Methods for treating nerve diseases

Abstract

To provide treatment of nerve diseases, in particular Alzheimer's disease in a specific subpopulation having one or more copies of ApoE4 (or ε4) allele.SOLUTION: Disclosed herein is a method for treating and / or preventing Alzheimer's disease in a patient having one or two copies of ApoE4 allele. Also disclosed herein is a composition for treatment and / or prevention. More specifically, disclosed herein is a method for treating or preventing Alzheimer's disease in a patient being heterozygous or homozygous for the ApoE4 allele. In one embodiment, a compound to be administered is represented by Formula I and pharmaceutically acceptable salts, hydrates and solvates. In the formula, AA1 and AA2 are amino acids.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] <CROSS REFERENCE TO RELATED APPLICATIONS> This application claims priority from U.S. Provisional Patent Application No. US 61 / 968,595, filed March 21, 2014, the contents of which are incorporated herein by reference.

[0002] This application incorporates by reference for all purposes U.S. Application Publication No. 2008 / 0146642, filed October 12, 2007, U.S. Application Publication No. 2009 / 0182056, filed January 30, 2009, and U.S. Application Publication No. 2010 / 0113591, filed November 5, 2009. [Background technology]

[0003] Alzheimer's disease (AD) is a progressive degenerative disease of the brain primarily associated with aging. The prevalence of AD in the United States in 2000 was close to 4.5 million. It was estimated that approximately 1 in 10 people over the age of 65 and approximately half of people over the age of 85 are affected by Alzheimer's disease. In the United States alone, approximately 360,000 patients will be diagnosed with AD each year.

[0004] The clinical symptoms of AD are characterized by loss of memory, cognition, reasoning, judgment, and orientation. As the disease progresses, motor, sensory, and language abilities are also affected until there is global impairment of multiple cognitive functions. These cognitive losses occur gradually, but usually over a period of 4-12 years, resulting in severe disability and ultimately death.

[0005] Alzheimer's disease is characterized by two major pathological observations in the brain: neurofibrillary tangles and beta-amyloid (or neuritic) plaques, which are composed primarily of aggregates of peptide fragments known as beta-amyloid peptide, Aβ. Individuals with AD exhibit characteristic beta-amyloid deposits in the brain (beta-amyloid plaques) and cerebrovascular (beta-amyloid angiopathy), as well as neurofibrillary tangles. Neurofibrillary tangles can occur not only in Alzheimer's disease, but also in other dementia-inducing disorders. Summary of the Invention [Means for solving the problem]

[0006] The present disclosure relates generally to the treatment of neurological disorders, and in particular, Alzheimer's disease in certain subpopulations that carry one or more copies of the ApoE4 (or ε4) allele.

[0007] L-Valyl-3-aminopropanesulfonate (Val-APS) is an orally available small molecule prodrug of tramiprosate with improved pharmaceutical properties. Tramiprosate has progressed into a Phase 3 program of approximately 2,000 patients, which was completed in 2007. However, the prodrug of Val-APS exhibits important advantages over tramiprosate, including improved GI tolerability, reduced nausea & vomiting, and reduced intersubject PK variability. In addition, administering the prodrug resulted in a beneficially extended t 1 / 2 Due to this, once-daily administration is provided. In particular, oral administration of Val-APS provides an approximately 2-fold increase in plasma and brain exposure of tramiprozate in animals compared to tramiprozate administered at an equimolar dose. Thus, the present disclosure provides for administration of certain compounds, including Val-APS, to ApoE4-positive patients for the treatment of Alzheimer's disease. Val-APS: [ka] [Brief description of the drawings]

[0008] [Figure 1] Decreased ADAS-Cog scores after treatment in Alzheimer's disease patients with tramiprozate. At week 26, -1.25 (82%) P = 0.0219 for 100 mg BID and -1.03 (57%) P = 0.118 for 150 mg BID. At week 52, -2.03 (35%) P = 0.002 for 100 mg BID and -1.85 (32%) P = 0.006 for 150 mg BID. At week 65, -1.52 (22%) P = 0.024 for 100 mg BID and -1.90 (27%) P = 0.005 for 150 mg BID. At week 78, -1.90 (27%) P = 0.005 for 100 mg BID and -1.86 (21%) P = 0.028 for 150 mg BID. (n=599). Data are from Caltagirone et al., "The potential protective effect of tramiprosate(homotaurine)against Alzheimer's disease: A review", Aging Clin Exp Res. 2012 Dec;24(6):580-7. [Diagram 2] A retrospective subgroup analysis in 599 ApoE4+ subjects using a mixed-effects repeated measures, covariate model (MERM) demonstrated significant effects on both cognition and function using ADAS-cog and CDR-SB. [Diagram 3] A retrospective subgroup analysis in 599 ApoE4+ subjects using a mixed-effects repeated measures, covariate model (MERM) demonstrated significant effects on both cognition and function using ADAS-cog and CDR-SB. [Figure 4] Brain exposure of tramiprozate after oral Val-APS (top line) or tramiprozate (bottom line) is shown. The AUC ratio of tramiprozate brain exposure attributable to Val-APS is approximately 2.1. [Diagram 5]We present results from a Phase 1 SAD clinical trial in normal healthy elderly subjects demonstrating that an oral Val-APS prodrug confers an extended t1 / 2 of tramiprozate. [Figure 6] We present results from a Phase 1 SAD clinical trial in normal healthy elderly subjects, showing reduced formation of the metabolite NRM5074 following administration of Val-APS. [Figure 7] We present a SAD study in normal HV demonstrating that orally administered Val-APS exhibits superior PK variability reduction versus tramiprozate in MR tablets or LF capsules. Loosely filled capsules of Val-APS reduced PK variability by approximately 50% and further extended the terminal t1 / 2 to 14.9 hours, allowing for once-daily dosing. [Figure 8] The data shows a beneficial effect of tramiprozate, the active agent of Val-APS, in specific subpopulations separated based on ApoE4 status. The data establishes substantially improved ADAS-cog scores over time versus placebo. Data are presented at weeks 13, 26, 39, 52, 65, and 78. The first column shows patients homozygous for ApoE4 ("ApoE4+ / +"), the second column shows combined data from patients heterozygous and homozygous for ApoE4 "ApoE4 all-visitors," and the third column shows patients negative for ApoE4 (non-ApoE4). ApoE4 prevalence correlates with improved cognitive scores. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] <Definition> The following definitions are used in connection with the present disclosure: Unless otherwise defined, the term "subject" as used herein is a mammal, such as a human, a mouse, a rat, a guinea pig, a dog, a cat, a horse, a cow, a pig, or a non-human primate, such as a monkey, a chimpanzee, or a baboon. In one embodiment, the subject is a human.

