.20, 122,55, 121.60, 1 13.28 (2C), 71 .68, 69,81 -69,03 (69.81 , 69,59, 69.45, 69.30, 69.24, 69.23, 69.03), 68.74, 60.44, 43.86. HR/MS (ESI+): Calcd for [( i : j Q-.S · Xa j 513.2030 found 513.2029 [M+Na] ^÷ .

[0161] BAM2-EG& (2). Ί Ι NMR (500 MHz, CDCb): δ 7,96 (d, IH), 7.93 (d, 2H), 7.84 (d, I H), 7.42 (t, I H), 7.29 (t, H), 6.76 (d, 2H), 3.72-3.28 (m, 24! ! }, 3,07 (s, 3H). ¹³ C NMR (500 MHz, CDCb): δ 168.94, 154.64, 151.39, 134.74, 129.17 (2C), 126.19, 124.40, 122.49, 121.57, 121.55, 111.80 (2C), 72.76, 71.0-70.50 (71.00, 70.88, 70.85, 70.80, 70.76, 70.75, 70.71, 70.50), 68.73, 61 .93, 52.29, 39,26. HR/MS (ESI-TOFMS +): Calcd for | Cu-i hr,N <OnS \a j 527,2191 found 527.2187 [M+Na] ^÷ .

[0162] 2-(4-(methylthio)phenyi)benzo[d]thiazole (14). 2-amino thiophenol 8 (376mg, 3 mmol, 1 equiv,), [pmlmJBr (400 mg, 0,5 equiv), 4-(methylthio)benzaldehyde 12 (457 mg, 3 mmol, 1 equiv.) were added respectively, into a 5 mL microwave tube with a stir bar. The reaction tube was microwaved for 4 min at 130°C. The reaction mixture was dissolved in diethyl ether and extracted with water to remove the ionic liquid solution. The diethyl ether was removed under reduced pressure and the crude solid 13 was purified by recrystallization in a 3 : 1 mixture of hexanes:EtOAc (547 mg, 71% yield). ¾ NMR (400 MHz, CDCb): δ 8.05 (d, IH), 8.01 (d, 2H), 7.90 (d, IH), 7.49 (t, IH), 7.38 (t, IH), 7.33 (d, 2H), 2.55 (s, 3H). ¹³ C NMR (300 MHz, CDCh): δ 143.00, 127.99, 126.56, 125.31 , 123.23, 121.81, 15.39. ESI-MS (m/z) 258.25 I M i ! i

[0163] 2-( 4-(methylsulfinyl)phenyl)benzo[d]thiazole (14). 2-(4-(methylthio jphenyi) benzo[d]thiazole 13 (300 mg, 1.1 mmol) was dissolved in 6 mL of DCM. meta- chloroperoxybenzoic acid (m-CPBA) (242 mg, 1.4 mmol) was dissolved in 4 mL of DCM and added dropwise at 0 °C to the methyl sulfide 13 solution over a period of 20 min. NaHCCb (80 mg) was added and the solution was let stir. The reaction mixture was monitored by TLC analysis (100% EtOAc) until completion. The white precipitate was filtered away and the DCM was removed under reduced pressure to afford a white solid. The solid was purified by recrystallization in 100% EtOAc to give product 14 (254 mg, 80% yield). ¾ MR (400 MHz, CDCh); δ 8,26 (d, 2H), 8.1 1 (d, 1H), 7,94 (d, 1H), 7.78 (d, 2H), 7,53 (t, 1H), 7.44 (t, 1H), 2.79 (s, 3H), ESI-MS (m/z): 274, 17 [M+H] ⁺ , 296, 10 [M+Na] ⁺ .

