Composition and method for treating neurodegenerative diseases

Abstract

The present disclosure relates to a composition for treating cognitive decline in companion animals comprising: a 5-benzylaminosalicylic acid compound of Formula I or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient, e.g., an excipient suitable for oral administration. A composition comprising a 5-benzylaminosalicylic acid compound of Formula I or a pharmaceutically acceptable salt thereof may be used to treat progressive cognitive decline in neurological diseases, including cognitive impairment syndrome (CDS), hypothymia, chronic depression, and confusion syndrome, in older companion animals.

Description

Technology Field

[0001] The present disclosure relates to a pharmaceutical composition for treating cognitive impairment in aging companion animals, comprising a compound of 5-benzylaminosalicylic acid of formula I or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient suitable for oral administration. The present disclosure relates to a method for treating cognitive impairment in dogs, including CDS, dysthymia, involutive depression, and confusional syndrome. Background Technology

[0002] The number of companion animals is steadily increasing worldwide. The number of pet dogs and cats in the top 20 countries is estimated at approximately 265 million and 236 million, respectively. Today, dogs and cats live much longer due to improved nutrition, disease treatment, excellent veterinary care, and care by pet owners. Consequently, there is growing interest in the treatment of age-related diseases in companion animals.

[0003] Many aged or senior dogs and cats suffer from cognitive impairments caused by neurological disorders, including CDS, dysthymia, involutive depression, and confusional syndrome. Cognitive impairment is defined as a disorder in memory, learning new things, concentration, or decision-making that can affect daily life. The prevalence of CSD has been reported to range from 14% to 60% in dogs over 8 years of age [1-4]. Another report indicates that 62% of pet dogs aged 11 to 16 years suffer from CSD, and the prevalence increases significantly with age [5]. Consequently, a large number of dogs are infected with CDS, which can worsen the human-animal bond, reduce the animal's quality of life, and consequently shorten the animal's lifespan [6-8].

[0004] Pathophysiological changes observed in canine CDS include cerebrocortical and basal ganglia atrophy; increased ventricular size; demyelination; increased size and number of glial cells; neuronal loss, particularly in cortical regions above the hippocampus; axonal degeneration; and accumulation of beta-amyloid plaques [6, 9, 10]. Cats with CDS also exhibit a decrease in the number of neurons, beta-amyloid deposition, and an increase in glial cells similar to that in canine CDS. Unlike human Alzheimer's disease (AD), neurofibrillary tangles, which are prevalent in AD, were not identified in the brains of dogs and cats with CDS, suggesting that canine and feline CDS can be distinguished from AD

[11] .

[0005] Dogs and cats diagnosed with CDS show progressive impairment in cognitive and neurological function. They exhibit various behavioral problems such as getting lost at home, being less active during the day, no longer greeting family or other familiar animals, not responding when their names are called, wandering in circles, or urinating in abnormal areas [10, 12-15].

[0006] Although a surge in the number of dogs and cats with CDS has recently been observed, CDS remains an unmet medical need. Selegiline, a selective irreversible inhibitor of monoamine oxidase B (MAO-B), is the only drug approved by the FDA for the treatment of CDS

[16] . Previous reports indicated that selegiline improved cognitive function and behavioral function. However, recent data suggest that its beneficial effects are not long-lasting, indicating that selegiline therapy is merely a symptomatic treatment. For example, in dogs with CDS, cognitive function improved within the first two weeks after selegiline treatment, but in most dogs, the beneficial effects disappeared by eight weeks after treatment [17-19]. Furthermore, a large clinical trial involving 474 dogs with CDS aged eight years or older concluded that selegiline treatment should be administered at the onset of early clinical signs

[19] .

[0007] Many non-drug therapies are commercially available, including dietary supplements containing antioxidants, L-carnitine, and omega-3 fatty acids, intended to improve the well-being of dogs by alleviating anxiety and supporting cognitive function. To achieve optimal results, these dietary supplements should be initiated in the early stages of canine CDS. Since there is no cure for CDS in dogs and cats, disease-modifying compounds and methods must be developed to stop or slow the progression of CDS.

[0008] Although more than 400 clinical trials for the treatment of AD were conducted between 2002 and 2012, memantine, a low- to moderate affinity N-methyl-D-aspartate receptor antagonist, was the only drug approved for the symptomatic treatment of AD based on research results showing improvements in the ability to perform daily activities and mental function in moderate-to-serve AD. Subsequently, large-scale phase clinical trials were conducted on drugs targeting beta-amyloid, inflammation, or oxidative stress for AD, but the situation worsened as none demonstrated beneficial effects. However, almost all failed drugs reduced amyloid plaque burden and improved cognitive function in two standard mouse models of AD, Tg2576 and APP / PS1, respectively, which express familial AD mutations in the gene, mutant amyloid precursor protein (APP), or APP and presenilin. Therefore, the pharmacological efficacy of drug candidates demonstrated in preclinical animal models of AD is not applicable to the treatment of AD in humans. The problem to be solved

[0009] The present disclosure provides pharmaceutical compositions and methods useful for treating cognitive and / or neurobehavioral disorders in neurological diseases such as CDS, dysthymia, involutive depression, and confusional syndrome in companion animals, for example. means of solving the problem

[0010] The present disclosure provides a compound of Formula I or a pharmaceutically acceptable salt thereof for treating cognitive and / or neurobehavioral disorders, e.g., neurological diseases, in companion animals:

[0011] [Chemical Formula I]

[0012]

[0013] At this time,

[0014] X is CO, SO2 and (CH2) n Selected from;

[0015] R1 is selected from hydrogen, C1-C6 alkyl and C1-C6 alkanoyl;

[0016] R2 is selected from hydrogen and C1-C6 alkyl;

[0017] R3 is selected from hydrogen and C1-C5 acetyl groups; and

[0018] R4 is selected from a phenyl group, a phenoxy group, and a 5- to 10-membered aryl group, each of which is independently unsubstituted or substituted with one or more substituents selected from nitro, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C5 alkoxy, and C1-C5 haloalkoxy;

[0019] n is an integer from 1 to 5. Effects of the invention

[0020] A composition comprising a compound of 5-benzylaminosalicylic acid of formula I or a pharmaceutically acceptable salt thereof may be used to treat cognitive and / or neurobehavioral disorders in companion animals. Specific details for implementing the invention

[0021] [Related Application]

[0022] This application claims the benefit and priority of U.S. Provisional Patent Application No. 62 / 785,903 filed on December 28, 2018, the entirety of which is incorporated herein by reference.

[0023] 5-benzylaminosalicylic acid, or its pharmaceutically acceptable salt, has been used in the treatment of AD and neurodegenerative diseases (U.S. Patent No. 6,964,982). In previous studies, 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid was verified to be an effective potent spin-trapping molecule and microsomal prostaglandin E(2) synthase-1 (mPGES-1) inhibitor at nanomolar concentrations, which was verified to cause neuronal cell death, axonopathy, and blockade of autophagosome formation, as well as increase motor function activity and lifespan in a mouse model of amyotrophic lateral sclerosis

[20] .

[0024] 5-benzylaminosalicylic acid or its pharmaceutically acceptable salts were explored for the treatment of CDS in companion animals. Surprisingly, oral administration of 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid for more than 4 weeks significantly improved cognitive and neurobehavioral functions in older dogs suffering from severe CDS. Furthermore, the beneficial effects of 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid were maintained for at least 4 weeks after the final administration. Accordingly, it has been suggested that 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid may be a potential therapeutic option for treating CDS by inhibiting both oxidative stress and inflammation. In one embodiment, the present disclosure relates to a composition and a method comprising a compound of 5-benzylaminosalicylic acid of formula I or a pharmaceutically acceptable salt thereof for the treatment of cognitive and / or neurobehavioral disorders in companion animals, for example, in neurological diseases.