[0010] The term "pharmaceutically acceptable salt," as used herein, unless otherwise defined, refers to a salt of a basic group, such as an amino group, or an acidic group, such as a carboxyl group, contained in the compounds disclosed herein. Examples of salts of basic groups include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronic acid, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Examples of salts of acidic groups include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, aluminum salts, chromium salts, iron salts, copper salts, zinc salts, cadmium salts, ammonium salts, guanidinium salts, pyridinium salts, and organic ammonium salts.

[0011] The terms "hydrate" and "solvate," as used herein, unless otherwise defined, describe a compound or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of water or other solvent bound by non-covalent intermolecular forces.

[0012] An "effective amount" as used in connection with another therapeutic agent is an amount that is effective in combination with a compound to treat or prevent a condition. "In combination with" includes administration within the same composition as well as via a separate composition. In the latter case, the other therapeutic agent is effective to treat or prevent a condition during the time that the compound exerts its prophylactic or therapeutic effect, and vice versa.

[0013] When used in connection with a designated reference numerical value, the term "about" means a range of plus or minus 10% of the designated reference numerical value. For example, the term "about 50" covers a range of 45 to 55.

[0014] The term "amino acid" generally refers to organic compounds that contain both a carboxylic acid group and an amine group. The term "amino acid" includes both "natural" and "unusual" or "unnatural" amino acids. Additionally, the term amino acid includes O- or N-alkylated amino acids, or S-alkylated or S-substituted or P-containing amino acids, as well as amino acids with nitrogen- or oxygen- or sulfur- or phosphorus-containing side chains (e.g., Lys, Orn, or Ser, Met) in which the nitrogen- or oxygen- or sulfur- or phosphorus-containing atom is acylated or alkylated. In some embodiments, the nitrogen-, oxygen-, sulfur-, or phosphorus atom of the side chain is derivatized with other than an acyl or alkyl group. The amino acids can be pure L or D isomers, or mixtures of L and D isomers (including racemic mixtures).

[0015] The term "natural amino acid" and equivalent expressions refer to L-amino acids commonly found in naturally occurring proteins. Examples of natural amino acids include, but are not limited to, alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asp), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), and beta-alanine (β-ALA). In other embodiments, the amino acid may not be an L-amino acid, such as gamma-aminobutyric acid (GABA).