[0164] ((4-(benzo[d]thiazol-2-yl)phenyl)thio)methyl 2,2,2-trifluoroacetate (15). 2-(4- (methyisulfinyl)phenyl)benzo[d]thiazole (14) (50 mg, 0.18 mmol) was dissolved in 2 mL of freshly distilled DCM in an oven dried 50 mL round bottom, Trifluoroacetic anhydride (TFAA) (0.15 mL) was added to the reaction flask and the reaction was gently refluxed at 40 °C for 2 h under N2. The solvent was removed under reduced pressure to afford the crude product 15 (72 mg, approximately quantitative conversion). The product was taken on to the next step without further purification, ¾ N R (500 MHz, CDCh): δ 8.07 (m, 3H), 7,92 (d, ! 1 1 ),. 7.58 (d, 8Hz, 2H), 7.53 (t, 1H), 7,43 (t, 1H), 5,70 (s, 2H).

[0165] 4-(benzo[d]thiazol-2-yl)benzenethiol (16). ((4-(benzo[ d]thiazol-2-yl)phenyl)thio) methyl 2,2,2-trifluoroacetate (15) (72mg, 0.19 mmol) was dissolved in 3 mL of MeOH and 0.6 mL of 1M NaOH was added to the reaction flask and refluxed under N? for 1 h. The reaction mixture was cooled and the solvent was removed under reduced pressure. 0,6 mL of 1 M HQ was then added to the crude mixture and the product was extracted into EtOAc by washing the aqueous layer with 3 x 2 mL of EtOAc. The organic layer was washed with a saturated NaCl solution and dried over Na?.S04. The EtOAc was removed under reduced pressure to afford the crude product 16 (44 mg, 93% crude yield). ¾NMR (500 MHz, CDCh): δ 8,08 (d, 1H), 7.95 (d, 2H), 7.90 (d, 1H), 7.51 (t, 1H), 7.39 (m, 3H), 3.68 (s, H i ). KSI-MS (m/z): 244.28 ( M I I I . [0166] 17-((4-(benzo[d]thiazol-2-yl)phenyl)thio)-3,6,9, 12,15-pentaoxaheptadecan-l-ol (3). In an oven dried 50 mL round bottom, solid sodium hydride (NaH) (2 mg, 0,074 mmol) was added and the round bottom was tightly capped with a rabber septum. The round bottom was purged with N ₂ . The crude 4-(benzo[d]thiazol-2-yl)benzenethiol (17) (12mg, 0.05 mmol, 1 equiv.) was dissolved in 1 mL of freshly distilled dimethylformamide (DMF) and added dropwise to the round bottom flask containing NaH. The reaction mixture was stirred for 30 min. 17-iodo- 3,6,9, 12,15-pentaoxaheptadecan-l-ol (11) (EGe-I, 20 mg, 0.05 mmol, 1 equiv.) was dissolved in 1 mL of freshly distilled DMF in a separate vial and added dropwise into reaction mixture. The reaction was then refluxed under N2 for 12 h. The reaction mixture was cooled to RT and the solvent was removed under reduced pressure. The product was purified via silica gel flash chromatography (using a gradient of EtOAc:MeOH 0-4%) to afford the desired product 3 as a yellow oil (Rf=0.24, 100% EtOAc). The yellow oil product was purified once more using a reverse-phase preparatory plate (using a 3 : 1 mixture of MeOFLEkO as eluent) to give final product 3 (1 mg, 44% yield). [0167] BAM3-EG¾ (3), ¾ NMR (500 MHz, CDCb): δ 8.04 (d, 1 H), 7.99 (d, 2H), 7.89 (d, 1H), 7.48 (t, 1H), 7,41 (d, 2H), 7.37 (t, 2H), 3.74-3.70 (m, 4H), 3.64 (m, 16H), 3.60-3,58 (m, 2H), 3.20, (t, 2H). ¹³ C NMR (500 MHz, CDCb): δ 167.42, 154.09, 140.57, 134.88, 130.83, 128.01, 127.86, 126.38, 125.18, 123.08, 121.62, 72.50, 70.64-70.30 (70.64, 70.59, 70.55, 70.53, 70,50, 70.30), 69.68, 61 .74, 32.08. HR/MS: calcd for C25H33NO6S2 [M+Na] 530.1641 found 15 [M+Na] 530.1640.