[0025] The present disclosure provides a compound of Formula I or a pharmaceutically acceptable salt thereof for treating cognitive and / or neurobehavioral disorders, e.g., neurological diseases, in companion animals:

[0026] [Chemical Formula I]

[0027]

[0028] At this time,

[0029] X is CO, SO2 and (CH2) n Selected from;

[0030] R1 is selected from hydrogen, C1-C6 alkyl and C1-C6 alkanoyl;

[0031] R2 is selected from hydrogen and C1-C6 alkyl;

[0032] R3 is selected from hydrogen and C1-C5 acetyl groups; and

[0033] R4 is selected from a phenyl group, a phenoxy group, and a 5- to 10-membered aryl group, each of which is independently unsubstituted or substituted with one or more substituents selected from nitro, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C5 alkoxy, and C1-C5 haloalkoxy;

[0034] n is an integer from 1 to 5.

[0035] The present disclosure provides a method for treating cognitive and / or neurobehavioral disorders, e.g., neurological disorders in a companion animal, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a companion animal in need of:

[0036] [Chemical Formula I]

[0037]

[0038] At this time,

[0039] X is CO, SO2 and (CH2) n Selected from;

[0040] R1 is selected from hydrogen, C1-C6 alkyl and C1-C6 alkanoyl;

[0041] R2 is selected from hydrogen and C1-C6 alkyl;

[0042] R3 is selected from hydrogen and C1-C5 acetyl groups; and

[0043] R4 is selected from phenyl groups, phenoxy groups, and 5- to 10-membered aryl groups, each of which is independently unsubstituted or substituted with one or more substituents selected from nitro, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C5 alkoxy, and C1-C5 haloalkoxy;

[0044] n is an integer from 1 to 5.

[0045] In one embodiment, a number of compounds of Formula I were prepared and evaluated. In one embodiment, the composition and method comprise a 5-benzylaminosalicylic acid compound of Formula I or a pharmaceutically acceptable salt thereof.

[0046] In one embodiment, the 5-benzylaminosalicylic acid compound is the 5-benzylaminosalicylic acid compound itself.

[0047] Preferred examples of 5-benzylaminosalicylic acid compounds include 2-hydroxy-5-phenethylamino-benzoic acid (compound 1), 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid (compound 2), 2-hydroxy-5-[2-(3-trifluoromethyl-phenyl)-ethylamino]-benzoic acid (compound 3), and 5-[2-(3,5-bis-trifluoromethyl-phenyl)-ethylamino]-2-hydroxy-benzoic acid (5-[2-(3,5-bis-trifluoromethyl-phenyl)-ethylamino]-2-hydroxy-benzoic acid, compound 4), 2-hydroxy-5-[2-(2-nitro-phenyl)-ethylamino]-benzoic acid (2-hydroxy-5-[2-(2-nitro-phenyl)-ethylamino]-benzoic acid, compound 5), 5-[2-(4-chloro-phenyl)-ethylamino]-2-hydroxy-benzoic acid (5-[2-(4-chloro-phenyl)-ethylamino]-2-hydroxy-benzoic acid, compound 6), 5-[2-(3,4-difluoro-phenyl)-ethylamino]-2-hydroxy-benzoic acid (5-[2-(3,4-difluoro-phenyl)-ethylamino]-2-hydroxy-benzoic acid, compound 7), 5-[2-(3,4-dichloro-phenyl)-ethylamino]-2-hydroxy-benzoic acid (5-[2-(3,4-dichloro-phenyl)-ethylamino]-2-hydroxy-benzoic acid, compound 8),5-[2-(4-fluoro-2-trifluoromethyl-phenyl)-ethylamino]-2-hydroxy-benzoic acid (compound 9), 5-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-hydroxy-benzoic acid (compound 10), 2-hydroxy-5-[2-(4-methoxy-phenyl)-ethylamino]-benzoic acid (compound 11), 2-hydroxy-5-(2-o-tolyl-ethylamino)-benzoic acid (2-hydroxy-5-(2-o-tolyl-ethylamino)-benzoic acid, Compound 12), 2-hydroxy-5-(3-phenyl-propylamino)-benzoic acid (Compound 13), 2-hydroxy-5-[3-(4-trifluoromethyl-phenyl)-propylamino]-benzoic acid (Compound 14), 5-[3-(4-fluoro-phenyl)-propylamino]-2-hydroxy-benzoic acid (Compound 15), 5-[3-(3,4-dichloro-phenyl)-propylamino]-2-hydroxy-benzoic acid (5-[3-(3,4-dichloro-phenyl)-propylamino]-2-hydroxy-benzoic acid, compound 16), 2-hydroxy-5-(3-p-tolyl-propylamino)-benzoic acid (2-hydroxy-5-(3-p-tolyl-propylamino)-benzoic acid, compound l7),2-acetoxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid (compound 18), 5-[2-(2-chloro-phenyl)-ethylamino]-2-hydroxy-benzoic acid (compound 19), 5-benzylaminosalicylic acid (compound 20), 5-(4-nitrobenzyl)aminosalicylic acid (compound 21), 5-(4-chlorobenzyl)aminosalicylic acid (compound 22), 5-(4-trifluoromethylbenzyl)aminosalicylic acid (compound 23), 5-(4-fluorobenzyl)aminosalicylic acid (compound 24), 5-(4-methoxybenzyl)aminosalicylic acid (compound 25), 5-(2,3,4,5,6-pentafluorobenzyl)aminosalicylic acid (compound 26), 5-(4-nitrobenzyl)amino-2-hydroxy ethylbenzoate (compound 27), 5-(4-nitrobenzyl)-N-acetylamino-2-hydroxy ethylbenzoate (compound 28),5-(4-nitrobenzyl)-N-acetylamino-2-acetoxy ethylbenzoate (compound 29), 5-(4-nitrobenzoyl)aminosalicylic acid (compound 30), 5-(4-nitrobenzenesulfonyl)aminosalicylic acid (compound 31), 5-[2-(4-nitrophenyl)-ethyl]aminosalicylic acid (compound 32), and 5-[3-(4-nitro-phenyl)-n-propyl]aminosalicylic acid It includes, but is not limited to, (5-[3-(4-nitro-phenyl)-n-propyl]aminosalicylic acid, Compound 33). In a specific preferred embodiment, the compound of Formula I is 2-hydroxy-5-[2-(4-trifluoro-phenyl)ethylamino]benzoic acid (2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid, Compound 2). In one embodiment, the compound of Formula I has the following structure.

[0048]

[0049] The 5-benzylaminosalicylic acid compound of the present disclosure or a pharmaceutically acceptable salt thereof may be prepared through the reaction scheme disclosed in US. Pat. No. 6,573,402, but is not limited thereto.

[0050] In one embodiment, the cognitive and / or neurobehavioral disorder is CDS, hypothymia, chronic depression, or confusional syndrome. In some embodiments, the compound of Formula I treats cognitive and / or neurobehavioral disorders in companion animals. In one embodiment, the cognitive and / or neurobehavioral disorder is CDS.

[0051] In one embodiment, treatment of cognitive and / or neurobehavioral disorders is achieved through the simultaneous pharmacological inhibition of oxidative stress and inflammation. In one embodiment, treatment of cognitive and / or neurobehavioral disorders is achieved through the inhibition of oxidative stress and prostaglandin E2 synthesis. In one embodiment, treatment of cognitive and / or neurobehavioral disorders is achieved through the inhibition of oxidative stress and microsomal prostaglandin E synthase-1.