[0016] The term "unusual amino acid" refers to any derivative of a natural amino acid, including the D-form, and α- and β-amino acid derivatives, as well as any synthetic compound that contains an amino and carboxy group. "Unusual amino acid" and "unnatural amino acid" are used interchangeably herein and are meant to include the same moiety. It should be noted that certain amino acids classified as unnatural amino acids herein, such as hydroxyproline, may occur naturally in certain organisms or in certain proteins. Amino acids with many different protecting groups suitable for immediate use in solid phase synthesis of peptides are commercially available.Thus, in addition to the 20 most common naturally occurring amino acids, the following examples of unnatural amino acids and amino acid derivatives may be used (common abbreviations in parentheses): 2-aminoadipic acid (Aad), 3-aminoadipic acid (β-Aad), 2-aminobutyric acid (2-Abu), α,β-dehydro-2-aminobutyric acid (8-AU), 1-aminocyclopropane-1-carboxylic acid (ACPC), aminoisobutyric acid (Aib), 3-aminoisobutyric acid (β-Aib), 2-amino -Thiazoline-4-carboxylic acid, 5-aminovaleric acid (5-Ava), 6-aminohexanoic acid (6-Ahx), 2-aminoheptanoic acid (Ahe), 8-aminooctanoic acid (8-Aoc), 11-aminoundecanoic acid (11-Aun), 12-aminododecanoic acid (12-Ado), 2-aminobenzoic acid (2-Abz), 3-aminobenzoic acid (3-Abz), 4-aminobenzoic acid (4-Abz), 4-amino-3-hydroxy-6-methylheptanoic acid (statin, St a), aminooxyacetic acid (Aoa), 2-aminotetralin-2-carboxylic acid (ATC), 4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA), para-aminophenylalanine (4-NH2-Phe), 2-aminopimelic acid (Apm), biphenylalanine (Blp), para-bromophenylalanine (4-Br-Phe), ortho-chlorophenylalanine (2-Cl-Phe), meta-chlorophenylalanine (3-Cl-Phe) ), para-chlorophenylalanine (4-Cl-Phe), meta-chlorotyrosine (3-Cl-Tyr), para-benzoylphenylalanine (Bpa), tertiary butylglycine (TLG), cyclohexylalanine (Cha), cyclohexylglycine (Chg), desmosine (Des), 2,2-diaminopimelic acid (Dpm), 2,3-diaminopropionic acid (Dpr), 2,4-diaminobutyric acid (Dbu), 3,4-dichlorophenylalanine (3,4-C. 12-Phe), 3,4-difluorophenylalanine (3,4-F2-Phe), 3,5-diiodotyrosine (3,5-I2-Tyr), N-ethylglycine (EtGly), N-ethylasparagine (EtAsn), ortho-fluorophenylalanine (2-F-Phe), meta-fluorophenylalanine (3-F-Phe), para-fluorophenylalanine (4-F-Phe), meta-fluorophenylalanine (3-F-Tyr), homoserine (Hse), Homophenylalanine (Hfe), homotyrosine (Htyr), hydroxylysine (Hyl), allo-hydroxylysine (aHyl), 5-hydroxytryptophan (5-OH-Trp), 3- or 4-hydroxyproline (3- or 4-Hyp), para-iodophenylalanine (4-I-Phe), 3-iodotyrosine (3-I-Tyr), indoline-2-carboxylic acid (Idc), isodesmosine (Ide), allo-isoleucine (a-Ile), iso Nipecotic acid (lnp), N-methylisoleucine (MeIle), N-methyllysine (MeLys), meta-methyltyrosine (3-Me-Tyr), N-methylvaline (MeVal), 1-naphthylalanine (1-NaI), 2-naphthylalanine (2-NaI), para-nitrophenylalanine (4-NO2-Phe), 3-nitrotyrosine (3-NO2-Tyr), norleucine (Nle), norvaline (Nva), ornithine (Orn), ortho-phosphotyrosine (Phe), These are proline (H2PO3-Tyr), octahydroindole-2-carboxylic acid (Oic), penicillamine (Pen), pentafluorophenylalanine (F5-Phe), phenylglycine (Phg), pipecolic acid (Pip), propargylglycine (Pra), pyroglutamic acid (PGLU), sarcosine (Sar), tetrahydroisoquinoline-3-carboxylic acid (Tic), thienylalanine, and thiazolidine-4-carboxylic acid (thioproline, Th).

[0017] "C max " means the peak plasma concentration of a drug or compound of the invention following administration.

[0018] "T max " is C maxmeans the time to reach.

[0019] “AUC 0-t ” refers to the area under the curve in the plot of the plasma concentration of the drug or compound of the present invention against time. In certain embodiments of the present invention, t is infinity (∞), and AUC 0-∞ refers to the total drug exposure over time.

[0020] “T 1 / 2 ” means the biological half-life of the drug, and is the time required for the drug or compound of the present invention to lose half of its pharmacological, physiological, or biological activity.

[0021] <ApoE4 and Alzheimer's Disease> The ε4 allele of the apolipoprotein E gene is the strongest genetic risk factor for late-onset AD patients. ApoE4+ subjects with at least one ε4 allele account for 50% - 60% in AD cases compared to a disease prevalence of 25% in healthy individuals. ApoE4+ AD patients show a decrease in onset age, an increase in severity, and accelerated AD progression. Subjects with two ε4 alleles account for 10% - 14% of AD and show a more aggressive disease progression. The ε4 allele leads to increased cerebral Aβ amyloid deposition, increased CSF tau and p-tau, and faster cognitive decline. In addition, dementia patients with one or two ε4 alleles of ApoE are highly likely to have AD, resulting in a significant reduction in misdiagnosis of the disease in clinical trials of patients (2% compared to 42% of non-ApoE4 patients).

[0022] Among patients with dementia, the ApoE4 allele is strongly correlated with Alzheimer's disease, and thus the presence of the ApoE4 allele is used to reduce misdiagnosis in clinical trials. The misdiagnosis rate of dementia patients with AD is 2% in ApoE4-positive patients. In contrast, it has been reported that 42% of non-ApoE4 dementia patients are misdiagnosed as having AD.

[0023] <Methods and Compositions for Treating ApoE4+ Patients> Disclosed herein are methods for treating and / or preventing Alzheimer's disease in patients with one or two copies of the ApoE4 allele. Compositions for treatment and prevention are also disclosed. 3-Amino-1-propanesulfonic acid (3-APS, tramiprozate, Alzhemed™) TM ]) is a promising investigational drug candidate for the treatment of Alzheimer's disease undergoing Phase III clinical trials in North America and Europe (Wright, TM, Drugs of Today (2006), 42(5):291-298). The product was developed by Neurochem Inc. (Laval, QC, Canada) and is believed to act by reducing amyloid aggregation, deposition and / or amyloid burden in the brain via binding to soluble Aβ monomers. To increase the efficacy of 3-APS treatment, it would be desirable to increase parent exposure, metabolic stability and / or 3-APS exposure after oral administration, as well as minimize pharmacokinetic variability between subjects. These and other needs are met by prodrug compounds of 3-amino-1-propanesulfonic acid (3-APS), pharmaceutical compositions thereof. Advantageously, treatment of certain subpopulations with these agents shows remarkable efficacy. Specifically, disclosed herein are methods for treating and / or preventing Alzheimer's disease in patients who are homozygous or heterozygous for the ApoE4 allele.