References:

[0168] [I] Finkelstein, H. (1910) Darstellung organischer Iodide aus den entsprechenden Bromiden und Chloriden. Berichte der Dtsch. Chem. Gesellschaft 43, 1528-1532; [2]

Chittiboyina, A. G., Venkatraman, M. S., Mizuno, C. S., Desai, P. V, Patny, A., Benson, S. C, Ho, C. I., Kurtz, T. W., Pershadsingh, H. A,, and Avery, M. A. (2006) Design and synthesis of the first generation of dithioiane thiazolidinedione- and phenylacetic acid-based PPARgamma agonists. J. Med. Chem. 49, 4072-84; [3] Namboodiri, V. V., and Varum, R. S. (2002) Solvent- Free Sonochemical Preparation of Ionic Liquids. Org. Lett. 4, 3161-3163; [4] Ranu, B. C, and Jana, R. (2006) Ionic Liquid as Catalyst and Reaction Medium - A Simple, Efficient and Green Procedure for Knoevenagel Condensation of Aliphatic and Aromatic Carbonyi Compounds Using a Task-Specific Basic Ionic Liquid. European J. Org. Chem. 2006, 3767-3770; [5] Schaumann, E. (ed.) (2007) Sulfur-Mediated Rearrangements I, Springer Berlin Heidelberg, Berlin, Heidelberg; [6] Yang, J., Gabriel e, B,, Belvedere, S., Huang, Y., and Breslow, R, (2002) Catalytic Oxidations of Steroid Substrates by Artificial Cytochrome P-450 Enzymes. J. Org. Chem, 67, 5057-5067; [7] Prangkio, P., Rao, D. K,, Lance, K. D., Rubinshtein, M,, Yang, J., and Mayer, M. (201 1) Self-assembled, cation-selective ion channels from an oligo(ethylene glycol) derivative of benzothiazole aniline. Biochim. Biophys. Acta 1808, 2877-85.

Example 2. Treaties TBI symptoms in an adult male with a benzothiazole amphiphile compound [0169] A 17-year old male patient without prior history of traumatic brain injury is

experiencing disorientation, dizziness and a headache after having been unconscious for about 30 seconds as a result of being tackled during a football game. The patient's symptoms are observed and it is recognized that the head injury can be diagnosed as a TBI Within about 30 minutes after receiving the head injury, a medical specialist at the scene confirms the patient's diagnosis of a moderate to mild traumatic brain injury using the Rivermead Post-Concussion Questionnaire, with a score of 32. The results of the RPQ assessment also showed that the patient was experiencing sensitivity to light, irritability, and aphasia. The patient is administered treatment for his traumatic brain injury,

[0170] The patient is treated with a benzothiazole amphiphile compound, BAMl-EGe, administered in dosages of about 15 mg per kg once daily in the form of a capsule for several weeks. Thus, daily doses of BAMl-EGe, in the range of 1 155 mg per day, over a period of about 14 to 35 days, will be used as an effective treatment for TBI

[0171] During the course of his treatment, the patient's progress will be monitored by administering the RPQ assessment and will provide the barometer of the patient's overall improvement from treatment using the methods of the invention. The RPQ assessment will be given both before administration of BAMl-EGe (i.e., to diagnose the patient) and after administration of BAMl-EGe. The RPQ assessment will be carried out on days 1 , 7, 14, 21 , 28 and 35. [0172] The patient will be given 1155 milligrams of BAM 1 -EGe once per day orally, over 35 days. By the seventh day of his treatment, the patient's Rivermead Post-Concussion

Questionnaire scores are expected to decline from about 32 to about 24. This is indicative of a 25% improvement in the performance of one or more functional domains, specifically the physical, visual, cognitive-communication, and neurobehavioral domains. When the results of the RPQ are evaluated after the 35 day period, the patient will show an amelioration of a traumatic brain injury. Indeed, the patient is expected to improve in the performance of the effected domains by about 30% to 70%> after the 35-day treatment.

[0173] This example illustrates how doses of benzothiazole amphiphile compounds, in the range of about 1 155 mg per day, given once daily over a relatively short period of time— about 35 days— are expected to reduce the symptoms of traumatic brain injury in a human patient.