[0052] In one embodiment, the pet exhibits symptoms including changes in appetite, drinking behavior, vocalization, elimination behavior, sleep patterns, aimless behavior, adaptability, social behavior, perceptual ability, disorientation, and behavior selected from memory. In one embodiment, the pet exhibits symptoms including changes in vocalization, elimination behavior, sleep patterns, aimless behavior, social behavior, perceptual ability, disorientation, and behavior selected from memory. In one embodiment, the pet exhibits symptoms including changes in sleep patterns, social behavior, disorientation, and behavior selected from memory. In one embodiment, the pet exhibits symptoms including changes in memory. In one embodiment, the pet exhibits symptoms including changes in direction (e.g., staring blankly and getting lost in the house), memory (e.g., lack of recognition of the owner and contamination of the house), apathy (e.g., reduced time spent on activities and avoidance of contact with the owner), olfactory impairment (e.g., difficulty finding food), and movement.

[0053] In one embodiment, the companion animal exhibits symptoms including changes in spatial orientation, social interaction, sleep-wake cycle, and selected behaviors regarding house soiling.

[0054] In one embodiment, the companion animal exhibits pathophysiological changes. In one embodiment, the pathophysiological changes are selected from cerebral cortical atrophy; basal ganglia atrophy; ventricular enlargement; demyelination; glial cell enlargement; glial cell number enlargement; neuronal loss in cortical regions, particularly above the hippocampus; axonal degeneration; and accumulation of beta-amyloid plaques. In one embodiment, the pathophysiological changes are selected from glial cell enlargement; glial cell number enlargement; neuronal loss; and increased beta-amyloid deposition.

[0055] In one embodiment, the companion animal is selected from a cat, chinchilla, dog, ferret, gerbil, guinea pig, hamster, hedgehog, mouse, rabbit, and rat. In a specific preferred embodiment, the companion animal is a cat or a dog. In one embodiment, the companion animal is a canine or a feline.

[0056] definition

[0057] The definitions of terms described below may be applied whether the terms themselves are used or in combination with other terms.

[0058] The term "acetoxy" refers to a group represented by the general formula hydrocarbyl C(O)O-(hydrocarbyl C(O)O-), preferably alkyl C(O)O-.

[0059] The term "acetyl" refers to the group represented by the general formula CH3C(O)-.

[0060] An "alkyl" group (including the 'alkyl' of a haloalkyl) or an "alkane" is a fully saturated straight-chain or branched non-aromatic hydrocarbon. Typically, a straight-chain or branched alkyl group has 1 to about 20 carbon atoms, preferably 1 to about 10 carbon atoms, unless otherwise defined. A C1-C6 straight-chain or branched alkyl group is also referred to as a "lower alkyl" group. In one embodiment, the alkyl is C l -C5 alkyl, more preferably C l - It is a C3 alkyl. More specifically, the preferred alkyl group includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tet-butyl.

[0061] Furthermore, the term “alkyl” (or “lower alkyl”) used throughout the specification, examples, and claims is intended to include both “unsubstituted alkyl” and “substituted alkyl,” the latter referring to an alkyl moiety having a substituent that replaces a hydrogen at one or more carbons of a hydrocarbon backbone. Unless otherwise specified, these substituents are, for example, halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl such as alkyl C(O)), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, silyl ether, sulfhydryl, alkylthio, sulfate, It may include sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moiety. Those skilled in the art will understand that the moiety substituted on the hydrocarbon chain may substitute itself, if appropriate.For example, the substituents of the substituted alkyl may include amino, azido, imino, amido, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamido, sulfamoyl and sulfonates), and silyl groups, as well as substituted and unsubstituted forms such as ethers, alkyl thiols, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN, etc. Exemplary substituted alkyls are described below. The cycloalkyl may be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF3, CN, etc.

[0062] The term "C" when used with chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy. x-y " means including a group containing x to y carbons in the chain. For example, the term "C x-y "alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group comprising straight-chain alkyl and branched alkyl groups containing x to y carbons, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. CO alkyl indicates a hydrogen where the group is at a terminal position, and indicates a bond when internal. The term "C 2-y "Alkenyl" and "C" 2-y "Alkynyl" refers to a substituted or unsubstituted aliphatic group that has a similar length and possible substitution to the alkyl described above, but each contains at least one double or triple bond.

[0063] The term "alkanoyl" refers to a group represented by the general formula hydrocarbyl-C(O)-, preferably alkyl-C(O)-.

[0064] The term "alkoxy" (including the 'alkoxy' of haloalkoxy) refers to an oxygen-attached alkyl group, preferably a lower alkyl group. In one embodiment, preferably, the alkoxy refers to a C1-C5 alkoxy, and more preferably, a C1-C3 alkoxy. More specifically, preferred alkoxys include, but are not limited to, methoxy, ethoxy, and propanoxy. Halogens include, but are not limited to, fluoride, chloride, bromide, and iodide. Preferably, the alkanoyl is C2-C 10 Alkanoyls, more preferably C3-C5 alkanoyls. More specifically, preferred alkanoyls include, but are not limited to, ethanoyl, propanoyl, and cyclohexanecarbonyl.

[0065] The terms "amine" and "amino" refer to unsubstituted and substituted amines and salts thereof recognized in the art, and moietyes that can be represented, for example, as follows.

[0066] or .

[0067] At this time, each R 10 is independently a hydrogen or hydrocarbyl group, or two Rs 10 They complete a heterocycle having 4 to 8 atoms in a ring structure together with the N atoms to which they are attached.

[0068] As used herein, the term "aryl" comprises a substituted or unsubstituted single-ring aromatic group in which each atom of the ring is a carbon. Preferably, the ring is a 5- to 10-membered ring, and more preferably a 6- to 10-membered ring or a 6-membered ring. The term "aryl" also comprises a polycyclic ring system having two or more rings in which two or more carbons are common to two adjacent rings, wherein at least one of the rings is aromatic, and, for example, the other ring may be a cycloalkyl, cycloalkenyl, cycloalkynyls, aryl, heteroaryl, and / or heterocyclyls. The aryl group includes benzene, naphthalene, phenanthrene, phenol, aniline, etc. Exemplary substitutions for the aryl group are, for example, halogens, haloalkyls such as trifluoromethyl, hydroxyl, carbonyls (e.g., carboxyl, alkoxycarbonyl, formyl, or alkyl C(O) acyls), thiocarbonyls (e.g., thioesters, thioacetates, or thioformates), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, silyl ether, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or It may include heteroaromatic moiety.

[0069] The terms “halo” and “halogen” as used herein mean halogen and include chloro, fluoro, bromo, and iodo.

[0070] When used with chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, the term “lower” means comprising a group having 10 or fewer non-hydrogen atoms, preferably 6 or fewer, in the substituent. For example, “lower alkyl” refers to an alkyl group containing 10 or fewer carbon atoms, preferably 6 or fewer. In certain embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents are each lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, and appear alone or in combination with other substituents, as in the references to hydroxyalkyl and aralkyl. Appearing alone or in combination with other substituents (in this case, for example, atoms within the aryl group are not counted when counting the carbon atoms of the alkyl substituent).

[0071] The term “substituted” refers to a moiety having a substituent that replaces a hydrogen at one or more carbons of the backbone. “Substitution” or “substituted” implies that such substitution depends on the allowable valence of the substituted atom and the substituent, and it will be understood that the substitution produces a stable compound that does not spontaneously undergo modifications such as rearrangement, cyclization, or removal. As used herein, the term “substituted” is considered to include all allowable substituents of an organic compound. In a broad sense, allowable substituents include acyclic and cyclic, branched and undranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of the organic compound. For a suitable organic compound, there may be one or more allowable substituents, which may be the same or different. For the purposes of the present invention, a heteroatom such as nitrogen may have any allowable substituent of the organic compound described herein that satisfies the hydrogen substituent and / or the valence of the heteroatom. The substituents may be any of the substituents described herein, for example, hydrogen, haloalkyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidin, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moiety. Those skilled in the art will understand that, where appropriate, the substituents may be substituted on their own. Unless specifically stated as "unsubstituted," references to chemical moiety in this invention are understood to include substituted variants. For example, references to an "aryl" group or moiety implicitly include both substituted and unsubstituted variants.