[0024] <Compound> In one embodiment, the compound administered is of formula I, and pharma- ceutical acceptable salts, hydrates, and solvates thereof, where AA1 and AA2 are amino acids: [ka]

[0025] In certain embodiments, AA1 and AA2 are independently selected from the group of natural amino acids and unnatural amino acids. In further embodiments, AA1 and AA2 are independently selected from the group of natural amino acids.

[0026] In certain embodiments, AA1 and AA2 are independently selected from the group consisting of alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (trp), tyrosine (Tyr), β-alanine (β-ALA), and γ-aminobutyric acid (GABA). In other embodiments, one or both of AA1 and AA2 are O-benzylserine (O-BnSer) or O-benzylglutamine (O-BnGln).

[0027] In a further embodiment, AA1 and AA2 of formula I are as follows: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12]

[0028] Preferred embodiments are I-11, I-199, I-208, I-214, I-221, I-231, I-236, I-240, I-419, and I-438. Also preferred are OBnSer-Val, Ile-OBnSer, and OBnSer-Ile.

[0029] In one embodiment, disclosed herein is a compound of formula II: [ka] and pharma- ceutically acceptable salts, hydrates, and solvates thereof, in which AA1 is an amino acid. In certain embodiments, AA1 is selected from the group of natural amino acids and unusual amino acids. In further embodiments, AA1 is selected from the group of natural amino acids.

[0030] In certain embodiments, AA1 is selected from alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), β-alanine (β-ALA), and γ-aminobutyric acid (GABA). In other embodiments, AA1 is O-benzylserine (O-BnSer), or O-benzylglutamic acid (O-BnGlu).

[0031] Thus, embodiments disclosed herein include AA1 of formula II: [Table 2]

[0032] In certain embodiments, AA1 is selected from Val, Leu, Ser, Ala, OBnSer, and Ile.

[0033] <Pharmaceutical Composition> For the purpose of administration, in certain embodiments, the compounds described herein are administered as raw chemicals or are formulated as pharmaceutical compositions. The pharmaceutical compositions of the present disclosure contain the compounds of formula I and II and one or more pharma- ceutically acceptable carriers. The compounds of formula I and II are present in the composition in an amount effective to treat the specific disease or condition of interest. The activity of the compounds of formula I and II can be determined by those skilled in the art, for example, as described in the examples below. The appropriate concentration and dosage can be easily determined by those skilled in the art.

[0034] The compounds and compositions thereof can be administered orally. The compounds and compositions thereof can also be administered by any other convenient route, for example, by intravenous infusion or bolus injection, by absorption through epithelial or mucosal linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and can be administered together with another biologically active agent. Administration can be systemic or local. Various delivery systems, for example, encapsulation in liposomes, microparticles, microcapsules, capsules, are known and can be used to administer the compounds. In certain embodiments, two or more compounds are administered to a subject. Methods of administration include, but are not limited to, intradermal, intramuscular (including depot), intraperitoneal, intravenous, subcutaneous (including depot), intranasal, epidural, oral, sublingual (fast dissolving tablet, gum or equivalent), intranasal, intracerebral, intravaginal, transdermal, rectal, intrapulmonary (aerosol or equivalent, including by inhalation), or topical administration, particularly to the ear, nose, eye, or skin.

[0035] The compositions of the present invention contain a therapeutically effective amount of a compound of the present disclosure (optionally two or more compounds), together with a suitable amount of a pharma- ceutically acceptable vehicle so as to provide the form for administration to a subject.

[0036] The compositions of the present invention can take the form of a solution, suspension, emulsion, tablet, pill, pellet, capsule, liquid-containing capsule, powder, sustained release formulation, suppository, emulsion, aerosol, spray, suspension, or any other form suitable for use. In one embodiment, the pharma- ceutically acceptable vehicle is a capsule (see, e.g., U.S. Pat. No. 5,698,155). Other examples of suitable pharmaceutical vehicles are described in "Remington's Pharmaceutical Sciences" by EW Martin, which is incorporated herein in its entirety for its teaching of pharmaceutical compositions and methods of administration.

[0037] In certain embodiments of the invention, the compound of the invention or a pharmaceutical salt thereof may be coated onto or impregnated into a medical device suitable for implantation. In further embodiments of the invention, such a coated or impregnated device will provide a controlled release of said compound of the invention or a pharmaceutical salt thereof. In certain embodiments of the invention, said medical device is a disk.

[0038] In some embodiments, the compounds and compositions are routinely formulated as pharmaceutical compositions adapted for intravenous administration to humans. Compounds and compositions of the compounds for intravenous administration can be solutions in sterile isotonic aqueous buffer. The compositions can also include a solubilizing agent. The components can be supplied separately, for example, as lyophilized powders or water-free concentrates in sealed containers such as ampoules or sachets, or mixed together in unit dosage form.