Example 3. Evaluating the efficacy of benzothiazole amphiphile compounds functional outcomes in rats with TBI

[0174] To demonstrate the efficacy of the compounds of this invention for treating TBI, the effect of benzothiazole amphiphiles on sensorimotor function, cognitive function, and dendritic spine density in rats after administering a controlled cortical impact TBI was investigated.

Specifically, the following terra (ethylene glycol) derivative of benzothiazole aniline compound (BTA-EG4, also referred to as SPG101), as described in International application number PCT/US2017/012139, was used in this study:

All experimental procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of Henry Ford Health System. All functional tests were performed by investigators blinded to the treatment status,

3.1. The An mal Model of TBI

[0175] A controlled cortical impact (CCI) rat model of TBI was utilized to induce moderate focal brain injury (contusion) in male Wistar rats weighing 305±10 g (2-3 months old, Charles River Breeding Company, Wilmington, MA). See, for example, J. Neurotrauma, 14, 23-34, 1997; Nat. Rev. Neurosci. 14, 128-142, 2013; J. Neurosurg. 126, 782-795, 2017. The moderate CCI-TBI model is one of the most widely used clinically relevant animal models of focal TBI. See, for example, Br. J. Pharmacol 164, 1207-1229, 2011 and Injury 41 Suppl 1 , S10-S13, 2010. The moderate CCI-TBI model causes cortical injury and selective neuronal death in the hippocampus in rats, leading to sensorimotor dysfunction and spatial learning and memory deficits, respectively. See, for example, J. Neurotrauma, 16, 109-122, 1999; Restor. Neurol. Neurosci. 14, 285-294, 1999; Neuropharmacology 49, 410-424, 2005; J. Neurotrauma, 25, 235- 247, 2008; J. Neurotrauma, 22, 252-265, 2005; J. Neurotrauma, 19, 415-425, 2002; J.

Neurotrauma, 19, 1029-1037, 2002; J. Neurotrauma, 12, 1015-1025, 1995. [0176] In general, each rat was anesthetized with an intraperitoneal (i.p.) injection of ketamine/xylazine (100/10 mg/kg). Rectal temperature was maintained at 37±5°C using a feedback-regulated water-heating pad. Rats were placed in a stereotactic frame. Two 10-mm- diameter craniotomies were performed adjacent to the central suture, midway between lambda and bregma. The second craniotomy allowed for lateral movement of cortical tissue. The dura mater was kept intact over the cortex. Cortical injury was delivered by impacting the left cortex (ipsilateral cortex) with a pneumatic piston containing a 6-mm-diameter tip at a rate of 4 m/s and 2.5 mm of compression.

3.2. TBI Treatment Using BTA-EG4

[0177] TBI animals were randomly divided into two groups: "TBI + Vehicle ^' " at 1 hr (n=7) and "TBI + BTA-EG4" (30 mg/kg) at 1 hr (n=7). BTA-EG4 was intraperitoneally (i.p) administered to the rats of the "TBI + BTA-EG4" group daily for 35 days, starting at 1 hr after TBI, at a dose of 30 mg/kg. Animals of the "TBI + Vehicle" group (i.e., the control group) were treated with 1 % DMSO (i.e., the vehicle) daily over the same time period.

3.3. Results of the TBI treatment using BTA-EG4

[0178] The neurological outcome of the TBI treatment study was assessed using a battery of behavior tests (i.e., primary endpoints), as summarized below in Table I . All sensorimotor tests, such as the footfault, adhesive removal, and modified neurological severity score (mNSS) tests, were performed preinjury, and 1, 7, 14, 21, 35 days after TBI. Spatial cognition was tested by performing the Morris water maze (MWM) test 31 -35 days after TBI. The Novel Object Recognition (NOR) test and the three-chamber social interaction test were also performed as a means of assessing spatial cognition. The NOR and social interaction tests were performed 14 days and 35 days after TBI. Results of each study are described in detail below. All personnel were blinded to the treatment groups for tests. Animal behavioral outcomes were compared between the two groups (i .e., "TBI + Vehicle" and "TBI + BTA-EG4"). Secondary endpoints were effects of BTA-EG4 on dendritic spine density measured by Afraxis.