[0072] The term “pharmaceuticalally acceptable salt” in this disclosure means a salt produced by an acid or base that is non-toxic or has little to no toxicity. If the compound of this disclosure is acidic, a base-added salt of the compound of this disclosure may be prepared by reacting the organic base of the compound with a sufficient amount of a preferred base and a suitable inert solvent. Pharmaceutically acceptable base-added salts include, but are not limited to, salts prepared from sodium, potassium, calcium, ammonium, magnesium, or organic aminos. If the compound of this disclosure is basic, an acid-added salt of the compound may be prepared by reacting the free base of the compound with a sufficient amount of a preferred acid and a suitable inert solvent.Pharmaceutically acceptable acid addition salts are propionic acid, isobutylic acid, oxalic acid, malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, [-p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, hydrochloric acid, bromic acid, nitric acid, carbonic acid, monohydrogen-carbonic acid, phosphoric acid, monohydrogen-phosphoric acid, Dihydrogen-phosphoric acid, sulfuric acid, monohydrogen-sulfuric acid, hydrogen iodide, and phosphorous acid are included, but not limited thereto. Additionally, pharmaceutically acceptable salts of the present disclosure include, but are not limited to, salts of amino acids such as arginate and analogs of organic acids such as glucuronic or galactunoric.

[0073] For example, a pharmaceutically acceptable salt of 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid (Compound 2), which is a preferred example of the present disclosure of the invention, can be prepared by the following Reaction Scheme 1. However, the following reaction method is provided as an example and is not intended to limit the scope of the present disclosure.

[0074] <Reaction Equation 1>

[0075]

[0076] In reaction scheme 1, M is a pharmaceutically acceptable metal or basic organic compound such as diethylamine, lithium, sodium, and potassium.

[0077] More specifically, diethylamine salts can be prepared by dissolving a compound in alcohol, adding diethylamine dropwise, stirring the mixture, vacuum distilling, and crystallizing the residue by adding ether. Alkali metal salts can be prepared by preparing the desired salt with inorganic reagents such as lithium hydroxide, sodium hydroxide, and potassium hydroxide in a solvent such as alcohol, acetone, or acetonitrile, and then freeze-drying it. In addition, in a similar manner, lithium salts can be prepared as lithium acetate, sodium salts can be prepared as sodium 2-ethylhexanoate or sodium acetate, and potassium salts can be prepared as potassium acetate.

[0078] Some of the compounds of the present disclosure may be in a hydrated form and may exist in a solvated or unsolved form. Some of the compounds according to the present disclosure may exist in a crystalline or amorphous form, and any physical form is also included within the scope of the present disclosure. Additionally, some of the compounds of the present disclosure may contain one or more asymmetric carbon atoms or double bonds and thus may exist in two or more stereoisomeric forms, such as racemates, enantiomers, diastereomers, geometric isomers, etc. The present disclosure includes such individual stereoisoomers of the compounds.

[0079] composition

[0080] The present disclosure also provides a composition comprising a 5-benzylaminosalicylic acid derivative represented by Formula I or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient or additive. The 5-benzylaminosalicylic acid derivative represented by Formula I of the present disclosure or a pharmaceutically acceptable salt thereof may be administered alone. In one embodiment, a composition comprising a compound of Formula I is administered together with any simple carrier, diluent, etc.

[0081] In one embodiment, the composition comprises about 1 mg to about 1,000 mg of a compound of Formula I. In one embodiment, the composition comprises about 10 mg to 1,000 mg of a compound of Formula I. In one embodiment, the composition comprises about 1 mg to about 500 mg of a compound of Formula I. In one embodiment, the composition comprises about 1 mg to about 100 mg of a compound of Formula I. In one embodiment, the composition comprises about 2 mg to about 50 mg of a compound of Formula I.

[0082] In one embodiment, the formulation for administration may be a single-dose unit or a multiple-dose unit. In one embodiment, the composition comprises a single-dose unit. In one embodiment, the composition comprises a multiple-dose unit.

[0083] The composition for oral administration of the present disclosure may be formulated in a solid or liquid form. Solid formulations include, but are not limited to, powders, granules, tablets, capsules, suppositories, etc. Additionally, solid formulations may further include, but are not limited to, diluents, flavoring agents, binders, preservatives, disintegrating agents, lubricants, fillers, plasticizers, etc. Liquid formulations include, but are not limited to, solutions such as aqueous solutions and polyethylene glycol solutions, suspensions, emulsions, etc., and may be prepared by adding suitable excipients such as coloring agents, flavoring agents, stabilizers, thickeners, etc. In one embodiment, the composition is administered in a form selected from capsules, tablets, powders, and solutions. In one embodiment, the composition is administered mixed with a dietary supplement. In one embodiment, the composition is administered as a dietary supplement. In one embodiment, the composition is administered mixed with food. In one embodiment, the composition is dissolved in water and administered. In one embodiment, the composition is administered as a capsule with water. In one embodiment, the composition is administered as a chewable tablet.

[0084] For example, the powder may be prepared by simply mixing the 5-benzylaminosalicylic acid derivative of the present disclosure with pharmaceutically acceptable excipients such as lactose, starch, or microcrystalline cellulose. The granules may be prepared as follows: by mixing the compound of the present disclosure with pharmaceutically acceptable excipients. In one embodiment, the pharmaceutically acceptable excipient comprises a diluent and / or a pharmaceutically acceptable binder. In one embodiment, the binder is polyvinylpyrrolidone, hydroxypropylcellulose, etc.

[0085] In one embodiment, the composition is formed by wet-granulating with a suitable solvent such as water, ethanol, isopropanol, etc. In one embodiment, the composition is formed by direct-compressing with a compressive force. Additionally, the tablet may be prepared by mixing the granules with a pharmaceutically acceptable lubricant such as magnesium stearate and forming the mixture into a tablet.

[0086] The pharmaceutical compositions of the present disclosure may be administered, but are not limited to, oral formulations, injectable formulations (e.g., intramuscular, intraperitoneal, intravenous, infusion, subcutaneous, implantable), inhalable, intramuscular, vaginal, rectal, sublingual, transdermal, topical, etc., depending on the disease to be treated and the condition of the animal. Depending on the route of administration, the compositions of the present disclosure may be formulated into appropriate dosage units comprising pharmaceutically acceptable and non-toxic carriers, excipients, and / or vehicles commonly used in the art. Depot-type formulations capable of continuously releasing the drug for a desired period of time are also included within the scope of the present disclosure.

[0087] In one embodiment, the composition is a capsule comprising the following:

[0088] About 1 mg to 1000 mg of a compound of formula I;

[0089] Lactose monohydrate of about 50% w / w to about 70% w / w;

[0090] About 2% w / w to about 8% w / w croscarmellose sodium;

[0091] About 0.1% w / w to about 1% w / w magnesium stearate; and

[0092] About 0.1% w / w to about 2% w / w sodium lauryl sulfate.

[0093] In one embodiment, the composition is a capsule comprising the following:

[0094] About 1 mg to about 1000 mg of a compound of formula I;

[0095] Approximately 60% w / w lactose monohydrate;

[0096] Approximately 5% w / w croscarmellose sodium;

[0097] Approximately 0.5% w / w magnesium stearate; and

[0098] Approximately 1% w / w sodium lauryl sulfate.