[0039] The compounds and compositions of the compounds for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs. The compounds and compositions of the compounds for oral delivery can be formulated into food and food mixtures. The compositions administered orally can contain one or more optional agents to provide a pharma- ceutically palatable preparation, such as sweeteners, such as fructose, aspartame, or saccharin; flavorings, such as peppermint, wintergreen oil, or cherry; coloring agents; and preservatives. The compositions can be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a long period of time. Selectively permeable membranes surrounding the osmotically active driving compound are also suitable for the compounds and compositions administered orally. Time-delay materials, such as glycerol monostearate or glycerol stearate, can also be used. Oral compositions can include standard vehicles, such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate.

[0040] In certain embodiments, the compound or composition may be in the form of beads or minitabs.Minitabs, also described in the literature as microtabs or minitablets, are small tablets that typically have a diameter (or length) of about 0.5 mm to about 10 mm.Minitabs are generally prepared by techniques known in the art, such as wet or dry granulation followed by compression of the granules, direct compression of blended materials, or any other tableting technique known in the art.

[0041] In further embodiments, the compounds and compositions of the compounds can be formulated in multi-dose form, i.e., in the form of a multiparticulate dosage form (e.g., hard gelatin capsules or conventional tablets prepared using a rotary tablet press) containing one or more bead or minitab populations for oral administration. Conventional tablets disperse rapidly when placed in the stomach. One or more coated bead or minitab populations can be compressed into tablets with suitable excipients (e.g., binders, diluents / fillers, and disintegrants for conventional tablets).

[0042] The tablets, pills, beads, or minitabs of the compound or composition of the compound may be coated or otherwise compounded to provide a dosage form that provides the advantage of controlled release, including delayed or sustained release, or protects against the acidic conditions of the stomach. For example, the tablet or pill may comprise an inner dosage component and an outer dosage component, the latter being in the form of a coating over the former. These two components may be separated by a polymer layer that controls the release of the inner dosage.

[0043] In certain embodiments, the layer can include at least one enteric polymer. In further embodiments, the layer can include at least one enteric polymer in combination with at least one water-insoluble polymer. In yet other embodiments, the layer can include at least one enteric polymer in combination with at least one water-soluble polymer. In yet other embodiments, the layer can include at least one enteric polymer in combination with a pore-forming agent.

[0044] In certain embodiments, the layer can include at least one water-insoluble polymer. In yet other embodiments, the layer can include at least one water-insoluble polymer in combination with at least one water-soluble polymer. In yet other embodiments, the layer can include at least one water-insoluble polymer in combination with a pore-forming agent.

[0045] Representative examples of water-soluble polymers include polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyethylene glycol, and the like.

[0046] Representative examples of enteric polymers include esters of cellulose and its derivatives (cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate), polyvinyl acetate phthalate, pH sensitive methacrylic acid-methyl methacrylate copolymers, and shellac. These polymers can be used as dry powders or aqueous dispersions. Some commercially available materials that can be used are methacrylic acid copolymers sold under the trade names Eudragit (L100, S100, L30D) manufactured by Rohm Pharma, Cellacefate (cellulose acetate phthalate) available from Eastman Chemical Co., Aquateric (cellulose acetate phthalate aqueous dispersion) available from FMC Corporation, and AQOAT (hydroxypropyl methylcellulose acetate succinate aqueous dispersion) available from Shin-Etsu Chemical Co.

[0047] Representative examples of useful water-insoluble polymers include ethyl cellulose, polyvinyl acetate (e.g., Kollicoat SR#30D available from BASF), cellulose acetate, cellulose acetate butyrate, neutral copolymers based on ethyl acrylate and methyl methacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups such as Eudragit NE, RS and RS30D, RL or RL30D, and the like.

[0048] Any of the above polymers can be further plasticized with one or more pharma- ceutically acceptable plasticizers. Representative examples of plasticizers include triacetin, tributyl citrate, triethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, castor oil, dibutyl sebacate, acetylated monoglycerides, and the like, or mixtures thereof. When used, plasticizers can comprise about 3-30% by weight, more typically about 10-25% by weight, based on the polymer. The type of plasticizer and its content will depend on the polymer or polymers and the nature of the coating system (e.g., aqueous or solvent based, solution or dispersion based, and total solids).

[0049] The term "carrier" refers to diluents or fillers, disintegrants, suspending agents, surfactants, glidants, binders, lubricants, antioxidants, and other excipients or vehicles with which the compound is administered. Carriers are generally described herein and in "Remington's Pharmaceutical Sciences" by E. W. Martin. Examples of carriers include, but are not limited to, aluminum monostearate, aluminum stearate, carboxymethylcellulose, sodium carboxymethylcellulose, crospovidone, glyceryl isostearate, glyceryl monostearate, hydroxyethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxyoctacosanyl hydroxystearate, hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 188, poloxamer 237, poloxamer 407, povidone, silicon dioxide, colloidal silicon dioxide, silicone, silicone adhesive 4102, and silicone emulsion. It should be understood that the carrier selected for the pharmaceutical composition provided in the present disclosure and the amount of such carrier in the composition may vary depending on the method of formulation (e.g., dry granulation formulation, solid dispersion formulation).