[0179] Ail data are presented as the means with standard deviations. Analysis of variance (ANOVA) followed by post hoc Student-Newman-Keuls tests was used for repeated

measurements of cognitive and sensorimotor function to compare the difference between the BTA~EG4-treated and vehicle-treated groups. Differences were considered significant if the p value was <0.05.

3, 3.1. Side effects and safety

[0180] In addition to multiple functional tests, weight gain was monitored as the only major safety index. There were no significant differences in body weight between the "TBI + BTA- EG4" group and the "TBI + Vehicle" group over the 35-day study (Fig. 2, p>0.05).

Furthermore, the ammals gained weight over time in both groups (p<0.01). No other side effects of BTA-EG4 or Vehicle (i.e., death, seizures, dehydration, etc.) were observed. A total of 14 animals were included in the study, none of which died during the 35-day study period. 3,3.2. Sensorimotor tests

[0181] Motor function was assessed by the footfault test and the adhesive removal test.

Neurological functions were assessed by the modified neurological severity score (mNSS).

[0182] To evaluate sensorimotor function, the footfault test was carried out prior to TBI and at 1, 7, 14, 21, and 35 days after TBI. The rats were allowed to walk on a grid. With each weight- bearing step, a paw might fall or slip between the wires and, if this occurred, it was recorded as a foot fault. A total of 50 steps were recorded for the right forelimb (Fig. 3, p<0.05 vs DM SO) and hindlimb (Fig, 4, p<0.05). Starting at day 7, and lasting through day 35, the group of rats treated with BTA-EG4 showed improvement in sensorimotor recovery compared to the Vehicle control group, as shown in Fig. 3 and Fig. 4.

[0183] Sensorimotor function was also assessed using the adhesive patch removal test, which was carried out on each rat preinjury and at 1 , 7, 14, 21 , and 35 days after TBI. Two pieces of adhesive-backed paper (113.1 mm ¹ ) were used as bilateral tactile stimuli occupying the distal- radial region on the wrist of each forelimb. Each animal received three trials per testing day and the mean time (seconds) required to remove stimuli from right forelimb was recorded. The average of three trials was used for statistical analysis, and the results are shown in Fig. 5 (p<0.05 vs DMSO). The results of the adhesive removal test also show a significant

improvement in sensorimotor recover}' for the "TBI + BTA-EG4" group compared to the "TBI + Vehicle" group, from day 7 to day 35 (Fig. 5). [0184] The neurological functional outcome was evaluated using the modified neurological severity score (mNSS) test. mNSS is a composite of the motor (muscle status, abnormal movement), sensory (visual, tactile, and proprioceptive), and reflex tests and has been used in previous studies, as described in: Stroke 32, 2682-2688, 2001. The test was carried out on rats preinjury and at 1 , 7, 14, 21 , and 35 days after TBI. Neurological function was graded on a scale of 0 to 18 (normal score 0; maximal deficit score 18), One point is awarded for each abnormal behavior or for lack of a tested reflex; thus, the higher the score, the more severe the injury. The results are summarized in Fig. 6 (p<0.05 vs DMSO). As with the sensorimotor tests described above, the group of rats treated with BTA-EG4 demonstrated marked improvement in sensorimotor behavior, from day 7 to day 35, as compared to the control group (Fig. 6). 3.3.3. Cognitive tests