[0099] In one embodiment, the composition is a food composition comprising the following:

[0100] About 1 mg to about 1000 mg of a compound of formula I;

[0101] About 30% w / w to about 50% w / w of starch;

[0102] Crude protein of about 15% w / w to about 25% w / w;

[0103] About 10% w / w to about 20% crude fat;

[0104] About 0.1% w / w to about 5% w / w crude fiber;

[0105] About 1% w / w to about 10% crude ash;

[0106] About 0.1% w / w to about 5% w / w of arginine;

[0107] Calcium of about 0.1% w / w to about 2.5% w / w;

[0108] About 0.1% w / w to about 3% w / w lysine;

[0109] About 0.1% w / w to about 3% w / w of methionine + cystine; and

[0110] Phosphorus of about 0.1% w / w to about 2.5% w / w.

[0111] In one embodiment, the composition is a food composition comprising the following:

[0112] About 1 mg to about 1000 mg of a compound of formula I;

[0113] Approximately 42.7% w / w starch;

[0114] Approx. 21.0% w / w crude protein;

[0115] Approximately 14% w / w crude fat;

[0116] Approximately 1.9% w / w crude fiber;

[0117] Approximately 6.1% w / w views;

[0118] Approx. 1.4% w / w arginine;

[0119] Approx. 0.75% w / w calcium;

[0120] Approximately 1.1% w / w lysine;

[0121] Approximately 1.18% w / w methionine + cystine; and

[0122] Approximately 0.5% w / w phosphorus.

[0123] In one embodiment, the composition is a dietary supplement comprising the following:

[0124] About 1 mg to about 1000 mg of a compound of formula I;

[0125] About 5% w / w to about 20% w / w crude protein;

[0126] About 0.1% w / w to about 5% w / w crude fat;

[0127] About 0.1% w / w to about 5% w / w crude fiber;

[0128] About 0.1% w / w to about 5% w / w ash;

[0129] About 0% w / w to about 1% w / w calcium;

[0130] About 0% w / w to about 2% w / w potassium; and

[0131] About 60% w / w to about 95% w / w water.

[0132] In one embodiment, the composition is a dietary supplement comprising the following:

[0133] About 1 mg to about 1000 mg of a compound of formula I;

[0134] Approx. 12.0% w / w crude protein;

[0135] Approximately 1.5% w / w crude fat;

[0136] Approx. 0.4% w / w crude fiber;

[0137] Approximately 1.5% w / w of views;

[0138] Approx. 0.02% w / w calcium;

[0139] Approximately 0.1% w / w potassium; and

[0140] Approximately 78.0% w / w water.

[0141] In one embodiment, the composition is a chewable tablet comprising the following:

[0142] About 1 mg to about 1000 mg of a compound of formula I;

[0143] About 0.1% w / w to about 5% w / w silicon dioxide;

[0144] About 0% w / w to about 2% w / w benzoic acid;

[0145] About 0% w / w to about 1% w / w sorbic acid;

[0146] About 0.1% w / w to about 10% w / w magnesium stearate;

[0147] About 10% w / w to about 30% w / w cellulose;

[0148] About 30% w / w to about 50% w / w chicken sauce;

[0149] About 0.1% w / w to about 5% w / w dry yeast; and

[0150] About 10% w / w to about 30% w / w glucose.

[0151] In one embodiment, the composition is a chewable tablet comprising the following:

[0152] About 1 mg to about 1000 mg of a compound of formula I;

[0153] Approximately 3% w / w silicon dioxide;

[0154] Approximately 0.05% w / w benzoic acid;

[0155] Approximately 0.01% w / w sorbic acid;

[0156] Approximately 5% w / w magnesium stearate;

[0157] Approximately 20% w / w cellulose;

[0158] Approximately 40% w / w chicken powder;

[0159] About 3% w / w dry yeast; and

[0160] Approximately 19% w / w glucose.

[0161] The present disclosure also provides the use of a 5-benzylaminosalicylic acid derivative or a pharmaceutically acceptable salt thereof for treating cognitive decline in animals. That is, the present disclosure provides a pharmaceutical composition for treating cognitive decline in animals comprising a 5-benzylaminosalicylic acid derivative represented by Formula I or a pharmaceutically acceptable salt thereof. More specifically, the 5-benzylaminosalicylic acid derivative or a pharmaceutically acceptable salt thereof may be used for the treatment of cognitive decline in animals, including cognitive impairment syndrome (e.g., cognitive impairment syndrome in dogs), dysthymia, chronic depression, and confusion syndrome. In one embodiment, cognitive decline is caused by CDS.

[0162] In one embodiment, the composition is used to manufacture a drug for the treatment of cognitive dysfunction syndrome (CDS) in companion animals. In one embodiment, the composition is used to manufacture a drug for treating CDS through the simultaneous pharmacological inhibition of oxidative stress and inflammation. In one embodiment, the composition is used to manufacture a drug for treating CDS by inhibiting oxidative stress and prostaglandin E2 synthesis. In one embodiment, the composition is used to manufacture a drug for treating CDS by inhibiting oxidative stress and microsomal prostaglandin E synthase-1. However, the use of 5-benzylaminosalicylic acid derivatives or pharmaceutically acceptable salts thereof according to the present disclosure is not limited to the specific names of the diseases.

[0163] The present disclosure provides the use of a 5-benzylaminosalicylic acid derivative or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical product for treating cognitive and / or neurobehavioral disorders. For example, the treatment of said cognitive and / or neurobehavioral disorders is to reduce or slow the decline in social interaction, reduce age-related behavioral changes, improve trainability, improve attention, maintain the health of brain function, reduce memory loss, and treat cognitive decline in companion animals such as canids or felines. In one embodiment, said companion animal exhibits symptoms including appetite, drinking behavior, vocalization, elimination behavior, sleep patterns, aimless behavior, adaptability, social behavior, perceptual ability, disorientation, and behavioral changes selected from memory. In one embodiment, said companion animal exhibits symptoms including vocalization, elimination behavior, sleep patterns, aimless behavior, social behavior, perceptual ability, disorientation, and behavioral changes selected from memory. In one embodiment, the pet exhibits symptoms including sleep patterns, social behavior, disorientation, and behavioral changes selected from memory. In one embodiment, the pet exhibits symptoms including memory changes. In one embodiment, the pet exhibits symptoms including orientation (e.g., staring blankly and getting lost in the house), memory (e.g., lack of recognition of the owner and house contamination), apathy (e.g., reduced time spent on activities and avoidance of contact with the owner), olfactory impairment (difficulty finding food), and behavioral changes selected from movement. In one embodiment, the pet exhibits symptoms including spatial orientation, social interaction, sleep-wake cycle, and behavioral changes selected from house contamination.

[0164] In one embodiment, the companion animal exhibits pathophysiological changes. In one embodiment, the pathophysiological changes are selected from cerebral cortical atrophy; basal ganglia atrophy; increased ventricular size; demyelination; increased size of glial cells; increased number of glial cells; neuronal loss, particularly in cortical regions above the hippocampus; axonal degeneration; and accumulation of beta-amyloid plaques. In one embodiment, the pathophysiological changes are selected from increased size of glial cells; increased number of glial cells; neuronal loss; and accumulation of beta-amyloid.

[0165] To treat cognitive decline in feline companion animals, the compound of the present disclosure may be administered daily at a dosage of about 0.01 mg / kg to about 200 mg / kg, preferably about 0.1 mg / kg to about 30 mg / kg. In one embodiment, the compound of Formula I is administered at a dosage of about 0.1 mg per kg of body weight to 10 mg per kg of body weight. However, the dosage may vary depending on the animal's condition (age, sex, weight, etc.), the degree of disease of the animal requiring treatment, the active ingredient used, diet, etc. The compound of the present disclosure may be administered once a day or in divided doses several times a day as needed. In one embodiment, the compound of Formula I is administered once, twice, or three times a day. In one embodiment, the compound of Formula I is administered once a day.