[0050] The term "diluent" or "filler" generally refers to a substance that is used to dilute the compound of interest before delivery.Diluent can also help stabilize the compound.Examples of diluents include starch, monosaccharides, disaccharides, sucrose, lactose, polysaccharides, cellulose, cellulose ethers, hydroxypropyl cellulose, sugar alcohols, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium carbonate or sodium carbonate, lactose, lactose monohydrate, dicalcium phosphate, cellulose, compressed sugar, dehydrated dibasic calcium phosphate, mannitol, microcrystalline cellulose, and tribasic calcium phosphate.

[0051] The term "disintegrant" generally refers to a substance that, when added to a solid formulation, facilitates its break-up or disintegration after administration, and allows its rapid dissolution as efficiently as possible, releasing the active ingredient. Examples of disintegrants can include corn starch, sodium starch glycolate, croscarmellose sodium, crospovidone, microcrystalline cellulose, modified corn starch, sodium carboxymethyl starch, povidone, pregelatinized starch, and alginic acid.

[0052] The term "precipitation inhibitor" generally refers to a substance that prevents or inhibits the precipitation of an active agent. An example of a precipitation inhibitor includes hydroxypropyl methylcellulose.

[0053] The term "surfactant" generally refers to a compound that reduces the surface tension between two liquids or between a liquid and a solid. Examples of surfactants include poloxamer and sodium lauryl sulfate.

[0054] The term "glidant" generally refers to substances used in tablet and capsule formulations to improve flow characteristics during tablet compression and to provide an anti-caking effect. Examples of glidants include colloidal silicon dioxide, talc, fumed silica, starch, starch derivatives, and bentonite.

[0055] The term "binder" generally refers to any pharma- ceutically acceptable film that can be used to bind the active ingredient and the inactive ingredient of the carrier together to maintain a cohesive, separate part. Examples of binders can include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copovidone, ethyl cellulose, gelatin, and polyethylene glycol.

[0056] The term "lubricant" generally refers to a substance added to a powder blend to prevent the compressed powder mass from sticking to the equipment during the tableting or encapsulation process. Lubricants can aid in the ejection of the tablet from the die and can also improve the flowability of the powder. Examples of lubricants include magnesium stearate, stearic acid, silica, fats, calcium stearate, polyethylene glycol, sodium stearyl fumarate, or talc; and lauric acid, oleic acid, and C8 / C 10 Solubilizers such as fatty acids, including fatty acids, may be included.

[0057] In certain embodiments, the doses are given in terms of the weight of 3-amino-1-propanesulfonic acid (3-APS or APS). In further embodiments, the doses refer to the prodrugs or compounds of the present disclosure, their pharma- ceutically acceptable salts, hydrates, and solvates. The doses described herein refer to the total amount administered; that is, if multiple compounds are administered, the doses can correspond to the total amount of compounds administered. Oral compositions can contain 10%-95% active ingredient by mass.

[0058] In certain embodiments, the dosage range for oral administration is generally about 0.001 mg to about 2000 mg of compound per kg body weight. In some embodiments, the oral dosage is 0.01 mg to 100 mg per kg body weight, 0.1 mg to 50 mg per kg body weight, 0.5 mg to 20 mg per kg body weight, or 1 mg to 10 mg per kg body weight. In some embodiments, the oral dosage is 5 mg of compound per kg body weight.

[0059] In further embodiments, the dose is from about 10 mg to about 1000 mg, including all ranges and subranges therebetween: for example, from about 10 mg to about 900 mg, from about 10 mg to about 800 mg, from about 10 mg to about 700 mg, from about 10 mg to about 600 mg, from about 10 mg to about 500 mg, from about 10 mg to about 400 mg, from about 10 mg to about 300 mg, from about 10 mg to about 250 mg, from about 10 mg to about 200 mg, from about 10 mg to about 150 mg, from about 10 mg to about 100 mg, from about 10 mg to about 50 mg, from about 50 mg to about 900 mg, from about 5 ...150 mg, from about 10 mg to about 100 mg, from about 10 mg to about 50 mg, from about 50 mg to about 150 mg, from about 10 mg to about 100 mg, from about 10 mg to about 50 mg, from about 50 mg to about 150 mg, from about 10 mg to about 100 mg, from about 10 mg to about 150 mg, from about 10 mg to about 100 mg, from about 10 mg to about 150 mg, from about 10 mg to about 100 mg, from about 10 mg to about 150 mg, from about 10 mg to about 100 mg, from about mg ~ approx. 800 mg, approx. 50 ~ approx. 700 mg, approx. 50 mg ~ approx. 600 mg, approx. 50 mg ~ approx. 500 mg, approx. 50 mg ~ approx. 400 mg, approx. 0mg to about 100mg, about 100mg to about 900mg, about 100mg to about 800mg, about 100 to about 700mg, about 100mg to about 600mg, about 100mg to about 500mg, about 100mg to about 400mg, about 100mg to about 300mg, about 100mg to about Approximately 250mg, approximately 100mg to approximately 200mg, approximately 100mg to approximately 150mg, approximately 150mg to approximately 200mg, approximately 150mg to approximately 250mg, approximately 150 to approximately 300mg, approximately 150mg to approximately 400mg, approximately 150mg to approximately 500mg, approximately 200mg to approximately 900 mg, approx. 200 mg to approx. 800 mg, approx. 200 to approx. 700 mg, approx. 200 mg to approx. 500 mg, approx. 200 mg to approx. 400 mg, approx. 200 mg to approx. 300 mg, approx. 300 to about 700 mg, about 300 to about 600 mg, about 300 mg to about 500 mg, about 300 mg to about 400 mg, about 400 mg to about 900 mg, about 400 mg to about 800 mg, about 400 to about 700 mg, about 400 to about 600 mg, about 400 mg to about 500 mg, about 500 mg to about 900 mg, about 500 mg to about 800 mg, about 500 mg to about 700 mg, about 500 mg to about 600 mg, about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 250 mg. In a specific embodiment, the range is about 150 mg to about 400 mg.