[0185] Cognitive performance of the rats was assessed by the Morris water maze (MWM) test, rating spatial learning function, as described in: J. Neurosci. Methods, 156, 182-193, 2006 and J, Neurosurg. 122, 843-855, 2015. Cognitive function was also assessed via the novel object recognition (NOR) test and the three-chamber social interaction test. The NOR test was used to rate the spontaneous tendency of rodents to spend more time exploring a novel object than a familiar object, as described in: PLoS One 8, e75467, 2013. The social interaction test was used to rate the tendency of animals to spend more time interacting with a novel rat versus one they have previously encountered. See, for example, Biomol. Ther. (Seoul) 23, 251-260, 2015. [0186] The modified MWM test was performed daily for 5 days in ail rats, starting about one month {e.g., days 31 -35 after injur)'). The Morris water maze apparatus consisted of a circular water tank (180 cm in diameter), which was placed in a large test room with many external cues which were visible to the rats {e.g., pictures, lamps, camera, etc.). A transparent platform (10 cm in diameter) was submerged 2 cm below the surface of the water at a random location within the northeast (correct) quadrant of the maze. For each trial, the rat was placed randomly at one of the four fixed starting points (north, south, east, and west), and allowed to swim for a maximum of 90 seconds. If the animal did not locate the platform within 90 seconds, they were gently guided to it by the experimenter. All animals were allowed to remain on the platform for 10 seconds before being removed from the tank. The swim speed, latency to find the hidden platform, and the time spent within the correct quadrant were recorded. Data are presented as the percentage of time spent within the correct quadrant relative to the total amount of time spent to find the hidden platform .

[0187] The MWM test confirmed previous studies that TBI induced by CO caused spatial learning deficits in rats (See: J. Neurosurg. 114, 102-115, 2011; Brain Res. 1263, 183-191 , 2009; J. Neurosurg. 122, 856-867, 2015; J. Neurosurg. 126, 782-795, 2017). Compared to the DMSO group, BTA-EG4 treatment significantly reduced the time (latency, Fig, 7, p<0.05) for animals to reach the hidden platform in the water maze, and increased the % time spent in the correct quadrant (Fig. 8, p<0.()5), indicating that BTA-EG4 significantly improved spatial learning and memory in rats after TBI. There was no significant difference on the swim speed between the two TBI groups (Fig, 9, p>0.05), indicating that the swim speed did not contribute to spatial learning and memory deficits in these rats.

[0188] The NOR task is a well-characterized behavioral measure of hippocampal -based working and non-spatial visual recognition memory in rodents. The choice to explore a novel object reflects the use of learning and recognition memory. Given the more subtle nature of the histological damage, it is likely that traditional behavioral tasks used for TBI models may lack the sensitivity to detect deficits after a mild injur}'. The hippocampus and the perirhinal cortex play different roles in object recognition memory. The NOR test is a method that does not need external motivation reward or punishment; however, some training or habituation is required. It can be completed in a short time so animals do not feel stressed, and it can assess the recognition memory after only one trial, as described in: Front Biosci. (Schol. Ed.) 7, 10-29, 2015. The NOR test was performed on all rats at 14 days and 35 days after injury. Compared to the DM SO treatment, BTA-EG4 treatment significantly improved the NOR task measured at 14 and 35 days in rats after TBI (Fig. 10, p 0.05 ).

[0189] The three-chamber social interaction test is used to assess memory for interactions with novel conspecifics (Ment. Retard. Dev. Disabil. Res. Rev. 10, 248-258, 2004). Rats tend to spend more time interacting with a rat over an object (sociability), or a novel rat versus one they have previously encountered (social novelty). Decreased duration and/or decreased number of contacts may be associated with depressive- and/or anxiety-like behavior, which are common after TBI, especially after mild TBI or in posttraumatic stress disorder (PTSD) (J. Neurotrauma, 29, 2564-2575, 2012). The three chamber test can help identify rodents with deficits in sociability and/or social novelty, and was performed, for example, as described in: J.

Neurotrauma, 29, 2672-2683, 2012. The sociability test was performed on ail rats at 14 days and 35 days after injury. Compared to the DMSO treatment, BTA-EG4 treatment significantly improved the sociability and social novelty in rats measured at 14 days (Fig, 11, p<0.05) and 35 days (Fig. 12, p<0.05) after TBI.

3.3.4. Conclusions

[0190] Collectively, the randomized, placebo-controlled, and blinded study as described above demonstrates that benzothiazoie amphiphile compound BTA-EG4 at 30 mg/kg, administered 1 hour after TBI and daily for a total of 35 days, significantly improved sensorimotor and cognitive functional outcomes over time, starting at 7 days post injury and up to at least 35 days post injur}'.

[0191] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and puiview of this application and scope of the appended claims.