[0166] Examples

[0167] Compound 2,2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid was used as a representative compound. Hereinafter, the present invention is described in detail so that those skilled in the art to which the present invention pertains may understand the present invention. However, the following examples are provided by way of example and are not intended to limit the scope of the present disclosure. It is evident that various modifications may be made without departing from the spirit and scope of the present disclosure or without sacrificing all material advantages thereof.

[0168] 1. Research Design and Subjects

[0169] In preliminary data, maximally beneficial effects, such as improvements in cognitive and motor functions, were observed in animal models of AD (APP / PS1 mice) and amyotrophic lateral sclerosis (G93A mice) after oral administration of a dose of 2.5 mg / kg of compound 2.

[0170] After orally administering compound 2 to mice at a dose of 2.5 mg / kg, C max The average maximum plasma concentration (AUC) and AUC (area under the plasma level-time curve) were measured as 5.19 ± 0.96 μg / mL and 9.61 ± 1.38 μg·hr / mL, respectively.

[0171] The potential systemic toxicity of Compound 2 in Beagle dogs was investigated at Huntington Life Science, a large-scale nonclinical contract research organization located in Cambridgeshire, UK. Compound 2 was administered to three groups, each consisting of three males and three females, at doses of 20, 65, or 200 mg / kg / day for 13 weeks. Daily administration of Compound 2 in Beagle dogs resulted in adaptive changes in the liver and kidneys, as well as secondary findings in the thyroid. Although there was no evidence of toxicity, the treated animals tended to experience difficulty with dose administration. The results of the primary treatment-related study all showed at least partial recovery during a 4-week recovery period, with most showing complete recovery. Consequently, 200 mg / kg / day was considered the no-observed-adverse-effect level (NOAEL) in dogs.

[0172] In a pharmacokinetic study, after oral administration of 20 mg / kg / day of compound 2 to a Beagle dog, C max The AUCs were 10.6 μg / mL and 75.1 μg·hr / mL, respectively. Based on the stability and pharmacokinetic profile of compound 2, a dosage of 10 mg / kg / day was selected to investigate the stability and efficacy of compound 2 in canine CDS.

[0173] In stability tests, compound 2 was stable at 25°C for at least 60 months. In addition, the capsule and chewable formulations of compound 2 were stable at 25°C for at least 24 and 12 months, respectively.

[0174] The companion animals tested in this study were 22 senior dogs (12–19 years old) diagnosed with CDS. The subjects of the examples are presented in Table 1. Each dog enrolled in this study met the following criteria: body weight <12 kg (regardless of gender), had lived with its owner for at least 90 days, was able to take oral medication, and was diagnosed with CDS by an investigator (Canine Cognitive Dysfunction Rating (CCDR) scale Dogs that received prior consent from their owners (50 points). Dogs that were pregnant or lactating, hypersensitive to salicylic acid derivatives, or had underlying conditions (i.e., renal impairment, visual loss, heart failure, or renal failure) were excluded. Additionally, dogs that had participated in another clinical trial within 90 days or had CDS as well as other neurodegenerative diseases were excluded.

[0175] This study was a randomized, blind, placebo-controlled clinical trial to investigate the efficacy and safety of Compound 2 in dogs with CDS. To investigate the efficacy of Compound 2, questionnaires of the CCDR scale and the Canine Dementia Emissions Scale (CADES) were evaluated. To measure the safety of Compound 2, vital signs, physical examinations, and blood tests were performed on the dogs, as well as the occurrence of adverse events. Compound 2 was prescribed for oral administration at a dose of 10 mg / kg once daily for 8 weeks. Subjects 3 and 4 received Compound 2 for an additional 4 weeks with the approval of the principal investigator. Instead of Compound 2, subjects 18–22 received a placebo for 8 weeks. In this study, Will allowed Compound 2 to be administered in various ways: mixed with dietary supplements (Subjects 1 and 3), mixed with food (Subjects 2 and 6), dissolved in water (Subject 4), or with water and capsules (Subject 5), or with water and chewable tablets (Subjects 7-22)

[0176] [Table 1] Subjects of Experimental Examples

[0177]

[0178] 2. Questionnaire for dogs with CDS

[0179] Rating scales are essential tools for the diagnosis, staging, evaluation, and careful monitoring of disease symptoms of CDS, as well as for assessing the efficacy of treatment strategies. Over the past decade, several rating scales, such as the CCDR scale [21-24], have been developed. In this study, to assess the severity of CDS, two questionnaires (the CCDR scale and CADES) were administered by veterinarians before and after the oral administration of Compound 2. The questionnaires include a wide range of items measuring appetite, drinking behavior, barking, elimination behavior, day-night sleep patterns, aimless behavior, adaptability, social behavior, perceptual ability, disorientation, and memory.

[0180] 2.1 Investigation based on CCDR scale

[0181] The CCDR scale consists of 13 items based on CDS symptoms (Table 2). The 13 behavioral items included orientation (staring blankly, getting lost in the house), memory (lack of owner recognition, house contamination), apathy (reduced activity time, avoidance of contact with owner), olfactory impairment (difficulty finding food), and various mobility-related problems. These problems impair both the dog's quality of life and the bond between the dog and the owner [25, 26]. A CCDR score of 50 or higher indicates CDS in senior dogs (12–19 years). In this study, we compared CCDR scores in CDS dogs before and after the administration of Compound 2.

[0182] [Table 2] Canine Dysfunction Rating (CCDR) Scale

[0183]

[0184] The study began with a total of 22 dogs with CDS, but 17 dogs received treatment with Compound 2 for 8 weeks, and subjects 1 and 2 experienced age-dependent nephrotoxicity and natural death 7 weeks after administration. Even 4 weeks after oral administration of Compound 2, most dogs with CDS showed a significantly reduced tendency for behavior on the CCDR scale, indicating that dogs treated with Compound 2 demonstrated nearly normal cognitive function within 4 weeks (Table 3). Furthermore, the frequency of abnormal behaviors decreased in most dogs, and their social interactions improved. Improved CCDR scores were observed up to 8 weeks after administration of Compound 2.

[0185] [Table 3] Subjects' CCDR scores after administration of Compound 2

[0186]

[0187] To determine whether the beneficial effects of Compound 2 persisted even after the discontinuation of drug administration, a follow-up study was conducted on six dogs. In subjects 3, 4, 7, 8, 10, and 11, who were treated with Compound 2 for 8 or 12 weeks, the beneficial effects of Compound 2 were observed over 4 or 8 weeks after the last administration of the drug (Tables 4 and 5). Importantly, social interaction, appropriate elimination, and changes in the sleep-wake activity cycle were significantly improved. This implies that Compound 2 can be applied to the treatment of CDS by improving cognitive deficits and slowing disease progression.

[0188] [Table 4] Subjects' CCDR scores after administration and discontinuation of Compound 2

[0189]

[0190] [Table 5] Subjects' CCDR scores after administration and discontinuation of Compound 2

[0191]

[0192] 2.2 Inspection according to CADES

[0193] To supplement and verify the CCDR scale, we used CADES, an additional questionnaire containing 17 items distributed across four domains related to changes in canine behavior: spatial orientation, social interaction, sleep-wake cycle, and house contamination (Table 6) [3]. It can be classified into mild, moderate, and severe cognitive impairments depending on the various stages of cognitive impairment. It is also well known that CADES is suitable for evaluating the long-term progression of cognitive impairment in canines and for reading potential efficacy for treatment.

[0194] [Table 6] Canine Dementia Scale (CADES)

[0195]

[0196] Scores for spatial orientation and change are presented in Table 7. After 4 weeks of administration, 10 out of 17 dogs (59%) showed improvement in spatial orientation loss. Subjects 3, 4, and 10 exhibited nearly normal behavior in the spatial orientation category. In 9 out of 15 dogs (60%), a beneficial effect was observed 8 weeks after oral administration of Compound 2. Overall, these results indicate that Compound 2 improves the spatial orientation ability of dogs with CDS.