[0060] In further embodiments, the dose is 10mg, 25mg, 50mg, 60mg, 70mg, 75mg, 80mg, 85mg, 90mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 225mg, 250mg, 275mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, or 1000mg.

[0061] <Treatment Method> The present disclosure also provides the use of the compounds disclosed herein in the manufacture of a medicament for the treatment of ApoE4 positive Alzheimer's disease patients.The present disclosure also provides a method for the treatment or prevention of the above-mentioned disease, comprising administering a therapeutically effective amount of a compound or a composition containing the same to a subject, preferably a human subject, in need thereof.Accordingly, a related aspect of the present disclosure relates to the prevention and / or treatment of Alzheimer's disease in ApoE4 positive humans by administering an effective amount of a compound or composition of the present disclosure to a human subject in need thereof.

[0062] The present disclosure also provides a method for the treatment or prevention of the above diseases, comprising administering a therapeutically effective amount of a compound or a composition containing same to a subject, preferably a human subject, in need thereof, wherein the patient is heterozygous or homozygous for the ApoE4 (or ε4) allele (i.e., an ApoE4 positive patient).

[0063] Identification of ApoE4 positive patients can be performed by any specific approach that allows the patient to be determined as having one or two copies of the ApoE4 (or ε4) allele. In certain embodiments, the patient's genotype is determined using sequencing technology prior to administering the compound.

[0064] In certain embodiments, the efficacy of a compound can be determined via the ADAS-cog (Alzheimer's Disease Assessment Scale-cognitive subscale). The ADAS was designed to measure the severity of the most important symptoms of Alzheimer's disease (AD). Its subscale, the ADAS-Cog, is the most widespread cognitive testing instrument used in clinical trials of nootropics. The instrument consists of 11 tasks that measure impairments in memory, language, habits, attention and other cognitive abilities that are often referred to as core symptoms of AD. The ADAS-Cog helps to assess cognition and distinguishes between normal and impaired cognitive function. It is particularly useful for measuring the degree of cognitive decline based on a person's answers and scores, and can also help to assess at what stage of Alzheimer's disease a person is in. The ADAS-Cog can be used in clinical trials to determine the gradual improvement or decline of cognitive function. An increased ADAS-Cog score compared to placebo indicates improved cognitive function.

[0065] The compound or a composition comprising the compound can be administered once, twice, three times, or four times a day using any suitable mode described above. Also, in certain embodiments, administration or treatment with a compound of any formula described herein may continue for several weeks. For example, a typical treatment will continue for at least 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 100 weeks, or 104 weeks. In yet another embodiment, administration or treatment with a compound according to any formula described herein may continue for several months. For example, a typical treatment will continue for at least 2 months, 4 months, 6 months, 8 months, 10 months, 12 months, 15 months, 18 months, 20 months, or 24 months. In yet another embodiment, administration or treatment with a compound according to any of the formulas described herein may be continued indefinitely. In yet another embodiment, administration or treatment with a compound according to any of the formulas described herein may be continued until the ADAS-Cog score is improved by about 1.5-fold to about 4.5-fold. In some embodiments, the improvement in score is about 1.5-fold, about 2.0-fold, about 3.5-fold, about 4.0-fold, about 4.5-fold, about 5.0-fold, about 7.5-fold, about 10.0-fold, about 15.0-fold. In certain embodiments, the improvement is about 1.5-fold to about 10.0-fold.

[0066] In yet another embodiment, administration or treatment with a compound according to any of the formulas described herein may be continued until the metabolite NRM5074 is present in the plasma. The appearance of the metabolite can be detected and quantified by LC / MS / MS bioanalytical methods.

[0067] In certain embodiments, Val-APS is orally administered in a loosely packed capsule to provide an extended half-life, for example, Val-APS provided in a loosely packed capsule provides a half-life of about 10 hours to about 18 hours.

[0068] Each of the cited applications and journal articles is incorporated herein by reference as if each were fully set forth herein. EXAMPLES

[0069] Example 1 3APS treatment improves ADAS-Cog scores in all ApoE4+ visits (heterozygous and homozygous) subjects Patients were administered 3APS at 150 mg BID and 100 mg BID or given a placebo. ADAS-Cog results were measured. The data established that score decline was delayed by 3APS. See Figure 1 and table below. At week 13, a small improvement in ADAS-Cog was observed. The difference increased over time. Beginning at about week 52, placebo patients showed substantially greater cognitive decline compared to both treatment arms of the study (i.e., 100 mg BID and 150 mg BID). ADAS-Cog by ApoE4 subgroups in the combined dataset [Table 3] Change in ADAS-Cog by ApoE status (<80 years) in the combined dataset [Table 4] Change in ADAS-Cog by ApoE status in North American studies [Table 5]

[0070] Tramiprozate also produced clinically meaningful improvements in cognition (ADAS-cog) and function (CDR-SB) through 18 months versus treatment with an acetylcholinesterase inhibitor and / or memantine (tramiprozate 150 mg BID, n=183; ADAS-cog: slope vs. placebo p<0.01 and p<0.05 at week 78; slope vs. placebo p<0.01 and p<0.05 at week 78). See Figures 2 and 3.