[0197] [Table 7] CADES scores of spatial orientation (Items 1-5) in subjects at 0, 4, and 8 weeks after administration of Compound 2

[0198]

[0199] Social interactions in CADES are presented in Table 8. Four weeks after the administration of Compound 2, social interactions significantly improved in most participating dogs, with the exception of subjects 5, 8, 11, 12, 14, and 17. Although three dogs (subjects 3, 4, and 10) exhibited severely abnormal social behavior prior to treatment with Compound 2, their social behavior became nearly similar to that of normal elderly dogs four weeks after treatment. Furthermore, most dogs showed improved social activity eight weeks after treatment with Compound 2. More importantly, eight out of 15 dogs (53%) showed further improvement in social interactions eight weeks after administration of Compound 2 compared to the improvement observed four weeks after administration. Overall, these results indicate that Compound 2 improves social interactions in dogs with CDS.

[0200] [Table 8] CADES scores of subjects' social interactions (items 6-10) at 0, 4, and 8 weeks after administration of Compound 2

[0201]

[0202] Changes in the sleep-wake cycle in CADES were quantified in Table 9. Before the administration of Compound 2, all dogs except Subject 14 exhibited severe abnormal behavior in the sleep-wake cycle (Item 11), but 10 out of 15 dogs (67%) showed significant improvement after 8 weeks of administration of Compound 2. Meanwhile, a transition from insomnia to hypersomnia (Item 12) was observed in 14 out of 17 dogs (82%), but most of the abnormal changes disappeared after the administration of Compound 2.

[0203] [Table 9] CADES scores of subjects' sleep-wake cycles (Items 11-12) at 0, 4, and 9 weeks after administration of Compound 2

[0204]

[0205] The frequency of house contamination is shown in Table 10. After 8 weeks of administration of Compound 2, house contamination behavior was reduced in all subjects except subjects 4, 12, 13, and 18. In particular, subjects 3, 5, and 19 did not exhibit house contamination at 8 weeks after administration of Compound 2.

[0206] [Table 10] CADES scores of subjects' home contamination at 0, 4, and 8 weeks after administration of Compound 2 (Items 13-17)

[0207]

[0208] The total CADES scores are presented in Table 11. The scores indicated that cognitive dysfunction behaviors gradually decreased after the administration of Compound 2 in all dogs except Subject 9, who had CDS. At 8 weeks after oral administration of Compound 2, significant improvement in cognitive function was observed, ranging from severe to moderate, mild, or normal levels.

[0209] [Table 11] Total CADES scores of subjects at 0, 4, and 8 weeks after administration of Compound 2

[0210]

[0211] In six companion dogs (Subjects 3, 4, 7, 8, 10, and 11), the beneficial effects of Compound 2 were observed for the following 4 or 8 weeks after discontinuation of administration (Tables 12 and 13). Sleep patterns, house contamination, social interactions, and behavioral activities improved significantly after treatment with Compound 2. Additionally, the subjects became more obedient to their owners and aggression decreased. These results suggest that Compound 2 can be administered to reduce cognitive impairment and slow disease progression in canine CDS.

[0212] [Table 12] Subjects' total CADES scores after administration and discontinuation of Compound 2

[0213]

[0214] [Table 13] Subjects' total CADES scores after administration and discontinuation of Compound 2

[0215]

[0216] 2.3 CCDR and CADES results of dogs administered placebo

[0217] To clarify the effect of Compound 2 on cognitive impairment, five dogs with CDS (Subjects 18–22) received a placebo. In most dogs that received the placebo, there was no significant change or increase in CCDR and CADES scores at 8 weeks after placebo administration, indicating that placebo administration did not affect cognitive function. Overall, this strongly suggests that Compound 2 can be administered to reduce cognitive impairment in canine CDS.

[0218] [Table 14] Subjects' CCDR scores after placebo administration

[0219]

[0220] [Table 15] Total CADES scores of subjects after placebo administration

[0221]

[0222] 3. Safety assessment in dogs with CDS

[0223] During this study, the safety of compound 2 in CDS-containing dogs was evaluated at every visit. As a result, no significant changes were observed in blood toxicity tests, and no treatment-related side effects occurred.

[0224] 4. Conclusion

[0225] Two questionnaires were used to evaluate the effects of Compound 2 on cognitive function in dogs with CDS. On the CCDR scale, administration of Compound 2 substantially improved cognitive function to near-normal scores. Consistent with the CCDR scale, severe cognitive and neurobehavioral disorders in dogs with CDS were significantly alleviated within 8 weeks of administration of Compound 2. These beneficial effects were maintained for 4 or 8 weeks after the completion of the 8 or 12-week administration of Compound 2. Furthermore, no adverse effects or toxicities were observed during the study. In contrast, there was no significant improvement in the placebo group. Taken together, these findings suggest that Compound 2 may be applicable to the treatment of CDS in canines and felines.

[0226] Industrial applicability

[0227] The present disclosure provides a composition comprising compound 2 and a method of administering a therapeutically effective amount of compound 2 to treat cognitive and neurobehavioral disorders in neurological diseases, including CDS, hypothymia, chronic depression, and confusion syndrome, in canids or felines. The composition and method of the present disclosure are highly useful for reducing or slowing cognitive and neurobehavioral disorders in age-related neurological diseases in canids or felines.

[0228] Other Publications

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[0230] 2. Neilson, JC, et al., Prevalence of behavioral changes associated with age-related cognitive impairment in dogs. J Am Vet Med Assoc, 2001. 218 (11): p. 1787-91.

[0231] 3. Madari, A., et al., Assessment of severity and progression of canine cognitive dysfunction syndrome using the CAnine DEmentia Scale (CADES). Appl Anim Behav Sci., 2015.171 : p. 138-45.

[0232] 4. Salvin, H.E., et al., Under diagnosis of canine cognitive dysfunction: a cross-sectional survey of older companion dogs. The Veterinary Journal, 2010. 184 (3): p. 277-281.

[0233] 5. Hart, B.L. and L.A. Hart, Selecting, raising, and caring for dogs to avoid problem aggression. Journal of the American Veterinary Medical Association, 1997. 210 (8): p. 1129.

[0234] 6. Landsberg, G.M., J. Nichol, and J.A. Araujo, Cognitive dysfunction syndrome: a disease of canine and feline brain aging. Vet Clin North Am Small Anim Pract, 2012. 42 (4): p. 749-68, vii.

[0235] 7. Landsberg, G.M., T. Deporter, and J.A. Araujo, Clinical signs and management of anxiety, sleeplessness, and cognitive dysfunction in the senior pet. Vet Clin North Am Small Anim Pract, 2011. 41 (3): p. 565-90.

[0236] 8. Gonzalez-Martinez, A., et al., Effect of age and severity of cognitive dysfunction on two simple tasks in pet dogs. Vet J, 2013. 198 (1): p. 176-81.

[0237] 9. Cummings, B.J., et al., β -amyloid accumulation correlates with cognitive dysfunction in the aged canine. Neurobiology of learning and memory, 1996. 66 (1): p. 11-23.

[0238] 10. Cummings, B.J., et al., β -amyloid deposition and other measures of neuropathology predict cognitive status in Alzheimer's disease. Neurobiology of aging, 1996. 17(6): p. 921-933.

[0239] 11. Cummings, B.J., et al., Diffuse plaques contain C-terminal Aß42 and not Aß40: evidence from cats and dogs. Neurobiology of aging, 1996. 17 (4): p. 653-659.

[0240] 12. Ozawa, M., et al., The Relation between canine cognitive dysfunction and age-related brain lesions. J Vet Med Sci, 2016. 78 (6): p. 997-1006.