[0071] Example 2 Val-APS exhibits improved brain accumulation and improved plasma half-life versus 3APS FIG. 4 shows the improved accumulation in the brain obtained with the Val-APS prodrug versus tramiprozate. By using the prodrug, enhanced accumulation at the site of action is achieved. FIG. 5 further shows the improved pharmacological properties of Val-APS. When tramiprozate is administered as Val-APS (NRM8499), APS shows an extended t1 / 2. FIG. 7 summarizes the data showing the improved properties of loosely packed Val-APS capsules over 3APS (tramiprozate) in capsule and tablet form. The data shows an increase in t1 / 2 to 14.9±3.9 when Val-APS is administered in a loosely packed capsule.

[0072] Example 3 3APS shows remarkable efficacy in ApoE4-positive patients Patients were administered 3APS and ADAS-Cog results were obtained at various time points. Patients were then genotyped to detect the presence of the ApoE4 allele. Figure 8 shows the beneficial effect of tramiprozate, the active agent of Val-APS, in specific subpopulations separated based on ApoE4 status. The data established substantially improved ADAS-cog scores versus placebo over time. Data are presented at weeks 13, 26, 39, 52, 65, and 78. The first column shows patients homozygous for ApoE4 ("ApoE4+ / +"), the second column shows combined data from patients heterozygous and homozygous for ApoE4 "ApoE4 all-visitors," and the third column shows patients negative for ApoE4 (non-ApoE4). ApoE4 prevalence correlates with improved cognitive scores. Notably, patients who were heterozygous for the E4 allele showed particularly marked improvement. Taken together, these data show a 4-point improvement in cognition versus placebo (tramiprozate; 150 mg BID, n=34) in ApoE4 homozygous patients, reaching 4.62 points on the ADAS-cog after 18 months of treatment (p<0.01). For example, the present invention provides the following: (Item 1) 1. A method of treating Alzheimer's disease in an ApoE4 positive patient, comprising: (i) testing an Alzheimer's patient for the ApoE4 allele; (ii) characterizing patients having the ApoE4 allele as ApoE4 positive; (iii) administering to said ApoE4 positive patient for a period of time a compound of formula I: [ka] Where: said period being at least 13 weeks; At the end of said period, the ADAS-cog score is tested and is improved by at least about 1.5-fold compared to administration of a placebo to ApoE4 positive patients over said same period. (Item 2) The method of claim 1, wherein the Alzheimer's patient is heterozygous for the ApoE4 allele. (Item 3) The method of claim 1, wherein the Alzheimer's patient is homozygous for the ApoE4 allele. (Item 4) 2. The method of claim 1, wherein said period is at least 26 weeks and said improvement is at least about 2.20 fold. (Item 5) 2. The method of claim 1, wherein said period is at least 39 weeks and said improvement is at least about 3.0 fold. (Item 6) 2. The method of claim 1, wherein said period is at least 65 weeks and said improvement is at least about 4.5 fold. (Item 7) 2. The method according to item 1, wherein AA1 and AA2 are independently selected from the group consisting of alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (trp), tyrosine (Tyr), β-alanine (β-ALA), and γ-aminobutyric acid (GABA). (Item 8) 1. A method of treating Alzheimer's disease in an ApoE4 positive patient, comprising: (i) testing an Alzheimer's patient for the ApoE4 allele; (ii) characterizing patients having the ApoE4 allele as ApoE4 positive; (iii) administering to said ApoE4 positive patient for a period of time a compound of formula I: [ka] Where: said period being at least 13 weeks; At the end of said period, the ADAS-cog score is tested and is improved by at least about 1.5-fold compared to administration of a placebo to ApoE4 positive patients over said same period. (Item 9) The method of claim 8, wherein the Alzheimer's patient is heterozygous for the ApoE4 allele. (Item 10) The method of claim 8, wherein the Alzheimer's patient is homozygous for the ApoE4 allele. (Item 11) 9. The method of item 8, wherein said period is at least 26 weeks and said improvement is at least about 2.20 fold. (Item 12) 9. The method of item 8, wherein said period is at least 39 weeks and said improvement is at least about 3.0 fold. (Item 13) 9. The method of item 8, wherein said period is at least 65 weeks and said improvement is at least about 4.5 fold. (Item 14) 9. The method according to item 8, wherein AA1 is selected from the group consisting of alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (trp), tyrosine (Tyr), β-alanine (β-ALA), and γ-aminobutyric acid (GABA). (Item 15) The method according to item 14, wherein AA1 is selected from the group consisting of alanine (Ala), isoleucine (Ile), leucine (Leu), serine (Ser), and valine (Val). 16. The method according to item 15, wherein AA1 is valine (Val). (Item 17) 9. The method of claim 8, wherein the compound is administered once a day.

Claims

[Claim 1] A composition as described in the specification.

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