[0241] 13. Rofina, J., et al., Cognitive disturbances in old dogs suffering from the canine counterpart of Alzheimer's disease. Brain research, 2006. 1069 (1): p. 216-226.

[0242] 14. Head, E., et al., Visual-discrimination learning ability and β -amyloid accumulation in the dog. Neurobiology of aging, 1998. 19 (5): p. 415-425.

[0243] 15. Tapp, P.D., et al., Frontal lobe volume, function, and β -amyloid pathology in a canine model of aging. Journal of Neuroscience, 2004. 24 (38): p. 8205-8213.

[0244] 16. Druce, K., Canine cognitive dysfunction-recognition and treatment. Veterinary Nursing Journal, 2014. 29 (8): p. 268-270.

[0245] 17. Ruehl, W., et al., Canine cognitive dysfunction as a model for human age-related cognitive decline, dementia and Alzheimer's disease: clinical presentation, cognitive testing, pathology and response to 1-deprenyl therapy , in Progress in Brain Research . 1995, Elsevier. p. 217-225.

[0246] 18. Head, E., et al., Spatial learning and memory as a function of age in the dog. Behavioral neuroscience, 1995. 109 (5): p. 851.

[0247] 19. Campbell, S., A. Trettien, and B. Kozan, A noncomparative open-label study evaluating the effect of selegiline hydrochloride in a clinical setting. Vet Ther, 2001. 2 (1): p. 24-39.

[0248] 20. Shin, JH, et al., Concurrent blockade of free radical and microsomal prostaglandin E synthase-1-mediated PGE2 production improves safety and efficacy in a mouse model of amyotrophic lateral sclerosis. Journal of neurochemistry, 2012. 122 (5): p. 952-961.

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Claims

Claim 1 A composition for the treatment of cognitive impairment syndrome (CDS) in companion animals requiring this, wherein the composition is characterized by comprising 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid or a pharmaceutically acceptable salt thereof. Claim 2 A composition according to claim 1, wherein the composition comprises 1 mg to 1000 mg of 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid or a pharmaceutically acceptable salt thereof. Claim 3 In claim 1, the composition is a composition intended for oral administration. Claim 4 In claim 1, the composition is a pharmaceutical composition. Claim 5 The composition of claim 1, wherein the composition is characterized by comprising: 1 mg to 1000 mg of 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid or a pharmaceutically acceptable salt thereof, 50% w / w to 70% w / w lactose monohydrate, 2% w / w to 8% w / w croscarmellose sodium, 0.1% w / w to 1% w / w magnesium stearate, and 0.1% w / w to 2% w / w sodium lauryl sulfate. Claim 6 The composition of claim 1, wherein the composition is characterized as being a capsule comprising: 1 mg to 1000 mg of 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid or a pharmaceutically acceptable salt thereof, 60% w / w lactose monohydrate, 5% w / w croscarmellose sodium, 0.5% w / w magnesium stearate, and 1% w / w sodium lauryl sulfate. Claim 7 The composition of claim 1, wherein the composition is characterized by comprising: 1 mg to 1000 mg of 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid or a pharmaceutically acceptable salt thereof, 30% w / w to 50% w / w starch, 15% w / w to 25% w / w crude protein, 10% w / w to 20% crude fat, 0.1% w / w to 5% w / w crude fiber, 1% w / w to 10% w / w crude ash, 0.1% w / w to 5% w / w arginine, 0.1% w / w to 2.5% w / w calcium, 0.1% w / w to 3% w / w lysine, 0.1% w / w to 3% w / w methionine + cystine, and 0.1% w / w to 2.5% w / w phosphorus. Claim 8 The composition of claim 1, wherein the composition is characterized by comprising: 1 mg to 1000 mg of 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid or a pharmaceutically acceptable salt thereof, 42.7% w / w starch, 21.0% w / w crude protein, 14% w / w crude fat, 1.9% w / w crude fiber, 6.1% w / w crude ash, 1.4% w / w arginine, 0.75% w / w calcium, 1.1% w / w lysine, 1.18% w / w methionine + cystine, and 0.5% w / w phosphorus. Claim 9 The composition of claim 1, wherein the composition is characterized by comprising: 1 mg to 1000 mg of 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid or a pharmaceutically acceptable salt thereof, 5% w / w to 20% w / w crude protein, 0.1% w / w to 5% w / w crude fat, 0.1% w / w to 5% w / w crude fiber, 0.1% w / w to 5% w / w crude ash, 0% w / w to 1% w / w calcium, and 0% w / w to 2% w / w potassium. Claim 10 The composition of claim 1, wherein the composition is characterized by comprising: 1 mg to 1000 mg of 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid or a pharmaceutically acceptable salt thereof, 12.0% w / w crude protein, 1.5% w / w crude fat, 0.4% w / w crude fiber, 1.5% w / w crude ash, 0.02% w / w calcium, 0.1% w / w potassium, and 78.0% w / w water. Claim 11 The composition of claim 1, wherein the composition is characterized by comprising: 1 mg to 1000 mg of 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid or a pharmaceutically acceptable salt thereof, 0.1% w / w to 5% w / w silicon dioxide, 0% w / w to 2% w / w benzoic acid, 0% w / w to 1% w / w sorbic acid, 0.1% w / w to 10% w / w magnesium stearate, 10% w / w to 30% w / w cellulose, 30% w / w to 50% w / w chicken sauce, 0.1% w / w to 5% w / w dried yeast, and 10% w / w to 30% w / w glucose. Claim 12 The composition of claim 1, wherein the composition is characterized as being a chewable tablet comprising: 1 mg to 1000 mg of 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid or a pharmaceutically acceptable salt thereof, 3% w / w silicon dioxide, 0.05% w / w benzoic acid, 0.01% w / w sorbic acid, 5% w / w magnesium stearate, 20% w / w cellulose, 40% w / w chicken sauce, 3% w / w dried yeast, and 19% w / w glucose. Claim 13 delete Claim 14 In claim 1, the composition is characterized by treating cognitive impairment syndrome (CDS) through one of the following: a) simultaneous pharmacological inhibition of oxidative stress and inflammation; b) inhibition of oxidative stress and prostaglandin E2 synthesis; or c) inhibition of oxidative stress and microsomal prostaglandin E synthase-1. Claim 15 A composition according to claim 1, wherein 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid or a pharmaceutically acceptable salt thereof is administered once a day at a dose of 1 mg to 200 mg per kg of body weight. Claim 16 A composition according to claim 1, wherein 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid or a pharmaceutically acceptable salt thereof is administered once a day at a dose of 0.1 mg to 30 mg per kg of body weight. Claim 17 A composition according to claim 1, wherein 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid or a pharmaceutically acceptable salt thereof is administered once a day at a dose of 0.1 mg to 10 mg per kg of body weight. Claim 18 A composition characterized in that, in any one of claims 1 to 12 and claims 14 to 17, the companion animal is an individual. Claim 19 A composition characterized in that, in any one of claims 1 to 12 and claims 14 to 17, the companion animal is a cat. Claim 20 In claim 18, the composition is characterized by improving the cognitive function of a dog for at least 8 weeks. Claim 21 A composition according to claim 20, wherein the cognitive function is selected from social interaction, appropriate elimination, spatial orientation, and sleep-wake activity cycle. Claim 22 In paragraph 18, the composition is characterized by: a) improving the cognitive function of a dog from severe to moderate, weak, or normal; or b) restoring the cognitive function of a dog to near normal. Claim 23 A composition according to claim 22, wherein the cognitive function is selected from social interaction, appropriate elimination, spatial orientation, and sleep-wake activity cycle. Claim 24 delete Claim 25 delete Claim 26 delete Claim 27 delete Claim 28 delete Claim 29 delete

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